N-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(2-methylpropyloxy)phenylmethyl) carbamide salts and preparation of said salts

FIELD: chemistry.

SUBSTANCE: invention relates to novel N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide salts of formula I , containing an anion selected from a group consisting of phosphate, sulphate, succinate, malate, citrate, fumarate, maleate and edisilate. The invention also relates to a method for synthesis of salts in paragraph 1, to a pharmaceutical composition, a method of inhibiting monoamine receptor activity, as well as to use of at least one salt in paragraph 1.

EFFECT: obtaining novel biologically active compounds which are active as inhibitors or inverse agonists of the monoamine receptor.

50 cl, 9 ex, 9 tbl

 

The level of technology

The technical field to which the invention relates,

The present invention relates to the fields of medicine and chemistry. In particular, the present invention relates to N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)urea, its salts and their methods of synthesis and use.

Description of the prior art,

In WO 01/66521 described N-azacycloheptan-N-aralkylated and amides of carboxylic acids, forming a new class of compounds effective in inhibiting the activity of monoamine receptors, including serotonin receptor subclass of 5-HT2A. Examples of painful conditions, which can be used such compounds include, without limitation, neuropsychiatric diseases such as schizophrenia and related idiopathic psychoses, depression, anxiety, sleep disorders, disorders of appetite, affective disorders, such as great depression, bipolar disorder, depression with psychotic properties and Tourette syndrome. Also, these compounds may be useful in the treatment of psychosis caused by drugs, and side effects of Parkinson's disease and psychosis, secondary to neurodegenerative disorders such as Alzheimer's or Huntington's, blood hyperten the AI, migraine, vascular spasm, ischemia and during primary treatment and secondary prevention of a variety of thrombotic conditions including myocardial infarction, thrombotic or ischemic attack, idiopathic and thrombotic thrombocytopenic purple and peripheral vascular disease.

The invention

One option run, disclosed in this application includes a salt of N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)urea of the formula I,

which includes an anion selected from the group consisting of phosphate, sulfate, nitrate, diphosphate, bicarbonate, carbonate, application, isothionate, borate, halide, nitrate, acetate, succinate, lactate, lactobionate, laurate, mandelate, malate, citrate, fumarata, maleate, oleate, oxalate, ascorbate, nicotinate, benzoate, nelfinavir, salicylate, stearate, tannate, tosilata, valerate, methansulfonate, aconsultant, bansilalpet, p-toluensulfonate, 2-atendimento and naphthalenesulfonate. In some embodiments, execution anion selected from the group consisting of citrate, fumarata, maleate, malate, phosphate, succinate, sulfate and edisylate. In one embodiment, when the anion is selected from the group consisting of citrate, maleate, malate, phosphate, succinate and sulfate, stoichiometric what the rate is 1:1, and when the anion is selected from the group consisting of edisylate and fumarata, the stoichiometric ratio is 2:1. In one embodiment, the salt is a citrate of the formula IV

According to one embodiment of citrate salt is characterized by a powder x-ray containing peaks with d values in angstroms, approximately equal to 31.8, approximately 15,9, approximately 7.9, approximately 6,3, approximately 5,96, approximately 5,23 and approximately 4,68.

In another embodiment, the salt is a fumarate of the formula V

In one embodiment, the fumaric salt is characterized by a powder x-ray containing peaks with d values in angstroms of approximately 21,7, approximately 18,3, approximately 15,7, approximately 14.5, approximately 12.6, about 12.3, about 10,9, approximately 5,52, approximately 4.72, and approximately 4,47. In another embodiment, the fumaric salt is characterized by a powder x-ray containing peaks with d values in angstroms of approximately 18,4, approximately 15,7, approximately 12.6, approximately 9,2, approximately 5,50, approximately 4,93, approximately 4,70, approximately 4,51, approximately 4,17 and approximately 4,06.

One in which the Rianta run salt is a maleate of the formula VI

In one embodiment, Malatya salt is characterized by a powder x-ray containing peaks with d values in angstroms of approximately 13,0, approximately 5,71, approximately 5,24, approximately 4,77, approximately 4,37 and approximately 4,19.

In another embodiment, the salt is a malate of formula VII

In one embodiment of Malatya salt is characterized by a powder x-ray containing peaks with d values in angstroms of approximately 13,1, approximately 12,0, approximately 5,35, approximately of 5.05, approximately a 4.83, approximately 4,75, approximately 4,71, approximately 4,37, approximately 4,29, approximately 4,17, approximately 4,00, approximately a 3.87 and approximately 3,83.

In another embodiment, the salt is a phosphate of the formula VIII

In one embodiment, the phosphate salt is characterized by a powder x-ray containing peaks with d values in angstroms of approximately 17,3, approximately 5,91, approximately 4,80, approximately 4,27, approximately 4,14 and approximately 3,86.

In another embodiment, the salt is a succinate of formula IX

In one of the variations is the execution succinate salt is characterized by a powder x-ray, containing peaks with d values in angstroms, approximately equal to 12.8, approximately 7,6, approximately 5,51, approximately 5,19, approximately 4,79, approximately 4,16 and approximately 4,05.

In another embodiment, the salt is a sulfate of the formula X

In one embodiment, the sulfate salt is characterized by a powder x-ray containing peaks with d values in angstroms of approximately 17,0, approximately 9.6 approximately 5,49, approximately 4,79, approximately 4,65, approximately 4,53, approximately 4,30, approximately 4,15, approximately 4,04 and approximately 3,89.

In another embodiment, the salt is edisylate (etandisulfonat) formula XI

In one embodiment, edisylate salt is characterized by a powder x-ray containing peaks with d values in angstroms, is equal to approximately 10.0, approximately 6,05 approximately 5,31, approximately equal to 4.97, approximately 4,68, approximately 4.26% and approximately 4,12.

Another option is run, disclosed in this application includes a process for the preparation of salts as described above, including

a) forming a solution of the compounds of formula I in an organic solvent;

b) adding an acid, selected the Oh group, consisting of citric acid, fumaric acid, maleic acid, L-(-)-malic acid, phosphoric acid, succinic acid, sulfuric acid or 1,2-ethicolegal acid in this solution and

c) selection of salt.

In one embodiment, the selection includes a selection of salt from the slurry formed after step b). In another embodiment, the selection includes the deposition of salt from a solution formed after step (b) by one or more cooling, solvent removal or adding a precipitant.

Another option is run, disclosed in this application includes a salt of N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)urea of the formula I

produced through a process comprising

a) forming a solution of the compounds of formula I in an organic solvent;

b) adding an acid selected from the group consisting of citric acid, fumaric acid, maleic acid, L-(-)-malic acid, phosphoric acid, succinic acid, sulfuric acid or 1,2-ethicolegal acid in this solution and

c) selection of salt.

Another option is run, disclosed in this application includes a pharmaceutical composition comprising a salt of N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmalonamide formula I

which includes an anion selected from the group consisting of phosphate, sulfate, nitrate, diphosphate, bicarbonate, carbonate, application, isothionate, borate, halide, nitrate, acetate, succinate, lactate, lactobionate, laurate, mandelate, malate, citrate, fumarata, maleate, oleate, oxalate, ascorbate, nicotinate, benzoate, nelfinavir, salicylate, stearate, tannate, tosilata, valerate, methansulfonate, aconsultant, bansilalpet, p-toluensulfonate, 2-atendimento and naphthalenesulfonate, and a pharmaceutically acceptable carrier.

Another option is run, disclosed in this application includes a method for the treatment of neuropsychiatric diseases, containing the introduction to the individual, at least one salt of N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)urea of the formula I

where salt contains an anion selected from the group consisting of phosphate, sulfate, nitrate, diphosphate, bicarbonate, carbonate, application, isothionate, borate, halide, nitrate, acetate, succinate, lactate, lactobionate, laurate, mandelate, malate, citrate, fumarata, maleate, oleate, oxalate, ascorbate, nicotinate, benzoate, nelfinavir, salicylate, stearate, tannate, tosilata, valerate, methansulfonate, aconsultant, bensalah the Nata, p-toluensulfonate, 2-atendimento and naphthalenesulfonate. In one embodiment, the neurological disease is selected from the group consisting of psychosis, schizophrenia, schizoaffective disorders, mania, psychotic depression, affective disorders, dementia, anxiety, sleep disorders, disorders of appetite, bipolar disorder, psychosis secondary to hypertension, migraine, vascular spasm and ischemia, motor tics, tremor, psychomotor slowing, bradykinesia and neuropathic pain.

Another option is run, disclosed in this application includes a method of inhibiting the activity of monoamine receptor, containing the introduction to the individual, at least one salt as described above.

Another option is run, disclosed in the present application includes a method for the treatment of neurodegenerative diseases, containing the introduction to the individual, at least one salt as described above. In some versions of the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Huntington's disease, Alzheimer's disease, cerebellar atrophy, Tourette's syndrome, Friedrich's ataxia, a disease Machado-Joseph, dementia with calves Levi, dystonia, progressive supranuclear palsy and frontotemporal dementia.

Another option negotiation is, disclosed in the present application includes a method for the treatment of dyskinesia associated with dopaminergic therapy, introducing the individual, at least one salt as described above.

Another option is run, disclosed in this application includes a method for the treatment of dystonia, myoclonus, or tremor associated with dopaminergic therapy, introducing the individual, at least one salt, described above.

Another option is run, disclosed in this application includes a method for treating thrombotic state, containing the introduction to the individual, at least one salt as described above. In some embodiments, execution of thrombotic condition selected from the group consisting of myocardial infarction, thrombotic or ischemic attack, idiopathic and thrombotic thrombocytopenic purpura, peripheral vascular disease and Raynaud's syndrome.

Brief description of drawings

Figure 1 is a powder x-ray crystalline citrate salt of compounds of formula IV.

Figure 2 is a powder x-ray forms A crystalline fumaric salts of compounds of formula V.

Figure 3 is a powder x-ray of the form B crystal fumaric salts of compounds of formula V.

4 is a powder x-ray crystal maleate salt joint is of the formula VI.

5 is a powder x-ray crystal malatnej salts of the compounds of formula VII.

6 is a powder x-ray crystalline phosphate salt of the compounds of formula VIII.

7 is a powder x-ray crystal succinate salts of the compounds of formula IX.

Fig - powder x-ray crystalline sulfate salt of the compound of formula X.

Figure 9 is a powder x-ray crystal edisylate salts of the compounds of formula XI.

A detailed description of the preferred option run

One useful N-azacycloheptan-N-aralkylated is N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)urea of the formula I:

Synthesis of N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)urea

One embodiment of representing the method of synthesis of compounds of formula (I), provides for the interaction of the compounds of formula II ((4-terbisil)-(1-methylpiperidin-4-yl)amine)

with the compound of the formula III (4-(2-methylpropyloxy)perimeterisation)

In one embodiment, the use of from about 0.9 to about 1.1 equivalent (4-terbisil)-(1-methylpiperidin-4-yl)amine per equivalent of 4-(2-methylprop is yloxy)perimeterisation. In some embodiments, execution of the resulting compound of formula I is recovered from the reaction mixture. In one embodiment, after the reaction add salt-forming acid. Formed salt may be isolated by solvent removal, precipitation or solvent removal and deposition, with subsequent release of the compounds of formula I in an alkaline aqueous conditions by dissolving in an organic solvent two-phase system, and excretion of compounds of formula I from the organic solution. In a preferred embodiment of the reaction using 1.0 equivalent of (4-terbisil)-(1-methylpiperidin-4-yl)amine per equivalent of 4-(2-methylpropyloxy)perimeterisation. The reaction can be performed in the presence as catalyst of Lewis acids such as metal salts or, more preferably, alkoxylate metals. Some examples are MgCl2, FeCl2, FeCl3, FeBr2, Fe(SO4)2, NiCl2, BCl3, AlCl3, BBr3, TiCl4, TiBr4, ZrCl4, BCl3, Al(O-C1-C4-alkyl)3and Ti(O-C1-C4-alkyl)3. The amount of catalyst may range from about 0.0001 to about 5 percent by weight and preferably from about 0.01 to about 3 percent by weight relative to the compound of formula I.

The reaction is preferably performed in the presence of an inert organic solvent, such as aliphatic ethers (e.g. diethyl ether, methylpropyloxy ether, disutility ether, ethylene glycol dimethyl ether, tetrahydrofuran or dioxane), esters of aliphatic carboxylic acids or alcohols (for example, esters of C2-C4the alkyl and acetic acid), lactones (for example, valerolactone), halogenated hydrocarbons (for example, di - or trichloromethane, tetrachlorethane) aliphatic or C3-C8ketones (e.g. acetone, methyl propyl ketone, diethylketone or methyl ISO - or tert-butylketone).

The reaction temperature is preferably in the range of from about -30°to about 60°C and more preferably in the range of from approximately 5°to approximately 30°C. the reaction Time can be monitored by tracking the consumption of compounds of formula II or formula III or by analysis of the process in real time, or by independent recovery and analysis of samples.

The selection of the compounds of formula I can be performed in any suitable way, including the removal of solvent by distillation residue of the reaction under reduced pressure and at low temperature, such as approximately 100°C, preferably about 80°C. the Selection of so what can be carried out by partial removal of the solvent to increase the concentration filter out impurities, solids from the compounds of formula I or further concentration or adding a precipitant, such as aliphatic hydrocarbons (e.g. pentane, hexane, heptane, octane, cyclohexane, methylcyclohexane or water), filtering off the solids and drying. Compound of formula I can be purified by known methods such as distillation or chromatographic methods.

It was found that the removal of impurities, such as formed by-products, to highlight is a convenient way of obtaining the compounds of formula I with a high degree of purification. Additionally, it was found that cleaning can be effectively improved by forming salts of urea, which can be precipitated in the form of crystalline compounds and recrystallized from solvents to remove impurities. Then the free urea of the formula I release by dissolution of salt in water, adding a base and urea extraction with organic solvent. Organic solutions can be rinsed with water and aqueous sodium chloride before removing the solvent by distillation, optionally under reduced pressure. In this way the impurities can be removed by precipitation or dissolution in water followed by the application of a two-phase system. When legalonline by filtration or centrifugation required the deposition of salt, can be performed partial removal of the organic solvent and the addition of fresh solvent. Suitable solvents with low solubility salts are aprotic organic solvents, such as hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters and lactones carboxylic acid, acetonitrile and alcohols containing at least 3 carbon atoms.

The raw materials for the reaction described above can be obtained by known and analogous ways. Specifically, the compound of formula II can be obtained by reaction of N-methylpiperid-4-one with 4-tormentilline in the presence of a metal hydride, for example, in accordance with the scheme

The compounds of formula III can be prepared by reaction of 4-hydroxybenzaldehyde with Isobutyraldehyde (for example, isobutylamino) for the formation of 4-isobutoxyethene, which can be converted with hydroxylamine in the form aldoxime:

This oxime can be catalytically gidrirovanny with a palladium catalyst in an appropriate 4-isobutoxyethene, which can be obtained ether isocyanates acid of the formula III by reaction with phosgene.

Salt N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)panelmate is)urea

Some embodiments of the represent a salt of N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)urea containing anion selected from the group consisting of phosphate, sulfate, nitrate, diphosphate, bicarbonate, carbonate, application, isothionate, borate, halide, nitrate, acetate, succinate, lactate, lactobionate, laurate, mandelate, malate, citrate, fumarata, maleate, oleate, oxalate, ascorbate, nicotinate, benzoate, nelfinavir, salicylate, stearate, tannate, tosilata, valerate, methansulfonate, aconsultant, bansilalpet, p-toluensulfonate, 2-ethanedisulfonate or naphthalenesulfonate.

Salts can be obtained in the form of crystalline solids. When the anion is a citrate, maleate, malate, phosphate, succinate or sulphate, salt has a stoichiometric ratio of 1:1. Etisilat shows the stoichiometric 2:1 ratio of free base to acid and fumarate supposedly has a stoichiometric ratio of 2:1. In some embodiments, execution of the salt may form a hydrate or other solvate. In particular, it was found that malate and succinate can form hydrates. In some embodiments, the execution are provided by various polymorphic forms salts. In some versions of the amorphous salt.

In one var is ante execution salt is a citrate of the formula IV

In one embodiment, the provided crystalline form of the citrate of the formula IV, which is characterized by a powder x-ray shown in figure 1; hereinafter referred to as crystalline citrate. In particular, x ray powder contains the following characteristic peaks expressed in d values (E): 31,8 (vs), 15,9 (m), 7,9 (m), 6,9 (w), and 6.3 (m), 5,96 (m)of 5.83 (w), 5,23 (m), and 4.68 (m), 4,56 (m), 4,17 (m), 4,05 (w), 3,95 (m), 3,91 (m), 3,79 (w), 3,49 (w) and 3,13 (w). Abbreviations in parentheses are used in this application as follows: (vs) =very high intensity, (s) = high intensity, (m) = medium intensity, (w) = low intensity; and (vw) = very low intensity. In different versions of the crystalline citrate is present in amounts of at least about 50%, 70%, 80%, 90%, 95% or 98%, where the remainder is another salt or crystalline form (including a hydrate and a solvate and/or amorphous forms of the compounds of formula I.

Another option run is a fumaric salt of the formula V

In one embodiment, the provided crystalline form fumarata formula V, which is characterized by a powder x-ray shown in figure 2; hereinafter referred to as form A crystalline fumarata. In particular, powder rent anogramma contains the following characteristic peaks, expressed in values of d (E): 21,7 (m), and 18.3 (s)15,7 (s)14,5 (s)12,6 (s)to 12.3 (m), or 10.9 (w), and 9.1 (w), 6,8 (w)6,40 (w), by 5.87 (w)5,52 (m), 5,26 (m), 5,12 (w), 4,72 (s)of 4.66 (s), 4,51 (m), 4,47 (s), 4,24 (m)to 3.64 (m). In different versions of the form A crystalline fumarata is present in amounts of at least about 50%, 70%, 80%, 90%, 95% or 98%, where the remainder is another salt or crystalline form (including a hydrate and a solvate and/or amorphous forms of the compounds of formula I.

Form A crystalline fumarata also exists in mixtures with an amorphous form and/or form B crystal fumarata. Form B crystal fumarata characterized by powder x-ray, shown in figure 3. In particular, x ray powder contains the following characteristic peaks expressed in d values (E): 18,4 (vs), 15,7 (vs), 12,6 (vs), 10,0 (w), and 9.2 (m), 6,8 (m), 6,37 (m), 6,12 (m)of 5.68 (m), 5,50 (vs), 5,13 (m), 4,93 (s), 4,70 (s), 4,51 (s), 4,39 (m), 4,30 (m), 4,17 (s)4,06 (s), 3,88 (m)3,81 (w), 3,66 (m)to 3.64 (m), 3,42 (m). In different versions of the form B crystal fumarata is present in amounts of at least about 50%, 70%, 80%, 90%, 95% or 98%, where the remainder is another salt or crystalline form (including a hydrate and a solvate and/or amorphous forms of the compounds of formula I.

Form A crystalline fumarata can be obtained by procedures fast crystallization speed chilled the I from approximately 10-100°C per hour more preferably, approximately 30-60°C per hour, and recovering the solids soon after cooling, the suspension is from about 60°C to 23±2°C or below. Form B crystal fumarata can be obtained in the slower procedures crystallization with cooling rate from 1-60°C per hour, more preferably from 5 to 20°C per hour, followed by stirring the resulting suspension at a temperature from 5°C to 40°C for at least one but not more than 60 hours, more preferably for about 24 hours at 23±2°C.

Another option run is maleato salt of the formula VI

In one embodiment, the provided crystalline form of the maleate of the formula VI, which is characterized by a powder x-ray shown in figure 4; hereinafter referred to as crystalline maleate. In particular, x ray powder contains the following characteristic peaks expressed in d values (E): 17,1 (w)13,0 (vs), 10,0 (w), or 8.6 (w), 7,9 (w), 5,71 (vs), 5,24 (m), to 4.98 (m), a 4.86 (w), 4,77 (m), 4,70 (w), 4,37 (m), 4,29 (w), 4,19 (vs), 3,92 (w)3,76 (w)to 3.67 (w), 3,62 (m), 3,52 (w), 3,38 (m), with 3.27 (m), 3,05 (m). In different versions of the crystalline maleate is present in amounts of at least about 50%, 70%, 80%, 90%, 95% or 98%, where the remainder is another salt or crystalline form (including guide the ATA and the solvate and/or amorphous forms of the compounds of formula I.

Another option run is malatoy salt of the formula VII

In one embodiment, the provided crystalline form of malate of formula VII, which is characterized by a powder x-ray depicted in figure 5; hereinafter referred to as crystalline malate. In particular, x ray powder contains the following characteristic peaks expressed in d values (E): 19,8 (m), and 16.2 (w), 13,1 (vs), 12,0 (s), and 7.7 (m), 7,2 (m)and 6.1 (m), 5,35 (s)of 5.05 (s), 4,89 (m)of 4.83 (s), and 4.75 (vs), 4,71 (vs), 4,63 (m)4,55 (m)4,37 (vs), 4,29 (vs), 4,17 (s)4,00 (s)of 3.97 (m), a 3.87 (s), 3,83 (s), 3,61 (m). Without being bound to any particular theory, this crystalline form of the malate of formula VII can be Politologija. In different versions of the crystalline malate is present in amounts of at least about 50%, 70%, 80%, 90%, 95% or 98%, where the remainder is another salt or crystalline form (including a hydrate and a solvate and/or amorphous forms of the compounds of formula I.

Another option run is a phosphate salt of the formula VIII

In one embodiment, the provided crystalline form of the phosphate of the formula V, which is characterized by a powder x-ray depicted in Fig.6; hereinafter referred to as crystalline phosphate. In particular, powder roentgenogram is and contains the following characteristic peaks, expressed in values of d (E): 17,3 (vs), 10,1 (m), 8,9 (m), 6,7 (w), 6,5 (m), 5,91 (s), 5,74 (m), 5,16 (w), is 4.93 (m), 4,80 (m), and 4.75 (w), 4,56 (m), 4,27 (m), 4,14 (m), 3,86 (m), 3,55 (m). In different versions of the crystalline phosphate present in amounts of at least about 50%, 70%, 80%, 90%, 95% or 98%, where the remainder is another salt or crystalline form (including a hydrate and a solvate and/or amorphous forms of the compounds of formula I.

Another option run is succinate salt of the formula IX

In one embodiment, the provided crystalline form succinate of formula IX, which is characterized by a powder x-ray depicted in Fig.7; hereinafter referred to as crystalline succinate. In particular, x ray powder contains the following characteristic peaks expressed in d values (E): 12,8 (vs), or 8.6 (w), 7,6 (m)of 6.4 (w), 5,51 (s), 5,27 (w), 5,19 (m), 4,79 (m), 4,42 (w), 4,32 (m), 4,16 (s)of 4.05 (s), 3,91 (m), 3,69 (w), and 3.31 (w), 3,27 (w), 3,14 (w), 2,97 (w), was 2.76 (w). In different versions of the crystalline succinate is present in amounts of at least about 50%, 70%, 80%, 90%, 95% or 98%, where the remainder is another salt or crystalline form (including a hydrate and a solvate and/or amorphous forms of the compounds of formula I.

Another option run is a sulfate salt of the formula X

In one embodiment, the provided crystalline form of the sulfate of the formula X, which is characterized by a powder x-ray depicted on Fig; hereinafter referred to as crystalline sulfate. In particular, x ray powder contains the following characteristic peaks expressed in d values (E): 17,0 (vs), and 9.6 (m), 8,3 (w), 6,8 (m), 6,4 (m)5,49 (vs), from 5.29 (w), 4,79 (s)and 4.65 (m), 4.53-in (s), 4,42 (m), 4,30 (vs), 4,18 (m), 4,15 (s)of 4.04 (m), 3,89 (w), 3,60 (m)3,56 (w). In different versions of the crystalline sulfate is present in amounts of at least about 50%, 70%, 80%, 90%, 95% or 98%, where the remainder is another salt or crystalline form (including a hydrate and a solvate and/or amorphous forms of the compounds of formula I.

Another option run is edisylate (atendimento) salt of the formula XI

In one embodiment, the provided crystalline form of edisylate formula XI,which is characterized by a powder x-ray depicted in Fig.9; hereinafter referred to as crystalline etisilat. In particular, x ray powder contains the following characteristic peaks expressed in d values (E): 12,1 (m)10,0 (s), and 9.3 (m)and 8.1 (m), and 6.6 (m), 6,05 (vs), 5,31 (s), 5,18 (m), equal to 4.97 (vs), 4,81 (w), 4,68 (s), 4,57 (m), 4,46 (m), 4,35 (m), 4.26 deaths (s)4,12 (s)3,96 (m), 3,88 (w in), 3.75 (m), 3,62 (m), 3,53 (w), 3,48 (m), 3,42 (w), and 3.31 (m), 3,15 (w)3,07 (w). In various VA is Ianto run crystal etisilat present in quantities at least approximately 50%, 70%, 80%, 90%, 95% or 98%, where the remainder is another salt or crystalline form (including a hydrate and a solvate and/or amorphous forms of the compounds of formula I.

Salts of the compounds of formula I, described in this application can be prepared by reaction of equivalent amounts of the base of formula I with an acid in a suitable inert organic solvent. Accordingly, one embodiment of is a process for the preparation of salts of N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)urea of the formula I containing anions selected from the group consisting of citrate, fumarata, maleate, malate, phosphate, succinate, sulfate and edisylate, which includes

a) forming a solution of the compounds of formula I in an organic solvent;

b) adding to the solution a suitable organic or mineral acid and

c) isolation of salts of the compounds of formula I from the resulting suspension or precipitation of the salt by cooling, solvent removal, adding a precipitant or a combination of these methods.

Suitable solvents include, without limitation, hydrocarbons, such as toluene, halogenated hydrocarbons such as di - or trichloromethane, tetrachlorethane, esters of aliphatic carboxylic acids and alcohols (C2-C43-C8ketones (acetone, methyl propyl ketone, diethylketone or methyl ISO - or tert-butylketone) and alcohols (methanol, ethanol, n - or isopropanol, and butanol).

Suitable soleobrazutaya acids include, without limitation, phosphoric acid, sulfuric acid, nitric, diphosphate, bicarbonate, carbonic acid, clavulanic acid, socionomy acid, boric acid, halogen acid (for example, chlorotalonil acid or pomodorino acid), nitric acid and aliphatic or aromatic carboxylic or sulfonic acids (e.g. acetic, succinic, lactic, lactobionic, lauric, almond, malic, tartaric, citric, fumaric, maleic, oleic, oxalic, ascorbic, nicotinic, benzoic, mailovou, salicylic, stearic, tanning, tailevu, Valerian, methansulfonate, econsultancy, benzosulfimide, p-toluensulfonate, salicylic, 2-identicalto or naphtalenesulfonic acid).

The precipitator may be an aliphatic hydrocarbon such as petroleum ether, pentane, hexane, heptane, octane, cyclopentane, cyclo is exan or methylcyclohexane when using it. Other precipitants can be determined by means of tests on the solubility of the selected salt in various solvents.

For the formation and selection of crystalline compounds can be used different methods of crystallization, such as a stirring suspension (alignment phase), precipitation, recrystallization, evaporation of the solvent, cooling to initiate crystallization and cooling down to -100°C (for example, up to -30°C). For crystallization can be used diluted or saturated solutions with the formation of the seed with the help of suitable nucleating additives or without him. The obtained crystalline solid can be purified using methods of crystallization, known from the prior art. To form solutions can be used in temperatures up to 100°C.

Salt described in this application can be obtained with a good yield. Recrystallization produces purified form suitable for use in pharmaceutical compositions. Salt can be in more than one crystalline form. For example, some of the salts may form a hydrate or a solvate.

Salt described in this application are particularly suitable as active compounds or prodrugs in the pharmaceutical preparations for inhib the financial activity of the receptor monoamine, preferably serotonin receptor subclass of 5-HT2A. Salts of formula IV are well soluble in water systems, and the free base is liberated in the physiological ranges of pH, providing high bioprospect. Salts of the formula IV and formula XI in the crystalline forms disclosed in the present application, have high storage stability. Crystalline compounds facilitate the processing and conversion for the production of salts and their preparation.

Accordingly, one embodiment of is a pharmaceutical composition comprising at least one salt as described in this application and a pharmaceutically acceptable carrier or diluent. The amount of salt depends on the type of drug and the required dosage at intervals of administration. This number in the form for oral administration can range from 0.1 to 500 mg, preferably from 0.5 to 300 mg and, more preferably, from 1 to 100 mg.

Forms for oral administration can consist of solid preparations such as capsules, tablets, pills and lozenges or liquid preparations such as aqueous suspensions, elixirs and syrups. Solid and liquid preparations also include the addition of salts in liquid or solid food. Liquids also include salt solutions for parenteral applications, such as injection or inject who I am.

Crystalline solid salts described in this application can be used directly in the form of a powder (fine particles), granules, suspensions or solutions, or they can be combined with other pharmaceutically acceptable ingredients by mixing the components and optional exact distribution, and subsequent filling of capsules, for example, consisting of hard or soft gelatin, pressing of tablets, pills or tablets, or suspension or dissolution of them in the media for suspensions, elixirs and syrups. For the formation of pills after pressing can be applied coatings.

Pharmaceutically acceptable ingredients well known for various types of drugs and, for example, can constitute a binding substance such as natural or synthetic polymers, molding, lubricants, surfactants, sweeteners and flavoring agents, coating materials, preservatives, dyes, thickeners, adjuvants, anti-microbial additives, antioxidants and media for different types of drugs.

Examples of binding agents are tragakant, gum Arabic, starch, gelatin and biodegradable polymers, such as Homo - or complex sobolifera dicarboxylic acids, alkalophile, polyalkyleneglycol is/or aliphatic hydroxycarbonic acid; Homo - or copolyamids dicarboxylic acids, alkylenediamines and/or aliphatic aminocarbonyl acids; the corresponding copolymers, polyester-polyamide, polyanhydride, polyarteritis, polyphosphazene and polycarbonates. Biodegradable polymers can be linear, branched or crosslinked type. Specific examples are polyglycolic acid, polylactic acid and poly-d,l-lactide/glycolide. Other examples of polymers are water-soluble polymers, such as polyoxyalkylene (for example, polyoxyethylene, polyoxypropylene and their mixtures), polyacrylamides and hydroxyalkylated polyacrylamides, primulina acid and its esters or amides, polyacrylic acid and its esters or amides, polyvinyl alcohol and its complex or simple esters, polyvinylimidazole, polyvinylpyrrolidone, and natural polymers such as chitosan.

Examples of inert fillers are phosphates such as dicalcium phosphate.

Examples of lubricants are natural or synthetic oils, fats, waxes or salts of fatty acids such as magnesium stearate.

Surfactants can be anionic, cationic, amphoteric or neutral. Examples of surfactants include lecithin, phospholipids, octisalate, decylsulfate, dodecyl sulphate, tetrad is calculat, hexadecylsulfate and octadecylsilyl, Na oleate or Na capret, 1-acylaminoacyl-2-sulfonic acid, such as 1-actinomycetes-2-sulfonic acid, 1-decanoylamino-2-sulfonic acid, 1-dodecanesulfonate-2-sulfonic acid, 1-tetradecanoylphorbol-2-sulfonic acid, 1-hexadecylamine-2-sulfonic acid and 1-octadecadienoate-2-sulfonic acid and human beings need it to acid and taurodeoxycholic acid, bile acids and their salts such as cholic acid, desoxycholic acid and glycocholate sodium, sodium capret or sodium laurate, sodium oleate, sodium lauryl sulfate, tamilselvam sodium, sulfated castor oil and dioctylsulfosuccinate sodium, cocamidopropylbetaine and laurylether, fatty alcohols, cholesterol, mono - or distearate glycerol, mono - or dioleate glycerol and mono - or dipalmitate of glycerol and polyoxyethylene stearate.

Examples of sweeteners are sucrose, fructose, lactose or aspartame.

Examples of the flavors are peppermint, oil of Grushenka or fruit flavors, such as cherry or orange flavor.

Examples of coating materials are gelatin, wax, shellac, sugar or biodegradable polymers.

Examples of preservatives are methyl - or propylparaben, sorbic acid is, chlorobutanol, phenol and thimerosal.

Examples of adjuvants are odorants.

Examples of thickeners are synthetic polymers, fatty acids and salts and esters of fatty acids and fatty alcohols.

Examples of antioxidants include vitamins such as vitamin a, vitamin C, vitamin D, or vitamin E, extracts of vegetables or fish fats.

Examples of liquid carriers are water, alcohols, such as ethanol, glycerin, propylene glycol, liquid polyethylene glycols, triacetin, and oil. Examples of solid carriers are talc, clay, microcrystalline cellulose, silica, alumina, etc.

The pharmaceutical preparations can also contain isotonic agents such as sugars, buffers or sodium chloride.

Salt described in this application can also be prepared in the form of effervescent tablets or powder, which disintegrate in water, for drinking solution.

A syrup or elixir may contain salts, described in this application, sucrose or fructose as a sweetener, a preservative such as methyl paraben, dye and flavoring.

Preparations for slow release can also be prepared from salts described in this application, to achieve controlled release of the active substance in contact with body fluids in docno-intestinal tract and provide substantially constant and effective level of the active substance in the blood plasma. For this purpose, any of the compounds of formula IV-XI can be included in the polymer matrix of biodegradable polymer, water soluble polymer or mixture of both, and, optionally, suitable surface-active substances. In this context, the inclusion may mean the inclusion of microparticles in a polymeric matrix. Drugs for controlled release also get by encapsulating dispersed particles or emulsified droplets with known technologies of the coating dispersion or emulsion.

Salt described in this application can also be useful for applying combinations of therapeutic agents to an animal. Such combination therapy can be carried out using at least one additional therapeutic agent, which may be optionally dispersed or dissolved in the product.

Salt described in this application, and preparations containing salts, can also be introduced in combination with other therapeutic agents effective in the treatment of this condition is to provide combination therapy.

In some embodiments, execution of the crystalline salts and pharmaceutical composition disclosed in the present application, used for the treatment of neuropsychiatric disorders, including psychosis, schizophrenia, hitaffer the Toms disorders, mania, psychotic depression, affective disorders, dementia, anxiety, sleep disorders, disorders of appetite, bipolar disorder, psychosis secondary to hypertension, migraine, vascular spasm and ischemia, motor tics, tremor, psychomotor slowing, bradykinesia and neuropathic pain. In one embodiment, the salts and compositions are used for inhibiting the activity of monoamine receptor, preferably a serotonin receptor subclass of 5-HT2A.

Another option execution is a method for the treatment of neurodegenerative diseases, including Parkinson's disease, Huntington's disease, Alzheimer's disease, cerebellar atrophy, Tourette's syndrome, Friedrich's ataxia, a disease Machado-Joseph, dementia with calves Levi, dystonia, progressive supranuclear palsy and frontotemporal dementia, by introducing salt described in this application.

Another option execution is a method for the treatment of dyskinesia associated with dopaminergic therapy, by introducing salt described in this application.

Another option execution is a method for the treatment of dystonia, myoclonus, or tremor associated with dopaminergic therapy, by introducing salt described in this application.

Another variant of execution is particularly the method for the treatment of thrombotic state, including myocardial infarction, thrombotic or ischemic attack, idiopathic and thrombotic thrombocytopenic purple, peripheral vascular disease and Raynaud's disease, by introducing salt described in this application.

Another option execution is a method for the treatment of dependence, including alcohol dependence, opioid dependence, and nicotine dependence by introducing salt described in this application.

Another option run is a treatment for reducing sexual desire or ejaculation problems by introducing salt described in this application.

One embodiment of a method includes delivery of the compounds of formula I to an individual, with an introduction to the individual an effective amount of a salt selected from the compounds of formulas IV, V, VI, VII, VIII, IX, X or XI.

EXAMPLES

The experimental technique

Powder x-ray (PXRD) was prepared as follows: PXRD was performed by powder x-ray diffractometer Philips 1710 using CuK radiationαd - distances were calculated from the 2θ values using wavelength 1,54060 that is, essentially, the 2θ values were within ±0.1 to 0.2°. Due to these experimental error of the values of d - distances depended on the position of the peaks.

Differential scanning to latimeria (DSC): Perkin Elmer DSC 7 in gold cuvette for samples, sealed in nitrogen atmosphere. The heating rate 10 K/min

FT-Raman spectroscopy: Bruker RFS100. Nd: YAG excitation 1064 nm, the laser power of 100 mW, Ge detector, 64 scanning range 25-3500 cm-1, resolution 2 cm-1.

TG-FTIR: Thermogravimetric measurements were performed using thermomicrobia Netzsch TG 209 connected with FTIR spectrometer Bruker Vector 22 (cuvettes for sample transferred, the nitrogen atmosphere, heating rate 10K/min).

HPLC: measurement HPLC was performed using a HP LC1090M, column Symmetry C18, 3.0 to 150 mm

Solubility: Approximate solubility in water was determined by adding double-distilled water gradually to 5 ál of 5 mg of the substance and handling suspension with ultrasound for 2 minutes. Defined limit value is completely dissolved. Determination of solubility lower than 20 mg/l occurred during stirring of a suspension in water, filtering excess and measuring the amount of a substance in the filtrate.

Example 1: Preparation of N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)urea

a) Preparation

To a solution of N-methylpiperid-4-it (3,17 kg) and 4-forbindelsen (3,50 kg) in methanol (30 l) for 1.5 hours was added triacetoxyborohydride (6.5 kg) while maintaining the temperature below 27°C. the Reaction is mesh was stirred for 15 hours at 22°C. The residual amine was checked by gel chromatography (4-forbindelsen:<5%). After 75 minutes (min) solution was added 30% aqueous sodium hydroxide solution (12.1 kg) in water (13.6 kg) while maintaining the temperature below 20°C. Methanol drove to a residual volume of 26 liters. Added ethyl acetate (26 l), the solution was stirred for 15 minutes, phase decantation within 15 minutes and excluded the lower aqueous phase. The ethyl acetate drove away from the organic phase under reduced pressure at 73-127°C. At this stage, the residue was mixed with the second raw batch prepared in accordance with this method. Then the combined products were directed at 139-140°C/20 mbar to obtain 11,2 kg of product (>82%).

b) Preparation

In the solution isobutyramide (9,0 kg) in ethanol (15 l) was added 4-hydroxybenzaldehyde (4.0 kg) and ethanol (20 l). Was added potassium carbonate (13.6 kg) and the suspension was heated under reflux (74-78°C) for 5 days. The content of the remainder of the 4-hydroxybenzaldehyde was checked by HPLC (<10%). The suspension was cooled to 20°C and used in the next step.

c) Preparation

To the product from the previous step (b) (174 l, 176 kg) and ethanol (54 l) was added hydroxylamine (50% in water, 8,7 kg). The suspension was heated under reflux (77°C) for 3 hours. Narora revalee the residual quantity of the compound of step b was checked by HPLC (< 5%). The suspension was cooled to 30°C, filtered and the filter was washed with ethanol (54 l). The solution was concentrated by distillation under reduced pressure at 30°C to a residual volume of 67 litres. The solution was cooled to 25°C and was added water (110 l). The suspension was concentrated by distillation under reduced pressure at 30°C to a residual volume 102 liters. Added petroleum ether (fraction 60-90, 96 l) and the mixture was heated to the boiling temperature under reflux (70°C). The solution was cooled to 40°C and initiated crystallization by persecution. The suspension was cooled to 5°C and was stirred for 4 h, the Product was centrifuged and the precipitate layer was washed with petroleum ether (fraction 60-90 32 l). Moist layers of sediment were dried at approximately 40°C for 16 kg of product (63%).

d) Preparation

The product from the previous step (c) (15,7 kg) was dissolved in ethanol (123 l). Was added acetic acid (8.2 kg) and palladium on activated carbon with 5% humidity (1.1 kg). The oxime was hydrogenosomal at 22°C and 1.5 bar for 4 hours, the Flow rate of the reaction was checked by HPLC (for information). The catalyst was filtered and the solvent was distilled under reduced pressure at 36°C to a final volume of 31 liters was Added ethyl acetate (63 l)and the mixture was heated to the boiling temperature under reflux (75°C) to dissolve. The solution was cooled to 45 the C and initiated crystallization by persecution. The suspension was cooled to 6-10°C and was stirred for 2.5 hours, the Product was centrifuged and the precipitate layer was washed with 2 portions of ethyl acetate (2×0.8 l). The wet precipitate layer was dried at a temperature of approximately 40°C to obtain 8 kg (41%).

e) Preparation

In a suspension of the product from the previous step (d) to (7.9 kg) in heptane (41 l) was added aqueous sodium hydroxide (30%, 5,0 kg). The solution was heated to 47°C, stirred for 15 minutes and decantation within 15 minutes Check the pH (pH>12) and the separated aqueous phase. The solvent was removed by distillation under reduced pressure at 47-65°C. was Added heptane (15 l) and deleted it by distillation under reduced pressure at 58-65°C. was Added heptane (7 l), filtered the solution and washed the filter with heptane (7 l). The solvent was removed by distillation under reduced pressure at 28-60°C. was Added a tetrahydrofuran (THF, 107 l) and triethylamine (tea, 6,8 kg) and recorded the temperature at 22°C. In another reactor in tetrahydrofuran (88 l) were made pre-cooled to -3°C. phosgene (5,0 kg). In a solution of phosgene in 3 h 50 min solution was added THF, tea, keeping the temperature at -3°C. the Reactor was rinsed with tetrahydrofuran (22 l). The mixture was stirred for 45 minutes at 20°C and then for 90 minutes at boiling temperature under reflux (65°C). The solvent was distilled with onigen the m pressure at 25-30°C to a residual volume 149 HP Controlled the absence of phosgene. At this stage it is still the phosgene, and the suspension was degirolami by ozonation nitrogen. After this operation, the level of phosgene above solution was less than 0,075 frequent./million, the Suspension was filtered and washed with tetrahydrofuran (30 l). The solvent was distilled under reduced pressure at 20-25°C to a residual volume of 40 liters was Added tetrahydrofuran (51 l) and the solvent was distilled under reduced pressure at 20-25°C to a residual volume of 40 L. the Final volume brought up to about 52 liters by adding tetrahydrofuran (11 l). The solution was analyzed and used in the next step.

f) Preparation of the compounds of formula I in accordance with the header

To a solution of the product from step (a) (7.3 kg) in tetrahydrofuran (132 l) after 1 hour was added the product from the previous step e) (51 l) at 17°C. the Line was rinsed with tetrahydrofuran (12 l) and the mixture was stirred for 15 hours a Residual product from the first stage was checked by HPLC. The solvent was removed by distillation under reduced pressure at 20-38°C to a residual volume 165 HP was Added activated charcoal (Norit SX1-G, 0.7 kg), the mixture was stirred for 15 minutes and filtered. The line was rinsed with tetrahydrofuran (7 l) and the solvent was removed by distillation under reduced pressure at 20-25°C to a residual volume of 30 l To allali isopropylacetate (96 l) to obtain a solution of the compounds of formula I in accordance with title containing small amounts of impurities, which are mainly represented by-products from previous reactions. Removing the solvent from the sample network, largely amorphous solid.

g) Preparation hemitartrate N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)urea

Into a solution of the compounds of formula I in isopropylacetate (96 l) from step f at 23°C was added a previously prepared solution of tartaric acid (1.7 kg) in water (1.7 l) and tetrahydrofuran (23 l). The residual suspension was stirred for 2.5 days at 22°C. the Raw product tartrate was centrifuged and the precipitate layer was washed 4 parts isopropylacetate (4×23 l). In total retained 107 kg uterine fluids for subsequent use in preparation of tartrate salt. Moist layers of sediment were dried at approximately 40°C to obtain 8.3 kg (50%) of the product.

h) First clean

The raw product tartrate stage g) (8.1 kg) was dissolved in demineralized water (41 l) at 22°C. was Added isopropylacetate (40 l), 30% aqueous sodium hydroxide (4.3 kg) and sodium chloride (2 kg). Check the pH (>12) and the solution was stirred for 15 minutes the Solution decantation within 15 minutes and the separated aqueous phase. The aqueous phase was extragonadal isopropylacetate (12 l). In the combined organic phases add recipients who do demineralized water (20 l) and sodium chloride (2.0 kg), the solution was stirred for 15 minutes, decantation within 15 minutes and were excluded aqueous phase. Added activated charcoal (0.4 kg), the mixture was stirred for 20 minutes and filtered. After washing line isopropylacetate (12 l) and the solvent was removed under reduced pressure at 20-25°C. was Added heptane (49 l) and stirred suspension for 15 minutes at 40°C. Then 8 l of solvent was removed by distillation under reduced pressure at 38-41°C. the Suspension was cooled to 20°C and was stirred for 1 hour. The product was centrifuged and the precipitate layer was washed with heptane (5 l). Wet compound of formula I (5.5 kg) was dissolved in ethanol (28 l) at 45°C. was Added a solution of tartaric acid (0.72 kg) in ethanol (11 l) at 45°C and the line was rinsed with ethanol (9 l). The solution was cooled to 43°C, strassle tartrate salt of the compounds of formula I, then after 30 minutes the suspension was cooled to 35°C, stirred at this temperature for 1 hour and cooled to -5°C. after 14 hours at this temperature the product was centrifuged and washed with two portions of ethanol (2×6 l). Moist layers of sediment were dried at approximately 45°C for 76 hours to obtain 4 kg hemitartrate.

i) Recrystallization

150,0 g hemitartrate obtained in h), was dissolved under stirring at 65°C in 112 ml of absolute ethanol and then cooled with stirring to 48°C at a speed of a cooling gap is placed 1°C/min Crystallization at a given temperature began after a few minutes, and the suspension turned into a thick paste within 1 hour. The suspension was again heated to 60°C and then cooled to 48°C at a speed of 1°C/min, the resulting suspension was stirred and cooled to 15°C at a cooling rate of 3°C/h Crystalline precipitate was separated by filtration and the container was rinsed with 10 ml of absolute ethanol, cooled to 5°C. the Crystalline residue was dried in vacuum at 40°C for 50 hours to obtain 146 g of crystalline pure hemitartrate.

j) a Second cleaning

In 130 ml of water was dissolved 15,78 g tartrate salt prepared in step i). Added 500 ml of TBME and the pH brought to 9.8 by adding 2n NaOH solution. After precipitation of white solids aqueous phase was extracted 5 times with 500 ml of TBME. The organic phase was concentrated as long as there was a volume of approximately 400 ml of the Solution was kept at 6°C. the Precipitate was filtered, washed with TBME and, finally, dried in vacuum for 5 hours. Output: 8,24 g of white powder. The mother liquor was concentrated to a quarter and kept at 6°C. the Precipitate was filtered and dried under vacuum for 18 hours. Yield: 1.6 g of white powder.

Using PXRD revealed the crystalline compound of formula I. Raman peaks of tartaric acid were not detected. The first DSC scan (-50°LMS 210°C, 10°K/min) showed a melting point at 123,6°C. Above about 190°C, the sample began to crumble.

Example 2: Preparation of citrate N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)urea of the formula IV

a) In 5.0 ml of ethyl acetate added 90 mg of the product from example 1 and 40 mg of citric acid. The suspension was stirred at 60°C for 15 minutes (min), cooled to 23±2°C and then kept for 30 minutes at 23±2°C. the Precipitate was filtered and was dried in air for 30 minutes to obtain 52 mg of a white crystalline powder. Optical microscopy shows that the obtained solid material was crystalline.

b) In 10.0 ml of ethyl acetate suspended 182 mg of the product from example 1 and is 78.4 mg of citric acid. The suspension was stirred at 60°C for 30 minutes, then stirred at 40°C for 90 minutes and, ultimately, was stirred for 60 minutes at 23°C. the Suspension was filtered and washed with heptane to obtain 237 mg of a white crystalline powder with an endothermic peak at about 153°C enthalpy of melting approximately 87 j/g), determined by differential scanning calorimetry at a speed of 10K/min (DSC). Using thermogravimetry (TG-FTIR) revealed a weight loss of approximately 0.7% between 60 and 160°C, which was attributed to absorbed water. The destruction began when PR is approximately 170°C. Solubility in water was approximately 14 mg/ml Crystalline powder mainly unchanged after storage for 1 week at 60°C and about 75% relative humidity in an open vessel (area HPLC was 99.4% in comparison with the standard value of 99.9%). Elemental analysis and1H-NMR correspond to the stoichiometry of 1:1.

Powder x-ray (PXRD) obtained citrate salt is shown in figure 1, and the characteristic peaks in the values of 2 theta with the corresponding values of the d distance E shown in table 1.

6,3
Table 1
d-Distance for the compounds of formula IV
Angle [°2θ]d-distance [E]Intensity (qualitative)
2,8of 31.8vs
5,615,9m
11,27,9m
12,67,0vw
12,96,9w
14,0m
14,95,96m
15,2of 5.83w
16,95,23m
17,94,94vw
18,14,89vw
18,9to 4.68m
19,54,56m
21,34,17m
of 21.94,05w
22,53,95m
22,73,91m
23,43,79w
24,13,70vw
24,53,62 vw
25,53,49w
28,53,13w
29,92,99vw
31,02,89w

Example 3: Preparation fumarata N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)urea of the formula V

a) In 5.0 ml of ethyl acetate added 90 mg of the product from example 1 and 24.3 mg of fumaric acid. The suspension was stirred at 60°C for 15 minutes, then kept for 75 minutes at 23±2°C. using optical microscopy revealed crystalline substance. The suspension was filtered and washed with tert-butylmethylamine ether (TBME). Yield: 83 mg of a white powder. PXRD and Raman spectroscopy indicate the presence of crystalline forms A, containing the amorphous part.

Powder x-ray (PXRD) is shown in figure 2, and the characteristic peaks in the values of 2 theta with the corresponding values of d-distances in E are shown in table 2.

Table 2
d-Distance to form A compound of formula V
In the ol [°2θ] d-distance [E]Intensity (qualitative)
4,121,7m
4,818,3s
5,615,7s
6,114,5s
7,012,6s
7,212,3m
8,110,9w
the 9.79,1w
13,16,8w
13,86,40w
15,1by 5.87w
16,05,52m
16,85,26m
the 17.35,12w
18,84,72s
19,0of 4.66s
19,74,51m
19,84,47s
20,94,24m
24,5of 3.64m

b) In 10.0 ml of ethyl acetate suspended 180 mg of the product from example 2 and 48.2 mg of fumaric acid. The suspension was stirred at 60°C for 30 minutes, then for 90 minutes at 40°C and, ultimately, for 70 minutes at 23°C. the Precipitate was filtered and washed with heptane to obtain 167 mg of crystalline white powder. TG-FTIR shows a weight loss of approximately 8.6 per cent between 60 and 170°C, which was attributed to absorbed water, ethyl acetate and CO2. The destruction began at approximately 160°C.1H-NMR corresponds to a stoichiometry of 1:0.75 in (base:fumaric acid). PXRD and Raman spectroscopy indicate the presence of crystalline form B.

c) In 10.0 ml of ethyl acetate added to 4.6 mg of the product of example 2. 180 mg of fumaric acid was dissolved in 1 ml ethanol and added to the suspension. The resulting mixture was stirred at 50°C for 1 hour and then at 23°C for 21 hours. After this was added 12 ml of ethyl acetate and the solution was further stirred for 24 hours at 23°C. the Volume of solvent was reduced to half by a stream of nitrogen and then added to 9 ml of heptane. Formed suspension was further stirred for 24 hours at 23±2°C. the Precipitate was filtered to obtain 191 mg of crystalline white powder. PXRD and Raman spectroscopy indicate the presence of crystalline form B. the solubility in water was >500 mg/ml TG-FTIR showed a weight loss of approximately 0.9 percent between 70 and 140°C, which was attributed to ethyl acetate. Storage at 75% relative humidity in an open vessel detects the change of the substance after 3 days, the recorded Raman-spectroscopy.1H-NMR corresponds to a stoichiometry of 1:0.75 in (base:fumaric acid). Crystalline powder remained largely unchanged during storage for 1 week at 60°C and about 75% relative humidity in an open vessel (area HPLC was 96.7% in comparison with the standard value of 99.4%). It is possible that the crystalline powder is a mixture of fumarata and hemifumarate.

Powder x-ray (PXRD) display is as in figure 3, and the characteristic peaks in the values of 2 theta with the corresponding values of d-distances in E are given in table 3.

24,3
Table 3
d-Distance to form the compounds of formula V
Angle [°2θ]d-distance [E]Intensity (qualitative)
4,818,4vs
5,615,7vs
7,012,6vs
8,810,0w
9,69,2m
10,58,4m
10,98,1w
11,37,8vw
11,87,5w
13,16,8 m
13,96,37m
14,56,12m
the 15.6of 5.68m
16,15,50vs
the 17.35,13m
18,0is 4.93s
18,94,70s
19,74,51s
20,24,39m
20,64,30m
21,34,17s
of 21.94,06s
22,93,88m
23,33,81w
3,66m
24,4of 3.64m
26,13,42m
28,73,11w

Example 4: Preparation of the maleate of N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)urea of the formula VI

a) In 10.0 ml of ethyl acetate was dissolved 181 mg of the product from example 1 and 48.2 mg of maleic acid. The solution was stirred at 60°C for 15 minutes, then for 20 minutes at 23±2°C. after this time began the precipitation of white solids. The suspension was kept at 5°C for 48 hours and then the volume of solvent was reduced to a quarter of a stream of nitrogen. Storage at 5°C was continued for 72 hours. White solid was filtered to obtain 113 mg of crystalline powder. PXRD and Raman spectroscopy indicate the presence of crystalline forms. TG-FTIR shows a weight loss of approximately 7.2 per cent between 60 and 160°C, which was attributed to absorbed water and ethyl acetate. The destruction begins at approximately 160°C.

Powder x-ray (PXRD) shown in figure 4, and the characteristic peaks in the values of 2 theta with choosing the appropriate values of the d distance E shown in table 4.

Table 4
d-Distance for the compounds of formula VI
Angle [°2θ]d-distance [E]Intensity (qualitative)
5,217,1w
6,813,0vs
8,910,0w
10,38,6w
11,27,9w
12,57,1vw
14,76,03vw
15,55,71vs
16,95,24m
17,8to 4.98m
18,24,86w
18,64,77m
18,94,70w
20,34,37m
20,74,29w
of 21.24,19vs
21,84,08vw
22,73,92w
23,73,76w
24,2to 3.67w
24,63,62m
to 25.33,52w
26,03,42vw
5,217,1w
6,813,0vs
8,9 10,0w
26,33,38m
26,83,32vw
27,3with 3.27m
28,43,14vw
28,73,10w
29,33,05m
30,12,97w
32,62,75w

b) In 3.0 ml of acetone was dissolved 181 mg of the product from example 2 and 48.0 mg of maleic acid. The solution was kept at 5°C for 5 days. The volume of solvent was reduced to a quarter of a stream of nitrogen and stored at 5° was continued for 48 hours. The solvent is evaporated at ambient conditions and was added 2 ml of heptane and 100 μl of acetone under stirring. Stirring was continued for 24 hours. The precipitated solid was filtered to obtain 182 mg of crystalline white powder. PXRD and Raman spectroscopy indicate that cash is having a crystalline maleate, which was probably mixed with another crystalline form. TG-FTIR shows a weight loss of approximately 5.9% between 60 and 160°C, which was attributed to absorbed water, acetone and heptane. The destruction began at approximately 170°C.1H-NMR corresponds to a stoichiometry of 1:1. Solubility in water was>500 mg/ml

Example 5: Preparation of malate, N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)urea of the formula VII

In 10.0 ml of ethyl acetate added 181 mg of the product from example 1 and 56.0 mg of L-(-)-malic acid. The suspension was stirred at 60°C for 30 minutes for forming a transparent solution. The solution was kept at 5°C for 1 day. From the formed suspension was filtered, the solid to obtain 155 mg of crystalline white powder. PXRD and Raman spectroscopy indicate the presence of crystalline form A. TG-FTIR shows a weight loss of approximately 5.5% between 50 and 160°C, which was attributed to water and CO2. The destruction began at approximately 160°C. Elemental analysis and1H-NMR correspond to the stoichiometry of 1:1. Solubility in water was >500 mg/ml

Powder x-ray (PXRD) is shown in figure 5, and the characteristic peaks in the values of 2 theta with the corresponding values of d-distances in E are given in table 5.

Table 5
d-Distance for the compounds of formula VII
Angle [°2θ]d-distance [E]Intensity (qualitative)
4,419,8m
5,516,2w
6,813,1vs
7,4to 12.0s
the 10.18,8w
10,38,6w
11,57,7m
12,27,2m
14,56,1m
15,0of 5.92w
16,55,35s
of 17.55,5 s
18,14,89m
18,4a 4.83s
18,74,75vs
18,84,71vs
19,24,63m
19,54,55m
20,34,37vs
20,74,29vs
21,34,17s
22,24,00s
22,43,97m
23,0a 3.87s
23,23,83s
23,73,75 vw
24,73,61m
25,0of 3.56vw
27,53,24m
29,23,05w
29,92,98w
30,52,93w

Example 6: Preparation of phosphate N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)urea of the formula VIII

In 3 ml of 2-propanol was dissolved 181 mg of the product of example 1. Added 842 μl of phosphoric acid (0,5 molar), and formed a clear solution. The sample was stored at 5°C for 1 day. The precipitate was filtered and dried in vacuum for 15 hours. The output was 60 mg of white crystalline powder. PXRD and Raman spectroscopy indicate the presence of crystalline form A. TG-FTIR shows a weight loss of approximately 3.9 per cent between 80 and 160°C, which was attributed to 2-propanol. The destruction began at approximately 170°C.1H-NMR corresponds to a stoichiometry of 1:1. Solubility in water was >250 mg/ml

Powder the new radiograph (PXRD) is shown in Fig.6, and the characteristic peaks in the values of 2 theta with the corresponding values of the d distance E shown in table 6.

Table 6
d-Distance for the compounds of formula VIII
Angle [°2θ]d-distance [E]Intensity (qualitative)
5,1the 17.3vs
8,7the 10.1m
10,08,9m
13,36,7w
13,76,5m
15,05,91s
15,45,74m
16,35,44vw
17,25,16w
18,0is 4.93 m
18,54,80m
18,74,75w
19,44,56m
20,84,27m
a 21.54,14m
23,03,86m
23,53,78vw
25,03,55m
30,92,89w

Example 7: Preparation of succinate N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)urea of the formula IX

a) In 5.0 ml of ethyl acetate added 90 mg of the product from example 1 and 24.7 mg of succinic acid. The mixture was stirred at 60°C for 15 minutes to form a transparent solution. The solution was kept for 30 minutes at 23±2°C and then cooled to 5°C. Precipitation occurs after 30 minutes the Suspension was kept for 16 hours at 5°C and about what ADOC was filtered, washed with TBME and heptane to obtain 55 mg of white crystalline solid. PXRD and Raman spectroscopy indicate the presence of crystalline form.

b) In 10.0 ml of ethyl acetate suspended 179 mg of the product from example 1 and 48,9 mg of succinic acid. The mixture was stirred at 60°C for 15 minutes to form a transparent solution. The solution was kept for 40 minutes at 23±2°C and then cooled to 5°C. Precipitation occurs after 30 minutes the Suspension was stirred for 1 hour at 23°C and the precipitate was filtered, washed with heptane to obtain 147 mg of crystalline white powder. PXRD and Raman spectroscopy indicate the presence of crystalline forms. TG-FTIR shows a weight loss of approximately 18.8 per cent between 60 and 250°C, which was attributed mainly CO2and the water. Elemental analysis indicates the formation of the dihydrate.1H-NMR corresponds to a stoichiometry of 1:1. Solubility in water was >500 mg/ml

Powder x-ray (PXRD) is shown in Fig.7, and the characteristic peaks in the values of 2 theta with the corresponding values of the d distance E shown in table 7.

28,0
Table 7
d-Distance for the compounds of formula IX
Angle [°2θ]d-distance [E] Intensity (qualitative)
of 5.416,7vw
6,912,8vs
10,38,6w
the 11.67,6m
13,86,4w
16,15,51s
16,85,27w
17,15,19m
17,75,00vw
18,54,79m
19,14,65vw
19,44,58vw
20,14,42w
20,54,32 m
21,44,16s
of 21.94,05s
22,73,91m
23,23,83vw
24,13,69w
24,73,60vw
of 5.416,7vw
6,912,8vs
10,38,6w
the 11.67,6m
13,86,4w
26,33,38vw
26,93,31w
27,3with 3.27w
3,19vw
28,43,14w
30,12,97w
32,4was 2.76w
33,62,66w
34,12,62w

Example 8: Preparation of sulfate N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)urea of the formula X

In 5 ml of ethanol was dissolved 180 mg of the product of example 1. Added 842 μl of sulfuric acid (0.5 in molar) and formed a clear solution was kept at 5°C for 48 hours. The solvent is evaporated using a stream of nitrogen. The dry residue is suspended in 3 ml of TBME and 0.1 ml of ethanol and stirred suspension for 17 hours at 23±2°C. the Filter network 80 mg crystalline white powder. PXRD and Raman spectroscopy indicate the presence of crystalline form.

Powder x-ray (PXRD) is shown in Fig.7, and the characteristic peaks in the values of 2 theta with the corresponding values of the d distance E shown in table 8.

Table 8
d-Distance for the compounds of formula X
Angle [°2θ]d-distance [E]Intensity (qualitative)
2,930,8w
5,2of 17.0vs
9,29,6m
10,78,3w
11,57,7vw
13,16,8m
13,96,4m
16,15,49vs
16,7of 5.29w
2,930,8w
5,2of 17.0vs
9,29,6/td> m
10,78,3w
11,57,7vw
13,16,8m
18,54,79s
19,14,65m
19,64,53s
20,14,42m
20,64,30vs
of 21.24,18m
21,44,15s
22,04,04m
22,93,89w
24,73,60m
25,0of 3.56 w
26,33,38vw
27,03,30w
28,03,19vw
28,53,13vw
29,23,05vw
31,62,83vw
32,72,74w

Example 9: Preparation of edisylate N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)urea of the formula XI

In 2 ml of dioxane was dissolved 180 mg of the product from example 1 and then was added a solution of 48 mg of the dihydrate of 1,2-ethicolegal acid in 4 ml of dioxane. The solution was kept at 8°C for 10 days. The precipitated solid was filtered to obtain 206 mg of crystalline white powder. PXRD and Raman spectroscopy indicate the presence of crystalline forms. TG-FTIR shows a weight loss of approximately 1.2% between 60 and 160°C, which was attributed to dioxane. The destruction begins at approximately 170°C. Elemental analyzethe on the stoichiometry of 2:1 (compound of formula I:1,2-ethicality acid). 1H-NMR correspond to the stoichiometry of 2:1 or 1:1. Solubility in water was 4 mg/ml Crystalline powder remains white powder when stored for 1 week at 60°C and about 75% relative humidity in a closed container (square HPLC was 97,4% in comparison with the standard value of 96.8 per cent). Storage for 1 week at 100°C in a sealed vial does not destroy the crystalline product and the white powder remains largely unchanged (area HPLC of 97.4%).

Powder x-ray (PXRD) is shown in Fig.9, and the characteristic peaks in the values of 2 theta with the corresponding values of the d distance E shown in table 9.

Table 9
d-Distance for the compounds of formula XI
Angle [°2θ]d-distance [E]Intensity (qualitative)
7,312,1m
8,110,9vw
8,910,0s
9,59,3m
0,9 8,1m
13,36,6m
14,16,3vw
14,66,05vs
16,75,31s
17,15,18m
17,8equal to 4.97vs
18,44,81w
18,9to 4.68s
19,44,57m
to 19.94,46m
20,44,35m
20,84.26 deathss
a 21.54,12s
of 21.9 4,05vw
22,53,96m
22,93,88w
23,73,75m
24,63,62m
25,23,53w
25,63,48m
26,03,42w
26,93,31m
28,33,15w
29,1of 3.07w
29,63,01vw
35,92,49w

1. Salt N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)urea of the formula I:

containing anion,selected from the group consisting of phosphate, sulfate, succinate, malate, citrate, fumarata, maleate and edisylate.

2. Salt according to claim 1, which represents a citrate.

3. Salt according to claim 2, characterized by a powder x-ray containing peaks with d values in angstroms, approximately equal to 31.8, approximately 15,9, approximately 7.9, approximately 6,3, approximately 5,96, approximately 5,23 and approximately 4,68.

4. Salt according to claim 1, which represents fumarate.

5. Salt according to claim 4, characterized by a powder x-ray containing peaks with d values in angstroms, approximately equal to 18.3, approximately 15,7, approximately 14.5, approximately 12.6, approximately 4.72, and approximately 4,47.

6. Salt according to claim 4, characterized by a powder x-ray containing peaks with d values in angstroms of approximately 18,4, approximately 15,7, approximately 12.6, approximately 5,50 and approximately 4,51.

7. Salt according to claim 1, which represents maleate.

8. Salt according to claim 7, characterized by a powder x-ray containing peaks with d values in angstroms of approximately 13,0, approximately 5,71, approximately 4,77 and approximately 4,19.

9. Salt according to claim 1, which represents malate.

10. Sol according to claim 9, characterized by a powder x-ray containing peaks with values of the s d in angstroms, approximately 13,1, approximately 12,0, approximately 5,35, approximately 4,75, approximately 4,37, approximately 4.2 9, approximately 4.00 and approximately a 3.87.

11. Salt according to claim 1, which represents a phosphate.

12. Salt according to claim 11, characterized by a powder x-ray containing peaks with d values in angstroms of approximately 17,3, approximately 5,91, approximately 4,80, approximately 4,27, approximately 4,14 and approximately 3,86.

13. Salt according to claim 1, which represents succinate.

14. Salt according to item 13, which is characterized by a powder x-ray containing peaks with d values in angstroms, approximately equal to 12.8, approximately 5,51, approximately 4,79, approximately 4,16 and approximately 4,05.

15. Salt according to claim 1, which represents a sulfate.

16. Salt § 15, which is characterized by a powder x-ray containing peaks with d values in angstroms of approximately 17,0, approximately 5,49, approximately 4,53 and approximately 4,30.

17. Salt according to claim 1, in which the salt is edisylate (etandisulfonat).

18. Salt 17, which is characterized by a powder x-ray containing peaks with d values in angstroms, is equal to approximately 10.0, approximately 6,05 approximately 5,31, approximately equal to 4.97, approximately 4.26% and approximately 4,12.

So obtain a salt according to claim 1, including
a) forming a solution of the compounds of formula I in an organic solvent;
b) adding an acid selected from the group consisting of citric acid, fumaric acid, maleic acid, L-(-)-malic acid, phosphoric acid, succinic acid, sulfuric acid or 1,2-ethicolegal acid in this solution and
c) selection of salt.

20. The method according to claim 19, in which the specified selection contains a selection of salt from the slurry formed after step (b).

21. The method according to claim 19, in which the specified selection includes the deposition of salt from a solution formed after step (b) by one or more cooling, solvent removal or adding a precipitant.

22. Salt N-(4-terbisil)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)urea of the formula I:

obtained by the method including
a) forming a solution of the compounds of formula I in an organic solvent;
b) adding an acid selected from the group consisting of citric acid, fumaric acid, maleic acid, L-(-)-malic acid, phosphoric acid, succinic acid, sulfuric acid or 1,2-ethicolegal acid in this solution and
c) selection of salt.

23. Pharmaceutical composition having activity as an inhibitor or inverse agonist of the receptor manam is on, containing one or more salts according to claim 1 and a pharmaceutically acceptable carrier.

24. A method of inhibiting the activity of monoamine receptor comprising the administration to an individual, at least one salt according to claim 1.

25. The use of at least one salt according to claim 1 for the preparation of drugs for the treatment of neuropsychiatric disorders.

26. Use A.25, in which neuropsychiatric disease selected from the group consisting of psychosis, schizophrenia, schizoaffective disorders, mania, psychotic depression, affective disorders, dementia, anxiety, sleep disorders, disorders of appetite, bipolar disorder, psychosis secondary to hypertension, migraine, vascular spasm and ischemia, motor tics, tremor, psychomotor slowing, bradykinesia and neuropathic pain.

27. The use of at least one salt according to claim 1 for the preparation of drugs for the treatment of neurodegenerative diseases.

28. The application of item 27, in which the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Huntington's disease, Alzheimer's disease, cerebellar atrophy, Tourette's syndrome, Friedrich's ataxia, a disease Machado-Joseph, dementia with calves Levi, dystonia, progressive supranuclear palsy and frontotemporal dementia.

p> 29. The use of at least one salt according to claim 1 for the preparation of drugs for the treatment of dyskinesia associated with dopaminergic therapy.

30. The use of at least one salt according to claim 1 for the preparation of drugs for the treatment of dystonia, myoclonus, or tremor associated with dopaminergic therapy.

31. The use of at least one salt according to claim 1 for the preparation of drugs for the treatment of thrombotic state.

32. Use p in which thrombotic condition selected from the group consisting of myocardial infarction, thrombotic or ischemic attack, idiopathic and thrombotic thrombocytopenic purpura, peripheral vascular disease and Raynaud's syndrome.

33. The pharmaceutical composition according to item 23, which represents a solid dosage form.

34. The pharmaceutical composition according p, where the solid dosage form intended for oral administration.

35. The pharmaceutical composition according to clause 34, in which the content of citrate is from about 1 to 100 mg.

36. Salt according to claim 2, characterized by a powder x-ray containing peaks with d values in angstroms of approximately 15,9, approximately 7.9, approximately 6,3, and approximately 4,68.

37. Salt according to claim 4, which character is by powder x-ray, containing peaks with d values in angstroms of approximately 15,7, approximately 12.6, approximately 4.72, and approximately 4,47.

38. Salt according to claim 4, characterized by a powder x-ray containing peaks with d values in angstroms of approximately 18,4, approximately 15,7, approximately 12.6 and approximately 5,50.

39. Salt according to claim 7, characterized by a powder x-ray containing peaks with d values in angstroms of approximately 13,0, approximately 5,71, and approximately 4,19.

40. Sol according to claim 9, characterized by a powder x-ray containing peaks with d values in angstroms of approximately 13,1, approximately 4.75 V and approximately 4,29.

41. Salt according to claim 11, characterized by a powder x-ray containing peaks with d values in angstroms of approximately 17,3, approximately 5,91, approximately 4,27 and approximately 4,14.

42. Salt according to item 13, which is characterized by a powder x-ray containing peaks with d values in angstroms, approximately equal to 12.8, approximately 5,51 and approximately 4,05.

43. Salt § 15, which is characterized by a powder x-ray containing peaks with d values in angstroms of approximately 17,0, approximately 5,49, and approximately 4,30.

44. Salt 17, the which is characterized by a powder x-ray, containing peaks with d values in angstroms, is equal to approximately 10.0, approximately 6,05, and approximately equal to 4.97.

45. Citrate salt according to claim 2, characterized by the formula IV:

46. Malata salt according to claim 7, characterized by the formula VI:

47. Phosphate salt according to claim 11, characterized by the formula VIII:

48. Edisylate salt 17, characterized by the formula XI:
.

49. Malata salt according to claim 9, where this salt is in the form of a hydrate.

50. Succinate salt 13, where this salt is in the form of a hydrate.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and their acid-additive and basic salts as FAAH enzyme inhibitors, method of producing said compounds, a pharmaceutical composition based on said compounds and their use, as well as to intermediate compounds of formula (IIa). In general formula (I) , m is an integer ranging from 1 to 4; n is equal to 1 or 2; o is equal to 1 or 2; A is selected from one or several groups X, Y; X denotes a methylene group optionally substituted with one group which is C1-6-alkyl; Y denotes a C2-alkynylene group; B denotes a covalent bond or C1-6-alkylene group; G denotes a covalent bond, an oxygen atom; R1 denotes an R4 group optionally substituted with one or more R5 and/or R6 groups; R4 denotes a group selected from oxazolyl, isoxazolyl, thiazolyl, phenyl, pyridinyl, naphthyl, quinolinyl, isoquinolinyl; R5 denotes a halogen atom, a cyano group, C1-6-alkyl, C1-6-alkoxy, C1-6-fluoroalkyl, C1-6-fluroalkoxy, NR7R8; R6 denotes a phenyl group, phenyloxy or pyrimidinyloxy; where R6 group(s) can be substituted with one or two R5 groups which are identical or different from each other; R7 and R8 independently denote a C1-6-alkyl group; R2 denotes a hydrogen atom; R3 denotes a hydrogen atom or C1-C6-alkyl group. In general formula (IIa) , m is an integer ranging from 1 to 2; n equals 2, o equals 2; A denotes X, X denotes a methylene group; B denotes a C1-6-alkylene group; G denotes a covalent bond; R1 denotes an R4 group optionally substituted with one or more R5 and/or R6 groups; R4 denotes phenyl; R5 denotes a halogen atom, C1-6alkoxy; R6 denotes a phenyl group; R2 denotes a hydrogen atom.

EFFECT: compounds can be used for treating and preventing diseases mediated by FAAH enzyme activity, such as acute and chronic pain, dizziness, vomiting, nausea, disrupted eating behaviour, neurologic and psychiatric pathologies, acute and chronic neurodegenerative diseases etc.

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound N-(1-{(3R)-3-(3,5-difluorophenyl)-3-[1-(methylsulfonyl) piperidin-4-yl]propyl}piperidin-4-yl)-N-ethyl-2-[4- (methylsufonyl)phenyl]acetamide or its pharmaceutically acceptable salts. The invention also relates to a method for synthesis of the compound in paragraph 1, as well as to a pharmaceutical composition.

EFFECT: obtaining a novel biologically active compound with activity towards CCR5 (chemokine receptor 5).

6 cl, 6 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of formula (I): , in which: Ra and Ra', identical or different, mean atom of hydrogen or alkyl, R1 means atom of hydrogen or alkyl, cycloalkyl, heterocycloalkyl or aryl, R2 means group of formula -(CH2)x-(CO)y-Y or -(CO)y-(CH2)x-Y, in which, x = 0, 1, 2, 3 or 4, y = 0 or 1, Y means atom of hydrogen or the following group: hydroxyl, alkyl, cycloalkyl, alkyloxyl, aryl, heteroaryl or -NR11R12, besides, Y is not an atom of hydrogen, when x=y=0, R11 and R12, identical or different, mean atom of hydrogen or the following group: alkyl, cycloalkyl, alkyloxyl or -NR13R14, or R11 and R12 together with atom of nitrogen, to which they are connected, create mono- or bicyclic structure, which contains 4-10 links and unnecessarily contain additionally 1-3 heteroatoms and/or 1-3 ethylene unsaturated links, besides this cycle is not necessarily substituted in any of positions with 1-3 groups, selected from atoms of halogen and hydroxyl, alkyl, cycloalkyl and alkyloxygroups; R13 and R14, identical or different, mean atom of hydrogen or alkyl, R3 means 1-3 groups, identical or different, available in any position of cyclic structure, to which they are connected, and selected from atoms of halogen; R5 means atom of hydrogen, R4 is selected from groups of formulae (a), (b), (c), which are not necessarily substituted with aryl group, described below: (a), (b), (c), in which p=0,1,2 or 3; m=0,1 or 2, and either a) X means link -N(R10)-, in which R10 is selected from: -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, - or R10 with atom of nitrogen, with which it is connected, and with atom of carbon, available in any position of cyclic structure of formula (a), but not with neighboring to mentioned atom of nitrogen, creates bridge, containing 3-5 links, or, b) X means link -C(R6)(R7)-, where R6 is selected from the following: atom of hydrogen, atom of halogen, group -(CH2)x-OR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9 or -(CH2)x-NR8-COR9, in which x=0,1,2,3 or 4, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocycloalkyl, condensed with aryl, besides, alkyl, cycloalkyl or aryl groups are not necessarily substituted with 1 or several groups, selected from groups: R, R', -OR, -NRR', -COR; R7 is selected from atoms of hydrogen and halogen and the following groups: alkyls, -OR, -NRR', -NR-CO-R', -NR-COOR', -R8 and R9 are selected, independently from each other, from atom of hydrogen and the following groups: alkyls, cycloalkyls, aryls, -CO-alkyls, besides, alkyls and aryls are unnecessarily substituted with one or several groups, selected from groups: R, R', -OR, or R8 and R9 together create heterocycloalkyl,- R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, besides, mentioned hetero aryl groups represent aromatic groups, including from 5 to 10 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen and/or sulfur; besides mentioned heterocycloalkyl groups represent cycloalkyl groups, including from 5 to 6 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen or sulfur; in the form of base or acid-additive salt, and also in the form of hydrate or solvate. Invention is also related to medicinal agent, to pharmaceutical composition, to application, to method of production, and also to compounds of formulas (VI), (XVIII), (XIX).

EFFECT: new biologically active compounds have activity of agonists of melanocortin receptors.

27 cl, 16 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the general formula: , where R1 is an inferior alkyl, -(CH2)n-aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluormethyl, or pyridine; R2 is an inferior alkyl, -(CH2)n- aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluoromethyl, nitro-, cyano-, -NR'R", hydroxy-, or heteroaryl group that is a monovalent heterocyclic 5- or 6-membered aromatic radical with N atoms, either R2 is a heteroaryl that is monovalent heterocyclic 5- or 6-membered aromatic radical where heteroatoms are chosen from N, O or S group, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl or halogen; R3 is pyridine or aryl, unsubstituted or substituted by a halogen or inferior alkyl; R4 is hydrogen or hydroxy-. A is -S(O)2- or -C(O)-; X, Y are -CH2- or -O- independently from each other, though both X and Y should not be -O- at the same time; R'R" are hydrogen or inferior alkyl independently from each other; n is 0, 1 or 2. Also the invention concerns pharmaceutically acceptable additive salts and acids of the compounds, and a medicine based on it.

EFFECT: new biologically active compounds show inhibition effect in glycine absorption.

21 cl, 214 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula I: , where: a is 0 or whole number of 1 to 3; each R1 is selected independently out of the halogens; b is 0 or whole number of 1 to 3; each R2 is selected independently out of the halogens; W is linked in 3 or 4 position against the nitrogen atom in piperidine ring and is O; c is 0 or whole number of 1 to 4; each R3 is selected independently out of (1-4C)alkyls; or two groups of R3 are linked together forming (1-3C)alkylene or oxyrane-2,3-diyl; R4 is a bivalent group of the formula: -(R4a)d-(A1)e-(R4b)t-Q-(R4c)g-(A2)h-(R4d)i-, where each of d, e, f, g, h and i is selected independently out of 0 or 1; each of R4a, R4b, R4c and R4d is selected independently out of (1-10C)alkylene, where each alkylene group is unsubstituted or substituted by 1-5 substitutes selected independently out of (1-4C)alkyl, fluorine and hydroxy-; each of A1 and A2 is selected independently out of (3-7C)cycloalkylene, (6-10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene and (3-6C)heterocyclene where each cycloalkylene is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogens, (1-4C)alkyl, (1-4C)alkoxy-, -S(O)2-(1-4C)alkyl, hydroxy-, nitro- and trifluormethoxy; Q is selected out of -O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-; -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and -N(Qk) links; each of Qa, Qb, Qc, Qd, Qe, Qf and Qk is selected independently out of hydrogen, (1-6C)alkyl and A3, where alkyl group is unsubstituted or substituted by 1-3 substitutes selected independently out of fluorine, hydroxy- and (1-4C)alkoxy-; or together with nitrogen atom and R4b or R4c group to which they are linked they form 4-6-membered azacycloalkylene group; A3 is selected independently out of (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroalkyl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogen, (1-4C)alkyl and (1-4C)alkoxy-, if the number of adjacent atoms in the shortest chain between two nitrogen atoms, to which R4 is linked, lies within 4 to 16; R5 is hydrogen or (1-4C)alkyl; R6 is -NR6aCR6b(O), and R7 is hydrogen; either R6 and R7 together form -NR7aC(O)-CR7b=CR7c-; each of R6a and R6b is hydrogen or (1-4C)alkyl independently; and each of R7a, R7b and R7c is hydrogen or (1-4C)alkyl independently; or the pharmaceutically acceptable salts, solvates or stereoisomers of the claimed compounds. The invention also concerns compounds of the formula I, 1-[2-(2-chlor-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxuphenylcarbamoyl)ethyl] piperidine-4-yl ether of biphenyl-2-ylcarbamine acid or its pharmaceutically acceptable salt or solvate, pharmaceutical composition, method of pulmonary disease treatment, method of bronchial lumen dilation for a patient, method of treatment of chronic obstructive pulmonary disease or asthma, method of obtaining the compound of the formula I, medicine based on it, and application of compounds described in any of the paragraphs 1, 13, 14, 24, 25, 26, 27 or 28.

EFFECT: obtaining of new biologically active compounds with high activity rate of both antagonist of muscarine receptors and β2 agonist of adrenergic receptors.

42 cl, 186 ex

FIELD: chemistry.

SUBSTANCE: description is given of amides of piperazinyl- or piperidinylaminesulphoamic acid with genera formula (I) , in which R1 and R2 together with a nitrogen atom, to which they are bonded, represent a 6-member aliphatic heterocyclyl, containing two atoms of nitrogen as heteroatoms. The indicated extra atom of nitrogen is substituted with radical R, where R represents COOR', and R' represents (C1-C6)alkyl or benzyl, or phenyl, substituted with trifluoromethyl and aminocarbonyl, or R1 represents hydrogen, and R2 represents a group with formula , in which R9 represents (C1-C8)alkoxycarbonyl or phenyl, substituted with haloid(C1-C6)alkyl or aminocarbonyl; R3 represents phenyl or phenyl(C1-C4)alkyl, containing two substitutes, chosen from halogen and haloid(C1-C6)alkyl. Description is given of the use of formula (I) compounds as inhibitors of steroid sulphatase.

EFFECT: compound has inhibition effect to steroid sulphatase.

7 cl, 2 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds, namely, to N-substituted derivatives of piperidine of the formula (I): or their pharmaceutically acceptable salts, amides, esters wherein values R1, R, R3, m, X, n, W, Ar1 and Ar2 are disclosed in the invention claim. Also, invention relates to methods for inhibition of activity and methods for inhibition of activation of monoamine receptors. Methods involve contacting monoamine receptors or system comprising monoamine receptors with the effective amount of one or some compounds of the formula (I). Except for, invention relates to using compounds of the formula (I) in treatment of psychotic diseases.

EFFECT: valuable medicinal properties of compounds.

35 cl, 1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes derivatives of aminotetraline of the formula (I) wherein R1 means (C1-C6)-alkyl; R2 means halogen atom or -OR'; R3 means hydrogen atom (H) or -OR' wherein R' means (C1-C6)-alkyl or -SO2R'' wherein R'' means phenyl, thienyl, isoxazolyl; R4 means (C1-C6)-alkyl, phenyl, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, diazepinyl, furanyl, isoxazolyl, imidazolyl and pyrazolyl that can be substituted optionally, and pharmaceutical compositions containing derivatives of aminotetraline. Proposed compounds are selective antagonists of M2/M3 muscarinic receptors and designated for treatment and prophylaxis of diseases associated with smooth muscle disorder.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 1 tbl, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel 4-(dipeptidylamino)-piperidine-1-carboxamidines of the general formula (1): or their optical isomers or pharmaceutical acceptable salts wherein R1 is chosen from hydrogen atom (H), lower alkyl, R4-CO wherein R4 means -OCCH2, R5-OCO wherein R means -SO2; R2 is chosen from lower alkyl, cycloalkyl, (C5-C12)-cycloalkylalkyl, phenylalkyl and others; R3 is chosen from H, -OH and group O-lower alkyl; R4 is chosen from H, lower alkyl and phenyl; R5 is chosen from lower alkyl, phenyl and benzyl. Proposed compounds are inhibitors of kallikrein and can be used in treatment of intestine inflammatory disease, arthritis, septic shock, hypotension or cancer.

EFFECT: valuable medicinal properties of compounds.

12 cl, 2 tbl, 60 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to use of dihydrochloride 9-diethylaminoethyl-2,3-dihydroimidzo[1,2-a]benzimidazole as a compound which inhibits erythrocyte aggregation and reduces blood viscosity, and also reduces insulin resistance and restores tolerance of the body to glucose. The invention also relates to a pharmaceutical composition based on the said dihydrochloride.

EFFECT: new potential of the of the said compound has been studied.

3 cl, 4 dwg, 9 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: in treatment of children with pyoinflammatory diseases with possibility of development of local necrotic and septicopyemic complications deeply subcutaneously enoxaparin (Klexane) is introduced in amount 0.5 mg/kg of body weight. Introduction is performed 1 time a day during all acute phase of inflammation.

EFFECT: method allows to increase treatment efficiency due to reduction of blood clot formation in lesion focus resulting from introduction in individually selected dose and in definite phase of disease of low-molecular heparin preventing in this way disease complications in children.

2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds having general formula (I) given below, , where R1 represents a hydrogen atom, C1-C6 alkyl group, C3-C6 cycloalkyl group or C1-C6 alkoxy group; R2 is a hydrogen atom or C1-C6 alkyl group; R3 is a substituted C1-C6 alkyl group {said substitute is a heterocyclyl group or heterocyclyl group substituted with 1-5 substitutes selected from <a group of substitutes α> (said heterocyclyl groups can be substituted with 1-4 oxo groups); a heteroaryl group or a heteroaryl group substituted with 1-5 substitutes selected from <a group of substitutes α>; or a substitute selected from <a group of substitutes β>}, or a heterocyclyl group or a heterocyclyl group substituted with 1-5 substitutes selected from <a group of substitutes α> (said heterocyclyl groups can be substituted with 1-4 oxo groups); where the heteroaryl group is a 5- or 6-member aromatic heterocyclic group containing at least one nitrogen atom, and the heterocyclyl group is a partially or completely reduced 5- or 6-member heterocyclic group containing 1-3 sulphur atoms, oxygen atoms and/or nitrogen atoms; X1, X2, X3, X4 and X5 each independently represents a hydrogen atom or a halogen atom; n equals 1, < group of substitutes α> is a carboxy group, C2-C7 alkoxycarbonyl group, carbamoyl group, hydroxyl group, C1-C6 alkyl group, C2-C7 alkanoyl group, C2-C7 alkylcarbamoyl group, di(C1-C6 alkyl)carbamoyl group or a group of formula R4-CO-CR5R6-(CH2)m-, where R4 represents a hydroxyl group or a C1-C6 alkoxy group; R5 and R6 are identical or different and each represents a hydrogen atom or a C1-C6 alkyl group; and m equals an integer ranging from 0 to 5; and <group of substitutes β> is represents a carboxy group, C2-C7alkoxycarbonyl group, carbamoyl group, cyano group, hydroxyl group, C1-C6 alkoxy group, C2-C7 alkylcarbamoyl group, di(C1-C6 alkyl)carbamoyl group and a group of formula R9-CO-(CH2)k-N(R10)- {where R9 represents a hydroxyl group or C1-C6 alkoxy group; R10 represents a hydrogen atom or C1-C6 alkyl group; and k equals an integer from 0 to 5}, to pharmacologically acceptable salts thereof and to C1-C6 alkanoyl derivatives. The invention also relates to a pharmaceutical composition, to use as well as to a method of preventing or therapy for diseases related to thrombosis or embolus formation.

EFFECT: obtaining novel biologically active compounds having inhibitory activity towards thrombocyte aggregation.

24 cl, 118 ex, 8 tbl

FIELD: medicine.

SUBSTANCE: invention relates to compound of general formula , where R represents unsaturated linear or branched hydrocarbon chain of atoms. Invention also relates to application of said compounds as means for inhibition of platelet aggregation.

EFFECT: obtaining novel compound, characterised by high rate of reaction with sulphur-containing groups of atoms of platelet components, actively inhibiting platelet activity, possessing high stability.

2 cl, 1 tbl, 6 dwg, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to 2-cycloalkylamino-5-thienyl-1,2,3-thiadiazines hydrobromides with antiaggregant activity , where R=H; CH3; Br, = morpholino-; thiomorpholino-; pyrrolidino-; 2,6-dimethylmorpholino-; hexamethylenimino-.

EFFECT: obtaining novel compounds which can be used in medicine for treating and preventing such diseases as myocardial infarcation, stroke, rejection of transplanted organs and tissue, and can also prevent embolism and thrombosis formation.

1 cl, 5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolidine-3,4-dicarboxamide derivatives of formula (I): , where: X is N or C-R6; R1 is C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7alkyl, fluoro-C1-7alkyl, hydroxy-C1-7alkyl, CN-C1-7alkyl, R10C(O), R10OC(O)-, N(R11,R12)C(O)-; R10OC(O)C1-7alkyl, N(R11,R12)C(O)-C1-7alkyl, R10SO2, R10-SO2-C1-7alkyl, N(R11, R12)-SO2, N(R11,R12)-SO2-C1-7alkyl, aryl-C1-7alkyl, 5-member monocyclic heteroaryl containing a nitrogen atom, where the ring carbon atom can be substituted with a carbonyl group, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents an aromatic -member monocyclic ring with 1 S atom or a 6-member monocyclic ring with 1 N atom, C1-7alkoxy-C1-7alkyl, C1-7alkoxycarbonyl-C3-10cycloalkyl-C1-7alkyl or halogen substituted 4-member heterocyclyl-C1-7alkyl with one O atom; R2 is H, C1-7alkyl; R3 is aryl, aryl-C1-7alkyl, heteroaryl, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents a 5-member monocyclic ring with 1 S atom, a 6-member monocyclic ring with 1 or 2 N atoms, 9-, 10-member bicyclic system with 1 or 2 N atoms in one ring; R4 is H, C1-7alkyl, OH; R5, R6, R7, R8 are independently selected from a group consisting of H, halogen, C1-7alkyl, C1-7alkoxy, flouro-C1-7alkyl, fluoro-C1-7alkyloxy; R9 is aryl, heterocyclyl, heteroaryl, heterocyclyl-C(O)-; R10 is H, C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7alkyl, fluro-C1-7alkyl, heteroaryl, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents a 5-member monocyclic ring with 4 N atoms, a 5-member heterocyclyl with 1 N atom; R11, R12 are independently selected from a group consisting of H, C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7 alkyl; and pharmaceutically acceptable salts thereof; where the term "aryl" represents a phenyl group which can be optionally substituted with 1 to 5 substitutes which are independently selected from a group consisting of the following: halogen, CF3, NH2, C1-7alkylsulphonyl, C1-7alkoxy, fluoro-C1-7alkyl, fluoro-C1-7 alkoxy; the term "heterocyclyl" represents a nonaromatic monocyclic 5-, 6-member heterocyclic group with 1, 2 N atoms, or with 1 N atom and 1 O atom, where the heterocyclyl group can be substituted as indicated with respect to the term "aryl", and one carbon atom of the ring system of the heterocyclyl group can be substituted with a carbonyl group; the term "heteraryl" represents an aromatic 5- or 6-member monocyclic ring system which can have 1, 2, 3 N atoms, or 1 N atom and 1 S atom, where the heteroaryl group can be substituted as indicated with respect to the term "aryl", and one carbon atom of the ring system of the heteroaryl group can be substituted with a carbonyl group. Formula I compounds have inhibitory activity towards coagulation factor Xa.

EFFECT: possibility of using said compounds in a pharmaceutical composition and for preparing a medicinal agent.

27 cl, 90 ex

FIELD: medicine.

SUBSTANCE: invention refers to medical products and concerns method for making solid oral pharmaceutical composition containing a hydrophilised form of 5-chlor-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidine-5-yl}-methyl)-2-thiophencarboxaime (I), differing that at first by spraying granulation, a granulated material is prepared. It contains a hydrophilised form of active substance (I). Then said granulated material if necessary is transformed into a pharmaceutical composition with pharmaceutically acceptable additives added.

EFFECT: method allows improving biological availability of the active substance.

6 cl, 2 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and concerns an agent expressing antithrombotic activity and containing an antagonist of purine R2U1-receptors, namely 2-(4-methoxyphenyl)-(9-morpholinoethyl)imidazo[1,2-a]benzimidazole dihydrochloride of formula .

EFFECT: there is described antithrombotic agent affecting regulation of thrombocyte capacity.

3 tbl

FIELD: pharmacology.

SUBSTANCE: there is produced synthetic derivative of phthalyl-glycyl-agginyl-piperidide peptide expressing anticoagulant activity estimated by inhibiting amidolytic thrombin activity in system in vitro and double prolongation of rats' blood plasma coagulation as compared with the control values in tests activated partial thromboplastin and thrombin time tests and having formula 1, including pharmaceutically acceptable salts.

EFFECT: new synthetic peptide derivative expressing anticoagulant activity.

1 dwg, 2 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: carboxylic acid compounds are presented by formula (I) where R1 represents (1) hydrogen atom, (2) C1-4alkyl; E represents -CO-; R2 represents (1) halogen atom, (2) C1-6 alkyl, (3) trihalogen methyl; R3 represents (1) halogen atom, (2) C1-6alkyl; R4 represents (1) hydrogen atom; R5 represents (1) C1-6alkyl; represents phenyl; G represents (1) C1-6alkylene; represents 9-12-merous bicyclic heterocycle containing heteroatoms, chosen of 1-4 nitrogen atoms, one or two oxygen atoms; m represents 0 or an integer 1 to 4, n represents 0 or an integer 1 to 4, and i represents 0 or an integer 1 to 11 where R2 can be identical or different provided m is equal to 2 or more, R3 can be identical or different provided n is equal to 2 or more, and R5 can be identical or different provided i is equal to 2 or more; both R12 and R13, independently represent (1) C1-4alkyl, (2) halogen atom, (3) hydroxyl or (4) hydrogen atom, or R12 and R13 together represent (1) oxo or (2) C2-5alkylene and where provided R12 and R13 simultaneously represent hydrogen atom, carboxylic acid compound presented by formula (I), represents a compound chosen from the group including the compounds (1) - (32), listed in cl.1 of the patent claim. Besides the invention concerns a pharmaceutical composition based in the compound of formula I and to application of the compound of formula I for making the pharmaceutical composition.

EFFECT: there are produced new carboxylic acid derivatives with antagonistic activity with respect to DP receptor.

14 cl, 74 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel naphthalene derivatives of general formula I , as well as to their pharmaceutically acceptable salts, which can be used for treating and/or preventing diseases associated with H-3 receptor modulation. In formula I, R1 is selected from hydrogen, lower alkyl, phenyl, phenyl-lower alkyl and lower alkoxyalkyl; R2 is selected from hydrogen, lower alkyl, C3-C7-cycloalkyl, lower alkoxyalkyl or lower alkylsuphanylalkyl (all values of R1 and R2 are given in the formula of inventions); or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-7-member saturated or partially unsaturated heterocyclic ring which can contain one more heteroatom selected from nitrogen, oxygen and sulphur atoms, where the said heterocyclic ring can be unsubstituted or substituted with 1-2 groups, or can be condensed with an unsubstituted phenyl ring; A is selected from (values of R3-R7, R9, R10, X, m, n, t, p, q and s are given in the formula of invention). Invention also pertains to a pharmaceutical composition containing formula I compounds.

EFFECT: increased effectiveness of application.

30 cl, 2 tbl, 188 ex

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