3-(diazolidinylurea-4-piperazinil)-1h-indazols

 

(57) Abstract:

The invention relates to 3-/1-diazolidinyl butyl-4-piperazinil/ 1H-indazols formula I

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

R3and R4independently represent hydrogen or lower alkyl, or R3and R4taken together with the carbon atom to which they are attached, form a cyclopentane or cyclohexane ring;

R5is hydrogen or lower alkyl;

X is halogen;

m is an integer of 0 or 1, to their pharmaceutically acceptable acid additive salts, and where applicable, optical, geometric and stereoisomers and racemic mixtures.

The compounds of this invention are useful as antipsychotic agents. 9 C.p. f-crystals, 1 table.

The invention relates to compounds of formula 1

< / BR>
where R1and R2each independently represents hydrogen or lower alkyl, or R1and R2taken together with the carbon atom to which they prisoediniv represents hydrogen or lower alkyl, or R3and R4taken together with the carbon atom to which they are attached, form a cyclopentane, cyclohexane or Cycloheptane ring; R5represents hydrogen, lower alkyl, alkanoyl or aroyl; X is a halogen, lower alkyl or alkoxy; m is an integer from 0 to 3, to their pharmaceutically acceptable acid additive salts and, where applicable, to their optical, geometric and stereoisomers and racemic mixtures. These compounds of this invention are useful as antipsychotic agents.

The preferred embodiments of the invention are those of 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 R5the hydrogen.

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 1 to 6 carbon atoms. The term "alkyl" refers to hydrocarbons with straight or branched chain, not alkoxy" refers to monovalent Deputy, which consists of an alkyl group linked through an ether oxygen having a link to its free valence from the ether oxygen, e.g. methoxy, ethoxy, propoxy, butoxy, intoxi etc. the term "alkanoyl" refers to the Deputy, having the formula

< / BR>
where alkyl has the previously defined values, for example, acetyl, etc. the term aroyl refers to the Deputy, having the formula, for example, benzoyl, Naftoli etc. where aryl represents a group of the formula

< / BR>
where

Z is hydrogen, halogen, lower alkyl, lower alkoxy, trifluoromethyl, nitro and amino, and n is an integer of 1 to 3. for example, phenyl, o-tolyl, m-methoxyphenyl etc.

the term "halogen" refers to the representative of the family of Halogens comprising fluorine, chlorine, bromine and iodine.

Compounds of the present invention can be obtained as follows.

The compound of formula II

< / BR>
is introduced into the reaction with the compound of the formula III

< / BR>
giving 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 the in which R5the lower alkyl, the compound I, in which R5represents hydrogen, is subjected to interaction with NaH and methyliodide or other suitable alkylating agent in a suitable medium such as dimethylformamide or acetonitrile, at a temperature of 60-85oC.

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, at a temperature of about 23-70oC.

Compound III is obtained as described in EP-A-0417653.

The compound of formula IV

< / BR>
in which the divalent group-R - plus spiropent in combination is a cyclopentane, cyclohexane or Cycloheptane ring, can be obtained in the following way:

3-/4-Bromobutyl/4 thiazolidinone formula II

< / BR>
where

R1and R2hydrogen is introduced into the reaction with bis/(trimethylsilyl)/amidon lithium and a compound of formula V

Hal-R6-Hal,

where

R6lower alkyl, and Hal is bromine or iodine, in a suitable medium, such as tetrahydrofur is, what if you use monobromide or monoidal formula R6-Hal instead of compound V can be obtained compound VI and/or connection VII.

If you want to obtain compound VI of the formula

< / BR>
as the predominant product, it is preferable to keep the molar ratio of R6-Hal, compound IIa formula

< / BR>
and bis/(trimethylsilyl)/ amidon lithium to about 1:1, whereas, if you want to obtain the compound of formula VII

< / BR>
as the predominant product, it is preferable to bring this ratio to approximately 1:2.

Compounds of the present invention are potentially useful as antipsychotic agents as defined by the method of climbing mice /MCA/.

Analysis climbing mice /climbing to a height of/ described by the authors P. Protais, etc. Psychopharmacol. 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"x4"x10"/ and give them one hour to adapt and explore new environments. Subcutaneously injected apomorphine dose of 1.5 mg/kg dose, the caller climbing all subjects within 30 minutes Coedine of apomorphine at a screening 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 in mice: Assessment

4.Shuffling his feet on the bottom /no climbing/ 0

2 Shuffling his feet on the wall /occasionally/ 1

4 Shuffling his feet on the wall /full climbing/ 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 contrast, climbing due to only stimulate the movement usually lasts only a few seconds.

Assessment of the effect of climbing individually added /maximum score of 6 for one mouse at 3 withdrawals readings/, and the overall 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.

The connection Assessment lasagna mice ED50mg/kg

3-(4-(1-[1H-indazol-3-yl] -4-piperazinil)-butyl)-5,5-dimethyl-4 - thiazolidinone 1.3 I. ii.

3-(4-(1-[1H-ind is sinil)-butyl)-1-thia-3 - azaspiro[4.5] Decan-4-one 0.65 I. ii.

3-(4-[1-(6-fluoro-1H-indazol-3-yl)-4-piperazinil] butyl)-5-mctel - 4-thiazolidinone 0.11 I. ii.

3-(4-[1-(6-fluoro-1H-indazol-3-yl)-4-piperazinil] butyl)-1-thia-3 - azaspiro[4.5]-Decan-4-one 0.04 I. p. 0.67 R. O.

clozapine /standard/ 8.1 I. ii.

sulpiride /standard/ 14.5 I. ii.

Antipsychotic effect is achieved when the compounds of this invention are assigned to the subject in need of treatment at an effective oral, parenteral or vnutrivennoi 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 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 invention may be administered to a subject using any of various methods, for example, orally in the form of capsules or tablets, parenteral in denene of the present invention, being effective themselves, may be formulated and administered in the form of their pharmaceutical 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 similar. Preparations should contain at least 0.5% of active compound, but the number can vary depending on the specific shape and can be a convenient way between 4% and about 75% vetsa 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, Primogelcorn starch and similar; lubricating agent such as magnesium stearate or Sarotexsliding agent /or facilitating a smooth passage of the/ such as colloidal silicon dioxide; 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 can contain other various materials that option is whether can be covered 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 injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol is HN; antioxidants, such as ascorbic acid or sodium bisulfate; 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. Parenterally the 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 - trimethyl-4-thiazolidone;

3-(4-1-[6-fluoro-1H-indazol-3-yl] -4-piperazinil)butyl)-of 2.2.5.5 - methyl-4-thiazolidinone;

3-(4-(1-[6-fluoro-1H-indazol-3-yl] -4-piperazinil)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-azaspiro[4.5]Decan-4-one;

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

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

3-(4-[1-acetyl-1H-indazol-3-yl] -4-piperazinil)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]Decan-4-one;

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

Examples are given for illustration only and should not be construed as limiting the invention. All temperatures are given in degrees Celsius /oC/.

Example 1. a. 3-(4-bromobutyl)-4-thiazolidinone.

A mixture of 4-oxothiazolidines /25 g/, dimethylformamide /500 ml/ and KOH /27,16 g/ stirred in 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 room 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 saline /300 ml, dried over sodium sulfate and concentrated in vacuo to an oil. HPLC aliquots in 44,95 g gave to 7.15 g of oil which upon distillation gave the pure liquid, so Kip. 134 - 139oC/0.12 mm RT.article.

Calculated C 35,30; H 5,08; N 5,88

C7H12BrNOS.

Found, C 35,24; H 5,09; N OF 5.83

b. 3-(4-bromobutyl)-5-methyl-4-thiazolidinone

TO -74oC to a solution of 3-(4-bromobutyl)-4-thiazolidinone /5.20 g/ tetrahydrofuran /70 ml/ nitrogen atmosphere was rapidly added bis-trimethylsilyl)/lithium amide /0,023 mol/ tetrahydrofurane - min /cooled with the help of CO2/ isopropanole baths/, referred to be heated to -40oC and pagkilala 1 N. HCl /200 ml/. The resulting aqueous mixture was extracted three times with 100 ml portions of 25% benzene/ether. The combined extracts were washed with saline /200 ml, dried with sodium sulfate and concentrated in vacuo, giving the fluid that 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 3-/4-bromobutyl/-5-methyl-4-thiazolidinone, so Kip. 123 125oC at 0.20 mm RT.article.

Calculated C 38,10; H ceiling of 5.60; N 5,55

C8H14BrNOS.

Found, C 38,12; H 5,58; N 5,48

Example 2. a. 3-/4-bromobutyl/2,5,5-trimethyl-4-thiazolidinone.

K 73oC to a solution of 3-/4-bromobutyl/-5-methyl-4 - thiazolidinone /6,00 g/, iodotope bromide /10,99 g/ and tetrahydrofuran /50 ml/ in an atmosphere of nitrogen was added bis/(trimethylsilyl)/lithium amide /0,0500 mol/ tetrahydrofuran /50 ml/ speed, ensuring that the internal temperature of less than -55oC. the Resulting solution was stirred at a temperature of less than -55oC for 10 min, were left to be heated to -40oC and at this temperature was added 1 N. HCl/250 ml/. The aqueous mixture was extracted three times with 125 ml portions of 25% b which was tribalise to liquid, which was chromatographically on silica gel /345 g/, when the elution 35-65% gradient of ethyl acetate in hexano, giving 5,07 g of liquid. This liquid was converted, giving 3.80 g 3-/4-bromobutyl/-2,5,5-trimethyl-4-thiazolidinone, so Kip. 109-114oC at 0.20 mm RT.article.

C10H18BrNOS.

Calculated C 42,86; H 6,47; N 5,00

Found, C 42,93; H 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 /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 75-oC in nitrogen atmosphere. After 17 hours the 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, dried /sodium sulfate/ and concentrated to a liquid. The liquid was purified using chromatography on silica gel. Elution with 5% methanol in dichloromethane gave 4,22 g solids. Recrystallization from a mixture of ether/hexane gave 2,22 g of 3-[4-[1-/H-indazol-3-and the LASS="ptx2">

Calculated C 62,81; H 7,78; N 17,44

Found, C 62,88; H 7,66; N 17,47

Example 3. a. 3-/4-bromobutyl/-1-thia-3-azaspiro/4.5/DCN-4-one.

To a solution of 3-/4-bromobutyl/-4-thiazolidinone /25 g/ in tetrahydrofuran /350 ml) cooled to -60oC, was added 1,5-diiodopentane /100 g/. The resulting suspension was left to cool down to -65oC and added dropwise over a period of 30 min while maintaining the internal temperature is equal to or below -55oC was added a solution of bis/trimethylsilyl/lithium amide /36,8 g/ hexano /220 ml/. The resulting mixture was mixed for 15 min and the internal temperature was allowed to rise to 0oC. was Added to 0.5 N. 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, washed with water /400 ml/ and saline /400 ml) and dried /sodium sulfate/ and concentrated to a liquid. The liquid chromatographically on silica gel /elution 20% acetate/hexane/ giving liquid.

b. 3-/4-1-[1H-indazol-3-yl] -4-piperazinil/butyl/-1-thia-3-azaspiro [4.5] Decan-4-one.

A mixture of 3-/4-bromobutyl/-1-thia-3-azaspiro[4,5] Decan-4-it /4,06 g/, 3-/1-piperazinil/-1H-/indazol /2.95 g/, potassium carbonate /5.50 g/, acetonitril the 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 /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 3-/4-1-[1H-indazol-3-yl]-4-piperazinil/butyl/-1-thia-3-azaspiro[4.5]Decan - 4-it, so pl. 159-161oC.

C23H33N5OS

Calculated C 64,60; H 7,78; N 16,38

Found, C 64,50; H 7,86; N 16,49

Example 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 g/ 150 ml dry acetonitrile was heated up to 80oC under stirring in nitrogen atmosphere. After 18 hours was left with no source of piperazine, which can be judged according to TLC. The mixture was cooled to room temperature and filtered, and Phil is methanol:ethyl acetate as eluent, giving solid. This product was precrystallization from a mixture of ether/hexane, giving 2,593 g 2-/4-(1-[1H-indazol-3-yl]-piperazinil))-butyl/-5-methyl-thiazolidinone, so pl. 105-108oC.

C19H27N5OS

Calculated C 61,10; H 7,29; N 18,75

Found, C 61,13; H 7,21; N 18,67

Example 5. a. 3-/4-robutel/-1-thia-3-azaspiro/4.4/nonan-4-one.

K -76oC to a solution of 3-/4-bromobutyl/-4-thiazolidinone /4,75 g/ and tetrahydrofuran /120 ml/ in an atmosphere of nitrogen was added bis/(trimethylsilyl)/lithium amide /0,0203 mol/ tetrahydrofuran /a 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)/lithium amide /0,0620 mol/ tetrahydrofuran /62/ ml over a period of 30 minutes Resulting reaction mixture was left to warmed to -45oC and at this temperature was added 1 n HCl /250 ml/. The resulting aqueous mixture was extracted 4 times 110 ml portions of ether. The combined extracts were washed with saline /250 ml, dried /sodium sulfate/ and concentrated to a liquid. The liquid chromatographically on silica gel /elution with 40% ethyl acetate in hexano/ giving to 3.34 g of liquid. This liquid was converted using a distillation apparatus which SUB>H18NOS

Calculated, C45,21; H6,22; N4,79

Found, C45,33; H6,19 N4,18

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-azaspiro/4.4/nonan-4-it/4,00 g/3-/1-piperidinyl/ -1H-indazole/3,05 g/, potassium carbonate /6,63 g/, iodine sodium /320 g/ and acetonitrile/210 ml/ was heated at 85oC in nitrogen atmosphere. After 4 hours 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 diclomelan /210 ml/ were washed with water /100 ml, saline solution /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% methanol 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 3-/4-/1/[1H-indazol-3-yl]-4-piperazinil/butyl/-1-thia-3-azaspiro[4.4] nonan-4-it, so pl. 166,5-168oC.

C22H31N5OS.

Calculated, C63,89; H7,56; N16,93

The LASS="ptx2">

A mixture of 3-/4-bromobutyl/-2-methyl-1-3-azaspiro[4.4]nonan-4-[4,20 g] 3-/1-piperazinil/-1H-indazole/3.0 g/, potassium carbonate /of 5.68 g/ NaI/310 mg/, and acetonitrile /220 ml/ was heated at a temperature of between 60 and 80oC in nitrogen atmosphere. After 18 hours the TLC analysis 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 diclomelan /230 ml/ were washed with water /130 ml/, saline /130 ml, dried by 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-indazol-3-yl]-4-piperazinil/butyl/-2-methyl-1-thia-azaspiro [4.4]nonan-4-it, so pl. 113-115oC.

Calculated, C64,60; H7,78; N16,38

C23H33N5OS

Found C,71; H8,08; N16,52

Example 7. a. 6-Fluoro-3-/1-piperazinil/-1H-indazol-hydrochloride.

To stir the mixture under nitrogen atmosphere 4-/6-fluoro-1-phenyl-sulfonyl-1H-indazol-3-yl/-1-piperazinylcarbonyl /u ion mixture is stirred and heated under reflux for 3 hours was 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 chlorothieno salt. Rubbing the resin when delegirovano ethyl acetate gave dopolnitelno,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-chloridrate, so pl. 268-270oC.

Calculated, C51,47; H5,50; N21,82

C11H13FN4HCL

Found, C51.38; H5,37; N21,61

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-piperazinil/-1H-indazol-hydrochloride /4.0 g/, potassium carbonate /6.5 g/, 3-/4-bromobutyl/-1-thia-3-azaspiro[4.5] Decan-4-it /5.2 g/, iodotope potassium 200 mg/ dimethylformamide /100 ml was mixed with 75oC stayed with ethyl acetate. An ethyl acetate extract was washed with water, dried by magnesium sulfate and concentrated, yielding 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]-decane-4-it, so pl. 163-165oC.

Calculated, C62,00; H7,24; N15,72

C23H32FH5OS

Found, C61,81; H7,15; N15,62

Example 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 the hydrochloride of 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 ml stirred for 16 hours at 65oC 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 sample was purified using preparative HPLC /silica gel, 6% methanol/dichloromethane/ giving 3,0, Recrystallization, ist.sq.132-134oC.

Calculated, C61,23; H7,01; N16,23

C22H30FN5OS

Found, C61,37; H6,93; N16,21

Example 9. 3-{4-[1-(6-Fluoro-1H-indazol-3-yl)-piperazinil]butyl}-5-methyl-4-thiazolidinone.

A mixture of 6-fluoro-3-/1-piperazinil/-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/ dimethylformamide /100 ml was mixed with 80oC in nitrogen atmosphere for a period of 7.5 hours and then was left to stand for 16 hours 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 3-{4-4-[1-(6-fluoro-1H-indazol-3-yl)-piperazinil] butyl}-5-methyl-4 - thiazolidine, so pl. 119-120oC.

Calculated, C58,29; H6,69; N17,89

C19H26FN5OS

Found, C58,24; H6,74; N17,80

Example 10. 3-{4-(6-Fluoride--1H-indazol-3-yl)-4-piperazinil]butyl}-5,5-dimethyl - 4-thiazolidinone.

To a stirred mixture of 6-fluoro-3-/1-piperazinil/-1H-indazole /4.4 g/, potassium carbonate /2.8 g/, 3-/4-trombotic/-5,5-dimethyl-4-as in 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 2.9 g 3-{ 4[1-(6-fluoro-1H-indazol-3-yl)-4-piperazinil] butyl}-5,5 - dimethyl-4-thiazolidinone, so pl. 123-125oC.

Calculated, C59,24; H6,96; N17,27

C20H28FN5OS

Found, C59,37; H6,99; N17,32

Example 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, so pl. 153-155oC.

Calculated, C65,32; H6,98; N27,70

C11H14N4< / BR>ofor 1.25 h, the Reaction mixture was poured in water, dried /magnesium sulfate and the solvent was concentrated, giving a solid. The solid substance was pulverized 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/butyl/-5,5-dimethyl - 4-thiazolidinone, so pl. 139-142oC.

Calculated, C61,98; H7,54; N18,07

C20H29N5OS

Found, C62,12; H7,51; N17,85

Example 12. 3-{ 4-[1-Methyl-1H-indazol-3-yl)-4-piperazinil] butyl} -5,5 - dimethyl-4-thiazolidin.

To a stirred mixture of hydrate of sodium /0,66 g/, in dimethylformamide /20 ml/ nitrogen atmosphere dobavlialsea-[1-(1H-indazol-3-yl)-4-piperazinil]butyl} -5,5-dimethyl-4-thiazolidin /4.4 g/, dissolved in hot dimethylformamide /30 ml/. The mixture was left to mix at ambient temperature for one hour, and then it was cooled to -1oC Allegany bath. Was added dropwise itmean /1.78 g/ dissolved in dimethylformamide /10 ml/, so that the temperature did not exceed 1oC. After complete addition the ice bath was removed and the reaction mixture was left who stayed in the water, dried by salvaton magnesium 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 of 3-{4-[1-methyl-1H-indazol-3-yl)-4-piperazinil] butyl}-5,5 - dimethyl-4-thiazolidin, so pl. 91-93oC.

Calculated, C62,81; H7.78; N17,44

C21H31N5OS

Found, C62,97; H7,80; N17,423

1. 3-(1-Diazolidinylurea-4-piperazinil)-1H-indazols General formula I

< / BR>
where R1and R2each independently represents 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 represents hydrogen or lower alkyl, or R3and R4taken together with the carbon atom to which they are attached, form a cyclopentane or cyclohexane ring;

R5hydrogen or lower alkyl;

X halogen;

m is the integer 0 or 1,

or their pharmaceutically acceptable acid additive salt.

2. Connection on p. 1, in which R3, R4and R5each independently represents hydrogen or is about represents hydrogen or methyl, R5hydrogen, X is fluorine and m is 0 or 1.

4. Connection on p. 3 in which R1and R2each independently represents hydrogen or methyl, or R1and R2taken together with the carbon atom to which they are attached, form a cyclopentane or cyclohexane ring.

5. Connection on p. 1, representing 3-(4-1-[1H-indazol-3-yl]-4-piperidinyl)butyl)-1-thia-3-azaspiro [4,5]Decan-4-one.

6. Connection on p. 1, representing 3-(4-[1-(6-fluoro-1H-indazol-3-yl)-4-piperazinil]butyl)-5-methyl-4-thiazolidin.

7. Connection on p. 1, representing 3-(4-[1-(6-fluoro-1H-indazol-3-yl)-4-piperazinil]butyl)-1-thia-3-azaspiro[4,5]Decan-4-one.

8. Connection on p. 1, representing 3-(4-(1-[1H-indazol-3-yl]-4-piperazinylmethyl)-1-thia-3-azaspiro[4,4]-nonan-4-one.

9. Connection on p. 1, representing 3-(4-(1-[1H-indazol-3-yl]-4-piperazinil)butyl)-5,5-dimethyl-4-thiazolidinone.

10. Connection on p. 1 with antipsychotic activity.

 

Same patents:

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The invention relates to a series of new piperidyl - occaisonally and khinuklidinilbenzilata derivatives that can be used in the treatment and prevention of various disorders, especially senile dementia / including disease of Alzheimer/

The invention relates to new heterocyclic derivatives of substituted 2-acylamino-5-thiazolo exhibiting affinity to the receptor cholecystokinin and gastrin to a method for producing such compounds and to pharmaceutical compositions based on

The invention relates to benzothiazole derivative that is highly effective as a medicinal product, namely, benzothiazole derivative, useful as a preventive and therapeutic agent for diseases in which the function of suppressing the production of leukotrienes and thromboxanes are effective

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of dihydropyrimidine of the general formula (I):

or its isomeric form of the formula (Ia):

that can be used, for example, for treatment and prophylaxis of hepatitis B. In indicated formulas R1 means unsubstituted phenyl or phenyl substituted once or many times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, nitro-, amino-group, hydroxyl and alkyl with 1-6 carbon atoms, or residues of formulas:

, or ; R2 means residue of the formula -XR5 wherein X means a bond or oxygen atom; R5 means alkenyl with 2-4 carbon atoms or alkyl with 1-4 carbon atoms that can be unsubstituted or substituted with phenoxy-group; R3 means amino-group, alkyl with 1-4 carbon atoms or cyclopropyl; R4 means pyridyl that is substituted with up to three times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, alkoxy-group with 1-6 carbon atoms and alkyl with 1-6 carbon atoms, and their salts. Also, invention relates to 3,5-difluoro-2-pyridincarboxyimidamide and 3,5-difluoro-2-pyridincarbonitrile that can be sued as intermediates products for preparing compounds of the formula (I) or (Ia) and to a medicinal gent.

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

10 cl, 2 sch, 4 tbl, 9 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of aminomethylpyrrolidine of the formula (I) , their salts or hydrates wherein R1 represents aryl with from 6 to 10 carbon atoms or heteroaryl wherein heteroaryl is a five-membered ring or a six-membered ring and comprises from 1 to 2 heteroatoms taken among nitrogen, oxygen and sulfur atom; aryl and heteroaryl can comprise one or more substitutes taken among the group consisting of halogen atom or (C1-C6)-alkoxyl; each radical among R2, R3, R4, R5, R6, R7 and R8 represents hydrogen atom (H) independently; Q represents incomplete structure representing by the following formula: wherein R9 means (C3-C6)-cyclic alkyl that can be substituted with halogen atom; R10 means hydrogen atom (H); R11 means hydrogen atom (H), NH2; X1 means halogen atom; A1 represents incomplete structure representing by the formula (II): wherein X2 means hydrogen atom (H), halogen atom, halogenmethoxyl group, (C1-C6)-alkyl or (C1-C6)-alkoxyl group; X2 and above indicated R9 can be combined to form the ring structure and inclusion part of the main skeleton and such formed ring comprises oxygen, nitrogen or sulfur atom as a component atom of the ring and the ring can comprise (C1-C6)-alkyl as a substitute; Y means hydrogen atom (H). Compounds of the formula (I) elicit an antibacterial effect and can be used for preparing a therapeutic agent.

EFFECT: valuable medicinal properties of compounds.

2 tbl, 61 ex

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

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

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

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, chemical technology, agriculture.

SUBSTANCE: invention describes substituted azadioxocycloalkenes of the general formula (I): wherein A means unsubstituted or methyl-substituted dimethylene; Ar means unsubstituted or fluorine-substituted ortho-phenylene, thiophendiyl or pyridindiyl; E means group of the formula: wherein G means oxygen atom, groups -O-CH2-, -CH2-O- or -C(CH3)=N-O-CH2-; Z means unsubstituted or substituted phenyl, pyrimidinyl or thiadiazolyl, or naphthyl. Invention describes 4 methods for preparing compounds of the formula (I), 5 species of intermediate compounds used for preparing compounds of the formula (I), fungicide agents comprising compound of the formula (I) as an active substance, a method for preparing fungicide agents, method for control of harmful fungi using compound of the formula (I). Compounds of the formula (I) show fungicide properties and therefore they can be used in agriculture.

EFFECT: improved preparing methods, valuable properties of compounds.

13 cl, 5 tbl, 18 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

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

26 cl, 4 tbl, 476 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide of the formula: and to its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition inhibiting activity of protein-tyrosine kinases and comprising the indicated compound, a method for treatment of disorders associated with protein-tyrosine kinases, such as an immune disorder, and oncology disease, and a method for cancer treatment.

EFFECT: valuable biochemical and medicinal properties of compounds and composition.

5 cl, 2 tbl, 581 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of pyrrole of the formula (I): wherein R1 and R1' mean independently hydrogen atom (H) or (lower)-alkyl, unsubstituted or substituted (lower)-alkoxy-group; R2 means hydrogen atom (H), nitro-group (-NO2), cyano-group (-CN), halogen atom, unsubstituted (lower)-alkyl or substituted with halogen atom or (lower)-alkoxy-group; R2' means thiazolyl, thiophenyl, isothiazolyl, furanyl and pyrazolyl that is unsubstituted or substituted with (lower)-alkyl, pyrimidinyl, unsubstituted morpholinyl, unsubstituted pyrrolidinyl and imidazolyl that is unsubstituted or substituted with (lower)-alkyl, unsubstituted piperidinyl or piperazinyl that is unsubstituted or substituted with (lower)-alkyl, or ethoxy-group substituted with imidazolyl, or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit cell proliferation in G2/M phase of mitosis that allows their using in the pharmaceutical composition.

EFFECT: valuable biological properties of compounds.

36 cl, 4 sch, 1 tbl, 21 ex

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