Derivatives of n-(1,5-diphelyl-1h-pyrazol-3-yl)sulphonamide with affinity to cb1 receptors

FIELD: chemistry.

SUBSTANCE: present invention refers to compounds of general formula (I) in the state of base salt or acid-addition salt, to method of their preparation and to the pharmaceutical composition thereof In the said formula R1 is (C1-C6)alkyl; (C3-C7)cycloalkyl unsubstituted or substituted once or more than once; (C3-C7)cycloalkylmethyl unsubstituted or substituted once or more than once; phenyl unsubstituted or substituted ; benzyl unsubstituted or substituted once or twice ; thienyl unsubstituted or substituted ; R2 is atom hydrogen or (C1-C3)alkyl; R3 is (C1-C5)alkyl; R4, R5, R6, R7, each R8 and R9 independently represents the atom of hydrogen, atom of halogen, (C1-C7)alkyl, (C1-C5)alkoxy or trifluoromethyl radical; n is 0, 1 or 2; Alk is (C1-C4)alkyl.

EFFECT: new compounds possess useful biological activity.

5 cl, 5 tbl, 4 ex

 

The object of the present invention are derivatives of N-[(1,5-diphenyl-1H-pyrazole-3-yl)methyl]sulfonamida, obtaining them and their use in therapy.

Derivatives diphenylpyrazine having affinity to the receptors CB1cannabinoids, described in particular in patents EP 0576357, EP 0656354 and US 5624941.

Now found new derivatives of N-[(1,5-diphenyl-1H-pyrazole-3-yl)methyl]sulfonamida that have the properties of antagonists of cannabinoid receptors CB1.

The object of the present invention are compounds corresponding to the formula (I)

in which:

- R1means (C1-C6)alkyl;

(C3-C7)cycloalkyl, not substituted or substituted one or more times (C1-C3)alkyl group;

(C3-C7)cycloalkenyl, not substituted or substituted one or more times in carbocycle (C1-C3)alkyl;

phenyl, unsubstituted or mono-, di - or tizamidine Deputy, selected independently from halogen atom, (C1-C4)alkyl, (C1-C3)alkoxy, cyano, triptoreline radical, triptoreline radical, a group S(O)nAlk, (C1-C3)alkylcarboxylic group, phenyl;

benzyl, unsubstituted or mono - or disubstituted by Deputy, selected independently from halogen atom, alkyl, (C1 -C3)alkoxy; triptorelin radical;

thienyl, not substituted or substituted by a halogen atom or isoxazolyl;

- R2means a hydrogen atom or a (C1-C3)alkyl;

- R3means a hydrogen atom or a (C1-C5)alkyl;

- R4, R5, R6, R7, R8and R9each denotes independently a hydrogen atom, halogen atom, (C1-C7)alkyl, (C1-C5)alkoxy, triptoreline radical or a group S(O)nAlk;

- n means 0, 1 or 2;

- Alk means (C1-C4)alkyl.

The compounds of formula (I) may contain one or more asymmetric carbon atoms. Therefore, they can exist as enantiomers or diastereomers. These enantiomers, diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the invention.

The compounds of formula (I) may exist in the form of bases or acid additive salts. Such an acid additive salt form part of the invention.

These salts are mainly derived from pharmaceutically acceptable acids, but the salts of other acids suitable for the purification or separation of compounds of formula (I)are also part of the invention.

The compounds of formula (I) may also exist in the form of a hydrate or of a solvate, namely in the form of aggregates or combinations with one of the second or more water molecules or with a solvent. Such hydrate and solvate are also part of the invention.

Under the halogen atom means an atom of bromine, chlorine, fluorine or iodine.

Under (C1-C3)alkyl or (C1-C4)alkyl, (C1-C5)alkyl, (C1-C6)alkyl or (C1-C7)alkyl understand linear or branched alkyl radical with 1-3 carbon atoms or from 1 to 4 carbon atoms, with 1-5 carbon atoms, 1-6 carbon atoms, or 1 to 7 carbon atoms, such as methyl, ethyl, sawn, ISO-propyl, boutigny, isobutylene, second-boutigny, tert-boutigny, pentelenyi, isopentenyl, sexily, isohexyl, Gately radical.

Under (C1-C3)alkoxy or (C1-C5)alkoxy understand linear or branched CNS radical with 1-3 carbon atoms or, respectively, 1-5 carbon atoms, such as metaxylene, amoxilina, propoxyphenyl, isopropoxyphenyl, butoxyphenyl, second-butoxyl, tert-butoxyphenyl, pentoxil, isointensity radical.

Under (C3-C7)cycloalkyl understand cyclic alkyl group having 3-7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentamine, tsiklogeksilnogo, cycloheptyl group.

Of the compounds of formula (I) objects of the invention it is possible to call pre is respectful connection defined as follows:

- R1means

ethyl, isopropyl, n-butyl;

cyclohexyl;

cyclohexylmethyl;

2-chlorophenyl, 3-chlorophenyl, 2-forfinal, 3-chloro-4-forfinal, 4-bromo-2-ethylphenyl, 3-were, 4-tert-butylphenyl, 3, 5dimethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 2-(triptoreline)phenyl, 3-(triptoreline)phenyl, 2-(methylsulphonyl)phenyl, 3-(methylsulphonyl)phenyl, 3-acetylphenyl, 3-biphenyl, 2-biphenyl;

3 Chlorobenzyl, 2-tormentil, 4-tormentil, 3-(trifluoromethyl)benzyl, 4-(trifluoromethyl)benzyl;

5-bromo-2-thienyl; 5-isoxazol-3-yl-2-thienyl;

and/or R2means a hydrogen atom or methyl;

and/or R3means methyl or ethyl;

and/or R4means a hydrogen atom;

and/or R5is in position-4 - phenyl and means atom of bromine, chlorine, fluorine or methoxy;

and/or R6means a hydrogen atom;

and/or R7means a hydrogen atom;

and/or R8is in position-4 - phenyl and means a hydrogen atom, a chlorine atom, a fluorine atom;

and/or R9is in position-2 - phenyl and means chlorine atom or fluorine; in the form of a base or an acid additive salt, and also in the form of a hydrate or of MES.

From the last of preferred compounds is particularly preferred compounds of formula (I), in which:

- R1means

ethyl, isopropyl, n-butyl;

cyclohexyl;

cyclohexylmethyl;

2-chlorophenyl, 3-chlorophenyl, 2-forfinal, 3-chloro-4-forfinal, 4-bromo-2-ethylphenyl, 3-were, 4-tert-butylphenyl, 3, 5dimethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 2-triptoreline)phenyl, 3-(triptoreline)phenyl, 2-(methylsulphonyl)phenyl, 3-(methylsulphonyl)phenyl, 3-acetylphenyl, 3-biphenyl, 2-biphenyl;

3 Chlorobenzyl, 2-tormentil, 4-tormentil, 3-(trifluoromethyl)benzyl, 4-(trifluoromethyl)benzyl;

5-bromo-2-thienyl; 5-isoxazol-3-yl-2-thienyl;

- R2means a hydrogen atom or methyl;

- R3means methyl or ethyl;

- R4means a hydrogen atom;

- R5is in position-4 - phenyl and means atom of bromine, chlorine, fluorine or methoxy;

- R6means a hydrogen atom;

- R7means a hydrogen atom;

- R8is in position-4 - phenyl and means a hydrogen atom, a chlorine atom, a fluorine atom;

- R9is in position-2 - phenyl and means chlorine atom or fluorine;

in the state of a base or an acid additive salt, and also, hydrate, or MES.

Of the compounds of formula (I) objects of the invention can, in particular, include the following compounds:

- -[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]butane-1-sulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]cyclohexanesulfonic;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]cyclohexanesulfonic;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-3-chlorobenzenesulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-4-tert-butylbenzenesulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-3-methoxybenzenesulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-4-methoxybenzenesulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-4-(trifluoromethyl)benzosulfimide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-2-(methylsulphonyl)benzosulfimide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-1-(3-chlorophenyl)methanesulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-1-[3-(trifluoromethyl)phenyl]methanesulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-3-chloro-4-forbindelsesfaneblad;

- N-[[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-butane-1-sulfonamide;

- 3-chloro-N-[[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]benzosulfimide;

- 4-tert-butyl-N-[[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-the l]methyl]benzosulfimide;

- N-[[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-3-methoxybenzenesulfonamide;

- N-[[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-3-cyanobenzenesulfonyl;

- N-[[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-4-(trifluoromethyl)benzosulfimide;

- N-[[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-2-(triptoreline)benzosulfimide;

- N-[[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-2-(methylsulphonyl)benzosulfimide;

- 3-chloro-N-[[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-4-forbindelsesfaneblad;

- 4-bromo-N-[[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-2-ethylbenzaldehyde;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]econsultant;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]propane-2-sulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]butane-1-sulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]cyclohexanesulfonic;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-1-cyclohexylacetophenone;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-3-chlorobenzenesulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-2-chlorobenzenesulfonamide;

- N-[[5-(4-shall Romper)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-3-methylbenzenesulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-4-tert-butylbenzenesulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-4-methoxybenzenesulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-3-methoxybenzenesulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-4-(trifluoromethyl)benzosulfimide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-3-(trifluoromethyl)benzosulfimide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-2-(trifluoromethyl)benzosulfimide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-3-(triptoreline)benzosulfimide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-2-(triptoreline)benzosulfimide;

- 3-acetyl-N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]benzosulfimide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]biphenyl-3-sulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-1-[4-(trifluoromethyl)phenyl]methanesulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-1-[3-(trifluoromethyl)phenyl]methanesulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl] - for 3,5-dimethylbenzenesulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-these is-1H-pyrazole-3-yl]methyl] - for 3,5-bis(trifluoromethyl)benzosulfimide;

- 3-chloro-N-[[1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]benzosulfimide;

- N-[[1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-2-forbindelsesfaneblad;

- N-[[1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-3-cyanobenzenesulfonyl;

- N-[[1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-3-methoxybenzenesulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-3-methoxybenzenesulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-3-cyanobenzenesulfonyl;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-1-(2-forfinal)methanesulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-1-(4-forfinal)methanesulfonamide;

- 5-bromo-N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]thiophene-2-sulfonamide;

- N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-5-isoxazol-3-althofen-2-sulfonamide;

- 3-chloro-N-[[1-(2,4-dichlorophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-yl]methyl]benzosulfimide;

N-[[1-(2,4-dichlorophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-3-methylbenzenesulfonamide;

in the form of a base or an acid additive salt, and also, hydrate, or MES.

Next, the protective group Pg is a group that allows, on the one hand, to protect reactio nesposobny functional group, such as hydroxy or amino group, during a synthesis and, on the other hand, to regenerate the reactive functional group at the end of the synthesis unchanged.

Examples of protective groups and methods of protection and removal of protection are given in "Protective Group in Organic Synthesis", Green et al., 2ndEdition (John Wiley & Sons, Inc., New York), 1991.

Under the leaving group in the following presentation is a group which can be easily derived from the molecule by heterolytic rupture due to the departure of a pair of electrons. This group can also be easily replaced by another group, for example, in substitution reactions. Such leaving groups are, for example, Halogens or an activated hydroxy-group such as methanesulfonate, bansilalpet, p-toluensulfonate, triflate, acetate, etc. are Examples of leaving groups and references for them are given in "Advances in Organic Chemistry", J. March, 3rdEdition, Wiley Interscience, 1985, p. 310-316.

According to the invention the compounds of formula (I) can be obtained according to the method, which is characterized by the fact that in the presence of a base and in a solvent a compound of the formula

in which R2, R3, R4, R5, R6, R7, R8and R9defined for the compounds of formula (I), is introduced into reaction with sulphonylchloride formula

in which R1defined for the compounds of formula (I), and Hal means a halogen atom.

If necessary, the compound of formula (I) is transferred into one of its acid additive salts.

The reaction is carried out in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane or tetrahydrofuran and at a temperature of from room temperature and the boiling point of the solvent. The reaction is carried out preferably with the use of the compounds of formula (III)in which Hal signifies chlorine atom.

According to another variant of the method the compound of formula (I)in which R2means (C1-C3)alkyl, can be obtained by reaction of compounds of formula (I), in which

R2=H, halide (C1-C3)alkyl, in the presence of a base such as sodium hydride or potassium carbonate, in a solvent such as N,N-dimethylformamide, and at a temperature of from room temperature and the boiling point of the solvent.

Thus obtained compounds of formula (I) can be further separated from the reaction medium and purified according to the classical methods, for example by crystallization or chromatography.

The compounds of formula (II) obtained by the reaction of compounds of formula

in which R3, R4, R5, R6, R7, R8and R9such, the AK is defined for the compounds of formula (I), and Y represents a leaving group, such as defined above, preferably a halogen atom or an activated hydroxy-group, such as methanesulfonate, benzolsulfonate, p-toluensulfonate or triflate group, with the compound of the formula

in which R2the same as defined for the compounds of formula (I).

The reaction is carried out in a solvent such as N,N-dimethylformamide, acetonitrile, dichloromethane, toluene or propan-2-ol, and in the presence or in the absence of base. When using the base, it is chosen from organic bases such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine. The reaction is carried out at a temperature of from 0°C to the boiling point of the solvent.

According to one variant, the compound of formula (II)in which R2=H, can also be obtained by reaction of compounds of formula (IV)in which Y=Cl, 1,3,5,7-tetraazatricyclo[3.3.13,7]Dean (or hexamethylenetetramine), followed by hydrolysis in a strong acid, such as hydrochloric acid.

The compounds of formula (III) are commercially available or described in the literature, or can be obtained by the methods described in the literature, such as in J. Org. Chem. USSR, 1970, 6, 2454-2458; J. Am. Chem. Soc., 1952, 74, 2008; J. Med.Chem., 1977, 20(10), 1235-1239; EP 0469984; WO 95/18105.

For example, the compounds of formula (III) can be obtained halogenide what W the corresponding sulfonic acids or their salts, for example their sodium or potassium salts. The reaction is carried out in the presence of a halogenation agent, such as oxochloride phosphorus, thionyl chloride, trichloride phosphorus, tribromide phosphorus or pentachloride phosphorus, without solvent or in a solvent such as a halogenated hydrocarbon or N,N-dimethylformamide, and at a temperature of from -10°C to 200°C.

The compounds of formula (IV) are obtained from compounds of the formula

in which R3, R4, R5, R6, R7, R8and R9such as defined for the compounds of formula (I)according to the classical methods mentioned previously.

For example, when the compound of the formula (IV), Y represents a halogen atom, the compound of formula (VI) is treated with a halogenation agent, such as PCl5,

PBr3, HBr or BBr3in a solvent such as dichloromethane, and at a temperature of from 0°C to room temperature.

When in the compound of formula (IV), Y represents methanesulfonate, bansilalpet, p-toluensulfonate or triftorbyenzola, the compound of formula (VI) enter into reaction with sulphonylchloride formula X-SO2-Cl, in which X is methyl, phenyl, p-tolyl or trifluoromethyl. The reaction is carried out in the presence of a base, such as triethylamine, pyridine or N,N-diisopropylethylamine, in a solvent such as dichlo the methane or toluene, and when the temperature of -20°C and the boiling point of the solvent.

The compounds of formula (V) is known.

The compounds of formula (VI) are obtained by reduction reaction of compounds of the formula

in which R3, R4, R5, R6, R7, R8and R9are as defined for compounds of formula (I), and Z signifies hydroxy or (C1-C2)alkoxy.

The reaction is carried out in the presence of a reducing agent such as sodium borohydride or aluminum hydride and lithium, in a solvent such as tetrahydrofuran, and at a temperature of from -20°C to room temperature. When restore the connection of the formula (VII)in which Z=OH, the acid may be activated before this reaction with etelcharge.com in the presence of triethylamine.

The compounds of formula (VII) are known and are obtained by known methods such as described in documents EP 0656354, EP 0576357 or in WO 00/46209.

In the following examples describe some of the compounds according to the invention. These examples are not limiting and only illustrate the present invention. Numbers are shown in the examples of the compounds correspond to the numbers shown below in table V, which shows the chemical structure and physical properties of some compounds according to the invention.

In blue is Utah and in the examples the following abbreviations are used:

ether: diethyl ether

saafir: diisopropyl ether

DMSO: dimethyl sulfoxide

DMF: N,N-dimethylformamide

THF: tetrahydrofuran

DHM: dichloromethane

AcOEt: ethyl acetate

DIPEA: diisopropylethylamine

TFA: triperoxonane acid

2n. hydrochloric ether: 2n. a solution of hydrochloric acid in diethyl ether

F: melting point

TA: room temperature

Eb: boiling point

HPLC: high performance liquid chromatography

Silica gel H: silica gel 60 H, sold by Merck (Darmstadt)

Buffer solution pH 2: a solution of 16.66 g KHS4and 32,32 g K2SO4in 1 liter of water.

The spectra of nuclear magnetic resonance recorded at 200 MHz in DMSO-d6. In the interpretation of the spectra, the following abbreviations are used: s: singlet, d: doublet, t: triplet, wt: mass, m: multiplet, Sirs: broad singlet.

Compounds according to the invention analyzed in the aggregate LC/UV/MS (liquid chromatography/UV detection/mass spectrometry). Measure the molecular peak (MH+) and retention time (tr) in minutes.

Used appliance, supplied by Agilent, consists of a chromatograph HP 1100, equipped with a detector diode matrix company and Agilent quadrupole mass spectrometer MSD Quad.

Method A:

Use column Waters Xterra® MS C18 production Waters, 2.1 x 30 mm, 3.5 µm, when to the room temperature, flow rate 1 ml/min

Eluent is the following connection:

solvent A: 0.025% of triperoxonane acid (TFA) in water;

solvent B: 0.025% of TFA in acetonitrile.

Gradient: the Percentage of solvent B varies from 0 to 100% for 2 minutes with a horizontal section at 100% B for 1 minute.

UV detection is carried out in the range from 210 nm to 400 nm, and the weight measurement - mode chemical ionization at atmospheric pressure.

Method B:

Use column Symmetry C18 2,1x50 mm, 3.5 µm, at 30°C, the rate of 0.4 ml/min.

Eluent is the following connection:

solvent A: 0,005% triperoxonane acid (TFA) in water at pH 3.15;

solvent B: from 0.005% TFA in acetonitrile.

Gradient:

Time (minutes)%A%B
01000
101090
151090
161000
201000

UV-dete the aims is carried out at λ=210 nm and the mass determination is performed in the positive mode electrospray-ionization (ESI).

Method C:

Use C18 column 2,1x50 mm, 3.5 µm, at 30°C, the rate of 0.4 ml/min.

Eluent is the following connection:

solvent A: 0,005% TFA in water at pH 3.15;

solvent B: from 0.005% TFA in acetonitrile.

Gradient:

Time (minutes)%A%B
01000
201090
301090
351000
401000

UV detection is performed at λ=210 nm, and the mass determination is performed in the positive mode electrospray-ionization (ESI).

Method D:

Use column Xterra MS C18, 2,1x50 mm, 3.5 µm, at 30°C, the rate of 0.4 ml/min.

Eluent is the following connection:

solvent A: ammonium acetate (AcONH4) 10 nm in water at pH 7;

solvent B: acetonitrile.

Gradient:

Time (minutes) %A%B
01000
101090
151090
161000
201000

UV detection is performed at λ=220 nm, and the definition of the mass in the positive mode electrospray-ionization (ESI).

Method E:

Use column Xterra MS C18, 2,1x50 mm, 3.5 µm, at 30°C, the rate of 0.4 ml/min.

Eluent is the following connection:

solvent A: AcONH410 nm in water at pH 7;

solvent B: acetonitrile.

Gradient:

Time (minutes)%A%B
01000
201090
301090
35 1000
401000

SYNTHESIS

1. Obtaining compounds of formula (VII).

Synthesis 1.1

5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid.

(VII): R3=-CH3; R4=H; R5=4-Br; R6=H; R7=H; R8=4-CL; R9=2-Cl; Z=-OH.

A) A Lithium salt of ethyl-[4-(4-bromophenyl)-3-methyl-2-oxo-4-oxidant-3-enoate].

A solution of 43 g of the lithium salt hexamethyldisilazane in 300 ml of ether cooled to -60°C, is added dropwise a solution of 50 g of 4-bromopropiophenone in 500 ml of ether and allowed to mix until the temperature does not rise to -30°C. Then add 38 g of diethyloxalate and left to mix for 18 hours, raising the temperature to TA. Formed precipitate is drained, washed it with ether and dried in vacuum. Obtained 62 g of the expected product.

B) ethyl-[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate].

To a solution of 30 g of the compound obtained in the preceding step in 150 ml of acetic acid, add 20 g of the hydrochloride of 2,4-dichloropyridazine and refluxed for 3 hours. After cooling to TA, the reaction mixture was poured into a mixture of ice water, extracted with ether, the organic phase is washed with saturated NaCl solution, dried over MgSO4the solvent is actiono is evaporated in vacuum and the resulting crystallized product press. Received of 33.4 g of the expected product.

C) 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid.

To a solution of 26 g of the compound obtained in the preceding stage in 50 ml of EtOH added 6.5 g of KOH, followed by 20 ml of water and refluxed for 2 hours. After cooling to TA, the reaction mixture was poured into a mixture of ice water containing 10 ml of concentrated HCl are formed precipitate is drained, washed in water and dried in vacuum. Received 24 g of the expected product.

Synthesis 1.2

methyl-[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate].

(VII): R3=-CH3; R4=H; R5=4-Cl; R6=H; R7=H; R8=4-Cl; R9=2-Cl; Z=-OCH3.

A) 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid.

This connection receive in accordance with the method of synthesis described in EP 0656354B.

B) methyl-[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate].

To a solution of 30 g of the compound obtained in the previous step, in 500 ml of MeOH added 3 g of para-toluensulfonate acid and refluxed for 2 hours. The reaction mixture was concentrated by half, the formed precipitate is drained, washed his MeOH and dried. Received 30 g of the expected product.

Synthesis 1.3

5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-carboxylic acid.

(VII): R 3=-CH2CH3; R4=H; R5=4-Br; R6=H; R7=H; R8=4-Cl; R9=2-Cl; Z=-OH.

This connection receive in accordance with the procedure of synthesis described in WO 00/46209.

Following the procedure of synthesis described above in the synthesis of 1, obtain the compounds of formula (VII)below in table I.

Cl
ReceivingR3R5R8R9Z
1.1-CH3BrClCl-OH
1.2-CH3ClClCl-OCH3
1.3-CH2CH3BrClCl-OH
1.4-CH3ClH-OCH2CH3
1.5-CH3FHCl-OCH2CH3
1.6-CH3-OCH3HCl-OCH2CH3
1.7-CH3-OCH3HF-OCH2CH3
1.8-CH3-OCH3ClCl-OCH2CH3
1.9-CH3-OCH3FF-OCH2CH3

2. Obtaining compounds of formula (VI).

Synthesis 2.1

[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methanol.

(VI):R3=-CH3; R4=H; R5=4-Br; R6=H; R7=H; R8=4-Cl; R92 is Cl.

A mixture of 24 g of compound obtained in synthesis 1.1 200 ml of THF is cooled to -10°C, add to 7.8 ml of triethylamine, and then added dropwise 5,38 ml ethylchloride and left to mix for 15 minutes at -10°C. Then, when the temperature is below -10°C type at a time of 6.3 g of sodium borohydride, and then added dropwise to 100 ml of MeOH and allowed to mix for 30 minutes at 0°C. the Reaction mixture was hydrolized by adding 100 ml of 10%HCl, concentrated in vacuo, the residue is introduced into water, extracted with AcOEt, the organic the phase is washed with saturated NaCl solution, dried over MgSO4and the solvent is evaporated in vacuum. The residue is subjected to chromatography on silica gel, elwira with a mixture of cyclohexane/AcOEt (75/25;./vol.). Obtained 22 g of the expected product.

Synthesis 2.2

[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methanol.

(VI): R3=-CH3; R4=H; R5=4-Cl; R6=H; R7=H; R8=4-Cl; R9=2-Cl.

Cooled to -5°C. a solution of 30 g of the compound obtained in synthesis 1.2, in 500 ml of THF, small portions added, keeping the temperature in the range from -5°C to 0°C, 4.6 g of aluminum hydride and lithium and left to mix for 1 hour at TA. The reaction mixture was cooled to 0°C, hydrolyzing by adding 20 ml of 1N NaOH, the inorganic phase is filtered off, washed with THF and the filtrate concentrated in vacuo. The residue is extracted with ether, the PR is onicescu phase is washed with saturated NaCl solution, dried over Na2SO4and the solvent was partially evaporated under vacuum. The formed precipitate is drained, washed it with ether and dried. Received 25 g of the expected product.

Synthesis 2.3

[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methanol.

(VI): R3=-CH2CH3; R4=H; R5=4-Br; R6=H; R7=H; R8=4-Cl; R9=2-Cl.

Cooled to -10°C a mixture of 24.6 g of compound obtained in synthesis 1.3, in 200 ml of THF, add to 7.8 ml of triethylamine, and then added dropwise 5,38 ml chloroformate ethyl and left to mix for 15 minutes at -10°C. Then, when the temperature is below -10°C type at a time of 6.3 g of sodium borohydride, and then added dropwise to 100 ml of MeOH. The reaction mixture was hydrolized at 0°C by adding 100 ml of 10%HCl, then concentrated in vacuo. The residue is extracted with AcOEt, the organic phase is twice washed with 50 ml saturated NaCl solution, dried over Na2SO4and the solvent is evaporated in vacuum. The residue is subjected to chromatography on silica gel, elwira with a mixture of cyclohexane/AcOEt (60/40;./vol.). Received 20 g of the expected product.

Following the procedure of synthesis described above in the synthesis of 2, obtain the compounds of formula (VI)shown below in table II.

td align="center"> 2.8
Table II
SynthesisR3R5R8R9
2.1-CH3BrClCl
2.2-CH3ClClCl
2.3-CH2CH3BrClCl
2.4-CH3ClHCl
2.5-CH3FHCl
2.6-CH3-OCH3HCl
2.7-CH3-OCH3HF
-CH3-OCH3ClCl
2.9-CH3-OCH3FF

3. Obtaining compounds of formula (IV)

Synthesis 3.1

5-(4-bromophenyl)-3-(chloromethyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole.

(IV): R3=-CH3; R4=H; R5=4-Br; R6=H; R7=H; R8=4-Cl; R9=2-Cl; Y=Cl.

A solution of 20 g of compound obtained in synthesis 2.1, 250 ml DHM cooled to 0°C under nitrogen atmosphere, in small portions at a temperature below 5°C added 10.6 g of pentachloride phosphorus and left to mix for 2 hours, raising the temperature to TA. The reaction mixture is poured into 150 ml of a mixture of ice water and left to mix for 10 minutes. Extracted DHM, the organic phase is washed with 5%solution of NaHCO3saturated NaCl solution, dried over MgSO4and the solvent is evaporated in vacuum. Received 24 g of the expected product.

Synthesis 3.2

3-(chloromethyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole.

(IV): R3=-CH3; R4=H; R5=4-Cl; R6=H; R7=H; R8=4-Cl; R9=2-Cl; Y=Cl.

A solution of 25 g of the compound obtained in synthesis 2.2, 250 ml DHM cooled to 0°C in the atmosphere is the monk, small portions at a temperature of from 0°C to 5°C, add 14.8 g of pentachloride phosphorus and left to mix for 3 hours, raising the temperature to TA. The reaction mixture is poured into 200 ml of water and allowed to mix for 10 minutes. After settling the organic phase is washed with a saturated solution of NaHCO3saturated NaCl solution, dried over Na2SO4and the solvent is evaporated in vacuum. Received 25 g of the expected product in the form of foam.

Synthesis 3.3

5-(4-bromophenyl)-3-(chloromethyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole.

(IV): R3=-CH2CH3; R4=H; R5=4-Br; R6=H; R7=H; R8=4-Cl; R9=2-Cl; Y=Cl.

This connection receive in accordance with the procedure of synthesis described in the synthesis of 3.2 based on 9 g of the compound obtained in synthesis 2.3, 200 ml DHM and 4.6 g of pentachloride phosphorus. Obtained 9.4 g of the expected product.

Following modes of synthesis described above in the synthesis of 3, get the compounds of formula (IV)below in table III.

Table III
SynthesisR3RSR8R9Y
3.1-CH3BrClClCl
3.2-CH3ClClClCl
3.3-CH2CH3BrClClCl
3.4-CH3ClHClCl
3.5-CH3FHClCl
3.6-CH3-OCH3HClCl
3.7-CH3-OCH3HFCl
-CH3-OCH3ClClCl
3.9-CH3-OCH3FFCl

4. Obtaining compounds of formula (II)

Synthesis 4.1

Hydrochloride [[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]amine.

(II)HCl: R2=H; R3=-CH3; R4=H; R5=4-Br; R6=H; R7=H; R8=4-Cl; R9=2-Cl.

To a solution of 20 g of compound obtained in synthesis 3.1, 200 ml of chloroform, add 7 g of hexamethylenetetramine and left to mix for 5 days at TA. Then add 50 ml of ether, wring out the precipitate and dried it. The precipitate is introduced into 50 ml of EtOH, add 15 ml of concentrated HCl and heated to 50°C for 5 hours. Filtered white insoluble fraction and the filtrate concentrated in vacuo. The remainder is injected into the ether, the organic phase is washed with 50 ml of 5N NaOH, dried over Na2SO4and the solvent is evaporated in vacuum. The residue is introduced into 2N solution of hydrochloric acid ester formed precipitate is drained, washed it with ether and dried. Received 14,37 g of the expected product.

Synthesis 4.2

Hydrochloride[[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]amine.

(II)HCl: R2=H; R3=-CH3; R4=H; R5=4-Cl; R6=H; R7=H; R8=4-Cl; R9=2-Cl.

This connection receive in accordance with the procedure of synthesis described in the synthesis of 4.1 based on 25 g of the compound obtained in synthesis 3.2, in 150 ml of chloroform, 9 g of hexamethylenetetramine, 100 ml of ether, 250 ml of EtOH and 30 ml of concentrated HCl. Received 24 g of the expected product.

Synthesis 4.3

Hydrochloride [[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]amine.

(II)HCl: R2=H; R3=-CH2CH3; R4=H; R5=4-Br; R6=H; R7=H; R8=4-Cl; R9=2-Cl.

To a solution of 9 g of the compound obtained in synthesis 3.3, in 100 ml of chloroform added 2.9 g of hexamethylenetetramine and left to mix for 10 days at TA. Then add 50 ml of ether, and allowed to mix for 10 minutes, the reaction mixture is twice as concentrated in vacuo, add 50 ml of ether and the formed precipitate press. The precipitate is introduced into 50 ml of EtOH, add 15 ml of concentrated HCl and refluxed for 2 hours. Filtered off the insoluble white faction and the filtrate concentrated in vacuo. The residue is extracted with ether, the organic phase is washed with 20 ml of 1N NaOH, saturated NaCl solution, dried over Na2SO4and the solvent is evaporated in vacuum. The residue is introduced into 2N solution of hydrochloric acid ester is formed precipitate press. Obtained 8.5 g of the expected product.

Following modes of synthesis described above in the synthesis of 4, get the compounds of formula (II)shown below in table IV.

Table IV
SynthesisR2R3R5R8R9
4.1H-CH3BrClCl
4.2H-CH3ClClCl
4.3H-CH2CH3BrClCl
4.4H-CH3ClHCl
4.5 H-CH3FHCl
4.6H-CH3-OCH3HCl
4.7H-CH3-OCH3HF
4.8H-CH3-OCH3ClCl
4.9H-CH3-OCH3FF

5. Obtaining compounds of formula (III)

Cyclohexanesulfonyl.

A mixture of 25 g cyclohexanol in 83 ml of acetic acid and 4 ml of water cooled to 0°C, then bubbled for 3 hours gaseous chlorine, until remains nonvanishing yellow staining. The reaction mixture was poured into water, extracted three times with ether, the organic phase together twice Ave is myauth water, dried over Na2SO4and the solvent is evaporated in vacuum. The residue is distilled at a pressure of 4 PA and obtain 13.3 g of the expected product, Eb=154°.

EXAMPLE 1. Connection # 8

N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-4-(trifluoromethyl)benzosulfimide

To a solution of 0.7 g of the compound obtained in synthesis 4.1, in 20 ml of DHM type of 0.42 ml of triethylamine and then dropwise added 0.39 g of 4-(trifluoromethyl)benzosulfimide and leave overnight to mix with TA. Add 10 ml of water and allowed to mix for 10 minutes. After settling the organic phase is twice washed with a saturated solution of NaHCO3twice buffer solution with pH 2, two times with saturated solution of NaCl, dried over Na2SO4and the solvent is evaporated in vacuum. The resulting product is crystallized in a mixture of cyclohexane/AcOEt (95/5;./vol.). Obtained 0.75 g of the expected product, F=195°C.

1H-NMR:DMSO-d6:δ(ppm):1,95:s:3H; 4,15:s:2H; 7,0:d:2H; 7,2-8,1:m:9H; 8,5:s:1H.

EXAMPLE 2: Compound N 28

N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-Ls-pyrazole-3-yl] methyl]-3-chlorobenzenesulfonamide.

To a solution of 0.7 g of the compound obtained in synthesis 4.3, in 30 ml DHM add 0.4 ml of triethylamine and then dropwise added 0.32 g of 3-chlorobenzenesulfonamide and leave paramashiva the change over night at TA. The reaction mixture was concentrated in vacuo, the residue is extracted with AcOEt, the organic phase is washed twice with saturated solution of NaHCO3double-buffer solution with pH 2, two times with saturated solution of NaCl, dried over Na2SO4and the solvent is evaporated in vacuum. The residue is subjected to chromatography on silica gel, elwira with a mixture of cyclohexane/AcOEt (90/10;./about.) to (75/25;./vol.). The resulting product is injected in 1.5 ml AcOEt add cyclohexane formed precipitate wring out and dry it. Obtained 0.31 g of the expected product, F=169°C.

1H-NMR:DMSO-d6:δ(ppm):1,0:t:3H; 2,4:q:2H; 4,15:s:2H; 7,0:d:2H; 7,2-7,9:m:9H; 8,4:s:1H.

EXAMPLE 3: Compound N 42

N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-1-[3-(trifluoromethyl)phenyl]methanesulfonamide.

To a solution of 0.5 g of the compound obtained in synthesis 4.3, in 25 ml DHM add 0.3 ml of triethylamine, then 0.28 g of [3-(trifluoromethyl)phenyl]methanesulfonamide and left to mix overnight at TA. The reaction mixture was concentrated in vacuo, the residue is introduced into water, extracted with AcOEt, the organic phase is washed with a saturated solution NaHC3, the buffer solution with pH 2, saturated NaCl solution, dried over Na2SO4and the solvent is evaporated in vacuum. The residue is subjected to chromatography on silica gel, elwira with a mixture of cyclohexane/AcOEt (90/10; V/V.) to (85/15; about./vol.). Obtained 0.3 g of the expected compound, F=108°C.

1H-NMR:DMSO-d6:δ(ppm):1,03:t:3H; 2,5:m:2H; 4,23:d:2H; 4,5:s:2H; 7,13:d:2H; 7,4-7,75:m:9H; 7,80:t:1H.

EXAMPLE 4: Compound No. 73

N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-3-chloro-N-methylbenzenesulfonamide.

To a mixture of 0.41 g of compound No. 28 and 0.1 g of K2CO3in 34 ml of DMF) add 0.05 ml under the conditions, then refluxed for 2 hours and allowed to mix overnight at TA. The reaction mixture was concentrated in vacuo, the residue is introduced into water, extracted with DHM, the organic phase is washed with a buffer solution with pH 2, saturated solution of NaHCO3saturated NaCl solution, dried over Na2SO4and the solvent is evaporated in vacuum. The residue is subjected to chromatography on silica gel, elwira with a mixture of cyclohexane/AcOEt (90/10;./about.) to (80/20;./vol.). After drying in vacuum obtained to 0.263 g of the expected compound, F=78°C.

The following table shows the chemical structure and physical properties of some examples of compounds according to the invention. In this table:

- in the column "salt" "-" connection means in the form of a free base, whereas "HCl" denotes a compound in the form of the hydrochloride;

- in the column of the word "method" means one of the methods of analysis used to determine the molecular peak MH+

Table 1
Compound No.R1R2R3R5R8R9Salt;
F°C;
MH+; tr
(method)
1
(a)
-CH2CH2CH2CH3H-CH3BrClCl-
-
530,36; 2,33
(method A)
2
(a)
H-CH3BrClCl-
98;
-
3
(a)
H-CH3 BrClCl-
145;
-
4H-CH3BrClCl-
-
584,32; 2,41
(method A)
5
(a)
H-CH3BrClCl-
-
606,05; 2,31
(method A)
6
(a)
H-CH3BrClCl-
-
579,97; 2,21
(method A)
7
(a)
H-CH3BrClCl-
95;
-
8 H-CH3BrClCl-
195;
-
9
(a)
H-CH3BrClCl-
-
672,93; 2,21
(method A)

10
(a)
H-CH3BrClCl-
95;
-
11
(a)
H-CH3BrClCl-
96;
-
12
(a)
H-CH3Br ClCl-
-
602,29; 2,43
(method A)
13
(b)
-CH2CH2CH2CH3H-CH3ClClCl-
-
486,42; 2,30
(method A)
14
(b)
H-CH3ClClCl-
-
540,36; 2,39
(method A)
15
(b)
H-CH3ClClCl-
115;
-
16
(b)
H-CH3ClClCl-
-
536,06; 2,20
(method A)
(b)H-CH3ClClCl-
-
531,02; 2,16
(method A)
18
(b)
H-CH3ClClCl-
189;
-
19
(b)
H-CH3ClClCl-
-
590,01; 2,25 (method A)
20
(b)
H-CH3ClClClCl
21
(b)
H-CH3ClCl-
-
558,4; 2,41
(method A)
22
(b)
H-CH3ClClCl-
-
611,96; 2,33 (method A)
23
(c)
-CH2CH3H-CH2CH3BrClCl-
125;
-
24
(c)
H-CH2CH3BrClCl-
157;
-
25
(c)
-CH2CH2CH2CH3H-CH2CH3BrClCl-
65;
-
26
(c)
H-CH2CH3BrClCl-
98;
-
27
(c)
H-CH2CH3BrClCl-
72;
-

28
(c)
H-CH2CH3BrClCl-
169;
-
29
(c)
H-CH2CH3BrClCl-
135;
-
30
(c)
H -CH2CH3BrClCl-
165;
-
31
(c)
H-CH2CH3BrClCl-
82;
-
32
(c)
H-CH2CH3BrClCl-
121;
-
33
(c)
H-CH2CH3BrClCl-
131;
-
34
(c)
H-CH2CH3BrClCl-
65;
-
35
(c)
H-CH2CH3BrClCl-
95;
-
36
(c)
H-CH2CH3BrClCl-
168;
-
37
(c)
H-CH2CH3BrClCl-
75;
-

38
(c)
H-CH2CH3BrClCl-
145;
-
39
(c)
H -CH2CH3BrClCl-
88;
-
40
(c)
H-CH2CH3BrClCl-
183;
-
41
(c)
H-CH2CH3BrClCl-
87;
-
42
(c)
H-CH2CH3BrClCl-
108;
-
43
(c)
H-CH2CH3BrClCl-
153;
-
44
(c)
H-CH2CH3BrClCl-
105;
-
45
(d)
H-CH3ClHCl-
-
506; 10,9
(method B)
46
(d)
H-CH3ClHCl-
-
490; 10,4
(method B)
47
(d)
H-CH3ClHCl-
-
497; 10,2
(method B)

48
(d)
H/td> -CH3ClHCl-
172;
497; 10,19
(method B)
49
(d)
H-CH3ClHCl-
151;
502; 10,5
(method B)
50
(d)
H-CH3ClHCl-
110;
550; 9,77
(method B)
51
(d)
H-CH3ClHCl-
-
554; 11,1
(method B)
52
(e)
H-CH3FHCl53
(e)
H-CH3FHCl-
147;
474; 9,9
(method B)
54
(e)
H-CH3FHCl-
80;
481; 9,7
(method B)
55
(e)
H-CH3FHCl-
66;
538; 10,6 (method B)
56
(f)
H-CH3-OCH3HCl-
73;
502; 10,1
(method B)
57
(f)
H-CH3-OCH3HCl-
66;
482; 10 (method B)
58
(f)
H-CH3-OCH3HCl-
65;
498; 9,7 (method B)
59
(f)
H-CH3-OCH3HCl-
89;
510; 9,3 (method B)
60
(f)
H-CH3-OCH3HCl-
64;
500; 9,8 (method B)
61
(f)
H-CH3-OCH3H Cl-
61;
550; 10,3 (method B)
62
(f)
H-CH3-OCH3HCl-
140;
544; 10,6
(method D)
63
(g)
H-CH3-OCH3HF-
-
486; 9,9 (method B)

64
(g)
H-CH3-OCH3HF-
225;
470; 9,4 (method B)
65
(g)
H-CH3-OCH3HF-
114;
477; 9,3
(method B)
66
(g)
H-CH3-OCH3HF-
60;
534; 10,3 (method B)
67
(a)
H-CH3BrClCl-
108;
573; 11
(method B)
68
(c)
H-CH2CH3BrClCl-
69;
596; 11,6 (method B)
69
(c)
H-CH2CH3BrClCl-
76;
596; 11,3
(method B)
70
(c)
H-CH2CH3BrClCl-
143;
648; 18,9 (method E)
71
(c)
H-CH2CH3BrClCl-
143;
648; 18,9
(method B)
72-CH3-CH2CH3BrClCl-
78;
612; 12,8
(method B)
73
(h)
H-CH3-OCH3ClCl-
173;
536; 10,8
(method B)
74
(h)
H-CH3-OCH3 ClCl-
155;
516; 10,6 (method B)
75
(h)
H-CH3-OCH3ClCl-
118;
544; 10 (method B)
76
(h)
H-CH3-OCH3ClCl-
78;
584; 11 (method B)
77
(h)
H-CH3-OCH3ClCl-
80;
578; 11,5
(method B)
78
(i)
H-CH3-OCH3FF-
-
504; 10,1
(method B)
79
(i)
H-CH3-OCH3FF-
-
488; 9,6 (method B)
80
(i)
H-CH3-OCH3FF-
69;
552; 10,41 (method B)
(a) the Compound obtained in accordance with the procedure of synthesis described in example 1 from the compound obtained in synthesis 4.1, and the corresponding compounds of formula (III).
(b) the Compound obtained in accordance with the procedure of synthesis described in example 1 from the compound obtained in synthesis 4.2, and the corresponding compounds of formula (III).
(c) the Compound obtained in accordance with the procedure of synthesis described in example 1 from the compound obtained in synthesis 4.3, and the corresponding compounds of formula (III).
(d) the Compound obtained in accordance with the procedure of synthesis described in example 1 from the compound obtained in the synthesis is 4.4, and the corresponding compounds of formula (III)
(e) the Compound obtained in accordance with the procedure of synthesis described in example 1 from the compound obtained in the synthesis of 4.5, and the corresponding compounds of formula (III).
(f) the Compound obtained in accordance with the procedure of synthesis described in example 1 from the compound obtained in the synthesis of 4.6, and the corresponding compounds of formula (III).
(g) the Compound obtained in accordance with the procedure of synthesis described in example 1 from the compound obtained in the synthesis of 4.7, and the corresponding compounds of formula (III).
(h) the Compound obtained in accordance with the procedure of synthesis described in example 1 from the compound obtained in the synthesis of 4.8, and the corresponding compounds of formula (III).
(i) the Compound obtained in accordance with the procedure of synthesis described in example 1 from the compound obtained in the synthesis of 4.9, and the corresponding compounds of formula (III).

The compounds of formula (I) have very good affinityin vitro(IC50≤5·10-7M) to the receptors cannabinoids CB1in the experimental conditions described by M. Rinaldi-Carmona et al. (FEBS Letters, 1994, 350, 240-244).

The antagonistic nature of the compounds of formula (I) was proved by the results obtained with the models Engibarov is of adenylate cyclase, as described in M. Bouaboula et al., J. Biol. Chem., 1995, 270, 13973-13980, M. Rinaldi-Carmona et al., J. Pharmacol. Exp. Ther., 1996, 278, 871-878 and M. Bouaboula et al., J. Biol. Chem., 1997, 272, 22330-22339.

The toxicity of the compounds of formula (I) is compatible with their use as medicaments.

Thus, according to one of the other aspects, the object of the invention is medicaments which contain the compound of formula (I) or additive salt of the latter with a pharmaceutically acceptable acid, as well as MES or hydrate of the compound of formula (I).

Thus, the compounds according to the invention can be used to treat or prevent diseases in humans or animals are involved receptors cannabinoids CB1.

For example and without limitation, the compounds of formula (I) suitable as psychotropic medicaments, in particular for the treatment of psychiatric disorders, including anxiety, depression, mood disorders, insomnia, delusional States, obsessive-compulsive disorder, shared psychotic disorders, schizophrenia, disorders of attention and hyperactivity (TDAH) in hyperkinetic children (MBD), as well as to treat disorders associated with the use of psychotropic substances, in particular, in the case of substance abuse and/or dependence on substances, including alcohol dependence and nicotine dependence.

The compounds of formula (I) according to the but the invention can be used as medicaments for the treatment of migraine, stress, disease, psychosomatic nature, crises, panic attacks, epilepsy, movement disorders, in particular, dyskinesia or Parkinson's disease, jitter and dystonia.

The compounds of formula (I) according to the invention can also be used as medicaments in the treatment of memory disorders, congitive disorders, in particular, for the treatment of senile dementia, Alzheimer's disease, and for treating disorders of attention or vigilante. In addition, the compounds of formula (I) can be used as neuroprotective agents in the treatment of ischemia, cranial injuries and in the treatment of neurodegenerative diseases, including horei, Horai Huntington's, Tourette's syndrome.

The compounds of formula (I) according to the invention can be used as drugs for the treatment of pain: neuropathic pain, acute peripheral pain, chronic pain of inflammatory origin.

The compounds of formula (I) according to the invention can be used as medicaments in the treatment of disorders of appetite, desire (for sugars, carbohydrates, drugs, alcohol, or any geeky appetite substances) and/or eating disorders, particularly in the treatment of obesity or bulimia, as well as in the treatment of type II diabetes or non-insulin-dependent diabetes and for the treatment of dyslipidemia, metabolic what about the syndrome. Also, the compounds of formula (I) according to the invention suitable for the treatment of obesity and the risks associated with obesity, in particular, cardiovascular risks. In addition, the compounds of formula (I) according to the invention can be used as drugs for the treatment of gastrointestinal disorders, diarrhea, ulcers, vomiting, disorders of the bladder and urethra, disorders of endocrine origin, cardiovascular disorders, hypotension, hemorrhagic shock, septic shock, chronic liver cirrhosis, hepatic steatosis, steatohepatitis, asthma, Raynaud's syndrome, glaucoma, disorders, reproductive dysfunction, inflammation, diseases of the immune system, in particular autoimmune and neuropeptidergic diseases, such as rheumatoid arthritis, reactive arthritis, diseases, leading to demyelination, multiple sclerosis, infectious and viral diseases such as encephalitis, cerebral vascular damage, and also as medicaments for anticancer chemotherapy, for the treatment of Guillain-Barre syndrome and for the treatment of osteoporosis.

According to the present invention the compounds of formula (I) are particularly suitable for the treatment of psychotic disorders, particularly schizophrenia, disorders of attention and hyperactivity (TDAH) in giperkineticeski the children (MBD); for the treatment of disorders of appetite and obesity; for the treatment of insufficient memory and congitive disorders; for treating alcohol dependence, nicotine dependence, i.e. abstinence from alcohol and tobacco during treatment.

According to one aspect the present invention relates to the use of one of the compounds of formula (I), its pharmaceutically acceptable salt and solvate or hydrate for the treatment of the above disorders and diseases.

According to another aspect of the present invention relates to pharmaceutical compositions containing as active ingredient the compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, MES or hydrate the specified connection, and at least one pharmaceutically acceptable excipient.

These excipients are chosen according to the pharmaceutical form and the desired method from the usual excipients which are specialist known.

In the pharmaceutical compositions according to the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal PR the EMA active substance of the above formula (I) or its salt, MES or hydrate can be in the form of a single form of introducing mixed with classical pharmaceutical excipients, to animals and human beings for the prophylaxis or treatment of the above disorders or diseases.

The appropriate common forms of introduction include forms for oral administration such as tablets, gelatin capsules, soft or hard, powders, granules and oral solutions or suspensions, forms for reception under language, through the mouth, intratracheal, intraocular, intranasal, by inhalation, topical forms of reception, transdermal, subcutaneous, intramuscular or intravenous, rectal forms of administration and implants. For topical administration the compounds according to the invention can be used in creams, gels, lipsticks or lotions.

For example, the common form of the reception of the connection according to the invention in the form of tablets may contain the following components:

The connection according to the invention: 50.0 mg

Mannitol: 223,75 mg

Sodium crosscarmellose: 6.0 mg

Corn starch: 15,0 mg

The hypromellose: 2.25 mg

Magnesium stearate: 3.0 mg

For oral administration the dose of the active substance for daily intake can be from 0.01 to 100 mg/kg, in one or several stages, preferably from 0.02 to 50 mg/kg

May be special cases when suitable higher or the more low dosage; such dosages are not beyond the invention. According to usual practice, the dosage appropriate for each patient is determined by the physician in accordance with the route of administration, the weight and susceptibility of the specified patient.

The present invention, according to another aspect, relates also to a method of treatment of the above pathologies, which includes the patient an effective dose of the compounds according to the invention or one of its pharmaceutically acceptable salt, or hydrate or solvate.

1. Derivatives of N-(1,5-diphenyl-1H-pyrazole-3-yl)sulfonamida corresponding to the formula (I):

in which R1means
(C1-C6)alkyl;
(C3-C7)cycloalkyl, unsubstituted or substituted one or more times (1-C3)alkyl group;
(C3-C7)cycloalkenyl, unsubstituted or substituted one or more times in carbocycle (C1-C3)alkyl;
phenyl, unsubstituted or mono-, di - or tizamidine Deputy, selected independently from halogen atom, (C1-C4)alkyl, (C1-C3)alkoxy, cyano, triptoreline radical, triptoreline radical, a group S(O)nAlk, (C1-C3)alkylcarboxylic group, phenyl;
benzyl, unsubstituted or mono - or disubstituted by a Deputy selected by the independent the IMO from a halogen atom, (C1-C3)alkyl, (C1-C3)alkoxy;
triptoreline radical;
thienyl, unsubstituted or substituted by a halogen atom or isoxazolyl;
R2means a hydrogen atom or (C1-C3)alkyl;
R3means (C1-C5)alkyl;
R4, R5, R6, R7, R8and R9each independently mean a hydrogen atom, halogen atom, (C1-C7)alkyl, (C1-C5)alkoxy or triptorelin radical;
n means 0, 1 or 2;
Alk means (C1-C4)alkyl.
in the state of a base or an acid additive salt.

2. The compound of formula (I) according to claim 1, in which:
R1means
ethyl, isopropyl, n-butyl;
cyclohexyl;
cyclohexylmethyl;
2-chlorophenyl, 3-chlorophenyl, 2-forfinal, 3-chloro-4-forfinal,
4-bromo-2-ethylphenyl, 3-were, 4-tert-butylphenyl,
3, 5dimethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-cyanophenyl,
4-cyanophenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl,
4-(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl,
2-(triptoreline)phenyl, 3-(triptoreline)phenyl,
2-(methylsulphonyl)phenyl, 3-(methylsulphonyl)phenyl, 3-acetylphenyl,
3-biphenyl, 2-biphenyl;
3 Chlorobenzyl, 2-tormentil, 4-tormentil, 3-(trifluoromethyl)benzyl,
4-(trifluoromethyl)benzyl;
5-bromo-2-thienyl; 5-isoxazol-3-yl-2-thienyl;
R2means a hydrogen atom or METI is;
R3means methyl or ethyl;
R4means a hydrogen atom;
R5is in position-4 - phenyl and means atom of bromine, chlorine, fluorine or methoxy;
R6means a hydrogen atom;
R7means a hydrogen atom;
R8is in position-4 - phenyl and means a hydrogen atom, a chlorine atom, a fluorine atom;
R9is in position-2 - phenyl and means chlorine atom or fluorine;
in the state of a base or an acid additive salt.

3. The compound of formula (I) according to claim 1, chosen from:
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]butane-1-sulfonamida;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl] methyl]cyclohexanesulfonic;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]cyclohexylmaleimide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-3-chlorobenzenesulfonamide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-4-tert-butylbenzenesulfonamide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-3-methoxybenzenesulfonamide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-4-methoxybenzenesulfonamide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-4-(trifluoromethyl)benzosulfimide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-2-(meth sulfonyl)benzosulfimide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-1-(3-chlorophenyl)methanesulfonamide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-1-[3-(trifluoromethyl)phenyl]methanesulfonamide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-3-chloro-4-forbindelsesfaneblad;
N-[[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-butane-1-sulfonamida;
3-chloro-N-[[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]benzosulfimide;
4-tert-butyl-N-[[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]benzosulfimide;
N-[[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-3-methoxybenzenesulfonamide;
N-[[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-3-cyanobenzenesulfonyl;
N-[[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-4-(trifluoromethyl)benzosulfimide;
N-[[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-2-(triptoreline)benzosulfimide;
N-[[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-2-(methylsulphonyl)benzosulfimide;
3-chloro-N-[[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-4-forbindelsesfaneblad;
4-bromo-N-[[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-2-ethylbenzaldehyde;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]this is sulfonamida;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]propane-2-sulfonamida;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]butane-1-sulfonamida;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]cyclohexanesulfonic;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-1-cyclohexylmaleimide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-3-chlorobenzenesulfonamide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-2-chlorobenzenesulfonamide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-3-methylbenzenesulfonamide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-4-tert-butylbenzenesulfonamide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-4-methoxybenzenesulfonamide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-3-methoxybenzenesulfonamide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-4-(trifluoromethyl)benzosulfimide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-3-(trifluoromethyl)benzosulfimide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-2-(trifluoromethyl)benzosulfimide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-3-(triptoreline)benzosulfimide;
N-[[5-(4-bromophenyl)-1-(4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-2-(triptoreline)benzosulfimide;
3-acetyl-N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]benzosulfimide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]biphenyl-3-sulfonamida;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-1-[4-(trifluoromethyl)phenyl]methanesulfonamide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-1-[3-(trifluoromethyl)phenyl]methanesulfonamide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl] - for 3,5-dimethylbenzenesulfonamide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl] - for 3,5-bis(trifluoromethyl)benzosulfimide;
3-chloro-N-[[1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]benzosulfimide;
N-[[1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-2-forbindelsesfaneblad;
N-[[1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-3-cyanobenzenesulfonyl;
N-[[1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-3-methoxybenzenesulfonamide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-3-methoxybenzenesulfonamide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-3-cyanobenzenesulfonyl;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-1-(2-forfinal)methanesulfonamide;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-1-(4-forfinal)methanesulfonamide;
5-br the m-N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]thiophene-2-sulfonamida;
N-[[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-yl]methyl]-5-isoxazol-3-althofen-2-sulfonamida;
3-chloro-N-[[1-(2,4-dichlorophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-yl]methyl]benzosulfimide;
N-[[1-(2,4-dichlorophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-yl]methyl]-3-methylbenzenesulfonamide;
in the state of a base or an acid additive salt.

4. The method of obtaining compounds of formula (I) according to claim 1, characterized in that the compound of the formula

in which R2, R3, R4, R5, R6, R7, R8and R9such as defined for the compounds of formula (I) in claim 1, in the presence of base and solvent, lead reacts with sulphonylchloride formula

in which R1the same as defined for the compounds of formula (I) in claim 1, and Hal means a halogen atom.

5. Pharmaceutical composition having an affinity for the receptors CB1cannabinoids, characterized in that it contains a compound of the formula (I) according to any one of claims 1 to 3, or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention refers to the aminopyridin compound of general formula (I) or its salt wherein X1, X2, X3, Z, Y1, Y2 are carbon or nitrogen atom, R, R1, R5, R6 are hydrogen atom, alkyl group, further see formula of the invention, and R7 is hydrogen or halogen atom, nitro or cyano group, -CpH2(p-1)(Ra1)(Ra2)-O-Ra3, -C(=O)-Rd1, 5-or 6-membered saturated heterocycle group, aromatic heterocycle group, -N(Rh1)(Rh2), further see formula of the invention. The invention refers also to the pharmaceutic composition thereof intended for treatment or prevention of allergic diseases, autoimmune diseases caused by malignant tumour, to the Syk inhibitor containing the compound of formula I and to the therapeutic and/or preventive agent.

EFFECT: compounds which not only possess high Syk inhibition activity but are selective Syk inhibitors are obtained and described.

24 cl, 24 ex, 2 tbl

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry, medicine.

SUBSTANCE: invention refers to the triheterocylic compounds of formula (Ia) and their pharmaceutically acceptable salts used as growth inhibitors of the cancer or tumor cells, to the preparation method and pharmaceutical compositions thereof, to the treatment method used aforesaid compounds as well as to the intermediates of formula (II) the to the method of its preparation. In general formulas (Ia) and

, Q1 is -N(R1)-; Q2 is -C(R3)-; Q3 is -C(R5)-; Q4 is -C(R9)-; R1 is -Ym(Ra), where -Ra is -H, -OH, -C(O)R14, -O-C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OS(O)2ONa-; R2 is -H; R3, R4 and R5 independently are -Ym(Rb), where Rb is -H, halogen, -C1-C8 alkyl, -O-(C1-C8 alkyl) or -OR14, -at condition that if value m of radical Ym(Rb) is equal 0, then R5 is not H; R6 is -H; R7 is -Ym-(RC), where -RC is -O-(C1-C8 alkyl) or -NH(phenyl), R8 is -Ym(Rd), where - Rd is -H, -OH, R9, R10, R11, R12 and R13 independently are -Ym(Re), where Re is -H, halogen, 5-6-membered heterocycle containing 2 heteroatoms selected from N or O, -OR14, or -O-C(O)OR14; every R14 independently is -H, -C1-C8 alkyl, -phenyl, 5-6-membered heterocycle containing one heteroatom being S; every Y independently is -C1-C8 alkylene-; every m independently is equal 0 or 1.

EFFECT: claimed compounds can find application for treatment of different cancer species.

41 cl, 4 tbl, 4 dwg, 8 ex

FIELD: chemistry; medicine.

SUBSTANCE: compounds of claimed invention possess properties of positive allosteric modulator mGluR5. In general formula I , W represents 6-member heterocycloalkyl ring with 1-2 heteroatoms, selected from N, O; R1 and R2 independently represent hydrogen, C1-C6-alkyl; P and Q each independently is selected from: , R3, R4, R5, R6 and R7 independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-member heteroaryl with 1-2 atoms N as heteroatoms; 6-member heterocycle with 2 heteroatoms representing N, O; phenyl, optionally substituted with halogen; naphtyl; -OR8; where optionally two substituents together with located between them atoms form 9-10-member bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S; R8 represents hydrogen, C1-C6-alkyl; D, E, F, G and H independently represent -C(R3)=, -O-, -N=, -N(R3)- or -S-; A represents ethinyl, -C(=O)NR8- or group of formula . B represents -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6-alkenyl-. Invention also relates to pharmaceutical composition based on invention compounds.

EFFECT: novel compounds possess useful biological proprties.

20 cl, 3 dwg, 75 ex

FIELD: chemistry.

SUBSTANCE: invention can be applied in medicine and concerns inhibitors of MaR-kinase p38 of formula where W represents N or O, when Y represents C, and W represents C, when Y represents N; U represents CH or N; V represents C-E or N; X represents O, S, SO, SO2, NH, C=O,-C=NOR1 or CHOR1; B represents H or NH2; R1, E and A stands for H or various alkyl, heteroalkyl, aromatic and heteroaromatic substitutes.

EFFECT: production of new biologically active compounds.

48 cl, 138 ex, 54 dwg

FIELD: pharmacology.

SUBSTANCE: claimed invention relates to novel 2,4-pyridindiamine compounds of formula (1). In structural formula (I) L1 is direct bond; L2 is direct bond; R2 is phenyl group, three times substituted with three groups R8; R4 is X represents N; Y is selected from group consisting of O, NH, S, SO and SO2; Z is selected from group consisting of O, NH; on condition that if Y is selected from group consisting of NH, S, SO and SO2, Z is not the same as Y; R5 is selected from group consisting from R6, halogen; each R6 is independently selected from group consisting of hydrogen, halogen; R8 is selected from group consisting from Ra, Rb, Ra substituted with one or several similar or different groups Ra or Rb, -ORa, -O-CHRaRb; each R35 independently on others is selected from group consisting of hydrogen and R35, or in alternative case, two groups R35, bound to one and the same carbon atom are taken together with formation of oxogroup (=O), and the remaining two groups R35 each independently on each other are selected from group consisting from hydrogen and R8; each Ra is independently selected from group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl; each Rb is suitable group which is independently selected from group consisting of -ORd, halogen, -CF3, -C(O)NRcRc, and -OC(O)ORd; each Rc is independently protective group or Ra; each Rd is independently protective group or Ra; each index m is independently integer number from 1 to 3.

EFFECT: novel compounds can be used for treatment or prevention of autoimmune diseases, for instance such as rheumatoid arthritis and/or related to it symptoms, systemic lupus erythematosus and/or related to it symptoms, as well as and/or related to it symptoms.

41 cl, 14 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: described is novel compound of formula (I)

or its pharmaceutically acceptable salt, values of radicals are given in invention formula Compound has ability to inhibit receptor mGluR5, which intends it for prevention and/or treatment of receptor mGluR5- associated disturbances. Also described is pharmaceutical composition, method of inhibiting activation of receptors mGluR5, using compound of formula (I). Described is method of obtaining compound of formula 1a or 1b structure.

EFFECT: increasing output of suitable product.

18 cl, 825 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

FIELD: medicine.

SUBSTANCE: formula bond

or it pharmaceutically comprehensible salt where value of radicals are specified in the invention formula is described. The bonds are effective as inhibitors of protein kinases FLT-3 or KIT. A way of inhibition of activity kinases FLT-3 or KIT in the biological sample in vitro and application of bonds for manufacture of a medical product, suitable for treatment or simplification of gravity of disease or a condition, the chosen acute myelogenetic leukosis, acute progranulocytic leukemia or acute lymphocytic leukosis or cancer of ovaries are described also.

EFFECT: rising of efficiency of a composition and the method of treatment.

11 cl, 86 ex

FIELD: medicine.

SUBSTANCE: invention offers analogues of quinazoline of the formula I

where A is bound at least with one of atoms of carbon in position 6 or 7 of the dicyclic ring; X represents N. A represents the group Q or Z including tautomeric group Z form where Q and Z, have the formulas resulted more low in which symbols and radicals, have the value specified in item 1 of the formula of the invention. R1 represents phenyl, substituted -(G)nOAr or -O(G)nAr and where phenyl is unessentially replaced by halogen or C1-C10alkyl; where G represents C1-C4alkylene, n is peer 0 or 1. And Ar represents phenyl either pyridyl or thiazolyl where Ar is unessentially substituted by 1-2 substituents chosen from halogen or C1-C10alkyl; R2 and R3 represent N. The bonds of the formula I are inhibitors of the receptor tyrosine kinases of type 1. The invention includes also a way of treatment of hyperproliferative diseases, such as a cancer, application of bonds of the formula 1 in manufacture of medical products and pharmaceutical composition on the basis of these bonds.

EFFECT: rising of efficiency of a composition and the method of treatment.

14 cl, 6 dwg, 63 ex

FIELD: chemistry.

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

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

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of formula (I): and to its salts with acid, where: R1 and R2 represent hydrogen; Q represents (CH2)m-X-(CH2)n-A; A represents direct bond, O, SO2, NR5; X represents direct bond, O, SO2, C(O) or NR5; Z represents group selected from : m and n represent, each independently, 0, 1, 2, 3 or 4; p represents 1, 2, 3 or 4; q represents 0, 1 or 2; dotted line means that R8 and/or R9 can be situated in any position of benzothiophene ring; R3 and R8 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11 or NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10; when Q-Z represents n 0, 1 or 2 and p represents 1, one of R3 and R8 represents hydroxy, nitro, NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CONR10R11, and the other represents hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11 OSO2NR10R11, NR12SO2NR10R11, CO2R10; R4 and R9 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CHO; when p represents 2, 3 or 4, R9 can be similar or different; R6 and R7 represent hydrogen; each R5, R10, R11 and R12 represents hydrogen; when Z represents and p represents 1, then R8 and R9 can also together with phenyl ring form benzoxathiazine dioxide. Invention also relates to pharmaceutical composition and to application of derivatives by any of ii.1-25.

EFFECT: obtaining novel biologically active compounds which possess inhibiting activity with respect to aromatase and/or steroid-sulfatase and/or carboanhydrase.

36 cl, 67 ex, 5 tbl

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: invention refers to Sertaconasole mononitrate process by reaction of 1-(2,4-dichlorphenyl)-2-(1H-imidazole-1-yl)ethanol and 3-bromomethyl-7-chlorbenzo[b]thiophene with tetrabutylammonium hydrosulphate and sodium hydroxide in toluene at 30-45°C. Produced free base of Sertaconasole is transferred into Sertaconasole mononitrate monohydrate with the latter being transferred into Sertaconasole mononitrate. There is disclosed and characterised intermediate Sertaconasole mononitrate monohydrate.

EFFECT: method allows simplifying process technology considerably.

6 cl, 5 dwg, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I) where R1 stands for hydrogen or linear, branched, saturated or unsaturated hydrocarbon radical; D stands for nitrogen atom or C-R2; E stands for nitrogen atom or C-R3; F stands for nitrogen atom or C-R4; G stands for nitrogen atom or C-R5; R2, R3, R4 and R5 are identical or different and individually represent hydrogen, halogen, alkoxy, linear or branched, saturated or unsaturated hydrocarbon radical; W stands for oxygen atom; X stands for radical of formula radical -(CH2)k-C(O)-(CH2)m-, -(CH2)n- or -(CH2)r-O-(CH2)s-, where k, m, r and s are equal to integers 0 to 6, and n is equal to an integer 1 to 6. Said radicals are optionally substituted with one or more substitutes independently chosen from the group consisting of R7; Y stands for radical of formula radical -(CH2)i-NH-C(O)-(CH2)j-, -(CH2)n-, -(CH2)r-O-(CH2)s-, -(CH2)t-NH-(CH2)u-, where i, j, n, r, s, t and u are equal to integers 0 to 6. Said radicals are optionally substituted C1-3alkyl, or C1-3alkyl-C1-3alkylsulphonylamino; radicals R7, B, R8, A, R9 are as it is presented in the patent claim. The invention also describes the pharmaceutical composition possessing inhibitory activity of receptor tyrosine kinase to KDR receptor including described compounds.

EFFECT: compounds possess inhibitory activity of receptor tyrosine kinase to KDR receptor and can be effective in therapy of the diseases associated uncontrolled angiogenesis.

29 cl, 746 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with general formula I, where R1 represents -(CHR')q-aryl or -(CHR')q-thiophen, which are unsubstituted or mono-, di- or tri-substituted with (inferior)alkyl, (inferior)alkoxy, CF3 or haloid, or represents (inferior)alkyl, (inferior)alkenyl, -(CH2)n-Si(CH3)3, -(CH2)n-O-(inferior)alkyl, -(CH2)n-S- (inferior)alkyl, -(CH2)q-cycloalkyl, -(CH2)n-[CH(OH)]m-(CF2)p-CHqF(3-q), or represents -(CH2)n-CR2-CF3, where two radicals R together with a carbon atom form a cycloalkyl ring; R' represents hydrogen or (inferior)alkyl; n is 1, 2 or 3; m is 0 or 1; p is 0, 1,2, 3, 4, 5 or 6; q is 0, 1, 2 or 3; R2 represents hydrogen or (inferior)alkyl; R3 represents hydrogen, (inferior)alkyl, CH2F, aryl, optionally mono-, di- or tri-substituted with a haloid, or represents -(CH2)nNR5R6, where R5 and R6 independently represent hydrogen or (inferior)alkyl; R4 represents one of the following groups a) or b), where R7 represents inferior)alkyl or -(CH2)ncycloalkyl; R8 and R9 independently represent hydrogen, (inferior)alkyl, -(CH2)n-cycloalkyl or -C(O)-phenyl. The invention also relates to pharmaceutically used acid addition salts of these compounds, optically pure enantiomers, racemates or diastereomeric mixtures, as well as compounds with general formula I-1, and medicinal agent.

EFFECT: obtaining new biologically active compounds, designed for inhibiting γ-secretase.

16 cl, 83 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel compound represented by formula I, where R1 and R2 are similar or different and each represents: (I) C1-10alkyl group optionally substituted with 1-3 substituents selected from C3-10cycloalkyl group, C1-6alkoxycarbonyl group b C1-6alkoxygroup; (2) C6-14aryl group optionally substituted with 1-3 substituents selected from halogen atom, carboxyl group, C1-6alkoxycabonyl group b carbamoyl group; or (3) C7-13aralkyl group; R3 represents C6-14aryl group optionally substituted with 1-3 substituents selected from C1-6alkyl group, optionally substituted with 1-3 halogen atoms, halogen atom, C1-6alkoxycarbonyl group, carboxyl group, hydroxy group, C1-6alkoxygroup, optionally substituted with 1-3 halogen atoms; R4 represents amino group; L represents C1-10alkylene group; Q represents bond, C1-10alkylene group or C2-10alkenylene group; and X represents: (1) hydrogen atom; (2) cyanogroup; (3) (3a) carboxyl group; (3b) carbamoyl group; and further as presented in invention formula. Invention also describes medication for treating diabetes, peptidase inhibitor, application of formula I compound, method of prevention or treatment of diabetes, method of peptidase inhibiting and method of obtaining formula I compounds.

EFFECT: obtaining novel compounds which have peptidase-inhibiting activity and are useful as medication for prevention and treatment of diabetes.

16 cl, 433 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds satisfying general formula (I): where: R1 stands for direct or branched (C1-C7)alkyl, X stands for hydrogen atom, R2 stands for the group chosen from naphthalenyl, pyridinyl, isoquinoleinyl, thienyl, imidazolyl, benzothienyl, benzimidazolyl, indolyl, benzotriazolyl and optionally substituted with one or more substitutes chosen from halogen atoms and following groups: (C1-C4)alkyls, thio(C1-C4)alkyls or phenyls, optionally substituted with one or more substitutes chosen from halogen atoms or trifluoromethyl, as free base or additive salt with acid. Additionally, the invention concerns medical product, pharmaceutical composition, and application.

EFFECT: production of new biologically active compounds active to specific inhibitors of glycine glyt 1 and/or glyt 2 carriers.

6 cl, 3 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns enantiomers of thiophene hydroxami acid derivatives of general formula I and their pharmaceutically acceptable salts. , where Ar is aryl or heteroaryl group selected out of thiophene, morpholine, which can be non-substituted or mono-, di- or trisubstituted by halogen, phenyl, alkyl, -O-alkyl, -OH; R1 is hydrogen, phenyl or alkyl; together with Ar-group R1 forms tetrahydronaphthaline or indane cycle; R2 is hydrogen or alkyl; and their pharmaceutically acceptable salts.

EFFECT: application as histondesacetylase inhibitors in obtaining medicine for neoplasm treatment in hemopoietic and lymphatic system.

29 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel malononitryl derivatives of formula (I), which can be applied to fight pest insects. In formula (I) R1 represents hydrogen atom; R2 represents hydrogen atom; R represents hydrogen atom; R4 represents C1-C5-alkyl group substituted with at least one halogen atom, C2-C5-alkenyl group; R5 represents hydrogen atom, halogen atom, C1-C5-alkyl group; at least one of X1, X2 and X3 values represents CR6, the other represent nitrogen atoms; R represents hydrogen atom, halogen atom, cyanogroup, nitrogroup, formyl group, C1-C5-alkyl group optionally substituted with at least one halogen atom, C1-C5-alkyltiogroup, substituted with at least one halogen atom, C2-C6-alkylcarbonyl group substituted with at east one halogen atom, C2-C5-alkoxycarbonyl group or group (CH2)mQ, where m = 0, and Q stands for phenyl; and in case when one of R5 and R6 is bonded with two atoms in adjacent positions or two R6 are bonded with two atoms in adjacent positions, they can be bonded to each other in end positions with formation of C2-C6-alkandiyl group, or C4-C6-alkenediyl group. Invention also relates to composition and method used to fight pest-insects.

EFFECT: obtaining novel malononitryl derivatives of formula (I), which can be applied to fight pest-insects.

11 cl, 90 ex

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