Derivatives of piperazinylalkylthiopyrimidine, pharmaceutical composition containing thereof and method for preparing

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of piperazinylalkylthiopyrimidine of the formula (I): wherein R1 represents hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkanoyl or di-(C1-C4-alkyl)-amino-(C1-C4-alkyl); R2 means hydrogen atom or benzyl substituted with 1-3 substitutes taken among the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy-group, di-(C1-C4-alkyl)-amino-group, hydroxyl group and halogen atom; n = 2, 3 or 4, and to its pharmaceutically acceptable acid addition salt. Also, invention describes a method for preparing compounds and pharmaceutical composition based on thereof. Compounds are useful for treatment of diseases arising as result of the central nervous system injury.

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

14 cl, 3 tbl, 26 ex

 

The invention concerns new derivatives of piperazinecarboxamide, pharmaceutical compositions containing them, and method of producing active substances. New substances can be used mainly for the treatment of diseases that occur due to lesions of the Central nervous system.

In more detail, the invention relates to a new derived piperazinecarboxamide formula (I)

where

R1represents a hydrogen atom, a C1-4alkyl, C1-4alkanoyl or di(C1-4alkyl)amino(C1-4alkyl),

R2means a hydrogen atom or a benzyl, substituted by 1-3 substituents selected from the group consisting of C1-4of alkyl, C1-4alkoxygroup, di(C1-4alkyl)amino group, hydroxyl group and halogen atom,

n has the value 2, 3 or 4,

and its pharmaceutically acceptable salts accession acid.

From patent application WO 97/16429 known derivatives piperazinecarboxamide, characterized in that pieperazinove ring is substituted phenyl or benzyl group on the nitrogen atom in position 4. Known compounds are suitable mainly for the treatment of disorders of the Central nervous system and have, for example, a significant anxiolytic activity. An important feature of the known compounds is the tsya, they affect serotonin receptors (5-HT2A, 5-HT2C). A significant disadvantage of this connection is that the connection with the greatest anxiolytic effect, is very rapidly metabolized in vivo, and have undesirable side sedative effects. Thus, the known compounds have low biological usefulness, which inhibits the development of drugs used in clinical practice.

The purpose of this invention was to provide new compounds which are effective mainly within the above-mentioned biological activity, are more stable than known compounds from the point of view of metabolism, and does not have a sedative side effects.

The above objective has been achieved by providing new derivatives piperazinecarboxamide formula (I)having ansioliticos activity. However, new connections do not have any effect on serotonin receptors and not so quickly metabolized.

In the description of C1-4alkyl represents methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl or isopropyl. Preferably, C1-4the alkyl was methyl or isopropyl.

C1-4alkoxygroup includes mainly methoxy-, ethoxy-, n-propoxy or n-butoxy the PPU, preferably the methoxy group.

The halogen atom represented mainly by fluorine atom, chlorine or bromine, preferably, a chlorine atom or a fluorine atom.

Under C1-4alkanoyl mean formyl, acetyl, n-propanol, n-butanol etc., preferably acetyl.

Pharmaceutically acceptable salts of the accession of the acid compounds of formula (I) are salts formed pharmaceutically acceptable inorganic or organic acids including sulfonic acids. Preferred salts accession acids are salts formed with hydrogen halides, for example, chlorocarbon or bromadiolon, carbonates, bicarbonates, sulfates, phosphates, acetates, fumarate, maleate, citrates, ascorbates and benzosulfimide.

A preferred subgroup of the compounds of the present invention consists of compounds of formula (I) and their pharmaceutically acceptable salts accession acids, where

R1represents a hydrogen atom, a dimethylamino(C1-4alkyl) or (C1-4alkanoyl,

R2the same as defined in connection with formula (I),

n has a value of 2 or 3.

Especially preferred derivatives of piperazinecarboxamide of the present invention consists of compounds of formula (I), where

R1represents a hydrogen atom or a dimethylamino(C1-4alkyl),

R2means benzo is l, replaced With1-4alkoxygroup or fluorine atom,

n has the value 2,

and their pharmaceutically acceptable salts accession acids.

The value of R2With1-4alkoxygroup, respectively, is orthopaedie.

The compounds of this invention are obtained by reaction of 2-mercaptopyrimidine formula:

where R2defined above, or its salt of the alkali metal with halogensilberemulsionen formula:

where R1and n are such as defined above, Hlg represents a halogen atom, preferably chlorine atom or bromine, or its salt accession acid, and if necessary, conversion of the compounds of formula (I) and its pharmaceutically acceptable salt accession acid or release it from salt accession acid.

If necessary, the obtained compound of formula (I) can be converted into another compound of formula (I). These additional transformations may be known by. Thus, the obtained compound of formula (I), where R1represents a hydrogen atom, can be alkilirovanii with obtaining the compounds of formula (I), where R1means1-4alkyl. The compounds of formula (I), where R1is dialkylaminomethyl can be obtained similar additional pre the education (alkylation or acylation). According to another example of the conversion, the compound of formula (I), where R2means alkoxybenzyl, obtained by alkylation of compounds of formula (I). where R2is hydroxybenzyl. or the compound of formula (I), where R1presents a hydrogen atom, is obtained from the corresponding compounds of formula (I), where R1is formyl, which is removed by hydrolysis.

The method of the invention is performed in an organic solvent or mixture of solvents, which are neutral reagents. Can be used, for example, aliphatic alcohols such as methyl alcohol, isopropyl alcohol, dialkylamide, preferably dimethylformamide, water or their mixture. The reaction between the compounds of formula (II) and (III) is carried out either with the use of a salt of an alkali metal 2-mercaptopyrimidine formula (II) or in the presence of an agent that binds acid. Preferably, for this purpose we have used the carbonates of alkali metals such as sodium bicarbonate or potassium hydroxides of alkali metals such as sodium hydroxide or potassium hydroxide, hydroxides of alkaline earth metals such as calcium hydroxide. or tertiary amines, such as pyridine, triethylamine or other trialkylamine.

Preferably, cyclotosaurus agent was potassium hydroxide, potassium carbonate or Carbo is at sodium.

Sometimes the reaction can be accelerated by using a catalyst. As the catalyst used, mainly, halides of alkali metals or the alkaline earth metal halides (such as potassium iodide, potassium fluoride, sodium bromide or calcium chloride). Preferably, the reaction is performed in the presence of a catalyst of potassium iodide.

The reaction is carried out at a temperature ranging from room temperature to the boiling point of the reaction mixture, depending on the reactivity of the starting materials. In aqueous solution the reaction is carried out at room temperature, in other cases, it is preferable that the reaction temperature was 60 to 80°C. the reaction Time ranges from 2 to 20 hours, depending on the reactivity of the starting compounds and temperature.

The initial compounds of formulas II and III can be used in equimolar amounts, or galgenlieder formula III is added to the reaction mixture is not more than 10% excess. Kislorodsvyazyvayushchei agent is used in equimolar amounts, however, it can be used in 10-fold excess. If the original substance is a salt of mercaptoethane, you usually have fewer kislorodsvyazyvayushchei agent. For each mole of 2-mercaptopyrimidine formula II is typically used from 0.1 to 0.2 moles of catalyst; preferably Reactiv the presence of 0.1 mole of catalyst.

The reaction mixture is treated with well-known specialists of ways. The product distinguish preferably as follows: the solution separated from the precipitated inorganic salts by filtration, the filtrate is evaporated under reduced pressure, and the residue crystallized from water or organic solvent, or the precipitated product and the inorganic salt is filtered together, and inorganic salts are removed by washing with water. In accordance with another possibility, the reaction mixture was poured into water to remove inorganic salts, and then extracted product or filtered the precipitated product. If necessary, the product is distilled known purification methods such as recrystallization or chromatography.

The compounds of formula I can be isolated in the form of pharmaceutically acceptable salts of the accession of the acids listed above, or the compounds of formula I obtained in the form of the base, turned into salt accession acid through reaction of the base with the appropriate acid in a neutral solvent. Salt accession acid base can re-release and then turn it into another salt accession acid.

From literature is known of starting compound of the formula II. They can be obtained, as described in the application WO 97/16429. Galogenangidridy formula III are also known, except connected to the I, where R1submitted by isopropyl. They can be obtained in the manner specified in US-P 2,851,458. Obtaining halogen compounds, where R1means formyl, described in article Arzneim. Forsch., 12, 937-942 (1962), and getting allogennogo compounds, where R1means acetyl, described in VE-R 645 602.

The compounds of formula 1 have an impact on the Central nervous system and have a particularly strong psychotropic effect.

The biological effects of the compounds of formula 1 is confirmed by the following tests:

1. Elevated plus-maze test

The tests were carried out in male SPRD rats weighing between 220 and 260, Each group of animals consisted of 8-10 individuals. Want to study the substance or solvent (i.e. distilled water or 0.4% solution of methylcellulose) oral was administered to animals in a volume of 5 ml/kg in the form of a solution or suspension for 60 min before the test.

Elevated plus-maze consists of two open and two closed 40 cm wall branches of equal size (50×15 cm), arranged in the shape of a cross. Branches of the same form are located opposite each other. The connection of the four branches forms a Central square region (15×15 cm). The device is made of wood, raised to a height of 50 cm and poorly illuminated from above. The essence of the method lies in the fact that during the study the project for the animals spend more time in the closed arms, than open branches due to the natural fear of open space and height. Compounds with anxiolytic effect, can significantly increase the time spent in open arms and the number of outputs in open branches. Average values of these parameters were calculated and after a statistical analysis determined the minimum effective dose for each connection [Pelow. S., Chopin, P., File SE, Briley, M.: Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J. Neurosci. Methods., 14, 149-167 (1985)].

The results obtained are shown in Table 1. Diazepam (7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one) was used as a control substance.

Table 1
Connection (no sample)The minimum effective dose in mg/kg, administered orally
1(besilate)1
1(fumarate)3
21
41
53
60,03
7<1
83
93
101
121
131
141
163
171
181
190,01
260,3
diazepam1

From table 1 we can see that the compounds of this invention have one the same or better - in some cases by several orders of magnitude better anxiolytic effect than that of diazepam in this test.

2. Determination of spontaneous motor activity

For experiments used male NMRI mice weighing from 20 to 25, Each group consisted of 10 mice. The substance to be verified or the solvent (i.e. 0.4% solution of methyl cellulose) was administered to animals orally in a volume of 20 ml/kg in suspension for 60 min before the test. This method gives basic information about the effect of the analyte on the natural mobility of the animals, thus, this method detects any sedative effect of the substance. In the case of anxiety the value of the anxiolytic effects depends on the presence or absence of a sedative action (the latter is preferable). For experiments used the device "digital meter movement, with 10 of the measuring space. On the movement of animals SVID who was testoval interruption of three parallel rays of infrared light at each measurement area, and these interrupts were recorded by the apparatus. Activity one animal was determined at each measurement area. From the results of the experiment was calculated ID value50(i.e. the dose producing 50% inhibition)[rsy, I., Csanyi.E., Lazar. I., Arch. Int. Pharmacodyn., 124, 180-190 (1960); Stille, G., Leuenerer, H. and Eichenberger, E., Farmaco Ed. Pr., 26, 603-625 (1971)]. The data obtained are shown in Table 2. Diazepam was used as a control substance.

Table 2
Connection (no sample)ID50in mg/kg taken orally
1(besilate)>90
1(fumarate)>100
2>100
432,8
5>100
6>100
7>100
8>100
16>100
17>100
18>100
19>100
26>100
diazepam6,9

From Table 2 one can see that the compounds of this invention do not affect the locomotor activity of mice even at a dose, which is 14 times higher than the value ID 50for diazepam, used as the control connection.

In summary, it can be argued that the compounds of this invention have a very significant anxiolytic effect, however, sedative side effect is not observed even at doses that are several orders of magnitude higher anxiolytic dose.

The results of the above studies suggest that the anxiolytic effects of new derivatives of piperazinecarboxamide more preferable than the same effect benzodiazepines are widely used in therapy, as these latter drugs are characterized by a high side sedative effect.

Below are data on the stability of compounds of the invention from the point of view of metabolism.

Table 3
Example of connectionsMetabolicheskaya stability in humans (%)Metabolicheskaya stability in rats (%)
Example 1 of the invention3169
Example 6 of the invention3857
Example 16 of the invention4650
Example 36 (WO 97/16429)35

The results, presented the data in Table 3, show that the compounds of the invention are significantly more stable than the compounds of WO 97/16429.

Thus, the new derivatives of piperazinecarboxamide formula I can be used as active ingredients in pharmaceutical compositions.

The pharmaceutical compositions of this invention contain a therapeutically active amount of the compound of formula 1 or its pharmaceutically acceptable salt accession acid and one or more of the standard bearers.

The pharmaceutical compositions of this invention suitable for oral, parenteral or rectal injection or for local processing and can be used in solid or liquid form.

Solid pharmaceutical compositions that are acceptable for oral administration may be presented in the form of powders, capsules, tablets, coated tablets, microcapsules, etc. and may include binding agents such as gelatin, sorbitol, polyvinylpyrrolidone, etc.; fillers such as lactose, glucose, starch, calcium phosphate, etc.; excipients for tableting, such as magnesium stearate, talc, polyethylene glycol, silicon dioxide, etc.; moisturizing agents, such as sodium lauryl sulfate, etc. as a carrier.

Liquid pharmaceutical compositions suitable for oral administration may shall be presented in the form of solutions, suspensions or emulsions, and may include, for example, suspendresume agents, such as gelatin, karboksimetilcelljuloza etc.; emulsifiers, such as sorbitan monooleate etc.; solvents such as water, oil, glycerine, propylene glycol, ethanol and so on; preservatives, such as methyl-para-hydroxybenzoate etc. as a carrier.

Pharmaceutical compositions suitable for parenteral administration include usually sterile solutions of the active ingredient.

Dosage forms listed above, as well as other dosage forms known in the art, see, for example, in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, USA (1990).

The pharmaceutical compositions of this invention usually contain from 0.1 to 95.0 wt.% the compounds of formula I or its pharmaceutically acceptable salt accession acid. The usual dose for adults is 0.1 to 1000 mg of the compounds of formula I or its pharmaceutically acceptable salt accession acid per day. The above dose may be administered once or in several stages. The actual dose depends on many factors and is determined by the doctor.

The pharmaceutical compositions of this invention are prepared by mixing the compounds of formula I or its pharmaceutically acceptable salt accession acid with one or more carriers and pre the treatment of the mixture in the pharmaceutical composition known in the art. Suitable methods known from the literature, for example, from Remington's Pharmaceutical Sciences mentioned above.

Preferably, the pharmaceutical compositions of this invention contain derived piperazinecarboxamide formula I, where

R1represents a hydrogen atom, a dimethylamino(C1-4alkyl) or (C1-4alkanoyl,

R2the same as defined in connection with formula I,

n has a value of 2 or 3.

or its pharmaceutically acceptable salt accession acid as the active ingredient.

Especially preferred pharmaceutical compositions of this invention include derived piperazinecarboxamide formula I, where

R1represents a hydrogen atom or a dimethylamino(C1-4alkyl),

R2represents benzyl, substituted C1-4alkoxygroup or fluorine atom,

n has the value 2,

or its pharmaceutically acceptable salt accession acid as the active ingredient.

In addition, the invention relates to a method of treatment of diseases, which includes the use of a therapeutically effective non-toxic amount of a derivative piperazinecarboxamide formula I or its pharmaceutically acceptable salt accession acid to patients suffering from disorders of the Central nervous system.

In addition, the invention includes the use of derivative piperazinecarboxamide formula I or its pharmaceutically acceptable salt accession acid to prepare a pharmaceutical composition having anxiolytic effect.

The invention is further illustrated by the following Examples.

Example 1.

4,6-Diamino-5-(2-methoxybenzyl)-2-[2-(1-piperazinil)ethylthio]pyrimidine.

5,71 g (19 mmol) of 4,6-diamino-2-mercapto-5-(2-methoxybenzyl)pyrimidine are suspended in a solution of 6.73 g (120 mmol) of potassium hydroxide in 120 ml of water and the resulting suspension is added dropwise a solution 4,43 g (20 mmol) 1-(2-chloroethyl)piperazine dihydrochloride in 20 ml of water at 25°C. the Reaction mixture was stirred at room temperature for 3 hours, then add 140 ml of water and 200 ml of methyl alcohol. The mixture is heated to the boiling temperature, then filtered hot and the filtrate crystallized at 0°C.

The resulting material purified by chromatography through a column Packed with 130 g of Kieselgel 60 using a mixture of methyl alcohol and toluene in the ratio of 1:1. The product is re-crystallized from 100 ml of a mixture of ethanol and water in the ratio 1:1 and dried over anhydrous calcium chloride at 80°C under reduced pressure.

So get 4,69 g (60%) of the named compound.

Education fumaric salt is islote (fumarata):

with 4.64 g (12.4 mmole) is suspended in 75 ml of ethyl alcohol. The suspension is heated to boiling and a solution of 1.47 g (12.6 mmol) of fumaric acid are added to 60 ml of ethanol. After crystallization at room temperature gain of 6.02 g (99%) salt of fumaric acid these compounds.

TPL: 195°C (decomposition).

Analysis: With22H30N6O3S (490,59)

calculated: 53,86%, N 6,16%, N 17,13%, S 6,54%;

found: 53,54%, H 6.08%in General, N 16,97%, S 6,55%.

Education salts benzosulfimide (besilate)

1.0 g (2.67 mmol) are suspended in 20 ml of ethanol and the resulting suspension is added dropwise a solution of 0.42 g (2.67 mmol) of benzosulfimide in 2 ml of ethanol at 0°C. the Mixture is shaken at room temperature for 5 hours and then filtered. Thus earn 1.25 g (88%) salt benzosulfimide these compounds.

TPL: 173-174°C.

Analysis: With24H32N6O4S2(532,69)

calculated: 54,12%, N 6,06%, N 15,78%, S 12,04%;

found: 54,01%, N 6,15%, N 15,59%, S 12,27%.

Example 2.

4,6-Diamino-5-(2-methoxybenzyl)-2-[2-(1-piperazinil)ethylthio]pyrimidine fumarate.

2,99 g (9.5 mmol) of 4,6-diamino-2-mercapto-5-(2-ethoxybenzyl)pyrimidine are suspended in the solution 3,37 g (60 mmol) of potassium hydroxide in 60 ml of water and the resulting suspension is added dropwise a solution 2,22 g (10 mmol) 1-(2-chloroethyl)piperazin is as dihydrochloride in 10 ml of water at 25°C. The reaction mixture was stirred at room temperature for 2 hours, then add 50 ml of water and 100 ml of methyl alcohol. The mixture is heated to the boiling point, filtered hot and the filtrate crystallized at 0°C. the resulting material purified by chromatography through a column Packed with 130 g of Kieselgel 60 using a mixture of methyl alcohol and toluene in the ratio 2:3. The resulting crystalline product is re-crystallized from a mixture of 20 ml methanol and 20 ml of water to obtain 2.20 g of the substance, which is a dihydrate of the base. This compound is dissolved in 40 ml of ethanol under heating, and the resulting solution was added to a solution of 0.64 g of fumaric acid in 15 ml of ethanol. After crystallization at room temperature gain of 2.56 g (53%) of the named product.

TPL: 187-189°C.

Analysis: C23H32N6O5S (504,61)

calculated: 54,75%, N 6,39%, N 16,65%, S 6,35%;

found: 54,72%, N 6,37%, N 16,93%, S 6,33%.

Example 3.

4,6-Diamino-2-[3-(4-methyl-1-piperazinil)propylthio]-5-(2-methoxybenzyl)-pyrimidine trihydrochloride.

To a suspension of 6.0 g (20 mmol) of potassium salt of 4,6-diamino-2-mercapto-5-(2-methoxybenzyl)pyrimidine added 2.76 g (20 mmol) of potassium carbonate and 0.33 g (2 mmole) of potassium iodide in 100 ml of methanol, 5.0 g (20 mmol) 1-(3-chloropropyl)-4-methylpiperazine dihydrochloride and the reaction mixture to Patt for 20 hours. The mixture is cooled to room temperature, the inorganic salts filtered off, the filtrate is evaporated under reduced pressure, the resulting oil is crystallized from water, crystalline substance is filtered and dried. The resulting base is subjected to the reaction in ethanol with 3 equivalents of hydrogen chloride, using isopropanol containing hydrogen chloride.

Thus obtained 5.5 g (53,7%) of the named product.

TPL: above 280°C.

Analysis: With20H33CL3N6OS (511,95)

calculated: 46,92%, N 6,50%, N 16,42%, S Of 6.26%, Cl (ionic) 20,78%;

found: 46,31%, N 6,54%, N 16.14%, S Of 6.26%, Cl (ionic) 20,44%.

Example 4.

4,6-Diamino-2-[2-(4-methyl-1-piperazinil)propylthio]-5-(2-methoxybenzyl)-pyrimidine trihydrochloride hydrate.

To a suspension of 6.0 g (20 mmol) of potassium salt of 4,6-diamino-2-mercapto-5-(2-methoxybenzyl)pyrimidine add 5,52 g (40 mmol) of potassium carbonate and 0.66 g (4 mmole) of potassium iodide in 50 ml of dimethylformamide, 4.71 g (20 mmol) 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride, and the reaction mixture was shaken at 80°C for 10 hours. After cooling the mixture is poured into 100 ml of water, the precipitated crystals filtered and dried. The resulting material purified by chromatography through a column Packed with Kieselgel 60 using a mixture of methanol and dichloromethane in the ratio of 1:8. The net basis is subjected to the reaction of the alcohol with 3 equivalents of hydrogen chloride, using isopropanol, which contains hydrogen chloride. So get at 6.84 g (65,9%) of the named product.

TPL: 241 to 243°C.

Analysis: C19H33Cl3N6O2S (515,94)

calculated: 44,23%, N 6,45%, N 16,29%, S 6,21%, Cl (ionic) 20,61%;

found: 44,32%, N 6,35%, N 16,37%, S 6,22%, Cl (ionic) 20,92%.

Example 5.

4,6-Diamino-2-[2-(4-isopropyl-1-piperazinil)ethylthio]-5-(2-methoxybenzyl)-pyrimidine trihydrochloride hydrate.

A mixture of 6.0 g (20 mmol) of potassium salt of 4,6-diamino-2-mercapto-5-(2-methoxybenzyl)pyrimidine, 5,52 g (40 mmol) of potassium carbonate, 0.66 g (4 mmole) of potassium iodide, 5,27 g (20 mmol) 1-(2-chloroethyl)-4-isopropylpiperazine dihydrochloride, and 150 ml of methyl alcohol is boiled for 20 hours. The reaction mixture is subjected to the procedure described in Example 3, however, the salt is formed from the oil obtained after evaporation.

So get 6,63 g (61,1%) of the named product.

TPL: 253-255°C.

Analysis: C21H37Cl3O2S (543,99)

calculated: 46,37%, N 6,86%, N 15,45%, S Of 5.89%, Cl (ionic) 19,55%;

found: 45,98%, N Is 6.78%, N 15,03%, S 5,76%, Cl (ionic) 19,61%.

Example 6.

4,6-Diamino-2-[2-/4-(2-dimethylaminoethyl)-1-piperazinil/-ethylthio]-5-(2-methoxybenzyl)pyrimidine tetrahydrochloride dehydrate.

A mixture of 1.0 g (3 mmole) of potassium salt of 4,6-diamino-2-mercapto-5-(2-methoxybenzyl)pyrimidine, of 1.65 g (12 mmol) of potassium carbonate, 0.1 g (0.6 mmole) of potassium iodide, 1.1 g (3 m is Olya) 1-(2-chloroethyl)-4-(2-dimethylamino)ethylpiperazine trihydrochloride hydrate and 20 ml of methyl alcohol is subjected to reaction for 12 hours while heating under reflux. The reaction mixture is subjected to the procedure described in Example 4, however, at the stage of purification using column chromatography using a mixture of methanol and dichloromethane in the ratio of 1:1, and the salt formation is carried out using isopropyl alcohol containing 4 equivalents of hydrogen chloride. So get 0,82 g (41,2%) of the named product.

TPL: 254-257°C.

Analysis: With22H43Withl4About3S (627,51)

calculated: 42,11%, N 6,91%, N 15.62 Wide%, S 5,11%, Cl (ionic) 22,60%;

found: 42,75%, N 6,85%, N 15,38%, S 5,26%, Cl (ionic) 22,18%.

Example 7.

4,6-Diamino-2-[3-(4-formyl-1-piperazinil)propylthio]-5-(2-ethoxybenzyl)-pyrimidine.

A mixture of 3.14 g (10 mmol) of potassium salt of 4,5-diamino-2-mercapto-5-(2-ethoxybenzyl)pyrimidine, 2.76 g (20 mmol) of potassium carbonate, 0.33 g (2 mmole) of potassium iodide, and 1.9 g (10 mmol) of 1-formyl-4-(3-chloropropyl)piperazine and 30 ml of dimethylformamide is stirred at 80°C for 9 hours. Inorganic compounds are removed by filtration, the filtrate is evaporated and the product purified by chromatography through a column Packed with Kieselgel 60 using a mixture of dichloromethane and methanol in the ratio of 8:1. Thus receive 1.83 g (42.5 per cent) of these compounds.

TPL: 154-156°C.

Analysis: C21H30N6O2S (430,58)

calculated: 58,58%, N 7,02%, N 19,52%, S 7,45%;

found: 58,10%, N 6,99%, N 19,39%, S 7,33%.

Example 8.

A mixture of 2.6 g (8.6 mmol) of potassium salt of 4,6-diamino-2-mercapto-5-(2-methoxybenzyl)-pyrimidine, 2,4 g (17 mmol) of potassium carbonate, 0.15 g (0.9 mmole) of potassium iodide, and 2.26 g (8.6 mmol) of 1-methyl-4-(4-chlorobutyl)piperazine dihydrochloride and 40 ml of dimethylformamide is subjected to reaction at 140°C for 20 hours as described in Example 7. The reaction mixture is subjected to procedures as in Example 7, then the base is dissolved in ethanol and subjected to reaction with isopropyl alcohol, which contains 3 equivalents of hydrogen chloride.

Thus obtain 1.85 g (39.5 per cent) of these compounds.

Tel: 202°C.

Analysis: C21H37Cl3N6O2S (543,99)

calculated: 46,37%, N 6,86%, N 15,45%, S Of 5.89%, Cl (ionic) 19,55%;

found: 46,82%. N 6,82%, N 15,38%, S 5.74 per cent, Cl (ionic) 19,35%;

Example 9.

4,6-Diamino-2-[3-(4-formyl-1-piperazinil)propylthio]-5-(2-methoxybenzyl)-pyrimidine.

A mixture of 3.94 g (13 mmol) of potassium salt of 4,6-diamino-2-mercapto-5-(2-methoxybenzyl)pyrimidine, 1.8 g (13 mmol) of potassium carbonate and 0.22 g (1.3 mmole) of potassium iodide, 2.5 g (13 mmol) of 1-formyl-4-(3-chloropropyl)piperazine and 50 ml of dimethylformamide is subjected to a reaction for 7 hours as described in Example 7. The product obtained after the stage of evaporation, is subjected to crystallization using 150 ml of ice water, the crystals are filtered and dried.

Thus obtained 4.8 g (88.6 per cent) named connection is of high value.

TPL: 174-176°C.

Analysis: C20H28N6O2S (416,55)

calculated: 57,67%, N Is 6.78%, N 20,18%, S of 7.70%;

found: 57,23%, N For 6.81%, N fall of 19.88%, S of 7.64%.

Example 10.

4,6-Diamino-2-[3-(1-piperazinil)propylthio]-5-(2-methoxybenzyl)pyrimidine trihydrochloride.

Method (a)

To a suspension of 2.3 g (5.5 mmol) of 4,6-diamino-2-[3-(4-formyl-1-piperazinil)propylthio]-5-(2-methoxybenzyl)pyrimidine in 20 ml of ethyl alcohol add isopropanol containing 4 equivalents of hydrogen chloride, and the reaction mixture is boiled for 2.5 hours. After cooling, the solid is filtered and washed with diisopropyl ether.

So get 1,89 g (66.6%) with these compounds.

TPL: 198°C.

Analysis: C19H31Cl3N6OS (497,92)

calculated: 45,83%. N 6,28%, N 16.88 In%, S 6,44%, Cl (ionic) 21,36%;

found: 45,41%, H 6.34%, N 16,38%, S 6,33%, Cl (ionic) 21,69%.

Method b)

A mixture of 3.0 g (10 mmol) of potassium salt of 4,6-diamino-2-mercapto-5-(2-methoxybenzyl)pyrimidine, 2.76 g (20 mmol) of potassium carbonate, 0.33 g (2 mmole) of potassium iodide, a 2.36 g (10 mmol) of 1-(3-chloropropyl)piperazine dihydrochloride and 30 ml of dimethylformamide is subjected to reaction for 5 hours as described in Example 7. The product obtained after the stage of evaporation, is subjected to crystallization from 120 ml of ice water and the crude product is purified by passing through a column containing Kieselgel 60. The eluate contains a mixture of dichloromethane and m is delovogo alcohol in the ratio 8:2. A purified base is dissolved in ethanol and subjected to reaction with isopropanol containing 3 equivalents of hydrogen chloride, to obtain trihydrochloride.

Thus obtained 2.1 g (42.2 per cent) of these compounds.

TPL: 197-198°C.

Analysis: C19H31Cl3N6OS (497,92)

calculated: 45,83%, N 6,28%, N 16.88 In%, S 6,44%, Cl (ionic) 21,36%;

found: 45,38%, N 6,30%, N 16,43%, S 6,32%, Cl (ionic) 21,30%.

Example 11.

4,6-Diamino-2-[2-(1-piperazinil)ethylthio]-5-(2-butoxyphenyl)pyrimidine trihydrochloride hydrate.

0.25 g (11 mmol) of metallic sodium are dissolved in 50 ml of ethanol, and then a solution of 3.6 g (10 mmol) of 4,6-diamino-2-[2-(1-piperazinil)ethylthio]-5-(2-hydroxybenzyl)pyrimidine add 50 ml of ethanol. The reaction mixture is stirred for 20 minutes, then added dropwise to 1.37 g (10 mmol) of n-butylbromide and the solution stirred at the boiling temperature for 12 hours. The mixture is cooled, filtered inorganic salts, the filtrate is evaporated and the crude product purified by column chromatography, passing through a column Packed with Kieselgel 60 using a mixture of dichloromethane and methanol in the ratio 8:2. A purified base is dissolved in ethanol and subjected to reaction with isopropanol containing 3 equivalents of hydrogen chloride, to obtain trihydrogen is Yes.

So get of 2.54 g (45.2 percent) of these compounds.

TPL: 180°C.

Analysis: With21H39CLCN6About3S (562,01)

calculated: 44,88%, N 6,99%, N 14,95%, S 5,71%, Cl (ionic) 18,92%;

found: From 45,00%, H 7.04 per cent, N 14,81%, S Of 5.82%, Cl (ionic) 18,76%.

Example 12.

4,6-Diamino-2-[3-(4-acetyl-1-piperazinil)propylthio]-5-(2-methoxybenzyl)-pyrimidine.

A mixture of 2.05 g (10 mmol) 1-acetyl-4-(3-chloropropyl)piperazine, 2.85 g (9.5 mmol) of potassium salt of 4,6-diamino-2-mercapto-5-(2-methoxybenzyl)pyrimidine and 10 ml of ethanol is boiled for 2 hours. After cooling the mixture is poured into 40 ml of water, the precipitated product is filtered, washed with water, dried and purified by column chromatography, passing through a column Packed with Kieselgel 60. using a mixture of methanol and toluene in a ratio of 1:9. The resulting crude product is recrystallized from methyl alcohol. So get of 1.34 g (33,0%) of these connections.

TPL: 208-209°C.

Analysis: C21H30N6O2S (430,58)

calculated: 58,58%, N 7,02%, N 19,52%, S 7,45%;

found: 58,95%, N 6,88%, N 19,42%, S 7,51%.

Example 13.

4,6-Diamino-2-[4-(4-methyl-1-piperazinil)ethylthio]-5-(2-ethoxybenzyl)pyrimidine trihydrochloride hydrate.

3,14 g (10 mmol) of potassium salt of 4,6-diamino-2-mercapto-5-(2-ethoxybenzyl)pyrimidine, 2.76 g (20 mmol) of potassium carbonate, 0.33 g (2 mmole) of potassium iodide and of 2.36 g (10 mmol) of 1-methyl-4-(2-chloroethyl)Pipera the ina dihydrochloride subjected to reaction in 25 ml of methyl alcohol, as described in Example 3 for 28 hours. After evaporation the resulting product is subjected to crystallization with the use of ice water, and then the crude product is subjected to chromatography by passing through a column Packed with Kieselgel 60 using a mixture of dichloromethane and methanol in the ratio 8:2. The net basis is subjected to reaction with isopropanol containing 3 equivalents of hydrogen chloride, to obtain the salt. So get of 1.93 g (36.4 per cent) of these compounds.

TPL: 121°C.

Analysis: With20H35With3N6About2S (529,964)

calculated: 45,33%, N 6,66%, N 15,86%, S 6,05%, Cl (ionic) 20,07%;

found: 44,99%, N 6,75%, N 15,78%, S 5,96%, Cl (ionic) of 19.57%.

Example 14.

4,6-Diamino-2-[3-(1-piperazinil)ethylthio]-5-(2-ethoxybenzyl)pyrimidine trihydrochloride trihydrate.

to 4.73 g (15 mmol) of potassium salt of 4,6-diamino-2-mercapto-5-(2-ethoxybenzyl)pyrimidine, 2,08 g (15 mmol) of potassium carbonate, 0.25 g (1.5 mmole) of potassium iodide and 3.57 g (15 mmol) of 1-(3-chloropropyl)piperazine dihydrochloride is stirred in 50 ml of dimethylformamide at 120-125°C for 20 hours. The reaction mixture is subjected to the procedure described in Example 7. The resulting oil is purified using chromatography, passing through a column Packed with Kieselgel 60 using a mixture of dichloromethane and methanol in the ratio 8:2. The net basis is subjected to reaction Waterbom alcohol with isopropanol, containing 3 equivalents of hydrogen chloride, to obtain the salt.

So get to 3.92 g (46,17%) of these connections.

TPL: 116°C.

Analysis: With20H39Cl3N6O4S (565,995)

calculated: 42,44%, N 6,95%, N 14,85%, S 5,67%, Cl (ionic) 18,79%;

found: Of 42.46%, H 7.04 per cent, N 14,74%, S 5,77%, Cl (ionic) 19,60%.

Example 15.

4,6-Diamino-2-[3-(1-piperazinil)propylthio]-5-(3,4,5-trimethoxybenzyl)-pyrimidine trihydrochloride trihydrate.

3.6 g (10 mmol) of potassium salt of 4,6-diamino-2-mercapto-5-(3,4,5-trimethoxybenzyl)pyrimidine, 2.76 g (20 mmol) of potassium carbonate, 0.33 g (2 mmole) of potassium iodide and of 2.36 g (10 mmol) of 1-(3-chloropropyl)piperazine dihydrochloride is stirred in 30 ml of dimethylformamide at 60-80°C for 5 hours. The reaction mixture is subjected to the procedure described in Example 7. The resulting oil is purified using chromatography, passing through a column Packed with Kieselgel 60 using a mixture of dichloromethane and methanol in the ratio 8:2. The net basis is subjected to the reaction in ethyl alcohol and isopropanol containing 3 equivalents of hydrogen chloride, to obtain the salt.

Thus obtained 2.2 g (35,95%) of these connections.

TPL: 175°C.

Analysis: C21H41Cl3N6O6S (612,021)

calculated: 41,21%, N 6,75%, N 13,73%, S Of 5.24%, Cl (ionic) 17,38%;

found: 41,99%, N 6,72%, N 13,78%, S 5,44%, Cl (ionic) 17.32 percent.

Prima is 16.

4,6-Diamino-2-[2-(4-acetyl-1-piperazinil)ethylthio]-5-(2-methoxybenzyl)-pyrimidine.

2,22 g (10 mmol) 2-chloroethylamine dihydrochloride dissolved in 10 ml of water, the resulting solution was cooled to 0°C, add an aqueous solution of 1.60 g (40 mmol) cooled to -5°C. sodium hydroxide, then dropwise add quickly to 1.4 ml of 1.57 g, 20 mmol) acetyl chloride while maintaining the temperature below 5°C. the Reaction mixture is stirred for 5 minutes at this temperature, then extracted with ethyl acetate and the organic phase is evaporated. Thus obtained 1.64 g (86%, 8.6 mmol) of 4-acetyl-1-(2-chloroethyl)piperazine are dissolved in 15 ml of ethanol. The resulting solution is boiled with 2,46 g (8.2 mmol) of 4,6-diamino-5-(2-methoxybenzyl)-2-mercaptopyrimidine potassium salt and 0.57 g (4.1 mmole) of potassium carbonate for 2 hours, then poured into 60 ml of water, filtered and washed with water. The resulting crude product is recrystallized from methanol.

Thus obtain 1.70 g (50%) of the named compound.

TPL: 198,5-199,5°C.

Analysis: C20H28N6O2S (416,55)

calculated: 57,67%, N Is 6.78%, N 20,18%, S of 7.70%;

found: 57,57%, N 6,79%. N 20,15%, S OF 7.64%.

Example 17.

4,6-Diamino-2-[3-(1-piperazinil)propylthio]-5-(4-Chlorobenzyl)pyrimidine trihydrochloride trihydrate.

3,05 g (10 mmol) of potassium salt of 4,6-diamino-2-mercapto-5-(4-Chlorobenzyl)pyrimidine, 2.76 g (20 mmol) is of carbonate potassium, 0.33 g (2 mmole) of potassium iodide and of 2.36 g (10 mmol) of 1-(3-chloropropyl)piperazine dihydrochloride is stirred in 30 ml of dimethylformamide at 60-80°C for 7 hours. Inorganic compounds are removed by filtration, the mother liquor is evaporated and the VAT residue is treated with water. The resulting crystalline product is subjected to chromatography by passing through a column Packed with Kieselgel 60 using a mixture of dichloromethane and methanol in the ratio 8:2. The net basis is subjected to the reaction in ethyl alcohol and isopropanol containing 3 equivalents of hydrogen chloride, to obtain the salt.

Thus obtain 2.76 g (49.7 per cent) of these compounds.

TPL: 187°C.

Analysis: With18H34CL4N6About3S (556,39)

calculated: 38,86%, N 6,16%, N 15,10%, S 5,76%, Cl (total) 25,49%, Cl (ionic) 19,12%;

found: 39,20%, N 6,24%, N 15,22%, S 5,95%, Cl (total) 25,77%, Cl (ionic) 19,05%.

Example 18.

4,6-Diamino-2-[4-(1-piperazinil)butylthio]-5-(2-methoxybenzyl)pyrimidine trihydrochloride.

3.0 g (10 mmol) of potassium salt of 4,6-diamino-2-mercapto-5-(2-methoxybenzyl)pyrimidine, to 4.14 g (30 mmol) of potassium carbonate, 0.33 g (2 mmole) of potassium iodide and 2.5 g (10 mmol) of 1-(4-chlorobutyl)piperazine dihydrochloride is stirred in 50 ml of dimethylformamide at 120-130°C for 22 hours. Inorganic compounds are removed by filtration, and the crude product purified, campisano in Example 17. Pure product is subjected to reaction with isopropanol containing 3 equivalents of hydrogen chloride, to obtain the salt.

So get of 2.38 g (46.6%) of the named compound.

TPL: 255°C.

Analysis: With20H33CL3N6OS (511,949)

calculated: 46,92%, N 6,50%, N 16,42%, S Of 6.26%, Cl (ionic) 20,78%;

found: 46,38%, H 6.58 Percent, N 16,08%, S 6.08%in General, Cl (ionic) 20,31%.

Example 19.

4,6-Diamino-2-[2-(1-piperazinil)ethylthio]-5-(4-terbisil)pyrimidine trihydrochloride hydrate.

is 2.88 g (10 mmol) of potassium salt of 4,6-diamino-2-mercapto-5-(4-terbisil)pyrimidine, 2.76 g (20 mmol) of potassium carbonate, 0.33 g (2 mmole) of potassium iodide and 2,22 g (10 mmol) 1-(2-chloroethyl)piperazine dihydrochloride is stirred in 30 ml of dimethylformamide at 60-80°C for 6.5 hours. Inorganic compounds are removed by filtration, the mother liquor is evaporated and the residue is subjected to chromatography by passing through a column Packed with Kieselgel 60 using a mixture of dichloromethane and methanol in the ratio 8:2. The net product is subjected to reaction in ethyl alcohol and isopropanol containing 3 equivalents of hydrogen chloride, to obtain the salt.

So get of 1.81 g (36,94%) of these connections.

TPL: 168-170°C.

Analysis: C17H28Cl3FN6OS (489,874)

calculated: 41,68%, N 5,76%. N 17,16%, S 6,55%, Cl (ionic) 21,71%;

found: 41,72%, N 5,79%, N 17,26%, S Of 6.49%, Cl (and the config) 21,54%.

Example 20.

4,6-Diamino-2-[3-(1-piperazinil)propylthio]-5-(4-terbisil)pyrimidine trihydrochloride hydrate.

To a solution of 5.6 g (100 mmol) of potassium hydroxide in 140 ml of water add 5,76 g (20 mmol) of potassium salt of 4,6-diamino-2-mercapto-5-(4-terbisil)-pyrimidine and the stirred mixture is added dropwise a solution of 4.71 g (20 mmol) 1-(3-chloropropyl)piperazine dihydrochloride in 20 ml of water. The reaction mixture was stirred at room temperature for 20 hours. The precipitated crystals filtered, washed with water and dried. The resulting product is subjected to chromatography by passing through a column Packed with Kieselgel 60 using a mixture of dichloromethane and methanol in the ratio 8:2. Then the base is subjected to the reaction in ethyl alcohol and isopropanol containing 3 equivalents of hydrogen chloride, to obtain the salt. Thus obtain 6.6 g (65.5 per cent) of these compounds.

TPL: 269-271°C.

Analysis: With18H30CL3FN6OS (503,901)

calculated: 42,91%, N 6,0%, N 16,68%, S 6,36%, Cl (ionic) 21,11%;

found: 42,74%, N 6,07%, N 16,36%, S 6,28%, Cl (ionic) 20,68%.

Example 21.

4,6-Diamino-2-{2-[4-(2-dimethylaminoethyl)-1-piperazinil]ethylthio}-5-(4-terbisil)pyrimidine tetrahydrochloride trihydrate.

To a solution of 2.6 g (48 mmol) of potassium hydroxide in 50 ml water is added 2,31 g (8 mmol) of potassium salt of 4,6-diamino-2-mercapto-5-(4-terbisil)pyrimidine and p is obtained mixture is added dropwise a solution 2,78 g (8 mmol) of 1-(2-chloroethyl)-4-(2-dimethylamino)piperazine trihydrochloride hydrate in 30 ml of water. The reaction mixture was stirred at room temperature for 8 hours, the resulting crystals are filtered and washed with water. The resulting base is subjected to the reaction in ethyl alcohol and isopropanol containing 3 equivalents of hydrogen chloride, to obtain the salt. So get 2,96 g (58,41%) of these connections.

TPL: 218-220°C.

Analysis: With21H42CL4FN7About3S (633,488)

calculated: 39,82%, N 6.68 Percent, N 15,48%, S Of 5.06%, Cl (ionic) 23,39%;

found: 39,84%, N 6,50%, N 15,59%, S 5,19%, Cl (ionic) 22,69%.

Example 22.

4,6-diamino-2-[3-(1-piperazinil)propylthio]-5-(4-methoxybenzyl)pyrimidine trihydrochloride dehydrate.

3.0 g (10 mmol) of potassium salt of 4,6-diamino-2-mercapto-5-(4-methoxybenzyl)pyrimidine, 2.76 g (20 mmol) of potassium carbonate, 0.33 g (2 mmole) of potassium iodide and of 2.36 g (10 mmol) of 1-(3-chloropropyl)piperazine dihydrochloride is subjected to reaction in 30 ml of dimethylformamide at 60-80°C for 8 hours. Then follow the procedure described in Example 17. Thereby obtaining 2.6 g (48.7 percent) of these compounds.

TPL:110-113°C.

Analysis: C19H35Cl3N6O3S (533,95)

calculated: 42,74%, N 6.61 Percent, N 15,74%, S 6,01%, Cl (ionic) 19,92%;

found: 42,25%, N 6,72%, N 15,38%, S 5,95%, Cl (ionic) 19,27%.

Example 23.

4,6-Diamino-2-[2-(1-piperazinil)ethylthio]-5-(4-methoxybenzyl)pyrimidine hydrate.

3.0 g (10 mmol) of potassium salt of 4,6-diamino-3-mercapto-5-(-methoxybenzyl)pyrimidine, 2.76 g (20 mmol) of potassium carbonate, 0.33 g (2 mmole) of potassium iodide and 2,22 g (10 mmol) 1-(2-chloroethyl)piperazine dihydrochloride is subjected to reaction in 30 ml of dimethylformamide at 80°C for 14 hours. Organic compounds are removed by filtration, the mother liquor is evaporated and the residue is subjected to chromatography by passing through a column Packed with Kieselgel 60 using a mixture of dichloromethane and methanol in the ratio 8:2.

So get 2,03 g (51,72%) of these connections.

TPL: 135-136°C.

Analysis:C18H28N6O2S (392,527)

calculated: 55,08%, N 7,19%, N 21,41%, S 8,17%;

found: 54,86%, N 7,17%, N 21,11%, S 8,11%.

Example 24.

4,6-Diamino-2-[3-(1-piperazinil)propylthio]-5-(4-dimethylaminobenzoyl)-pyrimidine tetrahydrochloride trihydrate.

3.13 g (10 mmol) of potassium salt of 4,6-diamino-2-mercapto-5-(4-dimethylaminobenzoyl)pyrimidine, 2.76 g (20 mmol) of potassium carbonate, 0.33 g (2 mmole) of potassium iodide and of 2.36 g (10 mmol) 1-(2-chloropropyl)piperazine dihydrochloride is boiled in 50 ml of methanol for 5 hours. Inorganic compounds are removed by filtration, the mother liquor is evaporated and the residue is subjected to chromatography by passing through a column Packed with Kieselgel 60 using a mixture of dichloromethane and methanol in the ratio 8:2. The resulting base is subjected to the reaction in ethyl alcohol and isopropanol containing 3 equivalent x is aristovo hydrogen, to obtain salt.

Thus obtain 2.65 g (44,06%) of these connections.

TPL: 120-124°C.

Analysis: C20H41Cl4N7O3S (601,47)

calculated: 39,94%, N 6,87%, N 16,30%, S 5,33%, Cl (ionic) 23,58%;

found: 40,32%, N 6,82%, N 15,85%, S Of 5.45%, Cl (ionic) 23,16%.

Example 25.

4,6-Diamino-2-[2-(1-piperazinil)ethylthio]-5-(4-isopropylbenzyl)pyrimidine.

2.0 g (7 mmol) of 4,6-diamino-2-mercapto-5-(4-isopropylbenzyl)pyrimidine, 2.9 g (28 mmol) of potassium carbonate, 0.33 g (2 mmole) of potassium iodide and 1.7 g (7 mmol) of 1-(2-chloroethyl)piperazine dihydrochloride is subjected to reaction in 30 ml of dimethylformamide at 60-80°C for 5 hours. Inorganic compounds are removed by filtration, the mother liquor is evaporated and the residue is subjected to chromatography by passing through a column Packed with Kieselgel 60 using a mixture of dichloromethane and methanol in the ratio 8:2. Thus obtain 1.56 g (57,65%) of these connections.

TPL: 63-64°C.

Analysis: C20H30N6S (386,655)

calculated: 62,14%, N Of 7.82%, N 21,74%, S 8,29%;

found: 61,94%, N Of 7.75%, N 21,38%, S of 8.15%.

Example 26.

4,6-Diamino-2-{2-[4-(3-dimethylaminopropyl)-1-piperazinil]ethylthio}-5-(2-methoxybenzyl)pyrimidine tetrahydrochloride hydrate.

To a solution 3,37 g (60 mmol) of potassium hydroxide in 60 ml of water is added 3.0 g (10 mmol) of potassium salt of 4,6-diamino-2-mercapto-5-(2-methoxybenzyl)-pyrimidine and mixed in Crespo drops add a solution 3,61 g (10 mmol) 1-(2-chloroethyl)-4-(3-dimethylaminopropyl)piperazine of trihydrochloride hydrate in 30 ml of water. The reaction mixture was stirred at room temperature for 30 hours, the resulting crystals filtered and washed with water. The base is subjected to the reaction in ethyl alcohol and isopropanol containing 4 equivalents of hydrogen chloride, to obtain the salt.

So get of 3.31 g of the named compound.

TPL: 262 to 264°C.

Analysis: C23H43Cl4N7O2S (623,521)

calculated: 44,31%, N 6,95%, N 15,72%, S 5,14%, Cl (ionic) 22,74%;

found: 44,21%, N 6,90%, N 15,19%, S Of 5.05%, Cl (ionic) 22,17%.

1. Derived piperazinecarboxamide formula

where

R1represents a hydrogen atom, a C1-4alkyl, C1-4alkanoyl or di(C1-4alkyl)-amino(C1-4alkyl),

R2means a hydrogen atom or a benzyl, substituted by 1-3 substituents selected from the group consisting of C1-4of alkyl, C1-4alkoxygroup, di(C1-4alkyl)-amino group, hydroxyl group and halogen atom,

n has the value 2, 3 or 4,

and its pharmaceutically acceptable salt accession acid.

2. Derived piperazinecarboxamide according to claim 1, where

R1represents a hydrogen atom, a C1-4alkyl, C1-4alkanoyl or di(C1-4alkyl)-amino-ethyl,

R2means a hydrogen atom is whether benzyl, substituted by 1-3 substituents selected from the group consisting of C1-4of alkyl, C1-4alkoxygroup, di(C1-4alkyl)-amino group and halogen atom,

n has the value 2, 3 or 4,

and its pharmaceutically acceptable salt accession acid.

3. Derived piperazinecarboxamide according to claim 2, where

R1represents a hydrogen atom or dimethylaminoethyl,

R2means a hydrogen atom or a benzyl, substituted by 1-3 substituents selected from the group consisting of C1-4of alkyl, C1-4alkoxygroup, di(C1-4alkyl)-amino group and halogen atom,

n has a value of 2 or 3,

and its pharmaceutically acceptable salt accession acid.

4. Derived piperazinecarboxamide according to claim 3, where

R1represents a hydrogen atom or dimethylaminoethyl,

R2means benzyl, substituted C1-4alkoxygroup,

n has the value 2,

and its pharmaceutically acceptable salt accession acid.

5. Derived piperazinecarboxamide according to claim 1, where

R1represents a hydrogen atom, a dimethylamino(C1-4alkyl or C1-4alkanoyl,

R2means a hydrogen atom or a benzyl, substituted by 1-3 substituents selected from the group consisting of C1-4 of alkyl, C1-4alkoxygroup, di(C1-4alkyl)-amino group, hydroxyl group and halogen atom,

n has a value of 2 or 3,

and its pharmaceutically acceptable salt accession acid.

6. Derived piperazinecarboxamide according to claim 5, where

R1represents a hydrogen atom or a dimethylamino(C1-4alkyl),

R2means benzyl, substituted C1-4alkoxygroup or fluorine atom,

n has the value 2,

and its pharmaceutically acceptable salt accession acid.

7. The method of obtaining the derived piperazinecarboxamide formula I, where R1, R2and n are such as defined in claim 1, or its pharmaceutically acceptable salt accession acid, characterized in that conduct the reaction of 2-mercaptopyrimidine formula

where R2listed above, or its salt of alkaline metal

with halogensilberemulsionen formula

where R1and n described above, Hlg represents a halogen atom, preferably chlorine atom or bromine, or its salt accession acid, and, optionally, the compound of formula I is transformed into its pharmaceutically acceptable salt accession acid or free of its salt accession acid.

8. The method according to claim 7 obtain the derived piperazinecarboxamide formula I, where R1, R2and n are such as defined in claim 2, or pharmaceutically acceptable salt accession acid, characterized in that conduct the reaction of 2-mercaptopyrimidine formula (II), where R2as mentioned above, or its salt of the alkali metal with halogensilberemulsionen formula (III), where R1and n are such as defined above, Hlg represents a halogen atom, preferably chlorine atom or bromine, or its salt accession acid, and, optionally, the compound of formula I is transformed into its pharmaceutically acceptable salt accession acid or free of its salt accession acid.

9. The pharmaceutical composition exhibiting anxiolytic effects, and comprising as an active ingredient derived piperazinecarboxamide formula I, where R1, R2and n are such as defined in claim 1, or its pharmaceutically acceptable salt accession acid and one or more standard media.

10. The pharmaceutical composition according to claim 9, comprising as an active ingredient derived piperazinecarboxamide formula I, where R1, R2and n are such as defined in claim 2, or pharmaceutically acceptable salt accession acid and one or more standard media.

11. The pharmaceutical composition of claim 10, comprising as an active ingredient derived piperazinecarboxamide formula I, where R1, R2and n are such as defined in claim 3, or its pharmaceutically acceptable salt accession acid and one or more standard media.

12. The pharmaceutical composition according to claim 11, comprising as an active ingredient derived piperazinecarboxamide formula I, where R1, R2and n are such as defined in claim 4, or pharmaceutically acceptable salt accession acid and one or more standard media.

13. The pharmaceutical composition according to claim 9, comprising as an active ingredient derived piperazinecarboxamide formula I, where R1, R2and n are such as defined in claim 5, or its pharmaceutically acceptable salt accession acid.

14. The pharmaceutical composition according to item 13, comprising as an active ingredient derived piperazinecarboxamide formula I, where R1, R2and n are such as defined in claim 6, or its pharmaceutically acceptable salt accession acid.



 

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Thrombin inhibitors // 2221808
The invention relates to compounds of formula I, the values of the radicals defined in the claims and their pharmaceutically acceptable salts

The invention relates to substituted cyclic aminoven compounds of formula (I)

< / BR>
where Ar represents thienyl, substituted pyridine, phenyl unsubstituted or substituted with halogen, hydroxy, alkoxy, C1-C4the alkyl, phenyloxy, NO2or phenyl; R1is NHOR2where R2is hydrogen; W is one or more hydrogen atoms; Y is independently one or more members of the group consisting of hydroxy, SR3, alkoxy, NR6R7where R6and R7independently selected from hydrogen, alkyl, pyridylethyl, SO2R8, COR9or R6and R7can be combined with the formation of the ring containing the nitrogen to which they relate, formulas

< / BR>
where Y' is CH2OH , SO2; R3represents hydrogen, alkyl, aryl, benzothiazolyl, pyrazinyl, N-methylimidazole; R8represents C1-C4alkyl, phenyl; R9represents hydrogen, alkyl, phenyl; Z is hydrogen; n = 1, and its optical isomer, diastereoisomer, or enantiomer, or its pharmaceutically acceptable salt

The invention relates to compounds of formula (I)

< / BR>
in which Ar1denotes a heterocyclic group, which represents a pyrazole which may be substituted by one or more radicals R1, R2or R3; Ar2denotes phenyl, naphthyl or tetrahydronaphthyl, each of which optionally is substituted by one to three groups R2; L denotes a saturated or unsaturated, branched or unbranched carbon C1-C10chain; in which one or more methylene groups are optionally independently replaced by O, NH or S, and in which the linking group is optionally substituted by 0-2 of doxography; Q has a value selected from a range of: a) phenyl, naphthyl, pyridine, imidazole, Piran, etc. b) tetrahydropyran, morpholine, thiomorpholine, thiomorpholine and t

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< / BR>
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< / BR>
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< / BR>
or

< / BR>
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FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a new method for preparing 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrol-3-carboxylic acid phenylamide that involves conversion of methylcyano acetate to the end compound for 8 or less stages. Also, invention relates to value intermediate compounds that are synthesized as result of realization of above indicated stages of the claimed method. 5-(4-Fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrol-3-carboxylic acid phenylamide is a value intermediate compound used in synthesis of the drug atorvastatin calcium that is used as hypolipidemic and/or hypocholesterolemic agent. Proposed method allows avoiding usage of expensive chiral parent substances and to reduce the synthesis process time.

EFFECT: improved preparing method.

12 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

The invention relates to new derivatives of 4-phenylpyrimidine and their pharmaceutically acceptable acid additive salts, which possess the properties of receptor antagonists neirokinina(NK-1), and can be used to treat diseases, oposredstvovanii NK-1 receptor, for example, headache, Alzheimer's disease, multiple sclerosis, cardiovascular changes, oedema, chronic inflammatory diseases and so on

The invention relates to the use of compounds of formula I to obtain medical drug suitable for the treatment of asthma, seasonal or chronic allergic rhinitis, sinusitis, conjunctivitis, food Allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombosis and otitis and preferably asthma, seasonal and chronic allergic rhinitis

The invention relates to new derivatives of benzene or pyridine of the formula (I)

where R denotes H, C1-C7alkyl and halogen; R1denotes H or halogen, provided that in the 4th position R1not denotes bromine or iodine; R2denotes H or CF3; R3denotes N or C1-C7alkyl; R4denotes H, halogen, C1-C7alkyl and others; R5denotes N or C1-C7alkyl; X represents-C(O)N(R5)-, -N(R5)-C(O)- or-C(O)O-; Y represents -(CH2)n-, -O-, -S-, -SO2-, -C(O)- or N(R5’)-; R5’means (ness.)alkyl; Z represents =N-, -CH= or-C(C1)=; n denotes a number from 0 to 4; and their pharmaceutically acceptable salts

The invention relates to pharmaceutically acceptable salts of the compounds of formula (I) or solvate specified salts in which the compound of formula (I) is in the form of (R)-enantiomer, (S)-enantiomer or the racemate

The invention relates to pharmaceutically acceptable salts of the compounds of formula (I) or solvate specified salts in which the compound of formula (I) is in the form of (R)-enantiomer, (S)-enantiomer or the racemate

The invention relates to the field of synthesis of medicinal substances, specifically, to obtain the dihydrochloride of 1-(2,3,4-trimethoxybenzyl)piperazine (I), which is the substance of a drug Trimetazidine

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

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