The method of obtaining 3-(1-diazolidinylurea-4-piperazinil)-1h - indazols

 

(57) Abstract:

Usage: in medicine as an antipsychotic agent. The inventive product 3-(1-diazolidinylurea-4-piperazinil) 1 N-indazols total f-ly 1, specified in the description, where R1and R2independently from each other hydrogen, lower alkyl, or R1and R2together with the carbon to which they are attached, form a cyclopentane or cyclohexane ring, R3and R4independently from each other hydrogen or lower alkyl, R5hydrogen or lower alkyl, X is hydrogen or halogen, or their pharmaceutically acceptable acid salt additive. Reagent 1: derived 4-thiazolidinone f-crystals 2, where R1, R2, R3and R4above. Reagent 2: 3-(1-piperazinil)-1H-indazol f-crystals 3, where X is specified above. Reaction conditions: in a medium of an organic solvent, is heated in an atmosphere of inert gas. In the case of obtaining compounds, R5- lower alkyl, connection f-ly 1, where R3- hydrogen alkylate. table 1.

This invention relates to the production of compounds of the formula I

where R1and R2each independently represents hydrogen or lower alkyl, or R1and R2taken together with atomo each independently represents hydrogen or lower alkyl; R5represents hydrogen or lower alkyl, X represents hydrogen or halogen, or their pharmaceutically acceptable acid additive salts and, where applicable, to their optical, geometric and stereoisomers and racemic mixtures. These compounds are useful as antipsychotic agents.

Preferred are those compounds 1, in which R1and R2taken together with the carbon atom to which they are attached, form a five - or six-membered cycloalkyl ring, X is fluorine and R5represents hydrogen.

Throughout the description and the attached claims are given the formula or name cover all geometric, optical and stereoisomers of the compounds and racemic mixtures, when there are such isomers and mixtures.

In the above definitions, the term "lower" means that the group, which he characterizes contains from 1 to 6 carbon atoms. The term "alkyl" refers to hydrocarbons with straight or branched chain, containing the desaturation, for example, stands, ethyl, isopropyl, tert-butile, neopentyl, n-hexyl.

The method according to the present invention is as follows.

The compound of formula II

is introduced into the reaction with the compound of the formula III

H-N-yielding compound I of the invention of formula

< / BR>
The above reaction is usually carried out in the presence of a suitable medium such as dimethylformamide or acetonitrile, acid acceptor, such as potassium carbonate or sodium carbonate, and a catalytic amount of iodotope potassium or sodium iodide, at a temperature of about 25-120aboutC.

To obtain compounds I in which R5-NISSEI alkyl, compound I, in which R5represents hydrogen, is subjected to interaction with Pan and methyliodide or other panchadasi alkylating agent in a suitable medium such as dimethylformamide or acetonitrile, at a temperature of 60-85aboutC.

Compound II is usually obtained as follows.

The connection formulas

+Br-subjected to reaction with 1,4-dibromobutane, giving compound II. This reaction is usually conducted in the presence of a suitable medium such as dimethylformamide or tetrahydrofuran, and bases, such as potassium hydroxide, sodium hydroxide or sodium hydride, priyanie of the present invention are potentially useful as antipsychotic agents as defined by the method of climbing mice (MCA).

Analysis climbing mice (climbing in height) is described by the authors P. Protais, etc. Psychpharmacol, 50, I (1976) and B. Costall, Eur. J. Pharmacol. 50, 39 (1978).

Male mice with SK-1 (weighing 23-27 g) placed by the group in standard laboratory conditions. Mice are placed individually in wire cages (size 4" x 4" x 10") and give them 1 hour to adapt and explore new environments. Subcutaneously injected apomorphine dose of 1.5 mg/kg, a dose that causes climbing all subjects within 30 minutes of the Compounds tested for antipsychotic activity, inherits intraperitoneal (I. p.) for 30 min prior to injection of apomorphine when orinigally dose of 10 mg/kg

To evaluate the response of climbing removed 3 readings after 10, 20 and 30 min after the injection of apomorphine according to the following scale: tree-Climbing behavior Assessment mice 4 perebiraniya legs on the bottom (no climbing) 0 2 perebiraniya paws on the wall (occasionally) 1 4 perebiraniya paws on the wall (full lasagna) 2

Mice, bravely climbing before injection of apomorphine, is discarded.

When fully developed reaction climbing animals hanging on the walls of the cells quite motionless for long periods of time. In the CLASS="ptx2">

Assessment of the effect of climbing individually summed (maximum score 6 for one mouse at 3 withdrawals readings) and the total score of the control group (media intraperitonal; apomorphine subcutaneously) is set to 100% Values U50with 95% confidence limits, calculated by linear regression analyses of some of the compounds of this invention are presented in the table.

Antipsychotic effect is achieved when the compounds of this invention are assigned to the subject in need of treatment an effective oral, parenteral or intravenous dose of from 0.01 to 50 mg/kg of body weight per day. Especially preferred effective dose is an amount of about 25 mg/kg of body weight per day. It should be understood, however, that for any particular subject should be administered a specific dosage regimen in accordance with individual needs and professional approach of the person appointing or guideline for the appointment of the above compounds. It should also be understood that the doses presented here are only approximate, and they in no way limit the scope of the invention.

Effective amounts of compounds of the present izobreteniya, parenteral in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. Compounds of the present invention, being effective themselves, may be formulated and administered in the form of pharmaceutically acceptable additive salts in order to achieve stability, convenience or crystallization, increased solubility and similar.

Preferred pharmaceutically acceptable additive salts include salts of inorganic acids such as hydrochloric, Hydrobromic, sulphuric, nitric, phosphoric, Perlina acid; and organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric and oxalic acids.

Active compounds of the present invention may be administered orally, for example, with an inert diluent or with other edible carrier. They can be enclosed in gelatin capsules or pressoffice in tablets. For the purpose of oral therapeutic purposes, the compounds can be administered with excipients and used in the form of tablets, pills or pellets, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. Preparations should contain at measuring conveniently between 4 and about 75% by weight of a particular form of dosage units. The number of compounds present in such compositions is such to get the right dose. Preferred compositions and preparations according to the present invention are prepared so that an oral form of dosage unit contains between 1.0 to 300 mg of active compound.

Tablets, pills, capsules, pellets or similar forms may also contain the following ingredients: a binder such as microcrystalline cellulose, gum tragakant, or gelatin; excipients, such as starch or lactose, disintegrity agent, such as alginic acid, Primogel, corn starch and similar; lubricating agent such as magnesium stearate or Sarotex; sliding agent (or facilitating a smooth passage), such as colloidal dioxide cremene; and a sweetening agent such as sucrose or saccharin or a flavoring or flavoring agent such as peppermint, methyl salicylate, or can be added orange flavoring additive. When the form of the dosage unit is a capsule, it may contain in addition to the substances of the above type, a liquid carrier such as fatty oil. Other forms of dosage units, for example, such as coating. Thus, tablets or pills may be coated with sugar, shellac, or other enterococci covering agents. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives additives, dyes, and coloring and flavoring substances. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the quantities used.

For purposes of parenteral pharmaceutical purposes active compounds of the invention may be introduced into the solution or suspension. These preparations should contain at least 0.1% of the above compounds, but the number can vary between 0.5 and about 30% by weight of the preparation. The number of active compound in such compositions is such that to get the right dose. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.5 and 100 mg of active compound.

The solutions or suspensions may also include the following components: a sterile diluent such as water for in the systematic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents to establish a tone, such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or vessels with multiple doses, made of glass or plastic.

Examples of compounds of this invention include:

3-(4-(1-[6-fluoro-1H-indazol-3-yl] -4-piperazinil)butyl)-2,5,5-trim - Teal-4-thiazolidinone; 3-(4-(1-[6-fluoro-1H-indazol-3-yl]-4-piperazinil)butyl)-of 2.2.5.5 - tetramethyl-4-thiazolidinone;

3-(4-(1-[6-fluoro-1H-indazol-3-yl] -4-PI-pyrazinyl)butyl-2-methyl-1 - thia-3-azaspiro(4.4)nonan-4-one;

3-(4-(1H-indazol-3-yl)-4-piperazinil)butyl)-2-methyl-1-thia-3 - Aza-Spiro[4.5]Decan-4-one;

3-(4-(1-[6-fluoro-1H-indazol-3-yl] -4-PI - pyrazinyl)butyl)-2-methyl - 1-thia-3-azaspiro[4.5]Decan-4-one;

3-(4-(1[6-fluoro-1H-indazol-3-yl] -4-Pipa - retinyl)butyl)-2,2-dimethyl - 1-thia-3-azaspiro[4.5]Decan-4-one;

3-(4-[1-acetyl-1H-indazol-3-yl] -4-Pipa - retinyl)butyl)-5-methyl-4 - thiazolidinone;

3-(4-[1-(1-acetyl-6-fluoro-1H-indazol-3-yl)-4-piperazinil] butyl)-1 - thia-3-azaspiro[4.5]Dail-6-fluoro-1H-indazol-3-yl] -4-piperazinil)butyl)- 5-methyl-4-thiazolidinone;

3-(4-(1-[1-benzoyl-6-fluoro-1H-indazol-3-yl] -4-piperazinil)butyl)- 1-thia-3-azaspiro[4.5]Decan-4-one.

The following examples are given only for illustration purposes and should not be construed as limiting the invention. All temperatures are given in degrees Celsius (aboutC).

P R I m e R 1. A. 3-(4-bromobutyl)-4-thiazolidinone. A mixture of 4-oxothiazolidines (25 g), dimethylformamide (500 ml) and KOH (27,16 g) were mixed in a nitrogen atmosphere at room temperature for 1.5 hours. To the resulting mixture was added 1,4-dibromobutane (101 ml), and stirring was continued at rooms temperature for 44 hours. The reaction mixture was poured into water (1000 ml) and the aqueous mixture was extracted three times with 300 ml portions of ethyl acetate. The combined extracts were washed with water (300 ml) and brine (300 ml), dried over sodium sulfate and concentrated in vacuo to an oil. MPLC aliquots in 44,95 g gave to 7.15 g of oil which upon distillation gave pure liquid temp. the TRC. 134-137aboutWith/0.12 mm RT.article.

Analysis: for C7H12BrNOS: Calculated: C,30 N 5,08 N 5,88%

Found: 35,24% N 5,09% N OF 5.83%

b. 3-(4-bromobutyl)-5-methyl-4-thiazolidinone. TO -74aboutWith the solution of 3-(4-bromobutyl)-4-thiazolidinone (5.20 g) and Tourane (23 ml) followed by immediate addition under the conditions (7,74 g). The resulting solution was mixed for 20 minutes (was cooled using a CO2/isopropanole baths), referred to be heated to -40aboutWith and pagkilala 1 standards. HCl (200 ml). The resulting aqueous mixture was extracted three times with 100 ml portions of 25% benzene/ether. The combined extracts were washed brine (200 ml), dried with sodium sulfate and concentrated in vacuum giving liquid, which was chromatographically on silica gel, elution with 45% ethyl acetate in hexano, giving of 3.84 g of oil. The oil was converted, giving 2,60 g of 3-(4-bromobutyl)-5-methyl-4-thiazolidinone pace.the TRC. 123-125aboutWith 0.20 mm RT. Art.

Analysis: for C8H14BrNOS: calculated: 38,10% N ceiling of 5.60 N 5,55%

found: 38,12% N 5,58% N 5,48%

P R I m m e R 2. A. 3-(4-bromobutyl)-2,5,5,-trimethyl-4-thiazolidinone.

TO -73aboutWith the solution of 3-(4-bromobutyl)-5-methyl-4-thiazolidinone (6,00 g), iodotope bromide (10,99 g) and tetrahydrofuran (50 ml) under nitrogen atmosphere was added bis(trimethylsilyl)amide lithium (0,0500 mol) in tetrahydrofuran (50 ml) at a rate that ensures the maintenance of internal temperature of less than -55aboutC. the Resulting solution was mixed at a temperature of less than -55aboutC for 10 min, were left to be heated to -40aboutWith that angry/ether. The combined extracts were washed brine (200 ml), dried (sodium sulfate), and concentrated to a liquid, which was chromatographically on silica gel (345 g) with elution 35-65% gradient of ethyl acetate in hexano, giving 5,07 g of liquid. This liquid was converted, giving 3.80 g of 3-(4-bromobutyl)-2,5,5-trimethyl-4-thiazolidinone, temp.the TRC. 109-114aboutWith 0.20 mm RT.article.

Analysis: for C10H18BrNOS: Calculated: 42,86% N 6,47% N 5,00%

Found: 42,93% N 6,47% N 5,00%

b. 3-(4-(1-(1H-indazol-3-yl)piperazinil(butyl)-2,5,5-trimethyl - 4-thiazolidinone. A mixture of 3-(4-bromobutyl)-2,5,5,-trimethyl-4-thiazolidinone (of 4.00 g), 1-(1H-indazol-3-yl)piperazine (3,18 g), potassium carbonate (6,00 g), iodine sodium (300 g) and acetonitrile (200 ml) was heated at 75aboutC in nitrogen atmosphere. After 17 hours, TLC analysis showed the absence of starting bromide. The mixture was cooled to ambient temperature, filtered, the inorganic substance was rinsed with dichloromethane, and the filtrate was concentrated under reduced pressure until the liquid. The crude residue was taken in dichloromethane (220 ml) were washed with water (130 ml), saline solution (130 ml), dried (sodium sulfate) and concentrated to a liquid. The liquid was purified using chromatography on and ether/hexane gave 2,22 g of 3-[4-[1-(1H-indazol-3-yl)piperazinil] butyl]-2,5,5-trimeth - yl-4-thiazolidinone, the pace. pl. 111-112aboutC.

Analysis: for C21H31N5OS: Calculated: C 62,81% N 7,78% 17,44%

Found: 62,88% N 7,66% 17,47%

P R I m e R 3. A. 3-(4-bromobutyl)-1-thia-3-azaspiro[4.5]Decan-4-one. To a solution of 3-4(4-bromobutyl)-4-thiazolidinone (25 g) in tetrahydrofuran (350 ml), cooled to -60aboutC, was added 1,5-diiodopentane (100 g). The resulting suspension was left to cool down to -65aboutWith, and dropwise over a period of 30 min while maintaining the internal temperature is equal to or below -55aboutC was added a solution of bis(trimethylsilyl)amide lithium cases (36.8 g) in hexano (220 ml). The resulting mixture was mixed for 15 min and the internal temperature was allowed to rise to 0aboutC. was Added 0.5 norms. HCl (500 ml) for repayment of the reaction, and the mixture was concentrated in vacuo to remove THF. The aqueous mixture was extracted twice with 250 ml portions of ether, was washed with water (400 ml) and brine (400 ml), dried (sodium sulfate) and concentrated to a liquid. The liquid chromatographically on silica gel (elution with 20% acetate/hexane), giving the liquid.

b. 3-(4-(1-[1H-indazol-3-yl]-4-piperazinil)butyl)-1-thia-azaspiro[4.5] Decan-4-on N. a Mixture of 3-(4-bromobutyl)-1-thia-3-Aza - Spiro[4.5]Decan-4-it (4,06 g), 3-(1-pee nitrogen. After 20 h, TLC analysis (silica gel, 50% ether/hexane) showed only traces of the original bromide. The mixture was cooled to ambient temperature, was added ethyl acetate (150 ml), inorganic substances were filtered off, and the filtrate was concentrated under reduced pressure. The residue was taken in dichloromethane (220 ml) were washed with water (110 ml), saline solution (130 ml), dried (sodium sulfate) and concentrated to a foam. The foam was chromatographically on silica gel with elution with 10% methanol in dichloromethane, giving 4.83 g of foam, which hardened adding ethyl acetate. The solid was precrystallization from a mixture of ethyl acetate/hexane, giving 2.76 g of 3-(4-(1-[1H-indazol-3-yl] -4-piperazinil)butyl)-1-thia-3-azaspiro[4.5] Decan-4 - it, rate. the melt. 159-161aboutC.

Analysis for C23H33N5OS Calculated: C 64,60% N 7,78% N 16,38%

Found: 64,50% N 7,86% N 16,49%

P R I m e R 4. 3-(4-(4-(1-[1H-indazol-3-yl]piperazinil))-butyl)-5-methyl-thiazolidine. A mixture of 3-(4-bromobutyl)-5-methyl-4-thiazolidinone (3,9 g), 3-(1-piperazinil)-1H-indazole (3.0 g), potassium carbonate (4.1 g) and iodine sodium (200 mg) in 150 ml of dry acetonitrile was heated up to 80aboutWith under stirring in nitrogen atmosphere. After 18 h was left with no source of piperazine, which was koncentriruetsa in vacuum. The residue was chromatographically on silica using 5:95 methanol:ethyl acetate as eluent, giving a solid. This product was precrystallization from a mixture of ether/hexane, giving 2,593 g 2-(4-(4-(1-[1H-indazol-3-yl] piperazinil))-butyl)-5-methyl-thiazolidinone, temp. pl. 105-108aboutC.

Analysis for C19H27N5OS: Calculated: 61,10% N 7,29% N 18,75%

Found: 61,13% N 7,21% N 18,67%

P R I m e R 5. A. 3-(4-bromobutyl)-1-thia-3-azaspiro[4.4]nonan-4-one. TO -76aboutWith the solution of 3-(4-bromobutyl)-4-thiazolidinone and 4.75 g) and tetrahydrofuran (120 ml) under nitrogen atmosphere was added bis(trimethylsilyl)amide lithium (0,0203 mol) in tetrahydrofuran (20,3 ml) quickly, followed by immediate addition of 1,4-diiodobutane (15,51 g). After 12 min was added to a solution of bis(trimethylsilyl)amide lithium (0,0620 mol) in tetrahydrofuran (62 ml) over a period of 30 minutes Resulting reaction mixture was left to warmed to -45aboutWith, and at this temperature was added 1 standards. NS (250 ml). Poluchasa aqueous mixture was extracted 4 times 110 ml portions of ether. The combined extracts were washed brine (250 ml), dried (sodium sulfate), and concentrated to a liquid. The liquid chromatographically on silicagel the m distilling apparatus with a short coil with 0.20 mm RT.article giving of 2.35 g of 3-(4-bromobutyl)-1-thia-azaspiro[4.4]nonan-4-it.

Analysis for C11H18NOS: Calculated: 45,21% N 6,21% N 4,79%

Found: 45,33% N IS 6.19% N 4,81%

b. 3-(4-(1-[1H-indazol-3-yl]-4-piperazinil)butyl)-1-thia-3-azaspiro[4.4] nonan-4 - one. A mixture of 3-(4-bromobutyl)-1-thia-3-Aza - Spiro[4.4]nonan-4-it (of 4.00 g of 3-(1-piperazinil)-1H-indazole (3,05 g), potassium carbonate (6,63 g), iodine sodium (320 mg) and acetonitrile (210 ml) was heated at 85aboutC in nitrogen atmosphere. After 4 h, TLC analysis (silica gel, 40% ethyl acetate in hexano) showed that the starting bromide was completely consumed. The mixture was cooled to ambient temperature, was added ethyl acetate (100 ml), inorganic substances were filtered off, and the filtrate was concentrated under reduced pressure. The residue was taken in dichloromethane (210 ml) were washed with water (100 ml), brine (100 ml), dried (sodium sulfate) and concentrated under reduced pressure until the liquid. The liquid was purified using chromatography on silica gel with elution with 5% ethanol in dichloromethane, giving of 4.75 g of foam, which hardened after adding ether. The solid was precrystallization from ethyl acetate, giving 3.51 g of 3-(4-(1-[1H-indazol-3-yl]-4-piperazinil)butyl)-1-thia-3-azaspiro[4.4] but Nan-4-it, rate. pl. 166,52% N TO 7.61% N 16,73%

P R I m e R 6. 3-(4-(1-[1H-indazol-3-yl]-4-piperazinil)butyl-2-methyl-1-thia-3 - azaspiro[4.4]nonan-4-one. A mixture of 3-(4-Brembo - Tyl)-2-methyl-1-thia-3-azaspiro[4.4] nonan-4-it (4,20 g), 2-(1-piperazinil)-1H-indazole (3.0 g), potassium carbonate (of 5.68 g), and (310 mg), and acetonitrile (220 ml) was heated at a temperature of between 60 and 80aboutC in nitrogen atmosphere. After 18 h, TLC analysis showed only traces of the original bromide. Smeas was cooled to ambient temperature, was added ethyl acetate (150 ml), inorganic substances were filtered off, and the filtrate was concentrated under reduced pressure. The residue was taken in dichloromethane (230 ml) were washed with water (130 ml), saline solution (130 ml), dried with sodium sulfate, and concentrated to a foam. The foam was chromatographically on silica gel with elution with 8% methanol in dichloromethane, giving 5,04 g foam, which hardened after adding a mixture of ether/hexane. The solid was precrystallization from a mixture of ethyl acetate/hexane, giving and 3.72 g of 3-(4-(1-[1H-Inda - Zol-3-yl]-4-piperazinil)butyl)-2-methyl-1-thia-3-azaspiro[4.4]nonan-4-it, rate. pl. 113-115aboutC.

Analysis for C23H33N5OS: Calculated: 64,60% N 7,78% N 16,38%

Found: 64,71% N 8,08% N 16,52%

P R I m e R 7. A. 6-fluoro-3-(1-piperazinil)-1H-indazol-hydrochloride. g) in tetrahydrofuran (400 ml) was added dropwise to alumoweld lithium in tetrahydrofuran (130 ml of 1 M solution). The reaction mixture is stirred and heated under reflux for 3 h, cooled in an ice bath, was added dropwise water. The reaction mixture was filtered, and the filter cake was rinsed with tetrahydrofuran and twice with methanol. Concentration of the filtrate gave a resin, which when crushed with ether gave 14.6 g of a solid substance. The solid was dissolved in methanol, and ether was added HCl to the solution until then, until it became acidic. Then ether was added to the solution which was initially given resin. Floating above the solution was decenterable with resin, and after adding to the solution more ether was going 5,4 g chlorhydrate salt. Rubbing the resin when delegirovano ethyl acetate gave additional 3.2 g of salt. More abundant sample was precrystallization twice from methanol/ether, yielding 2.2 g of 6-fluoro-3-(1-piperazinil)-1H-indazol-hydrochloride, temp. pl. 268-270aboutC.

Analysis for C11H13FN4HCl: Calculated: 51,47% N 5,50% N 21,82%

Found: 51,38% N 5.37 PERCENT N 21,61%

b. 3-{4-(1-(6-fluoro-1H-indazol-3-yl)-4-piperazinil)butyl}-1 - thia-3-azaspiro[4.5]Decan-4-one. A mixture of 6-fluoro-3-(1-PI pyrazinyl)-1H - indazol-hydrochloride (4.0 g), potassium carbonate (6.5 g), 3-(4-bromobutyl)-1-thia-3-azaspiro[nitrogen for 17 hours The cooled reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. An ethyl acetate extract was washed with water, dried by magnesium sulfate and concentrated giving 10.3 g of a solid substance. The sample was purified using preparative liquid chromatography high resolution (HPLC) (silica gel, 6% methanol-dichloromethane as eluent), giving 4,1, Recrystallization of the compound from isopropyl alcohol gave 3.1 g 3-{4-[1-(6-fluoro-1H-indazol-3-yl)-4-piperazinil] butyl} -1-thia-3-azaspiro[4.5] d e - Kan-4-it, rate. pl. 163-165aboutC.

Analysis for C23H32FN5OS: Calculated: 62,00% N 7,24% N 15,72%

Found: 61,81% N 7,15% N 15.62 WIDE%

P R I m e R 8. 3-{4-[1-(6-fluoro-1H-indazol-3-yl)-4-piperazinil] butyl}-1-thia-3-azaspiro[4.4] nonan-4-one. A mixture of chlorine - hydrate 6-fluoro-3-(1-piperazinil)-1H-indazole (4.0 g), potassium carbonate (6.5 g), 3-(4-bromobutyl)-1-thia-3-azaspiro[4.4] nonan-4-it (5.0 g), dimethylformamide (100 ml) and iodotope potassium (200 mg), stirred for 16 h at 65aboutC in nitrogen atmosphere. The cooled reaction mixture is then poured into water and the aqueous mixture was extracted with ethyl acetate. An ethyl acetate extract was dried with magnesium sulfate and concentrated, giving 6.8 g of a solid substance. The image is saprophilous ethanol gave 2.1 g 3-{4-[1-(6-fluoro-1H-indazol-yl)-4-piperazinil] butyl} -1-thia-3-azaspiro[4.4] nonan-4-it, the pace. pl. 132-134aboutC.

Analysis for C22H30FN5OS: Calculated: 61,23% N 7,01% N 16,23%

Found: 61,37% N 6,93% N 16,21%

P R I m e R 9. 3-{4-[1-(6-fluoro-1H-indazol-3-yl)piperazinil] butyl}-5-methyl-4-thiazolidinone. A mixture of 6-fluoro-3-(1-piperazin - nil)-1H-indazol-hydrochloride (4.0 g), potassium carbonate (6.5 g), 3-(4-bromobutyl)-5-methyl-4-thiazolidinone (4.3 g), iodotope potassium (200 mg) and dimethylformamide (100 ml) were mixed at 80aboutC in nitrogen atmosphere for a period of 7.5 h, and then was left to stand for 16 h at room temperature. The reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. An ethyl acetate extract was dried with magnesium sulfate and concentrated, yielding 8.0 g of liquid. The sample was purified using preparative HPLC (silica gel, 6% methane-dichloromethane), giving 3,6, Recrystallization from isopropyl alcohol gave 2.2 g of 3-{4-[1-6-fluoro-1H-indazol-3-yl)-piperazinil]butyl}-5-methyl-4 - thiazolidinone, temp. pl. 119-120aboutC.

Analysis for C19H26FN5OS: Calculated: 58,29% H 6.69 per cent N 17,89%

Found: 58,24% N 6,74% N 17,80%

P R I m e R 10. 3-{4-[1-(6-fluoro-1H-indazol-3-yl)-4-piperazinil]butyl}-5,5-dimeth-yl-4 - thiazolidinone. To a stirred mixture of 6-fluoro-3-(1-piperazinil)-1H-indazole (4.4 g), carbonate is over 4 hours The reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. An ethyl acetate extract was washed (water), dried (magnesium sulfate) and the solvent was concentrated, giving an oil. After standing, the oil crystallized, and when the mass was pulverized with ether, collected and 3.3 g of solid substance. The connection was precrystallization from a mixture of toluene-hexane, giving 2.8 g 3-{4-[1-(6-fluoro-1H-indazol-3-yl)-4-piperazinil/butyl-5,5-dimethyl-4 - thiazolidinone, temp. pl. 123-125aboutC.

Analysis for C20H28FN5OS: Calculated: 59,24% N Of 6.96% N 17,27%

Found: 59,37% N 6,99% N 17,32%

P R I m e R 11. A. 3-(1-piperazinil)-1H-indazol. A mixture of 4-(1H-indazol-3-yl)-1-piperidinecarbonitrile (8.0 g), and 25% sulfuric acid (100 ml) were mixed at the temperature of reflux distilled over 4.5 hours, the Reaction mixture was cooled in an ice bath and was podslushivaet added dropwise a 50% sodium hydroxide. The basic solution was extracted with ethyl acetate. An ethyl acetate extract was washed with water, dried by magnesium sulfate and concentrated, giving 5.2 g of the desired compound in the form of a solid substance. The sample was precrystallization twice from toluene, giving 3.0 g of unsubstituted indazole, temp. pl. 153 to 155aboutC.

Analia-3-yl]-4-piperazinil)butyl)-5,5-dimethyl - 4-thiazolidinone. Stir a mixture of 3-(1-piperazinil)-1H-indazole (5.0 g), 3-(4-bromobutyl)-5,5-dimethyl-4-thiazolidinone (6.6 g) and dimethylformamide (120 ml) was heated at 70-75aboutC for 1.25 h, the Reaction mixture was poured into water, dried (magnesium sulfate) and the solvent was concentrated, giving a solid. The solid is dissolved with hexane and collected, giving 7.2 g of a solid substance. Recrystallization from toluene gave 5.7 g of 3-(4-(1-[1H-indazol-3-yl]-4-piperazinil)BU - Tyl-5,5-dimethyl-4-thiazolidinone, temp. pl. 139-142aboutC.

Analysis for C20H29N5OS: Calculated: 61,98% N rate of 7.54% N 18,07%

Found: 62,12% N 7,51% N 17,85%

P R I m e R 12. 3-{4-[1-Methyl-1H-indazol-3-yl)-4-piperazinil]-butyl}-5,5-dime-Tyl - 4-thiazolidin.

To a stirred mixture of sodium hydride (0.66 g) in dimethylformamide (20 ml) under nitrogen atmosphere was added 3-{4-[1-(1H-indazol-3-yl)-4-piperazinil] butyl} -5,5-dime - Tyl-4-thiazolidin (4.4 g), dissolved in hot dimethylformamide (30 ml). The mixture was left to mix at ambient temperature for 1 h, and then it was cooled to -1aboutWith salt-ice bath. Was added dropwise itmean (1.78 g) dissolved in dimethylformamide (10 ml), so that the temperature did not exceed 1aboutC. Posta at ambient temperature for 3.5 hours. The reaction mixture was poured into water, dried by magnesium sulfate and concentrated, giving 5.0 g of liquid. The liquid was pulverized with hexane, giving a solid which was collected and dried, giving a 2.5, the Connection was precrystallization from hexane, giving 2.0 g 3-{4-[1-(1-methyl-1H-indazol-3-yl)-4-piperazinil]butyl}-5,5 - dimethyl-4-thiazolidin, temp. pl. 91-93aboutC.

Analysis for C21H31N5OS: Calculated: 62,81% N 7,78% N 17,44%

Found: 62,97% N 7,80% N 17,42%

The METHOD of OBTAINING 3-(1-DIAZOLIDINYLUREA-4-PIPERAZINIL)-1H-INDAZOLS General formula I

< / BR>
where R1and R2each independently from each other hydrogen or lower alkyl, or R1and R2taken together with the carbon atom to which they are attached, form a cyclopentane or cyclohexane ring;

R3and R4each independently from each other hydrogen or lower alkyl;

R5hydrogen or lower alkyl;

X is hydrogen or halogen,

or their pharmaceutically acceptable acid additive salts, characterized in that the derived 4-thiazolidinone General formula II

< / BR>
where R1, R2, R3and R4have the specified values,

subjected to interaction with 3-(1-piperazin is soedineniya General formula I, where R5is hydrogen and R1, R2, R3, R4and X have the above meanings, in the form of free base or pharmaceutically acceptable acid additive salt and the compound optionally subjected to interaction with the alkylating agent, followed by separation of the compounds of General formula I, where R5alkyl, and R1, R2, R3, R4and X have the above meanings, in the form of free base or pharmaceutically acceptable acid salt additive.

 

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