Synthesis of substituted pyrazoline carboxamidine derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing pyrazoline carboxamidine derivatives of formula . Said compounds are known as powerful 5-HT6 antagonists. The disclosed method comprises reacting a corresponding substituted 4,5-dihydro-(1H)-pyrazole or an isomer thereof with isothiocyanate R6-N=C=S to obtain an amide of substituted 4,5-dihydro-(1H)-pyrazole-1-carbothioic acid or tautomeric substituted 4,5-dihydro-(1H)-pyrazole-1-carboxymidothioic acid . The obtained intermediate compounds are reacted with a corresponding alkylating agent to obtain an intermediate S-alkylated compound . Said intermediate compound is reacted with a sulphonamide derivative R7SO2NH2 and the target compound of formula (I) is separated from the reaction mixture. The invention also relates to novel intermediate products (IIIa), (IIIb) and (IV). Symbols given in the formulae have values given in the description.

EFFECT: providing an alternative method which improves atom efficiency of synthesis of desired compounds with higher output compared to existing methods for synthesis of said compounds.

8 cl, 1 tbl, 3 ex

 

The present invention relates to organic chemistry, in particular to methods of obtaining derivatives of pyrazoline carboxamidine, known as a potent antagonist of 5-HT6. In addition, the invention relates to new intermediate products formed during the preparation of these compounds.

Background of the INVENTION

Derivative sulfonylation of carboxamidine were first disclosed as effective antagonists of 5-HT6in WO 2008/034863. Related (hetero)arylsulfonate carboxamidine with similar pharmacological activity have been disclosed in WO 2009/115515. Described in these applications the synthesis pathway provide acceptable outputs, but they are not very well suited for the synthesis at the scale required for clinical trials of drugs, not to mention the scale required for the release of medications on the market.

The present invention was to develop new ways of synthesis of sulfonylation of carboxamidine with improved nuclear performance [Trost, B. M.Science1991,254, 1471; Sheldon, R. A.Pure Appl. Chem.2000,72, 1233] and higher outputs compared with the known synthesis routes, using convenient or readily available building blocks, in mild conditions and with limited use and generation of hazardous chemicals in�of the EU ETS.

Disclosure of the INVENTION

It was discovered that new way of synthesis of derivatives (aryl)sulfonylation of carboxamidine, characterized by a high atomic efficiency and much higher outputs than that of the known ways, carried out in milder conditions more amenable to scaling. The present invention relates to a method for producing compounds of formula (I):

or tautomers, stereoisomers or pharmaceutically acceptable salts of any of these compounds where:

R1selected from a hydrogen atom or a (C1-4)alkyl group, optionally substituted with one to three fluorine atoms or hydroxy-group,

R2represents a hydrogen atom or a (C1-4)alkyl group, optionally substituted with one to three fluorine atoms, hydroxy-group, benzoyloxymethyl group, amino group, monomethylamine, dimethylaminopropoxy or Boc-, Fmoc - or Cbz-protected amino group, where (C1-4)alkyl group may include Citigroup, sulfonyloxy group or atom is N, O or S,

R3represents a hydrogen atom or a (C1-4)alkyl group, optionally substituted with one to three fluorine atoms, hydroxy-group, benzoyloxymethyl group, amino group, monomethylamine, dimethylaminopropoxy �whether Boc-, Fmoc - or Cbz-protected amino group, where (C1-4)alkyl group may include Citigroup, sulfonyloxy group or atom is N, O or S, or

R1and R2together with the carbon atoms marked with the symbols 'a' and 'b' form a C5-8cycloalkyl, optionally substituted with one to three fluorine atoms, hydroxy-group or (C1-4)alkyl group, or

R2and R3together with the carbon atom marked 'b' form a C3-8cycloalkyl, optionally substituted with one to four fluorine atoms, one or two methyl groups or by a hydroxy-group, or

R2and R3together with the carbon atom marked 'b' form a C5-8heteroseksualci, optionally substituted with one to four fluorine atoms, one or two methyl groups, a benzyl group or a hydroxy-group,

R4represents a hydrogen atom or a (C1-4)alkyl group, optionally substituted with one to three fluorine atoms or hydroxy-group, or R4means monocyclic aryl or heteroaryl group, optionally substituted with one to five substituents Q which can be identical or different, selected from halogen, trifloromethyl, triptoreline, cyano, C1-3alkyl, C1-3alkoxy, hydroxy, amino, acetyl, atsetamido, crypto�atsetamido, -CONH2, -SO2NH2or-CO2H, or

R3and R4together with the carbon atoms marked with symbols 'b' and 'c' form C3-8cycloalkyl, optionally substituted with one to four fluorine atoms, one or two methyl groups or by a hydroxy-group, or

R3and R4together with the carbon atoms marked with symbols 'b' and 'c' form C5-8heteroseksualci, optionally substituted with one to four fluorine atoms, one or two methyl groups, a benzyl group or a hydroxy-group,

R5is a hydrogen atom or a bromide

R6selected from a hydrogen atom or a (C1-4)alkyl group, optionally substituted with one to three fluorine atoms or hydroxy-group,

R7represents a monocyclic or condensed bicyclic aromatic or heteroaromatic group, where these groups are unsubstituted or substituted with one to five substituents Q as defined above, or

R7is a 2-arelatively group or 2-arelatively group, or

R7is piperidinyloxy group, unsubstituted or substituted with one to four fluorine atoms or by a group of CF3or

R7represents a 2,3-dihydroindole group or a group benzimidazol-2-it,

VK�uchumi stages:

(i) interaction of substituted 4,5-dihydro-(1H)-pyrazole of the formula (IIa) or isomeric substituted 4,5-dihydro-3H-pyrazole of the formula (IIb):

where R1, R2, R3, R4and R5have the above values, with an isothiocyanate of formula R6-N=C=S, where R6has the above value, to obtain an amide substituted 4,5-dihydro-(1H) - pyrazol-1-carbothiolate of formula (IIIa) or tautomeric substituted 4,5-dihydro-(1H) - pyrazol-1-carboxymethylate of formula (IIIb):

(ii) interaction of the compounds of formula (IIIa) or (IIIb) with an alkylating reagent of the General formula Rx-L, where Rxis a linear (C1-8)alkyl group, and L means a leaving group, preferably selected from Br, Cl or I, to produce a compound of formula (IV):

(iii) interaction of the obtained compound of formula (IV) with a derivative of sulfonamide of the formula R7SO2NH2where R7has the above value, to produce a compound of formula (I):

At the stage of (i) the reagents in the form of free bases or their salts are dissolved in a suitable solvent, preferably a polar solvent, more preferably the alcohol (C1-8

Similarly, in step (ii) reagents in the form of free bases or their salts are dissolved in a suitable solvent, preferably a polar solvent, e.g., acetonitrile, methyl ethyl ketone, an alcohol (C1-8), or mixtures of polar solvents, most preferably, methanol or acetonitrile. The reaction is preferably carried out at elevated temperature, but it is possible to conduct the reaction at room temperature. The preferred temperature is from about 40°C to about 50°C. the Most preferred temperature of the reaction mixture to 50°C and time of reaction from about 1 to about 5 hours. Preferred alkylating reagents of the General formula RX-L, where RXmean linear (C1-8)alkyl group, and L means a leaving group, preferably selected from Br, Cl or I, are methylvaleramide. Most preferred are the methyl iodide.

At the stage (iii) reagents in the form of free bases or their salts are dissolved in a suitable solvent, preferably a polar solvent, most preferably acetonitrile. Ethereally preferably carried out at elevated temperature, preferably at the boiling point, for about 16-72 hours, preferably for from about 10 to about 16 hours.

The present invention relates to racemates, mixtures of diastereomers, as well as to the individual diastereoisomers of the compounds of formula (I). In addition, the present invention relates to E-isomer, Z-isomers and mixtures of E/Z isomers of compounds of formula (I) and their salts. In addition, the invention relates to racemates, mixtures of diastereomers and the individual stereoisomers of the compounds of formulas (IIIa), (IIIband (IV) and salt forms of the compounds of formulas (IIIa), (IIIband (IV).

Further, the invention relates to a method for producing compounds of formula (I) in which:

R1selected from a hydrogen atom or a (C1-2)alkyl group,

R2represents a hydrogen atom or a (C1-3)alkyl group, optionally substituted with one to three fluorine atoms or hydroxy-group,

R3represents a hydrogen atom or a (C1-3)alkyl group, optionally substituted with one to three fluorine atoms or hydroxy-group, or

R1and R2together with the carbon atoms marked with the symbols 'a' and 'b' form a C5-8cycloalkyl, or R2and R3together with the carbon atom marked 'b' form a C3-8cycloalkyl, niobate�till then substituted by one to four fluorine atoms or hydroxy-group, or

R2and R3together with the carbon atom marked 'b' form a C5-8heteroseksualci, optionally substituted with a methyl or benzyl group, or a hydroxy-group,

R4represents a hydrogen atom or a (C1-2)alkyl group, or R4means monocyclic aryl or heteroaryl group, optionally substituted with one to three substituents Q as defined above, or

R3and R4together with the carbon atoms marked with symbols 'b' and 'c' form C5-8cycloalkyl, or

R3and R4together with the carbon atoms marked with symbols 'b' and 'c' form C5-8heteroseksualci, optionally substituted with a methyl or benzyl group,

R5is a hydrogen atom,

R6selected from a hydrogen atom or a (C1-3)alkyl group, optionally substituted with one to three fluorine atoms,

R7represents a monocyclic or condensed bicyclic aromatic or heteroaromatic group, where these groups are unsubstituted or substituted with one to five substituents Q as defined above, or

R7is a 2-arelatively group or 2-arelatively group, or

R7is piperidinyloxy group, or

R7/sub> represents a 2,3-dihydroindole group or a group benzimidazol-2-one.

Another embodiment of the invention relates to a method of obtaining compounds of formula (I), in which the fragment :

selected from:

R6selected from hydrogen or (C1-3)alkyl group, optionally substituted with one to three fluorine atoms,

R7represents a monocyclic or condensed bicyclic aromatic or heteroaromatic group, where these groups are unsubstituted or substituted with one to five substituents Q as defined above, or

R7is a 2-arelatively group or 2-arelatively group, or

R7is piperidinyloxy group, or

R7represents a 2,3-dihydroindole group or a group benzimidazol-2-one.

Another variant of implementation relates to a method of obtaining compounds of formula (I), where the fragment:

selected from:

R6selected from hydrogen or (C1-2)alkyl group, optionally substituted by three fluorine atoms,

R7represents a monocyclic or condensed bicyclic aromatic or heteroaromatic gr�foam, where these groups are unsubstituted or substituted by one or two substituents selected from methyl, methoxy, fluorine, chlorine, bromine, cyano, atsetamido, triptoreline, triptoreline, amino or hydroxy.

A specific variant of implementation relates to a method of obtaining compounds having the formula:

and its tautomeric and salt forms,

incorporating the following stages:

(i) the interaction of 2,3-diazaspiro[4.4]non-2-ena or 2,3-diazaspiro[4.4]non-1-ena or their salts synthesized according to the method disclosed in WO 2008/034863, with ethylisothiocyanate for ethylamide 2,3-diazaspiro[4.4]non-3-EN-2-carbothiolate or tautomer

(ii) interaction of the product of step (i) with iodomethane or methyl p-toluensulfonate, resulting in obtaining the methyl ester of N-ethyl-2,3-diazaspiro[4.4]non-3-EN-2-carboxymethylate,

(iii) interaction of the product of step (ii) in the form of the free base or salt, with 4-acetamidobenzaldehyde (CAS 121-61-9, commercially available) to give N-(4-{[(2,3-diazaspiro[4.4]non-3-EN-2-yl)ethylaminomethyl]sulfamoyl}phenyl)acetamide

(iv) of deprotection of the product of step (iii) in acidic medium to obtain 4-amino-N-[(2,3-diazaspiro[4.4]non-3-EN-2-yl)ethylaminomethyl]benzosulfimide

Another specific embodiment �of sushestvennee relates to the method described above, in which stage (iii) is in the interaction of methyl ester of N-ethyl-2,3-diazaspiro[4.4]non-3-EN-2-carboxymethylate with sulfanilamide (CAS 129-56-6, commercially available) to give 4-amino-N-[(2,3-diazaspiro[4.4]non-3-EN-2-yl)ethylaminomethyl]benzosulfimide:

Another embodiment of the invention relates to compounds of formula (IIIa), (IIIb) or (IV):

where R1, R2, R3, R4, R5and R6have the above values, and to the tautomers, the stereoisomers and the salts of any of these compounds, where these compounds have found application in the synthesis of compounds of formula (I).

Described in the present application compounds and intermediate products, if desired, can be isolated and purified by any suitable method of separating or purifying, such as, for example, by filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative liquid chromatography low or high pressure or a combination of these methods. In the description of the syntheses and examples show how to divide and allocate the compounds of the present invention, but in addition you can also use other equivalent methods.

Connection of infusion�him to the invention can contain one or more asymmetric centers and, consequently, there may be in the form of racemates and racemic mixtures, pure enantiomers, diastereomeric mixtures and individual diastereomers.

Depending on the nature of the existing substituents in the molecule may be additional asymmetric centers. Each such asymmetric center will independently lead to the emergence of two optical isomers. All possible optical isomers, enantiomers and diastereomers in mixtures and pure and partially purified compounds are included in the scope of the present invention. The present invention covers all such isomeric forms of compounds of the present invention. Formula (I) shows the structure of a class of compounds without preferred stereochemistry. Independent synthesis of these optical isomers or their chromatographic separation can be carried out by known methods with appropriate modifications of methods disclosed in the present application. Absolute spatial structure can be set by using x-ray crystallography of crystalline products or crystalline intermediates from which, if necessary, you can get a derivative with a reagent containing an asymmetric center of known absolute configuration. Racemic mixtures of compounds m�can be divided into individual enantiomers are well known methods, for example, the interaction of the racemic mixture of compounds with enantiomerically pure compound with the formation of diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, for example by fractional crystallization or chromatography. These interactions often involves the formation of salts with the use of enantiomerically pure acid or base, for example, (-)-di-p-toluoyl-D-tartaric acid or (+)-di-p-toluoyl-L-tartaric acid. Diastereomeric derivatives then can be converted into the pure enantiomers by cleavage of the attached chiral residue. The racemic mixture of the compounds can also be divided directly by well-known chromatographic methods using chiral stationary phases. Alternatively, any enantiomer in a given compound can be obtained by using stereoselective synthesis using optically pure starting materials or reagents of known configuration by use of techniques well known in the art.

CIS - and TRANS-isomers of a compound of formula (I) or their pharmaceutically acceptable salts are also included in the present invention, and the same applies to tautomers of compounds of formula (I).

The strategy of synthesis in the new method according to the present invention differs significantly from known�different ways of synthesis by introduction of substituents R 6and R7at other stages of the synthesis and/or by other structural units. Since the intermediate product having the tautomeric form (IIa) or (IIb), which is a common building block for new ways of synthesis and previously disclosed ways substituent R6administered using isothiocyanates and not amine (synthesis 1 and 3 disclosed in WO 2009/115515) or thiourea (method 2, disclosed in WO 2009/115515) block. As a result, new tautomeric intermediates (IIIa) or (IIIb) are formed in a neutral environment with a maximum atomic efficiency (100%), and the reaction is easily scaled. From intermediates (IIIa)/(IIIb) in the alkylation under mild conditions easily get new intermediate products of the formula (IV), in which there are easily substitutable leaving group S-alkyl. In contrast, path 3, disclosed in WO 2009/115515, requires much more stringent conditions for obtaining in situ compounds with a halogen as the leaving group, which is at the final stage is expected to replace the block R6Ameen. The final phase of a new method of synthesis is the substitution of the leaving group S-alkyl in the intermediate product (IV), but unlike route 1, as disclosed in WO 2009/115515, where a block of R6Amin replaces the fragment S-alkyl, a new method of synthesis for �astasia to the invention is completed by the introduction of block R 7a sulfonamide, remarkably, in a neutral medium low heat. In synthesis routes 1 and 3 disclosed in WO 2009/115515, Deputy R7sulfonyl is entered in more severe conditions at an earlier stage of the synthesis, while in method 2 disclosed in WO 2009/115515, Deputy R7sulfonyl is also entered on the final stage, but by using more reactive block R7sulphonylchloride the primary environment (which limits the use of unprotected nucleophilic fragments in the residue R7). Therefore, a new method of synthesis involves the improvement from the point of view of a wider choice of functional groups in the substituent R7that shown in this application in several examples, for example, in the synthesis of compounds 4, where the substituents R7containing aminoaniline groups were introduced selectively without the need for protection.

Not to mention the obvious difference in the strategy of synthesis and are associated with the difference mild conditions, which can usually be a stage of synthesis, a new way of synthesis of the present invention provides a distinct advantage in a number of other aspects that are crucial in scaling up the synthesis. In the method of synthesizing 3 disclosed in WO 2009/115515 involved corrosive halogenide agents,which limits its application. In the method of synthesis 1 disclosed in WO 2009/115515 used toxic component CS2in a strongly basic environment, and another disadvantage of this method is that we use two molar equivalent of an alkylating agent and method includes two stages, each of which is allocated one molar equivalent Alcantara. In the new method of synthesis not applicable strongly basic or acidic conditions, does not apply CS2applies only to one equivalent of alkylating agent and included only a stage, on which stands a molar equivalent Alcantara. Although the latter arguments also hold true for the pathway of synthesis of 2, as disclosed in WO 2009/115515 limiting factor in this method, not only of reactions, but in some cases also from the point of view of sustainability of those or other functional groups, may be the need to use reactive sulphonylchloride blocks. As shown for the synthesis of compound 4, the introduction of 4-aminophenylalanine fragments in the method of synthesis of 2 applications WO 2009/115515 require protection of the amino group. The removal of N-acetyl protective group (introduced via N-acetylsalicylamide, CAS 121-60-8, commercially available) involves an extra stage of synthesis in highly acidic (corrosive) environment, leading to the risk of concomitant hydrolysis� the sulfonamide, that is, as shown, leads only to modest outputs.

In an era when the availability of raw materials and the care for the environment are becoming of increasing importance, especially for large-scale productions, atomic efficiency has become accepted as a parameter for the evaluation of methods of synthesis. Atomic efficiency [Sheldon, R. A.Pure Appl.Chem.2000, 72, 1233] (expressed in percentage) can be calculated by calculating the ratio of the molecular weight of the final product to the total molecular weight of all used building blocks, including the atoms that make up the product synthesis. When comparing the synthesis of compound 4 of the present invention, based on the need to obtain the final products of the stages of synthesis, eliminating the synthesis of intermediates of formula (IIa)/(IIb), common to all methods, it becomes apparent that a new method of synthesis of the present invention is superior to the methods of prior art, from the point of view of atomic efficiency and total output:

Method 1 disclosed in WO 2009/115515:

Atomic efficiency: [349,46/(172,21+76,14+(2×141,93)+124,19+45,08)]×100%=50%;

Outlet: 40%×25%×67%=7%;

Method 2 disclosed in WO 2009/115515:

Atomic efficiency: [349,46/(104,18+141,93+124,19+233,67+36,46)]×100%=55%;

Outlet: 100×78%×77%×55%=33% (the 2 outputs of the final stages in this particular example is not given in WO 2009/115515, but defined in the present application).

A new method of synthesis:

Atomic efficiency: [349,46/(124,19+87,15+141,93+172,21)]×100%=67%;

Outlet: 83%×97%×67%=54% (First stage: synthesis technique with a large number of reagents, using as starting compound salt of a pyrazoline·HCl).

Definitions

The key terms used in the description of the compounds disclosed in the present application, have their usual meanings. The term "alkyl" means a monovalent saturated, branched or linear hydrocarbon residue. Unless otherwise indicated, the alkyl chains may contain from 1 to 18 carbon atoms. Typical examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, etc. If the alkyl group referred to as "lower alkyl", it must contain from 1 to 6 carbon atoms. A similar number of carbon atoms is applicable to the original term "alkane" and to derivative terms such as "alkoxy". The number of atoms of carbon in various carbon-containing fragments is shown by a prefix indicating the minimum and maximum number of carbon atoms�Yes from fragment, i.e., the prefix Cx-ydefines the number of carbon atoms from integer x to integer y, inclusive. For example, "(C1-3)alkyl" includes methyl, ethyl, n-propyl or isopropyl, and "(C1-4)alkyl" includes methyl, ethyl, n-propyl, isopropyl, isopropyl, n-butyl, 2-butyl, isobutyl or tert-butyl.

The term "aryl" includes mono - or polycyclic aromatic group including phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, fluorenyl, anthracene, phenanthrene, naphthacene and azulene. The term "heteroaryl" encompasses mono - or polycyclic heteroaromatic group, including furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, imidazo[2,1-b][1,3]thiazolyl, pyrazolyl, isoxazolyl, isothiazolin, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, indazole, indole, indolizine, isoindole, benzo[b]furanyl, 1,2,3,4-tetrahydroisoquinoline, indanyl, indenyl, benzo[b]thienyl, 2,3-dihydro-1,4-benzodioxin-5-yl, benzimidazolyl, indolinyl, carbazolyl, acridines, phenazines, phenothiazines, phenoxazines, benzothiazolyl, benzo[1,2,5]thiadiazolyl, purinol, chinoline, ethenolysis, hemolysins, phthalazine, hintline, honokalani, 1.8-naphthyridine and pteridine.

The term "halogen" refers to chlorine, fluorine, bromine or iodine; the term "hetero", for example, the terms "heteroalkyl", "heteroaromatic", etc. means the presence of one or more atoms of N, O or S. the Term "heteroalkyl" means an alkyl group with heteroatoms in any position, including, therefore, the alkyl groups linked through the atoms N, O or S.

The term "substituted" means that defined the group or the fragment bears one or more substituents. If any group can carry several deputies and there is a possibility of the presence of several different substituents, these substituents chosen independently and they need not be the same. The term "unsubstituted" means that the specified group bears the substituents. The term "independently", in respect of substituents, means that if possible the presence of more than one substituent, these substituents may be the same or different from each other.

"C3-8cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; the term "C5-8heteroseksualci" refers to the cycles containing heteroatoms, including piperidinyl, morpholinyl, azepane, pyrrolidine, thiomorpholine, piperazinyl, tetrahydrofuryl, tetrahydropyranyl;

The terms "oxy", "thio" and "Carbo", used as part of the name of another group, refer, respectively, to the oxygen atom, the sulfur atom and carbonyl group (C=O),�which act as linkers between the two groups, for example, hydroxyl, oxyalkyl, thioalkyl, carboxylic, etc., the Term "amino" as used by itself or as part of the name of another group, refers to the nitrogen atom, which can be either a terminal or a linker between two other groups, where the group may be primary, secondary or tertiary (respectively, with the nitrogen atom linked to two hydrogen atoms, one hydrogen atom or any atom of hydrogen) amino group. The terms "sulfinyl" and "sulfonyl" as part of the name of another group refers to groups-SO - and-SO2-, respectively.

For a more brief description, the terms "compound" or "compounds" include tautomers, stereoisomers, N-oxides, isotopically-labelled analogues, or pharmaceutically acceptable salts, even if they are not mentioned explicitly.

The term "leaving group" (L) includes a charged or uncharged atom or group, leaving the molecule during the reaction of substitution or displacement. This term refers to groups that can easily be replaced by the action nucleophils, such as amines, thiols or alcohols. Such leaving groups are well known. Their examples include N-hydroxysuccinimide, N-hydroxy-benzotriazole, Halogens (Br, Cl, I), triflate, mesylate, tosylate, etc.

For a more concise presentation, some of to�icestone expressions given in this application are not accompanied by the terms "about" or "approximately". Have in mind that regardless of whether you are using any of these terms explicitly or not, each given in the description of the quantitative value can have the value, and the values that are approximately equal to this given value, which can make the reasonable assumption, based on the standard of knowledge in this area, including the approximations associated with the experimental conditions or the conditions of measurement of this specific amount. In the text of the description and claims of this application does not assume that the word "include" and variations such as "comprising" and "comprises", exclude other additives, components, integers or stage.

Reduction

ACNacetonitrile
APIthe atmospheric pressure ionization
Boctert-butoxycarbonyl
Cbzbenzyloxycarbonyl
CUR"gas curtain"
DCMdihormati�
DiPEAN,N-diisopropylethylamine
DMSO (DMSO)dimethyl sulfoxide
EAthe ethyl acetate

ESIelectrospray ionization
Fmoc9-fluorenylmethoxycarbonyl
FPfocusing capacity
MeOHmethanol
m.p. (PL.)the melting point (or range of melting points)
MS (MS)mass spectrometry
PApetroleum ether (40-60)
Rfthe retention factor (thin layer chromatography)
Rtretention time (LC/MS)
RT (CT)room temperature
THF (THF)tetrahydrofuran

Example 1: Ana�political methods

Spectra1H NMRwere recorded on a Varian instrument UN400 (400 MHz) or the instrument Bruker Avance DRX600 (600 MHz), using as solvent DMSO-d6CD3CN or CDCl3and tetramethylsilane as an internal standard. Chemical shifts are given in M. D. (δ scale) in a relatively weak field of tetramethylsilane. The constants of spin-spin interaction (J) are expressed in Hz. Flash chromatography was performed using silica gel 60 (0,040-0,063 mm, Merck). Column chromatography was performed using silica gel 60 (0,063-0,200 mm, Merck) or alumina (act III). Chromatographic separation of the Sepacore system was carried out using equipment Supelco, columns VersaFLASHTMcartridge with silica VersaPakTMUV monitor Büchi C-630, Büchi pump module C-605, Büchi fraction collector C-660, control systems pump Büchi C-615. The melting point was recorded on the device for measuring temperatures of a Büchi melting point B-545 or was determined using the DSC technique (differential scanning calorimetry).

Liquid chromatography - mass spectrometry (LC-MS): The system LC-MS included two Micronase Perkin Elmer series 200. The pumps were connected to each other 50 µl T-mixer connected to an automatic dispenser Gilson 215. The following approach was used:

stagetotal timeflow (µl/min)A (%)B (%)
002000955
11,820000100
22,520000100
32,72000955
43,02000955

A=100% water with 0.025% of HCOOH and 10 mmol of NH4COOH pH ±3;

B=100% ACN with 0.025% of HCOOH.

Autoposter was fitted with a 2 ál injection loop and is connected with column Waters Atlantis C18 30*4.6 to the stationary phase particles sized 3 microns. Column thermostating at 40°C in an oven for columns (Perkin Elmer series 200. The column was connected to an UV detector Perkin Elmer series 200 equipped with a 2.7 ál flow cell. The detector worked at lengths� a wavelength of 254 nm. The UV detector was connected to the mass spectrometer Sciex API 150EX. The mass spectrometer was operated under the following parameters: scan range 150-900 at.ed.mass; polarity: positive; scan mode: profile; resolution Q1: UNIT; step size: 0.10 at.ed.mass.; one passage: 0,500 sec; NEB: 10; CUR: 10IS:5200; TEM: 325; DF: 30; FP: 225 and EP: 10. To a mass spectrometer Sciex API 150 was attached to the light scattering detector. As the light scattering detector was used Sedere Sedex 55, who worked at 50°C and a pressure of N2equal to 3 bar. The whole system was controlled by computer powermac G3.

Example 2: General aspects of synthesis

Substituted 4,5-dihydro-(1H)-pyrazoles of the formula (IIa) or substituted 4,5-dihydro-3H-pyrazoles of the formula (IIb) can be obtained according to the method disclosed in WO 2008/034863, and then you can enter into reaction with isothiocyanates of formula R6-N=C=S, where R6has the above values, to obtain the substituted amides 4,5-dihydro-(1H)-pyrazol-1-carbothiolate of formula (IIIa) or substituted 4,5-dihydro-(1R)-pyrazol-1-carboxymethylation of formula (IIIb). Compounds of formula (IIIa) or (IIIb) it is possible to alkylate the S atom, for example, alkylhalogenide, such as methyl iodide, to obtain compounds of formula (IV). The last connection you can enter into interaction with a derivative of sulfonamide of the formula R7SO2NH2where� R 7has the above value, to obtain compounds of formula (I). The person skilled in the art will notice that the group of S-alkyl in this particular reaction plays the role of the leaving group. In the above scheme, R1-R7have the above values. Compounds (IIa) and (IIb), as compounds (IIIaand (IIIb) are tautomers, and therefore, all these compounds are included in the scope of the present invention. Compounds of formula (IIIa), (IIIband (IV) are new.

Figure 1 depicts the synthesis of compounds of formula (I):

Pharmaceutically acceptable salts of the compounds can be obtained using well-known standard methods, for example by mixing the compounds of the present invention with a suitable acid, for example an inorganic acid such as hydrochloric acid, or organic acid such as fumaric acid.

The choice of specific methods of synthesis depends on factors known to specialists in this field. For example, compatibility of functional groups with the reagents used, the possibility of using protective groups, catalysts, activating and crosslinking reagents and the resulting structural features of end connections. For example, before the interaction with R6-NCS can protect am�of nography in R 2, R3or R4.

Example 3: synthesis of compounds of the present invention

Etelemed 2,3-diazaspiro[4.4]non-3-EN-2-carbothiolate(compound 1, synthesis with small amounts of reagents)

2,3-Diazaspiro[4.4]non-2-ene (obtained by the method described in WO 2008/034863) (1.05 g, 1 meaulnes. EQ.) and ethylisothiocyanate (0,95 ml, 1,3 meaulnes. EQ.) was added to 10 ml of ethanol. The reaction mixture was boiled to reflux for 2.5 hours, while stirring with a magnetic stirrer. Was added silica gel and the volatile components were removed in vacuum. The product was purified flash chromatography on silica gel (Et2A:PA=1:2) and after evaporation of volatile components, was stirred with diisopropyl ether and collected by filtration, getting 0,57 g (32%) of ethylamide 2,3-diazaspiro[4.4]non-3-EN-2-carbothiolate.1H NMR (400 MHz, CDCl3) δ 1,24 (t, J=7,2 Hz, 3H), 1,64-of 1.86 (m, 8H), 3,68 (D. kV, J=7,2, and 5.5 Hz, 2H), 4,00 (s, 2H), 6,80 (s, 1H), 7,08-to 7.18 (user.s, 1H).

Etelemed 2,3-diazaspiro[4.4]non-3-EN-2-carbothiolate(compound 1, the synthesis with a large number of reagents)

Hydrochloride of 2,3-diazaspiro[4.4]non-1-ena (15,4 g, was 95.9 mmol; obtained by the reaction of 2,3-diazaspiro[4.4]non-1-ena synthesized according to the method described in WO 2008/034863, with HCl in a mixture of isopropanol/toluene) was added to a mixture of 70 ml of methanol and 30 ml of water. To obtained�art via the dropping funnel was added ethylisothiocyanate (of 10.09 g, Shall be 115.1 mmol) and the funnel was washed with 40 ml of methanol. At 30°C dropwise within 10 minutes was added diisopropylethylamine (14,8 g of 114.5 mmol) and the dropping funnel was washed with 7 ml of water. The reaction mixture was stirred at 30°C for 1 hour, then the mixture was cooled to 10°C for 1 hour and then stirred at this temperature for another 2 hours. The precipitate was separated by filtration, twice washed with 20 ml of a cold mixture of methanol and water 3:1, and dried at 50°C, yielding 16.8 mg (83%) of ethylamide 2,3-diazaspiro[4.4]non-3-EN-2-carbothiolate in a solid color from off-white to white. Spectrum of1H NMR identical to a spectrum of the substance obtained in synthesis with small amounts of reagents (see above).

Methyl ester of N-ethyl-2,3-diazaspiro[4.4]non-3-EN-2-carboxymethylate (compound 2)

Etelemed 2,3-diazaspiro[4.4]non-3-EN-2-carbothioate (0.55 g, 1 meaulnes. EQ.) was dissolved in 15 ml of MeOH, was added itmean (3,4 ml, 21 meaulnes. EQ.) and stirred the reaction mixture a magnetic stirrer while heating to 45°C for 2 hours. Volatile components were removed under vacuum. The residue was mixed with dichloromethane (DCM) and was extracted with 5% aqueous solution of NaHCO3. The organic layer was twice washed with water, dried over Na2SO4, was filtered and was evaporated to dryness, obtaining of 0.57 g (97%) of methyl ester of N-ethyl-2,3-diesase�about[4.4]non-3-EN-2-carboxymethylate. 1H NMR (400 MHz, CDCl3) δ of 1.16 (t, J=7,3 Hz, 3H), 1,64-of 1.80 (m, 8H), 2,46 (s, 3H), 3,54 (kV, J=7,3 Hz, 2H), only 3.57 (s, 2H), 6,72 (s, 1H).

Methyl ester of N-ethyl-2,3-diazaspiro[4.4]non-3-EN-2-carboxymethylate (compound 2)

To a solution of ethylamide 2,3-diazaspiro[4.4]non-3-EN-2-carbothioate (1.0 g, 4.7 mmol) in 10 ml of methanol was added methyl p-toluensulfonate (1.1 g, 5.7 mmol). The mixture was boiled to reflux for 48 hours and concentrated under reduced pressure. The residue was triturated with 30 ml of diethyl ether and was removed from a selected oily product all volatile components under reduced pressure. The remaining oil was mixed with 40 ml of dichloromethane and 3 times was extracted with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, was filtered and was evaporated to dryness under reduced pressure, yielding 0.33 g (1.5 mmol, 31%) of methyl ester of N-ethyl-2,3-diazaspiro[4.4]non-3-EN-2-carboxymethylate in the form of a light brown oil. Spectrum of1H NMR identical to a spectrum of the substance obtained in synthesis with the use of iodomethane as meteorologi agent (see above).

N-(4-{[(2,3-Diazaspiro[4.4]non-3-EN-2-yl)ethylaminomethyl]sulfamoyl}phenyl)acetamide (compound 3, a new synthesis method)

Methyl ester of N-ethyl-2,3-diazaspiro[4.4]non-3-EN-2-carboximidic�of ocelote (157 mg, 1 meaulnes. EQ.) and 4-acetamidobenzenesulfonyl (157 mg, 1,05 meaulnes. EQ.) was mixed with 5 ml of acetonitrile. The reaction mixture was heated to reflux overnight, stirring a magnetic stirrer, and volatiles removed in vacuum. The residue was mixed with ethyl acetate and was extracted with 2 n NaOH. The organic layer was dried over Na2SO4, was filtered and was evaporated to dryness. Cleaning flash chromatography on silica gel (ethyl acetate) allowed to obtain 236 mg (87%) of N-(4-{[(2,3-diazaspiro[4.4]non-3-EN-2-yl)ethylaminomethyl]sulfamoyl}phenyl)acetamide.1H NMR (400 MHz, CDCl3) δ 1.14 in (t, J=7,2 Hz, 3H), 1,62-of 1.83 (m, 8H), of 2.20 (s, 3H), 3.43 points-3,51 (m, 2H), 3,80 (s, 2H), 6,80 (s, 1H), 6,87 (user.s, 1H), 7,56 (d, J=8,8 Hz, 2H), to 7.77 (user.s, 1H), 7,83 (d, J=8,8 Hz, 2H).

N-(4-{[(2,3-Diazaspiro[4.4]non-3-EN-2-yl)ethylaminomethyl]sulfamoyl}phenyl)acetamide (compound 3, the synthesis method disclosed in WO 2009/115515)

Hydrochloride N-ethyl-2,3-diazaspiro[4.4]non-3-EN-2-carboxamidine (60 g, 260,08 mmol; obtained by the reaction of N-ethyl-2,3-diazaspiro[4.4]non-3-EN-2-carboxamidine synthesized by the method described in WO 2009/115515, with HCl in isopropanol) was dissolved in 1000 ml of dichloromethane and was added 4-acetamidobenzenesulfonyl (60,7 g, 260,08 mmol). Within 20 minutes under stirring with a mechanical stirrer was added triethylamine (131,6 g, 1300,4 mmol) and then stirred the mixture in the Techa�their night at room temperature. The reaction mixture was extracted with water (250 ml) and concentrated the organic phase under reduced pressure (40°C, 600 mbar). The oily residue was evaporated twice together with 96% ethanol (250 ml) and mixed with 500 ml of dichloromethane. The organic phase was extracted with 1 n aqueous HCl solution (75 ml), then twice with water (200 ml) and evaporated to dryness under reduced pressure, yielding 78 g (199,2 mmol, 77%) of N-(4-{[(2,3-diazaspiro[4.4]non-3-EN-2-yl)ethylaminomethyl]sulfamoyl}phenyl)acetamide. Spectrum of1H NMR identical to a spectrum of a substance produced by the new method of synthesis (see above).

4-Amino-N-[(2,3-diazaspiro[4.4]non-3-EN-2-yl)ethylaminomethyl]benzolsulfonat (synthesis of compound 4 from compound 3)

N-(4-{[(2,3-Diazaspiro[4.4]non-3-EN-2-yl)ethylaminomethyl]sulfamoyl}phenyl)acetamide (179 g) was dissolved in 2685 ml EtOH and added 1370 ml of 1M HCl (3 meaulnes. EQ.). The resulting mixture was stirred at 55°C for 45 hours and concentrated under reduced pressure. The residue was mixed with 2200 ml of butyl acetate was added in 3800 ml of 5% aqueous NaHCO3with stirring for 55 minutes. Separated the organic phase and the aqueous phase was extracted with 200 ml of butyl acetate. The combined organic layers were washed with 1300 ml of water and evaporated to dryness, yielding 133 g of crude product. The residue is recrystallized from 800 ml of EtOH and dried in VA�the SMM at 50°C, getting 87,8 g (55%) of 4-amino-N-[(2,3-diazaspiro[4.4]non-3-EN-2-yl)ethylaminomethyl]benzosulfimide.1H NMR (400 MHz, CDCl3) δ 1.14 in (t, J=7,22 Hz, 3H), 1,47-1,89 (m, 8H), 3,35 is 3.57 (m, 2H), 3,79 (s, 2H), was 4.02 (user.s, 2H), of 6.65 (d, J=8,73 Hz, 2H), 6,78 (s, 1H), 6,91 (user.C, 1H), of 7.70 (d, J=8,73 Hz, 2H).

Etelemed 4,4-dimethyl-4,5-dihydropyrazol-1-carbothioate (compound 5)

4,4-Dimethyl-4,5-dihydro-3H-pyrazole (synthesized according to the method described in WO 2008/034863) (10 g, 1 meaulnes. EQ.) and ethylisothiocyanate (to 11.6 ml, 1,3 meaulnes. EQ.) was added to 100 ml of ethanol. The reaction mixture was boiled to reflux for 1 hour. Was added silica gel and removed volatiles in vacuo. Cleaning flash chromatography on silica gel (Et2A:PA=1:2) allowed us to obtain 15.2 g (80%) of ethylamide 4,4-dimethyl-4,5-dihydropyrazol-1-carbothioate.1H NMR (400 MHz, CDCl3) δ 1,19-of 1.30 (m, 9H), 3,63-and 3.72 (m, 2H), 3,93 (s, 2H), 6,74 (s, 1H), 7,14 (user.s, 1H).

Methyl ester of N-ethyl-4,4-dimethyl-4,5-dihydropyrazol-1-carboxymethylate (compound 6)

Etelemed 4,4-dimethyl-4,5-dihydropyrazol-1-carbothioate (15 g, 1 meaulnes. EQ.) was dissolved in 300 ml of methanol was added to 50.4 ml (10 meaulnes. EQ.) iodomethane and heated the reaction mixture at 50°C for 3 hours. Volatile components were removed under vacuum. The residue was mixed with DCM and extracted with 5% aqueous solution of NaHCO3. Org�organic layer was twice washed with water, was dried over Na2SO4, was filtered and was evaporated to dryness, yielding 15.5 g (96%) of methyl ester of N-ethyl-4,4-dimethyl-4,5-dihydropyrazol-1-carboxymethylate.1H NMR (400 MHz, CDCl3) δ of 1.16 (t, J=7,3 Hz, 3H), of 1.20 (s, 6H), of 2.45 (s, 3H), 3,49 (s, 2H), 3,53 (kV, J=7,3 Hz, 2H), 6,66 (s, 1H).

3-Chloro-N-[(4,4-dimethyl-4,5-dihydropyrazol-1-yl)ethylaminomethyl]benzolsulfonat (compound 7)

Methyl ester of N-ethyl-4,4-dimethyl-4,5-dihydropyrazol-1-carboxymethylate (0.75 g, 1 meaulnes. EQ.) and 3-chlorobenzenesulfonamide (0,76 g, 1.05 Molln. EQ.) was added to 10 ml of acetonitrile. The reaction mixture was heated to reflux overnight, and the volatile components were removed in vacuum. The residue was mixed with ethyl acetate and was extracted with 2 n NaOH. The organic layer was dried over Na2SO4, was filtered and was evaporated to dryness. Cleaning flash chromatography on silica gel (Et2O) resulted in the receipt of 1.26 g (98%) of 3-chloro-N-[(4,4-dimethyl-4,5-dihydropyrazol-1-yl)ethylaminomethyl]benzosulfimide.

1H NMR (400 MHz, CDCl3) δ of 1.17 (t, J=7,2 Hz, 3H), 1,23 (s, 6H), 3.43 points-3,52 (m, 2H), 3,79 (user.s, 2H), was 6.77 (s, 1H), 6,60-6,90 (user.s, 1H), value of 7, 37-of 7.42 (m, 1H), 7,43-7,47 (m, 1H), 7,81-a 7.85 (m, 1H), 7,94 (m, 1H).

3-Chloro-N-[(4,4-dimethyl-4,5-dihydropyrazol-1-yl)ethylaminomethyl]-4-methoxybenzenesulfonamide (compound 8)

Methyl ester of N-ethyl-4,4-dimethyl-4,5-dihyd�pyrazol-1-carboxymethylate (0.75 g, 1 meaulnes. EQ.) and 3-chloro-3-methoxybenzenesulfonamide (0,94 g, 1.05 Molln. EQ.) was added to 10 ml of acetonitrile. The reaction mixture was heated over night to reflux and the volatile components were removed in vacuum. The residue was mixed with ethyl acetate and was extracted with 2 n NaOH. The organic layer was dried over Na2SO4, was filtered and was evaporated to dryness. Cleaning flash chromatography on silica gel (Et2O) made it possible to obtain 1.43 g (97%) of 3-chloro-N-[(4,4-dimethyl-4,5-dihydropyrazol-1-yl)ethylaminomethyl]-4-methoxybenzenesulfonamide.1H NMR (400 MHz, CDCl3) δ of 1.17 (t, J=7,3 Hz, 3H), 1,22 (s, 6H), 3.43 points-3,52 (m, 2H), of 3.77 (user.s, 2H), 3,95 (s, 3H), 6.75 in (s, 1H), of 6.96 (d, J=8,6 Hz, 1H), 6,70-6,90 (user.s, 1H) 7,82 (DD, J=8,6, and 2.3 Hz, 1H), 7,95 (d, J=2,3 Hz, 1H).

Ethylamide 3-ethyl-4,5-dihydropyrazol-1-carbothioate (compound 9)

3-Ethyl-4,5-dihydro-1H-pyrazole (1.25 g, 1 meaulnes. EQ.) (synthesized according to the method described in WO 2008/034863) and ethylisothiocyanate (1,45 ml, 1,3 meaulnes. EQ.) was added to 10 ml of ethanol. The reaction mixture was boiled to reflux for 5 hours, was added silica gel and the volatile components were removed in vacuum. Cleaning flash chromatography on silica gel (Et2A:PA=1:1) resulted in the receipt of 1.54 g (65%) of ethylamide 3-ethyl-4,5-dihydropyrazol-1-carbothioate.1H NMR (400 MHz, CDCl3) δ of 1.18 (t, J=7.5 Hz, 3H), 1,25 (t, J=7,2 Hz, 3H), 2,38 (kV, J=7.5 Hz, 2H), 2,83 (t, J=9.9 Hz, H), 3,63-and 3.72 (m, 2H), 4,19 (t, J=9.9 Hz, 2H), 7,06 (user.s, 1H).

Methyl ester 3,N-diethyl-4,5-dihydropyrazol-1-carboxymethylate (compound 10)

Ethylamide 3-ethyl-4,5-dihydropyrazol-1-carbothioate (1,51 g, 1 meaulnes. EQ.) was dissolved in 30 ml of methanol, was added itmean (5,1 ml, 10 meaulnes. EQ.) and heated the reaction mixture at 50°C for 1 hour. Volatile components were removed under vacuum. The residue was mixed with DCM and extracted with 5% aqueous solution of NaHCO3. The organic layer was twice washed with water, dried over Na2SO4, was filtered and was evaporated to dryness, yielding 1.44 g (89%) of methyl ester 3,N-diethyl-4,5-dihydropyrazol-1-carboxymethylate.1H NMR (400 MHz, CDCl3) δ 1,12-to 1.21 (m, 6H), 2,39 (kV, J=7,4 Hz, 2H), 2,48 (c, 3H), 2,70 (t, J=9,7 Hz, 2H), 3,52 (kV, J=7,2 Hz, 2H), of 3.75 (t, J=9,7 Hz, 2H).

2-Chloro-N-[ethylamino-(3-ethyl-4,5-dihydropyrazol-1-yl)methylene]benzolsulfonat (compound 11)

Methyl ester 3,N-diethyl-4,5-dihydropyrazol-1-carboxymethylate (1.42 g, 1 meaulnes. EQ.) and 2-chlorobenzenesulfonamide (1.43 g, 1.05 Molln. EQ.) was added to 20 ml of acetonitrile. The reaction mixture was heated to reflux overnight and was removed under vacuum volatile components. The residue was mixed with ethyl acetate and was extracted with 2 n NaOH. The organic layer was dried over Na2SO4, was filtered and was evaporated� dry. The residue obtained after purification flash chromatography on silica gel (Et2O), triturated with diisopropyl ether, yielding 2.08 g (81%) of 2-chloro-N-[ethylamino-(3-ethyl-4,5-dihydropyrazol-1-yl)methylene]benzosulfimide.1H NMR (400 MHz, CDCl3) δ of 1.15 (t, J=7,3 Hz, 3H), of 1.17 (t, J=7,3 Hz, 3H), of 2.38 (q, J=7,3 Hz, 2H), 2,80 (t, J=9,8 Hz, 2H), 3,44-of 3.53 (m, 2H), 4,11 (t, J=9,8 Hz, 2H), 6,73 (user.s, 1H), to 7.33 (dt, J=7,6, 2,0 Hz, 1H), 7,38 (dt, J=7,6, 2,0 Hz, 1H), of 7.46 (DD, J=to 7.6, 2.0 Hz, 1H), 8,17 (DD, J=to 7.6, 2.0 Hz, 1H).

N-(2-Bromophenyl)-2,2,2-triptoreline (compound 12)

2 Bromoaniline (24,9 g, 1 meaulnes. EQ.) was dissolved in 200 ml of dichloromethane, was added triethylamine (28 ml, 1,4 meaulnes. EQ.), cooled the reaction mixture to 0°C and dropwise added trifluoroacetic aldehyde (24 ml, 1.2 Molln. EQ.) (maintaining the temperature below 10°C). When you are finished adding the mixture was heated to room temperature and stirred for another 2 hours. The resulting mixture was quenched with water, separated the organic layer was dried over Na2SO4, was filtered and was evaporated under reduced pressure. Cleaning flash chromatography on silica gel (Et2A:PA=1:6) allowed obtaining of 34.6 g (89%) of N-(2-bromophenyl)-2,2,2-trifurcated.1H NMR (400 MHz, CDCl3) δ 7,12 (dt, J=8,0, a 1.3 Hz, 1H), 7,39 (dt, J=8,0, a 1.3 Hz, 1H), 7,61 (DD, J=8,0, a 1.3 Hz, 1H), 8,31 (DD, J=8,0, a 1.3 Hz, 1H), 8,45 (user.s, 1H).

3-Bromo-4-(2,2,2-triptoreline)benzolsulfonat (compound 13)

N-(2-Bromophenyl)-2,2,2-trifurcated (15.0 g, 1.0 EQ.) while cooling in an ice bath four portions was added to chlorosulfonic acid (18,7 ml, 5 meaulnes. EQ.). The ice bath was removed, the mixture was heated to room temperature and then at 80°C. After stirring for 1 hour the mixture was cooled to room temperature and poured into ice. The resulting mixture was extracted with dichloromethane, dried over Na2SO4, was filtered and was evaporated to dryness, obtaining of 17.4 g (85%) of 3-bromo-4-(2,2,2-triptoreline)benzolsulfonat.1H NMR (400 MHz, CDCl3) δ 8,09 (DD, J=9,0, a 2.0 Hz, 1H), 8,30 (d, J=2,0 Hz, 1H), 8,69 (d, J=9,0 Hz, 1H), of 8.71 (user.s,1H).

N-(2-Bromo-4-sulfamoylbenzoyl)-2,2,2-triptoreline (compound 14)

3-Bromo-4-(2,2,2-triptoreline)benzolsulfonat (16,2 g, 1 meaulnes. EQ.) was dissolved in 150 ml of acetonitrile and cooled to 0°C. was added dropwise ammonium hydroxide (20,8 ml, 3 meaulnes. EQ.) and stirred the reaction mixture at room temperature for 10 min, and during this time a white precipitate appeared. Volatile components were removed under reduced pressure, the solid residue was washed with water and dried under vacuum, yielding 14.3 g (94%) of N-(2-bromo-4-sulfamoylbenzoyl)-2,2,2-trifurcated.1H NMR (400 MHz, DMSO-d6) δ members, 7.59 (s, 2H), 7,69 (d, J=8,2 Hz, 1H), of 7.88 (DD, J=8,2 and 1.8 Hz, 1H), 8,14 (d, J=1, Hz, 1H), 11,55 (c, 1H).

N-(2-Bromo-4-{[(4,4-dimethyl-4,5-dihydropyrazol-1-yl)ethylaminomethyl]sulfamoyl}phenyl)-2,2,2-triptoreline (compound 15)

Methyl ester of N-ethyl-4,4-dimethyl-4,5-dihydropyrazol-1-carboxymethylate (3,41 g, 1 meaulnes. EQ.) and N-(2-bromo-4-sulfamoylbenzoyl)-2,2,2-trifurcated (for 6.24 g, 1.05 Molln. EQ.) was added to 100 ml of acetonitrile. The reaction mixture was heated to reflux overnight, after which the volatile components were removed under reduced pressure. The residue was mixed with ethyl acetate, was extracted with 2 n NaOH, the organic layer was dried over Na2SO4, was filtered and was evaporated to dryness. Cleaning flash chromatography on silica gel (Et2O) made it possible to obtain 7.1 g (83%) of N-(2-bromo-4-{[(4,4-dimethyl-4,5-dihydropyrazol-1-yl)ethylaminomethyl]sulfamoyl}phenyl)-2,2,2-trifurcated.1H NMR (400 MHz, CDCl3) δ of 1.18 (t, J=7,3 Hz, 3H), 1,24 (s, 6H), 3.43 points-3,51 (m, 2H), 3,79 (user.s, 2H), 6,78 (s, 1H), 7,93 (DD, J=8,6, 2,0 Hz, 1H), to 8.19 (d, J=2,0 Hz, 1H), of 8.39 (d, J=8,6 Hz, 1H), 8,61 (user.s, 1H).

4-Amino-3-bromo-N-[(4,4-dimethyl-4,5-dihydropyrazol-1-yl)ethylaminomethyl]benzolsulfonat (compound 16)

N-(2-Bromo-4-{[(4,4-dimethyl-4,5-dihydropyrazol-1-yl)ethylaminomethyl]sulfamoyl}phenyl)-2,2,2-trifurcated (7.0 g, 1 meaulnes. EQ.) was dissolved in 225 ml of methanol was added potassium carbonate (10.3 g, 5 meaulnes. EQ.) and water (30 ml) � boil the reaction mixture to reflux for 2.5 hours. Evaporated volatile components under reduced pressure, and the residue was mixed with ethyl acetate and was extracted with 2 n NaOH. The organic layer was dried over Na2SO4, filtered and concentrated on silica gel. Cleaning flash chromatography on silica gel (Et2O) made it possible to obtain 4.1 g (73%) of 4-amino-3-bromo-N-[(4,4-dimethyl-4,5-dihydropyrazol-1-yl)ethylaminomethyl]benzosulfimide.1H NMR (400 MHz, CDCl3) δ of 1.17 (t, J=7,3 Hz, 3H), 1,21 (s, 6H), 3.43 points-3,52 (m, 2H), 3,74 (user.s, 2H), 4,45 (user.s, 2H), 6,73 (s, 1H), 6.75 in (d, J=8.4 Hz, 1H), 6,83-at 6.92 (user.s, 1H), 7,65 (DD, J=8,4, 2,0 Hz, 1H), 7,99 (d, J=2,0 Hz, 1H).

(4,4-Dimethyl-4,5-dihydropyrazol-1-yl)ethylaminomethyl 2-trifluoromethyl-1H-indole-5-sulfonic acid (compound 17)

In a vessel of Pyrex glass, purged and filled with nitrogen, was dissolved 4-amino-3-bromo-N-[(4,4-dimethylimidazolidin-1-yl)ethylaminomethyl]benzolsulfonat (2,23 g, 1 meaulnes. EQ.) in 33 ml of degassed toluene. Then to the reaction mixture was added Tris(dibenzylideneacetone)dipalladium (0) (2,54 g, 0,5 meaulnes. EQ.), 1,1'-bis(diphenylphosphino)ferrocene (4,61 g, 1,5 meaulnes. EQ.), the cesium carbonate (2,17 g, 1,2 meaulnes. EQ.) and 2-bromo-3,3,3-cryptochromes (1,94 g, 2 meaulnes. EQ.). The reaction mixture was heated overnight at 115°C, then cooled, was added ethyl acetate and the mixture was filtered through hyflo. Cleaning flash chromatography on silica gel (Et2O) after�following purification preparative TLC (Et 2O) made it possible to obtain 254 mg (10%) (4,4-dimethyl-4,5-dihydropyrazol-1-yl)ethylaminomethyl 2-trifluoromethyl-1H-indole-5-sulfonic acid.1H NMR (400 MHz, CDCl3) δ of 1.15 (t, J=7,3 Hz, 3H), 1,21 (c, 6H), 3.43 points-3,51 (m, 2H), 3,76 (user.s, 2H), 6,73 (s, 1H), 6,70-7,00 (user.s, 1H), 7,01 (s, 1H), 7,50 (d, J=to 8.7 Hz, 1H), of 7.88 (DD, J=to 8.7, 1.5 Hz, 1H), 8,31 (user.s, 1H), 9,39 (user.s, 1H).

Ethylamide 5-thiophene-3-yl-4,5-dihydropyrazol-1-carbothioate (compound 18)

5-Thiophene-3-yl-4,5-dihydro-1H-pyrazole (1,82 g, 1 meaulnes. EQ.) (synthesized according to the method described in WO 2008/034863) and ethylisothiocyanate (1,36 ml, 1,3 meaulnes. EQ.) was added to 15 ml of ethanol. The reaction mixture was boiled to reflux for 5 hours and then concentrated on silica gel under reduced pressure. Cleaning flash chromatography on silica gel (Et2A:PA=1:1) allowed to obtain 0.70 g (26%) of ethylamide 5-thiophene-3-yl-4,5-dihydropyrazol-1-carbothioate.1H NMR (400 MHz, CDCl3) δ 1,24 (t, J=7,2 Hz, 3H), 2,86 (DDD, J=18,5, of 3.3 and 1.7 Hz, 1H), 3,39 (DDD, J=18,5, 11,4, the 1.7 Hz, 1H), 3,56-of 3.77 (m, 2H), 6,01 (DD, J=11,4, 3.3 Hz, 1H), 6,93 (DD, J=5,0, 1.0 Hz, 1H), 7,02 (t, J=the 1.7 Hz, 1H), 7,13 (m, 1H), 7,26 (m, 1H).

Methyl ester of N-ethyl-5-thiophene-3-yl-4,5-dihydropyrazol-1-carboxymethylate (compound 19)

Ethylamide 5-thiophene-3-yl-4,5-dihydropyrazol-1-carbothioate (0.70 g, 1 meaulnes. EQ.) was dissolved in 14 ml of methanol, was added itmean (1,82 ml, 10 meaulnes. �sq) and the reaction mixture was heated at 50°C for 1 hour. Volatile components were removed under vacuum, the residue was mixed with dichloromethane and was extracted with 5% aqueous solution of NaHCO3. The organic layer was twice washed with water, dried over Na2SO4, was filtered and was evaporated to dryness. Cleaning flash chromatography on silica gel (EtOAc:MeOH=9:1) allowed to obtain of 0.48 g (64%) of methyl ester of N-ethyl-5-thiophene-3-yl-4,5-dihydropyrazol-1-carboxymethylate.1H NMR (400 MHz, CDCl3) δ of 1.03 (t, J=7,3, 3H), 2,44 (s, 3H), 2,84 (DDD, J=18,1, 10,4, 1.5 Hz, 1H), 3,23-3,51 (m, 3H), to 5.57 (t, J=10.4 Hz, 1H), 6,87 (user.s, 1H), 7,00 (d, J=4,8, 1H), 7,13 (d, J=3,0, 1H), from 7.24 (DD, J=4,8, and 3.0 Hz, 1H).

3-Chloro-N-[ethylamino-(5-thiophene-3-yl-4,5-dihydropyrazol-1-yl)methylene]benzolsulfonat (compound 20)

Methyl ester of N-ethyl-5-thiophene-3-yl-4,5-dihydropyrazol-1-carboxymethylate (0.47 g, 1 meaulnes. EQ.) and 3-chlorobenzenesulfonamide (0,37 g, 1.05 Molln. EQ. (0,37 g, 1.05 Molln. EQ.) was added to 7 ml of acetonitrile. The reaction mixture was heated over night to reflux and the volatile components were removed under reduced pressure. The residue was mixed with ethyl acetate and was extracted with 2 n NaOH. The organic layer was dried over Na2SO4, was filtered and was evaporated to dryness. Cleaning flash chromatography on silica gel (Et2O) allowed obtaining of 0.44 g (49%) of 3-chloro-N-[ethylamino-(5-thiophene-3-yl-4,5-dihydropyrazol-1-yl)methylene]benzosulfimide.13) δ 1,19 (t, J=7,2, 3H), 2,78 (DDD, J=18,6, of 6.0, 1.4 Hz, 1H), 3,31 (DDD, J=18,6, 11,8, a 1.4 Hz, 1H), 3,54-3,70 (m, 2H), to 5.62 (DD, J=11,8, 6,0 Hz, 1H), 6.75 in (d, J=4.3 Hz, 1H), at 6.92 (d, J=2,0 Hz, 1H), 7,02 (user.s, 1H), 7,17-7.23 percent (m, 2H), of 7.36 (m, 2H), 7,54 (user.s, 1H).

Amide 6-chloroimidazo[2,1-b]thiazole-5-sulfonic acid (compound 21)

6 Chloroimidazo[2,1-b]thiazole-5-sulphonylchloride (2 g, 1 meaulnes. EQ.) was dissolved in 20 ml of acetonitrile and cooled to 0°C. was added dropwise ammonium hydroxide (3.7 ml, 3 meaulnes. EQ.) and stirred the reaction mixture at room temperature for 10 min, and during this time formed a white precipitate. Volatiles were removed under reduced pressure, the solid residue was washed with water and dried under vacuum to give 1.62 g (88%) of amide 6-chloroimidazo[2,1-b]thiazole-5-sulfonic acid.1H NMR (400 MHz, DMSO-d6) δ 7.62 mm (d, J=4,6 1H), 7,98 (d, J=4,6 Hz, 1H), 8,00 (user.s, 2H).

Methylamide 8-ox-2,3-diazaspiro[4.5]Dec-3-EN-2-carbothioate (compound 22)

8-ox-2,3-diazaspiro[4.5]Dec-2-ene (0.8 g, 1 meaulnes. EQ.) (synthesized according to the method described in WO 2008/034863) and methylisothiocyanate (0.54 g, 1.3 Molln. EQ.) was added to 10 ml of ethanol and heated the reaction mixture to reflux for 5 hours. Was added silica gel and the volatile components were removed under reduced pressure. Cleaning flash chromatography on silica gel (E 2O) made it possible to obtain 0.52 g (35%) methylamide 8-ox-2,3-diazaspiro[4.5]Dec-3-EN-2-carbothiolate.1H NMR (400 MHz, CDCl3) δ 1,52-1,59 (m, 3H), 1,82-1,90 (m, 2H), 3,17 (d, J=5,0, 3H), 3,56-to 3.64 (m, 2H), 3,86-3,92 (m, 2H), 4,11 (s, 2H), 6,80 (s, 1H), 7,21 (user.s, 1H).

Methyl ester of N-methyl-8-ox-2,3-diazaspiro[4.5]Dec-3-EN-2-carboxymethylate (compound 23)

Methylamide 8-ox-2,3-diazaspiro[4.5]Dec-3-EN-2-carbothioate (0.50 g, 1 meaulnes. EQ.) was dissolved in 10 ml of methanol, was added itmean (1.2 ml, 10 meaulnes. EQ.) and heated the reaction mixture at 50°C for 5 hours. Volatile components were removed under reduced pressure, the residue was mixed with DCM and extracted with 5% aqueous solution of NaHCO3. The organic layer was twice washed with water, dried over Na2SO4, was filtered and was evaporated to dryness, obtaining of 0.43 g (99%) of methyl ester of N-methyl-8-ox-2,3-diazaspiro[4.5]Dec-3-EN-2-carboxymethylate.1H NMR (400 MHz, CDCl3) δ of 1.53 to 1.60 (m, 2H), 1,80-of 1.88 (m, 2H), 2,47 (s, 3H), 3,26 (s, 3H), 3,56-to 3.64 (m, 2H), 3,68 (s, 2H), 3,83-3,89 (m, 2H), 6,73 (s, 1H).

Methylamino-(8-ox-2,3-diazaspiro[4.5]Dec-3-EN-2-yl)MachineName 6 chloroimidazo[2,1-b]thiazole-5-sulfonic acid (compound 24)

Methyl ester of N-methyl-8-ox-2,3-diazaspiro[4.5]Dec-3-EN-2-carboxymethylate (0.42 g, 1 meaulnes. EQ.) and amide 6-chloroimidazo[2,1-b]thiazole-5-sulfonic acid (0.46 g, 1.05 Molln. EQ) was added to 7 ml of acetonitrile and heated the reaction mixture to reflux over night. Volatile components were removed under reduced pressure and the residue was mixed with ethyl acetate and was extracted with 2 n NaOH. The organic layer was dried over Na2SO4, was filtered and was evaporated to dryness. Cleaning flash chromatography on silica gel (EtOAc) allowed to obtain 0.56 g (69%) methylamino-(8-ox-2,3-diazaspiro[4.5]Dec-3-EN-2-yl)methanamine 6 chloroimidazo[2,1-b]thiazole-5-sulfonic acid.1H NMR (400 MHz, CDCl3) δ 1,51-of 1.57 (m, 2H), 1,80-1,89 (m, 2H), 3,10 (d, J=5.0 Hz, 3H), 3,51-3,59 (m, 2H), 3,83-3,90 (m, 4H), 3,89 (s, 2H), 6,89 (s, 1H), 6,99 (d, J=4,6 Hz, 1H), 7,12 (user.s, 1H), 8,01 (d, J=4,6 Hz, 1H).

Ethylamide 4-ethyl-4,5-dihydropyrazol-1-carbothioate (compound 25)

4-Ethyl-4,5-dihydro-1H-pyrazole (2.68 g, 1 meaulnes. EQ.) (synthesized according to the method described in WO 2008/034863) and ethylisothiocyanate (3,11 ml, 1,3 meaulnes. EQ.) was added to 20 ml of ethanol. The reaction mixture was heated to reflux overnight, was added silica gel and the volatile components were removed under reduced pressure. Cleaning flash chromatography on silica gel (Et2A:PA=1:3) allowed to obtain 1.80 g (36%) of ethylamide 4-ethyl-4,5-dihydropyrazol-1-carbothioate.1H NMR (400 MHz, CDCl3) δ 0,99 (t, J=7.5 Hz, 3H), 1,25 (t, J=7,2 Hz, 3H), 1,47-1,71 (m, 2H), is 3.08-3,18 (m, 1H), 3,63-and 3.72 (m, 2H), 3,86 (DD, J=11,5, 7,1 Hz, 1H), 4,25 (t, J=11.5 Hz, 1H), 6,90 (d, J=1.5 Hz, 1H), 7,12 (user.s, 1H).

Methyl ester 4,N-diethyl-4,5-dihydropyrazol-1-carboxymethylation� (compound 26)

Ethylamide 4-ethyl-4,5-dihydropyrazol-1-carbothioate (1.80 g, 1 meaulnes. EQ.) was dissolved in 36 ml of methanol, was added itmean (6,1 ml, 10 meaulnes. EQ.) and heated the reaction mixture at 50°C for 4 hours. Volatile components were removed under reduced pressure, the residue was mixed with DCM and extracted with 5% aqueous solution of NaHCO3. The organic layer was twice washed with water, dried over Na2SO4, was filtered and was evaporated to dryness, yielding 1,68 g (87%) of methyl ester 4,N-diethyl-4,5-dihydropyrazol-1-carboxymethylate.1H NMR (400 MHz, CDCl3) δ of 0.98 (t, J=7.5 Hz, 3H), of 1.16 (t, J=7,3 Hz, 3H), 1,45-1,70 (m, 2H), of 2.45 (s, 3H), 2,97-of 3.07 (m, 1H), 3,44 (DD, J=11,0, 8,3 Hz, 1H), 3,51-3,58 (m, 2H), 3,83 (t, J=11,0 Hz, 1H), is 6.81 (s, 1H).

Ethylamino-(4-ethyl-4,5-dihydropyrazol-1-yl)MachineName piperidine-1-sulfonic acid (compound 27)

Methyl ester 4,N-diethyl-4,5-dihydropyrazol-1-carboxymethylate (0.70 g, 1 meaulnes. EQ.) and the amide piperidine-1-sulfonic acid (0,61 g, 1.05 Molln. EQ.) was added to 7 ml of acetonitrile and heated the reaction mixture to reflux over night. Volatile components were removed under reduced pressure, the residue was mixed with ethyl acetate and was extracted with 2 n NaOH. The organic layer was dried over Na2SO4, was filtered and was evaporated to dryness. Cleaning flash chromatography on forces�the Kagel (Et 2A:PA=2:1) allowed to obtain 1.12 g (96%) of ethylamino-(4-ethyl-4,5-dihydropyrazol-1-yl)methylamide piperidine-1-sulfonic acid.1H NMR (400 MHz, CDCl3) δ 0,99 (t, J=7.5 Hz, 3H), 1,21 (t, J=7,2 Hz, 3H), 1,45-1,72 (m, 8H), 3,07-3,17 (m, 5H), 3,48 is 3.57 (m, 2H), 3,73 (DD, J=11,0, at 7.7 Hz, 1H), 4,08-4,19 (m, 1H), to 6.58 (user.s,1H), of 6.87 (d, J=1.3 Hz, 1H).

Amide, TRANS-2-phenylacetophenone acid (compound 28)

TRANS-2-phenylacetonitrile (3.3 g, 1 meaulnes. EQ.) was dissolved in 33 ml of acetonitrile and cooled to 0°C. was added dropwise ammonium hydroxide (7.7 ml, 3 EQ.) and stirred the reaction mixture at room temperature for 10 min the Volatile components were removed under reduced pressure, the solid residue was washed with water and dried under vacuum to give 1.13 g (38%) of an amide of TRANS-2-phenylacetophenone acid.1H NMR (400 MHz, DMSO-d6) δ 7,11 (user.s, 2H), 7.23 percent (d, J=16,0 Hz, 1H), 7,31 (d, J=16,0 Hz, 1H), 7,41 was 7.45 (m, 3H), of 7.64-7,71 (m, 2H).

Ethylamino-(4-ethyl-4,5-dihydropyrazol-1-yl)MachineName TRANS-2-phenylacetophenone acid (compound 29)

Methyl ester 4,N-diethyl-4,5-dihydropyrazol-1-carboxymethylate (0.70 g, 1 meaulnes. EQ.) and amide TRANS-2-phenylacetophenone acid (0,68 g, 1.05 Molln. EQ.) was added to 7 ml of acetonitrile and heated the reaction mixture to reflux over night. Volatile components were removed under low�nom pressure and the residue was mixed with ethyl acetate and was extracted with 2 n NaOH. The organic layer was dried over Na2SO4, was filtered and was evaporated to dryness. Cleaning flash chromatography on silica gel (Et2A:PA=2:1) allowed to obtain 1.00 g (81%) of ethylamino-(4-ethyl-4,5-dihydropyrazol-1-yl)methylamide TRANS-2-phenylacetophenone acid.1H NMR (400 MHz, CDCl3) δ of 0.98 (t, J=7.5 Hz, 3H), 1,21 (t, J=7,2 Hz, 3H), 1,46-1,70 (m, 2H), 3,06-3,16 (m, 1H), 3,51-3,59 (m, 2H), 3,74 (DD, J=11,3, 7.5 Hz, 1H), 4,13 (t, J=11.3 Hz, 1H), 6,70-at 6.92 (m, 1H), at 6.92 (d, J=1.3 Hz, 1H), 6,97 (d, J=to 15.4 Hz, 1H), 7,35-7,41 (m, 3H), 7,44 (d, J=to 15.4 Hz, 1H), of 7.46-7,50 (m, 2H).

Amide 5-chlorothiophene-2-sulfonic acid (compound 30)

5-Chlorothiophene-2-sulphonylchloride (3 g, 1 meaulnes. EQ.) was dissolved in 30 ml of acetonitrile and cooled to 0°C. was added dropwise ammonium hydroxide (6.5 ml, 3 meaulnes. EQ.) and stirred the reaction mixture at room temperature for 10 min the Volatile components were removed under reduced pressure, the solid residue was washed with water and dried under vacuum to give 2,49 g (91%) amide 5-chlorothiophene-2-sulfonic acid.1H NMR (400 MHz, DMSO-d6) δ 7,21 (d, J=4.0 Hz, 1H), 7,43 (d, J=4.0 Hz, 1H), 7,79 (user.s, 2H).

Amide 4,4-dimethyl-4,5-dihydropyrazol-1-carbothioate (compound 31)

4,4-Dimethyl-4,5-dihydro-3H-pyrazole (3.0 g, 1 meaulnes. EQ.) (synthesized according to the method described in WO 2008/034863) and trimethylsilyldiazomethane (5,6 ml, 1,3 meaulnes. EQ.) added K ml of ethanol and heated the reaction mixture to reflux for 5 hours. Was added silica gel and the volatile components were removed under reduced pressure. Cleaning flash chromatography on silica gel (Et2A:PA=2:1) allowed to obtain 3.91 g (81%) of amide 4,4-dimethyl-4,5-dihydropyrazol-1-carbothioate.1H NMR (400 MHz, CDCl3) δ of 1.27 (s, 6H), 3,94 (s, 2H), 5,82-system 6.34 (user.s,1H), 6,50-7,00 (user.s,1H), 6,80 (s, 1H).

Methyl ester of 4,4-dimethyl-4,5-dihydropyrazol-1-carboxymethylate (compound 32)

Amide 4,4-dimethyl-4,5-dihydropyrazol-1-carbothioate (1,50 g, 1 meaulnes. EQ.) was dissolved in 30 ml of methanol, was added itmean (5,9 ml, 10 meaulnes. EQ.) and stirred the reaction mixture at room temperature for 2 hours. Volatile components were removed under reduced pressure, the residue was mixed with DCM and extracted with 5% aqueous solution of NaHCO3. The organic layer was twice washed with water, dried over Na2SO4, was filtered and was evaporated to dryness, yielding 1.53 g (94%) of methyl ester of 4,4-dimethyl-4,5-dihydropyrazol-1-carboxymethylate.1H NMR (400 MHz, CDCl3) δ 1,24 (s, 6H), 2,32 (s, 3H), 3,65 (s, 2H), 6,63 (s, 1H), 6,66-of 6.85 (user.s, 1H).

Amino-(4,4-dimethyl-4,5-dihydropyrazol-1-yl)metronomic 5-chlorothiophene-2-sulfonic acid (compound 33)

Methyl ester of 4,4-dimethyl-4,5-dihydropyrazol-1-carboxymethylate (1.0 g, 1 meaulnes. EQ.) and amide 5-chlorothiophene-2-sulfonic �of islote (1.21 g, 1,05 meaulnes. EQ.) was added to 10 ml of acetonitrile. The reaction mixture was heated to reflux overnight, and the volatile components were removed under reduced pressure. The residue was mixed with ethyl acetate and was extracted with 2 n NaOH. The organic layer was dried over Na2SO4, was filtered and was evaporated to dryness. Cleaning flash chromatography on silica gel (Et2A:PA=2:1) resulted in obtaining 1.58 g (80%) of amino-(4,4-dimethyl-4,5-dihydropyrazol-1-yl)methylamide 5-chlorothiophene-2-sulfonic acid.1H NMR (400 MHz, CDCl3) δ 1,25 (s, 6H), 3,63 (s, 2H), 6,00-6,50 (user.s, 1H), of 6.79 (s, 1H), of 6.85 (d, J=4.0 Hz, 1H), 7,10-7,35 (user.s, 1H), value of 7, 37 (d, J=4.0 Hz, 1H).

(2,2,2-trifluoroethyl)amide of 4-ethyl-4,5-dihydropyrazol-1-carbothioate (compound 34)

A solution of 2,2,2-triptoreline (3.2 ml, 1 meaulnes. EQ.) in 60 ml of acetonitrile was added with stirring at room temperature to a solution of 1,1'-thiocarbonyldiimidazole (7.4 g, 2.1 Molln. EQ.) in 100 ml of acetonitrile. The reaction mixture was stirred overnight and added to her 4-ethyl-4,5-dihydro-1H-pyrazole (1,96 g, 1 meaulnes. EQ.) (synthesized according to the method described in WO 2008/034863). After 1 hour, the volatile components were removed under reduced pressure and the residue was purified by flash chromatography on silica gel (Et2A:PA=1:3) to give 2.85 g (60%) (2,2,2-trifluoroethyl)amide of 4-ethyl-4,5-dihydropyrazol-1-carbothioate.1H NMR (400 M�C, CDCl3) δ 1,01 (t, J=7.5 Hz, 3H), 1,50-of 1.74 (m, 2H), 3,13-3,23 (m, 1H), 3,86 (DD, J=11,6, 7,1 Hz, 1H), 4,27 (t, J=11,6 Hz, 1H), of 4.44 (m, 2H) 6,99 (d, J=1.5 Hz, 1H), 7,32-7,40 (user.s, 1H).

Methyl ester 4-ethyl-N-(2,2,2-trifluoroethyl)-4,5-dihydropyrazol-1-carboxymethylate (compound 35)

(2,2,2-trifluoroethyl)amide of 4-ethyl-4,5-dihydropyrazol-1-carbothioate (2,80 g, 1 meaulnes. EQ.) was dissolved in 56 ml of methanol, was added itmean (7.3 ml, 10 meaulnes. EQ.) and heated the reaction mixture at 50°C for 4 hours. Volatile components were removed under reduced pressure, the residue was mixed with DCM and extracted with 5% aqueous solution of NaHCO3. The organic layer was twice washed with water, dried over Na2SO4, was filtered and was evaporated to dryness. Cleaning flash chromatography on silica gel (Et2A:PA=1:1) allowed to obtain 0,57 g (19%) of methyl ester 4-ethyl-N-(2,2,2-trifluoroethyl)-4,5-dihydropyrazol-1-carboxymethylate.1H NMR (400 MHz, CDCl3) δ 0,99 (t, J=7.5 Hz, 3H), 1,46-1,70 (m, 2H), 2,48 (s, 3H), 3,01-3,11 (m, 1H), 3,50 (DD, J=11,5, and 7.8 Hz, 1H), 3,90 (t, J=11.5 Hz, 1H), 3,99-4,11 (m, 2H), of 6.85 (d, J=1.5 Hz, 1H).

3-Chloro-N-[(4-ethyl-4,5-dihydropyrazol-1-yl)-(2,2,2-triptoreline)methylene]benzolsulfonat (compound 36)

Methyl ester 4-ethyl-N-(2,2,2-trifluoroethyl)-4,5-dihydropyrazol-1-carboxymethylate (0,57 g, 1 meaulnes. EQ.) and 3-chloro-benzolsulfonat (3.0 g, 6.8 Molln. EQ.) added � 20 ml of acetonitrile. The reaction mixture was boiled to reflux for 72 hours and the volatile components were removed under reduced pressure. The residue was mixed with ethyl acetate and was extracted with 2 n NaOH. The organic layer was dried over Na2SO4, was filtered and was evaporated to dryness. Cleaning flash chromatography on silica gel (Et2A:PA=1:1) allowed to obtain 0.36 g (38%) of 3-chloro-N-[(4-ethyl-4,5-dihydropyrazol-1-yl)-(2,2,2-triptoreline)methylene]benzosulfimide.1H NMR (400 MHz, CDCl3) δ of 1.00 (t, J=7.5 Hz, 3H), 1,51-of 1.74 (m, 2H), 3,16-3,27 (m, 1H), a 3.87 (DD, J=11,2, 7.5 Hz, 1H), 4,03-to 4.14 (m, 2H), 4,28 (t, J=11.2 Hz, 1H), 7,03 (d, J=1.5 Hz, 1H), 7,41 (t, J=7,8 Hz, 1H), of 7.46-7,50 (m, 1H), 7,79-7,84 (m, 1H), 7,91-7,94 (m, 1H).

4-Amino-N-[(4,4-dimethyl-4,5-dihydropyrazol-1-yl)ethylaminomethyl]benzolsulfonat (compound 37)

Methyl ester of N-ethyl-4,4-dimethyl-4,5-dihydropyrazol-1-carboxymethylate (0.75 g, 1 meaulnes. EQ.) and sulfanilamide (0.65 g, 1.0 Molln. EQ.) was added to 10 ml of acetonitrile. The reaction mixture was heated to reflux overnight, and the volatile components were removed under reduced pressure. The residue was mixed with ethyl acetate and was extracted with 2 n NaOH. The organic layer was dried over Na2SO4, was filtered and was evaporated to dryness. Cleaning flash chromatography on silica gel (Et2O:EtOAc=1:1) allowed to obtain 1.13 g (86%) of 4-amino-N-[(4,4-dimethyl-4,5-dihydropyrazol-1-yl)e�illuminometer]benzosulfimide. 1H NMR (400 MHz, CDCl3) δ of 1.15 (t, J=7,2 Hz, 3H), of 1.20 (s, 6H), 3.43 points-3,51 (m, 2H), 3,74 (user.s, 2H), 3,98 (user.s, 2H), 6,66 (d, J=8,6 Hz, 2H), 6,71 (s, 1H), 7,71 (d, J=8,6 Hz, 2H).

4-Amino-N-[(2,3-diazaspiro[4.4]non-3-EN-2-yl)ethylaminomethyl]benzolsulfonat (synthesis of compound 4 from compound 2)

In a reactor equipped with a scrubber containing 50 ml of a 11% aqueous solution of NaOCl, 5 ml 50% aqueous NaOH solution and 50 ml of water, mixed methyl ester N-ethyl-2,3-diazaspiro[4,4]non-3-EN-2-carboxymethylate (4,00 g, 1 meaulnes. EQ.) and sulfanilamide (3,06 g, 1 meaulnes. EQ.) with 175 ml of acetonitrile. The reaction mixture was boiled to reflux for 18 h and then concentrated to about half volume by distillation of acetonitrile at atmospheric pressure. After cooling to room temperature was added 30 ml of 2 n NaOH and 100 ml of DCM and the mixture was stirred for 5 minutes. The layers were separated and the organic phase was twice washed with water (sediment released during the second washing was combined with the organic phase). The organic phase was concentrated to approximately 1/3 its original volume under reduced pressure, the solids were separated by filtration, twice washed with 5 ml DCM and dried under vacuum at 50°C, receiving 3,14 g of white solids. Even 0,99 g of a solid substance was isolated from the mother liquor after leaving for the night, Thu� allowed to raise the total yield to 67%. 1H NMR (400 MHz, CD3CN) δ was 1.04 (t, J=7.5 Hz, 3H), 1,58-of 1.83 (m, 8H), 3,36-3,44 (m, 2H), 3,68 (user.s, 2H), 4,63 (user.s, 2H), only 6.64 (d, J=to 8.7 Hz, 2H), 6,95 (s, 1H), 3,96 (user.s, 1H), 7,54 (d, J=to 8.7 Hz, 2H). HR-MS [M+H]+350,1670; MS-MS [m/z] 257, 195, 178, 156 and 125 (identical to the reference sample of compound 4, obtained by removing the protective connection 3 acid).

(2,3-Diazaspiro[4.4]non-3-EN-2-yl)ethylaminomethyl 1H-indole-5-sulfonic acid (compound 38)

Methyl ester of N-ethyl-2,3-diazaspiro[4.4]non-3-EN-2-carboxymethylate (100 mg, 1 meaulnes. EQ.) and amide 1H-indole-5-sulfonic acid (92,5 mg, 1,05 meaulnes. EQ.) was added to 3 ml of acetonitrile. The reaction mixture was heated over night to reflux and the volatile components were removed under reduced pressure. The residue was mixed with ethyl acetate and was extracted with 2 n NaOH. The organic layer was dried over Na2SO4, was filtered and was evaporated to dryness. Cleaning flash chromatography on silica gel (Et2O:EtOAc=1:1) allowed to obtain 152 mg (87%) of (2,3-diazaspiro[4.4]non-3-EN-2-yl)ethylaminomethyl 1H-indole-5-sulfonic acid.1H NMR (400 MHz, CDCl3) δ 1.14 in (t, J=7,2 Hz, 3H), 1,59-to 1.79 (m, 8H), 3,43-3,51 (m, 2H), 3,79 (user.s, 2H), 6,63-of 6.65 (m, 1H), 6,76 (s, 1H), 6,99 (user.s, 1H), 7,30 (t, J=2,8 Hz, 1H), 7,43 (d, J=8,6 Hz, 1H), 7,76 (DD, J=8,6, of 1.8 Hz, 1H), 8,27 (user.s, 1H), 8,54 (user.s, 1H).

Rf(x)=a value of Rfthat (x) in brackets: mobile phase in TLC: (a) diethyl ether:PA=1:1; (b)=ether; (c)=EA; (d)=diethyl ether:PA=1:3; (e)=DCM:MeOH=98:4; Rt=retention time (in minutes) in LC-MS

1. The method of obtaining compounds of formula (I):

or tautomers, stereoisomers or pharmaceutically acceptable salts, where:
R1selected from hydrogen or (C1-4)alkyl group, optionally substituted with one to three fluorine atoms or hydroxy-group,
R2represents a hydrogen atom or a (C1-4)alkyl group, optionally substituted with one to three fluorine atoms, hydroxy-group, benzoyloxymethyl group, amino group, monomethylamine, dimethylaminopropoxy or Boc-, Fmoc - or Cbz-protected amino group, where (C1-4)alkyl group may include Citigroup, sulfonyloxy group or N, O or S,
R3represents a hydrogen atom or a (C1-4)alkyl group, optionally substituted with one to three fluorine atoms, hydroxy-group, benzoyloxymethyl group, amino group, monomethylamine, dimethylaminopropoxy or Boc-, Fmoc - or Cbz-protected amino group, where (C1-4)alkyl group may include Citigroup, sulfonyloxy group or atom is N, O or S, or
R1and R2together with the carbon atoms marked with the symbols 'a' and 'b' form a C5-8cycloalkyl, optionally substituted with one to three fluorine atoms, hydroxy-group or (C1-4)alkyl group, or
R2and R3together with the carbon atom marked 'b' form a C3-8cycloalkyl, optionally substituted with one to four fluorine atoms, one or two methyl groups or by a hydroxy-group, or
R2and R3together with the carbon atom marked 'b' form a C5-8heteroseksualci, optionally substituted with one to four fluorine atoms, one or two methyl groups, a benzyl group or a hydroxy-group,
R4represents a hydrogen atom or a (C1-4)alkyl group, optionally substituted with one to three fluorine atoms or hydroxy-group, or R4means monocyclic aryl or heteroaryl group needed�optionally substituted with one to five substituents Q, which may be identical or different, selected from halogen, trifloromethyl, triptoreline, cyano, C1-3alkyl, C1-3alkoxy, hydroxy, amino, acetyl, atsetamido, triptoreline, -CONH2, -SO2NH2or-CO2H, or
R3and R4together with the carbon atoms marked with symbols 'b' and 'c' form C3-8cycloalkyl, optionally substituted with one to four fluorine atoms, one or two methyl groups or by a hydroxy-group, or
R3and R4together with the carbon atoms marked with symbols 'b' and 'c' form C5-8heteroseksualci, optionally substituted with one to four fluorine atoms, one or two methyl groups, a benzyl group or a hydroxy-group,
R5is a hydrogen atom or a bromide
R6selected from a hydrogen atom or a (C1-4)alkyl group, optionally substituted with one to three fluorine atoms or hydroxy-group,
R7represents a monocyclic or condensed bicyclic aromatic or heteroaromatic group, where these groups are unsubstituted or substituted with one to five substituents Q as defined above, or
R7is a 2-arelatively group or 2-arelatively group, or
R7is piperidinyloxy g�the SCP, unsubstituted or substituted with one to four fluorine atoms or by a group of CF3or
R7represents a 2,3-dihydroindole group or a group benzimidazol-2-one,
which includes stages:
(i) interaction of substituted 4,5-dihydro-(1H)-pyrazole of the formula (IIa) or isomeric substituted 4,5-dihydro-3H-pyrazole of the formula (IIb):

where R1, R2, R3, R4and R5have the above values, with an isothiocyanate of formula R6-N=C=S, where R6has the above value, to obtain an amide substituted 4,5-dihydro-(1H)-pyrazol-1-carbothiolate of formula (IIIa) or tautomeric substituted 4,5-dihydro-(1H)-pyrazol-1-carboxymethylate of formula (IIIb):

(ii) interaction of the compounds of formula (IIIa) or (IIIb) with an alkylating reagent of the General formula Rx-L, where Rxis a linear (C1-8)alkyl group, and L means a leaving group, to produce a compound of formula (IV):

(iii) interaction of the obtained compound of formula (IV) with a derivative of sulfonamide of the formula R7SO2NH2where R7has the above value, to produce a compound of formula (I):

(iv) selection of a compound of formula (I)from the reaction mixture.

2. The method of obtaining compounds of formula (I) according to claim 1, where:
R1selected from hydrogen or (C1-2)alkyl group,
R2represents a hydrogen atom or a (C1-3)alkyl group, optionally substituted with one to three fluorine atoms or hydroxy-group,
R3represents a hydrogen atom or a (C1-3)alkyl group, optionally substituted with one to three fluorine atoms or hydroxy-group, or
R1and R2together with the carbon atoms marked with the symbols 'a' and 'b' form a C5-8cycloalkyl, or
R2and R3together with the carbon atom marked 'b' form a C3-8cycloalkyl, optionally substituted with one to four fluorine atoms or hydroxy-group, or
R2and R3together with the carbon atom marked 'b' form a C5-8heteroseksualci, optionally substituted with a methyl or benzyl group, or a hydroxy-group,
R4represents a hydrogen atom or a (C1-2)alkyl group, or R4means monocyclic aryl or heteroaryl group, optionally substituted with one to three substituents Q as defined above, or
R3and R4together with the carbon atoms marked with symbols 'b' and 'c' form C5-8cycloalkyl, or
R3and R4together with a�Ohm carbon marked with the symbols 'b' and 'c' form C5-8heteroseksualci, optionally substituted with a methyl or benzyl group,
R5is hydrogen,
R6selected from a hydrogen atom or a (C1-3)alkyl group, optionally substituted with one to three fluorine atoms,
R7represents a monocyclic or condensed bicyclic aromatic or heteroaromatic group, where these groups are unsubstituted or substituted with one to five substituents Q as defined above, or
R7is a 2-arelatively group or 2-arelatively group, or
R7is piperidinyloxy group, or
R7represents a 2,3-dihydroindole group or a group benzimidazol-2-one.

3. The method of obtaining compounds of formula (I) according to claim 1, wherein the fragment:

selected from:

R6selected from hydrogen or (C1-3)alkyl group, optionally substituted with one to three fluorine atoms,
R7represents a monocyclic or condensed bicyclic aromatic or heteroaromatic group, where these groups are unsubstituted or substituted with one to five substituents Q as defined above, or
R7is a 2-arylate�yl group or 2-arelatively group or
R7is piperidinyloxy group, or
R7represents a 2,3-dihydroindole group or a group benzimidazol-2-one.

4. The method of obtaining compounds of formula (I) according to claim 1, wherein the fragment:

selected from:

R6selected from hydrogen or (C1-2)alkyl group, optionally substituted by three fluorine atoms,
R7represents a monocyclic or condensed bicyclic aromatic or heteroaromatic group, where these groups are unsubstituted or substituted by one or two substituents selected from methyl, methoxy, fluorine, chlorine, bromine, cyano, atsetamido, triptoreline, triptoreline, amino or hydroxy.

5. A method of producing compounds of the formula

its tautomeric and salt forms according to claim 1, which includes stages:
(i) the interaction of 2,3-diazaspiro[4.4]non-2-ena or 2,3-diazaspiro[4.4]non-1-ena or their salts synthesized according to the method disclosed in WO 2008/034863, with ethylisothiocyanate for ethylamide 2,3-diazaspiro[4.4]non-3-EN-2-carbothiolate or tautomer;
(ii) interaction of the product of step (i) with iodomethane or methyl p-toluensulfonate with obtaining methyl ester N-ethyl-2,3-diazaspiro[4.4]non-3-EN-2-carboxymethylate,

(iii) interaction of the product of step (ii) in the form of the free base or salt with 4-acetamidobenzenesulfonyl with obtaining N-(4-{[(2,3-diazaspiro[4.4]non-3-EN-2-yl)ethylaminomethyl]sulfamoyl}phenyl)acetamide
(iv) of deprotection of the product of step (iii) in acidic medium to obtain 4-amino-N-[(2,3-diazaspiro[4.4]non-3-EN-2-yl)ethylaminomethyl]benzosulfimide

6. A method according to claim 5, where stage (iii) is in the interaction of methyl ester of N-ethyl-2,3-diazaspiro[4.4]non-3-EN-2-carboxymethylate with sulfanilamide with 4-amino-N-[(2,3-diazaspiro[4.4]non-3-EN-2-yl)ethylaminomethyl]benzosulfimide:

7. A compound of formula (IIIa), (IIIb) or (IV):

where R1, R2, R3, R4and R5have the meanings given in claim 1, and tautomers, stereoisomers and salts of any of these compounds, where these compounds have found application in the synthesis of compounds of formula (I).

8. The connection according to claim 7 selected from compounds of formulae:



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 3-(4-methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-ene carboxylic acid or esters thereof of general formula 1 and stereoisomers. The compounds of formula 1 are intermediate products in synthesis of androgen receptor inhibitors of formula A1, A2, A3, which are of interest as anticancer drugs. The invention also relates to methods of producing compounds of formula 1 and compounds of formulae A1, A2, A3. In general formula 1 R1=H, C1-C4alkyl; R2=H, CH2OCH2CH2Si(CH3)3. The method of producing compounds of formula (1) involves reacting compounds of general formula 2 with compounds 3(1) or 3(2) in dimethylformamide, K2CO3 while simultaneously adding copper iodide, water and triethylamine to the reaction mass. 2: By reacting compounds of formula 1, obtained using said method, with 4-isothiocyanato-2-trifluoromethylbenzonitrile in a mixture of dimethyl sulphoxide and ethyl acetate in ratio of 1:2 and at high temperature, compounds A1, A2, A3, whose structure is given in the claim, are obtained, respectively.

EFFECT: use of novel intermediate products improves output and stereoselectivity of the method of producing compounds A1, A2, A3.

4 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes a group of substituted N-phenylbipyrrolidincarboxamides of formula (I), where m equals 1 or 2; n equals to 1 or 2; p equals to 1 or 2; R1 is hydrogen, (C1-C4)-alkyl, CF3, (C1-C4)-alkoxy-(C1-C4)-alkyl; and R2 is hydrogen, halogen, (C1-C4)-alkyl or CF3; or their salt, or enantiomer, or diastereomer. In particular, compounds in accordance with the invention are modulators of H3 receptors and, therefore, are suitable for application as pharmaceutical preparations, in particular, in treatment and (or) prevention of different diseases, modulated by H3 receptors, including diseases associated with the central nervous system.

EFFECT: obtained are novel compounds, possessing useful biological properties.

15 cl, 1 tbl, 44 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to spiro-5,6-dihydro-4H-2,3,5,10b-tetra-aza-benzo[e]azulene derivatives of formula I, where X-Y represents C(RaRb)-O, where each of Ra and Rb independently represents H or C1-4-alkyl, C(RcRd)-S(O)p, where each of Rc and Rd independently represents H, C(O)O, CH2OCH2, CH2CH2O, Z represents CH or N; R1 represents halogeno, R2 represents H, C1-6-alkyl, non-substituted or having as substituents one OH, -(CH2)q-Re, where Re represents pyridyl, -C(O)-C1-6-alkyl, -C(O)(CH2)qNRiRii, -C(O)O-C1-6-alkyl, -S(O)2NRiRii, each of Ri and Rii independently represents C1-6-alkyl, R3 represents Cl or F, n has value 1 or 2, m has value 0, 1, p has value 0 or 2, q has value 1, or to their pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition, possessing antagonistic activity with respect to receptors V1a, on the basis of said compounds.

EFFECT: obtained are novel compounds and pharmaceutical composition on their basis, which can be applied in medicine as drugs of peripheral and central action in case of the following states: dysmenorrhea, male or female sexual disfunction, hypertension, chronic heart failure, inadequate secretion of vasopressin, liver cirrhosis, nephritic syndrome, anxiety, depressive disorders, obsessive-compulsive disorder, autism spectrum disorders, schizophrenia and aggressive behaviour.

20 cl, 10 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula I where A is such as given in the invention formula, R is selected from the group consisting of H and C1-6 alkyl, n and p each is independently selected from 0, 1 and 2, on condition that n + p = 2; Y represents -O- or -S-; R1, R2, R3, R4 in each position are independently selected from H and C1-6 alkyl; R5 is selected from the group consisting of -C(O)-CH2-indol-3-yl, -C(O)-(CH2)2-indol-3-yl, -C(O)-(CH2)3-indol-3-yl, trans -C(O)-(CH=CH)-indol-3-yl, -SO2-4-fluorophenyl, -C(O)-CH(n-propyl)2, -C(O)-(4-hydroxy-3,5-di-tert-butylphenyl), -C(O)-CH(NH2)-CH2-indol-3-yl and -C(O)-CH2CH3; and R6 represents H. Invention also relates to pharmaceutical composition for modulation of muscarinic receptor M1, containing formula I compounds, and methods of treating disease or state, curable by modulator of muscarinic receptor M1.

EFFECT: formula I compounds as modulators of muscarinic receptor M1.

33 cl, 1 tbl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to spiro derivatives of parthenin of formula , where R/R' is selected from a group consisting of phenyl or a substituted phenyl such as 4-ClC6H4, 2-NO2C6H4; 2,4-(MeO)2C6H3, 4-MeC6H4, and formula , where R is 4-MeOC6H4, 2-NO2C6H4, 3-NO2C6H4, 3-MeC6H4, 3-MeCO2C6H4. The invention also relates to methods of producing said spiro derivatives and a pharmaceutical composition based on said derivatives.

EFFECT: compounds of formula 1b and 1d have anticancer activity.

14 cl, 6 dwg, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to spirocyclic cyclohexane derivatives of formula I where values of R1-10 are given in claim 1.

EFFECT: compounds have affinity for the ORL1 receptor, which enables use thereof in producing a medicinal agent for treating pain, especially sharp, neuropathic or chronic pain.

12 cl, 1 tbl, 52 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel spiro-linked 3H-pyrroles - 8-amino-1-imino-6-morpholin-4-yl-2-oxa-7-azaspiro[4.4]nona-3,6,8-triene-9-carbonitriles of general formula (1) , where R1=R2=CH3 (1a); R1+R2=(CH2)5 (1b); R1+R2=(CH2)6 (1c); R1+R2=(CH2)10 (1d). The method involves suspension of the corresponding 4-oxoalkane-1,1,2,2-tetracarbonitrile of formula (2) , , R1=R2=CH3 (2a); R1+R2=(CH2)5 (2b); R1+R2=(CH2)6 (2c); R1+R2=(CH2)10 (2d) in a mixture of water and propanol-2 in ratio of 10:1, followed by addition of morpholine in molar ratio of 1:2.

EFFECT: high efficiency of the method.

2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (IX) wherein radicals and symbols have values given in the claim, and pharmaceutically acceptable salts or tautomers thereof. Said compounds are inhibitors of poly(ADP-ribose)polymerase (PARP) and can be used to treat cancer, inflammatory diseases, reperfusion injuries, ischaemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infections, retinal damage, skin senescence and UV-induced skin damage, and as chemo- or radiosensitisers for cancer treatment. The invention also relates to a pharmaceutical composition containing said compounds, use of said compounds and a method of treating said diseases.

EFFECT: high efficiency of using the compounds.

10 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel spirocyclic cyclohexane derivatives of formula I: , where: R1 and R2 together form a ring and are -CH2CH2CH2-; R3 denotes a saturated, branched or straight, unsubstituted C1-5-alkyl; unsubstituted or monosubstituted with F, Cl, Br, I phenyl; 5-member heteroaryl containing sulphur as a heteroatom; unsubstituted or monosubstituted with F, Cl, Br, I phenyl, attached through a C1-3-alkyl group; R5 denotes H; R6 denotes H, F, Cl; R7, R8, R9 and R10 independently denote H, F, Cl, Br, I; X denotes O, NR17; R17 denotes H, COR12; R12 denotes H, unsaturated, branched or straight, unsubstituted or phenyl-substituted C1-5-alkyl; in form of a racemate; enantiomers, diastereomers, mixtures of enantiomers or diastereomers, or a separate enantiomer or diastereomer; bases and/or salts of physiologically compatible acids or cations.

EFFECT: compounds have binding action on the ORL1 receptor and the µ-opioid receptor, which enables their use to treat various diseases.

12 cl, 11 ex

FIELD: physics.

SUBSTANCE: light-sensitive composition contains 2,2-n-dianisyl-5,6-benzo-[2H]-chromene and 1,3,3-trimethyl-6'-formyl-8'-allyl-spiro-indoline-2,2'-[2H]-chromene in molar ratio 1:0.8-1.6, respectively. Photochromic polymer materials obtained from said composition have optimum optical properties needed to satisfy physiologically based requirements for protective and preventive optical materials: when illuminated with daylight, they "cut" off the spectral region from 400 to 555 nm, while keeping intensity of light incident on eyes with wavelength greater than 555 nm at a level of less than 30%, and in conditions of low-intensity dusk illumination provide full transmission of light with wavelength greater than 400 nm.

EFFECT: protecting eyes and preventing ophthalmic diseases associated with the damaging effect of optical radiation in the visible spectrum.

5 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula , wherein Y and Z are independently specified in a group of a) or b) so that one of Y or Z is specified in the group a), and another one - in the group b); the group a) represents i) substituted C6-10aryl; ii) C3-8cycloalkyl; iii) trifluoromethyl or iv) heteroaryl specified in a group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, pyridinyl, isoxazolyl, imidazolyl, furasan-3-yl, benzothienyl, thieno[3,2-b]thiophen-2-yl, pyrazolyl, triazolyl, tetrazolyl and [1,2,3]thiadiazolyl; the group b) represents i) C6-10aryl; ii) heteroaryl specified in a group consisting of thiazolyl, pyridinyl, indolyl, pyrrolyl, benzoxazolyl, benzothiazolyl, benzothienyl, benzofuranyl, imidazo[1,2-a]pyridin-2-yl, furo[2,3-b]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, thieno[2,3-b]pyridinyl, quinolinyl, quinazolinyl, thienyl and benzimidazolyl; iii) benzofused heterocyclyl attached through a carbon atom, and when a heterocyclyl component contains a nitrogen atom, the carbon atom is optionally substituted by one substitute specified in a group consisting of C3-7cycloalkylcarbonyl; C3-7cycloalkylsulphonyl; phenyl; phenylcarbonyl; pyrrolylcarbonyl; phenylsulphonyl; phenyl(C1-4)alkyl; C1-6alkylcarbonyl; C1-6alkylsulphonyl; pyrimidinyl and pyridinyl; C3-7cycloalkylcarbonyl, phenyl, phenylcarbonyl, phenyl(C1-4)alkyl and phenylsulphonyl are optionally substituted by trifluoromethyl, or by one or two fluor-substitutes; iv) phenoxatiynyl; vi) fluoren-9-on-2-yl; vii) 9,9-dimethyl-9H-fluorenyl; viii) 1-chlornaphtho[2,1-b]thiophen-2-yl; ix) xanthen-9-on-3-yl; x) 9-methyl-9H-carbazol-3-yl; xi) 6,7,8,9-tetrahydro-5H-carbazol-3-yl; xiii) 3-methyl-2-phenyl-4-oxochromen-8-yl; or xiv) 1,3-dihydrobenzimidazol-2-on-5-yl optionally substituted by 1-phenyl, 1-(2,2,2-trifluoroethyl), 1-(3,3,3-trifluoropropyl) or 1-(4,4-difluorocyclohexyl); 1-phenyl is optionally substituted by one or more fluor-substitutes or trifluoromethyl; or xv) 4-(3-chlorophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl; R1 represents C6-10aryl, C1-3alkyl, benzyloxymethyl, hydroxy(C1-3)alkyl, aminocarbonyl, carboxy, trifluoromethyl, spirofused cyclopropyl, 3-oxo or aryl(C1-3)alkyl; or when s is equal to 2 and R1 represents C1-3alkyl, the substitutes C1-3akyl is taken with a piperazine ring to form 3,8-diazabicyclo[3.2.1]octanyl or 2,5-diazabicyclo[2.2.2]octanyl ring system, and its pharmaceutical compositions.

EFFECT: preparing the new pharmaceutical compositions.

20 cl, 7 tbl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new aminotetraline derivatives of formula (I) and their physiologically tolerable salts. In formula

,

A means a benzene ring or a ring specified in a group consisting of a 5-merous ring

,

R means the group R1-W-A1-Q-Y-A2-X1-; R1 means hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, halogenated C1-C6-alkyl, tri-(C1-C4-alkyl)-silyl-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, amino-C1-C4-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, an optionally substituted phenyl, C1-C6-alkoxy, di-C1-C6-alkylamino, an optionally substituted 5 or 6-merous heterocyclyl containing 1-3 heteroatoms specified in nitrogen and/or oxygen or sulphur; W means a bond; A1 means a bond; Q means -S(O)2- or -C(O)-; Y means -NR9- or a bond; A2 means C1-C4-alkylene, or a bond; X1 means -O-, C1-C4-alkylene, C2-C4-alkynylene; R2 means hydrogen, halogen, or two radicals R2 together with the ring atom to which they are attached form a benzene ring; R3 means hydrogen. The other radical values are specified in the patent claim. The invention also refers to intermediate products for preparing the compounds of formula (I).

EFFECT: compounds possess the properties of glycine transporter inhibitors, particularly GlyT1 and can find application in treating neurological and psychiatric disorders, such as dementia, bipolar disorder, schizophrenia, etc or for managing pain related to glycerinergic or glutamatergic neurotransmission dysfunction.

20 cl, 2 tbl, 326 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds with structural formulas , as follows and their stereoisomers, wherein Y represents or and using them for an agent for treating and/or preventing glaucoma and/or ocular hypertension.

EFFECT: treating and/or preventing glaucoma and/or ocular hypertension.

7 cl, 32 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutically acceptable salts specified in a group consisting of sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, arginine salt, lysine salt, methanamine salt, dimethylamine salt, trimethylamine salt, ethylamine salt, diethylaminte salt, triethylamine salt, ethanolamine salt, piperazine salt, dibenzylethylene diamine salt, methyl glucamine salt, tromethamine salt, quaternary tetramethylammonium salt, quaternary tetraethylammonium salt and choline salt, bicyclosubstituted azopyrazole derivatives of general formula

.

The invention also refers to a method for preparing them, a pharmaceutical composition containing them, and using them as a therapeutic agent, particularly as thrombopoietin (TPO) mimetics, using them as TPO agonists. In general formula (I), Het is specified in a group consisting of phenyl, furanyl and thienyl; each R1, R2, R3 andR4 are independently specified in a group consisting of hydrogen and alkyl; n is equal to 0, 1 or 2.

EFFECT: improving the pharmokinetic properties of the compound of formula (I) ensured by better solubility.

19 cl, 1 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula or its therapeutically acceptable salts, wherein A1 represents furyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, piperidinyl, morpholinyl, dihydro-1,3,4-thiadiazol-2-yl, benzothien-2-yl, banzothiazol-2-yl, tetrahydrothien-3-yl, [1,2,4]triazolo[1,5-a]pyrimidin-2-yl or imidazo[2,1-b][1,3]-thiazol-5-yl; wherein A1 is unsubstituted or substituted by one, or two, or three, or four, or five substitutes independently specified in R1, OR1, C(O)OR1, NHR1, N(R1)2, C(N)C(O)R1, C(O)NHR1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br and CF3; R1 represents R2, R3, R4 or R5; R2 represents phenyl; R3 represents pyrazolyl or isoxazolyl; R4 represents piperidinyl; R5 represents C1-C10alkyl or C2-C10alkenyl each of which is not specified or specified by substitutes specified in R7, SR7, N(R7)2, NHC(O)R7, F and Cl; R7 represents R8, R9, R10 or R11; R8 represents phenyl; R9 represents oxadiazolyl; R10 represents morpholinyl, pyrrolidinyl or tetrahydropyranyl; R11 represents C1-C10alkyl; Z1 represents phenylene; Z2 represents piperidine unsubstituted or substituted by OCH3, or piperazine; both Z1A and Z2A are absent; L1 represents C1-C10alkyl or C2-C10alkenyl each of which is unsubstituted or substituted by R37B; R37B represents phenyl; Z3 represents R38 or R40; R38 represents phenyl; R40 represents cyclohexyl or cyclohexenyl; wherein phenylene presented by Z1 is unsubstituted or substituted by the group OR41; R41 represents R42 or R43; R42 represents phenyl, which is uncondensed or condensed with pyrrolyl, imidazolyl or pyrazole; R43 represents pyridinyl, which is uncondensed or condensed with pyrrolyl; wherein each cyclic fragment presented by R2, R3, R4, R8, R9, R10, R38, R40, R42 and R43 is independently unsubstituted or substituted by one or more substitutes independently specified in R57, OR57, C(O)OR57, F, Cl CF3 and Br; R57 represents R58 or R61; R58 represents phenyl; R61 represents C1-C10alkyl; and wherein phenyl presented by the group R58 is unsubstituted or substituted by one or more substitutes independently specified in F and Cl.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, and to a method of treating diseases involving the expression of anti-apoptotic Bcl-2 proteins.

7 cl, 2 tbl, 48 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinoxaline derivatives of general formula

,

a based pharmaceutical composition, using them as therapeutic agents, as well as to a based therapeutic agent for treating tumour diseases. In general formula I X represents: oxygen or sulphur; R1 represents hydrogen, R2/R3 represents hydrogen, R4 represents: (i) C1-C12-alkyl, (ii) saturated C3-C8-cycloalkyl, optionally substituted by C6-aryl, (iii) unsaturated C3-C8-cycloalkyl, (iv) heterocyclyl substituted by C(O)CF3, (v) C1-C6-alkyl substituted by C6-aryl, the above C6-aryl can be substituted by F, Cl, Br, I, -O-C1-C6-alkyl, C1-C6-alkyl, C6-aryl or hydroxy, (vi) C1-C6-alkyl substituted by C5-heteroaryl, (vii) C1-C8-alkylene, (viii) 1-adamantyl, (ix) C1-C6-alkyl substituted by C6-heterocyclyl containing a nitrogen atom and an oxygen atom, (x) C1-C6-alkyl substituted by C3-C6-cycloalkyl, or (xi) C1-C6-alkyl substituted by C6-heteroaryl; R5 represents hydrogen, R6 represents (i) aryl optionally substituted by C1-C6-alkyl, -O-C1-C6-alkyl, hydroxy, F, Cl, Br, I or amino, or (ii) C5-heteroaryl containing 2 nitrogen atoms optionally substituted by C1-C6-alkyl, R7 and R8 represent hydrogen.

EFFECT: producing the therapeutic agent for treating the tumour diseases.

7 cl, 3 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: described are novel heteroaryl-N-aryl-carbamates of general formula , where: Ar1 is phenyl, probably substituted with C1-C6halogenalkyl or C1-C6halogenalkoxy; Het is triazolyl; Ar2 is phenyl; X1 represents O or S; X2 - O; R4 - H or C1-C6alkyl; n=0, 1 or 2; and R1, R2 and R3 are independently selected from H, CN, C1-C6alkyl, C1-C6halogenalkyl, C3-C6cycloalkyl, C2-C6alkenyl, C2-C6alkinyl, C(=O)O(C1-C6alkyl), phenyl and Het-1, where Het-1 is a 5-membered unsaturated heterocyclic ring, containing one heteroatom, selected from sulphur or hydrogen, or a 6-membered unsaturated heterocyclic ring, containing one nitrogen atom as a heteroatom, and Het-1 can be substituted with F, Cl, C1-C6alkyl, C1-C6halogenalkyl or C1-C6alkoxy, and a method of fighting pest insects Lepidoptera or Homoptera with the application of the said compounds as insecticides and acaricides.

EFFECT: increased efficiency.

5 cl, 2 tbl, 80 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to a compound of Formula

,

where Y represents a group of formula -(CR9R10)-; X is selected from the group, consisting of -C(=O)-, -OC(=O)-, -NHC(=O)-, -(CR11R12)- and -S(-O)2-; Z represents a group of formula -(CR13R14)q-; R1 is selected from the group, consisting of C1-C12alkyl, optionally substituted with one substituent, selected from naphthyl, indole and biphenyl; C2-C12alkenyl, substituted with a substituent, selected from thienyl, naphthyl and phenyl, with the said phenyl being optionally substituted with 1-2 substituents; selected from halogen, trifluoroalkyl, C1-C6alkyl, methoxy and hydroxy; C3-C6cycloalkyl; C6-C10aryl, optionally substituted with 1-2 substituents, selected from halogen, phenyl, amino, phenoxy, C1-C6alkyl, methoxy, hydroxyl and carboxy; and C4-C9heteroaryl, selected from indole, quinoline, quinoxaline, benzofuranyl, benzothiophene, benzimidazole, benzotriazole, benzodioxin, benzothiasole, pyrazole, furyl and isoxazole, optionally substituted with a substituent, selected from C1-C6alkyl and phenyl; R2 and R3 each is independently selected from the group, consisting of H and C1-C12alkyl; R4a is selected from the group, consisting of H, C1-C12alkyl, optionally substituted with phenyl; C2-C12alkenyl, C3-C6cycloalkyl, C6aryl, C(=O)R15, C(=O)NR15R16, C(=O)OR15, SO2R15 and -C(=NR15)-NR16R17; R4d represents hydrogen or R4a and R4b, taken together with a nitrogen atom, which they are bound to, form an optionally substituted heterocyclic fragment, selected from piperidine, morpholine, pyrrolidine and azetidine, where the substituent is selected from C1-C12alkyl, hydroxy, halogen, carboxy and oxo; each R5a and R5b represents H, or R6, R7 and R8 each is independently selected from the group, consisting of H, C1-C12alkyl, C3-C6cycloalkyl, C6-C10aryl, optionally substituted with halogen, or taken together with a carbon atom, which they are bound to, two or more of R6, R7 and R8 form a fragment, selected from the group, consisting of C2-C12alkenyl; C3-C6cycloalkyl, optionally substituted with C1-C6alkyl; C6aryl, optionally substituted with 2 substituents, selected from halogen; each R9 and R10 represents H or C1-C12alkyl, substituted with naphthyl; each R11 and R12 represents H; R13 and R14 represent H, or each R15, R16 and R17 is independently selected from the group, consisting of H, C1-C12alkyl, C3-C6cycloalkyl, C6aryl, substituted with one substituent, selected from C1-C6alkyl; and C5-heteroaryl, additionally containing one nitrogen atom, with the said heteroaryl representing pyridyl; q represents an integer number, selected from the group, consisting of 2, 3 and 4; r represents 1; or its pharmaceutically acceptable salt. The invention also relates to particular compounds of 1,4-diazepan-2-one derivatives.

EFFECT: obtaining 3-aminoalkyl-1,4-diazepan-2-one melanocortin-5 receptor antagonists.

21 cl, 7 tbl, 110 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a novel derivative of N-acylanthranilic acid, represented by the following general formula 1, or to its pharmaceutically acceptable salt, in which R1, R2, R3, X1, X2, X3, X4 and A are determined in the invention formula.

EFFECT: invention relates to an inhibitor of collagen production, a medication for treating diseases, associated with the excessive production of collagen, containing N-acylanthranilic acid derivative Formula 1.

FIELD: chemistry.

SUBSTANCE: invention relates to a photoinitiator, a method for production and use thereof and a coating composition. The photoinitiator is a compound of formula: (PI-Sp)n-BB (I), where PI is a thioxanthone group, optionally including additional substitutes in the Sp group; Sp is a spacer link selected from a group consisting of or , BB is a backbone chain link selected from a group consisting of

The method of producing the photoinitiator includes the following steps: (a) optionally substituted thioxanthone, containing at least one hydroxy group, reacts with epichlorohydrin or haloacetic acid ester; (b) the compound from step (a) reacts with the corresponding backbone chain link containing a functional group, or the compound from step (a) reacts with a compound containing a functional group, and the obtained intermediate then reacts with the corresponding backbone chain link; optionally (c) obtaining derivatives of the compounds from step (b). The photoinitiator is used to cure a coating composition, preferably printing ink containing a polymerisable component.

EFFECT: invention enables to obtain a photoinitiator with good curing activity, faint odour and good compatibility with other components of the composition.

10 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to compounds of formula (I), wherein R1 and R2 independently represent C6-C10 aryl optionally substituted by -OH, halogen, -OC1-C3 alkyl, -NO2, -CF3 or C1-C3 alkyl, or 5- or 6-merous heteroaryl containing one heteroatom specified in N, S and O; A and M independently represent a methylene group or a single bond; an adjacent aromatic cycle is attached directly to an amide group; the group Y=Z represents together and irregularly oxygen atom (-O-), cis-vinylidene group (-CH=CH-), iminogroup (-N=CH- or -CH=N-) or methylene group with sp2-hybridised carbon atom (=CH-); X irregularly represents methine group (=CH-), cis-vinylidene group (-CH=CH-) or carbon atom (=N-), and W represents hydroxyl group (-OH), C1-C6 alkyl optionally substituted by -SH, 5- or 6-merous heteroaryl containing 1 to 2 nitrogen heteroatoms, or C6-C10 aryl, optionally substituted by -SH, -NH2, and their pharmaceutically acceptable salts.

EFFECT: described are the methods for preparing the compounds, using as a drug for treating cancer and the based pharmaceutical composition.

14 cl, 6 tbl, 49 ex

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