Derivatives of pyrazole as medicinal agents for treatment of diseases that occur as result of disfunction of nicotine receptors alfa7

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of common formula (I) , in which: A, if available, means (C1-C6)-alkyl; R1 means group NR6R7, (C4-C7)-azacycloalkyl, (C5-C9)-azabicycloalkyl, besides, these groups, unnecessarily, are substituted with one or more substituents, selected from (C1-C5)-alkyl or halogen; A-R1 is such that nitrogen of radical R1 and nitrogen in position 1 of pyrazole are necessarily separated at least by two atoms of carbon; R3 means radical H, OH, NH2, ORc, NHC(O)Ra or NHSO2Ra; R4 means phenyl or heteroaryl, unnecessarily, substituted with one or more substituents, selected from halogen, CN, NH2, OH, ORc, C(O)NH2, phenyl, polyfluoroalkyl, linear or ramified (C1-C6)-alkyl, besides these substituents, unnecessarily, are substituted with halogen, and moreover, heteroaryl radicals are 3-10-member, containing one or more heteroatoms, selected from sulphur or nitrogen; R5 means radical H, linear or ramified (C1-C6)-alkyl; Ra means linear or ramified (C1-C6)-alkyl; Rc means linear or ramified (C1-C6)-alkyl, (poly)fluoroalkyl or phenyl; R6 and R7, independently from each other, means hydrogen, (C1-C6)-alkyl; R6 and R7 may create 5-, 6- or 7-member saturated or non-saturated cycle, which includes one heteroatom, such as N, and which, unnecessarily, substituted with one or more atoms of halogen; to its racemates, enantiomers, diastereoisomers and their mixtures, to their tautomers and their pharmaceutically acceptable salts, excluding 3-(3-pyridinyl)-1H-pyrazole-1- butanamine, 4-(3-pyridinyl)-1H-pyrazole-1-butanamine and N-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine. Invention is also related to methods for production of compounds of formula (I) and to pharmaceutical composition intended for treatment of diseases that appear as a result of disfunction of nicotine receptors α7 or favorably responding to their modulation, on the basis of these compounds.

EFFECT: production of new compounds and pharmaceutically acceptable composition on their basis, which may find application in medicine for treatment, prophylaxis, diagnostics and observance over development of psychiatric or neurological disorders or diseases of central nervous system, when cognitive functions deteriorate or quality of sensor information processing drops.

16 cl, 106 ex

 

The present invention relates to novel ligands of nicotinic acetylcholine receptors type. These compounds are particularly distinguished by the fact that they are ligands of nicotinic α7 receptor type. These properties suggest that the compounds according to the invention can be used in the case of animals, including humans, as a means for therapeutic and/or symptomatic treatment in the prevention, diagnosis and/or monitoring of the development of disorders or diseases that lead to the disorder of the function of nicotinic receptors or positively respond to their modulation. More specifically, the compounds according to the invention may be suitable in the case of psychiatric or neurological disorders or diseases of the Central nervous system, leading to the deterioration of cognitive functions, attention, ability, concentration, learning ability and memory or processing sensory information. They can also be suitable in the case of treatment, prevention, diagnosis and/or monitoring of diseases that involve spontaneous or result from pathological changes in neurodegenerative processes, and diseases in which inflammatory phenomena. The present invention also relates to methods of treatment, of which the second will involve nicotinic receptors consisting in the introduction of animal, including human, a therapeutically effective dose of one or more compounds according to the invention. The present invention also relates to the application in the case of thin diagnostics analogues of these derivatives in which one or more atoms replaced by an isotope with an atomic mass or mass number different from the atomic mass or mass number of atoms, usually found in nature.

The object of the present invention, therefore, is the use of derivatives of pyrazole of the formula (I):

and their pharmaceutically acceptable salts to obtain drugs, pharmaceutical compositions, as ligands of nicotinic receptor α7.

Many disorders or diseases associated with dysfunction of the nicotinic receptors and, therefore, may be useful for their modulation by using the compounds according to the invention to alleviate the symptoms and/or slow down, stop or change the direction of development. Compounds according to the invention from this point of view they are interesting in the case of psychiatric or neurological disorders or diseases of the Central nervous system, such as, for example, impairment of learning ability, concentration and memorization, light ohutseinamavalu functions, senile dementia, vascular dementia, dementia Taurus Levi, Alzheimer's disease, Parkinson's disease, Huntington's chorea, the syndrome of Gilles de La Tourette's, subsequent to the injury of neural degeneration, ischemic cerebral ischemia or hypoxia, multiinstitutional atrophy, progressive pseudobulbar palsy, amyotrophic lateral sclerosis, peripheral neuropathy, disorders of motor functions, such as dyskinesia, slow dyskinesia, hyperkinesia, dystonia and epilepsy, attention deficits associated with hyperactivity, schizophrenia, depression, manic-depressive psychosis, anxiety, phobias, obsessive compulsive disorder, post-traumatic stress disorder, seizures panic, eating disorders such as anorexia, bulimia and obesity, sleep disorders, associated with the clock to a different time. Compounds according to the invention may be suitable for reducing drug consumption, to facilitate maintaining Asistencia against them or alleviate their symptoms of deprivation. In the framework of the present invention, the term "drug substance" refers to lawful act or illegal substances, the consumption of which can lead to abuse and/or dependence, such as, n is the sample, nicotine and tobacco, alcohol, derivatives of cannabis, opiates, cocaine, barbiturates, benzodiazepines and stimulants.

Compounds according to the invention can also be of interest in the treatment of acute or chronic pain, such as post-operative pain, pain due to amputation (phantom limb pain), pain associated with cancerous pathological changes, headaches, neuropathies and muscle pain, such as fibromyalgia. In addition, the compounds according to the invention can also be used in the treatment of disorders or diseases, mediating inflammatory processes, such as, for example, at the level of the gastrointestinal tract, ulcerative colitis, Crohn's disease, symptoms of irritation of the colon, diarrhea, and, in another place in the body, arthritis (including rheumatoid arthritis) and skin inflammation, such as acne. Finally, the compounds according to the invention may be suitable in the case of endocrine disorders such as pheochromocytoma, and disorders associated with smooth muscle contraction.

The present invention relates also to the use of compounds according to the invention for thin diagnostics or medical imaging. It includes methods of diagnosis and visualization, consisting in the analysis of non-invasive methods of distribution of radioactive soy is inane indicator inside the intact animal, including the person using physical methods, such as positron emission tomography, single-photon tomography, spectroscopy, nuclear magnetic resonance and imaging of nuclear magnetic resonance, tomodensitometry X-rays using a computer or a combination of these methods. In the framework of the present invention, the term "radioactive connection-indicator" means compounds according to the invention, their enantiomers or their proletarienne forms used or not in labeled form, allowing their detection by physical means, such as described above. Tagging is the replacement of one or more atoms in the compounds according to the invention isotope with an atomic mass or mass number different from the atomic mass or mass number of atoms, such that they are commonly found in nature. Tagging can also consist in the introduction in connection according to the invention the chemical groups of the holders of such isotopes, using, for example, meteorous reagents. Used isotopes can be, for example, radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, phosphorus, sulfur, chlorine, iodine or technetium, such as respectively2H,3H,11C,13C,14C,13N15O,17O,18F,35S36Cl123I12 I131I. Labeled compounds can be synthesized by the methods described in the methods according to the present invention, by replacing one or more reagents in synthesis methods identical reagents containing isotope labels.

The present invention relates to derivatives of formula (I)in which:

And, if present, means (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, and these radicals possibly substituted by one or more substituents selected among (C1-C5)-alkyl, (C2-C5-alkenyl, (C2-C5)-quinil, (C3-C7)-cycloalkyl, (C5-C7)-cycloalkenyl, arylalkyl, heteroaromatic, aryl, heteroaryl, halogen;

R1 means a group NR6R7, (C4-C7-azacyclonol, (C5-C7)-azacycloheptane, (C5-C9-azabicycloalkanes, (C5-C9)-azabicycloalkanes, and these groups may be substituted by one or more substituents selected among (C1-C5)-alkyl, (C3-C5)-cycloalkyl, halogen;

A-R1 is such that the nitrogen radical R1 and the nitrogen in position 1 of the pyrazole are necessarily separated by at least two carbon atoms;

R3 means a radical N, Galaga is, HE, SH, NH2, ORc, SRc, SORa, SO2Ra, NHCHO, NRaRb, NHC(O)Ra, NHC(S)Ra, NHSO2Ra;

R4 denotes aryl or heteroaryl, possibly substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2C(S)NH2, SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb, S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, O-C(O)Ra, -O-C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra, NHCONH2, NHCONRaRb, NHSO2Ra, aryl, heteroaryl, (C4-C7)-geterotsiklicheskie, polyfluoroankyl, cryptomelane, cryptometer, linear or branched (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6)-quinil, and these substituents may substituted by one (one) or more alkyl radicals, halogen atoms, HE, methoxypropane;

R5 means a radical of H, halogen, CF3, CHF2CH2F, linear or branched (C1-C6)-alkyl, (C3-C7-cycloalkyl;

Ra means a linear or branched (C1-C6)-alkyl, alkenyl, quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroaromatic, aryl, heteroaryl, polyfluoroankyl;

Rb independently Ra means a hydrogen atom, a linear or branched (C1-C6)-alkyl, alkenyl, quinil, (C3-C7)-cyclol the sludge, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroaromatic, aryl, heteroaryl, polyfluoroankyl;

Ra and Rb may form a 5-, 6 - or 7-membered saturated or unsaturated cycle or not one heteroatom such as O, S, N, and this cycle, possibly substituted by one or more alkyl radicals, halogen atoms;

Rc means a linear or branched (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, (hetero)arylalkyl, (hetero)aryl, (poly)foralkyl, C(O)R8, C(S)R8, SO2R8;

R6 and R7 independently of one another denote hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroallyl;

R6 and R7 may form a 5-, 6 - or 7-membered saturated or unsaturated cycle or not one heteroatom such as O, S, N, which is possibly substituted by one or more alkyl radicals, halogen atoms;

R8 means a radical Ra or NRaRb;

their racemates, the enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts.

Site is preferably present invention relates to derivatives of formula (I), in which:

And, if present, means (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, and these radicals possibly substituted by one or more substituents selected among (C1-C5)-alkyl, (C2-C5-alkenyl, (C2-C5)-quinil, (C3-C7)-cycloalkyl, (C5-C7)-cycloalkenyl, arylalkyl, heteroaromatic, aryl, heteroaryl, halogen;

R1 means a group NR6R7, (C4-C7-azacyclonol, (C5-C7)-azacycloheptane, (C5-C9-azabicycloalkanes, (C5-C9)-azabicycloalkanes, and these groups may be substituted by one or more substituents selected among (C1-C5)-alkyl, (C3-C5)-cycloalkyl, halogen;

A-R1 is such that the nitrogen radical R1 and the nitrogen in position 1 of the pyrazole are necessarily separated by at least two carbon atoms;

R3 means a radical, HE, NH2, OMe, H;

R4 denotes aryl or heteroaryl, possibly substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2C(S)NH2, SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb, S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, O-C(O)Ra, -O-C(S)Ra, NRaRb, NHC(O)Ra, NC(S)Ra, NHCONH2, NHCONRaRb, NHSO2Ra, aryl, heteroaryl, (C4-C7)-geterotsiklicheskie, polyfluoroankyl, cryptomelane, cryptometer, linear or branched (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6)-quinil, and these substituents may substituted by one (one) or more alkyl radicals, halogen atoms, HE, methoxypropane;

R5 means hydrogen or IU;

Ra means a linear or branched (C1-C6)-alkyl, alkenyl, quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroaromatic, aryl, heteroaryl, polyfluoroankyl;

Rb independently Ra means a hydrogen atom, a linear or branched (C1-C6)-alkyl, alkenyl, quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroaromatic, aryl, heteroaryl, polyfluoroankyl;

Ra and Rb may form a 5-, 6 - or 7-membered saturated or unsaturated cycle or not one heteroatom such as O, S, N, and this cycle, possibly substituted by one or more alkyl radicals, halogen atoms;

Rc means a linear or branched (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3- 6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, (hetero)arylalkyl, (hetero)aryl, (poly)foralkyl, C(O)R8, C(S)R8, SO2R8;

R6 and R7 independently of one another denote hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroallyl;

R6 and R7 may form a 5-, 6 - or 7-membered saturated or unsaturated cycle or not one heteroatom such as O, S, N, which is possibly substituted by one or more alkyl radicals, halogen atoms;

R8 means a radical Ra or NRaRb;

their racemates, the enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts.

More preferably the present invention relates to derivatives of formula (I)in which:

And, if present, means (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, and these radicals possibly substituted by one or more substituents selected among (C1-C5)-alkyl, (C2-C5-alkenyl, (C2-C5)-quinil, (C3-C7)-C is kloeckera, (C5-C7)-cycloalkenyl, arylalkyl, heteroaromatic, aryl, heteroaryl, halogen;

R1 means a group NR6R7, (C4-C7-azacyclonol, (C5-C7)-azacycloheptane, (C5-C9-azabicycloalkanes, (C5-C9)-azabicycloalkanes, and these groups may be substituted by one or more substituents selected among (C1-C5)-alkyl, (C3-C5)-cycloalkyl, halogen;

A-R1 is such that the nitrogen radical R1 and the nitrogen in position 1 of the pyrazole are necessarily separated by at least two carbon atoms;

R3 means a radical, HE, NH2, OMe, H;

R4 denotes aryl or heteroaryl, possibly substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2C(S)NH2, SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb, S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, O-C(O)Ra, -O-C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra, NHCONH2, NHCONRaRb, NHSO2Ra, aryl, heteroaryl, (C4-C7)-geterotsiklicheskie, polyfluoroankyl, cryptomelane, cryptometer, linear or branched (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6)-quinil, and these substituents may substituted by one (one) or more alkyl radicals, halogen atoms, HE, methoxypropane;

p> R5 means hydrogen;

Ra means a linear or branched (C1-C6)-alkyl, alkenyl, quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroaromatic, aryl, heteroaryl, polyfluoroankyl;

Rb independently Ra means a hydrogen atom, a linear or branched (C1-C6)-alkyl, alkenyl, quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroaromatic, aryl, heteroaryl, polyfluoroankyl;

Ra and Rb may form a 5-, 6 - or 7-membered saturated or unsaturated cycle or not one heteroatom such as O, S, N, and this cycle, possibly substituted by one or more alkyl radicals, halogen atoms;

Rc means a linear or branched (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, (hetero)arylalkyl, (hetero)aryl, (poly)foralkyl, C(O)R8, C(S)R8, SO2R8;

R6 and R7 independently of one another denote hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7)-heteros cloaker, arylalkyl, heteroallyl;

R6 and R7 may form a 5-, 6 - or 7-membered saturated or unsaturated cycle or not one heteroatom such as O, S, N, which is possibly substituted by one or more alkyl radicals, halogen atoms;

R8 means a radical Ra or NRaRb;

their racemates, the enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts.

In the above and the following definitions (C1-C6)-alkyl radicals contain 1 to 6 carbon atoms in linear or branched chain; and (C3-C7)-cycloalkyl radicals contain 3 to 7 carbon atoms; alkeneamine radicals contain 2 to 6 carbon atoms and from one to two conjugated or no double bonds in the linear or branched chain, and the double bond is not in the alpha-position to the heteroatom; alkyline radicals contain 2 to 6 carbon atoms and 1-2 paired or not triple bond in a linear or branched chain, and a triple bond is not in the alpha-position to the heteroatom; aryl radicals chosen among phenyl, naphthyl or indenyl; heteroaryl radicals are 3-10-membered, possibly containing one or more heteroatoms selected among the atoms of oxygen, sulfur and nitrogen, such as, in particular, thiazolyl, thienyl, pyrrolyl, pyrazolyl, pyridinyl, furyl, is imidazolyl, oxazolyl, pyrazinyl, pyrimidyl, tetrazolyl, oxadiazolyl, thiadiazolyl, isoxazole, isothiazole, isothiazoline, isoxazole, triazolyl, indolyl, benzofuranyl, benzothiazol, isoindolyl, pyrazolyl, indolyl; halogen represents chlorine, iodine, fluorine, bromine; and (C4-C7)-azacycloheptane radicals contain nitrogen and 4-7 carbon atoms and, in particular, mean azetidinol, pyrrolidinyl, piperidinyl; azacycloheptane radicals contain nitrogen and 5-7 carbon atoms; and (C5-C9)-azacycloheptane radicals containing 5 to 9 carbon atoms and represented not limiting the scope of protection of the invention in the list (A); and (C5-C9)-azabicycloalkanes radicals containing 5 to 9 carbon atoms and represented not limiting the scope of protection of the invention in the list (C); and (C4-C7)-heterocytolysine radicals containing 5-7 carbon atoms and one or more heteroatoms selected from among oxygen atoms, sulfur, nitrogen; politcially radicals contain 1 to 6 carbon atoms in linear or branched chains which are substituted by one or more fluorine atoms and are, in particular, trifluoromethyl, deformity.

As an illustration, in this context, presents the structure of the list (A), and these patterns can be associated with the primary core in either the x position:

As an illustration, in this context, presents the structure of the list (In), and these patterns can be associated with the primary core in any situation:

The compounds of formula (I) contain one or more asymmetric carbon atoms and can therefore exist in the form of isomers, racemates, enantiomers and diastereoisomers; they are also part of the invention, and mixtures thereof.

The present invention also relates to pharmaceutical compositions containing as an active beginning derivative of the formula (I)in which:

And, if present, means (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, and these radicals possibly substituted by one or more substituents selected among (C1-C5)-alkyl, (C2-C5-alkenyl, (C2-C5)-quinil, (C3-C7)-cycloalkyl, (C5-C7)-cycloalkenyl, arylalkyl, heteroaromatic, aryl, heteroaryl, halogen;

R1 means a group NR6R7, (C4-C7-azacyclonol, (C5-C7)-azacycloheptane, (C5-C9-azabicycloalkanes, (C5-C9)-azabicycloalkanes, and these groups is not possible, substituted by one or more substituents selected among (C1-C5)-alkyl, (C3-C5)-cycloalkyl, halogen;

A-R1 is such that the nitrogen radical R1 and the nitrogen in position 1 of the pyrazole are necessarily separated by at least two carbon atoms;

R3 means a radical of H, halogen, HE, SH, NH2, ORc, SRc, SORa, SO2Ra, NHCHO, NRaRb, NHC(O)Ra, NHC(S)Ra, NHSO2Ra;

R4 denotes aryl or heteroaryl, possibly substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2C(S)NH2, SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb, S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, O-C(O)Ra, -O-C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra, NHCONH2, NHCONRaRb, NHSO2Ra, aryl, heteroaryl, (C4-C7)-geterotsiklicheskie, polyfluoroankyl, cryptomelane, cryptometer, linear or branched (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6)-quinil, and these substituents may substituted by one (one) or more alkyl radicals, halogen atoms, HE, methoxypropane;

R5 means a radical of H, halogen, CF3, CHF2CH2F, linear or branched (C1-C6)-alkyl, (C3-C7-cycloalkyl;

Ra means a linear or branched (C1-C6)-alkyl, alkenyl, quinil, (C3/sub> -C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroaromatic, aryl, heteroaryl, polyfluoroankyl;

Rb independently Ra means a hydrogen atom, a linear or branched (C1-C6)-alkyl, alkenyl, quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroaromatic, aryl, heteroaryl, polyfluoroankyl;

Ra and Rb may form a 5-, 6 - or 7-membered saturated or unsaturated cycle or not one heteroatom such as O, S, N, and this cycle, possibly substituted by one or more alkyl radicals, halogen atoms;

Rc means a linear or branched (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, (hetero)arylalkyl, (hetero)aryl, (poly)foralkyl, C(O)R8, C(S)R8, SO2R8;

R6 and R7 independently of one another denote hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroallyl;

R6 and R7 may form a 5-, 6 - or 7-membered saturated or unsaturated C is CL, whether or not one heteroatom such as O, S, N, which is possibly substituted by one or more alkyl radicals, halogen atoms;

R8 means a radical Ra or NRaRb;

its racemates, the enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts.

Preferably the present invention relates to pharmaceutical compositions containing as an active beginning derivative of the formula (I)in which:

And, if present, means (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, and these radicals possibly substituted by one or more substituents selected among (C1-C5)-alkyl, (C2-C5-alkenyl, (C2-C5)-quinil, (C3-C7)-cycloalkyl, (C5-C7)-cycloalkenyl, arylalkyl, heteroaromatic, aryl, heteroaryl, halogen;

R1 means a group NR6R7, (C4-C7-azacyclonol, (C5-C7)-azacycloheptane, (C5-C9-azabicycloalkanes, (C5-C9)-azabicycloalkanes, and these groups may be substituted by one or more substituents selected among (C1-C5)-alkyl, (C3-C5)-cycloalkyl, halogen;

A-R1 is such that Thu is a nitrogen radical R1 and the nitrogen in position 1 of the pyrazole are necessarily separated by at least two carbon atoms;

R3 means a radical, HE, NH2, OMe, H;

R4 denotes aryl or heteroaryl, possibly substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2C(S)NH2, SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb, S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, O-C(O)Ra, -O-C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra, NHCONH2, NHCONRaRb, NHSO2Ra, aryl, heteroaryl, (C4-C7)-geterotsiklicheskie, polyfluoroankyl, cryptomelane, cryptometer, linear or branched (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6)-quinil, and these substituents may substituted by one (one) or more alkyl radicals, halogen atoms, HE, methoxypropane;

R5 means hydrogen or IU;

Ra means a linear or branched (C1-C6)-alkyl, alkenyl, quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroaromatic, aryl, heteroaryl, polyfluoroankyl;

Rb independently Ra means a hydrogen atom, a linear or branched (C1-C6)-alkyl, alkenyl, quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroaromatic, aryl, heteroaryl, polyfluoroankyl;

R and Rb may form a 5-, 6 - or 7-membered saturated or unsaturated cycle or not one heteroatom such as O, S, N, and this cycle, possibly substituted by one or more alkyl radicals, halogen atoms;

Rc means a linear or branched (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, (hetero)arylalkyl, (hetero)aryl, (poly)foralkyl, C(O)R8, C(S)R8, SO2R8;

R6 and R7 independently of one another denote hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroallyl;

R6 and R7 may form a 5-, 6 - or 7-membered saturated or unsaturated cycle or not one heteroatom such as O, S, N, which is possibly substituted by one or more alkyl radicals, halogen atoms;

R8 means a radical Ra or NRaRb;

its racemates, the enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts.

More preferably the present invention also relates to pharmaceutical compositions containing as an active beginning derivative of the formula (I)in which:

1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, and these radicals possibly substituted by one or more substituents selected among (C1-C5)-alkyl, (C2-C5-alkenyl, (C2-C5)-quinil, (C3-C7)-cycloalkyl, (C5-C7)-cycloalkenyl, arylalkyl, heteroaromatic, aryl, heteroaryl, halogen;

R1 means a group NR6R7, (C4-C7-azacyclonol, (C5-C7)-azacycloheptane, (C5-C9-azabicycloalkanes, (C5-C9)-azabicycloalkanes, and these groups may be substituted by one or more substituents selected among (C1-C5)-alkyl, (C3-C5)-cycloalkyl, halogen;

A-R1 is such that the nitrogen radical R1 and the nitrogen in position 1 of the pyrazole are necessarily separated by at least two carbon atoms;

R3 means a radical, HE, NH2, OMe, H;

R4 denotes aryl or heteroaryl, possibly substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2C(S)NH2, SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb, S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, O-C(O)Ra, -O-C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra, NHCONH2, HCONRaRb, NHSO2Ra, aryl, heteroaryl, (C4-C7)-geterotsiklicheskie, polyfluoroankyl, cryptomelane, cryptometer, linear or branched (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6)-quinil, and these substituents may substituted by one (one) or more alkyl radicals, halogen atoms, HE, methoxypropane;

R5 means hydrogen;

Ra means a linear or branched (C1-C6)-alkyl, alkenyl, quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroaromatic, aryl, heteroaryl, polyfluoroankyl;

Rb independently Ra means a hydrogen atom, a linear or branched (C1-C6)-alkyl, alkenyl, quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroaromatic, aryl, heteroaryl, polyfluoroankyl;

Ra and Rb may form a 5-, 6 - or 7-membered saturated or unsaturated cycle or not one heteroatom such as O, S, N, and this cycle, possibly substituted by one or more alkyl radicals, halogen atoms;

Rc means a linear or branched (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C 7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, (hetero)arylalkyl, (hetero)aryl, (poly)foralkyl, C(O)R8, C(S)R8, SO2R8;

R6 and R7 independently of one another denote hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroallyl;

R6 and R7 may form a 5-, 6 - or 7-membered saturated or unsaturated cycle or not one heteroatom such as O, S, N, which is possibly substituted by one or more alkyl radicals, halogen atoms;

R8 means a radical Ra or NRaRb;

its racemates, the enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts.

The present invention also relates to the use as a drug derivatives of pyrazole of the formula (I)in which:

And, if present, means (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, and these radicals possibly substituted by one or more substituents selected among (C1-C5)-alkyl, (C2-C5-alkenyl, (C2-C5)-quinil, (C3-C7 )-cycloalkyl, (C5-C7)-cycloalkenyl, arylalkyl, heteroaromatic, aryl, heteroaryl, halogen;

R1 means a group NR6R7, (C4-C7-azacyclonol, (C5-C7)-azacycloheptane, (C5-C9-azabicycloalkanes, (C5-C9)-azabicycloalkanes, and these groups may be substituted by one or more substituents selected among (C1-C5)-alkyl, (C3-C5)-cycloalkyl, halogen;

A-R1 is such that the nitrogen radical R1 and the nitrogen in position 1 of the pyrazole are necessarily separated by at least two carbon atoms;

R3 means a radical of H, halogen, HE, SH, NH2, ORc, SRc, SORa, SO2Ra, NHCHO, NRaRb, NHC(O)Ra, NHC(S)Ra, NHSO2Ra;

R4 denotes aryl or heteroaryl, possibly substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2C(S)NH2, SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb, S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, O-C(O)Ra, -O-C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra, NHCONH2, NHCONRaRb, NHSO2Ra, aryl, heteroaryl, (C4-C7)-geterotsiklicheskie, polyfluoroankyl, cryptomelane, cryptometer, linear or branched (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6)-quinil, and these substituents may substituted by one (one) or several is Kimi alkyl radicals, atoms of halogen, HE, methoxypropane;

R5 means a radical of H, halogen, CF3, CHF2CH2F, linear or branched (C1-C6)-alkyl, (C3-C7-cycloalkyl;

Ra means a linear or branched (C1-C6)-alkyl, alkenyl, quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroaromatic, aryl, heteroaryl, polyfluoroankyl;

Rb independently Ra means a hydrogen atom, a linear or branched (C1-C6)-alkyl, alkenyl, quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroaromatic, aryl, heteroaryl, polyfluoroankyl;

Ra and Rb may form a 5-, 6 - or 7-membered saturated or unsaturated cycle or not one heteroatom such as O, S, N, and this cycle, possibly substituted by one or more alkyl radicals, halogen atoms;

Rc means a linear or branched (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, (hetero)arylalkyl, (hetero)aryl, (poly)foralkyl, C(O)R8, C(S)R8, SO2R8;

R6 and R7 independently of one another denote hydrogen, (C1 -C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroallyl;

R6 and R7 may form a 5-, 6 - or 7-membered saturated or unsaturated cycle or not one heteroatom such as O, S, N, which is possibly substituted by one or more alkyl radicals, halogen atoms;

R8 means a radical Ra or NRaRb;

their racemates, enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts.

Preferably the present invention relates to the use as a drug derivatives of pyrazole of the formula (I)in which:

And, if present, means (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, and these radicals possibly substituted by one or more substituents selected among (C1-C5)-alkyl, (C2-C5-alkenyl, (C2-C5)-quinil, (C3-C7)-cycloalkyl, (C5-C7)-cycloalkenyl, arylalkyl, heteroaromatic, aryl, heteroaryl, halogen;

R1 means a group NR6R7, (C4-C7-azacyclonol, (C5-C7)-Azazello lceil, (C5-C9-azabicycloalkanes, (C5-C9)-azabicycloalkanes, and these groups may be substituted by one or more substituents selected among (C1-C5)-alkyl, (C3-C5)-cycloalkyl, halogen;

A-R1 is such that the nitrogen radical R1 and the nitrogen in position 1 of the pyrazole are necessarily separated by at least two carbon atoms;

R3 means a radical, HE, NH2, OMe, H;

R4 denotes aryl or heteroaryl, possibly substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2C(S)NH2, SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb, S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, O-C(O)Ra, -O-C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra, NHCONH2, NHCONRaRb, NHSO2Ra, aryl, heteroaryl, (C4-C7)-geterotsiklicheskie, polyfluoroankyl, cryptomelane, cryptometer, linear or branched (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6)-quinil, and these substituents may substituted by one (one) or more alkyl radicals, halogen atoms, HE, methoxypropane;

R5 means hydrogen or IU;

Ra means a linear or branched (C1-C6)-alkyl, alkenyl, quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4- 7-heteroseksualci, arylalkyl, heteroaromatic, aryl, heteroaryl, polyfluoroankyl;

Rb independently Ra means a hydrogen atom, a linear or branched (C1-C6)-alkyl, alkenyl, quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroaromatic, aryl, heteroaryl, polyfluoroankyl;

Ra and Rb may form a 5-, 6 - or 7-membered saturated or unsaturated cycle or not one heteroatom such as O, S, N, and this cycle, possibly substituted by one or more alkyl radicals, halogen atoms;

Rc means a linear or branched (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, (hetero)arylalkyl, (hetero)aryl, (poly)foralkyl, C(O)R8, C(S)R8, SO2R8;

R6 and R7 independently of one another denote hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroallyl;

R6 and R7 may form a 5-, 6 - or 7-membered saturated or unsaturated cycle or not one heteroatom such as O, S, N, that is, the possibility is about, substituted by one or more alkyl radicals, halogen atoms;

R8 means a radical Ra or NRaRb;

their racemates, enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts.

More preferably the present invention relates to the use as a drug derivatives of pyrazole of the formula (I)in which:

And, if present, means (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, and these radicals possibly substituted by one or more substituents selected among (C1-C5)-alkyl, (C2-C5-alkenyl, (C2-C5)-quinil, (C3-C7)-cycloalkyl, (C5-C7)-cycloalkenyl, arylalkyl, heteroaromatic, aryl, heteroaryl, halogen;

R1 means a group NR6R7, (C4-C7-azacyclonol, (C5-C7)-azacycloheptane, (C5-C9-azabicycloalkanes, (C5-C9)-azabicycloalkanes, and these groups may be substituted by one or more substituents selected among (C1-C5)-alkyl, (C3-C5)-cycloalkyl, halogen;

A-R1 is such that the nitrogen radical R1 and the nitrogen in position 1 of the pyrazole are necessarily separated by Myung is our least two carbon atoms;

R3 means a radical, HE, NH2, OMe, H;

R4 denotes aryl or heteroaryl, possibly substituted by one or more substituents selected among halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2C(S)NH2, SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb, S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, O-C(O)Ra, -O-C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra, NHCONH2, NHCONRaRb, NHSO2Ra, aryl, heteroaryl, (C4-C7)-geterotsiklicheskie, polyfluoroankyl, cryptomelane, cryptometer, linear or branched (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6)-quinil, and these substituents may substituted by one (one) or more alkyl radicals, halogen atoms, HE, methoxypropane;

R5 means hydrogen;

Ra means a linear or branched (C1-C6)-alkyl, alkenyl, quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroaromatic, aryl, heteroaryl, polyfluoroankyl;

Rb independently Ra means a hydrogen atom, a linear or branched (C1-C6)-alkyl, alkenyl, quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroaromatic, aryl, heteroaryl, polyfluoroankyl;

Ra and Rb mo is ut to form a 5-, 6 - or 7-membered saturated or unsaturated cycle or not one heteroatom such as O, S, N, and this cycle, possibly substituted by one or more alkyl radicals, halogen atoms;

Rc means a linear or branched (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, (hetero)arylalkyl, (hetero)aryl, (poly)foralkyl, C(O)R8, C(S)R8, SO2R8;

R6 and R7 independently of one another denote hydrogen, (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-quinil, (C3-C7-cycloalkyl, (C5-C7)-cycloalkenyl, (C4-C7-heteroseksualci, arylalkyl, heteroallyl;

R6 and R7 may form a 5-, 6 - or 7-membered saturated or unsaturated cycle or not one heteroatom such as O, S, N, which is possibly substituted by one or more alkyl radicals, halogen atoms;

R8 means a radical Ra or NRaRb;

their racemates, enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts.

Suitable according to the invention compounds of formula (I) include the following compounds:

1-[2-(3-methoxy-4-phenylpyrazol-1-yl)ethyl]piperidine;

1-(1-azabicyclo[2,2,2]Oct-ylmethyl)-4-phenyl-1H-pyrazole-1-ol;

3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]octane;

3-(3-methoxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]octane;

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-ol;

1-(2-peligrosas-1-retil)-4-phenyl-1H-pyrazole-3-ol;

1-[2-(2-methylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;

1-[2-(4-foreperiod-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;

1-[2-(3-methylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;

1-[2-(3,6-dihydro-2H-pyridine-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;

1-[2-(7-azabicyclo[2,2,1]hept-7-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;

1-[2-(2-azabicyclo[2,2,2]Oct-2-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;

1-[2-(2-azabicyclo[2,2,1]hept-2-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;

1-[2-dimethylaminoethyl]-4-phenyl-1H-pyrazole-3-ol;

1-[3-dimethylaminopropyl]-4-phenyl-1H-pyrazole-3-ol;

1-[2-((2S,6R)-2,6-dimethylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;

1-[2-diethylaminoethyl]-4-phenyl-1H-pyrazole-3-ol;

1-(2-diisopropylaminoethyl)-4-phenyl-1H-pyrazole-3-ol;

4-phenyl-1-(2-pyrrolidin-1-retil)-1H-pyrazole-3-ol;

3-(3-methoxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2,2,2]octane;

1-[2-(3-deformedarse-4-phenylpyrazol-1-yl)ethyl]piperidine;

4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-ylamine;

4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-ylamine;

N-[4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-yl]ndimethylacetamide;

N-[4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-yl]methanesulfonamide;

1-(2-dimethylamine is propyl)-4-phenyl-1H-pyrazole-3-ol;

1-(1-methylpiperidin-3-ylmethyl)-4-phenyl-1H-pyrazole-3-ol;

5-methyl-4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(3-AMINOPHENYL)-1-(2-dimethylaminoethyl)-1H-pyrazole-3-ol;

N-{3-[3-hydroxy-1-(2-dimethylaminoethyl)-1H-pyrazole-4-yl]phenyl}ndimethylacetamide;

4-(4-AMINOPHENYL)-1-(2-dimethylaminoethyl)-1H-pyrazole-3-ol;

1-(2-dimethylaminoethyl)-4-(4'-forbiden-3-yl)-1H-pyrazole-3-ol;

4-biphenyl-3-yl-1-(2-dimethylaminoethyl)-1H-pyrazole-3-ol;

1-(2-dimethylaminoethyl)-4-(4'-forbiden-4-yl)-1H-pyrazole-3-ol;

1-(2-piperidine-1-retil)-4-pyridin-2-yl-1H-pyrazole-3-ol;

1-(2-piperidine-1-retil)-4-pyridin-4-yl-1H-pyrazole-3-ol;

4-(4-forfinal)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(4-trifloromethyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-phenyl-1-(2-piperidine-1-ylpropyl)-1H-pyrazole-3-ol;

3-(4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]octane;

4-(5-chlorothiophene-2-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(3-methoxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(2-methoxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(3-hydroxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(4-hydroxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(4-methoxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(3-forfinal)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

1-(2-piperidine-1-retil)-4-(3-triptoreline)-1H-pyrazole-3-ol;

1-(2-piperidine-1-retil)-4-pyridin-3-yl-1H-feast of the evils-3-ol;

4-(4-chlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(3-chlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(2-forfinal)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(2-chlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazole-3-ol;

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(3-chlorophenyl)-1H-pyrazole-3-ol;

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(3-forfinal)-1H-pyrazole-3-ol;

1-(1-methylpyrrolidine-3-yl)-4-phenyl-1H-pyrazole-3-ol;

1-[2-(1-methylpyrrolidine-2-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;

1-(pyrrolidin-3-yl)-4-phenyl-1H-pyrazole-3-ol;

1-[(1-methylpyrrolidine-2-(S)-yl)methyl]-4-phenyl-1H-pyrazole-3-ol;

4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

1-[2-(4-phenylpyrazol-1-yl)ethyl]piperidine;

1-[2-(4-methylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;

3-(3-deformedarse-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]octane;

3-(4-phenylpyrazol-1-yl)-1-azabicyclo[2,2,2]octane;

4-benzo[b]thiophene-2-yl-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-phenyl-1-piperidine-3-yl-1H-pyrazole-3-ol;

1-(2-piperidine-1-retil)-4-thiophene-3-yl-1H-pyrazole-3-ol;

1-(2-piperidine-1-retil)-4-p-tolyl-1H-pyrazole-3-ol;

1-(1-azabicyclo[2,2,2]Oct-2-ylmethyl)-4-phenyl-1H-pyrazole-3-ol;

(S)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-ol;

(R)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-ol;

4-phenyl-1-pyrrolidin-3-ylmethyl-1H-pyrazole-3-ol;

1-(2-piperidine-1-retil)-thiophen-2-yl-1H-pyrazole-3-ol;

4-[3-hydroxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzamide;

3-[3-hydroxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzamide;

1-[(S)-1-(1-azabicyclo[2,2,2]Oct-3-yl)methyl]-4-phenyl-1H-pyrazole-3-ol;

1-[(R)-1-(1-azabicyclo[2,2,2]Oct-3-yl)methyl]-4-phenyl-1H-pyrazole-3-ol;

1-[(1S,4R)-2-(2-azabicyclo[2,2,1]hept-2-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;

1-[(1R,4S)-2-(2-azabicyclo[2,2,1]hept-2-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;

1-((R)-1-methylpyrrolidine-2-ylmethyl)-4-phenyl-1H-pyrazole-3-ol;

1-((S)-1-methylpyrrolidine-3-yl)-4-phenyl-1H-pyrazole-3-ol;

1-((R)-1-methylpyrrolidine-3-yl)-4-phenyl-1H-pyrazole-3-ol;

1-[1-(7-azabicyclo[2,2,1]hept-2-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;

1-(1-azabicyclo[2,2,1]hept-3-yl)-4-phenyl-1H-pyrazole-3-ol;

4-phenyl-1-piperidine-2-ylmethyl-1H-pyrazole-3-ol;

1-(1-methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazole-3-ol;

1-(1-ethylpyrrolidin-2-ylmethyl)-4-phenyl-1H-pyrazole-3-ol;

1-(1-methyl-2-piperidine-1-retil)-4-phenyl-1H-pyrazole-3-ol;

1-[2-(2-azabicyclo[2,2,1]hept-2-yl)-1-methylethyl]-4-phenyl-1H-pyrazole-3-ol;

1-(2-dimethylaminoacetyl)-4-phenyl-1H-pyrazole-3-ol;

1-(R)-1-azabicyclo[2,2,2]Oct-3-yl-4-(4-chlorophenyl)-1H-pyrazole-3-ol;

1-(S)-1-azabicyclo[2,2,2]Oct-3-yl-4-(4-chlorophenyl)-1H-pyrazole-3-ol;

1-(R)-1-azabicyclo[2,2,2]Oct-3-yl-4-(3-chlorophenyl)-1H-pyrazole-3-ol;

1-(S)-1-azabicyclo[2,2,2]Oct-3-yl-4-(3-chlorophenyl)-1H-pyrazole-3-ol;

1-(R)-1-azabicyclo[2,2,2]Oct-3-yl-4-(3-forfinal)-1H-pyrazole-3-ol;

1-(S)-1-azabicyclo[2,2,2]Oct-3-the l-4-(3-forfinal)-1H-pyrazole-3-ol;

4-(5-bromothiophene-2-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(5-phenylthiophene-2-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

1-(2-piperidine-1-retil)-4-(5-pyridin-2-althofen-2-yl)-1H-pyrazole-3-ol;

4-(4-chlorothiophene-2-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(4-bromophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

1-(2-piperidine-1-retil)-4-(3-trifloromethyl)-1H-pyrazole-3-ol;

4-(3,4-dichlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(3,5-dichlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(6-chloropyridin-2-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(1H-indol-6-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(1H-indol-5-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(1H-indol-3-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(1-methyl-1H-indol-3-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

N-{4-[3-hydroxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]phenyl}methanesulfonamide;

N-{3-[3-hydroxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]phenyl}methanesulfonamide;

4-[3-(1H-imidazol-2-yl)phenyl]-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-[4-(1H-imidazol-2-yl)phenyl]-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(3-chloro-4-hydroxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(4-hydroxy-3-were)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(4-amino-3-chlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(5-chlorothiophene-2-yl)-1H-piraso the-3-ol;

1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-(5-chlorothiophene-2-yl)-1H-pyrazole-3-ol;

1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-(4-chlorophenyl)-1H-pyrazole-3-ol;

1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-(3-chlorophenyl)-1H-pyrazole-3-ol;

1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-(3-forfinal)-1H-pyrazole-3-ol;

1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-(3-hydroxyphenyl)-1H-pyrazole-3-ol;

1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-(4-hydroxyphenyl)-1H-pyrazole-3-ol;

1-[2-(2-azabicyclo[2,2,1]hept-2-yl)ethyl]-4-(5-chlorothiophene-2-yl)-1H-pyrazole-3-ol;

1-[2-(2-azabicyclo[2,2,1]hept-2-yl)ethyl]-4-(4-chlorophenyl)-1H-pyrazole-3-ol;

1-[2-(2-azabicyclo[2,2,1]hept-2-yl)ethyl]-4-(3-chlorophenyl)-1H-pyrazole-3-ol;

1-[2-(2-azabicyclo[2,2,1]hept-2-yl)ethyl]-4-(3-forfinal)-1H-pyrazole-3-ol;

1-[2-(2-azabicyclo[2,2,1]hept-2-yl)ethyl]-4-(3-hydroxyphenyl)-1H-pyrazole-3-ol;

1-[2-(2-azabicyclo[2,2,1]hept-2-yl)ethyl]-4-(4-hydroxyphenyl)-1H-pyrazole-3-ol;

1-[2-(2-azabicyclo[2,2,1]hept-2-yl)ethyl]-4-(3-chloro-4-hydroxyphenyl)-1H-pyrazole-3-ol;

1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-(3-chloro-4-hydroxyphenyl)-1H-pyrazole-3-ol;

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(3-hydroxyphenyl)-1H-pyrazole-3-ol;

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-hydroxyphenyl)-1H-pyrazole-3-ol;

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(3-chloro-4-hydroxyphenyl)-1H-pyrazole-3-ol;

2-[1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzamide;

N-methyl-2-[1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzamide;

2-[1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzo is sulfonamid;

N-methyl-2-[1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzosulfimide;

{2-[1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]phenyl}methanol;

4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-thiol;

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-ylamine;

N-[1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-yl]methanesulfonamide;

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-thiol;

4-[1-(1-azabicyclo[2,2,2]Oct-3-yl)-1H-pyrazole-4-yl]-2-chlorophenol;

4-[1-(1-azabicyclo[2,2,2]Oct-3-yl)-1H-pyrazole-4-yl]phenol;

3-[4-(4-chlorophenyl)pyrazole-1-ylmethyl]-1-azabicyclo[2,2,2]octane;

4-[1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-1H-pyrazole-4-yl]phenol;

4-[1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-1H-pyrazole-4-yl]-2-chlorophenol;

3-(3-cyclopropylmethoxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]octane;

3-[4-(4-chlorophenyl)-3-cyclopropylmethoxy-1-ylmethyl]-1-azabicyclo[2,2,2]octane;

4-[1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-3-cyclopropylmethoxy-1H-pyrazole-4-yl]phenol;

4-[1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-3-cyclopropylmethoxy-1H-pyrazole-4-yl]-2-chlorophenol;

3-[4-phenyl-3-(2,2,2-triptoreline)pyrazole-1-ylmethyl]-1-azabicyclo[2,2,2]octane;

3-[4-(4-chlorophenyl)-3-(2,2,2-triptoreline)pyrazole-1-ylmethyl]-1-azabicyclo[2,2,2]octane;

4-[1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-3-(2,2,2-triptoreline)-1H-pyrazole-4-yl]phenol;

4-[1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-3-(2,2,2-triptoreline)-1H-pyrazole-4-yl]-2-chlorophenol;

N-[1-(1-azabicyclo[2,2,2]about the t-3-ylmethyl)-4-phenyl-1H-pyrazole-3-yl]methanesulfonamide;

1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-phenyl-1H-pyrazole-3-thiol;

1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-phenyl-1H-pyrazole-3-ylamine;

2-[2-(4-phenylpyrazol-1-yl)ethyl]-2-azabicyclo[2,2,1]heptane;

2-{2-[4-(4-chlorophenyl)pyrazole-1-yl]ethyl}-2-azabicyclo[2,2,1]heptane;

4-{1-[2-(2-azabicyclo[2,2,1]hept-2-yl)ethyl]-1H-pyrazole-4-yl}phenol;

4-{1-[2-(2-azabicyclo[2,2,1]hept-2-yl)ethyl]-1H-pyrazole-4-yl}-2-chlorophenol;

1-[2-(2-ethyl-4-methylpyrrolidine-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-thiol;

N-{1-[2-(2-azabicyclo[2,2,1]hept-2-yl)ethyl]-4-phenyl-1H-pyrazole-3-yl}methanesulfonamide;

1-[2-(2-azabicyclo[2,2,1]hept-2-yl)ethyl]-4-phenyl-1H-pyrazole-3-ylamine;

4-(4-chlorophenyl)-1-[2-(2-ethyl-4-methylpyrrolidine-1-yl)ethyl]-1H-pyrazole-3-thiol;

N-[1-[2-(2-azabicyclo[2,2,1]hept-2-yl)ethyl]-4-(4-chlorophenyl)-1H-pyrazole-3-yl]methanesulfonamide;

1-[2-(2-azabicyclo[2,2,1]hept-2-yl)ethyl]-4-(4-chlorophenyl)-1H-pyrazole-3-ylamine;

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazole-3-thiol;

N-[1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-(4-chlorophenyl)-1H-pyrazole-3-yl]methanesulfonamide;

1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-(4-chlorophenyl)-1H-pyrazole-3-ylamine;

1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-(4-chlorophenyl)-1H-pyrazole-3-thiol;

1-(1-methylpropenoate-3-yl)-4-phenyl-1H-pyrazole-3-ol;

1-(2-methylaminomethyl)-4-phenyl-1H-pyrazole-3-ol;

1-(3-dimethylaminophenyl)-4-phenyl-1H-pyrazole-3-ol;

1-(3-methylaminomethyl)-4-phenyl-1H-pyrazole-3-ol;

1-(2-dimethyl initlogger)-4-phenyl-1H-pyrazole-3-ol;

1-(2-methylenedicyclohexyl)-4-phenyl-1H-pyrazole-3-ol;

1-(3-dimethylaminoethoxy)-4-phenyl-1H-pyrazole-3-ol;

1-(3-methylenedicyclohexyl)-4-phenyl-1H-pyrazole-3-ol;

1-(octahedrons-3-ylmethyl)-4-phenyl-1H-pyrazole-3-ol;

1-((S)-1-ethylpyrrolidin-2-ylmethyl)-4-phenyl-1H-pyrazole-3-ol;

4-phenyl-1-pyrrolidin-3-ylmethyl-1H-pyrazole-3-ol;

1-((2R)-1-methylpyrrolidine-2-ylmethyl)-4-phenyl-1H-pyrazole-3-ol;

4-phenyl-1-(piperidine-3-yl)-1H-pyrazole-3-ol;

1-(1-methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazole-3-ol;

1-(1-mutilation-3-yl)-4-phenyl-1H-pyrazole-3-ol;

4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(thiophene-2-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(3,4-dichlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(4-bromophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(1H-indol-5-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

4-(5-bromothiophene-2-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

2-[1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzamide;

4-(2-hydroxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole;

4-(1H-indol-5-yl)-1-(2-piperidine-1-retil)-1H-pyrazole;

4-(4-were)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(1H-indol-5-yl)-1H-pyrazole;

(+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(1H-indol-5-yl)-1H-pyrazole;

(-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(1H-indol-5-yl)-1H-pyrazole;

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(5-chlorothiophene-2-yl)-1H-pyrazole-3-ol;

1-(1-and bicyclo[2,2,2]Oct-3-yl)-4-(5-chlorothiophene-2-yl)-1H-pyrazole-3-ol;

1-(1-azabicyclo[2,2,2]Oct-2-ylmethyl)-4-phenyl-1H-pyrazole-3-ol;

3-[4-(3,5-differenl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane;

4-benzo[b]thiophene-2-yl-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;

1-(2-piperidine-1-retil)-4-thiophene-3-yl-1H-pyrazole-3-ol;

4-[3-hydroxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzamide;

3-[3-hydroxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzamide;

(-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-ol;

(+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-ol;

(-)-1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-phenyl-1H-pyrazole-1-ol;

(+)-1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-phenyl-1H-pyrazole-1-ol;

1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-(4-chlorophenyl)-1H-pyrazole-3-ol;

(-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazole-3-ol;

(+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazole-3-ol;

(-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-forfinal)-1H-pyrazole-3-ol;

(+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-forfinal)-1H-pyrazole-3-ol;

3-[4-(4-chlorophenyl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane;

3-[4-(4-chlorophenyl)pyrazole-1-ylmethyl]-1-azabicyclo[2,2,2]octane;

3-[4-(3-chloro-4-methoxyphenyl)pyrazole-1-ylmethyl]-1-azabicyclo[2,2,2]octane;

4-[1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-1H-pyrazole-4-yl]-2-chlorophenol;

4-[1-(1-azabicyclo[2,2,2]Oct-3-yl)-1H-pyrazole-4-yl]-2-chlorophenol;

(-)-4-[1-(1-azabicyclo[2,2,2]Oct-3-yl)-1H-pyrazole-4-yl]-2-chlorophenol;

(+)-4-[1-(1-azabicyclo[2,2,2]Oct-3-yl)-1H-pyrazole-4-yl]-2-chlordene is;

(+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-pyridin-2-yl-1H-pyrazole-3-ol;

(-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-pyridin-2-yl-1H-pyrazole-3-ol;

(+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-ylamine;

(-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-ylamine;

(+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(1H-indol-4-yl)-1H-pyrazole;

(-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(1H-indol-4-yl)-1H-pyrazole;

their racemates, the enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts.

Methods of obtaining derivatives according to the present invention are explained below and, for a better understanding of the methods, the compounds of formula (I) is divided into eight subfamilies: (Ia) for R3 = OH; (Ib) for R3 = ORc; (Ic) for R3 = H; (Id) for R3 = NH2; (Ie) for R3 = NHCHO, NraRb, NHC(O)Ra, NHC(S)Ra, NHSO2Ra; (If) for R3 = SH; (Ig) for R3 = SRc; (Ih) for R3 = S(O)Ra, SO2Ra. Definitions of the various substituents have the same meaning as those in the case of the General formula (I), unless nothing else.

For ease of reading group GP, GP', GP, GP'Gpivand GPvrepresent a protective group of functional groups that are sensitive to reaction conditions, and is entered as indicated in the manual by T.W. Greene and other "Protective Groups in Organic Synthesis", Wiley-Interscience, third edition (1999), which may not be affected at later stages of synthesis and which can be removed under conditions that do not involve frequent rest the molecule.

Derivatives of formula (I)in which R3 means a hydroxy-group (Ia)can be obtained from derivatives of the formula (II) ((I) c R3 = OGP), where GP denotes a protective group of hydroxyl group.

Under GP understand the protective group of hydroxyl group, such as indicated in the manual by T.W. Greene and other "Protective Groups in Organic Synthesis", Wiley-Interscience, third edition (1999), which may not be affected at later stages of synthesis and which can be removed under conditions that do not affect the rest of the molecule. For example, the group GP can be a silyl group such as tert-butyldimethylsilyl, triisopropylsilyl or diphenylmethylene, alkyl, Uralkaliy, alkylidene, cycloalkylcarbonyl, heteroalkyl or heterologously residue, such as methyl, allyl, cyclohex-2-enyl, benzyl or tetrahydropyran-2-yl. The group GP is preferably benzyl or cyclohex-2-enyl. Delete group GP is carried out according to the methods described in T.W. Greene and others,"Protective Groups in Organic Synthesis", Wiley-Interscience, third edition (1999).

For example, when the group GP is a benzyl, delete, protection is carried out by hydrolysis in the presence of concentrated hydrochloric acid in alcohol, such as ethanol, methanol or isopropanol, at a temperature from 20°C to a temperature of Kipen the I reaction medium, preferably in ethanol, at the boiling temperature of the reaction medium.

Alternative dibenzylamine can be achieved through the following consecutive operations:

a) obtaining hydrochloride exposed unprotect compounds in the presence of hydrogen chloride in aqueous solution or in solution in an organic solvent, such as ethanol, methanol, dioxane or diethyl ether, at a temperature of about 20°C;

b) hydrogenation in the presence of a catalyst such as palladium-on-charcoal, in an alcohol, such as ethanol, methanol or isopropanol, at a hydrogen pressure from 1 bar to 20 bar and at a temperature from 20°C to the boiling temperature of the reaction medium.

Hydrogenolysis of benzyl groups may also be carried out in the presence of a catalyst such as palladium-on-charcoal, in the presence of concentrated hydrochloric acid in alcohol, such as ethanol, methanol or isopropanol, at a hydrogen pressure from 1 bar to 30 bar and at a temperature from 20°C to the boiling temperature of the reaction medium. The reaction can also be carried out using ammonium formate in the presence of a catalyst such as palladium-on-charcoal, in an alcohol, such as ethanol, methanol or isopropanol, at a temperature from 20°C to the boiling temperature of the reaction medium, preferably in methanol at the boiling temperature of the reaction is ionic environment.

When the group GP is cyclohexenyl group, removal of the protection is carried out by hydrolysis in an acidic medium, for example, in the presence of a solution of hydrogen chloride in ether or alcohol, in a solvent such as methanol or ethanol, at temperatures from 20°C to the boiling temperature of the reaction medium.

Derivatives of formula (I)in which R3 means ORc (Rc differs from C(O)R8, C(S)R8, SO2R8), H, NH2or OGP, (Ib), (Ic), (Id) or (II)can be obtained three different ways of synthesis.

The first path synthesis is the use of compounds of the formula (III):

The compounds of formula (Ib), (Ic), (Id) or (II) can be obtained from a pyrazole of the formula (III) and compounds of formula (IV) R1-A-X, in which X denotes a functional group, such as Cl, Br, I, Os, Os, Of. The alkylation is carried out in an inert atmosphere, for example in an atmosphere of argon or nitrogen, in an alkaline medium in an aprotic solvent, for example, in the presence of sodium hydride, in an aprotic solvent such as dimethylformamide, at temperatures from 20°C to the boiling temperature of the reaction medium or in the presence of potassium tert-butylate, in a solvent such as dimethylformamide, at temperatures from 20°C to the boiling temperature of the reaction medium. The reaction can also be carried out in the presence of potassium carbonate and, if necessary, iodine is Yes potassium in a solvent, such as acetone, methyl ethyl ketone, acetonitrile or dimethylformamide, preferably methyl ethyl ketone, at the boiling temperature of the reaction medium.

The compounds of formula (IV) are commercially available or can be obtained from the corresponding alcohols of formula R1-A-OH well-known specialist in this field means, such as described in J. March, Advanced Organic Chemistry, Wiley-Interscience, fourth edition (1992), or R.C. Larock, Comprehensive Organic Transformations, VCH Publishers (1989). The alcohols of the formula R1-A-OH are commercially available or can be obtained by adaptation of methods described in the literature using conventional specialist knowledge in this field.

The second way of synthesis can be used for compounds of formula (I)in which R3 means ORc (Rc differs from C(O)R8, C(S)R8, SO2R8), H or OGP, and R1-A means a group where the radical a is associated with R1 via the nitrogen atom.

The compounds of formula (Ib), (Ic) or (II) can be obtained in three or four stages of the pyrazoles of the formula (III) according to the following procedure:

a) Alkylation of pyrazole of the formula (III) with compounds of formula (V) GP'O-A-X, in which GP' means a protective group of the hydroxyl functional group, such as indicated in the manual by T.W. Greene and others, "Protective Groups in Organic Synthesis", Wiley-Interscience, third edition (1999), which may not be affected during stage alkylation and can the be removed under conditions not affecting the rest of the molecule (for example, GP' can be a silyl group such as tert-butyldimethylsilyl, triisopropylsilyl or diphenylmethylene; Aracely, alkylidene, cycloalkylcarbonyl, heteroalkyl or heterologously residue, such as allyl, cyclohex-2-enyl, benzyl or tetrahydropyran-2-yl); group GP' preferred means tetrahydropyran-2-yl or tert-butyldimethylsilyl; the radical X is a functional group, such as Cl, Br, I, Os, Os, Of. The alkylation is carried out in an inert atmosphere, for example in an atmosphere of argon or nitrogen, in an alkaline medium in an aprotic solvent, for example, in the presence of sodium hydride, in an aprotic solvent such as dimethylformamide, at temperatures from 20°C to the boiling temperature of the reaction medium or in the presence of potassium tert-butylate, in a solvent such as dimethylformamide, at temperatures from 20°C to the boiling temperature of the reaction medium. The reaction can also be carried out in the presence of potassium carbonate and, if necessary, potassium iodide, in a solvent such as acetone, methyl ethyl ketone, acetonitrile or dimethylformamide, preferably methyl ethyl ketone, at the boiling temperature of the reaction medium.

b) Receiving the intermediate products of the formula (VI) after removal of the protective group GP' ?what about the methods, described in the manual by T.W. Greene and others, "Protective Groups in Organic Synthesis", Wiley-Interscience, third edition (1999), and without affecting other functional groups in the molecule. For example, when a group of GP' means tetrahydropyran-2-yl, removing protection from alcohol can be carried out in an acidic medium, for example, in the presence of aqueous hydrochloric acid in a solvent such as ethanol or methanol, at temperatures from 20°C to the boiling temperature of the reaction medium, preferably in the presence of aqueous hydrochloric acid in ethanol, at a temperature of about 20°C.

a') Alternatively, when a represents ethyl or (C5-C7-cycloalkyl, and these radicals can be substituted by one or more substituents selected among (C1-C5)-alkyl, (C3-C7)-cycloalkyl, arylalkyl, heteroaromatic, aryl, heteroaryl, intermediate products of the formula (VI) can be obtained by introducing into the interaction of the compounds of formula (III) and the corresponding epoxide in the presence of a base, such as tert-butyl potassium, in an aprotic solvent such as dimethylformamide, at temperatures from 20°C to the boiling temperature of the reaction medium, according Villalgordo J.M., Synthesis, 1613 (1999).

C) activating the residual alcohol compounds of the formula (VI), for example, due to the formation of tosilata or nelfinavir specified in the scheme of synthesis as Act. The reaction is then carried out with mozillateam or methylchloride in an alkaline medium, for example, in the presence of pyridine, in a solvent such as dichloromethane, at a temperature from -20°C to the boiling temperature of the reaction medium, preferably at a temperature of from -10°C. to a temperature of about 20°C.

d) Substitution of activated residual alcohol with a primary or secondary amine of formula R1H. The reaction is carried out in an alkaline medium, for example in the presence of potassium carbonate, in a polar solvent such as dimethylformamide or acetonitrile, at temperatures from 20°C to the boiling temperature of the reaction medium, preferably in dimethylformamide, at a temperature of about 80°C.

The compounds of formula (V) are commercially available or can be obtained from the corresponding alcohols of formula GP'O-A-OH well-known specialist in this field means, such as described in J. March, Advanced Organic Chemistry, Wiley-Interscience, fourth edition (1992), or R.C. Larock, Comprehensive Organic Transformations, VCH Publishers (1989). The alcohols of formula GP'O-A-OH are commercially available or can be obtained, for example, by protecting one alcohol group diatomic alcohol formula BUT-BUT-IT according to well-known expert in the field of methods, such as described in J. March, Advanced Organic Chemistry, Wiley-Interscience, fourth edition (1992), or R.C. Larock, Comprehensive Organic Transformations, VCH Publishers (1989). The compounds of formula BUT-A-OH the com is Cesky available or can be obtained by the person skilled in the art by using or adapting methods, described in the literature.

The third way of synthesis, when R3 means ORc (Rc differs from C(O)R8, C(S)R8, SO2R8), H or OGP, is to carry out the synthesis, based on a derivative of formula (VII)according to the following synthesis scheme.

The compounds of formula (Ib), (Ic) and (II) can be obtained in two stages proceeding from compounds of formula (VII)in which Y = Br, I or Cl, preferably Br or I):

a) Alkylation of 4-halogenerator formula (VII) with compounds of formula (IV), such as the above. The reaction is carried out in an inert atmosphere, for example in an atmosphere of argon or nitrogen, in an alkaline medium in an aprotic solvent, for example, in the presence of sodium hydride, in an aprotic solvent such as dimethylformamide, at temperatures from 20°C to the boiling temperature of the reaction medium, or in the presence of potassium tert-butylate, in a solvent such as dimethylformamide, at temperatures from 20°C to the boiling temperature of the reaction medium. The reaction can also be carried out in the presence of potassium carbonate and, if necessary, potassium iodide, in a solvent such as acetone, methyl ethyl ketone, acetonitrile or dimethylformamide, preferably methyl ethyl ketone, at the boiling temperature of the reaction medium.

b) Linking by Suzuki obtained intermediate product and Bronevoy acid, altivo is Anata, cycloalkyl or (hetero)kildalkey formula (VIII), where Rx denotes alkyl or cycloalkyl. The reaction is carried out in an inert atmosphere in the presence of inorganic bases, such as3RHO4, Na2CO3or BA(OH)2salts of palladium (catalyst), as bistrifuormethylbenzene (PdCl2(PPh3)2), tetranitropentaerithrite (Pd(PPh3)4or diphenylphosphinylchloride (PdCl2dppf), in a solvent such as dimethylformamide, dimethoxyethane, tetrahydrofuran, dioxane, toluene, xylene or ethanol, in the presence of, if necessary, water, at temperatures from 20°C to the boiling temperature of the reaction medium (Kotha S., and others, Tetrahedron,58, 9633 (2002)).

Boranova acid, alkylboronic, cycloalkyl or (hetero)alldancing formula (VIII) are commercially available or they are obtained by using or adapting methods described in the literature, for example, according to G.W. Kabalka and others, Tetrahedron Letters,27, 3843 (1986); J.F. Nicoud and others, Tetrahedron Letters,34, 8237 (1993); J.M. Tour, etc., J. Amer. Chem. Soc.,116, 11723 (1994); or Mueller T.J.J. and other Synthesis,9, 1163 (2002).

Intermediates of formula (III) in the case where the radicals ORc (Rc differs from C(O)R8, C(S)R8, SO2R8) and OGP are in position 3 of the pyrazole, receive according to the following reaction scheme:

Pyrazoles f is rmula (III) can be obtained in four stages, proceeding from compounds of formula (IX)according to the following procedure:

a) Condensation (aryl)alkyl(hetero)arylacetic, where Rx = alkyl, aralkyl formula (IX), with the agent aminomethylpyridine or agent carbonyl of formula (X), where Ry denotes Cl, O-alkyl, O-aralkyl or O-CO-alkyl, preferably where Ry denotes O-alkyl. The reaction aminomethylpyridine can be carried out in the presence of reagent such as N,N,N',N',N",N"-hexamethylenetetramine,-methoxy-N,N,N',N'-tetramethylethylene or tert-butoxy-N,N,N',N'-tetramethylmethylenediamine, in the absence of solvent or in a solvent such as tetrahydrofuran or dioxane, at temperatures from 20°C to the boiling temperature of the reaction medium, preferably in the presence of P-tert-butoxy-N,N,N',N'-tetramethylethylene in tetrahydrofuran at a temperature from 20°C to the boiling temperature of the reaction medium. The carbonylation reaction between (aryl)alkyl(hetero)allazetta and carbonylation agent of the formula (X) is carried out in an inert atmosphere, for example in an atmosphere of argon or nitrogen, in an alkaline medium, for example, in the presence of sodium hydride, in an aprotic solvent such as dimethylformamide, at temperatures from -20°C to the boiling point of the solvent, preferably at a temperature of about 20°C.

b) Education cycle 1H-pyrazole-3-ol by introducing into the entries batch is e obtained at the previous stage intermediate product with hydrazine, usually managerfinance form, in alcohol, such as ethanol, propanol or isopropanol, at a temperature from 20°C to the boiling temperature of the reaction medium, preferably in ethanol, at the boiling temperature of the reaction medium.

(C) Protection of the nitrogen in position 1 1H-pyrazole-3-ol protecting group such as acetyl, allyloxycarbonyl or tosyl, preferably acetyl group. The reaction is carried out with the agent acetylation, allyloxycarbonyl or tiliouine, preferably with acetic anhydride without solvent or in the presence of a solvent, such as pyridine, at a temperature from 20°C to the boiling temperature of the reaction medium, preferably at a temperature of about 100°C.

d) protection of the hydroxyl group of the pyrazole or the introduction of balance-Rc in the hydroxyl of pyrazole with the subsequent removal of the protection of nitrogen in polozhenii 1 of the pyrazole. Protection of the hydroxyl group of the pyrazole and the introduction of the balance-Rc hydroxyl pyrazole can be implemented, for example, by alkylation of the hydroxyl group of the pyrazole using the compounds of formula GP-X or Rc-X, in which X denotes a functional group, such as Cl, Br, I, Os, Os, Of. In the case where Rc = methyl or ethyl, as agents of the alkylation can also be used and is preferably selected dimethylsulfate or diethylsulfate. The reaction is carried out in basic medium, for example the er in the presence of a base, such as potassium carbonate, in a solvent such as acetone, methyl ethyl ketone, acetonitrile or dimethylformamide, at temperatures from 20°C to the boiling temperature of the reaction medium, preferably in methylethylketone at the boiling temperature of the reaction medium. When Rc = -CHF2the alkylation can be carried out using methylchlorothiazide in basic medium, for example in the presence of a base such as potassium carbonate, in a solvent such as dimethylformamide, at temperatures from 20°C to the boiling temperature of the reaction medium, preferably at a temperature of about 65°C. Removal of protection of the nitrogen in position 1 of the pyrazole is carried out according to the methods opisannym guide T.W. Greene and others, "Protective Groups in Organic Synthesis", Wiley-Interscience, third edition (1999). For example, when the protecting group is acetyl, removing the protection can be carried out in the presence of a base such as sodium hydroxide or potassium carbonate, in an alcohol, such as ethanol or methanol, if necessary with addition of a solvent, such as tetrahydrofuran or dioxane, at temperatures from 20°C to the boiling temperature of the reaction medium, preferably in the presence of sodium hydroxide in a mixture of ethanol and tetrahydrofuran at a temperature of about 20°C.

The compounds of formula (IX) are commercially available or can be obtained by modulating the isawanya or adaptation described in the literature methods.

The compounds of formula (X) are commercially available or can be obtained by using or adapting opisannyh in the literature methods.

The compounds of formula GP-X commercially available. The compounds of formula Rc-X commercially available or can be obtained from the corresponding alcohols of the formula Rc-OH, by methods known to the person skilled in the art, such as described in J. March, Advanced Organic Chemistry, Wiley-Interscience, fourth edition (1992), or R.C. Larock, Comprehensive Organic Transformations, VCH Publishers (1989). The alcohols of the formula Rc-OH are commercially available or can be obtained by using or adapting described in the literature methods.

Intermediates of formula (III), in the case where the hydrogen atom is in position 3 of the pyrazole, receive according to the below reaction scheme:

The compounds of formula (III) can be obtained from compounds of formula (XI) or (XII) and hydrazine, usually in managerfinance form. The reaction is carried out, for example, in alcohol, such as ethanol, propanol or isopropanol, at a temperature from 20°C to the boiling temperature of the reaction medium, preferably in ethanol at the boiling temperature of the reaction medium.

The compounds of formula (XI) or (XII) are commercially available or can be obtained by using or adapting described in the literature methods.

Split timing is e products of the formula (III), in the case where the radical ORc (Rc differs from C(O)R8, C(S)R8, SO2R8) or OGP or N is in position 3 of the pyrazole, can also be obtained according to the below reaction scheme:

The compounds of formula (III) can be obtained in three or four stages based on compounds of the formula (VII):

a) protection of the compounds of the formula (VII), for example, using toiley, mesyl or acetyl group, preferably using toiley group. This reaction is carried out according to methods known to the person skilled in the art and described in the manual T.W. Green and others, "Protective Groups in Organic Synthesis", Wiley-Interscience, third edition (1999). For example, when the protective group is tosyl, the reaction is carried out with mozillateam in an alkaline medium, for example, in the presence of a hydride of sodium or of potassium tert-butylate, in an aprotic solvent such as dimethylformamide, at temperatures from -10°C to the boiling temperature of the reaction medium.

b) introducing a group R4 by binding assays for Suzuki or by two consecutive reactions Stille. Introduction group R4 by binding assays for Suzuki carry out on the basis of protected 4-halogenerator obtained at the previous stage, and Bronevoy acid, alkylborane, cycloalkyl or (hetero)kildalkey formula (VIII), where Rx denotes alkyl or cycloalkyl, inert is tmosphere, in the presence of inorganic bases, such as3RHO4, Na2CO3or BA(OH)2salts of palladium (catalyst)such as bistrifuormethylbenzene (PdCl2(PPh3)2), tetranitropentaerithrite (Pd(PPh3)4or diphenylphosphinylchloride (PdCl2dppf), in a solvent such as dimethylformamide, dimethoxyethane, tetrahydrofuran, dioxane, toluene, xylene or ethanol, in the presence of, if necessary, water, at temperatures from 20°C to the boiling temperature of the reaction medium. Alternative introduction group R4 can be carried out by two consecutive reactions Stille. First Stille reaction is carried out in an inert atmosphere on the basis of protected 4-halogenerator obtained at the previous stage, and bis(anti), in the presence of iodide monovalent copper salts of palladium such as palladium diacetate (Pd(SLA)2), and triphenylphosphine, in a solvent such as tetrahydrofuran, at temperatures from 20°C to the boiling temperature of the reaction medium, according to Scott, A.I. and others, Tetrahedron Lett.,37, 3247 (1996). The second Stille reaction carried out on the basis of previous ORGANOTIN compounds and halogenated aromatic derivative of formula R4-Z, in which Z denotes Br, I or Cl, preferably Br or I) when using a salt of palladium (catalysis is a torus), such as Tris(dibenzylidene)dipalladium (Pd2dba3), and distriburion in a solvent such as dioxane, at temperatures from 20°C to the boiling temperature of the reaction medium, according to the U. Hacksell, etc., Bioorg. and Med. Chem. Lett., 2837 (1994).

C) Cleavage of the protective group introduced at the first stage. This reaction is carried out according to methods known to the person skilled in the art and described in the manual T.W. Green and others, "Protective Groups in Organic Synthesis", Wiley-Interscience, third edition (1999). For example, when the protective group is tosyl, the reaction can be carried out tetrabutylammonium in a solvent such as tetrahydrofuran or dioxane, at temperatures from 20°C to the boiling temperature of the reaction medium, according to Sakamoto T., and others, Tetrahedron Lett.,39, 595 (1998).

Intermediates of formula (III), in the case where at position 3 of the pyrazole is the radical NH2can be obtained according to the following scheme:

The compounds of formula (III) can be obtained by the condensation reaction of hydrazine, usually in managerfinance the form of 2-(hetero)aryl-3-oxopropanenitrile in an acidic medium, for example, in the presence of acetic acid, in alcohol, such as ethanol, propanol or isopropanol, at a temperature from 20°C to the boiling temperature of the reaction medium, preferably in ethanol at the boiling temperature of the reality in the operating environment.

The compounds of formula (XIII) can be obtained by using or adapting described in the literature methods.

Intermediates of formula (VII), in which at position 3 of the pyrazole is N, OGP, ORc (Rc differs from C(O)R8, C(S)R8, SO2R8), is obtained from the derivative of formula (XIV):

Intermediates of formula (VII)in which Y = Br, I or Cl, preferably Br or I), commercially available or can be obtained from intermediates of formula (XIV). The reaction is carried out using a halogenation agent such as bromine or chloride of iodine, in a solvent such as dichloromethane or chloroform, in the presence of a base such as potassium carbonate, at temperatures from 10°C to the boiling temperature of the reaction medium, preferably using bromine in dichloromethane at a temperature of about 20°C.

Intermediates of formula (XIV), in which at position 3 of the pyrazole is a hydrogen atom, a commercially available or obtained by way of the use or adaptation described in the literature methods.

Intermediates of formula (XIV), in which at position 3 of the pyrazole is radical OGP or radical ORc (Rc differs from C(O)R8, C(S)R8, SO2R8), can be obtained in two stages proceeding from compounds of formula (XV)according to the following procedure:

a) protection of the nitrogen in position 1 1H-pyrazole-3-ol with a protective group such as acetyl, allyloxycarbonyl or tosyl, preferably with acetyl groups. The reaction is carried out with the agent acetylation, allyloxycarbonyl or tiliouine, preferably with acetic anhydride without solvent or in the presence of a solvent, such as pyridine, at a temperature from 20°C to the boiling temperature of the reaction medium, preferably at a temperature of about 100°C.

b) protection of the hydroxyl group of the pyrazole or the introduction of balance-Rc in the hydroxyl of pyrazole with a subsequent removal of the protection of the nitrogen in position 1 of the pyrazole. Protection of the hydroxyl group of the pyrazole and the introduction of the balance-Rc in the hydroxyl of the pyrazole is carried out by alkylation of the hydroxyl group of the pyrazole using the compounds of formula DR-X or Rc-X, in which X denotes a functional group, such as Cl, Br, I, Os, Os, Of. In the case where Rc denotes methyl or ethyl, as agents of the alkylation can also be used and is preferably selected dimethylsulfate or diethylsulfate. The reaction is carried out in basic medium, for example in the presence of a base such as potassium carbonate, in a solvent such as acetone, methyl ethyl ketone, acetonitrile or dimethylformamide, at temperatures from 20°C to the boiling point reacts the Onna environment, preferably methylethylketone at the boiling temperature of the reaction medium. When Rc means a group CHF2the alkylation can be carried out using methylchlorothiazide, in basic medium, for example in the presence of a base such as potassium carbonate, in a solvent such as dimethylformamide, at temperatures from 20°C to the boiling temperature of the reaction medium, preferably at a temperature of about 65°C. Removal of protection from the nitrogen atom of the pyrazole is carried out according to the methods described in the manual T.W. Green and others, "Protective Groups in Organic Synthesis", Wiley-Interscience, third edition (1999). For example, when the protecting group is acetyl, removing the protection can be carried out in the presence of a base such as sodium hydroxide or potassium carbonate, in an alcohol, such as ethanol or methanol, with the addition, if necessary, a solvent such as tetrahydrofuran or dioxane, at temperatures from 20°C to the boiling temperature of the reaction medium, preferably in the presence of sodium hydroxide in a mixture of ethanol and tetrahydrofuran at a temperature of about 20°C.

The compounds of formula (XV) is obtained by using or adapting described in the literature methods.

The compounds of formula (Id) can also be obtained in seven or eight stages proceeding from compounds of formula (XVI), in which Y = Br, I or Cl, preferably Br and I), according to the following procedure:

a) protection of the 4-halogen-3-nitropyrazole formula (XVI), for example, using 2-trimethylsilylamodimethicone group. This reaction is carried out according to methods known to the person skilled in the art and described in the manual T.W. Green and others, "Protective Groups in Organic Synthesis", Wiley-Interscience, third edition (1999). For example, the reaction is carried out with 2-trimethylsilylamodimethicone in an alkaline medium, for example in the presence of sodium hydride, in an aprotic solvent such as dimethylformamide, at temperatures from -10°C to the boiling temperature of the reaction medium.

b) introducing a group R4 by binding assays for Suzuki or by two consecutive reactions Stille. Introduction group R4 by binding assays for Suzuki carry out on the basis of protected 4-halogen-3-nitropyrazole obtained at the previous stage, and Bronevoy acid, alkylborane, cycloalkyl or (hetero)kildalkey formula (VIII), where Rx denotes alkyl or cycloalkyl, in an inert atmosphere, in the presence of inorganic bases, such as3RHO4, Na2CO3or BA(OH)2salts of palladium (catalyst)such as bistrifuormethylbenzene (PdCl2(PPh3)2), tetranitropentaerithrite (Pd(PPh3)4or diphenylphosphinylchloride (PdCl dppf), in a solvent such as dimethylformamide, dimethoxyethane, tetrahydrofuran, dioxane, toluene, xylene or ethanol, in the presence of, if necessary, water, at temperatures from 20°C to the boiling temperature of the reaction medium. Alternatively, the introduction of the group R4 may be carried out by two consecutive reactions Stille. First Stille reaction is carried out in an inert atmosphere on the basis of protected 4-halogen-3-nitropyrazole obtained at the previous stage, and bis(anti -) in the presence of iodide monovalent copper salts of palladium such as palladium diacetate (Pd(SLA)2), and triphenylphosphine, in a solvent such as tetrahydrofuran, at temperatures from 20°C to the boiling temperature of the reaction medium according to Scott AI other, Tetrahedron Lett.,37, 3247 (1996). The second Stille reaction carried out on the basis of previous ORGANOTIN compounds and halogenated aromatic derivative of formula R4-Z, in which Z denotes Br, I or Cl, preferably Br or I), using palladium salt (catalyst)such as Tris(dibenzylidene)dipalladium (Pd2dba3), and distriburion, in a solvent such as dioxane, at temperatures from 20°C to the boiling temperature of the reaction medium according to the U. Hacksell, etc., Bioorg. and Med. Chem. Lett., 2837 (1994).

e) Recovery of the nitro group according to the method, such as described in J. March, Avanced Organic Chemistry, Wiley-Interscience, fourth edition (1992); or R.C. Larock, Comprehensive Organic Transformations, VCH Publishers (1989). For example, this reaction can be carried out using iron in the presence of ammonium chloride in a mixture of alcohol, such as ethanol, and water at temperatures from 20°C to the boiling temperature of the reaction medium.

f) Double protection aminoacetate obtained at the previous stage, with protective group GPv. Group GPvrepresents aminosidine group, such as specified in the manual T.W. Green and others, "Protective Groups in Organic Synthesis", Wiley-Interscience, third edition (1999), and sustainable in terms of the removal of the protective group ALiv. For example, the group GPvcan represent allyl, benzyl or p-methoxybenzyl. Group GPvintroduced according to methods known to the person skilled in the art and described in the manual T.W. Green and others, "Protective Groups in Organic Synthesis", Wiley-Interscience, third edition (1999). For example, when the protective group GPvrepresents allyl, the reaction is carried out with allylbromide in the presence of a base such as cesium carbonate, in an aprotic solvent such as acetonitrile or dimethylformamide, at temperatures from 20°C to the boiling temperature of the reaction medium.

g) Removal of the protective group ALiventered at the first stage according to the methods known to the person skilled in the art and described in the lead the e T.W. Green and others, "Protective Groups in Organic Synthesis", Wiley-Interscience, third edition (1999). For example, when the protective group ALivis 2-trimethylsilylethynyl, the reaction can be carried out tetrabutylammonium in a solvent such as tetrahydrofuran or dioxane, at temperatures from 20°C to the boiling temperature of the reaction medium.

h) Alkylation obtained at the preceding stage of connection with the compounds of formula (IV) R1-A-X, such as the above. The reaction is carried out in an inert atmosphere, for example in an atmosphere of argon or nitrogen, in an alkaline medium, in an aprotic solvent, for example, in the presence of sodium hydride in an aprotic solvent such as dimethylformamide, at temperatures from 20°C to the boiling temperature of the reaction medium or in the presence of potassium tert-butylate, in a solvent such as dimethylformamide, at temperatures from 20°C to the boiling temperature of the reaction medium. The reaction can also be carried out in the presence of potassium carbonate and, if necessary, potassium iodide, in a solvent such as acetone, methyl ethyl ketone, acetonitrile or dimethylformamide, preferably methyl ethyl ketone, at the boiling temperature of the reaction medium.

i) Cleavage of the protective group GPventered at stage f), according to methods known to the person skilled in the art and described in the manual T.W.Green and others, "Protective Groups in Organic Synthesis", Wiley-Interscience, third edition (1999). For example, when the protective group GPvis allyl, the reaction can be carried out using palladium salt, such as tetranitropentaerithrite (Pd(PPh3)4), in the presence of acid, such as N,N-dimethylbarbituric acid, in an aprotic solvent such as dichloromethane, at a temperature from 20°C to the boiling temperature of the reaction medium.

The compounds of formula (XVI) are commercially available or they are obtained by analogy with the described in the literature methods.

The compounds of formula (Ib)where Rc denotes the radical C(O)R8, C(S)R8 or SO2R8 can be obtained from compounds of formula (Ia) according to methods known to the person skilled in the art and described, for example, J. March, Advanced Organic Chemistry, Wiley-Interscience, fourth edition (1992); R.C. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); or Branford P. Mundy and Michael G. Ellerd, Name Reactions and Reagents in Organic Synthesis, A. Wiley-Interscience Publication (1988).

The compounds of formula (Ie) can be obtained from compounds of formula (Id) according to methods known to the person skilled in the art and described, for example, J. March, Advanced Organic Chemistry, Wiley-Interscience, fourth edition (1992); R.C. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); or Branford P. Mundy and Michael G. Ellerd, Name Reactions and Reagents in Organic Synthesis, A. Wiley-Interscience Publication (1988).

The compounds of formula (If) can be obtained from compounds of formulas is (Ia) by reaction with an agent tonirovania, such as, for example, Lawesson reagent, and according to the methods described, for example, J. March, Advanced Organic Chemistry, Wiley-Interscience, fourth edition (1992).

The compounds of formula (Ig) can be obtained from compounds of formula (If) according to methods known to the person skilled in the art and described, for example, J. March, Advanced Organic Chemistry, Wiley-Interscience, fourth edition (1992); R.C. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); or Branford P. Mundy and Michael G. Ellerd, Name Reactions and Reagents in Organic Synthesis, A. Wiley-Interscience Publication (1988).

The compounds of formula (Ih) can be obtained by oxidation of compounds of formula (Ig), in which Rc = Ra, using reagents such as, for example, hydrogen peroxide, potassium permanganate or oxen, and following the methods described, for example, J. March, Advanced Organic Chemistry, Wiley-Interscience, fourth edition (1992).

The compounds of formula (I), in which the group R4 is substituted by one or more radicals IT can be obtained by demethylation of the corresponding methoxylamine compounds according to the method, not affecting the rest of the molecule, such as described in the manual T.W. Green and others, "Protective Groups in Organic Synthesis", Ed. Wiley, third edition (1999). This reaction can be carried out, for example, when using tribromide boron in a solvent such as dichloromethane, at a temperature from -5°C to the boiling temperature of the reaction medium.

The compounds of formula (I), in which the group R4 one or more radicals NH 2can be obtained by recovering the corresponding nitro compounds in accordance with the method, such as described in J. March, Advanced Organic Chemistry, Wiley-Interscience, fourth edition (1992); or R.C. Larock, Comprehensive Organic Transformations, VCH Publishers (1989). For example, this reaction can be carried out by hydrogenation in the presence of a catalyst such as palladium-on-charcoal, and, if necessary, acid, such as hydrochloric acid, in an alcohol, such as ethanol, methanol or isopropanol, at a hydrogen pressure from 1 bar to 20 bar and at a temperature from 20°C to the boiling temperature of the reaction medium.

The compounds of formula (Ib), (Ic) or (II)in which the group R4 is substituted by one or more radicals NRaRb, NHC(O)Ra, C(O)NRaRb, NHSO2Ra or NHC(S)Ra, can be obtained by recovering the corresponding nitro compounds, then the appropriate functionalization of the obtained amino derivatives. Recovery nitrocompounds carried out according to the method, not affecting the rest of the molecule, such as described in J. March, Advanced Organic Chemistry, Wiley-Interscience, fourth edition (1992); or R.C. Larock, Comprehensive Organic Transformations, VCH Publishers (1989). For example, this reaction can be carried out using a reducing agent such as iron powder, in the presence of ammonium chloride in a mixture of water and alcohol, such as methanol or ethanol, at temperatures from 20°C to the temperature of the TRC is of the reaction medium, preferably in ethanol at the boiling temperature of the reaction medium. The functionalization of the obtained amino derivatives is carried out according to methods that do not involve the rest of the molecule known to the person skilled in the art and described, for example, J. March, Advanced Organic Chemistry, Wiley-Interscience, fourth edition (1992); R.C. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); Branford P. Mundy and Michael G. Ellerd, Name Reactions and Reagents in Organic Synthesis, A. Wiley-Interscience Publication (1988); or J.F. Hartwig, Angew. Chem. Int. Ed. Engl., 2047 (1998).

The compounds of formula (Ib), (Ic) or (II)in which the group R4 is substituted by one or more aryl or heteroaryl radicals may be derived from the corresponding halogenated compounds (preferably brominated or iodinated) and related Baranovich acids, alkylboranes, cycloalkyl or (hetero)kildalkey by binding assays for Suzuki. This reaction is carried out in an inert atmosphere in the presence of inorganic bases, such as3RHO4, Na2CO3or BA(OH)2salts of palladium (catalyst)such as bistrifuormethylbenzene (PdCl2(PPh3)2), tetranitropentaerithrite (Pd(PPh3)4or diphenylphosphinylchloride (PdCl2dppf), in a solvent such as dimethylformamide, dimethoxyethane, tetrahydrofuran, dioxane, toluene, xylene or canal, in the presence of, if necessary, water, at temperatures from 20°C to the boiling temperature of the reaction medium.

The compounds of formula (I) allocate and they can be cleaned by the usual known methods, for example by crystallization, chromatography or extraction.

The compounds of formula (I), if necessary, can be transformed into additive salts of a mineral or organic acid by exposure to this acid in an organic solvent, such as alcohol, ketone, simple ether or a chlorinated solvent. These salts also form part of the invention.

As examples of pharmaceutically acceptable salts include salts: bansilalpet, hydrobromide, hydrochloride, citrate, aconsultant, fumarate, gluconate, Iodate, maleate, isetionate, methanesulfonate, nitrate, oxalate, palmoate, phosphate, salicylate, succinate, sulfate, tartrate, theophyllinate and p-toluensulfonate.

Compounds according to the invention were tested for their ability to bind nicotinic receptors containing the α7 subunit, with a test for binding when the drugs out of the brain membranes of rats according to the following methods.

Membrane preparations

Frozen samples of the hippocampus in brain of female rats of Sprague-Dawley kept at -20°C until use of the Oia. Hippocampi 10 rats were pooled and homogenized using a crusher type transmitter station in 10 volumes of chilled on ice buffer of the following composition: KCl (11 mm); KN2RHO4(6 mm); NaCl (137 mm); Na2HPO4(8 mm), HEPES (20 mm); todatetime (5 mm); EDTA (1.5 mm); PMSF (0.1 mm). The pH value was set equal to 7.4 using NaOH. The resulting mixture was centrifuged with acceleration 24000 g for 20 minutes at 4°C and the precipitate after centrifugation again suspended in 20 volumes of a mixture of water with ice. After incubation for 60 minutes at 4°C received a new precipitate by centrifugation with acceleration 24000 g for 20 minutes at 4°C. This last again suspended in the buffer of the above composition and frozen at -20°C. on the day of the experience membranes were thawed, centrifugable with acceleration 24000 g for 20 minutes, then re-suspended to a final concentration of 2-5 mg protein/ml in phosphate buffer, Dulbecco with pH 7.4, containing 0.05% bovine serum albumin.

Determination of affinity for receptors containing the α7 subunit

The binding of the compounds according to the invention with receptors containing the α7 subunit, was determined by competition in respect of [3H]-methyllycaconitine ([3H]-MLA), radioactive indicator that recognizes the receptor α7 (Davies and others, Neuropharmacology,38679-690 (1999)), according to the classical methods, adapted to the format of 96-well plates. The ability of compounds according to the invention to displace the link [3H]-MLA with membranes of rat hippocampus was determined in two repeated after incubation for 2 hours at room temperature. Each hole contained a sample mass of approximately 150 μg of membrane protein, 5 nm [3H]-MLA and one of the compounds according to the invention, diluted to a certain concentration in phosphate buffer, Dulbecco with pH 7.4, containing 0.05% bovine serum albumin in a final volume of 150 μl. Nonspecific binding was determined in the special holes containing 10 µmol its radioactive isotope MLA. The incubation was stopped by filtering the contents of each of the holes through the filters glass fiber (Whatman GF/B), pre-impregnated 0,33%solution polyethylenimine in phosphate buffer, Dulbecco to reduce nonspecific binding. The filters are then washed 3 times with phosphate buffer, Dulbecco, then dried at 50°C for about 2 hours. The residual radioactivity on the filters was measured by use of scintillant (MeltiLex A, Perkin Elmer) with the following calculation method luminometry (Trilux 1450 microbeta, Perkin Elmer).

Data analysis

For each test compound residual radioactivity on the filter, the Ah were expressed as the number of beats per minute. Determine the two-fold repetition were averaged and the concentration of a compound that inhibits half the specific binding of labeled atoms (CI50), was calculated by curvilinear regression using specific software (GraphPad Prism). The apparent affinity constants Ki of the compounds according to the invention was calculated using the equation of Cheng and Prusoff (Cheng and Prusoff, Biochem. Pharmacol.,22, 3099-3108 (1973)).

Compounds according to the invention, is studied in this test, have a Ki value below 10 Microm.

The following examples explain the invention without limiting its scope.

Example 1

1-[2-(3-methoxy-4-phenylpyrazol-1-yl)ethyl]piperidinemethanol

To a solution of 0.25 g of 3-methoxy-4-phenylpyrazole 20 cm3anhydrous DMF (dimethylformamide) gradually add in an argon atmosphere and at room temperature 0,303 g of sodium hydride (75 wt.% dispersion in vaseline oil). After stirring for 0.75 hour at a temperature of about 50°C in small portions add 0.793 g of 1-(2-chloroethyl)piperidinedione, then heated for 8 hours at a temperature of about 50°C. the Mixture is cooled to room temperature, then add 10 cm3water and concentrated to dryness under reduced pressure (3 kPa). The residue after evaporation is treated with 25 cm3water and extracted with 250 the m 3ethyl acetate. The organic phase polivaut 3 times by 25 cm3water, then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa)to give an oily residue, which is purified by chromatography on silica gel (grain size distribution 15-35 μm), elwira a mixture of ethyl acetate and cyclohexane (67:33 by volume). After concentrating the fractions under reduced pressure to obtain 0.3 g of colorless oil, which was dissolved in 15 cm3acetone and add 30 cm3approximately 3 M solution of hydrogen chloride in diethyl ether. Precipitated white precipitate is filtered off, then dried under vacuum (70 PA) at a temperature of 60°C. Thus receive 0,325 g of 1-[2-(3-methoxy-4-phenylpyrazol-1-yl)ethyl]piperidinemethanol in a solid white color, melting at 208°C (decomposition).

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1,40 (m, 1H); from to 1.60 to 1.90 (m, 5H); to 2.94 (m, 2H); from 3.40 in to 3.60 (m, 4H); of 3.95 (s, 3H); 4,47 (t, J=6.5 Hz, 2H); 7.29 trend (t ush., J=7.5 Hz, 1H); of 7.36 (t ush., J=7.5 Hz, 2H); 7,62 (l ush., J=7.5 Hz, 2H); to 8.14 (s, 1H); there is a 10.03 (array, 1H).

IR-spectrum (KBr): 3031; 2945; 2632; 2540; 1606; 1579; 1518; 1456; 1411; 1047; 1030; 764 and 697 cm-1.

3-methoxy-4-phenylpyrazol can be obtained in the following way:

A suspension of 2 g of 1-(3-hydroxy-4-phenylpyrazol-1-yl)ethanone, of 1.37 g of potassium carbonate and of 1.13 cm3(1.5 g) dimethylsulfate 70 cm 32-butanone stirred for 4 hours at 70°C. To this mixture 24 cm31,66 n sodium hydroxide solution and stirred for 4 hours at room temperature, then partially concentrated under reduced pressure (3 kPa) to remove 2-butanone. The residue is treated with 10 cm3water and extracted with 250 cm3ethyl acetate. The organic phase is washed with 3 times 25 cm3water, then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa)to give a solid residue, light brown, which is purified by chromatography on silica gel (grain size distribution 15-35 μm), elwira a mixture of dichloromethane and methanol (to 98.5:1.5 for all volumes). After concentrating the fractions under reduced pressure to obtain 0.3 g of 3-methoxy-4-phenylpyrazole in the form of a powder pale yellow, melting at 150°C.

1-(3-hydroxy-4-phenylpyrazol-1-yl)Etalon can be obtained in the following way:

To a solution of 6.4 g of 4-phenyl-1H-pyrazole-3-ol 64 cm3pyridine, preheated to a temperature of 100°C, for 10 minutes add 3.4 cm3acetic anhydride. After incubation for an additional 30 minutes at a temperature of 100°C. the mixture is cooled and poured into 600 cm3a mixture of water with ice. The precipitation is filtered off, washed the Ute 4 times in 100 cm 3a mixture of water with ice, then 4 times in 100 cm3heptane, then dried under vacuum (70 PA) at a temperature of 60°C. Thus receive 5,09 g of 1-(3-hydroxy-4-phenylpyrazol-1-yl)ethanone in the form of a powder beige color, melting at 215°C.

4-phenyl-1H-pyrazole-3-ol may be obtained according to the method described by L. Selwood, etc., J. Med. Chem.,44, 78-93 (2001).

Example 2

1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-phenyl-1H-pyrazole-1-adigitalife

A suspension of 0.67 g of 3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]octadecenoamide and 0.08 g of palladium-on-coal (10%) in 20 cm3ethanol is stirred in an autoclave at a hydrogen pressure of 500 kPa at 20°C for 20 hours. The reaction medium is then filtered through celite®and concentrated to dryness under reduced pressure (3 kPa)to give a paste-like residue, which is treated with 50 cm3acetone and proscout during the night. After filtering off sudivshegosya solid and drying under vacuum (70 PA) at a temperature of 60°With get 0,265 g of 1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-phenyl-1H-pyrazole-1-alligatoroidea in the form of hygroscopic crystals beige color, melting at about 240°C (decomposition).

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.65 to 1,95 (m, 4H); from 1.95 up to 2.15 (m, 1H); from 2.40 to 2,0 (m, 1H); 2,96 (DD ush., J=12.5 and 7.5 Hz, 1H); from of 3.10 to 3.40 (m, 5H); a 4.03 (DD, J=13.5 and 7.5 Hz, 1H); 4,10 (DD, J=13.5 and 7.5 Hz, 1H); 7,15 (t ush., J=7.5 Hz, 1H); 7,34 (t ush., J=7.5 Hz, 2H); 7,66 (l ush., J=7.5 Hz, 2H); 8,00 (s, 1H); 10,51 (array, 1H).

IR-spectrum (KBr): 3417; 2940; 2546; 1601; 1474; 1388; 1189; 768; 702 and 611 cm-1.

Example 3

3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]octadecenoate

To a suspension of 3.84 g of sodium hydride (0.75 wt.% dispersion in vaseline oil) in 20 cm3anhydrous dimethylformamide in an argon atmosphere and at room temperature, slowly add a solution of 5 g of 3-benzyloxy-4-phenylpyrazol 30 cm3anhydrous DMF (dimethylformamide). After stirring for 0.75 hour at a temperature of about 50°C, add small portions 11,78 g of 3-chloromethyl-1-azabicyclo[2,2,2]octahedrally, then heated for 18 hours at a temperature of about 50°C. the Mixture is cooled to room temperature, then slowly add 25 cm3water, and then poured into 300 cm3water and extracted 2 times with 300 cm3ethyl acetate. The combined organic phases are washed with 3 times 100 cm3water, then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue is purified by chromatography on aluminium oxide, elwira a mixture of ethyl acetate and methanol (90:10 by volume). After concentration f the shares under reduced pressure gain of 2.81 g of brown oil, which is dissolved in 200 cm3ethanol, and add 6,25 cm3approximately 6 M aqueous hydrochloric acid solution. The solution is concentrated to dryness under reduced pressure (3 kPa). The residue is 2 times treated with 200 cm3ethanol and brought to dryness. So get a 3.01 g of 3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]octadecenoamide in the form of a meringue beige color.

1H-NMR-spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): from 1.65 to 1.90 (m, 4H); to 2.06 (m, 1H); from 2.50 up to 2.65 (m, 1H); to 2.94 (DD, J=10 and 5 Hz, 1H); from of 3.10 to 3.40 (m, 5H); 4,11 (DD, J=10.5 and 6 Hz, 1H); to 4.16 (DD, J=10.5 and 6 Hz, 1H); 5,33 (s, 2H); 7,07 (t ush., J=7.5 Hz, 1H); of 7.36 (t ush., J=7.5 Hz, 3H); 7,43 (t ush., J=7.5 Hz, 2H); 7,50 (d ush., J=7.5 Hz, 2H); 7,65 (l ush., J=7.5 Hz, 2H); to 8.14 (s, 1H); 10,51 (array, 1H).

IR-spectrum (KBr): 3031; 2936; 2803; 2564; 1606; 1578; 1569; 1510; 1454; 1435; 1360; 1046; 1024; 764; 697; 615 and 511 cm-1.

3-benzyloxy-4-phenylpyrazol can be obtained as follows.

A suspension of 5.7 g of 1-(3-hydroxy-4-phenylpyrazol-1-yl)ethanone, of 3.9 g of potassium carbonate and 3.7 cm3(5.3g) benzylbromide 250 cm32-butanone stirred for 2.25 hours at the boiling temperature of the reaction medium. Insoluble inorganic part is removed by filtration and the filtrate is concentrated to dryness under reduced pressure (3 kPa). The residue is dissolved in 50 cm3of tetrahydrofuran, add 50 cm3methanol and 1 cm310 N. solution g is droxia sodium and stirred for 0.25 hours at room temperature, then concentrated to dryness under reduced pressure (3 kPa). The residue is treated with 5 cm3water and extracted with 250 cm3ethyl acetate. The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa)to give a solid residue is white, which proscout in a mixture of diisopropyl ether and petroleum ether. After filtering off and drying in the air get 4,43 g of 3-benzyloxy-4-phenylpyrazole in a solid white color, melting at 163°C.

Example 4

3-(3-methoxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]okeanologicheskie

To a solution of 0.9 g of 3-methoxy-4-phenylpyrazole 15 cm3anhydrous DMF (dimethylformamide) gradually add in an argon atmosphere and at room temperature 0,99 g of sodium hydride (75 wt.% dispersion in vaseline oil). After stirring for 0.75 hour at a temperature of about 50°C, add small portions totaling 3.04 g of 3-chloromethyl-1-azabicyclo[2,2,2]octahedrally, then heated for 15 hours at a temperature of about 50°C. the Mixture is cooled to room temperature, then slowly add 10 cm3water and concentrate under reduced pressure (3 kPa). The residue is treated with 25 cm3water and extracted with 3 times 100 cm3ethyl is Zetta. The combined organic phases are washed with 3 times 25 cm3water, then dried, filtered and concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue is purified by chromatography on aluminium oxide, elwira a mixture of ethyl acetate and methanol (90:10 by volume). After concentrating the fractions under reduced pressure to obtain 0.3 g of a brown oil which is dissolved in 40 cm3acetone and add 35 cm3approximately 3 M solution of hydrogen chloride in diethyl ether. The solution is concentrated to dryness under reduced pressure (3 kPa) and the pasty residue was washed with 2 times 50 cm3diethyl ether, then proscout 50 cm3diethyl ether overnight. After filtration of the obtained solid and drying under vacuum (70 PA) at a temperature of 60°With a gain of 0.25 g of 3-(3-methoxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]Octan-monohydrochloride in the form of a white powder, melting at about 125°C (with decomposition).

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from to 1.60 to 1.90 (m, 4H); 2,05 (array, 1H); from a 2.45 to 2.60 (m, 1H); 2,94 (DD ush., J=13 and 7 Hz, 1H); from of 3.05 to 3.40 (m, 5H); 3,93 (s, 3H); 4,12 (m, 2H); 7,17 (t ush., J=7.5 Hz, 1H); 7,35 (t ush., J=7.5 Hz, 2H); 7,62 (l ush., J=7.5 Hz, 2H); 8,10 (s, 1H); from 9,40 to 9.90 (array very ush., 1H).

IR-spectrum (KBr): 2942; 2562; 1609; 1579; 1517; 1458; 1406; 1048; 1030; 759; 698; 601 and 508 cm-1.

P is the iMER 5

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-adigitalife

Suspension 0,163 g of 3-(3-benzyloxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2,2,2]octane, 0,38 cm36 M hydrochloric acid and 0.024 g of palladium-on-coal (10%) in 20 cm3ethanol is stirred in an autoclave at a hydrogen pressure of 1000 kPa at 20°C for 8 hours. The reaction medium is filtered through celite and concentrated to dryness under reduced pressure (3 kPa), receiving hygroscopic oily residue which is dissolved in 10 cm3water and lyophilizers. So get 0.083 g of 1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-alligatoroidea in the form of an amorphous solid brown color.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.65 to 2.05 (m, 4H); to 2.41 (m, 1H); 3,26 (m, 3H); 3.40 in (m, 1H); of 3.77 (m, 2H); and 4.68 (m, 1H); 7,15 (t ush., J=7.5 Hz, 1H); 7,34 (t ush., J=7.5 Hz, 2H); 7,69 (l ush., J=7.5 Hz, 2H); by 8.22 (s, 1H); from 10,15 to 10.75 (array ush., 1H); 11,07 (array, 1H).

IR-spectrum (KBr): 3417; 2956; 2806; 2666; 1607; 1580; 1522; 1450; 1168; 995; 762; 697; 671 and 513 cm-1.

3-(3-benzyloxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2,2,2]octane can be obtained in the following way:

To a solution of 0.5 g of 3-benzyloxy-4-phenylpyrazol 30 cm3anhydrous DMF (dimethylformamide) gradually add in an argon atmosphere and at room temperature, 0.96 g of sodium hydride (75 wt.% dispersion in vaseline oil). After the remesiana for 0.75 hour at a temperature of about 50°C is added dropwise a solution of 0,725 g of 3-[(methanesulfonyl)oxy]-1-azabicyclo[2,2,2]octane in 5 cm 3anhydrous DMF (dimethylformamide), and then heated for 20 hours at a temperature of about 110°C. the Mixture is cooled to room temperature, then slowly add 5 cm3water and concentrate under reduced pressure (3 kPa). The residue is treated with 10 cm3water and extracted with 50 cm3ethyl acetate. The organic phase is washed with 3 times 10 cm3water, then dried, filtered and concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue purified preparative high performance liquid chromatography (HPLC) on a Kromasil C8, 10 μm, elwira with a mixture of acetonitrile and water (50:50 by volume), then acetonitrile and a solution of ammonia in methanol (7 M) (98:2 by volume). After concentrating the fractions under reduced pressure get 0,g 3-(3-benzyloxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2,2,2]octane in the form of a yellow oil used as is in the next stage.

3-[(methanesulfonyl)oxy]-1-azabicyclo[2,2,2]octane can be obtained according to the method described S.M. Jenkins and others, J. Med. Chem.,35, 2392-2406 (1992).

Example 6

1-(2-peligrosas-1-retil)-4-phenyl-1H-pyrazole-3-adigitalife

A suspension of 0.65 g of 1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]peligrosamente, of 1.44 cm36 M hydrochloric acid and 0,092 g of palladium-on-coal (10%) in 20 cm3ethanol var who're asked in an autoclave at a hydrogen pressure of 1000 kPa at 20°C for 8 hours. The reaction medium is then filtered through celite®and concentrate under reduced pressure (3 kPa). The remainder proscout 40 cm3acetone and was isolated by filtration. So get 0,541 g of 1-(2-peligrosas-1-retil)-4-phenyl-1H-pyrazole-3-alligatoroidea in the form of a powder beige color, melting at 228°C (decomposition).

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): of 1.64 (m, 4H); of 1.84 (m, 4H); 3,17 (m, 2H); from 3.25 to 3,55 (m, 4H); to 4.41 (t, J=6.5 Hz, 2H); 7,15 (t ush., J=7.5 Hz, 1H); 7,34 (t ush., J=7.5 Hz, 2H); 7,65 (l ush., J=7.5 Hz, 2H); with 8.05 (s, 1H); 10,35 (array, 1H); 10,49 (array, 1H).

IR-spectrum (KBr): 3431; 2934; 2638; 2422; 1608; 1582; 1572; 1528; 1452; 1210; 1179; 1013; 760; 692; 673 and 511 cm-1.

1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]peligrosas can be obtained in the following way:

A suspension of 1 g of 1-[(toluene-4-sulfonyl)oxy]-2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl, 0,29 cm3peligrosamente and 0.88 g of potassium carbonate in 25 cm3acetonitrile is stirred for 3 hours at a temperature of about 80°C, then add 0.15 cm3peligrosamente and heating continued for 2 hours. The mixture is concentrated to dryness under reduced pressure (3 kPa). The residue is treated with 50 cm3water and extracted with 200 cm3ethyl acetate. The organic phase is washed with 3 times 25 cm3water, then dry, filter and concentrate Dosh is under reduced pressure (3 kPa). The obtained oily residue is purified by chromatography on silica gel (grain size distribution 15-35 μm), elwira a mixture of dichloromethane and methanol (96:4 by volume). After concentrating the fractions under reduced pressure get to 0.72 g of 1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]peligrosamente in the form of a colorless viscous oil, which is used as what is in the next stage.

Mass spectrum (IE [= ionization by electron impact]): m/z = 375 (M+.); m/z = 112 (molecular ion peak).

1-[(toluene-4-sulfonyl)oxy]-2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl can be obtained as follows.

To a suspension of 13.7 g of 2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethanol in 400 cm3dichloromethane at room temperature is added dropwise 59 cm3of triethylamine. The reaction mixture is cooled to a temperature of 5°C. and for 0.5 hour and add a solution of 22.5 g of toluene-4-sulphonylchloride 200 cm3dichloromethane. After stirring for 15 hours at room temperature the mixture is concentrated to dryness under reduced pressure (3 kPa). The residue is treated with 100 cm3water and extracted with (500 + 250) cm3ethyl acetate. The combined organic phases are washed with 3 times 100 cm3water, then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). The obtained oily the STATCOM purify by chromatography on silica gel (grain size distribution 15-35 μm), elwira dichloromethane, then with a mixture of dichloromethane and methanol (95:5 by volume). After concentrating the fractions under reduced pressure to obtain 19 g of 1-[(toluene-4-sulfonyl)oxy]-2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl in the form of a colorless viscous oil, which is used as what is in the next stage.

Mass spectrum (IE): m/z = 448 (M+.); m/z = 91 (molecular ion peak).

2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethanol can be obtained in the following way:

To a solution of 17 g of 3-benzyloxy-4-phenyl-1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-pyrazole 750 cm3ethanol at room temperature add 750 cm337%hydrochloric acid. After stirring for 2 hours at room temperature the mixture is concentrated to dryness under reduced pressure (3 kPa). The residue 3 times treated using a 1 DM3ethanol and concentrate to dryness, obtaining 13.8 g of 2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethanol in the form of a solid, melting at 115°C, used as what is in the next stage.

3-benzyloxy-4-phenyl-1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-pyrazole can be obtained as follows.

To a solution of 16 g of 3-benzyloxy-4-phenylpyrazol 110 cm3anhydrous DMF (dimethylformamide) gradually add in an argon atmosphere and at room temperature of 3.07 g of sodium hydride (75 wt.% D. sparse in vaseline oil). After stirring for 0.75 hour at a temperature of about 50°C is added dropwise a solution of 11,06 cm3(15,31 g), 2-(2-bromoethoxy)-tetrahydropyran 40 cm3anhydrous DMF (dimethylformamide), and then heated for 0.75 hour at a temperature of about 50°C. thereafter, to the mixture is added slowly to 25 cm3water, then pour it in 90 cm3water and extracted 3 times with 300 cm3ethyl acetate. The combined organic phases are washed with 3 times 100 cm3water, then dried, filtered and concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue is purified by chromatography on silica gel (grain size distribution 20-45 μm), elwira a mixture of dichloromethane and ethyl acetate (90:10 by volume). After concentrating the fractions under reduced pressure gain of 17.35 g of 3-benzyloxy-4-phenyl-1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-pyrazole as a colourless paste-like solid, which use the same in the next stage.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.25 to 1.75 (m, 6H); from 3.25 to 3.45 points (m, 1H); of 3.60 (DDD, J=11,5 - 8,5 and 3 Hz, 1H); and 3.72 (m, 1H); of 3.94 (DDD, J=10,5 - 6 and 4.5 Hz, 1H); 4.16 the (m, 2H); 4,55 (m, 1H); 5,32 (s, 2H); 7,14 (TT, J=7.5 and 1.5 Hz, 1H); from of 7.25 to 7.45 (m, 3H); 7,33 (t ush., J=7.5 Hz, 2H); 7,50 (d ush., J=7.5 Hz, 2H); 7,63 (l ush., J=7.5 Hz, 2H); with 8.05 (s, 1H).

Example 7

1-[2-(2-methylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-adigitalife

A suspension of 0.58 g of 1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2-methylpiperidine, 1.29 cm36 M hydrochloric acid and 0,082 g of palladium-on-coal (10%) in 20 cm3ethanol is stirred in an autoclave at a hydrogen pressure of 1000 kPa at 20°C for 8 hours. The reaction medium is filtered through celite and concentrated to dryness under reduced pressure (3 kPa). The remainder proscout 40 cm3acetone and was isolated by filtration. So get of 0.54 g of 1-[2-(2-methylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-alligatoroidea in the form of a powder beige color, melting at 118°C (decomposition).

1H-NMR spectrum (300 MHz, (CD3)2SO-d6with the addition of a few drops CD3COOD-d4, δ in ppm): 1,29 (d, J=6.5 Hz, 3H); from 1,35 to 1,95 (m, 6H); totaling 3.04 (DDD, J=12 - 9 and 3.5 Hz, 1H); from 3,30 to 3.50 (m, 3H); from 3.50 to the 3.65 (m, 1H); 4,37 (t, J=6.5 Hz, 2H); 7,14 (t ush., J=7.5 Hz, 1H); 7,33 (t ush., J=7.5 Hz, 2H); to 7.64 (d ush., J=7.5 Hz, 2H); 8,02 (s, 1H).

IR-spectrum (KBr): 3051; 2949; 2653; 2565; 1606; 1581; 1522; 1441; 1228; 1171; 995; 768; 700; 671 and 587 cm-1.

1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2-methylpiperidin can be obtained in the following way:

A suspension of 1 g of 1-[(toluene-4-sulfonyl)oxy]-2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl, 0,46 cm32 methylpiperidine and 0.88 g of potassium carbonate in 25 cm3acetonitrile is stirred for 5 hours at a temperature of about 80°C. a Mixture of concentri the comfort to dryness under reduced pressure (3 kPa). The residue is treated with 50 cm3water and extracted with 200 cm3ethyl acetate. The organic phase is washed with 3 times 25 cm3water, then dried, filtered and concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue is purified by chromatography on silica gel (grain size distribution 15-35 μm), elwira a mixture of dichloromethane and methanol (97:3 by volume). After concentrating the fractions under reduced pressure to obtain 0.65 g of 1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2-methylpiperidine in the form of a colorless viscous oil, which is used as what is in the next stage.

Mass spectrum (IE): m/z = 375 (M+.); m/z = 112 (molecular ion peak).

Example 8

1-[2-(4-foreperiod-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-adigitalife

A suspension of 0.5 g of 1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-4-foreveryday, 1.1 cm36 M hydrochloric acid and 0,071 g of palladium-on-coal (10%) in 20 cm3ethanol is stirred in an autoclave at a hydrogen pressure of 1000 kPa at 20°C for 8 hours. The reaction medium is filtered through celite and concentrated to dryness under reduced pressure (3 kPa). The remainder proscout 40 cm3acetone and was isolated by filtration. So get of 0.54 g of 1-[2-(4-foreperiod-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-alligatoroidea in powder form boe is avago color, melting at 228°C (decomposition).

1H-NMR-spectrum (400 MHz, (CD3)2SO-d6with the addition of a few drops CD3COOD-d4, δ in ppm): from 2.00 to 2.25 (m, 4H); 3,29 (array, 4H); to 3.52 (t, J=6 Hz, 2H); however, 4.40 (t, J=6 Hz, 2H); 4,94 (l ush., J=48 Hz, 1H); 7,14 (t ush., J=7.5 Hz, 1H); 7,33 (t ush., J=7.5 Hz, 2H); 7,65 (l ush., J=7.5 Hz, 2H); to 7.99 (s, 1H).

IR-spectrum (KBr): 3054; 2963; 2633; 2531; 1608; 1582; 1528; 1452; 1177; 1031; 1015; 764; 698 and 509 cm-1.

1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-4-foreperiod can be obtained as follows.

A suspension of 1 g of 1-[(toluene-4-sulfonyl)oxy]-2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl, 0,702 g of 4-proceduredescribed and 1.18 g of potassium carbonate in 25 cm3acetonitrile is stirred for 5 hours at a temperature of about 80°C. the Mixture is concentrated to dryness under reduced pressure (3 kPa). The residue is treated with 50 cm3water and extracted with 200 cm3ethyl acetate. The organic phase is washed with 3 times 25 cm3water, then dried, filtered and concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue is purified by chromatography on silica gel (grain size distribution of 15-25 μm), elwira a mixture of dichloromethane and methanol (to 98.5:1.5 for all volumes). After concentrating the fractions under reduced pressure gain of 0.61 g of 1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-4-foreveryday in the form of a colorless viscous oil, which is used as what is, in the next stage.

Mass spectrum (IE): m/z = 379 (M+.); m/z = 250 and m/z = 116 (molecular ion peak).

Example 9

1-[2-(3-methylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-adigitalife

A suspension of 0.57 g of 1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-3-methylpiperidine, 1.27 cm36 M hydrochloric acid and of 0.081 g of palladium-on-coal (10%) in 20 cm3ethanol is stirred in an autoclave at a hydrogen pressure of 1000 kPa at 20°C for 8 hours. The reaction medium is filtered through celite and concentrated to dryness under reduced pressure (3 kPa). The remainder proscout 75 cm3acetone and was isolated by filtration. So get 0,198 g of 1-[2-(3-methylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-alligatoroidea in the form of a powder pale yellow, melting at 220°C (decomposition).

1H-NMR spectrum (300 MHz, (CD3)2SO-d6with the addition of a few drops CD3COOD, δ in ppm): 0,89 (d, J=7 Hz, 3H); of 1.05 (m, 1H); from 1,60 to 2.00 (m, 4H); of 2.58 (m, 1H); and 2.83 (t very ush., J=12 Hz, 1H); from 3,30 to 3,55 (m, 4H); 4,39 (t, J=6.5 Hz, 2H); 7,13 (t ush., J=7.5 Hz, 1H); 7,32 (t ush., J=7.5 Hz, 2H); 7,63 (l ush., J=7.5 Hz, 2H); to 7.99 (s, 1H).

IR-spectrum (KBr): 3057; 2960; 2651; 2550; 1607; 1581; 1523; 1454; 1179; 761; 697; 614 and 513 cm-1.

1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-3-methylpiperidin can be obtained as follows.

A suspension of 1 g of 1-[(toluene-4-sulfonyl)oxy]-2-(3-what ensilage-4-phenylpyrazol-1-yl)ethyl, 0,46 cm33 methylpiperidine and 0.88 g of potassium carbonate in 25 cm3acetonitrile is stirred for 5 hours at a temperature of about 80°C. the Mixture is concentrated to dryness under reduced pressure (3 kPa). The residue is treated with 50 cm3water and extracted with 200 cm3ethyl acetate. The organic phase is washed with 3 times 25 cm3water, then dried, filtered and concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue is purified by chromatography on silica gel (grain size distribution 15-35 μm), elwira a mixture of dichloromethane and methanol (97:3 by volume). After concentrating the fractions under reduced pressure gain of 0.58 g of 1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-3-methylpiperidine in the form of a colorless viscous oil, which is used as what is in the next stage.

Mass spectrum (IE): m/z = 375 (M+.); m/z = 112 (molecular ion peak).

Example 10

1-[2-(3,6-dihydro-2H-pyridine-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-adigitalife

A solution of 0.6 g of 1-[2-(3-benzyloxy-4-phenylpyrrole-1-yl)ethyl]-1,2,3,6-tetrahydropyridine in a mixture of 5 cm337%hydrochloric acid and 5 cm3ethanol is heated at a temperature of 80°C for 5 hours, then concentrated to dryness under reduced pressure (3 kPa). 4 times the residue is treated with 100 cm3ethanol and concentrate douhet proscout 40 cm 3acetone and was isolated by filtration. So get 0,403 g of 1-[2-(3,6-dihydro-2H-pyridine-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-alligatoroidea in the form of a brown powder, melting at 192°C.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 2,29 (D. very ush., J=18 Hz, 1H); from of 2.40 to 2.60 (m, 1H); of 3.07 (m, 1H); 3,47 (m, 1H); 3,55 (m, 2H); 3,62 (D. very ush., J=16.5 Hz, 1H); 3,84 (l ush., J=16.5 Hz, 1H); 4,47 (t, J=6.5 Hz, 2H); 5,72 (l ush., J=10.5 Hz, 1H); 5,93 (D. very ush., J=10.5 Hz, 1H); 7,15 (t ush., J=7.5 Hz, 1H); 7,34 (t ush., J=7.5 Hz, 2H); 7,66 (l ush., J=7.5 Hz, 2H); of 8.06 (s, 1H); from 10,20 10,80 to (array ush., 1H); 10,88 (array, 1H).

IR-spectrum (KBr): 3422; 2948; 2688; 2579; 1607; 1526; 1452; 1184; 1023; 768; 699; 667; 670 and 511 cm-1.

1-[2-(3-benzyloxy-4-phenylpyrrole-1-yl)ethyl]-1,2,3,6-tetrahydropyridine can be obtained as follows.

A suspension of 1 g of 1-[(toluene-4-sulfonyl)oxy]-2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl, 0,36 cm31,2,3,6-tetrahydropyridine and 0.88 g of potassium carbonate in 25 cm3acetonitrile is stirred for 5 hours at a temperature of about 80°C. the Mixture is concentrated to dryness under reduced pressure (3 kPa). The residue is treated with 50 cm3water and extracted with 200 cm3ethyl acetate. The organic phase is washed with 3 times 25 cm3water, then dried, filtered and concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue is purified by chromatography on forces is the Kagel (the grading of 15-35 μm), elwira a mixture of dichloromethane and methanol (97:3 by volume). After concentrating the fractions under reduced pressure to obtain 0.6 g of 1-[2-(3-benzyloxy-4-phenylpyrrole-1-yl)ethyl]-1,2,3,6-tetrahydropyridine in the form of a colorless viscous oil, which is used as what is in the next stage.

Mass spectrum (IC [= chemical ionisation]): m/z = 360 ([M+H]+) (molecular ion peak).

Example 11

1-[2-(7-azabicyclo[2,2,1]hept-7-yl)ethyl]-4-phenyl-1H-pyrazole-3-adigitalife

To a solution of 0.6 g of 7-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-7-azabicyclo[2,2,1]heptane at 40 cm3ethanol add 3 cm31 M hydrochloric acid, stirred for 0.25 hour at room temperature, then concentrated to dryness under reduced pressure (3 kPa). The obtained residue and 0,078 g of palladium-on-coal (10%) are suspended in 20 cm3ethanol and stirred in an autoclave at a hydrogen pressure of 1000 kPa at 20°C for 8 hours. The reaction medium is filtered through celite and concentrated to dryness under reduced pressure (3 kPa). The remainder proscout 25 cm3acetone and was isolated by filtration. So get 0,466 g of 1-[2-(7-azabicyclo[2,2,1]hept-7-yl)ethyl]-4-phenyl-1H-pyrazole-3-alligatoroidea in the form of a white powder, melting at 228°C (decomposition).

1H-NMR spectrum (300 MHz, (CD3 )2SO-d6, δ in ppm): 1,66 (array, 4H); 2.00 (array, 4H); 3.43 points (m, 2H); 3,93 (ush., 2H); 4,43 (t ush., J=6.5 Hz, 2H); 7,15 (t ush., J=7.5 Hz, 1H); 7,35 (t ush., J=7.5 Hz, 2H); 7,65 (l ush., J=7.5 Hz, 2H); 8,08 (s, 1H); from 10,35 to 10,55 (array ush., 1H); 10,47 (array, 1H).

IR-spectrum (KBr): 2988; 2789; 2661; 2537; 1608; 1533; 1449; 1279; 1179; 875; 761; 698; 674 and 510 cm-1.

7-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-7-azabicyclo[2,2,1]heptane can be obtained as follows.

A suspension of 1 g of 1-[(toluene-4-sulfonyl)oxy]-2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl, 0,616 g of 7-azabicyclo[2,2,1]heptahydrated and 0.88 g of potassium carbonate in 25 cm3acetonitrile is stirred for 5 hours at a temperature of about 80°C. the Mixture is concentrated to dryness under reduced pressure (3 kPa). The residue is treated with 30 cm3water and extracted with 250 cm3ethyl acetate. The organic phase is washed with 3 times 30 cm3water, then dried, filtered and concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue is purified by chromatography on silica gel (grain size distribution 15-35 μm), elwira a mixture of dichloromethane and methanol (98:2 by volume). After concentrating the fractions under reduced pressure to obtain 0.6 g of 7-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-7-azabicyclo[2,2,1]heptane in the form of a colorless viscous oil, which is used as what is in the next stage.

Mass spectrum (IC): m/z = 374 ([M+H]+) (p is to the molecular ion).

Example 12

1-[2-(2-azabicyclo[2,2,2]Oct-2-yl)ethyl]-4-phenyl-1H-pyrazole-3-adigitalife

To a solution of 0.9 g of 2-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2-azabicyclo[2,2,2]octane in 50 cm3ethanol is added 2 cm36 M hydrochloric acid, stirred for 0.25 hour at room temperature, then concentrated to dryness under reduced pressure (3 kPa). The obtained residue and 0.124 g of palladium-on-coal (10%) are suspended in 20 cm3ethanol and stirred in an autoclave at a hydrogen pressure of 1000 kPa at 20°C for 8 hours. The reaction medium is filtered through celite and concentrated to dryness under reduced pressure (3 kPa). The remainder proscout 25 cm3acetone and was isolated by filtration. Thus obtain 0.56 g of 1-[2-(2-azabicyclo[2,2,2]Oct-2-yl)ethyl]-4-phenyl-1H-pyrazole-3-alligatoroidea in the form of a powder beige color, melting at 171°C (decomposition).

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1.50-1.75 (m, 6H); 1,90 (with very ush., 1H); from 2.00 up to 2.15 (m, 1H); 2,28 (m, 1H); 2,86 (DD very ush., J=12 and 4.5 Hz, 1H); from to 3,35 3,55 (m, 1H); 3,38 (with very ush., 1H); 3,55 (t ush., J=6.5 Hz, 2H); 4,46 (t ush., J=6.5 Hz, 2H); 7,14 (t ush., J=7.5 Hz, 1H); 7,34 (t ush., J=7.5 Hz, 2H); 7,65 (l ush., J=7.5 Hz, 2H); 8,04 (s, 1H); 10,84 (array, 1H).

IR-spectrum (KBr): 2949; 2870; 2629; 2184; 1608; 1579; 1510; 1455; 1198; 870; 761; 692; 670 and 510 cm-1.

2-[2-(3-benzyloxy-4-phenylpyrazol-yl)ethyl]-2-azabicyclo[2,2,2]octane can be obtained as follows.

A suspension of 1 g of 1-[(toluene-4-sulfonyl)oxy]-2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl, 0,563 g 2-azabicyclo[2,2,2]octahedrally and 0.88 g of potassium carbonate in 25 cm3acetonitrile is stirred for 8 hours at a temperature of about 80°C. the Mixture is concentrated to dryness under reduced pressure (3 kPa). The residue is treated with 30 cm3water and extracted with 200 cm3ethyl acetate. The organic phase is washed with 2 times 30 cm3water, then dried, filtered and concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue is purified by chromatography on silica gel (grain size distribution 15-35 μm), elwira a mixture of dichloromethane and methanol (95:5 by volume). After concentrating the fractions under reduced pressure get to 0.92 g of 2-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2-azabicyclo[2,2,2]octane in the form of a colorless viscous oil, which is used as what is in the next stage.

Mass spectrum (IC): m/z = 388 ([M+H]+) (molecular ion peak).

2-azabicyclo[2,2,2]octahedrally can be obtained according to the method described Yokota, M. and others, Eur. J. Med. Chem. Chim. Ther.,32(5), 377-384 (1997).

Example 13

1-[2-(2-azabicyclo[2,2,1]hept-2-yl)ethyl]-4-phenyl-1H-pyrazole-3-adigitalife

To a solution of 0.7 g of 2-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2-azabicyclo[2,2,1]heptane 50 cm3ethanol add 1.6 cm36 M is aristolochioides acid, stirred for 0.25 hour at room temperature, then concentrated to dryness under reduced pressure (3 kPa). The obtained residue and 0.10 g of palladium-on-coal (10%) are suspended in 20 cm3ethanol and stirred in an autoclave at a hydrogen pressure of 1000 kPa at 20°C for 8 hours. The reaction medium is filtered through celite and concentrated to dryness under reduced pressure (3 kPa). The remainder proscout 40 cm3acetone and was isolated by filtration. So get 0.565 g of 1-[2-(2-azabicyclo[2,2,1]hept-2-yl)ethyl]-4-phenyl-1H-pyrazole-3-alligatoroidea in the form of a powder beige color, melting at 173°C (decomposition).

1H-NMR-spectrum (400 MHz, (CD3)2SO-d6with the addition of a few drops CD3COOD-d4at a temperature of 363 K, δ in ppm): from 1,45 to 1.55V (m, 1H); from 1.65 to 1.80 (m, 3H); from 1.95 to 2.05 (m, 2H); to 2.65 (m, 1H); from of 3.10 to 3.25 (array ush., 2H); of 3.48 (m, 1H); 3,59 (m, 1H); Android 4.04 (m, 1H); 4,34 (t ush., J=6.5 Hz, 2H); 7,15 (t ush., J=7.5 Hz, 1H); 7,32 (t ush., J=7.5 Hz, 2H); 7,62 (l ush., J=7.5 Hz, 2H); of 7.90 (s, 1H).

IR-spectrum (KBr): 2955; 2827; 2601; 2554; 1607; 1528; 1454; 1177; 1010; 767; 699; 672 and 515 cm-1.

2-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2-azabicyclo[2,2,1]heptane can be obtained in the following way:

A suspension of 1 g of 1-[(toluene-4-sulfonyl)oxy]-2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl, 0.51 g of 2-azabicyclo[2,2,1]heptahydrated and 0.88 g of potassium carbonate in 25 cm3 acetonitrile is stirred for 8 hours at a temperature of about 80°C. the Mixture is concentrated to dryness under reduced pressure (3 kPa). The residue is treated with 30 cm3water and extracted with 200 cm3ethyl acetate. The organic phase is washed with 2 times 30 cm3water, then dried, filtered and concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue is purified by chromatography on silica gel (grain size distribution 15-35 μm), elwira a mixture of dichloromethane and methanol (95:5 by volume). After concentrating the fractions under reduced pressure to obtain 0.75 g of 2-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2-azabicyclo[2,2,1]heptane in the form of a colorless viscous oil, which is used as what is in the next stage.

Mass spectrum (S): m/z = 373 (M+.); m/z = 110 (molecular ion peak).

2-azabicyclo[2,2,2]heptahydrate can be obtained according to the method described by J. R. Malpass, etc., J. C. S., Perkin Trans. 1,8, 874-884 (1977).

Example 14

1-[2-dimethylaminoethyl]-4-phenyl-1H-pyrazole-3-adigitalife

Follow the procedure of example 2, but using 0.10 g of [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]dimethylaminohydrolase and 0,012 g of palladium-on-coal (10%). So get 0,049 g of 1-[2-dimethylaminoethyl]-4-phenyl-1H-pyrazole-3-alligatoroidea in the form of a powder beige color, melting at prima is but 135°C (decomposition).

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 2,81 (d, J=5 Hz, 6H); 3,51 (m, 2H); to 4.38 (t, J=6.5 Hz, 2H); 7,16 (t ush., J=7.5 Hz, 1H); 7,35 (t ush., J=7.5 Hz, 2H); 7,65 (l ush., J=7.5 Hz, 2H); with 8.05 (s, 1H); 10,27 (array, 1H); from 10,30 to 10.70 (array very ush., 1H).

IR-spectrum (KBr): 3311; 2985; 2558; 2463; 1629; 1582; 1508; 1467; 1409; 1190; 985; 760; 687 and 673 cm-1.

[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]dimethylaminohydrolase can be obtained as follows.

To a solution of 0.25 g of 3-benzyloxy-4-phenylpyrazol 3 cm3anhydrous DMF (dimethylformamide) gradually add in an argon atmosphere and at room temperature 0,154 g of sodium hydride (75 wt.% dispersion in vaseline oil), then after the disappearance of the foam 0.5 g (2-bromacil)dimethylaminohydrolase. After stirring for 2 hours at room temperature the mixture is slowly poured into water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue is purified by chromatography on silica gel, elwira a mixture of dichloromethane, methanol and 28%aqueous ammonium hydroxide (90:8:2 by volume). After concentrating the fractions under reduced pressure to obtain 0.21 g of oil which was dissolved in diethyl ether, add 1 cm3approximately 3 M solution of hydrogen chloride in diethyl ether, then brought to dryness. The remainder proscout the acetone, then allocate by filtration. Thus obtained 0.1 g of [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]dimethylaminohydrolase in the form of white crystals, melting at 105°C.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 2,82 (d, J=5 Hz, 6H); of 3.57 (m, 2H); 4,34 (t, J=6.5 Hz, 2H); are 5.36 (s, 2H); 7.18 in (t ush., J=7.5 Hz, 1H); from 7,30 to 7.50 (m, 5H); 7,52 (d ush., J=7.5 Hz, 2H); 7,65 (l ush., J=7.5 Hz, 2H); 8,17 (s, 1H); 9,68 (array, 1H).

(2-bromacil)dimethylaminohydrolase can be obtained according to the method described L.H. Amudsen and others, J. Am. Chem. Soc.,63, 305-307 (1941).

Example 15

1-[3-dimethylaminopropyl]-4-phenyl-1H-pyrazole-3-adigitalife

Follow the procedure of example 2, but using 0,274 g of [3-(3-benzyloxy-4-phenylpyrazol-1-yl)propyl]dimethylaminohydrolase and 0.04 g of palladium-on-coal (10%). So get 0,209 g of 1-[3-dimethylaminopropyl]-4-phenyl-1H-pyrazole-3-alligatoroidea in the form of a powder beige color, melting at about 208°C (decomposition).

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 2,20 (m, 2H); 3,5 (d, J=5 Hz, 6H); of 3.07 (m, 2H); Android 4.04 (t, J=6.5 Hz, 2H); 7,13 (t ush., J=7.5 Hz, 1H); 7,33 (t ush., J=7.5 Hz, 2H); 7,66 (l ush., J=7.5 Hz, 2H); to 7.99 (s, 1H); 10,82 (array, 1H).

IR-spectrum (KBr): 3078; 2954; 2591; 2470; 1603; 1476; 1369; 1268; 1188; 881; 763; 700; 570 and 494 cm-1.

[3-(3-benzyloxy-4-phenylpyrazol-1-yl)propyl]dimethylaminohydrolase can be obtained as follows.

3water is added 3.6 cm31 n sodium hydroxide solution and stirred for 0.25 hour, then extracted with 3 times 25 cm3ethyl acetate. The combined organic phases are dried over magnesium sulfate, and then concentrated to dryness under reduced pressure (3 kPa). The resulting residue is dissolved in 25 cm3ethanol, add an excess of about 3 M solution of hydrogen chloride in diethyl ether, then brought to dryness. So get 0,274 g of [3-(3-benzyloxy-4-phenylpyrazol-1-yl)propyl]dimethylaminohydrolase in the form of a pasty solid white color, used same, at the next stage.

[3-(3-benzyloxy-4-phenylpyrazol-1-yl)propyl]dimethylaminoacetyl can be obtained in the following way:

To a solution of 0.25 g of 3-benzyloxy-4-phenylpyrazol 15 cm3anhydrous DMF (dimethylformamide) gradually add in an argon atmosphere and at room temperature 0,106 g of sodium hydride (75 wt.% dispersion in vaseline oil). After stirring for 0.75 hour at a temperature of about 50°C, add small portions 0,316 g (3-chlorpropyl)dimethylaminohydrolase, then stirred for 15 hours at room temperature. The mixture is then poured into 150 cm3water and extracted with 3 times 150 cm3ethyl acetate. The combined organic phases are washed with 50 cm3water, stimulat over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue (0.8 g) dissolved in 10 cm3diethyl ether and add a solution of 0.09 g of oxalic acid in 5 cm3diethyl ether. Precipitated white precipitate is filtered off, then dried under vacuum (70 PA) at room temperature. So get 0,395 g of [3-(3-benzyloxy-4-phenylpyrazol-1-yl)propyl]diethylaminoacetate in a solid white color, used same, at the next stage.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 2,15 (m, 2H); 30 (s, 6H); 2,98 (m, 2H); 4,08 (t, J=6.5 Hz, 2H); 5,33 (s, 2H); 7,16 (t ush., J=7.5 Hz, 1H); from 7,30 to 7.45 (m, 3H); 7,43 (t ush., J=7.5 Hz, 2H); 7,51 (l ush., J=7.5 Hz, 2H); 7,65 (l ush., J=7.5 Hz, 2H); of 8.09 (s, 1H).

Example 16

1-[2-((2S,6R)-2,6-dimethylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-adigitalife

Follow the procedure of example 2, but using 0,123 g (2S,6R)-1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2,6-dimethylpiperidine and of 0.014 g of palladium-on-coal (10%). So get 0.075 g of 1-[2-((2S,6R)-2,6-dimethylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-alligatoroidea in the form of a powder beige color, melting at about 206 C (With decomposition).

1H-NMR-spectrum (400 MHz, (CD3)2SO-d6at a temperature of 403 K, δ in ppm): 1,36 (d, J=6.5 Hz, 6H); 1.57 in (m, 1H); from 1.65 to 1.90 (m, 5H); 3,28 (array, 2H); 3,49 (array, 2); 4,36 (t ush., J=6.5 Hz, 2H); 7,15 (TT, J=7.5 and 1.5 Hz, 1H); 7,33 (t ush., J=7.5 Hz, 2H); 7,66 (l ush., J=7.5 Hz, 2H); 8,00 (s, 1H).

IR-spectrum (KBr): 3428; 3058; 2978; 2942; 2657; 2571; 1606; 1580; 1521; 1452; 1388; 1173; 997; 914; 766; 699; 671 and 511 cm-1.

(2S,6R)-1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2,6-dimethylpiperidine can be obtained as follows.

To a solution of 0,117 g (2S,6R)-1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2,6-dimethylpiperidine 25 cm3ethanol add 0.5 cm3approximately 3 M solution of hydrogen chloride in diethyl ether, then brought to dryness. So get 0,123 g (2S,6R)-1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2,6-dimethylpiperidine in the form of colorless pasty substances used as what is in the next stage.

(2S,6R)-1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2,6-dimethylpiperidin can be obtained as follows.

To a solution of 0.25 g of 3-benzyloxy-4-phenylpyrazol 20 cm3anhydrous DMF (dimethylformamide) gradually add in an argon atmosphere and at room temperature 0,211 g of sodium hydride (75 wt.% dispersion in vaseline oil). After stirring for 0.75 hour at a temperature of about 50°C, add small portions 0,636 g (2S,6R)-1-(2-chloroethyl)-2,6-dimethylpiperidine, then stirred for 15 hours at room temperature. The mixture is then poured into 150 cm3water and extracted with 2 x 150 cm 3ethyl acetate. The combined organic phases are washed with 50 cm3water, then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue is dissolved in 25 cm3diethyl ether and add a solution of 0.09 g of oxalic acid in 25 cm3diethyl ether. The resulting pasty product is washed with 3 times 25 cm3diethyl ether, then treated with 25 cm3water and add 4 cm31 n sodium hydroxide solution and stirred for 0.25 hour, then extracted with 2 times 25 cm3ethyl acetate. The combined organic phases are dried over magnesium sulfate, and then concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue is purified by chromatography on silica gel, elwira a mixture of ethyl acetate and methanol (80:20 by volume). After concentrating the fractions under reduced pressure get 0,117 g (2S,6R)-1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2,6-dimethylpiperidine in the form of a colorless oil used for what is, at the next stage.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1,08 (d, J=6.5 Hz, 6H); 1,17 (t DD ush., J=12 and 3 Hz, 2H); 1.28 (in m, 1H); 1,53 (l ush., J=12 Hz, 2H); of 1.62 (m, 1H); 2,48 (m, 2H); 2.95 points (t, J=6.5 Hz, 2H); 3,98 (t, J=6.5 Hz, 2H); 5,32 (s, 2H); 7,15 (TT, J=7.5 and 1.5 Hz, 1H); from 7,30 to 7.45 (m, 1H); 7,34 t ush., J=7.5 Hz, 2H); 7,42 (t ush., J=7.5 Hz, 2H); 7,52 (d ush., J=7.5 Hz, 2H); 7,66 (l ush., J=7.5 Hz, 2H); 8,10 (s, 1H).

(2S,6R)-1-(2-chloroethyl)-2,6-dimethylpiperidine can be obtained according to the method described by R. Dahlbom and others, Acta Pharmaceutica Suecica,6(3), 413-418 (1969).

Example 17

1-[2-diethylaminoethyl]-4-phenyl-1H-pyrazole-3-adigitalife

Follow the procedure of example 2, but using [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diethylaminoethylamine and 0.04 g of palladium-on-coal (10%). So get 0,139 g of 1-[2-diethylaminoethyl]-4-phenyl-1H-pyrazole-3-alligatoroidea in the form of a white powder, melting at about 174°C. (decomposition).

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): of 1.23 (t, J=7 Hz, 6H); 3,12 (kV very ush., J=7 Hz, 4H); 3.46 in (t very ush., J=6.5 Hz, 2H); however, 4.40 (t ush., J=6.5 Hz, 2H); 7,14 (t ush., J=7.5 Hz, 1H); 7,33 (t ush., J=7.5 Hz, 2H); 7,65 (l ush., J=7.5 Hz, 2H); 8,07 (s, 1H); 10,46 (array, 1H); from or 10.60 to 10.85 (array ush., 1H).

IR-spectrum (KBr): 3065; 2974; 2589; 2484; 1609; 1530; 1454; 1179; 1012; 765; 693; 677 and 508 cm-1.

[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]Diethylaminoethanol can be obtained as follows.

Follow the procedure of example 15, but using 0.31 g of [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diethylaminoacetate. Thus obtained 0.31 g of [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diethylaminoethylamine in the form of a colourless resin like substance used as what the EU is ü, at the next stage.

[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diethylaminoacetate can be obtained as follows.

Follow the procedure of example 15, but using 0,211 g of sodium hydride (75 wt.% dispersion in vaseline oil) and 0,516 g (2-chloroethyl)diethylaminotoluene. So get 0,376 g of [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diethylaminoacetate in the form of a white powder, melting at 133°C.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1,12 (t, J=7 Hz, 6H); 2,98 (kV ush., J=7 Hz, 4H); 3,35 (t very ush., J=6.5 Hz, 2H); or 4.31 (t ush., J=6.5 Hz, 2H); to 5.35 (s, 2H); 7,17 (t ush., J=7.5 Hz, 1H); of 7.36 (m, 3H); 7,43 (t ush., J=7.5 Hz, 2H); 7,51 (l ush., J=7.5 Hz, 2H); 7,65 (l ush., J=7.5 Hz, 2H); to 8.14 (s, 1H).

Example 18

1-(2-diisopropylaminoethyl)-4-phenyl-1H-pyrazole-3-adigitalife

Follow the procedure of example 2, but using 0.21 g of [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diisopropylaminoethanol and 0.025 g of palladium-on-coal (10%). So get 0,122 g of 1-[2-diisopropylaminoethyl]-4-phenyl-1H-pyrazole-3-alligatoroidea in the form of a powder beige color, melting at about 220°C (decomposition).

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1,32 (l ush., J=7 Hz, 6H); 1,34 (l ush., J=7 Hz, 6H); 3,47 (array, 2H); 3,71 (m, 2H); however, 4.40 (t ush., J=6.5 Hz, 2H); 7,14 (t ush., J=7.5 Hz, 1H); 7,33 (t ush., J=7.5 Hz, 2H); 7,65 (l ush., J=7.5 Hz, 2H); to 8.12 (s, 1H); 9,96 (array, 1H); 10,49 (ush., 1H).

IR-Spa is Tr (KBr): 2984; 2654; 2507; 2469; 1607; 1580; 1531; 1453; 1193; 759; 693; 673 and 511 cm-1.

[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diisopropylaminoethanol can be obtained as follows.

Follow the procedure of example 15, but using 0.31 g of [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diisopropylaniline. Thus obtained 0.21 g of [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diisopropylaminoethanol in the form of semi-solid substances beige color, used same, at the next stage.

[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diisopropylaminomethyl can be obtained as follows.

Follow the procedure of example 15, but using 0,211 g of sodium hydride (75 wt.% dispersion in vaseline oil) and 0.6 g of (2-chloroethyl)diisopropylaminoethanol. So get 0.312 g of [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diethylamine-oxalate in the form of a white powder, melting at 134°C.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6with the addition of a few drops CD3COOD-d4, δ in ppm): to 1.21 (d, J=6 Hz, 12H); 3,39 (t ush., J=6.5 Hz, 2H); of 3.57 (m, 2H); 4,30 (t, J=6.5 Hz, 2H); to 5.35 (s, 2H); 7,17 (t ush., J=7.5 Hz, 1H); 7,35 (m, 3H); 7,41 (t ush., J=7.5 Hz, 2H); 7,49 (l ush., J=7.5 Hz, 2H); 7,65 (l ush., J=7.5 Hz, 2H); 8,10 (s, 1H).

Example 19

4-phenyl-1-(2-pyrrolidin-1-retil)-1H-pyrazole-3-adigitalife

Follow the procedure of example 2, but using 0,285 g of 3-benzyloxy-4-phenyl-1-(2-Pierre is lidin-1-retil)-1H-presoldered and 0.037 g of palladium-on-coal (10%). So get 0,101 g of 4-phenyl-1-(2-pyrrolidin-1-retil)-1H-pyrazole-3-alligatoroidea in the form of a powder beige color, melting at a temperature of about 173°C. (decomposition).

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.80 to 2.10 (m, 4H); from 2,90 3,10 to (array, 2H); from 3.45 to 3,65 (array, 4H); 4,34 (t ush., J=6.5 Hz, 2H); 7,14 (t ush., J=7.5 Hz, 1H); 7,33 (t ush., J=7.5 Hz, 2H); 7,65 (l ush., J=7.5 Hz, 2H); 8,02 (s, 1H); from 10,30 to or 10.60 (array ush., 1H); 10,43 (array, 1H).

IR-spectrum (KBr): 3416; 3054; 2973; 2670; 2585; 2476; 2405; 1608; 1581; 1527; 1453; 1247; 1175; 1011; 768; 702; 673 and 514 cm-1.

3-benzyloxy-4-phenyl-1-(2-pyrrolidin-1-retil)-1H-pyrazolidone can be obtained as follows.

Follow the procedure of example 15, but using 0.34 g of 3-benzyloxy-4-phenyl-1-(2-pyrrolidin-1-retil)-1H-pyrazoloquinoline. So get 0,285 g of 3-benzyloxy-4-phenyl-1-(2-pyrrolidin-1-retil)-1H-persondirected in the form of retinoid substance beige color, used same, at the next stage.

3-benzyloxy-4-phenyl-1-(2-pyrrolidin-1-retil)-1H-personocall can be obtained as follows.

Follow the procedure of example 15, but using 0,211 g of sodium hydride (75 wt.% dispersion in vaseline oil) and 0.51 g of 1-(2-chloroethyl)pyrrolidinecarboxamido. So get 0,354 g of 3-benzyloxy-4-phenyl-1-(2-pyrrolidin-1-retil)-1H-pyrazoloquinoline in the form of a white powder, melting the ri a temperature of 144°C.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): to 1.87 (m, 4H); 3,10 (m, 4H); 3.46 in (m, 2H); to 4.33 (t, J=6.5 Hz, 2H); to 5.35 (s, 2H); 7.18 in (t ush., J=7.5 Hz, 1H); of 7.36 (m, 3H); 7,43 (t ush., J=7.5 Hz, 2H); 7,52 (d ush., J=7.5 Hz, 2H); 7,66 (l ush., J=7.5 Hz, 2H); 8,13 (s, 1H).

Example 20

3-(3-methoxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2,2,2]octahedrally

To a solution of 1.2 g of 3-methoxy-4-phenylpyrazole 20 cm3anhydrous DMF (dimethylformamide) gradually add in an argon atmosphere and at room temperature of 1.94 g of potassium tert-butylate. After stirring for 1.5 hours at room temperature is added dropwise a solution of 2.8 g of 3-[(methanesulfonyl)oxy]-1-azabicyclo[2,2,2]octane in 20 cm3anhydrous DMF (dimethylformamide), and then heated for 15 hours at a temperature of about 100°C. the Mixture is cooled to room temperature, then concentrated under reduced pressure (3 kPa). The residue is treated with 30 cm3water and extracted with 250 cm3ethyl acetate. The organic phase is washed with 3 times 30 cm3water, then dried, filtered and concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue is purified by chromatography on silica gel, elwira a mixture of ethyl acetate and methanol (90:10, then 75:25, by volume). After concentrating the fractions under reduced pressure to obtain 0.36 g of oil which was dissolved in 15 cm3acetone and add the keys 5 cm 3approximately 1 M solution of hydrogen chloride in diethyl ether. The precipitation proscout during the night, then allocate by filtration. So get 0,308 g of 3-(3-methoxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2,2,2]octahedrally in the form of a hygroscopic powder beige color, melting at about 207°C (decomposition).

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.65 to 2.05 (m, 4H); to 2.42 (m, 1H); or 3.28 (m, 3H); from to 3,35 3,55 (m, 1H); of 3.80 (m, 2H); of 3.97 (s, 3H); 4.75 in (m, 1H); 7.18 in (t ush., J=7.5 Hz, 1H); of 7.36 (t ush., J=7.5 Hz, 2H); 7,65 (l ush., J=7.5 Hz, 2H); 8,30 (s, 1H); 10,76 (array, 1H).

IR-spectrum (KBr): 3430; 2939; 2907; 2666; 2584; 1607; 1580; 1570; 1518; 1454; 1409; 1049; 1028; 764; 698; 623 and 513 cm-1.

Example 21

1-[2-(3-deformedarse-4-phenylpyrazol-1-yl)ethyl]piperidineacetic

Follow the procedure of example 1, but using 0.25 g of 3-deformedarse-4-phenyl-1H-pyrazole, 0,303 g of sodium hydride (75 wt.% dispersion in vaseline oil) and 0.6 g of 1-(2-chloroethyl)piperidinedione, then elwira a mixture of dichloromethane and methanol (95:5 by volume). So get 0,175 g of 1-[2-(3-deformedarse-4-phenylpyrazol-1-yl)ethyl]piperidineacetic in a solid white color, melting at about 174°C. (decomposition).

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1,40 (array, 1H); from to 1.60 to 1.90 (m, 5H); 2,94 (array, 2H); 3,47 (D. very ush., J=12 Hz, 2H); 3,54 (mA is the SIV 2H); 4,55 (t ush., J=6.5 Hz, 2H); 7.29 trend (TT, J=7.5 and 2.5 Hz, 1H); 7,41 (t, J=72 Hz, 1H); 7,44 (t ush., J=7.5 Hz, 2H); to 7.59 (d ush., J=7.5 Hz, 2H); 8,30 (s, 1H); from 10.00 to 10.20 (array, 1H).

IR-spectrum (KBr): 3100; 2931; 2644; 2543; 1609; 1581; 1507; 1482; 1456; 1364; 1049; 1181; 1125; 1100; 1076; 761; 694 and 513 cm-1.

3 deformedarse-4-phenyl-1H-pyrazole can be obtained as follows.

A suspension of 2.55 g of 1-(3-hydroxy-4-phenylpyrazol-1-yl)ethanone, of 1.75 g of potassium carbonate and 1,82 g of methyl 2-chloro-2,2-differenitate 40 cm3of dimethylformamide is stirred in an argon atmosphere at room temperature for 15 hours, then at 65°C for 8 hours. After cooling, to the reaction mixture add 10 cm310 n sodium hydroxide solution and stirred for 1 hour at room temperature, then concentrated under reduced pressure (3 kPa). The residue is extracted with 200 cm3ethyl acetate. The organic phase is washed with 3 times 25 cm3water, dried and concentrated under reduced pressure (3 kPa). The obtained oily residue is purified by chromatography on silica gel, elwira a mixture of dichloromethane and methanol (99:1 by volume). After concentrating the fractions under reduced pressure to obtain 0.8 g of 3-deformedarse-4-phenyl-1H-pyrazole in the form of a solid yellow color, melting at 125°C.

Mass spectrum (IE): m/z = 210 (M+.) (molecular ion peak); m/z = 160 [M-CF2]+../p>

Example 22

4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-reminderville

To a solution of 0.2 g of 4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-ylamine 10 cm3methanol is added in excess of 10 cm31 n solution of hydrogen chloride in diethyl ether, then concentrated to dryness under reduced pressure (3 kPa). The residue after powdering in diethyl ether is a 0,244 g of 4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-elementarychlorine in the form of white crystals, melting at a temperature of about 120°C.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.25 to 1.55V (m, 1H); from to 1.60 to 1.90 (m, 5H); 2.95 and (array, 2H); 3,44 (array, 2H); 3,51 (m, 2H); 4,53 (t, J=6.5 Hz, 2H); 7,27 (t ush., J=7.5 Hz, 1H); 7,42 (t ush., J=7.5 Hz, 2H); 7,56 (l ush., J=7.5 Hz, 2H); 8,07 (s, 1H); 10,46 (array, 1H).

IR-spectrum (KBr): 3277; 2945; 2630; 2545; 1612; 1540; 1451; 1099; 1005; 768; 707; 572 and 559 cm-1.

4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-ylamine can be obtained as follows.

A suspension of 1.59 g of 4-phenyl-1H-pyrazole-3-ylamine, 2.2 g of 1-(2-chloroethyl)piperidinedione, 4 g of potassium carbonate and 1.66 g of potassium iodide in 50 cm32-butanone stirred at the boiling temperature of the reaction medium for 22 hours. After cooling, the mixture is brought to dryness under reduced pressure (3 kPa). The residue is treated with 40 cm3of 0.5 n sodium hydroxide solution and extracted with 50 cm3 ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). The oily yellow residue purified by chromatography on basic aluminum oxide, elwira successively with a mixture of ethyl acetate and dichloromethane (50:50 by volume), and then pure ethyl acetate. Thus obtain 0.2 g of 4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-ylamine in a solid white color, melting at 96°C, With Rf= 0,4 (ethyl acetate; the plate is aluminum oxide, the number 105731, Merck).

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1,40 (m, 2H); for 1.49 (m, 4H); 2,39 (t ush., J=5 Hz, 4H); of 2.64 (t, J=6.5 Hz, 2H); 3,98 (t, J=6.5 Hz, 2H); 4,63 (s, 2H); 7,15 (TT, J=7.5 and 1.5 Hz, 1H); 7,34 (t ush., J=7.5 Hz, 2H); 7,49 (l ush., J=7.5 Hz, 2H); 7,74 (s, 1H).

4-phenyl-1H-pyrazole-3-ylamine can be obtained according to the method described S.A. Lang Jr. and others, J. Heterocyclic Chem.,14, 65-69 (1977).

Example 23

4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-reminderville

To a solution of 0.25 g of N-[4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-yl]formamide in 10 cm3anhydrous tetrahydrofuran is gradually added at room temperature in an argon atmosphere of 2 cm31 M solution of sociallyengaged. After stirring for 65 hours at room temperature to a mixture gradually add 1 cm31 N. retargetted sodium and extracted with 20 cm 3ethyl acetate. After removal of the gel by filtration, the organic phase is concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue is purified by chromatography on basic aluminum oxide, elwira a mixture of dichloromethane and ethyl acetate (80:20 by volume). After concentrating the fractions under reduced pressure to obtain a colorless oil, which was dissolved in 10 cm3diethyl ether, and add 1 cm3approximately 6 n solution of hydrogen chloride in dioxane, and then concentrated to dryness under reduced pressure (3 kPa). The remainder proscout in acetone and was isolated by filtration. So get 0,045 g of 4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-elementarychlorine in a solid white color, melting at about 165°C. (decomposition).

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.25 to 1.50 (array, 1H); from to 1.60 to 1.90 (m, 5H); 1,6 (s, 3H); 2,94 (array, 2H); from 3.40 in to the 3.65 (m, 4H); was 4.42 (t, J=6.5 Hz, 2H); 7,20 (t ush., J=7.5 Hz, 1H); 7,37 (t ush., J=7.5 Hz, 2H); 7,47 (l ush., J=7.5 Hz, 2H); 7,89 (s, 1H); to 9.93 (array, 1H).

IR-spectrum (KBr): 3289; 2943; 2600; 2534; 2481; 1627; 1530; 1446; 1342; 1189; 850; 770; 706 and 499 cm-1.

N-[4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-yl]formamide can be obtained as follows.

A solution of 0.24 g of 4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-ylamine 10 cm3ethylformate stirred at tempera is ur boiling reaction medium within 23 hours. After cooling, the mixture is concentrated to dryness under reduced pressure (3 kPa). Thus obtained 0.31 g of N-[4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-yl]formamide in the form of a colorless lacquer, which is used as is in the next stage.

1H-NMR-spectrum (400 MHz, (CD3)2SO-d6at a temperature of 373 K, δ in ppm): to 1.42 (m, 2H); of 1.52 (m, 4H); of 2.45 (t, J=5 Hz, 4H); 3,6 (t, J=6.5 Hz, 2H); to 4.17 (t, J=6.5 Hz, 2H); 7.24 to t ush., J=7.5 Hz, 1H); 7,38 (t ush., J=7.5 Hz, 2H); 7,49 (l ush., J=7.5 Hz, 2H); of 7.96 (s, 1H); 8.30 to (l ush., J=5 Hz, 1H); 9,49 (array, 1H).

IR-spectrum (KBr): 3434; 3218; 2955; 2799; 1683; 1631; 1607; 1325; 1289; 765; 698 and 592 cm-1.

Example 24

N-[4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-yl]acetamidoxime

To a solution of 0.27 g of 4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-ylamine 5 cm3chloroform add 0.1 cm3acetic anhydride, and then stirred at room temperature for 100 hours. After concentrating the mixture to dryness under reduced pressure (3 kPa) to the residue add 15 cm3a saturated solution of sodium bicarbonate and extracted with 20 cm3ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue is dissolved in 10 cm3acetone and add 0.1 g of oxalic acid. The resulting solution was concentrated to dryness under reduced pressure, the NII (3 kPa) and the residue proscout in diethyl ether and was isolated by filtration. Thus obtain 0.05 g of N-[4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-yl]acetamidoacrylate in the form of a hygroscopic solid white color.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): of 1.52 (m, 2H); to 1.70 (m, 4H); 2,01 (ush., 3H); 3,01 (array, 4H); 3,36 (t ush., J=6.5 Hz, 2H); of 4.44 (t ush., J=6.5 Hz, 2H); 7,25 (t ush., J=7.5 Hz, 1H); 7,38 (t ush., J=7.5 Hz, 2H); 7,47 (l ush., J=7.5 Hz, 2H); 8,11 (ush., 1H); 9,66 (array, 1H).

IR-spectrum (KBr): 3258; 3026; 2952; 2683; 2540; 1725; 1640; 1525; 1447; 1373; 1202; 1008; 765 and 700 cm-1.

Example 25

N-[4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-yl]methanesulfonamide

To a solution of 0.18 g of 4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-ylamine 5 cm3chloroform add 0,06 cm3methanesulfonanilide, then stirred at room temperature for 22 hours. To the mixture of 0.04 cm3methanesulfonanilide and stirring is continued for 3 hours at room temperature. To the mixture is added 15 cm3a saturated solution of sodium bicarbonate and extracted with 25 cm3ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue is purified by chromatography on basic aluminum oxide, elwira consistently pure ethyl acetate, then with a mixture of ethyl acetate and methanol (30:1 by volume). After koncentrirane the Oia fractions under reduced pressure to obtain a colorless residue, which is crystallized by trituration in diethyl ether and was isolated by filtration. Thus obtain 0.05 g of N-[4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-yl]methanesulfonamide in a solid white color, melting at 121°C.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.40 to 1.55V (m, 6H); 2,41 (t ush., J=5 Hz, 4H); 3,1 (t, J=6.5 Hz, 2H); 3,11 (s, 3H); 4,18 (t, J=6.5 Hz, 2H); 7.23 percent (t ush., J=7.5 Hz, 1H); 7,38 (t ush., J=7.5 Hz, 2H); 7,69 (l ush., J=7.5 Hz, 2H); of 8.06 (s, 1H); from 9.00 to 9.70 (array very ush., 1H).

IR-spectrum (KBr): 3105; 2928; 1610; 1440; 1321; 1149; 976; 765; 699; 524 and 518 cm-1.

Example 26

1-(2-dimethylaminopropyl)-4-phenyl-1H-pyrazole-3-adigitalife

To a solution of 0.42 g of {2-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-1-methylethyl}dimethylamine in 5 cm3methanol under stirring and at a temperature of about 20 To gradually add 1 cm34 n solution of hydrogen chloride in dioxane. After stirring for 15 hours at a temperature of about 20°C. the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and dried at 40°C under reduced pressure (2.7 kPa), receiving of 0.37 g of 1-(2-dimethylaminopropyl)-4-phenyl-1H-pyrazole-3-alligatoroidea in a solid white color, melting at 189°C.

Mass spectrum (IC): m/z = 246 (MH+), the peak of the molecular ion.

{2-[3-(cyclohex-2-enyloxy)-4-f is elpirata-1-yl]-1-methylethyl}dimethylamine can be obtained as follows.

To mix in the atmosphere of argon to a suspension of 1.3 g of sodium hydride (75%dispersion in mineral oil) in 5 cm3of dimethylformamide add a solution of 1 g of 3-(cyclohex-2-enyloxy)-4-phenyl-1H-pyrazole in 5 cm3of dimethylformamide. After stirring for 15 minutes at a temperature of about 20°C., then for 30 minutes at a temperature of 50°C. the reaction medium is cooled to a temperature of about 20°C. and with stirring, add 1.3 g of (2-chloro-1-methylethyl)dimethylaminohydrolase, then the mixture is heated for 15 hours at 50°C. After adding an additional 0.14 g of sodium hydride in the form of a 75%dispersion in vaseline oil and 0.7 g of (2-chloro-1-methylethyl)dimethylaminohydrolase, the reaction continued for 15 hours at a temperature of 50°C, then the reaction medium is cooled to a temperature of about 20°C. and concentrated to dryness under reduced pressure (2.7 kPa). The resulting residue is treated with 100 cm3water; the resulting aqueous phase is extracted with 3 times 30 cm3dichloromethane and the organic phase is dried over magnesium sulfate, concentrated to dryness under reduced pressure (2.7 kPa). Obtain 1.2 g of chestnut colored oil, which is purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: dichloromethane/methanol (95:5 by volume)]. After concentration to dryness of fractions when pengendali (2.7 kPa) gain of 0.42 g of {2-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-1-methylethyl}dimethylamine in the form of oil [TLC (thin layer chromatography): eluent: dichloromethane/methanol (95:5 by volume), Rf= 0,13].

Mass spectrum (IE): m/z = 325 (M+.); m/z = 72 (C4H10N+.).

3-(cyclohex-2-enyloxy)-4-phenyl-1H-pyrazole can be obtained as follows.

To 20 cm3methyl ethyl ketone with stirring and at a temperature of about 20°With add 2,02 g of 1-(3-hydroxy-4-phenylpyrazol-1-yl)ethanone, 1.27 cm33-bromocyclohexene and 1.52 g of potassium carbonate. After heating for 3 hours at boiling temperature under reflux of the solvent reaction medium is cooled to a temperature of about 20°C. and concentrated to dryness under reduced pressure (2.7 kPa). The resulting residue is treated with a mixture of 20 cm3of tetrahydrofuran and 20 cm3methanol, then with stirring, to it add 2 cm35 n sodium hydroxide solution. After stirring for 30 minutes at a temperature of about 20°C, the reaction medium was concentrated to dryness under reduced pressure (2.7 kPa)to give a residue which is dissolved in 100 cm3ethyl acetate. The organic solution is washed with 2 times 20 cm3of water and with 20 cm3saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid is treated with 5 cm3ethyl acetate under heating and under stirring, to the solution was added 40 cm3di is saprophilous ether, within 15 minutes, heated at boiling temperature under reflux of the solvent, and then cooled to a temperature of about 20°C. First lot of material after crystallization is filtered off, washed with 10 cm3diisopropyl ether and 10 cm3pentane and dried under reduced pressure (2.7 kPa)to give 1.07 g of 3-(cyclohex-2-enyloxy)-4-phenyl-1H-pyrazole in the form of a white powder. The filtrate after crystallization is evaporated to dryness under reduced pressure (2.7 kPa), treated with 20 cm3diisopropyl ether and add 20 cm3pentane; the second lot of material after crystallization is filtered off and dried under reduced pressure (2.7 kPa)to give 0.33 g is identical to the previous product. [TLC: eluent: cyclohexane/ethyl acetate (70:30 by volume), Rf= 0,23].

Mass spectrum (IE): m/z = 240 (M+.); m/z = 160 [(M-C6H8)+.].

Example 27

1-(1-methylpiperidin-3-ylmethyl)-4-phenyl-1H-pyrazole-3-ol

To 20 cm3ethanol at a temperature of about 20°With add 0,86 g of 3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-methylpiperidine, 0.1 g of 10%palladium-on-charcoal, 10 cm3cyclohexene and 20 cm3of ethanol. After standing for 15 hours at a temperature of 50°C in the reaction medium was added 0.1 g of 10%palladium-on-coal and 10 cm3cyclohexene; the reaction mixture n is grebaut when temperature boiling under reflux of the solvent for 1 hour, then add another 15 cm3cyclohexene and the reaction continued at the boiling point under reflux of the solvent for 5 hours. The catalyst is filtered off on Supercel, the solution is evaporated to dryness under reduced pressure (2.7 kPa), receiving of 0.48 g of solid, which proscout 10 cm3a mixture of diisopropyl ether and pentane. After filtering obtain 0.3 g of a solid substance that is administered in cooperation with 10 cm3ethanol, 10 cm3cyclohexene and 0.1 g of 10%palladium-on-coal under stirring and boiling under reflux of the solvent for 15 hours. The catalyst is filtered off on Supercel and the filtrate is evaporated to dryness under reduced pressure (2.7 kPa)to give 0.3 g of solid, which is purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: dichloromethane/methanol/38%aqueous ammonia solution (88:10:2 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 0.15 g of a solid substance of a yellowish color, which is treated with 70 cm3methanol at a temperature of about 20°C. To the solution was added 1 cm34 n solution of hydrogen chloride in dioxane, stirred for 15 minutes at a temperature of about 20°C, then it is evaporated to dryness under reduced pressure (2.7 kPa), receiving 0,19 g meringue, odorou proscout in diisopropyl ether and filtered off. Hygroscopic solid is treated with 1 cm31 n sodium hydroxide solution and the aqueous phase washed with dichloromethane, partially evaporated under reduced pressure (2.7 kPa), adjusted to pH 8 by adding 0.1 G. of hydrochloric acid and extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give 0.15 g of 1-(1-methylpiperidin-3-ylmethyl)-4-phenyl-1H-pyrazole-3-ol in the form of a meringue cream color, melting at 132°C.

Mass spectrum (ES) [mass spectrum with electronic ionization sputtering]: m/z = 272 (MN+).

3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-methylpiperidin can be obtained as follows.

To a solution of 1 g of 3-benzyloxy-4-phenyl-1H-pyrazole in 10 cm3of dimethylformamide in an argon atmosphere and with stirring, gradually add, at a temperature of about 20°C., 0.4 g of sodium hydride in the form of a 75%dispersion in vaseline oil, then the mixture for 10 minutes to stand at 50°C. After addition of 1.5 g of 3-chloromethyl-1-metilprednisolone the reaction mixture is heated for 15 hours at a temperature of 80°C, then cooled to a temperature of about 20°C and bring in 100 cm3water. The mixture is extracted with dichloromethane; the organic phase is dried over magnesium sulfate, filtered and the issue is more to dryness under reduced pressure (2.7 kPa), obtaining 1.6 g of chestnut colored oil, which is purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: dichloromethane/methanol (95:5 by volume)]. After concentrating the fractions to dryness under reduced pressure (2.7 kPa) get 0,86 g of 3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-methylpiperidine in the form of a yellow oil [TLC: eluent: dichloromethane/methanol/38%aqueous ammonia solution (88:10:2 by volume), Rf= 0,41].

Mass spectrum (IE): m/z = 361 (M+.); m/z = 270(M-C7H7)+.].

Example 28

5-methyl-4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-adigitalife

To a solution of 0.3 g of 1-{2-[3-(cyclohex-2-enyloxy)-5-methyl-4-phenylpyrazol-1-yl]ethyl}piperidine in 10 cm3methanol is gradually under stirring and at a temperature of about 20°C. add 1.5 cm34 n solution of hydrogen chloride in dioxane. After stirring for 15 hours at a temperature of about 20°C. the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The remainder proscout in diisopropyl ether, filtered off and dried under reduced pressure (2.7 kPa) at 40°C for 2 hours, getting to 0.19 g of 5-methyl-4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-alligatoroidea in the form of a cream solid color, melting at 222°C.

Mass spectrum (IC): m/z = 286 (MH+).

1-{2-[3-(cyclohex--enyloxy)-5-methyl-4-phenylpyrazol-1-yl]ethyl}piperidine can be obtained as follows.

To a solution and 0.46 g of 3-(cyclohex-2-enyloxy)-5-methyl-4-phenyl-1H-pyrazole in 15 cm3of dimethylformamide, with stirring in an argon atmosphere and at a temperature of about 20°C. gradually add 0.2 g of sodium hydride in the form of a 75%dispersion in vaseline oil. After heating for 5 minutes at a temperature of 50°C. to the reaction mixture of 0.67 g of 1-(2-chloroethyl)piperidinedione, then the solution is heated at a temperature of 80°C for 15 hours. Reaction medium make 100 cm3water; the aqueous phase is extracted with dichloromethane, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained chestnut color (0.8 g) purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: dichloromethane/methanol (95:5 by volume)]. After concentration to dryness of fractions under reduced pressure (2.7 kPa) to obtain 0.3 g of 3-(cyclohex-2-EN-1-yloxy)-5-methyl-4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole in the form of a yellow oil [TLC: eluent: dichloromethane/methanol (90:10 by volume), Rf= 0,27].

Mass spectrum (IC): m/z = 366 (MH+).

3-(cyclohex-2-enyloxy)-5-methyl-4-phenyl-1H-pyrazole can be obtained as follows.

With stirring to a solution of 0.8 g of 1-[3-(cyclohex-2-enyloxy)-5-methyl-4-phenylpyrazol-1-yl]ethanone in a mixture of 20 cm3methanol and 20 cm3tetrahydrofur the Ana at a temperature of about 20°C. gradually add 0,54 cm 35 n sodium hydroxide solution. After stirring for 5 hours at a temperature of about 20°C. the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is treated with 100 cm3dichloromethane and 10 cm3water; the organic phase is decanted, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa), receiving and 0.46 g of 3-(cyclohex-2-enyloxy)-5-methyl-4-phenyl-1H-pyrazole in the form of retinoid substance yellow [TLC: eluent: cyclohexane/ethyl acetate (70:30 by volume), Rf= 0,19].

Mass spectrum (S): m/z = 254 (M+.); m/z = 174 [(M-C6H8)+.].

1-[3-(cyclohex-2-enyloxy)-5-methyl-4-phenylpyrazol-1-yl]Etalon can be obtained as follows.

To 100 cm3methyl ethyl ketone at a temperature of 20°C and with stirring, add 2 g of 1-(3-hydroxy-5-methyl-4-phenylpyrazol-1-yl)ethanone, 1.3 g of potassium carbonate and 1.06 cm33-bromocyclohexene. After heating for 5 hours at boiling temperature under reflux of the solvent, the reaction mixture is cooled to a temperature of about 20°C, then concentrated to dryness under reduced pressure (2.7 kPa). The residue is treated with 100 cm3water and 100 cm3dichloromethane; the organic phase is decanted, dried over magnesium sulfate, filtered and concentrated to dryness under reduced is the t (2.7 kPa). The oil obtained chestnut color (2.7 g) purified flash chromatography on silica [eluent: cyclohexane/ethyl acetate (70:30 by volume)]. After concentration to dryness of fractions under reduced pressure (2.7 kPa) to obtain 0.8 g of 1-[3-(cyclohex-2-enyloxy)-5-methyl-4-phenylpyrazol-1-yl]ethanone in the form of a yellow oil [TLC: eluent: cyclohexane/ethyl acetate (70:30 by volume), Rf= 0,74].

Mass spectrum (S): m/z = 296 (M+.); m/z = 174 [(216-C2H2O)+.].

1-(3-hydroxy-5-methyl-4-phenylpyrazol-1-yl)Etalon can be obtained as follows.

To a solution of 1.74 g of 5-methyl-4-phenyl-1H-pyrazole-3-ol (catalog number: 64754-67-2) 17 cm3pyridine under stirring and maintaining the temperature of 100°C add 0,85 cm3acetic anhydride. After heating for 30 minutes at this temperature, the reaction medium is cooled to a temperature of about 20°C, then make it 100 cm3a mixture of water with ice. The solution is extracted with 2 times 50 cm3ethyl acetate; the combined organic phases are washed with 2 times 100 cm3water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa); receive 2 g of 1-(3-hydroxy-5-methyl-4-phenylpyrazol-1-yl)ethanone in the form of oil of orange-yellow color.

Mass spectrum (S): m/z = 216 (M+.); m/z = 174 [(M-C2H2O)+.].

Example 29

4-(3-AMINOPHENYL)--(2-dimethylaminoethyl)-1H-pyrazole-3-ultrahydrophobic

To a mixture of 860 mg of ammonium formate and 50 mg of 10%palladium hydroxide in 15 cm3methanol is added a solution of 500 mg of {2-[3-benzyloxy-4-(3-nitrophenyl)pyrazole-1-yl]ethyl}dimethylamine 15 cm3methanol, then heated for 3 hours at boiling temperature under reflux of the solvent under stirring. The reaction medium is then filtered through Supercel and the filtrate is evaporated under reduced pressure (2.7 kPa). The crude reaction product is treated with dichloromethane and the resulting mixture was washed successively aqueous saturated sodium hydrogen carbonate solution, water and aqueous saturated solution of sodium chloride. The aqueous phase are combined and evaporated under reduced pressure (2.7 kPa). The resulting residue is treated with methanol and the suspension is filtered. After evaporation of the filtrate under reduced pressure (2.7 kPa) residual solid proscout 3 N. solution of hydrogen chloride in ethanol. The precipitation is filtered off and dried under vacuum (2.7 kPa)to give 110 mg of 4-(3-AMINOPHENYL)-1-(2-dimethylaminoethyl)-1H-pyrazole-3-ultrahydrophobic in a solid beige color.

IR-spectrum (KBr): 3432; 2839; 2689; 2586; 1627; 1603; 1523; 1462; 1178; 786 and 696 cm-1.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 2,80 (s, 6H); of 3.45 (t, J=6.5 Hz, 2H); to 4.41 (t, J=6.5 Hz, 2H); 7,10 (l ush., J=8 Hz, 1H); 7,42 (t, J=8 Hz, 1H); 7,58 (l ush., J=8 Hz, 1H); to 7.67 (ush., 1H); 8,10 (1H); from 9,50 to 10.40 (array very ush., 1H); 10,50 (array, 1H); of 10.73 (array, 1H).

{2-[3-benzyloxy-4-(3-nitrophenyl)pyrazole-1-yl]ethyl}dimethylamine can be obtained as follows.

To a suspension of 1.13 g of sodium hydride (75%dispersion in mineral oil) in 50 cm3of dimethylformamide in an argon atmosphere and with stirring a solution of 3.45 g of 3-benzyloxy-4-(3-nitrophenyl)-1H-pyrazole in 50 cm3of dimethylformamide. After heating for 30 minutes at a temperature of 50°C. the mixture is stirred for 1 hour at a temperature of about 20°C, then cooled in a bath with ice and add a solution of 4.5 g (2-bromacil)dimethylaminohydrolase 50 cm3of dimethylformamide. The reaction medium is stirred for 15 hours at a temperature of about 20°C. and for 1.5 hours at 50°C, then cooled to a temperature of about 20°C and bring in 400 cm3water. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed successively with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give an orange oil, which was purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: ethyl acetate, then ethyl acetate/methanol (90:10 by volume)]. After concentrating the fractions under reduced davleniya 1.7 g {2-[3-benzyloxy-4-(3-nitrophenyl)pyrazole-1-yl]ethyl}dimethylamine in the form of an orange oil.

Mass spectrum (S): m/z = 366 (M+.); m/z = 91 (C7H7+); m/z = 71 (C4H9N+.); m/z = 58 (C3H8N+).

3-benzyloxy-4-(3-nitrophenyl)-1H-pyrazole can be obtained as follows.

To a suspension of 4.1 g of 1-[3-hydroxy-4-(3-nitrophenyl)pyrazole-1-yl]ethanone 50 cm3methyl ethyl ketone was added with stirring to 2.75 g of potassium carbonate and 2.2 cm3benzylbromide. The mixture is heated at the boiling point under reflux of the solvent for 2.5 hours, cooled to a temperature of about 20°C and filtered. The filtrate is evaporated under reduced pressure (2.7 kPa) and the residue is treated with 25 cm3of tetrahydrofuran and 25 cm3methanol, then to it add 1 cm310 n sodium hydroxide solution. After stirring for 30 minutes at a temperature of about 20°C. the reaction medium is evaporated under reduced pressure (2.7 kPa). The crude reaction product is treated with dichloromethane. The organic phase is washed successively with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give an oil, which proscout in diisopropyl ether. The precipitation is filtered off and dried under vacuum (2.7 kPa), receiving 3,47 g of 3-benzyloxy-4-(3-nitrophenyl)-1H-pyrazole in the form of a solid yellow color is the same.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): of 5.40 (s, 2H); of 7.36 (t ush., J=7.5 Hz, 1H); 7,44 (t ush., J=7.5 Hz, 2H); 7,55 (l ush., J=7.5 Hz, 2H); to 7.64 (t, J=8 Hz, 1H); 8,00 (DD, J=8 and 2 Hz, 1H); 8,13 (l ush., J=8 Hz, 1H); with 8.33 (s, 1H); to 8.62 (t, J=2 Hz, 1H); from 12,00 to 12,80 (array very ush., 1H).

1-[3-hydroxy-4-(3-nitrophenyl)pyrazole-1-yl]Etalon can be obtained as follows.

A solution of 3.8 g of dimethylammonium-4-(3-nitrophenyl)-1H-pyrazolate 40 cm3pyridine in an argon atmosphere and with stirring, heated to a temperature of 90°C., and then thereto is added dropwise 1.5 cm3acetic anhydride. After heating for 1 hour at a temperature of 90°C. the reaction medium is cooled to a temperature of about 20°C and make it 100 cm3a mixture of water with ice. The precipitation is filtered off, washed three times with water and dried under vacuum (2.7 kPa), getting to 4.33 g of solid substance that is administered in cooperation with 40 cm3pyridine and 0.39 cm3acetic anhydride according to the above method. Obtain 4.1 g of 1-[3-hydroxy-4-(3-nitrophenyl)pyrazole-1-yl]ethanone in the form of a solid pale yellow color.

IR-spectrum (KBr): 3118; 3082; 2669; 1730; 1604; 1520; 1390; 1349; 1256; 1223; 1101; 748 and 719 cm-1.

Dimethylammonium-4-(3-nitrophenyl)-1H-pyrazole-3-OST can be obtained as follows.

A solution of 9.3 g of benzyl ester of 3-dimethylamino-2-(3-nitrophenyl)acrylic acid and 1.4 cm3g is grainsoriginate 100 cm 3ethanol under stirring and heated for 3 hours at boiling temperature under reflux of the solvent, and then cooled in a bath with ice. The precipitation is filtered off, washed with water and dried under vacuum (2.7 kPa)to give 4.44 g of dimethylammonium-4-(3-nitrophenyl)-1H-pyrazole-3-olate in a solid orange color.

IR-spectrum (KBr): 3346; 3199; 3071; 2855; 2685; 2386; 1583; 1538; 1469; 1350; 934; 766; 747 and 681 cm-1.

Complex benzyl ester of 3-dimethylamino-2-(3-nitrophenyl)acrylic acid can be obtained as follows.

To a solution of 10 g of complex benzyl ester 2-(3-nitrophenyl)acrylic acid in 100 cm3tetrahydrofuran (THF) add 11.5 cm3With tert-butoxy-N,N,N',N'-tetramethylmethylenediamine and heated for 15 hours at boiling temperature under reflux of the solvent. After cooling to a temperature of about 20°C. the reaction mixture is evaporated to dryness under reduced pressure (2.7 kPa). The residue is treated with ethyl acetate and the organic solution is washed 3 times with water, then aqueous saturated solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The resulting brown oil purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (70:30 by volume)]. After the concentration of the investments of the fractions under reduced pressure to obtain 9.3 g of complex benzyl ester 3-dimethylamino-2-(3-nitrophenyl)acrylic acid in the form of an orange oil.

Mass spectrum (IE): m/z = 326 (M+.); m/z = 235(M-C7H7)+]; m/z = 91 (C7H7+).

Example 30

N-{3-[3-hydroxy-1-(2-dimethylaminoethyl)-1H-pyrazole-4-yl]phenyl}acetamidocinnamate

To a solution of 400 mg of N-{3-[3-benzyloxy-1-(2-dimethylaminoethyl)-1H-pyrazole-4-yl]phenyl}ndimethylacetamide 20 cm3ethanol add 1.8 cm33 n solution of hydrogen chloride in diethyl ether. After stirring for 15 minutes at a temperature of about 20°C. the solution is evaporated under reduced pressure (2.7 kPa). The residue is treated with 20 cm3of ethanol. The resulting solution was injected into the autoclave and add 50 mg of 10%palladium-on-charcoal, then it is placed in an atmosphere of hydrogen (5 bar). After stirring for 2 hours at a temperature of about 20°C. the reaction medium is filtered through Supercel and the filtrate is evaporated. The resulting yellow oil (440 mg) was dissolved in 20 cm3ethanol and injected into the reaction using 50 mg of 10%palladium-on-coal under hydrogen pressure of 5 bar at a temperature of 40°C and stirring for 4 hours. The reaction medium is then filtered through Supercel, the filtrate is evaporated and the residue proscout in diisopropyl ether. The precipitation is filtered off, dried under vacuum (2.7 kPa)to give 289 mg of N-{3-[3-hydroxy-1-(2-dimethylaminoethyl)-1H-pyrazole-4-yl]phenyl}acetamidomalonate in view of the solid pale yellow color.

IR-spectrum (KBr): 3242; 3130; 2967; 2573; 2464; 1678; 1614; 1588; 1525; 1462; 1258; 1187; 787 and 690 cm-1.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 2,05 (s, 3H); 2,80 (ush., 6H); 3,48 (t ush., J=6.5 Hz, 2H); 4,35 (t ush., J=6.5 Hz, 2H); 7.23 percent (t, J=7.5 Hz, 1H); 7,31 (l ush., J=7.5 Hz, 1H); 7,38 (d ush., J=7.5 Hz, 1H); 7,89 (ush., 1H); to 7.95 (s, 1H); from 9,60 to 9.85 (array ush., 1H); to 9.91 (ush., 1H); 10,45 (ush., 1H).

N-{3-[3-benzyloxy-1-(2-dimethylaminoethyl)-1H-pyrazole-4-yl]phenyl}ndimethylacetamide can be obtained as follows.

To a solution of 500 mg of 3-[3-benzyloxy-1-(2-dimethylaminoethyl)-1H-pyrazole-4-yl]phenylamine and 0,418 cm3of triethylamine in 20 cm3dichloromethane in an argon atmosphere and with stirring, add 0,116 cm3acetylchloride, maintaining a temperature of 5°C. After stirring for 15 hours at a temperature of about 20°C. to the reaction mixture add an additional 0.1 cm3of triethylamine and 0.1 cm3acetylchloride and the reaction continued for 2 hours. The reaction mixture was then washed successively twice with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give 540 mg of N-{3-[3-benzyloxy-1-(2-dimethylaminoethyl)-1H-pyrazole-4-yl]phenyl}ndimethylacetamide in the form of a yellow oil.

IR-spectrum (CCl4): 3444; 3305; 2945; 2822; 2773; 1670; 1614; 1588; 1549; 1502; 1452; 1423; 1357; 1177; 1018; 695 and 537 cm-1.

3-[3-benzyloxy-1-(2-dimethylene oethyl)-1H-pyrazole-4-yl]phenylamine can be obtained as follows.

To a mixture of 840 mg of iron powder, 200 mg of ammonium chloride in 15 cm3ethanol and 15 cm3water heated to the boiling temperature under reflux of the solvent, was added with stirring a solution of 1.1 g of {2-[3-benzyloxy-4-(3-nitrophenyl)pyrazole-1-yl]ethyl}dimethylamine 15 cm3of ethanol. Stirring is continued for 3 hours at boiling temperature under reflux of the solvent, and then for 15 hours at a temperature of about 20°C. the Reaction mixture is filtered and the filtrate is evaporated. The residue is treated with a mixture of ethyl acetate, water and 1 n sodium hydroxide solution. The organic phase is decanted, washed successively with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give 1 g of 3-[3-benzyloxy-1-(2-dimethylaminoethyl)-1H-pyrazole-4-yl]phenylamine in the form of an orange oil.

Mass spectrum (IE): m/z = 336 (M+.); m/z = 265(M-C7H7)+]; m/z = 91 (C7H7+); m/z = 71 (C4H9N+.); m/z = 58 (C3H8N+).

Example 31

4-(4-AMINOPHENYL)-1-(2-dimethylaminoethyl)-1H-pyrazole-3-adigitalife

To a solution of 250 mg of {2-[3-benzyloxy-4-(4-nitrophenyl)-pyrazol-yl]ethyl}dimethylamine in 20 cm3ethanol add 1.2 cm33 n solution of hydrogen chloride in diethyl ether. P is after stirring for 20 minutes at a temperature of about 20°C. the solution is evaporated to dryness under reduced pressure (2.7 kPa). The residue is treated with 20 cm3of ethanol. The resulting solution was injected into the autoclave and added 36 mg of 10%palladium-on-charcoal, then it is placed in an atmosphere of hydrogen (7 bar). After stirring for 5 hours at a temperature of 40°C. the reaction mixture was filtered through Supercel, the filtrate is evaporated and the residue proscout in diisopropyl ether. The precipitation is filtered off, dried under vacuum (2.7 kPa)to give 169 mg of 4-(4-AMINOPHENYL)-1-(2-dimethylaminoethyl)-1H-pyrazole-3-alligatoroidea in a solid yellow color.

IR-spectrum (KBr): 3372; 3296; 3205; 3025; 1627; 1592; 1522; 1514; 1451; 1280; 1177; 828; 612 and 525 cm-1.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 2,75 (s, 6H); 3.42 points (m, 2H); 4,27 (t, J=6 Hz, 2H); from 4,70 to 5.30 (array ush., 2H); 6,55 (d, J=8.5 Hz, 2H); 7,31 (d, J=8.5 Hz, 2H); of 7.75 (s, 1H); 10,08 (array, 1H).

{2-[3-benzyloxy-4-(4-nitrophenyl)pyrazole-1-yl]ethyl}dimethylamine can be obtained as follows.

To a suspension of 980 mg of sodium hydride (75%dispersion in mineral oil) in 50 cm3of dimethylformamide in an argon atmosphere and with stirring a solution of 3 g of 3-benzyloxy-4-(4-nitrophenyl)-1H-pyrazole in 50 cm3of dimethylformamide. After heating for 30 minutes at a temperature of 50°C. the mixture is stirred for 1 hour at a temperature of about 20°C, then cooled in a bath with ice and add a solution of 4.7 g (2-bromacil)Dima is illyngophobia 50 cm 3of dimethylformamide. The reaction medium is stirred for 15 hours at a temperature of about 20°C, then it make 400 cm3water. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed successively twice with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give an orange oil, which was purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: ethyl acetate, then ethyl acetate/methanol (90:10 by volume)]. After concentrating the fractions under reduced pressure to obtain 1.2 g of {2-[3-benzyloxy-4-(4-nitrophenyl)pyrazole-1-yl]ethyl}dimethylamine in the form of a brown oil.

Mass spectrum (IE): m/z = 366 (M+.); m/z = 91 (C7H7+); m/z = 71 (C4H9N+.); m/z = 58 (C3H8N+).

3-benzyloxy-4-(4-nitrophenyl)-1H-pyrazole can be obtained as follows.

To a suspension of 4.5 g of 1-[3-hydroxy-4-(4-nitrophenyl)pyrazole-1-yl]ethanone 50 cm3methyl ethyl ketone was added with stirring 3 g of potassium carbonate and 2.2 cm3benzylbromide. The mixture is heated at the boiling point under reflux of the solvent for 2.5 hours, cooled to a temperature of about 20°C and filtered. The filtrate is evaporated under reduced pressure (2,7 the PA) and the residue is treated with 25 cm 3of tetrahydrofuran and 25 cm3methanol, then add 2 cm310 n sodium hydroxide solution. After stirring for 30 minutes at a temperature of about 20°C. the reaction medium is evaporated under reduced pressure (2.7 kPa). The crude reaction product is treated with dichloromethane. The organic phase is washed successively with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give an oil, which proscout in diisopropyl ether. The precipitation is filtered off and dried under vacuum (2.7 kPa)to give 3 g of 3-benzyloxy-4-(4-nitrophenyl)-1H-pyrazole in the form of solids ochre.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 5,41 (s, 2H); from 7,30 to 7.60 (m, 5H); of 7.97 (d, J=9 Hz, 2H); 8,23 (d, J=9 Hz, 2H); at 8.36 (s, 1H); 12,49 (array, 1H).

1-[3-hydroxy-4-(4-nitrophenyl)pyrazole-1-yl]Etalon can be obtained as follows.

The solution is 4.85 g of dimethylammonium-4-(4-nitrophenyl)-1H-pyrazole-3-olate 40 cm3pyridine in an argon atmosphere and with stirring, heated to a temperature of 90°C., and then thereto is added dropwise to 2 cm3acetic anhydride. After heating for 1 hour at a temperature of 90°C. the reaction medium is cooled to a temperature of about 20°C and make it 100 cm3a mixture of water with ice. The precipitation ochiltree is up, washed three times with water and dried under vacuum (2.7 kPa)to give 4.5 g of 1-[3-hydroxy-4-(4-nitrophenyl)pyrazole-1-yl]ethanone in a solid yellow color.

IR-spectrum (KBr): 3370; 3128; 2980; 2587; 1721; 1615; 1600; 1509; 1341; 1224; 1111; 855; 757 and 643 cm-1.

Dimethylammonium-4-(4-nitrophenyl)-1H-pyrazole-3-OST can be obtained as follows.

A solution of 10.7 g of a complex of methyl ester of 3-dimethylamino-2-(4-nitrophenyl)acrylic acid and 2.1 cm3hydrazinoacetate 120 cm3ethanol under stirring and heated for 3 hours at boiling temperature under reflux of the solvent and cooled in a bath with ice. Saducees the solid is filtered off, washed with diisopropyl ether and dried under vacuum (2.7 kPa)to give 5 g of dimethylammonium-4-(4-nitrophenyl)-1H-pyrazole-3-olate in a solid orange color.

IR-spectrum (KBr): 3188; 3089; 2909; 2728; 2423; 1603; 1589; 1567; 1538; 1501; 1345; 1330; 1212; 1112; 923; 880; 761 and 581 cm-1.

Slojniy methyl ester of 3-dimethylamino-2-(4-nitrophenyl)acrylic acid can be obtained as follows.

To a solution of 10.5 g of complex methyl ester of 2-(4-nitrophenyl)acrylic acid in 100 cm3tetrahydrofuran (THF) add 16,6 cm3With tert-butoxy-N,N,N',N'-tetramethylmethylenediamine and heated for 2.5 hours at the boiling point under reflux of the solvent. After AC is shivani for 15 hours at a temperature of about 20°C. the reaction mixture is evaporated to dryness under reduced pressure (2.7 kPa). The residue is treated with ethyl acetate and the organic solution is washed 3 times with water, then dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give 10.7 g of a complex of methyl ester of 3-dimethylamino-2-(4-nitrophenyl)acrylic acid in the form of a brown oil.

IR-spectrum (CCl4): 2949; 1693; 1603; 1519; 1433; 1344; 1219; 1095; 1048 and 855 cm-1.

Example 32

1-(2-dimethylaminoethyl)-4-(4'-forbiden-3-yl)-1H-pyrazole-3-adigitalife

To a solution of 300 mg of {2-[3-benzyloxy-4-(4'-forbiden-3-yl)pyrazole-1-yl]ethyl}dimethylamine in 20 cm3ethanol add 1.2 cm33 n solution of hydrogen chloride in diethyl ether. After stirring for 30 minutes at a temperature of about 20°C. the solution is evaporated to dryness under reduced pressure (2.7 kPa). The residue is treated with 20 cm3of ethanol. The resulting solution was injected into the autoclave and add to it the 14 mg of 10%palladium-on-charcoal, then put it in an atmosphere of hydrogen (7 bar). After stirring for 5 hours at a temperature of 30°C. the reaction medium is filtered through Supercel and the filtrate is evaporated. To the residue add diisopropyl ether, which leads to the formation of the suspension, which is heated to the boiling temperature under reflux of the solvent and filtered in hot condition. The obtained solid is dried in vacuum (2,7 the PA) getting 84 mg of 1-(2-dimethylaminoethyl)-4-(4'-forbiden-3-yl)-1H-pyrazole-3-alligatoroidea in the form of white powder.

IR-spectrum (KBr): 3049; 2962; 2682; 2355; 1608; 1514; 1460; 1221; 1184; 1162; 843; 804; 703 and 560 cm-1.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): was 2.76 (ush., 6H); to 3.45 (m, 2H); 4,32 (t ush., J=6 Hz, 2H); to 7.32 (t, J=8.5 Hz, 2H); from of 7.35 to 7.50 (m, 2H); 7,66 (m, 1H); of 7.70 (DD, J=9 and 6 Hz, 2H); of 7.90 (ush., 1H); to 8.14 (s, 1H); 9,76 (array, 1H); 10,50 (ush., 1H).

{2-[3-benzyloxy-4-(4'-forbiden-3-yl)pyrazole-1-yl]ethyl}dimethylamine can be obtained as follows.

To a stirred solution of 620 mg of {2-[3-benzyloxy-4-(3-bromophenyl)pyrazole-1-yl]ethyl}dimethylamine in 25 cm3toluene in an argon atmosphere add 860 mg 4-ftorhinolonovy acid, 1.3 g of potassium phosphate and 330 mg of bis(triphenylphosphine)pallidiflora. After heating for 15 hours at boiling temperature under reflux of the solvent reaction medium is cooled to a temperature of about 20°C and add ethyl acetate and water, and then it is filtered through Supercel. The filtrate is decanted, then the organic phase is washed successively with 0.5 N. the sodium hydroxide solution, water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The resulting brown oil (1.3 g) purified flash chromatography on aluminium oxide STV1 under tablenamehere (50 kPa) [eluent: cyclohexane/ethyl acetate (80:20 by volume)]. After concentrating the fractions under reduced pressure to obtain 300 mg of {2-[3-benzyloxy-4-(4'-forbiden-3-yl)pyrazole-1-yl]ethyl}dimethylamine in the form of a yellow oil.

IR-spectrum (CCl4): 2823; 2773; 1610; 1571; 1515; 1462; 1358; 1235; 1158; 1014; 837; 696 and 559 cm-1.

{2-[3-benzyloxy-4-(3-bromophenyl)pyrazole-1-yl]ethyl}dimethylamine can be obtained as follows.

To a suspension of 2.25 g of sodium hydride (75%dispersion in liquid paraffin) in 70 cm3of dimethylformamide in an argon atmosphere and with stirring a solution to 7.67 g of 3-benzyloxy-4-(3-bromophenyl)-1H-pyrazole 70 cm3of dimethylformamide. After heating for 30 minutes at a temperature of 50°C. the mixture is stirred for 1 hour at a temperature of about 20°C, then cooled in a bath with ice and add a solution 10,85 g (2-bromacil)dimethylaminohydrolase 100 cm3of dimethylformamide. The reaction medium is stirred for 15 hours at a temperature of about 20°C and for 3 hours at 50°C, then cooled to a temperature of about 20°C and bring in 500 cm3water. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed successively twice with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give an orange oil, which cleaned the Ute flash chromatography on silica under pressure of argon (50 kPa) [eluent: ethyl acetate; the ethyl acetate/methanol (90:10 by volume)]. After concentrating the fractions under reduced pressure to obtain 2.4 g of {2-[3-benzyloxy-4-(3-bromophenyl)pyrazole-1-yl]ethyl}dimethylamine in the form of an orange oil.

Mass spectrum (IC): m/z = 400 (MH+); m/z = 322(M-Br+2H)+].

3-benzyloxy-4-(3-bromophenyl)-1H-pyrazole can be obtained as follows.

To a suspension of 4.4 g of 1-[3-benzyloxy-4-(3-bromophenyl)pyrazole-1-yl]ethanone 50 cm3methyl ethyl ketone was added with stirring 2.6 g of potassium carbonate and of 2.05 cm3benzylbromide. The mixture is heated at the boiling point under reflux of the solvent for 2.5 hours, cooled to a temperature of about 20°C and filtered. The filtrate is evaporated under reduced pressure (2.7 kPa) and the residue is treated with 25 cm3of tetrahydrofuran and 25 cm3methanol, then add 1 cm310 n sodium hydroxide solution. After stirring for 30 minutes at a temperature of about 20°C. the reaction medium is evaporated under reduced pressure (2.7 kPa). The crude reaction product is treated with dichloromethane. The organic phase is washed successively twice with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give oil, which was purified flash chromatography on silica under pressure of the argon (50 kPa) [eluent: cyclohexane/ethyl acetate (80:20 by volume)]. After concentrating the fractions under reduced pressure gain of 3.3 g of 3-benzyloxy-4-(3-bromophenyl)-1H-pyrazole in the form of a cream solid color.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): to 5.35 (s, 2H); from 7.25 to 7,40 (m, 3H); 7,42 (t ush., J=7.5 Hz, 2H); 7,51 (l ush., J=7.5 Hz, 2H); 7,71 (dt, J=7.5 and 2 Hz, 1H); 7,93 (ush., 1H); 8,18 (s, 1H); 12,25 (array, 1H).

1-[4-(3-bromophenyl)-3-hydroxypyrazol-1-yl]Etalon can be obtained as follows.

A solution of 4.3 g of 4-(3-bromophenyl)-1H-pyrazole-3-ol in 40 cm3pyridine in an argon atmosphere and with stirring, heated to a temperature of 90°C., and then thereto is added dropwise 1.6 cm3acetic anhydride. After heating for 1 hour at a temperature of 90°C. the reaction mixture is cooled to a temperature of about 20°C and make it 100 cm3a mixture of water with ice. The precipitation is filtered off, washed three times with water and dried under vacuum (2.7 kPa)to give 4.42 g of 1-[4-(3-bromophenyl)-3-hydroxypyrazol-1-yl]ethanone in the form of a cream solid color.

IR-spectrum (KBr): 3125; 2687; 2577; 1729; 1616; 1529; 1391; 1318; 1256; 1219; 945; 791; 715 and 629 cm-1.

4-(3-bromophenyl)-1H-pyrazole-3-ol may be obtained in the following way.

The solution 12,22 g complex methyl ester 2-(3-bromophenyl)-3-dimethylaminoethanol acid and 2.1 cm3hydrazinoacetate 100 cm3ethanol is heated with stirring for 3 hours pritemperature boiling under reflux of the solvent. The reaction mixture is evaporated to dryness under reduced pressure (2.7 kPa) and the residue proscout in diisopropyl ether. The formed solid is filtered off and dried under vacuum (2.7 kPa)to give 5.1 g of dimethylammonium-4-(3-bromophenyl)-1H-pyrazole-3-olate in the form of a cream solid color. The filtrate is evaporated under reduced pressure (2.7 kPa), the residue proscout in diisopropyl ether and the resulting solid is filtered off and dried under vacuum (2.7 kPa)to give 4.3 g of 4-(3-bromophenyl)-1H-pyrazole-3-ol in the form of a cream solid color.

IR-spectrum (KBr): 3099; 2768; 2668; 1620; 1590; 1410; 1241; 1081; 787; 712 and 689 cm-1.

Methyl ester 2-(3-bromophenyl)-3-dimethylaminoethanol acid can be obtained as follows.

To a solution of 10.5 g of complex methyl ester 2-(3-bromophenyl)acrylic acid in 100 cm3tetrahydrofuran (THF) add to 14.4 cm3With tert-butoxy-N,N,N',N'-tetramethylmethylenediamine and heated for 2.5 hours at the boiling point under reflux of the solvent. After stirring for 15 hours at a temperature of about 20°C. the reaction mixture is evaporated to dryness under reduced pressure (2.7 kPa). The residue is treated with ethyl acetate and the organic solution is washed 3 times with water, then dried over magnesium sulfate, filtered and evaporated under reduced pressure is (2.7 kPa), getting 12,22 g complex methyl ester 2-(3-bromophenyl)-3-dimethylaminoethanol acid in the form of a yellow oil.

IR-spectrum (CCl4): 2947; 2813; 1691; 1603; 1432; 1285; 1221; 1098 and 694 cm-1.

Example 33

4-biphenyl-3-yl-1-(2-dimethylaminoethyl)-1H-pyrazole-3-adigitalife

To a solution of 121 mg of {2-[3-benzyloxy-4-biphenyl-3-alprazol-1-yl]ethyl}dimethylamine in 20 cm3ethanol was added 1 cm33 n solution of hydrogen chloride in diethyl ether. After stirring for 30 minutes at a temperature of about 20°C. the solution is evaporated to dryness under reduced pressure (2.7 kPa). The residue is treated with 20 cm3of ethanol. The resulting solution was injected into the autoclave and add to it 11 mg of 10%palladium-on-charcoal, then it is placed in an atmosphere of hydrogen (7 bar). After stirring for 5 hours at a temperature of 30°C. the reaction medium is filtered through Supercel and the filtrate is evaporated. To the residue add diisopropyl ether, receiving the suspension, which is heated to the boiling temperature under reflux of the solvent and filtered in hot condition. The obtained solid is dried under vacuum (2.7 kPa)to give 69 mg of 4-biphenyl-3-yl-1-(2-dimethylaminoethyl)-1H-pyrazole-3-alligatoroidea in the form of white powder.

IR-spectrum (KBr): 3054; 2959; 2685; 2299; 1606; 1522; 1457; 1298; 1182; 760; 698 and 671 cm-1.

1H-NMR spectrum (300 MHz, (CD )2SO-d6, δ in ppm): 2,79 (array, 6H); 3,43 (array, 2H); or 4.31 (array, 2H); from of 7.25 to 7.55 (m, 5H); to 7.68 (m, 3H); 7,94 (ush., 1H); 8,15 (s, 1H); from 9,45 to 9,65 (array ush., 1H); 10,49 (ush., 1H).

{2-[3-benzyloxy-4-biphenyl-3-alprazol-1-yl]ethyl}dimethylamine can be obtained as follows.

To a stirred solution of 550 mg of {2-[3-benzyloxy-4-(3-bromophenyl)pyrazole-1-yl]ethyl}dimethylamine in 25 cm3toluene in an argon atmosphere add 503 mg of phenylboronic acid, 891 mg of potassium phosphate and 217 mg of bis(triphenylphosphine)pallidiflora. After heating for 15 hours at boiling temperature under reflux of the solvent to the reaction mixture 168 mg of phenylboronic acid, 297 mg of potassium phosphate and 148 mg of bis(triphenylphosphine)pallidiflora and the reaction continued at the same temperature for 15 hours. The mixture was then cooled to a temperature of about 20°C. to it was added ethyl acetate and water and filtered through Supercel. The filtrate is decanted, then the organic phase is washed successively with 0.5 N. the sodium hydroxide solution, water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The resulting brown oil (1.2 g) purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (80:20 by volume)]. After to the center of the fractions under reduced pressure to obtain 300 mg of orange oil, which enter into interaction for 15 hours with 25 cm3toluene, 503 mg of phenylboronic acid, 891 mg of potassium phosphate and 217 mg of bis(triphenylphosphine)allodiploid according to the above method. Get a brown oil (800 mg), which was purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (80:20 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 120 mg of {2-[3-benzyloxy-4-biphenyl-3-alprazol-1-yl]ethyl}dimethylamine in the form of a yellow oil.

IR-spectrum (CCl4): 3065; 3033; 2823; 2774; 1609; 1579; 1505; 1450; 1240 and 699 cm-1.

Example 34

1-(2-dimethylaminoethyl)-4-(4'-forbiden-3-yl)-1H-pyrazole-3-adigitalife

To a solution of 200 mg of {2-[3-benzyloxy-4-(4'-forbiden-4-yl)pyrazole-1-yl]ethyl}dimethylamine in 20 cm3ethanol add 0,06 cm312 n hydrochloric acid. The mixture is introduced into the autoclave, add it to 28 mg of 10%palladium-on-charcoal, then placed in an atmosphere of hydrogen (5 bar). After stirring for 4 hours at a temperature of 40°C. the reaction medium is filtered through Supercel and the filtrate is evaporated. The remainder proscout in diisopropyl ether. The obtained solid is dissolved in 20 cm3ethanol is introduced into the reaction in an autoclave using 10 mg of 10%palladium-on-the angle and pressure and hydrogen 7 bar. After stirring for 5 hours at a temperature of 35°C. the reaction mixture was filtered through Supercel and the filtrate is evaporated. The remainder proscout in diisopropyl ether, filtered and dried under vacuum (2.7 kPa)to give 77 mg of 1-(2-dimethylaminoethyl)-4-(4'-forbiden-4-yl)-1H-pyrazole-3-alligatoroidea in a solid beige color.

IR-spectrum (KBr): 2964; 2676; 2468; 1611; 1585; 1528; 1514; 1493; 1460; 1234; 1161; 826; 810 and 511 cm-1.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 2,79 (ush., 6H); 3,48 (array, 2H); 4,36 (t ush., J=6.5 Hz, 2H); 7,30 (t ush., J=9 Hz, 2H); 7,65 (l ush., J=8 Hz, 2H); from 7,70 to 7.80 (m, 4H); of 8.09 (s, 1H); 9,92 (array, 1H); 10,52 (ush., 1H).

{2-[3-benzyloxy-4-(4'-forbiden-4-yl)pyrazole-1-yl]ethyl}dimethylamine can be obtained as follows.

To a stirred solution of 500 mg of {2-[3-benzyloxy-4-(4-bromophenyl)pyrazole-1-yl]ethyl}dimethylamine in 25 cm3toluene in an argon atmosphere added 770 mg 4-ftorhinolonovy acid, 1.19 g of potassium phosphate and 290 mg of bis(triphenylphosphine)pallidiflora. After heating for 15 hours at boiling temperature under reflux of the solvent reaction medium is cooled to a temperature of about 20°C. to it was added ethyl acetate and water and filtered through Supercel. The filtrate is decanted, then the organic phase is washed successively with 0.5 N. the sodium hydroxide solution, water and aqueous saturated solution of CHL is reed sodium; it is dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The resulting brown oil (800 mg) purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (80:20 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 220 mg of {2-[3-benzyloxy-4-(4'-forbiden-4-yl)pyrazole-1-yl]ethyl}dimethylamine in the form of a yellow oil.

Mass spectrum (IE): m/z = 415 (M+.); m/z = 344(M-C4H9N)+]; m/z = 91 (C7H7+); m/z = 58 (C3H8N+).

{2-[3-benzyloxy-4-(4-bromophenyl)pyrazole-1-yl]ethyl}dimethylamine can be obtained as follows.

To a suspension of 1.36 g of sodium hydride (75%dispersion in mineral oil) in 50 cm3of dimethylformamide in an argon atmosphere and with stirring a solution of 5.2 g of 3-benzyloxy-4-(4-bromophenyl)-1H-pyrazole in 50 cm3of dimethylformamide. After heating for 30 minutes at a temperature of 50°C. the mixture is stirred for 1 hour at a temperature of about 20°C, then cooled in a bath with ice and add a solution of 5.5 g (2-bromacil)dimethylaminohydrolase 50 cm3of dimethylformamide. The reaction medium is stirred for 15 hours at a temperature of about 20°C, then cooled to a temperature of about 20°C and bring in 400 cm3water. The aqueous phase former is reginout twice with ethyl acetate. The combined organic phases are washed successively twice with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give a brown oil, which was purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: ethyl acetate; ethyl acetate/methanol (90:10 by volume)]. After concentrating the fractions under reduced pressure to obtain 2.3 g of {2-[3-benzyloxy-4-(4-bromophenyl)pyrazole-1-yl]ethyl}dimethylamine in the form of a yellow oil.

Mass spectrum (S): m/z = 399 (M+.); m/z = 328(M-C4H9N)+]; m/z = 91 (C7H7+.); m/z = 58 (C3H8N+).

3-benzyloxy-4-(4-bromophenyl)-1H-pyrazole can be obtained as follows.

To the suspension to 6.58 g of 1-[3-benzyloxy-4-(4-bromophenyl)pyrazole-1-yl]ethanone 70 cm3methyl ethyl ketone was added with stirring 3.88 g of potassium carbonate and 3.1 cm3benzylbromide. The mixture is heated at the boiling point under reflux of the solvent for 2.5 hours, cooled to a temperature of about 20°C and filtered. The filtrate is evaporated under reduced pressure (2.7 kPa) and the residue is treated with 50 cm3of tetrahydrofuran and 50 cm3methanol, then add 1.5 cm310 n sodium hydroxide solution. After stirring for 30 mi the ut at a temperature of about 20°C. the reaction medium is evaporated under reduced pressure (2.7 kPa). The crude reaction product is treated with dichloromethane. The organic phase is washed successively twice with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The obtained solid substance proscout in diisopropyl ether, filtered off and dried under vacuum (2.7 kPa)to give 2.9 g of 3-benzyloxy-4-(4-bromophenyl)-1H-pyrazole in the form of a solid beige color. The filtrate is evaporated under reduced pressure (2.7 kPa) and the residue treated with dichloromethane. The organic solution is washed with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The obtained solid substance proscout in diisopropyl ether, filtered off and dried under vacuum (2.7 kPa)to give an additional 2.3 g of 3-benzyloxy-4-(4-bromophenyl)-1H-pyrazole in the form of a solid beige color.

1H-NMR-spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): to 5.35 (s, 2H); 7,35 (t ush., J=7.5 Hz, 1H); 7,42 (t ush., J=7.5 Hz, 2H); 7,50 (d ush., J=7.5 Hz, 2H); 7,51 (l ush., J=8.5 Hz, 2H); 7,65 (l ush., J=8.5 Hz, 2H); of 8.09 (s, 1H).

1-[4-(4-bromophenyl)-3-hydroxypyrazol-1-yl]Etalon can be obtained as follows.

A solution of 6 g of 4-(4-bromophenyl)-1H-pyrazole-3-ol in 50 cm3pyridine in an argon atmosphere and with stirring, heated to a temperature which tours 90°C, then thereto is added dropwise to 2.25 cm3acetic anhydride. After heating for 1 hour at a temperature of 90°C. the reaction medium is cooled to a temperature of about 20°C and make it 150 cm3a mixture of water with ice. The precipitation is filtered off, washed three times with water and dried under vacuum (2.7 kPa)to give 6.6 g of 1-[4-(4-bromophenyl)-3-hydroxypyrazol-1-yl]ethanone in a solid white color.

IR-spectrum (KBr): 3132; 2968; 2696; 2653; 1714; 1621; 1533; 1417; 1392; 1328; 1279; 1231; 1008; 949; 822; 645 and 508 cm-1.

4-(4-bromophenyl)-1H-pyrazole-3-ol may be obtained in the following way.

A solution of 11.5 g of complex ethyl ester 2-(4-bromophenyl)-3-dimethylaminoethanol acid and 1.9 cm3hydrazinoacetate 100 cm3ethanol is heated for 3 hours at boiling temperature under reflux of the solvent. The reaction mixture is evaporated to dryness under reduced pressure (2.7 kPa) and the residue proscout in diisopropyl ether. The formed solid is filtered off and dried under vacuum (2.7 kPa)to give 6 g of 4-(4-bromophenyl)-1H-pyrazole-3-ol in the form of a solid white color.

IR-spectrum (KBr): 3299; 3123; 2958; 2674; 1606; 1579; 1517; 1488; 1399; 1163; 1080; 1008; 824 and 509 cm-1.

Complex ethyl ester 2-(4-bromophenyl)-3-dimethylaminoethanol acid can be obtained as follows.

To a solution of 10 g of complex ethyl ester -(4-bromophenyl)acrylic acid in 100 cm 3of tetrahydrofuran, add 13.5 cm3With tert-butoxy-N,N,N',N'-tetramethylmethylenediamine and heated for 3 hours at boiling temperature under reflux of the solvent. After stirring for 15 hours at a temperature of about 20°C. the reaction mixture is evaporated to dryness under reduced pressure (2.7 kPa). The residue is treated with ethyl acetate and the organic solution is washed 3 times with water, then dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give 11.3 g of complex ethyl ester 2-(4-bromophenyl)-3-dimethylaminoethanol acid in the form of a yellow oil.

Mass spectrum (IC): m/z = 298 (MH+).

Example 35

1-(2-piperidine-1-retil)-4-pyridin-2-yl-1H-pyrazole-3-adigitalife

To a solution of 1.6 g of 2-[3-(cyclohex-2-enyloxy)-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]pyridine in 20 cm3dioxane add 10 cm34 n solution of hydrogen chloride in dioxane. After stirring for 15 hours at a temperature of about 20°C. the suspension is filtered and the solid is washed once with dioxane, then three times with diisopropyl ether and dried under vacuum (2.7 kPa)to give 55 mg of 1-(2-piperidine-1-retil)-4-pyridin-2-yl-1H-pyrazole-3-alligatoroidea in the form of white powder.

IR-spectrum (KBr): 3037; 2943; 2644; 2541; 1633; 1606; 1577; 1454; 1179; 782 and 685 cm-1.

1H-NMR spectrum (300 MHz,(CD 3)2SO-d6, δ in ppm): 1,40 (m, 1H); from to 1.60 to 1.90 (m, 5H); 2.95 and (m, 2H); from to 3,35 3,55 (m, 4H); of 4.57 (t, J=6.5 Hz, 2H); 7,58 (m, 1H); 8,15 (l ush., J=7 Hz, 1H); 8,31 (t ush., J=7 Hz, 1H); 8,61 (l ush., J=5 Hz, 1H); 8,69 (ush., 1H); at 10.64 (array, 1H).

2-[3-(cyclohex-2-enyloxy)-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]pyridine can be obtained as follows.

To a suspension of 500 mg of sodium hydride (75%dispersion in mineral oil) in 15 cm3of dimethylformamide in an argon atmosphere and with stirring a suspension of 1.5 g of 2-[3-(cyclohex-2-enyloxy)-1H-pyrazole-4-yl]pyridine in 20 cm3of dimethylformamide. After heating for 30 minutes at a temperature of 50°C. the mixture is stirred for 30 minutes at a temperature of about 20°C, then to it was added a solution of 1.6 g of 1-(2-chloroethyl)piperidinedione. The reaction medium is stirred for 15 hours at a temperature of about 20°C, then make it into the water. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed successively with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give yellow oil, which was purified flash chromatography dioxide aluminum STV1 under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (90:10 by volume)]. After concentrating the fractions under reduced pressure to obtain 1.6 g -[3-(cyclohex-2-enyloxy)-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]pyridine in the form of oil pale yellow color.

Mass spectrum (IE): m/z = 352 (M+.); m/z = 271 [M-C6H9)+]; m/z = 111 (C7H13N+.); m/z = 98 (C6H12N+).

2-[3-(cyclohex-2-enyloxy)-1H-pyrazole-4-yl]pyridine can be obtained as follows.

To a suspension of 7.1 g of 1-(3-hydroxy-4-pyridine-2-alprazol-1-yl)ethanone 70 cm3methyl ethyl ketone was added with stirring to 5.4 g of potassium carbonate and 4.6 cm33-bromocyclohexene. The mixture is heated at the boiling point under reflux of the solvent for 4 hours, cooled to a temperature of about 20°C and it is evaporated under reduced pressure (2.7 kPa). The residue is treated with 50 cm3of tetrahydrofuran and 50 cm3methanol, then added 7 cm35 n sodium hydroxide solution and water until complete dissolution medium. After stirring for 15 hours at a temperature of about 20°C. the reaction medium is evaporated under reduced pressure (2.7 kPa). The crude reaction product is treated with ethyl acetate and water. The insoluble solid is filtered off and dried under reduced pressure (2.7 kPa)to give 5.3 g of 2-[3-(cyclohex-2-enyloxy)-1H-pyrazole-4-yl]pyridine in the form of white powder.

IR-spectrum (KBr): 3180; 2928; 2723; 1602; 1533; 1497; 1463; 1288; 1065; 786 and 700 cm-1.

1-(3-hydroxy-4-pyridine-2-alprazol-1-yl)Etalon can be obtained as follows.

Premesis is Amy and under argon atmosphere a solution of 7.3 g of 4-pyridine-2-yl-1H-pyrazole-3-algebrabased 70 cm 3pyridine is heated to a temperature of 100°C., and then thereto is added dropwise 3.75 cm3acetic anhydride. After heating for 1.5 hours at a temperature of 100°C. the reaction medium is cooled to a temperature of about 20°C and make it 150 cm3a mixture of water with ice. The precipitation is filtered off, washed three times with water and dried under reduced pressure (2.7 kPa), receiving of 7.1 g of 1-(3-hydroxy-4-pyridine-2-alprazol-1-yl)ethanone in the form of a solid pale yellow color.

IR-spectrum (KBr): 3157; 2396; 1719; 1608; 1391; 1274; 1223; 1000; 929; 790 and 618 cm-1.

4-pyridin-2-yl-1H-pyrazole-3-algebroid can be obtained as follows.

A solution of 18 g of complex ethyl ester of 3-dimethylamino-2-pyridin-2-elkrylova acid and 3.95 cm3hydrazinoacetate 120 cm3ethanol under stirring and heated for 3 hours at boiling temperature under reflux of the solvent. The reaction mixture was concentrated under reduced pressure (2.7 kPa), add 3 n solution of hydrogen chloride in ethanol, then cooled in a bath with ice. The formed solid is filtered off and dried under vacuum (2.7 kPa)to give 11.3 g of 4-pyridine-2-yl-1H-pyrazole-3-algebrabased in a solid yellow color.

IR-spectrum (KBr): 3166; 1644; 1620; 1587; 1551; 1430; 1209; 1159; 907; 774 and 518 cm-1.

Complex ethyl ester 3-dimethylene the o-2-pyridine-2-elkrylova acid can be obtained as follows.

To a solution of 13 g of complex ethyl ester of 2-pyridine-2-elkrylova acid in 100 cm3tetrahydrofuran (THF) add 20 cm3With tert-butoxy-N,N,N',N'-tetramethylmethylenediamine and heated for 15 hours at boiling temperature under reflux of the solvent, then the reaction mixture is cooled to a temperature of about 20°C and evaporated to dryness under reduced pressure (2.7 kPa). The resulting brown oil purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (90:10 by volume)]. After concentrating the fractions under reduced pressure to obtain 18 g of a complex of ethyl ester of 3-dimethylamino-2-pyridin-2-elkrylova acid in the form of an orange oil.

IR-spectrum (CCL4): 2980; 2929; 1686; 1619; 1602; 1297; 1271; 1219; 1096 and 1085 cm-1.

Example 36

1-(2-piperidine-1-retil)-4-pyridin-4-yl-1H-pyrazole-3-aminohydrocinnamic

To a stirred solution of 720 mg of 4-[3-benzyloxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]pyridine 7 cm3ethanol add 7 cm312 N. hydrochloric acid. After standing for 7 hours at boiling temperature under reflux of the solvent, and then for 15 hours at a temperature of about 20°C. the reaction medium is evaporated under reduced pressure (2.7 kPa). The residue is treated with ethanol, then with whom ect is evaporated to dryness under vacuum (2.7 kPa). Operation is repeated two times, then to solid substance added ethanol and the mixture is heated to boiling point under reflux of the solvent. After cooling the solution in a bath with ice, the resulting crystals are filtered and dried under vacuum (2.7 kPa)to give 300 mg of 1-(2-piperidine-1-retil)-4-pyridin-4-yl-1H-pyrazole-3-aminohydrocinnamic in a solid white color.

IR-spectrum (KBr): 3495; 3414; 3197; 2934; 2652; 2545; 1637; 1599; 1540; 1513; 1206; 813 and 523 cm-1.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.30 to 1.60 (array very ush., 1H); from to 1.60 to 1.90 (m, 5H); from 2.85 to 3,05 (array, 2H); from 3.30 is up to 3.45 (m, 2H); 3.49 points (t, J=6.5 Hz, 2H); of 4.54 (t, J=6.5 Hz, 2H); 8,12 (l ush., J=7 Hz, 2H); 8,67 (s, 1H); 8,69 (l ush., J=7 Hz, 2H); 11,75 (array, 1H).

4-[3-benzyloxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]pyridine can be obtained as follows.

To a suspension of 230 mg of sodium hydride (75%dispersion in mineral oil) in 10 cm3of dimethylformamide in an argon atmosphere and with stirring a solution of 720 mg of 4-(3-benzyloxy-1H-pyrazole-4-yl)pyridine in 20 cm3of dimethylformamide. After heating for 30 minutes at a temperature of 50°C. the mixture is stirred for 30 minutes at a temperature of about 20°C, then add to it a solution of 740 mg of 1-(2-chloroethyl)piperidinedione. The reaction medium is stirred for 15 hours at a temperature of okolo20°C, then make it into the water. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed successively with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give an orange oil, which was purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (90:10 then 80:20, by volume)]. After concentrating the fractions under reduced pressure to obtain 720 mg of 4-[3-benzyloxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]pyridine in the form of oil pale yellow color.

IR-spectrum (CH2Cl2): 2940; 1604; 1573; 1513; 1453; 1363; 1172; 992; 815; 676 and 534 cm-1.

4-(3-benzyloxy-1H-pyrazole-4-yl)pyridine can be obtained as follows.

To a suspension of 2.4 g of 1-(3-hydroxy-4-pyridin-4-alprazol-1-yl)ethanone 25 cm3methyl ethyl ketone with stirring, 1.8 g of potassium carbonate and 1.55 cm3benzylbromide. The mixture is heated at the boiling point under reflux of the solvent for 3 hours, cooled to a temperature of about 20°C and filtered. The filtrate is evaporated under reduced pressure (2.7 kPa). The resulting brown oil purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: ethyl acetate/cyclohexane (80:20 by volume)]. Poslegarantiynogoi fractions under reduced pressure to obtain 720 mg of 4-(3-benzyloxy-1H-pyrazole-4-yl)pyridine in the form of a solid white color.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 5,27 (s, 2H); of 7.36 (TT, J=7.5 and 1.5 Hz, 1H); 7,44 (TT, J=7.5 and 1.5 Hz, 2H); 7,52 (d ush., J=7.5 Hz, 2H); 7,66 (DD, J=5 and 2 Hz, 2H); with 8.33 (s, 1H); of 8.47 (DD, J=5 and 2 Hz, 2H); from 12,25 to 12.50 (array, 1H).

1-(3-hydroxy-4-pyridin-4-alprazol-1-yl)Etalon can be obtained as follows.

A suspension of 2.5 g of 4-pyridin-4-yl-1H-pyrazole-3-algebrabased 25 cm3pyridine under stirring and argon atmosphere heated to a temperature of 100°C., and then thereto is added dropwise 1.25 cm3acetic anhydride. After heating for 2 hours at a temperature of 100°C. the reaction medium is cooled in a bath with ice. The formed solid is filtered off, washed with water, then with heptane and dried under vacuum (2.7 kPa)to give 1-(3-hydroxy-4-pyridin-4-alprazol-1-yl)Etalon, which is directly used in the next stage.

4-pyridin-4-yl-1H-pyrazole-3-algebroid can be obtained as follows.

The solution 12,46 g complex ethyl ester of 3-dimethylamino-2-pyridin-4-elkrylova acid and 2.75 cm3hydrazinoacetate 80 cm3ethanol under stirring and heated for 3 hours at boiling temperature under reflux of the solvent. The reaction mixture is cooled in a bath with ice, the resulting solid is filtered off and treated with water. The suspension is brought to C is achene pH 6 using 1 N. hydrochloric acid, then filtered. The obtained solid is washed with water and dried under vacuum (2.7 kPa), receiving of 5.1 g of 4-pyridin-4-yl-1H-pyrazole-3-algebrabased in a solid yellow color.

IR-spectrum (KBr): 3355; 2464; 2059; 1965; 1637; 1575; 1527; 1207; 1193; 1075; 1022; 914; 838 and 519 cm-1.

Complex ethyl ester of 3-dimethylamino-2-pyridin-4-elkrylova acid can be obtained as follows.

To a solution of 15 cm3complex ethyl ester of 2-pyridine-4-elkrylova acid in 100 cm3tetrahydrofuran (THF) add 24 cm3With tert-butoxy-N,N,N',N'-tetramethylmethylenediamine and heated for 15 hours at boiling temperature under reflux of the solvent, then the reaction mixture is evaporated to dryness under reduced pressure (2.7 kPa). The residue is treated with ethyl acetate and the organic solution is washed 2 times with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The resulting brown oil purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (90:10 by volume)]. After concentrating the fractions under reduced pressure get 12,46 g complex ethyl ester of 3-dimethylamino-2-pyridin-4-elkrylova acid in the form of an orange oil.

p> IR-spectrum (CCl4): 2981; 1690; 1596; 1280; 1218; 1095 and 1051 cm-1.

Example 37

4-(4-forfinal)-(2-piperidine-1-retil)-1H-pyrazole-3-ol

0.5 g of 3-benzyloxy-4-(4-forfinal)-1-(2-piperidine-1-retil)-1H-pyrazolidinone injected into the autoclave with 12.8 mg of palladium-on-coal (10%) and 25 cm3of ethanol. The apparatus is maintained at a hydrogen pressure of 500 kPa at 25°C for 5 hours. After cooling to a temperature of about 20°C. the reaction medium is filtered through Suercel; the filtrate is washed with 3 times 100 cm3ethanol, concentrated to dryness under reduced pressure (2 kPa). The resulting residue is purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (grain size distribution 20-45 μm; diameter 1 cm, height 25 cm), elwira a mixture of dichloromethane and 2 n solution of ammonia in methanol (93:7 by volume). Concentrate under reduced pressure (2 kPa); receive 160 mg 4-(4-forfinal)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol in the form of a solid white color.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.30 to 1.55V (m, 6H); 2.40 a (t ush., J=5.5 Hz, 4H); to 2.65 (t, J=7 Hz, 2H); 4,00 (t, J=7 Hz, 2H); to 7.15 (t, J=9 Hz, 2H); the 7.65 (DD, J=9 and 5.5 Hz, 2H); to $ 7.91 (s, 1H); 10,32 (ush., 1H).

Mass spectrum (IE): m/z = 289 (M+.); m/z = 98 (molecular ion peak).

3-benzyloxy-4-(4-forfinal)-1-(2-piperidine-1-retil)-1H-pyrazole can be obtained as follows.

A suspension of 0.80 g of 3-benzo is loxi-4-bromo-1-(2-piperidine-1-retil)-1H-pyrazole, 1.12 g of 4-ftorhinolonovy acid, 0.20 g of dichlorobis(triphenylphosphine)palladium and 1.88 g of potassium phosphate in 30 cm31,2-dimethoxyethane stirred in argon atmosphere at the boiling temperature of the reaction medium within 14 hours. After cooling, to the mixture of 30 cm3a saturated solution of sodium bicarbonate and extracted with 30 cm3ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). The residue is purified by chromatography on silica gel, elwira a mixture of ethyl acetate and methanol (30:1 by volume). After concentrating the fractions under reduced pressure gain of 0.57 g of a yellowish oil, which is used as what is in the next stage. of 0.57 g of 3-benzyloxy-4-(4-forfinal)-1-(2-piperidine-1-retil)-1H-pyrazole treated with 5 cm3diethyl ether and 0.5 cm34 n solution of hydrogen chloride in diethyl ether. The precipitation is filtered off and dried. Obtain 0.5 g of 3-benzyloxy-4-(4-forfinal)-1-(2-piperidine-1-retil)-1H-pyrazolidinone.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.25 to 1.50 (m, 1H); from of 1.60 to 1.85 (m, 5H); only 2.91 (m, 2H); 3,44 (D. very ush., J=12,5 Hz, 2H); to 3.52 (m, 2H); 4,47 (t ush., J=6.5 Hz, 2H); of 5.34 (s, 2H); 7,72 (t, J=9 Hz, 2H); from 7,30 to 7.45 (m, 3H); 7,51 (l ush., J=7.5 Hz, 2H); to 7.68 (DD, J=9 and 6 Hz, 2H); is 8.16 (s, 1H); from 9,70 to 10.00 (array, 1H).

3-benzyl) - Rev. XI-4-bromo-1-(2-piperidine-1-retil)-1H-pyrazole can be obtained as follows.

To a solution of 8 g of 3-benzyloxy-4-bromo-1H-pyrazolidinone 100 cm3anhydrous DMF (dimethylformamide) add gradually and at a temperature of about 5°C., 5.6 g of sodium hydride (75 wt.% dispersion in vaseline oil) and 25 cm3anhydrous DMF (dimethylformamide). After stirring for 1 hour at room temperature add small portions 6,93 g of 1-(2-chloroethyl)piperidinedione and 30 cm3anhydrous DMF (dimethylformamide). After stirring for 21 hours at room temperature, the excess sodium hydride is decomposed by the slow addition of water, then the reaction medium was poured into 1 DM3water and extracted with 2 times 200 cm3ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue is treated with 20 cm3acetone and poured into a solution of 3.6 g of oxalic acid in 30 cm3of acetone. The resulting solid proscout, then allocate by filtration and dried at room temperature, receiving 11.3 g of 3-benzyloxy-4-bromo-1-(2-piperidine-1-retil)-1H-pyrazoloquinoline. To 5 g of the oxalate add 50 cm3a saturated solution of sodium bicarbonate and the mixture extracted with 2 times 100 cm3ethyl acetate. The combined organic phases are dried on the magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). So get of 3.84 g of 3-benzyloxy-4-bromo-1-(2-piperidine-1-retil)-1H-pyrazole in the form of a clear oil.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.25 to 1.55V (m, 6H); 2,35 (t ush., J=5 Hz, 4H); 2,61 (t, J=6.5 Hz, 2H); Android 4.04 (t, J=6.5 Hz, 2H); 5,20 (s, 2H); from 7,30 to 7.50 (m, 5H); 7,81 (s, 1H).

3-benzyloxy-4-bromo-1H-pyrazolidinone can be obtained as follows.

To a suspension 8,76 g of 3-benzyloxy-1H-pyrazole and 11 g of potassium carbonate in 100 cm3dichloromethane, cooled and maintained at a temperature of about 5°C with stirring, added dropwise over 0.5 hour a solution of 2.6 cm3bromine in 50 cm3dichloromethane. After stirring for 0.5 hour at this temperature, to the mixture of 20 cm30.1 G. of sodium thiosulfate solution and stirred for 1 hour at a temperature of about 5°C, then add 100 cm3dichloromethane and decanted. The organic phase is extracted again with 50 cm3the water and organic phases are combined and dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue is treated with 10 cm36 n solution of hydrogen chloride in dioxane and the resulting solid proscout in diethyl ether and was isolated by otherthrow the project. Thus obtain 12.5 g of 3-benzyloxy-4-bromo-1H-pyrazolidinone in a solid white color, melting at a temperature of about 80°C (with decomposition).

Mass spectrum (IE): m/z = 252 (M+.); m/z = 91 (molecular ion peak).

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 5,22 (s, 2H); from 7,30 to 7.50 (m, 5H); 7,81 (s, 1H); from 11,80 to 12,70 (array very ush., 1H).

3-benzyloxy-1H-pyrazole can be obtained as follows.

To 10.6 g of 3-benzyloxy-1H-pyrazolidinone add 50 cm3a saturated solution of sodium bicarbonate and the mixture extracted with 2 x 150 cm3dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa), receiving 8,76 g of 3-benzyloxy-1H-pyrazole in the form of oils, which are used as what is in the next stage.

3-benzyloxy-1H-pyrazolidinone can be obtained as follows.

A suspension of 11 g of 1-(3-hydroxypyrazol-1-yl)ethanone, 12.5 g of potassium carbonate and 11.3 cm3(16,25 g) benzylbromide 250 cm32-butanone stirred at the boiling temperature of the mixture in 1.25 hours. Insoluble inorganic part is then removed by filtration and the filtrate is concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue is dissolved in a mixture of 150 cm3those who of rageragerage and 100 cm 3methanol, then add 4 cm310 M sodium hydroxide solution. After stirring for 0.65 hours at room temperature the mixture is concentrated to dryness under reduced pressure (3 kPa). The obtained pasty residue is treated with 250 cm3ethyl acetate and washed with 2 times 10 cm3aqueous saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure (3 kPa). To the residue add 100 cm31 n solution of hydrogen chloride in diethyl ether and the resulting solid proscout, then allocate by filtration. The solid is dissolved in 250 cm3isopropanol at a temperature of about 60°C., then the mixture is partially concentrated until the appearance of the first crystals, add 5 cm3isopropylacetate and cooled to a temperature of about 0°C. After otfiltrovana and drying obtain 10.6 g of 3-benzyloxy-1H-pyrazolidinone in the form of crystals light pink color, melting at 100°C.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 5,16 (s, 2H); of 5.75 (d, J=3 Hz, 1H); from 7,30 to 7.50 (m, 5H); EUR 7.57 (d, J=3 Hz, 1H).

1-(3-hydroxypyrazol-1-yl)Etalon can be obtained as follows.

To a solution of 8.4 g of 1H-pyrazole-3-ol (catalog number 60456-92-0) 38 cm3pyridine, prior is sustained fashion heated to a temperature of 95°C, slowly over 0.33 hour add a solution of 9.5 cm3acetic anhydride (18 cm3pyridine, then maintain this temperature for 1 hour. The mixture was then concentrated under reduced pressure (3 kPa). To the residual suspension was added 100 cm3diethyl ether and triturated to complete the crystallization. After filtering off and drying obtain 11 g of 1-(3-hydroxypyrazol-1-yl)ethanone in the form of whitish crystals, sublimating at a temperature of about 215°C.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 2,50 (s, 3H); of 6.02 (d, J=3 Hz, 1H); 8,15 (d, J=3 Hz, 1H); from 10,80 to 11.20 (array, 1H).

Example 38

4-(4-trifloromethyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-adigitalife

600 mg of 3-(benzyloxy-4-(4-trifloromethyl)-1-(2-piperidine-1-retil)-1H-pyrazole 4.5 cm3ethanol and 4.5 cm312 N. hydrochloric acid is maintained at the boil under reflux at a temperature of about 100°C for 7 hours. After cooling to a temperature of about 20°C. the reaction mixture is concentrated to dryness under reduced pressure (2 kPa); the residue is precipitated from a mixture of diisopropyl ether and acetone. Receive 464 mg of 4-(4-trifloromethyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-alligatoroidea in the form of white powder.

IR-spectrum (KBr): 3428; 2951; 2642; 2538; 1615; 1591; 1533; 1456; 1275; 1219; 1159; 1012; 856 and 806 cm-1 .

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1,41 (m, 1H); from of 1.60 to 1.85 (m, 5H); 2,94 (array, 2H); 3.46 in (m, 4H); to 4.41 (m, 2H); 7,34 (l ush., J=8 Hz, 2H); 7,76 (d, J=8 Hz, 2H); of 8.09 (s, 1H); 10,04 (array ush., 1H); to 10.62 (ush., 1H).

3-(benzyloxy-4-(4-trifloromethyl)-1-(2-piperidine-1-retil)-1H-pyrazole can be obtained as follows.

Cool with stirring and in an inert atmosphere to a temperature of about -5°To 560 mg of 3-benzyloxy-4-(4-trifloromethyl)-1H-pyrazole in 15 cm3anhydrous dimethylformamide; reaction medium was added portion 140 mg of sodium hydride (75%dispersion in vaseline oil) and leave to return the temperature to about 20°C. Then add 431 mg of 1-(2-chloroethyl)piperidinedione and kept under stirring at this temperature for 15 hours. The reaction medium is treated with 300 cm3a mixture of ice water and 300 cm3ethyl acetate. The organic phase is decanted, washed with 200 cm3water and concentrated to dryness under reduced pressure (2 kPa). The residue is purified by using a column with silica FC50SI-HP, elwira a mixture of dichloromethane and methanol (95:5 by volume). The resulting product is again purified by using a column with silica FC50SI-HP, elwira a mixture of dichloromethane and methanol (98:2 by volume). Receive 600 mg of 3-benzyloxy-4-(4-reformational)-1-(2-Pipa is one-1-retil)-1H-pyrazole as a colourless oil.

Mass spectrum (IC): m/z = 446 ([M+H]+) (molecular ion peak).

3-benzyloxy-4-(4-trifloromethyl)-1H-pyrazole can be obtained as follows.

1.07 g of 1-(toluene-4-sulfonyl)-3-benzyloxy-4-(4-trifloromethyl)-1H-pyrazole, 5 cm31 n solution of n-tetrabutylammonium in tetrahydrofuran and 50 cm3of tetrahydrofuran with stirring, heated at boiling temperature under reflux of the solvent for 15 hours. The reaction medium is cooled to a temperature of about 20°C, treated with 300 cm3ethyl acetate and 100 cm3water. The organic phase is decanted, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa). The resulting residue is purified by using a column with silica FC50SI-HP, elwira dichloromethane. Obtain 560 mg of 3-benzyloxy-4-(4-trifloromethyl)-1H-pyrazole in the form of powder.

Mass spectrum (IE): m/z = 334 (M+.); m/z = 91 (molecular ion peak).

3-benzyloxy-1-(toluene-4-sulfonyl)-4-(4-trifloromethyl)-1H-pyrazole can be obtained as follows.

To a solution of 1.5 g of 3-benzyloxy-4-iodine-1-(toluene-4-sulfonyl)-1H-pyrazole in a mixture of 40 cm3toluene and ethanol (4:1 by volume) in a three-neck flask add 2,04 g of 4-triftormetilfullerenov acid, 4,96 cm3aqueous 2 n solution of potassium carbonate i496 mg tetrakis(triphenylphosphine)palladium. Three-neck flask containing the reaction medium, is placed on the bath, preheated to a temperature of about 120°C, incubated with stirring for 90 minutes at this temperature. The mixture is then cooled to a temperature of about 20°C, filtered through Supercel. The filtrate is treated with 300 cm3ethyl acetate and 100 cm3water. The organic phase is decanted and concentrated to dryness under reduced pressure (2 kPa). The obtained residue is purified on a column of silica FC50SI-HP, elwira with a mixture of cyclohexane and ethyl acetate (90:10 by volume). Obtain 1.07 g of 3-benzyloxy-1-(toluene-4-sulfonyl)-4-(4-trifloromethyl)-1H-pyrazole in the form of a yellow powder.

Mass spectrum (IC): m/z = 489 ([M+H]+); m/z = 335 (molecular ion peak).

3-benzyloxy-4-iodine-1-(toluene-4-sulfonyl)-1H-pyrazole can be obtained as follows.

Under stirring and in an inert atmosphere cooled to a temperature of about -5°C. 5 g of 3-benzyloxy-4-(4-itfinal)-1H-pyrazole 110 cm3of dimethylformamide. Portions add 587 mg of sodium hydride (75%dispersion in vaseline oil) and can stand up to return to a temperature of about 20°C. Then add 4.4 g of p-toluensulfonate and kept under stirring at this temperature for 15 hours. The reaction medium is treated with 300 cm3a mixture of ice water and 500 cm3ethyl is Zetta. The organic phase is decanted, washed with 300 cm3water and 300 cm3aqueous saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa). The residue is crystallized from diisopropyl ether. Get of 7.24 g of 3-benzyloxy-4-iodine-1-(toluene-4-sulfonyl)-1H-pyrazole in the form of powder.

Mass spectrum (IE): m/z = 454 (M+.); m/z = 299; m/z = 91 (molecular ion peak).

3-benzyloxy-4-iodine-1H-pyrazole can be obtained as follows.

A suspension of 0.32 g of 3-benzyloxy-1H-pyrazole, 0.3 g of sodium acetate and 0.65 g of iodine in 50 cm3chloroform is stirred at room temperature for 25 hours. To the mixture were then added 50 cm3a 0.5 n solution of sodium thiosulfate, stirred until the discoloration and decanted. The aqueous phase is again extracted with 25 cm3the chloroform. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure (3 kPa). The resulting residue is purified by chromatography on silica gel, elwira with a mixture of cyclohexane and ethyl acetate (80:20 by volume). After concentrating the fractions under reduced pressure to obtain a colorless oil which rapidly crystallized and give 0.4 g of 3-benzyloxy-4-iodine-1H-pyrazole in the form of a solid white color with Rfor = 0.6 [a mixture cyclohex is on and ethyl acetate (50:50 by volume); a plate of silica gel 60 F254, catalog number 105719, Merck].

Mass spectrum (IE): m/z= 300 (M+.) (molecular ion peak).

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 5,22 (s, 2H); from 7,30 to 7.50 (m, 5H); 7,74 (s, 1H); from 12,20 to 12,60 (array ush., 1H).

Example 39

4-phenyl-1-(2-piperidine-1-ylpropyl)-1H-pyrazole-3-adigitalife

To a mixture of 150 mg of 1-{2-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-1-methylethyl}piperidine in 5 cm3anhydrous methanol at a temperature of about 20°C add 2 cm34 n solution of hydrogen chloride in dioxane. The reaction medium is stirred at this temperature for 20 hours, concentrated to dryness under reduced pressure (2 kPa), treated with 20 cm3dichloromethane. The solution is concentrated to dryness under reduced pressure (2 kPa). The residue is precipitated with 20 cm3dichloromethane. The solution is concentrated to dryness under reduced pressure (2 kPa). The residue precipitated with 20 cm3diisopropyl ether. Obtain 110 mg of 4-phenyl-1-(2-piperidine-1-ylpropyl)-1H-pyrazole-3-alligatoroidea in a solid yellow color.

IR-spectrum (KBr): 3431; 2949; 2651; 2521; 1606; 1580; 1527; 1451; 1175; 1121; 1012; 765; 698 and 672 cm-1.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1,24 (d, J=6.5 Hz, 3H); of 1.44 (m, 1H); from 1.65 to 1,95 (m, 5H); 2.95 and (m, 1H); 3,10 (m, 1H); from to 3,35 3,55 (m, 2H); 3,71 (m, 1H); is 4.21 (DD, J=14.5 and 7.5 Hz, 1H); 4,43 (l is, J=14.5 and 5.5 Hz, 1H); 7,15 (t ush., J=7.5 Hz, 1H); 7,34 (t ush., J=7.5 Hz, 2H); 7,66 (l ush., J=7.5 Hz, 2H); 8,01 (s, 1H); 9,51 (array, 1H); 10,51 (s, 1H).

1-{2-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-1-methylethyl}piperidine can be obtained as follows.

A mixture of 0.5 g of complex 2-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-1-mutilative ether methanesulfonate, 0.4 cm3piperidine, 1.0 g of potassium carbonate in 20 cm3of dimethylformamide is heated with stirring at a temperature of about 80°C for 5 hours, then incubated for 15 hours at a temperature of about 20°C. the Reaction medium is treated with 100 cm3water and 100 cm3ethyl acetate. The organic phase is decanted, washed with 2 times 100 cm3water and 100 cm3aqueous saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa). The residue is purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (grain size distribution 20-45 μm; diameter 2 cm; height 40 cm), elwira with a mixture of cyclohexane and ethyl acetate (80:20 by volume). After concentrating the fractions under reduced pressure (2 kPa) receive 150 mg of 1-{2-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-1-methylethyl}piperidine in the form of a yellow oil.

Mass spectrum (IE): m/z = 365 (M+.); m/z = 112 (molecular ion peak).

Complex 2-[3-(cyclohex-2nd is yloxy)-4-phenylpyrazol-1-yl]-1-metaliteracy broadcast methansulfonate can be obtained as follows.

To a stirred solution of 550 mg of 1-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]propane-2-ol in 30 cm3dichloromethane at a temperature of about 20°C add 1 cm3methanesulfonanilide and at 2.59 cm3of triethylamine. The reaction medium is stirred for 7 hours at a temperature of about 20°C, treated with 50 cm3distilled water and 50 cm3ethyl acetate. The organic phase is decanted, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa). The residue is purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (grain size distribution 20-45 μm; diameter 4 cm; height 60 cm), elwira with a mixture of cyclohexane and ethyl acetate (80:20 by volume). After concentrating the fractions under reduced pressure (2 kPa) receive 300 mg of complex 2-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-1-mutilative ether methanesulfonate in the form of a colorless oil.

Mass spectrum (IE): m/z = 376 (M+.); m/z = 296 (molecular ion peak).

1-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]propane-2-ol may be obtained in the following way.

In an inert atmosphere and under stirring, 2.4 g of 3-(cyclohex-2-enyloxy)-4-phenyl-1H-pyrazole are dissolved in 25 cm3anhydrous DMF (dimethylformamide). At a temperature of about 20°With added 2.24 g of potassium tert-butylate, then 0.7 cm3methyloxiran is. The reaction medium is heated at a temperature of about 60°C for 1 hour. Then add another 0.7 cm3methyloxirane and heated for 1 hour at a temperature of about 60°C. the Mixture is cooled to a temperature of about 20°C, treated with 200 cm3water and 200 cm3ethyl acetate. The organic phase is decanted, washed with 3 times 200 cm3water and 200 cm3aqueous saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa). The residue is purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (grain size distribution 20-45 μm; diameter 4 cm; height, 50 cm), elwira with a mixture of cyclohexane and ethyl acetate (80:20 by volume). After concentrating the fractions under reduced pressure (2 kPa) to obtain 450 mg of 1-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]propane-2-ol as a colourless oil.

Mass spectrum (IE): m/z = 298 (M+.); m/z = 218; m/z = 173 (molecular ion peak).

Example 40

3-(4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]octadecenoate

A solution of 0.4 g of 3-(pyrazole-1-ylmethyl)-1-azabicyclo[2,2,2]octane in 5 cm3of dimethylformamide is added to a mixture of 0.4 g of sodium hydride (75%dispersion in vaseline oil) and 10 cm3of dimethylformamide. The reaction medium is heated at a temperature of about 50°C for about 1 hour, C is the solution is cooled to a temperature of about 20°C. Slowly add to 1.75 g of 3-chloromethylpyridine, the reaction medium is heated at 50°C for 15 hours, then cooled to a temperature of about 20°C. the Mixture is treated with 100 cm3water and 100 cm3ethyl acetate. The organic phase is decanted, washed with 2 times 100 cm3water and 100 cm3aqueous saturated solution of sodium chloride, then concentrated to dryness under reduced pressure (2 kPa). The residue is purified by chromatography under a nitrogen pressure of 50 kPa on a column of aluminum oxide STV1 (diameter 3 cm; height 40 cm), elwira with ethyl acetate, then with a mixture of ethyl acetate and methanol (98:2; 95:5; then 90:10, by volume) and collecting fractions of 60 cm3. Fractions 14-20 concentrated under reduced pressure. The resulting residue is purified a second time by chromatography under a nitrogen pressure of 50 kPa on a column of aluminum oxide STV1 (diameter 3 cm; height 40 cm), elwira with ethyl acetate, then with a mixture of ethyl acetate and methanol (98:2; 95:5; then 90:10, by volume) and collecting fractions of 60 cm3. Fractions 14-20 concentrated under reduced pressure. Receive 150 mg of 3-(4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]octane. The dihydrochloride obtained using 1.2 cm34,7 n solution of hydrogen chloride in isopropyl ether and 5 cm3of ethanol. Obtain 230 mg of 3-(4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]octadecenoamide.

1H-NMR-spectrum (30 MHz, (CD3)2SO-d6, δ in ppm): from 1.65 to 1,95 (m, 4H); from 2.00 up to 2.15 (m, 1H); 2,62 (m, 1H); 2,97 (DD ush., J=13 and 7 Hz, 1H); from of 3.10 to 3.40 (m, 5H); of 4.25 (DD, J=13 and 8 Hz, 1H); 4,32 (DD, J=13 and 8 Hz, 1H); 7,21 (t ush., J=7.5 Hz, 1H); 7,38 (t, J=7.5 Hz, 2H); to 7.59 (d ush., J=7.5 Hz, 2H); 7,94 (s, 1H); of 8.25 (s, 1H); 10,44 (array, 1H).

Mass spectrum (IE): m/z = 267 (M+.) (molecular ion peak); m/z = 183; m/z = 123.

4-phenyl-1H-pyrazole can be obtained as follows.

1,044 g of 4-phenyl-1-(toluene-4-sulfonyl)-1H-pyrazole, 7 cm31 n solution of n-tetrabutylammonium in tetrahydrofuran and 35 cm3of tetrahydrofuran is heated at a temperature of about 70°C for 5 hours. Add another 3.5 cm31 n solution of n-tetrabutylammonium in tetrahydrofuran and continue to heat for 15 hours at this temperature. The reaction medium is cooled to a temperature of about 20°C., concentrated to dryness under reduced pressure (2 kPa), then treated with 100 cm3ethyl acetate and 100 cm3water. The organic phase is decanted, washed with 100 cm3water and 100 cm3aqueous saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa). The resulting residue is treated with 20 cm3dichloromethane. The precipitate is filtered off and dried. Obtain 0.4 g of 4-phenyl-1H-pyrazole in the form of white powder.

M is SS-spectrum (IE): m/z= 144 (M +.) (molecular ion peak).

4-phenyl-1-(toluene-4-sulfonyl)-1H-pyrazole can be obtained as follows.

To a stirred solution of 8.7 g of 4-iodine-1-(toluene-4-sulfonyl)-1H-pyrazole 200 cm31,2-dimethoxyethane in an inert atmosphere add 11,72 g phenylboronic acid. The reaction medium is heated to a temperature of 110°C, then add 20,63 g of finely trehosnovnogo potassium phosphate and 2.18 g of bis(triphenylphosphine)allodiploid; the mixture is heated at the boiling point under reflux of the solvent for 3 hours, then cooled to a temperature of about 20°C and then filtered through Supercel. The filtrate is treated with 250 cm3ethyl acetate and washed 8 times 100 cm3water and 100 cm3aqueous saturated solution of sodium chloride. The organic phase is decanted, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa). The residue is purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (grain size distribution 20-45 μm; diameter 6 cm; height 45 cm), elwira with a mixture of cyclohexane and ethyl acetate (70:30 by volume) and collecting fractions of 20 cm3. Fractions 6-12 concentrated under reduced pressure. Get Android 4.04 g of 4-phenyl-1-(toluene-4-sulfonyl)-1H-pyrazole as white crystals.

Mass spectrum (IE): m/z = 298 (M+.) (peak mol the molecular ion); m/z = 234; m/z = 91.

4-iodine-1-(toluene-4-sulfonyl)-1H-pyrazole can be obtained as follows.

Mix a solution of 10 g of 4-iodine-1H-pyrazole 300 cm3of dimethylformamide in an inert atmosphere, cooled to a temperature of about -3°C. for 5 minutes, add 1.8 g of sodium hydride (75%dispersion in vaseline oil) and can withstand up to return the temperature to about 20°C. Then add a 13.9 g of p-toluensulfonate and maintain stirring for 3 hours at this temperature. The reaction medium is treated with 100 g of ice, then 700 cm3water and 700 cm3ethyl acetate. The organic phase is decanted, washed 9 times with 300 cm3water and 2 times 100 cm3an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure (2 kPa). The residue is recrystallized from 1000 cm3diisopropyl ether. Get to 10.9 g of 4-iodine-1-(toluene-4-sulfonyl)-1H-pyrazole as white crystals.

Mass spectrum (IE): m/z = 348 (M+.); m/z = 284; m/z = 91 (molecular ion peak).

Example 41

4-(5-chlorothiophene-2-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebroid

The product is obtained according to the method described for 4-(4-trifloromethyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol, on the basis of 400 mg of 3-benzyloxy-4-(5-chlorothiophene-2-yl)-1-(2-piperidine-retil)-1H-pyrazole, 3.3 cm312 N. hydrochloric acid and 3.3 cm3of ethanol. The environment is treated with diisopropyl ether and filtered through a sintered glass filter. The filtrate is precipitated in ethanol. Obtain 160 mg of the expected product in the form of powder.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.25 to 1.50 (m, 1H); from to 1.60 to 1.90 (m, 5H); from 2.80 to 3.00 (array, 2H); from the 3.35 to 3.50 (m, 4H); however, 4.40 (t ush., J=6.5 Hz, 2H); 7,00 (d, J=5.5 Hz, 1H); 7.03 is (d, J=5.5 Hz, 1H); of 7.97 (s, 1H); from 10.00 to 10.30 (array, 1H); 10,78 (ush., 1H).

Mass spectrum (IC): m/z = 312 ([M+H]+]) (molecular ion peak).

3-benzyloxy-4-(5-chlorothiophene-2-yl)-1-(2-piperidine-1-retil)-1H-pyrazole can be obtained as follows.

The product is obtained according to the method described for the preparation of 3-benzyloxy-4-(4-trifloromethyl)-1-(2-piperidine-1-retil)-1H-pyrazole, on the basis of 345 mg of 3-benzyloxy-4-(5-chlorothiophene-2-yl)-1H-pyrazole, 100 mg of sodium hydride in the form of a 75%dispersion in vaseline oil, 305 mg of 1-(2-chloroethyl)piperidine and 10 cm3anhydrous DMF (dimethylformamide). After purification on a column of silica FC50SI-HP, elwira a mixture of dichloromethane and methanol (95:5 by volume), receive 400 mg of the expected product in the form of an orange oil.

Mass spectrum (IC): m/z = 402 ([M+H]+]) (molecular ion peak).

3-benzyloxy-4-(5-chlorothiophene-2-yl)-1H-pyrazole can be obtained as follows.

The product is obtained in the determination of the e, described for the preparation of 3-benzyloxy-4-(4-trifloromethyl)-1H-pyrazole, on the basis of 740 mg of 3-benzyloxy-4-(5-chlorothiophene-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrazole, 3.8 cm31 n solution of n-tetrabutylammonium in tetrahydrofuran and 38 cm3tetrahydrofuran (THF). After purification on a column of silica FC50SI-HP, elwira a mixture of dichloromethane and methanol (95:5 by volume)obtain 345 mg of the expected product in the form of a powder harsh colors.

Mass spectrum (IC): m/z = 290 (M+.); m/z = 91 (molecular ion peak).

3-benzyloxy-4-(5-chlorothiophene-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrazole can be obtained as follows.

To a solution of 1.8 g of 3-benzyloxy-1-(toluene-4-sulfonyl)-4-tributylstannyl-1H-pyrazole in 20 cm3dioxane under stirring and in an inert atmosphere add 589 mg of 2-bromo-5-chlorothiophene, 32,5 mg of Tris(triphenyl)phosphine and 34.7 mg of Tris(dibenzylideneacetone)diplodia. The reaction medium is heated at a temperature of about 100°C for 15 hours. The mixture is then cooled to a temperature of about 20°C, filtered through Supercel. The filtrate is concentrated to dryness under reduced pressure (2 kPa), is treated with cyclohexane; insoluble part is filtered using sintered glass filter, the filtrate is concentrated to dryness under reduced pressure (2 kPa); the residue is purified on a column of silica FC50SI-HP, elwer the I with a mixture of cyclohexane and ethyl acetate (90:10 by volume). Receive 200 mg of 3-benzyloxy-4-(5-chlorothiophene-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrazole in the form of a yellow powder.

Mass spectrum (S): m/z = 444 (M+.); m/z = 289 and m/z = 91 (molecular ion peak).

3-benzyloxy-1-(toluene-4-sulfonyl)-4-tributylstannyl-1H-pyrazole can be obtained as follows.

To a solution of 4.4 g of 3-benzyloxy-4-iodine-1-(toluene-4-sulfonyl)-1H-pyrazole 45 cm3of dimethylformamide, with stirring and in an inert atmosphere add 325 mg of triphenylphosphine, 5,9 cm31,1,1,2,2,2-hexabutylditin and 141,3 mg of palladium diacetate. The reaction medium is heated at a temperature of about 80°C for 1 hour. The mixture is then cooled to a temperature of about 20°C, filtered through Supercel. The filtrate is treated with 200 cm3water and 100 cm3ethyl acetate. The organic phase is decanted, washed with 3 times 100 cm3water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa). The residue is purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (grain size distribution 20-45 μm; diameter 2 cm; height 40 cm), elwira with a mixture of cyclohexane and ethyl acetate (95:5 by volume). Obtain 4.5 g of 3-benzyloxy-1-(toluene-4-sulfonyl)-4-tributylstannyl-1H-pyrazole in the form of a yellow oil.

Mass spectrum (S): m/z = 618 (M+.); m/z = 561 (molecular ion peak).

Example 42

4-(3-methoxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebroid

The product is obtained according to the method described for 4-(4-trifloromethyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol, on the basis of 760 mg of 3-benzyloxy-4-(3-methoxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole, 6.5 cm312 N. hydrochloric acid and 6.5 cm3of ethanol. Wednesday concentrated to dryness under reduced pressure (2 kPa); the residue is precipitated in ethanol. Obtain 232 mg of the expected product in the form of powder.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.25 to 1.50 (array, 1H); from to 1.60 to 1.90 (m, 5H); from 2.80 to 3,05 (array, 2H); from to 3,35 3,55 (array, 4H); of 3.78 (s, 3H); to 4.38 (m, 2H); 6,72 (DDD, J=7 - 6 and 3 Hz, 1H); from to 7.15 to 7.30 (m, 3H); with 8.05 (s, 1H); from 9,80 to 10.10 (array ush., 1H); 10,45 (array, 1H).

Mass spectrum (S): m/z = 301 (M+.); m/z = 98 (molecular ion peak).

3-benzyloxy-4-(3-methoxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole can be obtained as follows.

The product is obtained according to the method described for the preparation of 3-benzyloxy-4-(4-trifloromethyl)-1-(2-piperidine-1-retil)-1H-pyrazole, on the basis of 590 mg of 3-benzyloxy-4-(3-methoxyphenyl)-1H-pyrazole, 176 mg of sodium hydride in the form of a 75%dispersion in vaseline oil, 542 mg of 1-(2-chloroethyl)piperidine and 10 cm3anhydrous DMF (dimethylformamide). After purification on a column of silica FC50SI-HP, elwira a mixture of dichloromethane and methanol (98: by volume), obtain 760 mg of the expected product in the form of a colorless oil.

Mass spectrum (S): m/z = 391 (M+.); m/z = 98 (molecular ion peak).

3-benzyloxy-4-(3-methoxyphenyl)-1H-pyrazole can be obtained as follows.

The product is obtained according to the method described for the preparation of 3-benzyloxy-4-(4-trifloromethyl)-1H-pyrazole, according to 1.32 g of 3-benzyloxy-4-(3-methoxyphenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole, 6,94 cm31 n solution of n-tetrabutylammonium in tetrahydrofuran and 80 cm3tetrahydrofuran (THF). After purification by precipitation in diethyl ether and purification on a column of silica FC50SI-HP, elwira a mixture of dichloromethane and methanol (95:5 by volume)obtain 590 mg of the expected product.

Mass spectrum (S): m/z = 280 (M+.); m/z = 91 (molecular ion peak).

3-benzyloxy-4-(3-methoxyphenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole can be obtained as follows.

The product is obtained according to the method described for the preparation of 3-benzyloxy-1-(toluene-4-sulfonyl)-4-(4-trifloromethyl)-1H-pyrazole, on the basis of 1.5 g of 3-benzyloxy-4-iodine-1-(toluene-4-sulfonyl)-1H-pyrazole, 1.5 g of 3-methoxyphenylacetic acid, 496 mg of tetrakis(triphenylphosphine)palladium, 4,96 cm32 N. an aqueous solution of potassium carbonate in a mixture of 30 cm3toluene and ethanol (4:1 by volume). After purification on a column of silica FC50SI-HP, elwira mix cyclohexane ethyl acetate (90:10 by volume), obtain 1.13 g of the expected product in the form of crystals of pale yellow color.

Mass spectrum (S): m/z = 434 (M+.); m/z = 279 and m/z = 91 (molecular ion peak).

Example 43

4-(2-methoxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebroid

The product is obtained according to the method described for 4-(4-trifloromethyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol, from 450 mg of 3-benzyloxy-4-(2-methoxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole, 3.8 cm312 N. hydrochloric acid and 3.8 cm3of ethanol. Wednesday concentrated to dryness under reduced pressure (2 kPa); the residue is precipitated in acetonitrile. Obtain 380 mg of the expected product in the form of a yellow powder.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.25 to 1.50 (m, 1H); from to 1.60 to 1.90 (m, 5H); to 2.94 (m, 2H); from 3.30 is to 3.60 (m, 4H); 3,86 (s, 3H); of 4.44 (t, J=6.5 Hz, 2H); 6,95 (t Razvan., J=7.5 and 1 Hz, 1H); 7,05 (l ush., J=7.5 Hz, 1H); 7,17 (t Razvan., J=7.5 and 1.5 Hz, 1H); to $ 7.91 (DD, J=7.5 and 1.5 Hz, 1H); 8,03 (s, 1H); from 10,10 to 10.30 (array, 1H); from 10,20 to 10,45 (array ush., 1H).

Mass spectrum (IC): m/z = 302 ([M+H]+) (molecular ion peak).

3-benzyloxy-4-(2-methoxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole can be obtained as follows.

The product is obtained according to the method described for the preparation of 3-benzyloxy-4-(4-trifloromethyl)-1-(2-piperidine-1-retil)-1H-pyrazole, on the basis of 382 mg of 3-benzyloxy-4-(2-methoxyphenyl)-1H-piraso is a, 114 mg of sodium hydride in the form of a 75%dispersion in vaseline oil, 351 mg of 1-(2-chloroethyl)piperidine and 11 cm3anhydrous DMF (dimethylformamide). After purification on a column of silica FC50SI-HP, elwira a mixture of dichloromethane and methanol (95:5 by volume)obtain 450 mg of the expected product in the form of oil pale yellow color.

Mass spectrum (S): m/z = 391 (M+.); m/z = 98 (molecular ion peak).

3-benzyloxy-4-(2-methoxyphenyl)-1H-pyrazole can be obtained as follows.

The product is obtained according to the method described for the preparation of 3-benzyloxy-4-(4-trifloromethyl)-1H-pyrazole, on the basis of 720 mg of 3-benzyloxy-4-(2-methoxyphenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole, 3,5 cm31 n solution of n-tetrabutylammonium in tetrahydrofuran and 50 cm3tetrahydrofuran (THF). After purification on a column of silica FC50SI-HP, elwira a mixture of dichloromethane and methanol (95:5 by volume), get 382 mg of the expected product in the form of a solid pinkish-beige color.

Mass spectrum (S): m/z = 280 (M+.); m/z = 91 (molecular ion peak).

3-benzyloxy-4-(2-methoxyphenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole can be obtained as follows.

The product is obtained according to the method described for the preparation of 3-benzyloxy-1-(toluene-4-sulfonyl)-4-(4-trifloromethyl)-1H-pyrazole, based on 1 g of 3-benzyloxy-4-iodine-1-(toluene-4-sulfonyl)-1H-pyrazole, 1 g of 3-m is toxiferine acid, 330 mg of tetrakis(triphenylphosphine)palladium, 3.3 cm32 N. an aqueous solution of potassium carbonate in a mixture of 15 cm3toluene and ethanol (4:1 by volume). After purification on a column of silica FC50SI-HP, elwira with a mixture of cyclohexane and ethyl acetate (80:20 by volume), obtain 720 mg of the expected product in the form of a powder beige color.

Mass spectrum (IC): m/z = 435 ([M+H]+) and m/z = 281 (molecular ion peak).

Example 44

4-(3-hydroxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebroid

Mix a solution of 516 mg of 4-(3-methoxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebrabased 13 cm3dichloromethane under inert atmosphere cooled to a temperature of about -78°C. Add to 4.38 cm3tribromide boron and kept under stirring for 15 hours at a temperature of about 20°C. the Solution is treated with methanol, then concentrated to dryness under reduced pressure (2 kPa). The residue is treated with 20 cm3water and 20 cm3dichloromethane. The organic phase is decanted; the aqueous phase is washed with aqueous saturated solution of sodium bicarbonate until the pH 8-8,4 (pH meter), and then treated with dichloromethane. The organic phase is decanted and concentrated to dryness under reduced pressure (2 kPa). The resulting white product is treated with 0.4 cm312 N. hydrochloric sour is s and 5 cm 3dioxane. The mixture is stirred for 10 minutes, then concentrated to dryness under reduced pressure (2 kPa). Obtain 198 mg of 4-(3-hydroxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebrabased in powder form harsh colors.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.25 to 1.50 (m, 1H); from to 1.60 to 1.90 (m, 5H); to 2.94 (m, 2H); from 3.30 is to 3,55 (m, 4H); however, 4.40 (t, J=6.5 Hz, 2H); 6,55 (DDD, J=8 - 3 and 1.5 Hz, 1H); from 7.00 to 7.15 (m, 3H); of 8.06 (s, 1H); from 9.10 to 9.40 (array ush., 1H); from 9,90 to 10.10 (array, 1H); from 10,30 to 10,45 (array, 1H).

Mass spectrum (S): m/z = 287 (M+.); m/z = 98 (molecular ion peak).

Example 45

4-(4-hydroxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebroid

200 mg of 4-(4-methoxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebrabased is brought to a pH value equal to 7 (paper Lyphan), using 1 N. aqueous sodium hydroxide solution. The organic phase is extracted with dichloromethane and concentrated to dryness under reduced pressure (2 kPa). The residue is treated with 5 cm3dichloromethane. Stir the solution is cooled to a temperature of about -78°C. Add 1.7 cm3tribromide boron and continue stirring for 15 hours at a temperature of about 20°C. the Solution is treated with 20 cm3ice water and 10 cm3dichloromethane. The organic phase is decanted; the aqueous phase is washed with dichloromethane, then water is asystem solution of sodium bicarbonate until the pH 8-8,4 (pH meter), then treated with dichloromethane. The organic phase is decanted and concentrated to dryness under reduced pressure (2 kPa). The resulting white powder is treated with 300 ál 12 N. hydrochloric acid and 5 cm3dioxane. The mixture is stirred for 10 minutes, then concentrated to dryness under reduced pressure (2 kPa). Obtain 101 mg of 4-(4-hydroxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebrabased in powder form harsh colors.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.25 to 1.50 (m, 1H); from to 1.60 to 1.90 (m, 5H); 2,92 (m, 2H); from 3.30 is to 3.50 (m, 4H); to 4.38 (t, J=6.5 Hz, 2H); 6.75 in (l ush., J=8.5 Hz, 2H); 7,45 (l ush., J=8.5 Hz, 2H); a 7.85 (s, 1H); from 9.10 to 9,35 (array ush., 1H); from 10.00 to 10.20 (array, 1H); from 10,15 to 10.30 (array, 1H).

Mass spectrum (S): m/z = 287 (M+.); m/z = 98 (molecular ion peak).

Example 46

4-(4-methoxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-adigitalife

To a solution of 640 mg of 1-{2-[3-benzyloxy-4-(4-methoxyphenyl)pyrazole-1-yl]ethyl}piperidine in 20 cm3ethanol add 7 cm31 n solution of hydrogen chloride in diethyl ether. After stirring for 30 minutes at a temperature of about 20°C. the solution is evaporated to dryness under reduced pressure (2.7 kPa). The residue is treated with 20 cm3of ethanol. The resulting solution was injected into the autoclave and added 87 mg of 10%palladium-on-charcoal, then egoboost in an atmosphere of hydrogen (8 bar). After stirring for 8 hours at a temperature of about 30°C. the reaction medium is filtered through Supercel and the filtrate is evaporated. To the residue add diisopropyl ether, which leads to the formation of the suspension, which is heated to the boiling temperature under reflux of the solvent and filtered in hot condition. The obtained solid is dried under vacuum (2.7 kPa)to give 400 mg of 4-(4-methoxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-alligatoroidea in the form of white powder.

IR-spectrum (KBr): 3052; 2933; 2655; 2559; 1578; 1569; 1518; 1501; 1453; 1248; 1170; 1020; 837; 810; 652 and 528 cm-1.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.30 to 1.50 (m, 1H); from to 1.60 to 1.90 (m, 5H); from 2.80 to 3,05 (m, 2H); 3.46 in (m, 4H); 3,76 (s, 3H); 4,37 (t ush., J=6 Hz, 2H); 6,93 (d, J=8.5 Hz, 2H); EUR 7.57 (d, J=8.5 Hz, 2H); 7,92 (ush., 1H); from 9,75 to 9.95 (array ush., 1H); 10,32 (ush., 1H).

1-{2-[3-benzyloxy-4-(4-methoxyphenyl)pyrazole-1-yl]ethyl}piperidine can be obtained as follows.

To a stirred solution of 1.2 g of 1-[2-(3-benzyloxy-4-bromopyrazole-1-yl)ethyl]piperidine in 60 cm31,2-dimethoxyethane in an argon atmosphere is added 2 g of 4-methoxyphenylacetic acid, 2.85 g of potassium phosphate and 750 mg of bis(triphenylphosphine)pallidiflora. After heating for 15 hours at boiling temperature under reflux of the solvent reaction medium is evaporated under reduced pressure (2.7 kPa). OS is ATCO add ethyl acetate and water and filtered through Supercel. The filtrate is decanted, then the organic phase is washed successively with water, aqueous saturated sodium hydrogen carbonate solution and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The resulting brown oil (3.6 g) purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (90:10 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 700 mg of 1-{2-[3-benzyloxy-4-(4-methoxyphenyl)pyrazole-1-yl]ethyl}piperidine in the form of a yellow oil.

Mass spectrum (S): m/z = 391 (M+.); m/z = 280(M-C7H13N)+.]; m/z = 111 (C7H13N+.); m/z = 98 (C6H12N+); m/z = 91 (C7H7+).

Example 47

4-(3-forfinal)-1-(2-piperidine-1-retil)-1H-pyrazole-3-adigitalife

To a stirred solution of 400 mg of 1-{2-[3-benzyloxy-4-(3-forfinal)pyrazole-1-yl]ethyl}piperidine 3.5 cm3ethanol add 3.5 cm312 N. hydrochloric acid. After standing for 7 hours at boiling temperature under reflux of the solvent, and then for 15 hours at a temperature of about 20°C. the reaction medium is evaporated to dryness under reduced pressure (2.7 kPa). The residue is dried under vacuum (2.7 kPa) at a temperature of 45 the C for 1 hour and proscout in diisopropyl ether. The formed precipitate is filtered off and dried under vacuum (2.7 kPa)to give 350 mg of 4-(3-forfinal)-1-(2-piperidine-1-retil)-1H-pyrazole-3-alligatoroidea in a solid white color.

IR-spectrum (KBr): 2951; 2647; 2540; 1619; 1586; 1530; 1456; 1267; 1178; 882; 785; 687 and 523 cm-1.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6with the addition of a few drops CD3COOD-d4, δ in ppm): to 1.42 (m, 1H); from to 1.60 to 1.90 (m, 5H); 2.95 and (m, 2H); from 3.40 in to 3,55 (m, 2H); 3.50 for each (t, J=6.5 Hz, 2H); 4,39 (t, J=6.5 Hz, 2H); 6,95 (TDD, J=7.5 to 3 and 1 Hz, 1H); from 7,30 to 7.50 (m, 3H); of 8.09 (s, 1H).

1-{2-[3-benzyloxy-4-(3-forfinal)pyrazole-1-yl]ethyl}piperidine can be obtained as follows.

To mix in an argon atmosphere to a solution of 1 g of 1-[2-(3-benzyloxy-4-bromopyrazole-1-yl)ethyl]piperidine in a mixture of 20 cm3toluene and 5 cm3ethanol added to 1.15 g of 3-ftorhinolonovy acid, 4.1 cm32 N. an aqueous solution of potassium carbonate and 475 mg of tetrakis(triphenylphosphine)palladium. After heating for 3 hours at boiling temperature under reflux of the solvent and curing for 15 hours at a temperature of about 20°C. to the reaction medium was added ethyl acetate and water and filtered through Supercel. The filtrate is decanted, then the organic phase is washed successively twice with water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate, filtered and viparita the t under reduced pressure (2.7 kPa). The resulting brown oil (2.1 g) purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: ethyl acetate]. After concentrating the fractions under reduced pressure receiving 400 mg of 1-{2-[3-benzyloxy-4-(3-forfinal)pyrazole-1-yl]ethyl}piperidine in the form of a yellow oil.

IR-spectrum (CCl4): 2939; 2854; 2802; 1617; 1586; 1509; 1463; 1432; 1359; 1272; 1187; 1169; 1160; 1043; 883; 695 and 687 cm-1.

Example 48

1-(2-piperidine-1-retil)-4-(3-triptoreline)-1H-pyrazole-3-adigitalife

To a stirred solution of 470 mg of 1-{2-[3-benzyloxy-4-(3-triptoreline)pyrazole-1-yl]ethyl}piperidine in 5 cm3ethanol add 5 cm312 N. hydrochloric acid. After standing for 7 hours at boiling temperature under reflux of the solvent, and then for 15 hours at a temperature of about 20°C. the reaction medium is evaporated to dryness under reduced pressure (2.7 kPa). The residue is dried under vacuum (2.7 kPa) at a temperature of 45°C for 1 hour and proscout in diisopropyl ether. The formed precipitate is filtered off and dried under vacuum (2.7 kPa)to give 350 mg of 1-(2-piperidine-1-retil)-4-(3-triptoreline)-1H-pyrazole-3-alligatoroidea in the form of a solid pale yellow color.

IR-spectrum (KBr): 2955; 2629; 2533; 1619; 1533; 1325; 1188; 1170; 1117; 1076; 800; 696 and 688 cm-1.

1H-NMR spectrum (300 MHz, (CD )2SO-d6, δ in ppm): 1,40 (m, 1H); from to 1.60 to 1.90 (m, 5H); to 2.94 (m, 2H); from 3.30 is to 3,55 (m, 4H); 4,43 (t, J=6.5 Hz, 2H); 7,50 (d ush., J=7.5 Hz, 1H); to 7.59 (t, J=7.5 Hz, 1H); 7,95 (l ush., J=7.5 Hz, 1H); 8,01 (ush., 1H); by 8.22 (s, 1H); 10,24 (array, 1H); from or 10.60 to 10.90 (array ush., 1H).

1-{2-[3-benzyloxy-4-(3-triptoreline)pyrazole-1-yl]ethyl}piperidine can be obtained as follows.

To mix in an argon atmosphere to a solution of 1 g of 1-[2-(3-benzyloxy-4-bromopyrazole-1-yl)ethyl]piperidine in a mixture of 20 cm3toluene and 5 cm3ethanol add 1,58 g 3-triftormetilfullerenov acid, 4.1 cm32 N. an aqueous solution of potassium carbonate and 475 mg of tetrakis(triphenylphosphine)palladium. After heating for 3 hours at boiling temperature under reflux of the solvent reaction medium is evaporated under reduced pressure (2.7 kPa). To the residue is added ethyl acetate and water and filtered through Suercel. The filtrate is decanted, then the organic phase is washed successively twice with water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The resulting brown oil (3 g) purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: ethyl acetate/methanol (95:5 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) receive the remainder, which process is primarily with ethyl acetate. The solution is treated with activated charcoal, filtered and evaporated under reduced pressure (2.7 kPa)to give 470 mg of 1-{2-[3-benzyloxy-4-(3-triptoreline)pyrazole-1-yl]ethyl}piperidine in the form of an orange oil.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.30 to 1.55V (m, 6H); 2.40 a (array, 4H); 2,70 (array, 2H); 4,10 (array, 2H); of 5.34 (s, 2H); from 7,30 to 7.55 (m, 6H); 7,58 (t, J=7.5 Hz, 1H); 7,92 (l ush., J=7.5 Hz, 1H); 8,03 (ush., 1H); of 8.25 (s, 1H).

Example 49

1-(2-piperidine-1-retil)-4-pyridin-3-yl-1H-pyrazole-3-adigitalife

To a stirred solution of 720 mg of 3-[3-benzyloxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]pyridine 7 cm3ethanol add 7 cm312 N. hydrochloric acid. After standing for 7 hours at boiling temperature under reflux of the solvent, and then for 15 hours at a temperature of about 20°C. the reaction medium is evaporated to dryness under reduced pressure (2.7 kPa). The residue is treated with ethanol, then the mixture is evaporated to dryness under vacuum (2.7 kPa). Operation is repeated twice, then the solid is dried under vacuum (2.7 kPa) at a temperature of 45°C for 1 hour and proscout in acetone. The formed precipitate is filtered off and dried under vacuum (2.7 kPa)to give 190 mg of 1-(2-piperidine-1-retil)-4-pyridin-3-yl-1H-pyrazole-3-alligatoroidea in a solid white color.

And the spectrum (KBr): 2970; 2434; 2931; 1601; 1551; 1460; 1307; 1178; 825; 691 and 624 cm-1.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1,40 (m, 1H); from to 1.60 to 1.90 (m, 5H); to 2.94 (m, 3H); from 3.25 to the 3.65 (m, 3H); 4,50 (t, J=6.5 Hz, 2H); 7,88 (DD ush., J=8 and 5 Hz, 1H); 8,39 (s, 1H); 8,55 (l ush., J=8 Hz, 1H); at 8.60 (d ush., J=5 Hz, 1H); 9,02 (l ush., J=1.5 Hz, 1H); or 10.60 (array, 1H); 11,20 (array, 1H).

3-[3-benzyloxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]pyridine can be obtained as follows.

To a stirred solution of 950 mg of 1-[2-(3-benzyloxy-4-bromopyrazole-1-yl)ethyl]piperidine in 100 cm3dioxane in an atmosphere of argon added 580 mg of 3-diethylbarbituric, 690 mg of potassium carbonate, dissolved in 20 cm3water, and 390 mg of tetrakis(triphenylphosphine)palladium. After heating for 3 hours at boiling temperature under reflux of the solvent reaction medium is cooled to a temperature of about 20°C, add ethyl acetate and water and filtered through Supercel. The filtrate is decanted, then the organic phase is washed with water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The resulting brown oil (2 g) is purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (97:3 by volume), then the ethyl acetate]. After concentrating the fractions under reduced pressure (2.7 kPa)receive the remainder, which purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: ethyl acetate/methanol (90:10 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 220 mg of 3-[3-benzyloxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]pyridine in the form of a yellow oil.

IR-spectrum (CCl4): 2940; 2854; 2801; 1599; 1575; 1505; 1453; 1362; 1167; 1020; 708 and 702 cm-1.

Example 50

4-(4-chlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-adigitalife

To a stirred solution of 470 mg of 1-{2-[3-benzyloxy-4-(4-chlorophenyl)pyrazole-1-yl]ethyl}piperidine 3.5 cm3ethanol add 3.5 cm312 N. hydrochloric acid. After standing for 7 hours at boiling temperature under reflux of the solvent, and then for 15 hours at a temperature of about 20°C. the reaction medium is evaporated to dryness under reduced pressure (2.7 kPa). The residue is dried under vacuum (2.7 kPa) at a temperature of 45°C for 2 hours, then it proscout in diisopropyl ether. The formed precipitate is filtered off and dried under vacuum (2.7 kPa)to give 430 mg of 4-(4-chlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-alligatoroidea in a solid white color.

IR-spectrum (KBr): 2952; 2640; 2534; 1607; 1578; 1552; 1521; 1455; 1191; 1093; 1011; 830; 818 and 516 cm-1.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1.39 in (m, 1H) from to 1.60 to 1.85 (m, 5H); 2,92 (m, 2H); from 3,35 up to 3.45 (m, 2H); 3.46 in (t ush., J=6.5 Hz, 2H); was 4.42 (t, J=6.5 Hz, 2H); 7,39 (DM, J=8.5 Hz, 2H); to 7.67 (DM, J=8.5 Hz, 2H); 8,08 (s, 1H); accounted for 10.39 (array, 1H).

1-{2-[3-benzyloxy-4-(4-chlorophenyl)pyrazole-1-yl]ethyl}piperidine can be obtained as follows.

To a suspension of 132 mg of sodium hydride (75%dispersion in mineral oil) in 15 cm3of dimethylformamide in an argon atmosphere and with stirring a solution of 440 mg of 3-benzyloxy-4-(4-chlorophenyl)-1H-pyrazole in 20 cm3of dimethylformamide. After heating for 30 minutes at a temperature of 50°C. the mixture is stirred for 30 minutes at a temperature of about 20°C. then there was added 400 mg of 1-(2-chloroethyl)piperidinedione. The reaction medium is stirred for 15 hours at a temperature of about 20°C, then make it into the water. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed successively with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give oil pale yellow color, which is purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (95:5 then 90:10 by volume)]. After concentrating the fractions under reduced pressure to obtain 470 mg of 1-{2-[3-benzyloxy-4-(4-chlorophenyl)pyrazole-1-yl]ethyl}piperidine in the form of oil pale yellow is the first color.

IR-spectrum (CCl4): 2938; 1574; 1509; 1482; 1452; 1358; 1171; 1094; 1037; 1014; 834; 695 and 511 cm-1.

3-benzyloxy-4-(4-chlorophenyl)-1H-pyrazole can be obtained as follows.

To mix in an argon atmosphere to a solution of 800 mg of 3-benzyloxy-4-(4-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in 20 cm3of tetrahydrofuran is added 2 cm31 N. solution tetrabutylammonium in tetrahydrofuran. After heating for 2 hours at boiling temperature under reflux of the solvent, add 0.5 cm31 N. solution tetrabutylammonium in tetrahydrofuran to the reaction medium, which was incubated for 15 hours at 60°C. Add 0.5 cm31 N. solution tetrabutylammonium in tetrahydrofuran to a solution, heated for 2 additional hours at the boiling point under reflux of the solvent. The reaction medium is then cooled to a temperature of about 20°C. and evaporated under reduced pressure (2.7 kPa). To the residue is added ethyl acetate and the organic phase is washed successively with two times water and a saturated aqueous sodium chloride solution; it is dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The obtained solid yellow clear flash chromatography on silica under pressure of argon (50 kPa) [e is uent: cyclohexane/ethyl acetate (80:20 by volume), then ethyl acetate)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 440 mg of 3-benzyloxy-4-(4-chlorophenyl)-1H-pyrazole in the form of a solid white color.

Mass spectrum (IE): m/z = 284 (M+.); m/z = 206 [M-C6H6)+.]; m/z = 91 (C7H7+).

3-benzyloxy-4-(4-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole can be obtained as follows.

To mix in an argon atmosphere to a solution of 1.1 g of 3-benzyloxy-4-iodine-1-(toluene-4-sulfonyl)-1H-pyrazole in 20 cm3toluene, to which was added 5 cm3ethanol added to 1.15 g of 4-Chlorfenvinphos acid, 3.6 cm32 N. an aqueous solution of potassium carbonate and 360 mg of tetrakis(triphenylphosphine)palladium. After heating for 15 hours at boiling temperature under reflux of the solvent reaction medium is evaporated under reduced pressure (2.7 kPa). To the residue is added ethyl acetate, water and activated charcoal and filtered through Supercel. The filtrate is decanted, then the organic phase is washed successively twice with water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The resulting brown oil (2.6 g) purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (90:10 by volume is m)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 800 mg of 3-benzyloxy-4-(4-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in the form of a solid orange color.

Mass spectrum (IC): m/z = 456 (MNH4+); m/z = 439 (MH+).

Example 51

4-(3-chlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-adigitalife

To a stirred solution of 550 mg of 1-{2-[3-benzyloxy-4-(3-chlorophenyl)pyrazole-1-yl]ethyl}piperidine in 5 cm3ethanol add 5 cm312 N. hydrochloric acid. After standing for 7 hours at boiling temperature under reflux of the solvent, and then for 15 hours at a temperature of about 20°C. the reaction medium is evaporated to dryness under reduced pressure (2.7 kPa). The residue is dried under vacuum (2.7 kPa) at a temperature of 45°C for 2 hours, then it proscout in diisopropyl ether. The formed precipitate is filtered off and dried under vacuum (2.7 kPa)to give 460 mg of 4-(3-chlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-alligatoroidea in a solid white color.

IR-spectrum (KBr): 2951; 2637; 2436; 1394; 1603; 1565; 1521; 1454; 1180; 778 and 689 cm-1.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1,40 (m, 1H); from to 1.60 to 1.90 (m, 5H); 2.95 and (m, 2H); from to 3,35 3,55 (m, 4H); however, 4.40 (t, J=6.5 Hz, 2H); 7,20 (DM, J=8 Hz, 1H); 7,37 (t, J=8 Hz, 1H); 7,62 (l ush., J=8 Hz, 1H); 7,73 (t, J=2 Hz, 1H); to 8.14 (s, 1H); 9,90 (array, 1H); 10,6 (array, 1H).

1-{2-[3-benzyloxy-4-(3-chlorophenyl)pyrazole-1-yl]ethyl}piperidine can be obtained as follows.

To the suspension 142 mg of sodium hydride (75%dispersion in mineral oil) in 15 cm3of dimethylformamide in an argon atmosphere and with stirring a solution of 500 mg of 3-benzyloxy-4-(3-chlorophenyl)-1H-pyrazole in 20 cm3of dimethylformamide. After heating for 30 minutes at a temperature of 50°C. the mixture is stirred for 30 minutes at a temperature of about 20°C. then there was added 500 mg of 1-(2-chloroethyl)piperidinedione. The reaction medium is stirred for 15 hours at a temperature of about 20°C, then make it into the water. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed successively with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give yellow oil, which was purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (95:5 by volume)]. After concentrating the fractions under reduced pressure to obtain 550 mg of 1-{2-[3-benzyloxy-4-(3-chlorophenyl)pyrazole-1-yl]ethyl}piperidine in the form of a yellow oil.

IR-spectrum (CCl4): 2938; 2853; 1603; 1574; 1507; 1452; 1357; 1260; 1174; 1046; 997; 695 and 687 cm-1.

3-benzyloxy-4-(3-chlorophenyl)-1H-pyrazole can the be obtained as follows.

To mix in an argon atmosphere to a solution of 810 mg of 3-benzyloxy-4-(3-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in 20 cm3tetrahydrofuran (THF) add to 4.6 cm31 N. solution tetrabutylammonium in tetrahydrofuran. After heating for 15 hours at boiling temperature under reflux of the solvent reaction medium is evaporated under reduced pressure (2.7 kPa) and the residue is added ethyl acetate. The organic phase is washed successively with two times water and a saturated aqueous sodium chloride solution; it is dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The oil obtained (0.7 g) purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (70:30 by volume), then ethyl acetate)]. After concentrating the fractions under reduced pressure (2.7 kPa) receive 500 mg of 3-benzyloxy-4-(3-chlorophenyl)-1H-pyrazole in the form of a solid white color.

IR-spectrum (KBr): 3148; 2957; 1601; 1505; 1446; 1422; 1355; 1237; 1229; 1046; 785; 729; 682 and 597 cm-1.

3-benzyloxy-4-(3-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole can be obtained as follows.

To mix in an argon atmosphere to a solution of 1 g of 3-benzyloxy-4-iodine-1-(toluene-4-sulfonyl)-1H-pyrazole in 20 cm3toluene, to which was added 5 cm3ethanol, a type of 1.03 g of 3-chlorfenvinfos the th acid, 3.3 cm32 N. an aqueous solution of potassium carbonate and 380 mg of tetrakis(triphenylphosphine)palladium. After heating for 2.5 hours at the boiling point under reflux of the solvent reaction medium is evaporated under reduced pressure (2.7 kPa). To the residue is added ethyl acetate, water and activated charcoal and filtered through Supercel. The filtrate is decanted, then the organic phase is washed successively twice with water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The resulting orange oil (2 g) is purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (97:3 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 810 mg of 3-benzyloxy-4-(3-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in the form of a solid yellow color.

IR-spectrum (KBr): 3098; 1604; 1508; 1372; 1357; 1189; 1180; 1094; 991; 790; 672; 586; 554 and 536 cm-1.

Example 52

4-(2-forfinal)-1-(2-piperidine-1-retil)-1H-pyrazole-3-adigitalife

To a mixed solution of 800 mg of 1-{2-[3-benzyloxy-4-(2-forfinal)pyrazole-1-yl]ethyl}piperidine in 10 cm3ethanol add 7 cm312 N. hydrochloric acid. After standing for 7 hours at boiling temperature with a reverse cold what linecom solvent, then for 15 hours at a temperature of about 20°C. the reaction medium is evaporated to dryness under reduced pressure (2.7 kPa). The crude product is treated with ethanol, then the mixture is evaporated to dryness under reduced pressure (2.7 kPa); the operation is repeated twice. The remainder proscout in diisopropyl ether and the precipitate is filtered off, then dissolve it by heating in ethanol. Appeared after cooling the solution in a bath with ice, the crystals are filtered and dried under vacuum (2.7 kPa)to give 470 mg of 4-(2-forfinal)-1-(2-piperidine-1-retil)-1H-pyrazole-3-alligatoroidea in a solid white color.

IR-spectrum (KBr): 2947; 2621; 2540; 1620; 1538; 1463; 1231; 1186; 1093; 970; 761 and 656 cm-1.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1,41 (m, 1H); from to 1.60 to 1.90 (m, 5H); to 2.94 (m, 2H); from to 3,35 3,55 (m, 4H); 4,46 (t ush., J=6.5 Hz, 2H); from to 7.15 to 7.30 (m, 3H); from 7.90 to 8.05 (m, 2H); 10,15 (array, 1H); 10,65 (ush., 1H).

1-{2-[3-benzyloxy-4-(2-forfinal)pyrazole-1-yl]ethyl}piperidine can be obtained as follows.

To a suspension of 200 mg of sodium hydride (75%dispersion in mineral oil) in 10 cm3of dimethylformamide in an argon atmosphere and with stirring a solution of 650 mg of 3-benzyloxy-4-(2-forfinal)-1H-pyrazole in 20 cm3of dimethylformamide. After heating for 30 minutes at a temperature of 50°C. the mixture is stirred for 30 minutes at same time is the temperature value of about 20°C, then there was added 625 mg of 1-(2-chloroethyl)piperidinedione. The reaction medium is stirred for 15 hours at a temperature of about 20°C, then make it 100 cm3water. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed successively twice with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give a yellow oil (1.1 g), which was purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (95:5 by volume)]. After concentrating the fractions under reduced pressure to obtain 800 mg of 1-{2-[3-benzyloxy-4-(2-forfinal)pyrazole-1-yl]ethyl}piperidine in the form of a yellow oil.

IR-spectrum (CCl4): 2938; 2855; 2801; 1572; 1512; 1486; 1358; 1175; 1044; 1027 and 696 cm-1.

3-benzyloxy-4-(2-forfinal)-1H-pyrazole can be obtained as follows.

To mix in an argon atmosphere to a solution of 1.25 g of 3-benzyloxy-4-(2-forfinal)-1-(toluene-4-sulfonyl)-1H-pyrazole in 30 cm3tetrahydrofuran (THF) add 7.4 cm31 N. solution tetrabutylammonium in tetrahydrofuran. After heating for 15 hours at boiling temperature under reflux of the solvent reaction medium is evaporated under reduced pressure (2.7 kPa) and the residue add Aut ethyl acetate. The organic phase is washed successively with two times water and a saturated aqueous sodium chloride solution; it is dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The oil obtained (0,92 g) purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (70:30 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 650 mg of 3-benzyloxy-4-(2-forfinal)-1H-pyrazole in the form of a solid white color.

IR-spectrum (KBr): 3161; 2954; 2691; 1572; 1474; 1440; 1353; 1264; 1045; 1036; 1027; 759; 729 and 654 cm-1.

3-benzyloxy-4-(2-forfinal)-1-(toluene-4-sulfonyl)-1H-pyrazole can be obtained as follows.

To mix in an argon atmosphere to a solution of 1.5 g of 3-benzyloxy-4-iodine-1-(toluene-4-sulfonyl)-1H-pyrazole in a mixture of 20 cm3toluene and 5 cm3ethanol is added 1.4 g of 2-ftorhinolonovy acid, 5 cm32 N. an aqueous solution of potassium carbonate and 500 mg of tetrakis(triphenylphosphine)palladium. After heating for 3 hours at boiling temperature under reflux of the solvent reaction medium is cooled to a temperature of about 20°C. and evaporated under reduced pressure (2.7 kPa). To the residue is added ethyl acetate, water and activated charcoal and filtered through Supercel. The filtrate is decanted, then the organic phase is washed sequence is entrusted twice with water and aqueous saturated solution of sodium chloride; it is dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The resulting orange oil (2 g) is purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (95:5 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) earn 1.25 g of 3-benzyloxy-4-(2-forfinal)-1-(toluene-4-sulfonyl)-1H-pyrazole in the form of an orange oil.

Mass spectrum (IE): m/z = 422 (M+.); m/z = 267 [M-C7H7O2S)+]; m/z = 91 (C7H7+.).

Example 53

4-(2-chlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebroid

To a stirred solution of 570 mg of 1-{2-[3-benzyloxy-4-(2-chlorophenyl)pyrazole-1-yl]ethyl}piperidine 7 cm3ethanol add 5 cm312 N. hydrochloric acid. After standing for 7 hours at boiling temperature under reflux of the solvent, and then for 15 hours at a temperature of about 20°C. the reaction medium is evaporated to dryness under reduced pressure (2.7 kPa). The residue is treated with ethanol, then the mixture is evaporated to dryness under vacuum (2.7 kPa). Operation is repeated twice, then the lacquer is dried under vacuum (2.7 kPa) at a temperature of 45°C for 30 minutes, after which it is dissolved by heating in ethanol. Crystals formed after cooling the solution is and the bath with ice, filtered off and dried under vacuum (2.7 kPa)to give 380 mg of 4-(2-chlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebrabased in a solid white color.

IR-spectrum (KBr): 3097; 2939; 2674; 2545; 1579; 1517; 1439; 1224; 1171; 935; 758 and 653 cm-1.

1H-NMR spectrum (200 MHz, (CD3)2SO-d6with the addition of a few drops CD3COOD-d4at a temperature of 363 K, δ in ppm): 1,60 (m, 2H); is 1.81 (m, 4H); 3,20 (array, 4H); 3,49 (t ush., J=6.5 Hz, 2H); 4,42 (t ush., J=6.5 Hz, 2H); 7,26 (t ush., J=7.5 Hz, 1H); 7,35 (t ush., J=7.5 Hz, 1H); of 7.48 (d ush., J=7.5 Hz, 1H); 7,66 (l ush., J=7.5 Hz, 1H); 7,93 (ush., 1H).

1-{2-[3-benzyloxy-4-(2-chlorophenyl)pyrazole-1-yl]ethyl}piperidine can be obtained as follows.

To a suspension of 140 mg of sodium hydride (75%dispersion in mineral oil) in 10 cm3of dimethylformamide in an argon atmosphere and with stirring a solution of 500 mg of 3-benzyloxy-4-(2-chlorophenyl)-1H-pyrazole in 20 cm3of dimethylformamide. After heating for 30 minutes at a temperature of 50°C. the mixture is stirred for 30 minutes at a temperature of about 20°C, then add 453 mg of 1-(2-chloroethyl)piperidinedione. The reaction medium is stirred for 15 hours at a temperature of about 20°C, then make it 100 cm3water. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed successively twice with water and aqueous saturated solution of chloride n is sodium, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give a yellow oil (0.8 g), which was purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (95:5 by volume)]. After concentrating the fractions under reduced pressure to obtain 570 mg of 1-{2-[3-benzyloxy-4-(2-chlorophenyl)pyrazole-1-yl]ethyl}piperidine as a colourless oil.

IR-spectrum (CCl4): 2938; 2853; 2801; 1573; 1506; 1456; 1450; 1357; 1174; 1125; 1036; 1025; 716 and 695 cm-1.

3-benzyloxy-4-(2-chlorophenyl)-1H-pyrazole can be obtained as follows.

To mix in an argon atmosphere to a solution of 1.2 g of 3-benzyloxy-4-(2-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in 30 cm3tetrahydrofuran (THF) add 6,9 cm31 N. solution tetrabutylammonium in tetrahydrofuran. After heating for 15 hours at boiling temperature under reflux of the solvent reaction medium is evaporated under reduced pressure (2.7 kPa) and the residue is added ethyl acetate. The organic phase is washed successively with two times water and a saturated aqueous sodium chloride solution; it is dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The oil obtained proscout in pentane. The formed precipitate is filtered off and dried under reduced pressure, receiving 50 mg of 3-benzyloxy-4-(2-chlorophenyl)-1H-pyrazole in the form of a solid yellow color.

Mass spectrum (IE): m/z = 284 (M+.); m/z = 249(M-Cl)+]; m/z = 91 (C7H7+).

3-benzyloxy-4-(2-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole can be obtained as follows.

To mix in an argon atmosphere to a solution of 1.5 g of 3-benzyloxy-4-iodine-1-(toluene-4-sulfonyl)-1H-pyrazole in 20 cm3toluene, to which was added 5 cm3ethanol, added 1.55 g of 2-Chlorfenvinphos acid, 5 cm32 N. an aqueous solution of potassium carbonate and 500 mg of tetrakis(triphenylphosphine)palladium. After heating for 5 hours at boiling temperature under reflux of the solvent reaction medium is evaporated under reduced pressure (2.7 kPa). To the residue is added ethyl acetate, water and activated charcoal and filtered through Supercel. The filtrate is decanted, then the organic phase is washed successively twice with water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The resulting orange oil purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (95:5 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 1.2 g of 3-benzyloxy-4-(2-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in the form of an orange oil.

Mass spectrum (S): m/z = 438 (M +.); m/z = 283 [M-C7H7SO2)+]; m/z = 91 (C7H7+).

Example 54

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazole-3-adigitalife

To a stirred solution of 220 mg of 3-[3-benzyloxy-4-(4-chlorophenyl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane in 5 cm3ethanol add 2.5 cm312 N. hydrochloric acid. After standing for 7 hours at boiling temperature under reflux of the solvent, and then for 15 hours at a temperature of about 20°C. the reaction medium is evaporated to dryness under reduced pressure (2.7 kPa). The residue is treated with ethanol, then the mixture is evaporated to dryness under vacuum (2.7 kPa). Operation is repeated twice, then the resulting meringue proscout in diisopropyl ether. The formed precipitate is filtered off and dried under vacuum (2.7 kPa)to give 170 mg of 1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazole-3-alligatoroidea in a solid white color.

IR-spectrum (KBr): 3052; 2926; 2793; 2559; 1606; 1576; 1520; 1486; 1454; 1195; 1167; 1090; 1010; 827; 626 and 515 cm-1.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.65 to 2.05 (m, 4H); to 2.42 (m, 1H); from a 3.15 to 3.50 (m, 4H); from 3.70 to 3.85 (m, 2H); of 4.67 (m, 1H); 7,40 (l ush., J=8 Hz, 2H); 7,71 (l ush., J=8 Hz, 2H); 8,35 (s, 1H); from 10.50 to 10.70 (array ush., 1H); of 10.73 (array, 1H).

3-[3-benzyloxy-4-(4-chlorophenyl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane can be p is obtained as follows.

To mix in an argon atmosphere to a solution of 500 mg of 3-benzyloxy-4-(4-chlorophenyl)-1H-pyrazole in 20 cm3of dimethylformamide is added 500 mg of potassium tert-butylate, then a solution of 660 mg of complex 1-azabicyclo[2,2,2]Oct-3-silt ester toluene-4-sulfonic 20 cm3of dimethylformamide. After heating for 15 hours at a temperature of 110°C. the reaction environment contribute 100 cm3water and the mixture extracted twice with ethyl acetate. The organic phase is washed successively with two times water and a saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The resulting orange oil (650 mg) purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: ethyl acetate and then dichloromethane/methanol (80:20 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 220 mg of 3-[3-benzyloxy-4-(4-chlorophenyl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane in the form of oil pale yellow color.

IR-spectrum (CCl4): 3035; 2941; 2873; 1605; 1574; 1508; 1481; 1454; 1165; 1095; 1014; 834; 695 and 513 cm-1.

Example 55

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(3-chlorophenyl)-1H-pyrazole-3-algebroid

To a stirred solution of 270 mg of 3-[3-benzyloxy-4-(3-chlorophenyl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane 6 cm3ethanol add 3 cm312 N. chlorotoluron the acid. After standing for 7 hours at boiling temperature under reflux of the solvent reaction medium is evaporated to dryness under reduced pressure (2.7 kPa). The residue is treated with ethanol, then the mixture is evaporated to dryness under vacuum (2.7 kPa). Operation is repeated twice, then the resulting meringue proscout in diisopropyl ether. The formed precipitate is filtered off and dried under vacuum (2.7 kPa)to give 180 mg of 1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(3-chlorophenyl)-1H-pyrazole-3-algebrabased in a solid white color.

IR-spectrum (KBr): 2931; 2801; 2660; 2557; 1599; 1563; 1517; 1459; 1425; 1165; 1095; 950; 891; 840; 788; 685; 627 and 440 cm-1.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.65 to 2.05 (m, 4H); 2,43 (m, 1H); from 3.15 and up to 3.45 (m, 4H); from 3.70 to 3.85 (m, 2H); of 4.67 (m, 1H); 7,20 (DDD, J=8 - 2 and 1 Hz, 1H); 7,38 (t, J=8 Hz, 1H); to 7.67 (d ush., J=8 Hz, 1H); of 7.75 (t, J=2 Hz, 1H); 8,31 (s, 1H); from 10,30 to or 10.60 (array ush., 1H); for 10.68 (ush., 1H).

3-[3-benzyloxy-4-(3-chlorophenyl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane can be obtained as follows.

To mix in an argon atmosphere to a solution of 570 mg of 3-benzyloxy-4-(3-chlorophenyl)-1H-pyrazole in 20 cm3of dimethylformamide added 560 mg of potassium tert-butylate, then a solution of 740 mg of complex 1-azabicyclo[2,2,2]Oct-3-silt ester toluene-4-sulfonic 20 cm3of dimethylformamide. After heating for 15 hours at a temperature of 110°With reacciona the environment contribute 100 cm 3water and the mixture extracted twice with ethyl acetate. The organic phase is washed successively with two times water and a saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The resulting orange oil (800 mg) purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: ethyl acetate/methanol (90:10 by volume)and then dichloromethane/methanol (80:20 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 270 mg of 3-[3-benzyloxy-4-(3-chlorophenyl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane in the form of oil pale yellow color.

IR-spectrum (CCl4): 3034; 1602; 1574; 1507; 1454; 1356; 1176; 1097; 1048; 695 and 687 cm-1.

Example 56

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(3-forfinal)-1H-pyrazole-3-algebroid

To a mixed solution of 85 mg of 3-[3-benzyloxy-4-(3-forfinal)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane 4 cm3ethanol is added 2 cm312 N. hydrochloric acid. After standing for 7 hours at boiling temperature under reflux of the solvent, and then for 15 hours at a temperature of about 20°C. the reaction medium is evaporated to dryness under reduced pressure (2.7 kPa). The residue is treated with ethanol, then the mixture is evaporated to dryness under vacuum (2.7 kPa). Operation is repeated twice, then poluchenno the meringue proscout in diisopropyl ether. The formed precipitate is filtered off and dried under vacuum (2.7 kPa)to give 63 mg of 1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(3-forfinal)-1H-pyrazole-3-algebrabased in a solid beige color.

IR-spectrum (KBr): 2932; 2765; 2663; 2577; 1617; 1586; 1521; 1457; 1436; 1265; 1180; 1165; 876; 783; 666; 625 and 521 cm-1.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.65 to 2.05 (m, 4H); 2,43 (m, 1H); from of 3.10 to 3.50 (m, 4H); 3,78 (l ush., J=7 Hz, 2H); of 4.67 (m, 1H); of 6.96 (t Razvan. ush., J=8 and 2.5 Hz, 1H); from of 7.25 to 7.55 (m, 3H); of 8.28 (s, 1H); 10,12 (array, 1H); 10,65 (s, 1H).

3-[3-benzyloxy-4-(3-forfinal)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane can be obtained as follows.

To mix in an argon atmosphere to a solution of 250 mg of 3-benzyloxy-4-(3-forfinal)-1H-pyrazole in 20 cm3of dimethylformamide added 260 mg of potassium tert-butylate, then a solution of 400 mg of complex 1-azabicyclo[2,2,2]Oct-3-silt ester toluene-4-sulfonic 20 cm3of dimethylformamide. After heating for 15 hours at a temperature of 110°C. the reaction environment contribute 100 cm3water and the mixture extracted twice with ethyl acetate. The organic phase is washed successively with two times water and a saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The resulting orange oil (345 mg) purified flash chromatography on silica under pressure ar is she (50 kPa) [eluent: cyclohexane/ethyl acetate (90:10 by volume), then dichloromethane/methanol (80:20 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 270 mg of 3-[3-benzyloxy-4-(3-forfinal)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane in the form of oil pale yellow color.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 0,80 (m, 1H); 1,53 (m, 1H); to 1.67 (m, 2H); of 2.09 (m, 1H); from 2.60 to 2.80 (m, 3H); 2,98 (m, 1H); is 3.21 (DDD, J=14 - 10 and 1.5 Hz, 1H); 3,37 (DD ush., J=14 and 5.5 Hz, 1H); 4.25 in (m, 1H); to 5.35 (s, 2H); 6,95 (t Razvan. ush., J=8 and 2.5 Hz, 1H); from of 7.25 to 7.55 (m, 8H); 8,31 (s, 1H).

Example 57

1-(1-methylpyrrolidine-3-yl)-4-phenyl-1H-pyrazole-3-algebroid

To a mixture of 165 mg of 1-(1-methylpyrrolidine-3-yl)-4-phenyl-1H-pyrazole-3-ol in 2 cm3ethyl acetate add a few drops of methanol to dissolve the medium, which is cooled to a temperature of 0°C before adding 5 cm33 M solution of hydrogen chloride in ethyl acetate. The reaction medium is stirred for 5 minutes at a temperature of 0°C, can withstand up to return to a temperature of about 20°C, then stirred at this temperature for 20 minutes before concentration under reduced pressure (2.7 kPa). The crude product is dried using a rotary-vane pump (10-3kPa)to give 160 mg of 1-(1-methylpyrrolidine-3-yl)-4-phenyl-1H-pyrazole-3-algebrabased as a very hygroscopic solid.

Liquid chromatography-mass spectrometry (LCMS) (electron ionization is the first spray): m/z = 244 (MH +).

1H-NMR spectrum (300 MHz, (CD3)2SO-d6at a temperature of 80°C., δ in ppm): 2.30 up to 2.65 (m, 2H); 2.91 in (s, 3H); from 3,10 to 4.00 (m, 4H); to 5.03 (m, 1H); 7,14 (t, J=7.5 Hz, 1H); to 7.32 (t, J=7.5 Hz, 2H); the 7.65 (t, J=7.5 Hz, 2H); 8,00 (s, 1H).

1-(1-methylpyrrolidine-3-yl)-4-phenyl-1H-pyrazole-3-ol may be obtained in the following way.

To a solution of 505 mg of 3-benzyloxy-1-(1-methylpyrrolidine-3-yl)-4-phenyl-1H-pyrazole 3.53 cm3ethanol type of 7.55 cm34 M hydrochloric acid. The reaction medium is stirred at the boil under reflux for 8 hours, then concentrated under reduced pressure (2.7 kPa). The oil obtained purple color treated three times with diethyl ether, evaporated to dryness under reduced pressure (2.7 kPa), treated three times with isopropanol, concentrated under reduced pressure and, finally, treated three times with dichloromethane, getting hardened oil, which, after drying using a rotary-vane pump (10-3kPa), to give 524 mg of solid substances. The residue is purified by chromatography on a column of 30 g of silicon dioxide (different grain size distribution of from 15 μm to 40 μm, Merck) [eluent: dichloromethane/methanol/39%ammonium hydroxide (95:5:0,4 by volume); flow rate: 8 cm3/min; detection: 250 nm]. After concentrating the fractions under reduced pressure receiving 279 mg of 1-(1-methylpyrrolidine-3-yl)-4-phenyl-1H-pee the azole-3-ol as a colorless amorphous solid.

LCMS (ionization electron spray): m/z = 334 (MH+).

3-benzyloxy-1-(1-methylpyrrolidine-3-yl)-4-phenyl-1H-pyrazole can be obtained as follows.

To a solution of 428 mg of 3-benzyloxy-4-phenyl-1H-pyrazole 8.5 cm3of dimethylformamide, stirred in nitrogen atmosphere and at 0°C, add 123 mg of sodium hydride (50%dispersion in oil). After stirring for 30 minutes at a temperature of about 20°C. add a solution of 398 mg slojnogo-methylpyrrolidine-3-silt ether methanesulfonate 5.6 cm3of dimethylformamide. The reaction medium is stirred for 1 hour at a temperature of 80°C, then bring in a mixture of water and ethyl acetate. After stirring for 5 minutes, the medium is decanted and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases, washed with aqueous saturated solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give 657 mg of oil, which is purified by chromatography on a column of 30 g of silicon dioxide (different grain size distribution of from 15 μm to 40 μm, Merck) [eluent: dichloromethane/methanol (97:3 by volume); flow rate: 8 cm3/min; detection: 250 nm]. After concentrating the fractions under reduced pressure get 511 mg of 3-benzyloxy-1-(1-methylpyrrolidine-3-yl)-4-phenyl-1H-pyrazole as a colorless amorphous solid the substances.

LCMS (ionization electron spray): m/z = 334 (MH+).

Complex 1 methylpyrrolidine-3-silt broadcast methansulfonate can be obtained as follows.

To a stirred solution of 0.39 cm31-methyl-3-hydroxypyrrolidine and 0.62 cm3triethylamine 7.7 cm3dichloromethane in a nitrogen atmosphere and at a temperature of -10°C. is added dropwise a solution of 0.33 cm3methanesulfonanilide in 7,07 cm3dichloromethane. The reaction medium is stirred for 5 minutes at a temperature of -10°C, then for 2 hours at a temperature of about 20°C., then concentrated to dryness under reduced pressure (2.7 kPa). The resulting residue is treated with water and ethyl acetate. The solution is stirred for 5 minutes, then decanted. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are washed successively with 5%aqueous solution of sodium bicarbonate and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give 399 mg of complex 1 methylpyrrolidine-3-silt ether methanesulfonate in the form of a colorless oil.

LCMS (ionization electron spray): m/z = 180 (MH+); m/z = 84 [MH+-(SO2CH3)].

Example 58

1-[2-(1-methylpyrrolidine-2-yl)ethyl]-4-phenyl-1H-pyrazole-3-adigitalife

The suspension 200 is g 3-benzyloxy-1-[2-(1-methylpyrrolidine-2-yl)ethyl]-4-phenyl-1H-pyrazole and the number at the tip of the spatula 10%palladium-on-coal 6 cm 3ethanol hydronaut at a temperature of about 20°C in an atmosphere of hydrogen at a pressure of 1600 mbar for 3 hours and 30 minutes. The reaction medium is treated with a mixture of dichloromethane and methanol, filtered through Clarcel. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa)to give 120 mg of 1-[2-(1-methylpyrrolidine-2-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol as a crystalline product. The second batch of 100 mg 1-[2-(1-methylpyrrolidine-2-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol get the same way, but based on 140 mg of 3-benzyloxy-1-[2-(1-methylpyrrolidine-2-yl)ethyl]-4-phenyl-1H-pyrazole.

A solution of 160 mg of 1-[2-(1-methylpyrrolidine-2-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol in 5 cm3methanol is acidified (pH 1) solution of hydrogen chloride in methanol. The reaction medium is stirred for 10 minutes at a temperature of about 20°C, then concentrated under reduced pressure (2.7 kPa) and placed overnight in a low temperature chamber. The residue is treated with acetonitrile, filtered off under vacuum, then washed with acetonitrile, and then dried in vacuum, obtaining 160 mg of 1-[2-(1-methylpyrrolidine-2-yl)ethyl]-4-phenyl-1H-pyrazole-3-alligatoroidea in the form of an amorphous hygroscopic powder of white color.

LCS (ionization electron spray): m/z = 272 (MH+).

1H-NMR-spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 1,65 (m, 1H); of 1.92 (m, 2H); of 2.09 (m, 1H); of 2.21 (m, 1H); to 2.41 (m, 1H); 2,77 (who, J=5.0 Hz, 3H); 3,01 (m, 1H); 3.15 in (m, 1H); to 3.52 (m, 1H); Android 4.04 (dt, J=14.0 and 6.5 Hz, 1H); 4,07 (dt, J=14.0 and 6.5 Hz, 1H); 7,11 (t, J=7.5 Hz, 1H); 7,31 (t, J=7.5 Hz, 2H); 7,63 (t, J=7.5 Hz, 2H); 7,98 (s, 1H); 10,70 (s, 1H).

3-benzyloxy-1-[2-(1-methylpyrrolidine-2-yl)ethyl]-4-phenyl-1H-pyrazole can be obtained as follows.

To a solution of 425 mg of 3-benzyloxy-4-phenyl-1H-pyrazole 2.5 cm3of dimethylformamide added in three portions 82 mg of sodium hydride (50%dispersion in oil). After the gas evolution reaction medium is stirred at a temperature of about 20°C for an additional 15 minutes, then add a solution of 250 mg of 1-methyl-2-(2-chloroethyl)pyrrolidine 0.5 cm3of dimethylformamide. The reaction medium is stirred at a temperature of about 20°C for 1 h, then at 50°C for 3 hours, after which bring in water. The solution is extracted with ethyl acetate. The organic phase is washed with aqueous saturated solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give 580 mg of crude product which is purified by chromatography on 25 g of silica gel [eluent: dichloromethane, then dichloromethane/methanol (90:10 by volume)]. After concentrating the fractions under reduced pressure to obtain 200 mg of 3-benzyloxy-1-[2-(1-methylpyrrolidine-2-yl)ethyl]-4-phenyl-1H-pyrazole in the form of an amorphous white powder, and 240 mg of a mixture of 3-benzyloxy-1-[2-(1-m is tiliroside-2-yl)ethyl]-4-phenyl-1H-pyrazole and 3-benzyloxy-4-phenyl-1H-pyrazole. The mixture was again purified by chromatography on 10 g of silica gel [eluent: dichloromethane/methanol (50:50, then 90:10, by volume)], receiving 90 mg of 3-benzyloxy-4-phenyl-1H-pyrazole and 140 mg of 3-benzyloxy-1-[2-(1-methylpyrrolidine-2-yl)ethyl]-4-phenyl-1H-pyrazole of the same species as the previous party.

LCMS (ei e raspyleniem): m/z = 362 (MH+).

1-methyl-2-(2-chloroethyl)pyrrolidine can be obtained as follows.

A solution of 330 mg of 1-methyl-2-(2-chloroethyl)pyrrolidinecarboxamido and 5 cm31 n sodium hydroxide solution in 20 cm3dichloromethane is stirred for 1 hour at a temperature of about 20°C. the Reaction medium is extracted with dichloromethane. The organic phase is washed with aqueous saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2.7 kPa)to give 255 mg of 1-methyl-2-(2-chloroethyl)pyrrolidine, who immediately introduced into the reaction.

Example 59

1-(pyrrolidin-3-yl)-4-phenyl-1H-pyrazole-3-adigitalife

Suspension 608 mg of 3-benzyloxy-4-phenyl-1-(pyrrolidin-3-yl)-1H-presoldered and 60 mg of 10%palladium-on-coal 18 cm3ethanol hydronaut at a temperature of about 20°C in an atmosphere of hydrogen at a pressure of 1300 mbar for 3 hours. The reaction medium is diluted with methanol, filtered through Hyflosupercel and washed with methanol. The filtrate is evaporated under reduced giving the situation (2.7 kPa), getting 365 mg of white powder. This crude reaction product is recrystallized from 20 cm3ethanol at the boiling point under reflux. The resulting solution was left to stand to return to a temperature of about 20°C, then placed in a bath of ice. The resulting crystals are filtered cold through Iéna, washed successively with ethanol and then diethyl ether and dried in vacuum (13 kPa)to give 185 mg of 1-(pyrrolidin-3-yl)-4-phenyl-1H-pyrazole-3-alligatoroidea in the form of white powder.

LCMS (ionization electron spray): m/z = 230 (MH+).

1H-NMR-spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 2,32 (m, 2H); 3,37 (m, water, 2H); of 3.45 (DD, J=12.5 and 5.0 Hz, 1H); of 3.60 (DD, J=12.5 and 7.0 Hz, 1H); 4,91 (m, 1H); 7,13 (t, J=7.5 Hz, 1H); to 7.32 (t, J=7.5 Hz, 2H): 7,66 (t, J=7.5 Hz, 2H); 8,11 (s, 1H); 9,44 (s, 2H); from the 10.40 (s, 1H).

3-benzyloxy-4-phenyl-1-(pyrrolidin-3-yl)-1H-pyrazolidone can be obtained as follows.

To a solution of 569 mg of 3-benzyloxy-1-(1-tert-butoxycarbonylamino-3-yl)-4-phenyl-1H-pyrazole 6 cm3ethyl acetate, stirred at 0°C is added dropwise to 6 cm33 M solution of hydrogen chloride in ethyl acetate. The reaction medium is stirred for 2 hours at a temperature of about 20°C., then concentrated under reduced pressure, getting 608 mg of 3-benzyloxy-4-phenyl-1-(pyrrolidin-3-yl)-1H-presoldered is ochloride in the form of a white powder, which immediately use.

3-benzyloxy-1-(1-tert-butoxycarbonylamino-3-yl)-4-phenyl-1H-pyrazole can be obtained as follows.

To a solution of 450 mg of 3-benzyloxy-4-phenyl-1H-pyrazole in 9 cm3of dimethylformamide, stirred in nitrogen atmosphere at a temperature of 0°C, add 129 mg of sodium hydride (50%dispersion in oil). After stirring for 30 minutes at a temperature of about 20°With add 621 mg of complex 1-tert-butoxycarbonylamino-3-silt ether methanesulfonate. The reaction medium is stirred for 1 hour at a temperature of 80°C, then bring in a mixture of water and ethyl acetate. After stirring for 5 minutes, the medium is decanted and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases, washed with aqueous saturated solution of sodium chloride, dried over magnesium sulfate, filtered through Iéna, washed with ethyl acetate and evaporated under reduced pressure (2.7 kPa), getting 998 mg of oil, which is purified by chromatography on a column with 70 g of silica (non-uniform grain size distribution from 15 to 40 μm; Merck) [eluent: dichloromethane/methanol (98:2 by volume); flow rate: 15 cm3/min; detection: 250 nm]. After concentrating the fractions under reduced pressure receiving 956 mg of product, which is again purified by chromatography on a column with 90 g of silicon dioxide (uneven Gras is allometry from 15 to 40 μm; Merck) [eluent: dichloromethane/ethyl acetate (98:2 by volume); flow rate: 15 cm3/min; detection: 250 nm]. After concentrating the fractions under reduced pressure to obtain 575 mg of 3-benzyloxy-1-(1-tert-butoxycarbonylamino-3-yl)-4-phenyl-1H-pyrazole as a colourless foam.

LCMS (ionization electron spray): m/z = 420 (MH+); m/z = 364 [MH+-tert-Bu]; m/z = 320 [MH+-Boc].

Complex 1-tert-butoxycarbonylamino-3-silt broadcast methansulfonate can be obtained as follows.

To a solution of 710 mg of 1-tert-butoxycarbonyl-3-hydroxy-pyrrolidine and 0.62 cm3of triethylamine in 14.2 cm3dichloromethane, stirred under nitrogen atmosphere at a temperature of -10°C. is added dropwise a solution of 0.33 cm3methanesulfonanilide 3.2 cm3dichloromethane. The reaction medium is stirred for 5 minutes at a temperature of -10°C, then for 2 hours at a temperature of about 20°C., then concentrated to dryness under reduced pressure (2.7 kPa). The resulting residue is treated with water and ethyl acetate. The solution is stirred for 5 minutes, then decanted. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are washed successively with 5%aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated under reduced d is the pressure (2.7 kPa), getting 938 mg of complex 1-tert-butoxycarbonylamino-3-silt ether methanesulfonate in the form of oil pale yellow color.

LCMS (ionization electron spray): m/z = 266 (MH+); m/z = 210 [MH+-tert-Bu].

1-tert-butoxycarbonyl-3-hydroxypyrrolidine can be obtained as follows.

To 0,848 cm33 hydroxypyrrolidine in a mixture of 30 cm3tetrahydrofuran (THF) and 9.6 cm3water is added a solution 2,78 cm3triethylamine 3.27 g of di-tert-BUTYLCARBAMATE. The reaction medium is stirred at a temperature of about 20°C for 3 hours, then concentrated to dryness under reduced pressure (2.7 kPa). The resulting residue is treated with water and ethyl acetate. The solution is stirred for 5 minutes, then decanted. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases, dried over magnesium sulfate, filtered through Iéna, then concentrated to dryness under reduced pressure (2.7 kPa), receiving 1,823 g of 1-tert-butoxycarbonyl-3-hydroxypyrrolidine in the form of colorless crystals.

LCMS (ionization electron spray): m/z = 188 (MH+); m/z = 132 [MH+-tert-Bu].

Example 60

1-[(1-methylpyrrolidine-2(S)-yl)methyl]-4-phenyl-1H-pyrazole-3-ol

To a solution of 263 mg of 3-benzyloxy-1-[(1-methylpyrrolidine-2(S)-yl)methyl]-4-phenyl-1H-pyrazole in 2 cm3ethanol add 3.75 cm34 M solution of chlorite is todarodes acid. The reaction medium is stirred at the boil under reflux for 7 hours, then concentrated under reduced pressure. The oil obtained purple color treated three times with 10 cm3isopropanol, then evaporated to dryness under reduced pressure, getting 259 mg retinoid substances purple color. This retinoid substance dissolved in a mixture of 0.6 cm3ethanol and 3 cm31,4-dioxane. After adding 0,665 cm34 M solution of hydrogen chloride in 1,4-dioxane and stirring at a room temperature environment concentrated under reduced pressure at 40°C. the Residue is dissolved in 10 cm3water and the resulting solution was washed with dichloromethane (3 times on 1 cm3), then the pH value was adjusted to 9-10 by adding sodium carbonate. After extraction with dichloromethane the combined organic phases are then dried over magnesium sulfate, filtered and concentrated under reduced pressure at 35°C. the Obtained solid pale pink color (124 mg) is recrystallized by heating from ethanol, receiving 73 mg of 1-[(1-methylpyrrolidine-2(S)-yl)methyl]-4-phenyl-1H-pyrazole-3-ol in the form of a solid white color.

LCMS (ionization electron spray): m/z = 258 (MH+).

1H-NMR-spectrum (400 MHz, DMSO-d6, δ in ppm): 1,63 (m, 1H); to 1.76 (m, 2H); 1,95 (m, 1H); 2.30 m partially hidden, 1H); of 2.34 (s, 3H); 2.82 from (m, 1H); 3,14 (m, 1H); 3,90 (DD, J=7 - 14 Hz, 1H); 4,11 (DD, J=6 to 14 Hz, 1H); 7.18 in (t ush., J=8 Hz, 1H); 7,35 (t ush., J=8 Hz, 2H); EUR 7.57 (s, 1H); 7,70 (l ush., J=8 Hz, 2H).

3-benzyloxy-1-[(1-methylpyrrolidine-2(S)-yl)methyl]-4-phenyl-1H-pyrazole can be obtained as follows.

To a solution of 283 mg of 3-benzyloxy-4-phenyl-1H-pyrazole 6 cm3of dimethylformamide, stirred in nitrogen atmosphere at room temperature, add 136 mg of sodium hydride (50%dispersion in oil). After stirring for 30 minutes at room temperature add a solution of 250 mg of 1-methyl-2(S)-chloromethylpyridine 6 cm3of dimethylformamide. The reaction medium is stirred for 1 hour at a temperature of 80°C, then cooled to room temperature and hydrolyzing. After extraction with ethyl acetate the combined organic phases, washed with aqueous saturated sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure at 35°C receives 554 mg of yellow oil. After purification by chromatography on a column of 30 g of silicon dioxide (non-uniform grain size distribution from 15 to 40 μm; Merck) [eluent: dichloromethane/methanol (98:2 by volume); flow rate: 15 cm3/min] and concentration of the fractions under reduced pressure to obtain 263 mg of 3-benzyloxy-1-[(1-methylpyrrolidine-2(S)-yl)methyl]-4-phenyl-1H-pyrazole.

LCMS (ionization power is essential spray): m/z = 348 (MH +).

1-methyl-2(S)-chloromethylpyridine can be obtained as follows.

To a solution of 250 mg of (S)-(-)-1-methyl-2-pyrrolidineethanol 2 cm3dichloromethane, cooled in a bath with a mixture of water with ice, slowly add 388 μl of thionyl chloride. The resulting solution is refluxed for three hours, then stirred at room temperature for 18 hours. After evaporation under reduced pressure at a temperature of 35°C. the resulting brown residue was dissolved in ethanol, then concentrate to dryness under reduced pressure. The obtained dry extract was dissolved in 1 cm3ethanol, then precipitated by the gradual addition of 6 cm3diethyl ether. The resulting suspension is cooled in a bath with a mixture of ice water and the solid is filtered off, then washed with diethyl ether. After drying in vacuo get 258 mg of 1-methyl-2(S)-chloromethylpyridine as a very hygroscopic solid ochre.

Mass spectrum (EI): m/z = 133 (M+.).

Example 61

4-phenyl-1-pyrrolidin-3-ylmethyl-1H-pyrazole-3-algebroid

In the reactor for microwave oven, equipped with a magnetic stirrer, enter 163,5 mg 1-(1-benzylpyrrolidine-3-ylmethyl)-4-phenyl-1H-pyrazole-3-algebrabased 5 cm3methanol, 139,4 mg of ammonium formate and 1 mg of 10%palladium-on-charcoal grill. The test tube is hermetically closed and placed in an apparatus for the irradiation of microwave for 60 seconds at a temperature of 100°C at a pressure of 10.5 bar. The reaction medium is filtered using Acodisc GHP Polypro (PALL), then washed with methanol. The filtrate is concentrated to dryness under reduced pressure, obtaining the resin like substance that hardens in ethanol. Thus receive 40 mg of white powder. Operation with the previous ethanol filtrate again, getting after the unification of the two parties 52 mg of a white powder. Last ethanolic filtrate is again concentrated to dryness, the resulting residue is treated with 10 cm3water. The solution is frozen, then all lyophilizer during the night. Various parties unite, receiving 80 mg of 4-phenyl-1-pyrrolidin-3-ylmethyl-1H-pyrazole-3-algebrabased in the form of white powder.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.66 (m, 1H); 1,99 (m, 1H); 2,73 (m, 1H); 2,92 (m, 1H); from 3,02 to 3.25 (m, 2H); 4,01 (d, J=7,0 Hz, 2H); 7,12 (t ush., J=7.5 Hz, 1H); 7,32 (t ush., J=7.5 Hz, 2H); 7,65 (l ush., J=7.5 Hz, 2H); to 7.99 (s, 1H); at 8.36 (ush., 1H); from 6,70 to 8.70 (m very ush., 1H).

Mass spectrum (IE): m/z = 244+(M+H)+.

1-(1-benzylpyrrolidine-3-ylmethyl)-4-phenyl-1H-pyrazole-3-algebroid can be obtained as follows.

Suspension 937 mg of 3-benzyloxy-1-(1-benzylpyrrolidine-3-ylmethyl)-4-phenyl-1H-pyrazolidinone and 93 mg of 10%-n is th palladium-on-coal 9.4 cm 3ethanol hydronaut at a temperature of about 20°C in an atmosphere of hydrogen at a pressure of 1500 mbar for 15 hours. The reaction medium is filtered through Hyflosupercel and washed with methanol. After concentration to dryness of the filtrate get 350 mg retinoid substance beige color, which is recrystallized from ethanol. After filtration through Iéna, washing with diethyl ether, then dried in a technical vacuum drying Cabinet obtain 178 mg of 1-(1-benzylpyrrolidine-3-ylmethyl)-4-phenyl-1H-pyrazole-3-algebrabased.

Mass spectrum (IE): m/z = 334+[(M+H)+-HCl].

3-benzyloxy-1-(1-benzylpyrrolidine-3-ylmethyl)-4-phenyl-1H-pyrazolidinone can be obtained as follows.

To a solution of 450 mg of 3-benzyloxy-4-phenyl-1H-pyrazole in 9 cm3anhydrous dimethylformamide, stirred in argon atmosphere at a temperature of 0°C, add one portion 129 mg of sodium hydride (50%dispersion in oil). After stirring for 30 minutes at a temperature of about 20°C. add a solution of 630 mg of complex 1-benzylpyrrolidine-3-Eletropaulo ether methanesulfonate 9 cm3anhydrous DMF (dimethylformamide). The reaction medium is stirred for 4 hours at a temperature of 80°C, then bring in a mixture of water and ethyl acetate. After stirring for 5 minutes, the medium is decanted and the aqueous phase is extracted three times atilas what tatom. The combined organic phases are washed twice with water, then once with aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered through Iéna. Magnesium sulfate is washed with ethyl acetate. The combined organic phases are evaporated under reduced pressure and the resulting residue dried overnight using a vane pump, getting 939 mg oil pale yellow color, which is purified by chromatography on a column with 90 g of silica (non-uniform grain size distribution from 15 to 40 μm; Merck) [eluent: dichloromethane/methanol (98:2 by volume); flow rate: 10 cm3/min; detection: 250 nm]. After concentrating the fractions under reduced pressure receiving 586 mg of 3-benzyloxy-1-(1-benzylpyrrolidine-3-ylmethyl)-4-phenyl-1H-pyrazole 83%purity in the form of foam. This foam is treated with water (pH 1), then add ethyl acetate. After stirring for 5 minutes, the medium is decanted and the aqueous phase extracted with ethyl acetate. The organic phase is brought to pH 9 with ammonium hydroxide solution, extracted three times with ethyl acetate, the combined, dried over magnesium sulfate, filtered, washed, and then concentrated to dryness under reduced pressure, getting 497 mg of 3-benzyloxy-1-(1-benzylpyrrolidine-3-ylmethyl)-4-phenyl-1H-pyrazole in the form of free base. The product is treated with 5 cm3etelaat the and. The medium is cooled to a temperature of 0°C, then add 5 cm33 M solution of hydrogen chloride in ethyl acetate. The solution is concentrated to dryness under reduced pressure, obtaining a brown oil. Attempts at recrystallization of the resulting crude residue was useless (ethyl acetate, ethanol, methanol, diethyl ether or hexane). Thus emit 940 mg of 3-benzyloxy-1-(1-benzylpyrrolidine-3-ylmethyl)-4-phenyl-1H-pyrazolidinone.

Mass spectrum (IE): m/z = 424+(M+H)+.

Complex 1-benzylpyrrolidine-3-ymetray broadcast methansulfonate can be obtained as follows.

To a solution of 1 g (1-benzylpyrrolidine-3-yl)methanol and services, 0.844 cm3of triethylamine in 20 cm3dichloromethane, stirred in argon atmosphere at a temperature of 0°C. is added dropwise a solution of 0,455 cm3methanesulfonanilide 9.7 cm3anhydrous dichloromethane. The reaction medium is stirred for 5 minutes at a temperature of 0°C., then for 2 hours at a temperature of about 20°C., then concentrated to dryness under reduced pressure. The resulting residue is treated with water and ethyl acetate. The solution is stirred for 5 minutes, then decanted. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are washed successively with 5%aqueous sodium hydrogen carbonate solution and water nasyscennosti sodium chloride, dried over magnesium sulfate, filtered and evaporated under reduced pressure, obtaining 1.2 g of complex 1-benzylpyrrolidine-3-Eletropaulo ether methanesulfonate.

Mass spectrum (IE): m/z = 270+(M+H)+.

(1-benzylpyrrolidine-3-yl)methanol can be obtained as follows.

To a solution of 2 g of methyl ester of 1-benzyl-5-oxopyrrolidin-3-carboxylic acid in 40 cm3tetrahydrofuran (THF), stirred at 0°C in a nitrogen atmosphere, add 17.1 cm31 M solution of sociallyengaged in tetrahydrofuran. After stirring for 15 minutes at a temperature of 0°C. the reaction environment can withstand up to return to a temperature of about 20°C. and stirred for 4 hours. To the reaction medium added dropwise a mixture of 0.65 cm3water and 6.5 cm3tetrahydrofuran (THF). Then add 0,65 cm315%aqueous sodium hydroxide solution and 1.95 cm3water. The medium is stirred at a temperature of about 20°C. up to the formation of filterable solids, to which is added in the amount of two spatulas magnesium sulfate. After filtration through Iéna, washing and concentrating to dryness under reduced pressure get 1,72 g (1-benzylpyrrolidine-3-yl)methanol as a colorless oil.

Mass spectrum (IE): m/z = 192+(M+H)+.

Example 62

1-((2R)-1-IU is iparralde-2-ylmethyl)-4-phenyl-1H-pyrazole-3-ol

To a solution of 211 mg of 3-benzyloxy-1-((2R)-1-methylpyrrolidine-2-ylmethyl)-4-phenyl-1H-pyrazole 1.5 cm3ethanol add 2,89 cm36 N. hydrochloric acid. The reaction medium is stirred for 5 hours and 30 minutes at a temperature of 110°C, then concentrated to dryness under reduced pressure. The residue is treated with isopropanol and concentrated to dryness, obtaining 136 mg of a foam which is recrystallized from a minimum volume of ethanol under heating. After freezing overnight no crystallization occurs. The residue is treated with 5 cm3water and extracted three times on 1 cm3dichloromethane, the pH value was adjusted to 9-10 by adding solid sodium carbonate. The aqueous phase is again extracted three times with dichloromethane. The combined organic phases, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure, receiving 100 mg of product, which is recrystallized from the minimum amount of ethanol. After standing over night in the fridge, filtering and drying obtain 58 mg of 1-((2R)-1-methylpyrrolidine-2-ylmethyl)-4-phenyl-1H-pyrazole-3-ol in the form of a solid white color.

1H-NMR-spectrum (400 MHz, (CD3)2SO-d6c addition of one drop of D-d4, δ in ppm): from 1.62 to 2.00 (m, 4H); to 2.42 (s, 3H); to 3.02 (m, 1H); is 3.21 (m, 2H); of 3.96 (DD, J=7,0 and 14.0 Hz, H); of 4.13 (DD, J=5,5 and 14.0 Hz, 1H); 7,13 (t ush., J=7.5 Hz, 1H); 7,33 (t ush., J=7.5 Hz, 2H); 7,65 (l ush., J=7.5 Hz, 2H); of 7.97 (s, 1H).

Mass spectrum (IE): 258(+) = (M+H)(+).

3-benzyloxy-1-((2R)-1-methylpyrrolidine-2-ylmethyl)-4-phenyl-1H-pyrazole can be obtained as follows.

A solution of 400 mg of 3-benzyloxy-4-phenyl-1-((2R)-pyrrolidin-2-ylmethyl)-1H-pyrazolidinone, 297 mg of potassium carbonate, 0,101 cm3methyliodide 4 cm3the dimethylformamide is stirred overnight at a temperature of about 20°C. the Medium is diluted with water, then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure, obtaining the crude reaction product, which is purified by chromatography on silica gel (eluent: dichloromethane with 3% methanol). After concentration to dryness of fractions obtain 215 mg of 3-benzyloxy-1-((2R)-1-methylpyrrolidine-2-ylmethyl)-4-phenyl-1H-pyrazole.

3-benzyloxy-4-phenyl-1-((2R)-pyrrolidin-2-ylmethyl)-1H-pyrazolidinone can be obtained as follows.

To a solution of 500 mg of 3-benzyloxy-1-((2R)-1-tert-butoxycarbonylamino-2-ylmethyl)-4-phenyl-1H-pyrazole in 5 cm3dioxane add 3,17 cm34 n solution of hydrogen chloride in dioxane. The reaction medium is stirred overnight at a temperature of about 20°C., then concentrated under reduced pressure, receiving 400 mg of 3-benzyloxy-4-phenyl-1-((2R)-1-pyrrolidin-2-ylmethyl)-1H-feast is salidroside in a solid white color.

Mass spectrum (IE): m/z = 334+(M+H)+; m/z = 667+(2M+H)+.

3-benzyloxy-4-phenyl-1-((2R)-1-tert-butoxycarbonylamino-2-ylmethyl)-1H-pyrazole can be obtained as follows.

A solution of 251 mg of 3-benzyloxy-4-phenyl-1H-pyrazole and 72 mg of sodium hydride (50%dispersion in oil) in 5 cm3of dimethylformamide is stirred for 1 hour, then add a solution of 364 mg of the compound (2R)-1-tert-butoxycarbonylamino-2-Eletropaulo ether methanesulfonate 5 cm3of dimethylformamide. The reaction medium is stirred at a temperature of 80°C for 3 hours, then poured into water. After extraction with ethyl acetate the organic phase is washed three times with aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered, and then concentrated to dryness, obtaining 440 mg of crude product which is purified by chromatography on silica gel (eluent: heptane/ethyl acetate; 80:20). After concentration to dryness of fractions obtain 202 mg of 3-benzyloxy-4-phenyl-1-((2R)-1-tert-butoxycarbonylamino-2-ylmethyl)-1H-pyrazole.

Mass spectrum (IE): m/z = 456+(M+Na)+; m/z = 434+(M+H)+; m/z = 334+[(M+H)+CO2-tert-Bu+H].

Complex (2R)-1-tert-butoxycarbonylamino-2-ymetray broadcast methansulfonate can be obtained as follows.

To a solution of 3 g of (2R)-1-tert-butoxycarbonyl-2-hydroxy-methylpyrrole the ins and 2,27 cm 3of triethylamine in 65 cm3dichloromethane, stirred under nitrogen atmosphere at a temperature of -10°C., added dropwise a solution of 1.2 cm3methanesulfonanilide 20 cm3dichloromethane. Reaction medium can withstand before increasing the temperature to 20°C, then concentrated to dryness under reduced pressure. The resulting residue is treated with water, extracted two times with 20 cm3ethyl acetate. The combined organic phases are washed three times with 20 cm35%aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure, obtaining 3.75 g of a mixture of compound (2R)-1-tert-butoxycarbonylamino-2-Eletropaulo ether methanesulfonate and (2R)-1-tert-butoxycarbonyl-2-hydroxyethylpyrrolidine. The mixture is injected into the interaction in the same conditions as the previous example, but with 0.3 EQ. of triethylamine and 0.3 EQ. methanesulfonanilide. After such processing receive 3,63 g complex (2R)-1-tert-butoxycarbonylamino-2-yl-methyl ester of methanesulfonate in the form of a colourless liquid.

Mass spectrum (IE): m/z = 280+(M+H)+.

Example 63

4-phenyl-1-(piperidine-3-yl)-1H-pyrazole-3-algebroid

A suspension of 130 mg of 3-benzyloxy-4-phenyl-1-(piperidine-3-yl)-1H-pyrazolidinone and 13 mg of 10%palladium-on-coal 4 cm3ethanol hydronaut when the temperature about 20°C in hydrogen atmosphere at a pressure of 1500 mbar for 3 hours. The reaction medium is treated with a mixture of 15 cm3dichloromethane/methanol (80:20 by volume), filtered under vacuum using Clarcel, then washed twice with 10 cm3a mixture of dichloromethane/methanol (80:20 by volume). After concentration to dryness crystalline product is treated with 5 cm3ethyl acetate, filtered off under vacuum and treated twice with 0.5 cm3ethyl acetate, receiving 70 mg of 4-phenyl-1-(piperidine-3-yl)-1H-pyrazole-3-algebrabased in the form of a crystalline product.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1,72 to 2.22 (m, 4H); of 2.86 (m, 1H); from 3,10 up of 3.57 (m, partially hidden, 3H); 4,36 (m, 1H); 7,14 (t ush., J=7.5 Hz, 1H); 7,33 (t ush., J=7.5 Hz, 2H); 7.68 per (l ush., J=7.5 Hz, 2H); 8,07 (s, 1H); 9,18 (m ush., 2H); 10,4 (ush., 1H).

Mass spectrum (IE): m/z = 244+(M+H)+.

3-benzyloxy-4-phenyl-1-(piperidine-3-yl)-1H-pyrazolidinone can be obtained as follows.

To a solution of 230 mg of 3-benzyloxy-1-(1-tert-butoxycarbonylamino-3-yl)-4-phenyl-1H-pyrazole in 2 cm3ethyl acetate, cooled with a bath with ice, add 2 cm34 n solution of hydrogen chloride in ethyl acetate. Reaction medium can withstand before returning to a temperature of about 20°C., then stirred for 2 hours 30 minutes, then concentrated to remove ethyl acetate. The residue is treated three times with 2 cm3Dyatlov the th ether and the insoluble part is filtered off, receiving 150 mg of 3-benzyloxy-4-phenyl-1-(piperidine-3-yl)-1H-pyrazolidinone.

Mass spectrum (IE): m/z = 334+(M+H)+; m/z = 36+/38+HCl+.

3-benzyloxy-1-(1-tert-butoxycarbonylamino-3-yl)-4-phenyl-1H-pyrazole can be obtained as follows.

To a solution of 725 mg of 3-benzyloxy-4-phenyl-1H-pyrazole 7 cm3anhydrous dimethylformamide, stirred in a nitrogen atmosphere, add three portions 153 mg of sodium hydride (50%dispersion in oil). After stirring for 45 minutes at a temperature of about 20°C. add a solution of 890 mg of complex 1-tert-butoxycarbonylamino-3-silt ether methanesulfonate 4.5 cm3anhydrous DMF (dimethylformamide). The reaction medium is stirred for 3 hours at a temperature of 80°C. then, after cooling, bring in the water. The aqueous phase is extracted four times with 50 cm3ethyl acetate. The combined organic phases are washed with aqueous saturated solution of sodium chloride, dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure. The resulting product is treated with dichloromethane, which after filtering off under vacuum to give 380 mg of 3-benzyloxy-4-phenyl-1H-pyrazole in the form of a solid beige color. The filtrate after concentration to dryness purified by chromatography on a column with 70 g of silica (Merck; eluent: what harmatan/ethyl acetate (95:5 by volume)). After concentrating the fractions under reduced pressure to obtain 280 mg of 3-benzyloxy-1-(1-tert-butoxycarbonylamino-3-yl)-4-phenyl-1H-pyrazole with a purity of 70%. These 280 mg of product is again purified on a column of 30 g of silica (Merck; eluent: dichloromethane/heptane (70:30 by volume)). After concentrating the fractions under reduced pressure to obtain 230 mg of 3-benzyloxy-1-(1-tert-butoxycarbonylamino-3-yl)-4-phenyl-1H-pyrazole.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1,20 (m, 1H); of 1.41 (s, 9H); from 1,45 to 2.16 (m, 3H); of 2.93 (m, 1H); from 3.00 to 3.40 (m ush., 1H); with 3.79 (m, 1H); from 3,98 up to 4.16 (m, 2H); 5,31 (ush., 2H); 7,15 (t ush., J=7.5 Hz, 1H); from 7,30 to 7.45 (m, 5H); 7,51 (l ush., J=7.5 Hz, 2H); 7,65 (l ush., J=7.5 Hz, 2H); to 8.14 (s, 1H).

Complex 1-tert-butoxycarbonylamino-3-silt broadcast methansulfonate can be obtained as follows.

To a solution of 750 mg of 1-tert-butyloxycarbonyl-3-hydroxypiperidine and 0,570 cm3of triethylamine in 7 cm3dichloromethane, stirred under nitrogen atmosphere at a temperature of -10°C. is added dropwise a solution of 0,305 cm3methanesulfonanilide. Reaction medium can withstand before increasing the temperature to about 20°C. and stirred for 3 hours, then concentrated to dryness under reduced pressure. The resulting residue is treated with ethyl acetate. The organic phase is washed successively with 5%aqueous solution of bicarbonate soda is I, then aqueous saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure, obtaining 0.9 g complex 1-tert-butoxycarbonylamino-3-silt ether methanesulfonate in the form of a colorless oil.

Mass spectrum (IE): m/z = 280+(M+H)+; m/z = 224+[(M+H)+-tert-Bu+H].

Example 64

1-(1-methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazole-3-algebroid

A solution of 610 mg of 3-benzyloxy-1-(1-methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazole 12 cm3ethyl acetate and 6 cm34 M solution of hydrogen chloride in ethyl acetate is stirred for 15 minutes at a temperature of about 20°C. After concentration to dryness under reduced pressure receiving 669 mg of 3-benzyloxy-1-(1-methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazolidinone, which immediately enter into interaction. Suspension 669 mg videolooking hydrochloride and 66 mg of 10%palladium-on-coal 15 cm3ethanol hydronaut at a temperature of about 20°C in an atmosphere of hydrogen at a pressure of 1500 mbar for 3 hours. The reaction medium is treated with a mixture of 25 cm3dichloromethane/methanol (80:20), then filtered under vacuum through Clarcel. After concentration to dryness, the obtained product was dissolved in 20 cm3water, then lyophilizer, receiving 500 mg of 1-(1-methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazole-3-Alger the chloride.

1H-NMR spectrum (300 MHz, (CD3)2SO-d6at a temperature of 353 K, δ in ppm): from 1.37 to to 1.87 (m, 6H); 2,86 (m ush., 4H); from 3,32 to 3.60 (m very ush., 2H); 4,24 (m ush., 1H); 4,50 (m ush., 1H); 7,16 (t ush., J=7.5 Hz, 1H); 7,34 (t ush., J=7.5 Hz, 2H); to 7.67 (d ush., J=7.5 Hz, 2H); of 7.97 (s, 1H); 10.0 to 10.6 (m very ush., 2H).

Mass spectrum (IE): m/z = 272+(M+H)+; m/z = 36+/38+HCl+.

Example 65

1-(1-mutilation-3-yl)-4-phenyl-1H-pyrazole-3-algebroid

1-(1-mutilation-3-yl)-4-phenyl-1H-pyrazole-3-algebroid can be obtained by the same method used to obtain 1-(1-methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazole-3-algebrabased, but on the basis of 470 mg of 3-benzyloxy-1-(1-mutilation-3-yl)-4-phenyl-1H-pyrazole, 10 cm3ethyl acetate, 5 cm34 M solution of hydrogen chloride in ethyl acetate, then 51 mg of 10%palladium-on-coal and 15 cm3of ethanol. According to the same processing conditions thus receive 400 mg of 1-(1-mutilation-3-yl)-4-phenyl-1H-pyrazole-3-algebrabased.

1H-NMR-spectrum (400 MHz, (CD3)2SO-d6at a temperature of 343 K, δ in ppm): from 1.62 to 2,32 (m, 6H); 2,86 (ush., 3H); from 2,92 to 3.76 (m partially hidden, 4H); from 4,62 to 4.92 (m very ush., 1H); 7,15 (t ush., J=7.5 Hz, 1H); 7,33 (t ush., J=7.5 Hz, 2H); 7,65 (l ush., J=7.5 Hz, 2H); 7,93 (ush., 1H); from 9,85 to 10.3 (m ush., 1H); from 10.7 to 11.4 (m very ush., 1H).

Mass spectrum (IE): m/z = 272+(M+H)+.

3-benzyloxy-1-(1-methylpiperidin-2-ylmethyl)-4-phenyl-1H-shall irsol and 3-benzyloxy-1-(1-mutilation-3-yl)-4-phenyl-1H-pyrazole can be obtained as follows.

To a solution of 2 g of 3-benzyloxy-4-phenyl-1H-pyrazole in 20 cm3anhydrous dimethylformamide, stirred in a nitrogen atmosphere, add three portions 426 mg of sodium hydride (50%dispersion in oil). After stirring for 30 minutes at a temperature of about 20°C is added dropwise 1.3 g of a mixture in the ratio of 75:25 1-methyl-2-chloromethylpyridine and complex 1 methylpiperidin-2-Eletropaulo ether methanesulfonate. The reaction medium is stirred for 3 hours at a temperature of 80°C. then, after cooling, make a mixture of water with ice. The aqueous phase is extracted with ethyl acetate. The organic phase is washed with aqueous saturated solution of sodium chloride, dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure. The product was then purified by two successive chromatography on a column with 119 g of silica (Merck; eluent: dichloromethane/methanol (97:3 by volume)). After concentrating the fractions under reduced pressure to obtain 460 mg of 3-benzyloxy-1-(1-mutilation-3-yl)-4-phenyl-1H-pyrazole and 650 mg of 3-benzyloxy-1-(1-methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazole.

3-benzyloxy-1-(1-methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazole:

1H-NMR-spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): from of 1.12 to 1.65 (m, 6H); to 2.06 (m, 1H); to 2.29 (s, 3H); of 2.34 (m, 1H); 2,77 (m, 1H); 3,86 (DD, J=7,5 and 14.0 Hz, 1H); 4.25 in (DD, J=5,5 and 14.0 Hz, 1H); and 5.30 (s, 2H); 7,14 (t ush., J=7.5 Hz, H); from 7,30 to 7,44 (m, 5H); 7,50 (d ush., J=7.5 Hz, 2H); to 7.64 (d ush., J=7.5 Hz, 2H); of 8.06 (s, 1H).

3-benzyloxy-1-(1-mutilation-3-yl)-4-phenyl-1H-pyrazole:

1H-NMR-spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): from 1.56 to 1.82 (m, 4H); from 1,96 to 2.08 (m, 2H); of 2.33 (s, 3H); from 2.50 to 2,93 (m partially hidden, 4H); 4.26 deaths (m, 1H); and 5.30 (s, 2H); 7,13 (t ush., J=7.5 Hz, 1H); from 7,28 to 7.45 (m, 5H); 7,51 (l ush., J=7.5 Hz, 2H); 7,65 (l ush., J=7.5 Hz, 2H); 8,11 (s, 1H).

A mixture of 2-chloromethyl-1-methylpiperidine and complex 1 methylpiperidin-2-Eletropaulo ether methanesulfonate can be obtained as follows.

To a solution of 1.31 cm3(1 methylpiperidin-2-yl)methanol and 1.53 cm3of triethylamine in 26 cm3dichloromethane, stirred under nitrogen atmosphere at a temperature of -10°C. is added dropwise a solution of 0,815 cm3methanesulfonanilide. Reaction medium can withstand before increasing the temperature to about 20°C. and stirred for 3 hours, then concentrated to dryness under reduced pressure. The resulting residue is treated with ethyl acetate. The organic phase is successively washed with 5%aqueous solution of sodium bicarbonate, then water saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure, obtaining 1.3 g of a mixture in the ratio of 75:25 2-chloromethyl-1-methylpiperidine and complex 1 methylpiperidin-2-Eletropaulo ether methanesulfonate.

+(M+H)+; m/z = 208+(M+H)+.

Example 66

4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebroid

Follow the procedure of example 38, but using 0.75 g of 3-benzyloxy-4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazoloquinoline, 5,9 cm312 N. hydrochloric acid and 5.9 cm3of ethanol. The mixture is heated for 4 hours at a temperature of about 100°C. After cooling to a temperature of about 20°C. the reaction mixture was treated with ethanol, concentrated to dryness under reduced pressure (2 kPa); the residue is precipitated in a mixture of diisopropyl ether and ethanol. Get 0,357 g of 4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebrabased in a solid white color.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): 1,40 (m, 1H); from 1.63 to to 1.87 (m, 5H); 2,92 (m, 2H); from 3,36 to 3.52 (m, 4H); 4,43 (t, J=6.5 Hz, 2H); 7,14 (TT, J=1.5 and 7.5 Hz, 1H); 7,33 (t ush., J=7.5 Hz, 2H); to 7.64 (d ush., J=7.5 Hz, 2H); with 8.05 (s, 1H); from 10,35 to of 10.72 (m ush., 2H).

IR-spectrum (KBr): 2939; 1606; 1581; 1520; 1454; 1444; 1170; 771; 700; 673 and 427 cm-1.

3-benzyloxy-4-phenyl-1-(2-piperidine-1-retil)-1H-personocall can be obtained as follows.

Follow the procedure of example 15, but using 0,166 g of sodium hydride (75 wt.% dispersion in vaseline oil), 0,515 g of 1-(2-chloroethyl)piperidinedione and 0.5 g of 3-benzyloxy-4-phenylpyrazole. So get 0,754 g of 3-benzyloxy-4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazoloquinoline in view of the powder of white color.

IR-spectrum (KBr): 2930; 2638; 2542; 1606; 1511; 1454; 1357; 1280; 1181; 763; 721; 697 and 501 cm-1.

Mass spectrum (IC): m/z = 362 (MH+) peak of the molecular ion.

4-phenyl-1-(2-piperidine-1-retil)-1H-personocall.

Follow the procedure of example 15, but using 0,231 g of sodium hydride (0.75 wt.% dispersion in vaseline oil), 0,715 g of 1-(2-chloroethyl)piperidinedione and 0.4 g of 4-phenylpyrazole. So get 0,832 g of 4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazoloquinoline in the form of white crystals.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): 1,60 (m, 2H); to 1.79 (m, 4H); a 3.06 (m, 4H); 3.43 points (t, J=6.5 Hz, 2H); 4,58 (t, J=6.5 Hz, 2H); 7,32 (t ush., J=7.5 Hz, 1H); of 7.48 (t ush., J=7.5 Hz, 2H); 7,69 (l ush., J=7.5 Hz, 2H); of 8.06 (s, 1H); with 8.33 (s, 1H).

IR-spectrum (KBr): 2949; 1679; 1713; 1606; 1460; 1187; 955; 763; 703 and 476 cm-1.

Example 67

4-(thiophene-2-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebroid

A suspension of 0.15 g of 4-(5-chlorothiophene-2-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebrabased and 5 mg of palladium-on-coal (10%) in 15 cm3methanol is stirred in an autoclave at a hydrogen pressure of 3000 kPa at 60°C for 20 hours. The reaction medium is then filtered through celite®, washed with methanol and concentrated to dryness under reduced pressure (3 kPa). The remainder proscout in diisopropyl ether; after filtering off the resulting solid and drying under vacuum (70 PA) at a temperature of 60°To obtain 0.1 g of 4-(thiophene-2-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebrabased in the form of a gray powder, melting at about 180°C (decomposition).

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): 1,40 (m, 1H); from 1.62 to 1.85 (m, 5H); from 2,82 up to 3.02 (m ush., 2H); from 3.30 is to 3.52 (m partially hidden, 4H); however, 4.40 (t ush., J=6.5 Hz, 2H); 7,02 (m, 1H); 7,19 (m, 1H); 7,32 (m, 1H); 7,93 (ush., 1H); from 10.1 to 10.65 (m ush., 2H).

IR-spectrum (KBr): 2952; 2539; 1605; 1545; 1455; 1404; 1175; 969 and 697 cm-1.

Example 68

4-(3,4-dichlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebroid

Follow the procedure of example 38, but using of 0.47 g of 3-benzyloxy-4-(3,4-dichlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole, 3 cm312 N. hydrochloric acid and 10 cm3of ethanol. The mixture is heated for 24 hours at a temperature of about 100°C. After cooling to a temperature of about 20°C. the reaction medium is treated with 3 times 30 cm3toluene, then 3 times in 30 cm3acetone, ethanol, concentrated to dryness under reduced pressure (2 kPa); the residue is precipitated in 30 cm3of acetone. Obtain 0.26 g of 4-(3,4-dichlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebrabased in the form of a whitish powder.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1.32 to 1.92 (m, 6H); from 2.85 to 3.60 (m, 6H); 4,36 (m ush., 2H); from 7,55 up to 7.68 (m, 2H); of 7.90 (d, J=2.0 Hz, 1H); 8,15 (ush., 1H); from 9,35 to 9.48 (m ush., 1H); 10,8 (ush., 1H).

IR-spectrum (KBr): 2945; 2533; 1604; 1525; 1448; 1180; 1028 and 806 cm-1.

3-benzyloxy-4-(3,4-dichlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole

Follow m is todoke example 15, but using is 0.135 g of sodium hydride (75 wt.% dispersion in vaseline oil), 0,519 g of 1-(2-chloroethyl)piperidinedione and 0.45 g of 3-benzyloxy-4-(3,4-dichlorophenyl)pyrazole. After heating the reaction medium for 1 hour at a temperature of 50°C., then keeping at a temperature of 20°C for 15 hours, the medium is treated with 150 cm3ethyl acetate and 150 cm3water; the organic phase is decanted, washed with 2 times 100 cm3distilled water and 100 cm3aqueous saturated solution of sodium chloride, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). Thus obtained 0.6 g of 3-benzyloxy-4-(3,4-dichlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole in the form of butter yellow-orange color.

1H-NMR-spectrum (400 MHz, DMSO-d6, δ in ppm): to 1.38 (m, 2H); to 1.48 (m, 4H); of 2.38 (m, 4H); in 2.68 (t, J=6.5 Hz, 2H); 4,07 (t, J=6.5 Hz, 2H); 5,33 (s, 2H); of 7.36 (TT, J=1.5 and 7.5 Hz, 1H); 7,41 (t ush., J=7.5 Hz, 2H); 7,51 (d, J=7.5 Hz, 2H); from EUR 7.57 to 7.65 (m, 2H); 7,88 (d, J=2.5 Hz, 1H); 8,21 (m, 1H).

Mass spectrum (IC): m/z = 430 (MN+) peak of the molecular ion.

3-benzyloxy-4-(3,4-dichlorophenyl)-1H-pyrazole

Follow the procedure of example 38, but using 0.3 g of 1-(toluene-4-sulfonyl)-3-benzyloxy-4-(3,4-dichlorophenyl)-1H-pyrazole and 1.6 cm31 N. solution tetrabutylammonium in tetrahydrofuran and 15 cm3tetrahydrofuran (THF). Thus obtain 0.2 g of 3-benzyloxy-4-(3,4-dichlorophen the l)-1H-pyrazole in the form of oil, which crystallizes.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): to 5.35 (s, 2H); from 7,32 to 7.46 (m, 3H); 7,50 (d ush., J=7.5 Hz, 2H); to 7.59 (d, J=9.0 Hz, 1H); of 7.70 (DD, J=2.5 and 9.0 Hz, 1H); to 7.95 (d, J=2.5 Hz, 1H); 8,23 (s, 1H); 12,3 (m ush., 1H).

Mass spectrum (IE): m/z = 318 (M+.); m/z = 91 (C7H7+) peak of the molecular ion.

3-benzyloxy-1-(toluene-4-sulfonyl)-4-(3,4-dichlorophenyl)-1H-pyrazole

Follow the procedure of example 38, but using 0.3 g of 1-(toluene-4-sulfonyl)-3-benzyloxy-4-iodine-1H-pyrazole, to 2.29 g of 3,4-dichlorophenylamino acid, 2,547 g tribalista, 0,421 g dichlorobis(triphenylphosphine)palladium 40 cm3dimethoxyethane. After purification by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (grain size distribution 20-45 μm; diameter 4 cm; height 60 cm), elwira a mixture of ethyl acetate and cyclohexane (5:95, 10:90 by volume), fractions 9-12 unite, concentrate to dryness under reduced pressure (3 kPa). Thus obtain 0.3 g of 3-benzyloxy-1-(toluene-4-sulfonyl)-4-(3,4-dichlorophenyl)-1H-pyrazole in the form of white powder.

Mass spectrum (IE): m/z = 472 (M+.); m/z = 317 [(M-C7H7SO2)+]; m/z = 91 (C7H7+) peak of the molecular ion.

Example 69

4-(4-bromophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol

Follow the procedure of example 38, but using 0.32 g of 3-benzyloxy-4-(4-bromophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole, 3 cm312 N. x is olistostromes acid and 10 cm 3of ethanol. The mixture is heated for 20 hours at a temperature of about 100°C. After cooling to a temperature of about 20°C. the reaction medium is treated with 5 times 30 cm3of acetone. After concentration to dryness under reduced pressure (3 kPa), the residue proscout 30 cm3diisopropyl ether, and then purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (grain size distribution 20-45 μm; diameter 2 cm; height 20 cm), elwira with ethyl acetate, then with a mixture of ethyl acetate and methanol (95:5 then 90:10 then 80:20 by volume). Faction 10-28 unite, concentrate to dryness under reduced pressure (3 kPa). Thus receive 0.11 mg of 4-(4-bromophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol in the form of white powder.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1.32 to 1.55V (m, 6H); 2,39 (m, 4H); to 2.65 (t, J=6.5 Hz, 2H); 4,00 (t, J=6.5 Hz, 2H); 7,50 (d ush., J=8.5 Hz, 2H); 7,62 (l ush., J=8.5 Hz, 2H); of 7.96 (s, 1H); 10.3 to 10.50 (m ush., 1H).

IR-spectrum (KBr): 2941; 1631; 1601; 1529; 1173; 1007; 824 and 510 cm-1.

3-benzyloxy-4-(4-bromophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole

Follow the procedure of example 15, but using 2,77 g of sodium hydride (75 wt.% dispersion in vaseline oil), 1,063 g of 1-(2-chloroethyl)piperidinedione and 0.95 g of 3-benzyloxy-4-(4-bromophenyl)pyrazole. After heating the reaction medium for 1 hour at a temperature of 50°C. the medium is cooled to a temperature of about 20°C, treated with the help of 300 cm 3ethyl acetate and 300 cm3water; the organic phase is decanted, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). The residue is purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (grain size distribution 20-45 μm; diameter 3 cm; height 40 cm), elwira a mixture of ethyl acetate and cyclohexane (5:95, 10:90 by volume). Faction 19-35 unite, concentrate to dryness under reduced pressure (3 kPa). Thus obtain 0.32 g of 3-benzyloxy-4-(4-bromophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole as a colourless oil.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1,34 up of 1.53 (m, 6H); of 2.38 (m, 4H); in 2.68 (t, J=6.5 Hz, 2H); 4,07 (t, J=6.5 Hz, 2H); 5,32 (s, 2H); from 7,32 to 7.55 (m, 7H); 7,60 (l ush., J=8.5 Hz, 2H); 8,10 (s, 1H).

Mass spectrum (ES): m/z = 440 (MH+) peak of the molecular ion.

3-benzyloxy-4-(4-bromophenyl)-1H-pyrazole

Follow the procedure of example 38, but using 1.5 g of 1-(toluene-4-sulfonyl)-3-benzyloxy-4-(4-bromophenyl)-1H-pyrazole and 7.1 cm31 N. solution tetrabutylammonium in tetrahydrofuran and 50 cm3tetrahydrofuran (THF). So get 0,93 g of 3-benzyloxy-4-(4-bromophenyl)-1H-pyrazole in the form of a whitish powder.

1H-NMR-spectrum (400 MHz, DMSO-d6, δ in ppm): of 5.34 (s, 2H); 7,35 (TT, J=1.5 and 7.5 Hz, 1H); 7,41 (t ush., J=7.5 Hz, 2H); from 7,47 to 7.54 (m, 4H); 7,66 (m, 2H); 8,13 (s, 1H); 12,2 (m ush., 1H).

Mass spectrum (IE): m/z = 328 (M+.); m/z = 91 (C7 H7+) peak of the molecular ion.

3-benzyloxy-1-(toluene-4-sulfonyl)-4-(4-bromophenyl)-1H-pyrazole

Follow the procedure of example 38, but using 1,817 g of 1-(toluene-4-sulfonyl)-3-benzyloxy-4-iodine-1H-pyrazole, to 2.41 g of 4-brompheniramine acid, of 2.54 g of tribalista, 0,421 g dichlorobis(triphenylphosphine)palladium 40 cm3dimethoxyethane. After purification by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (grain size distribution 20-45 μm; diameter 4 cm; height 60 cm), elwira a mixture of ethyl acetate and cyclohexane (5:95 by volume), fractions 15-30 unite, concentrate to dryness under reduced pressure (3 kPa). Thereby obtaining 1.5 g of 3-benzyloxy-1-(toluene-4-sulfonyl)-4-(4-bromophenyl)-1H-pyrazole in the form of a yellow oil, which crystallizes.

1H-NMR spectrum (300 MHz, DMSO-d6for 7%of the mixture, δ in ppm): to 2.42 (s, 3H); 5,33 (s, 2H); from 7,33 to 7.50 (m, 7H); to 7.59 (d ush., J=8.5 Hz, 2H); 7,72 (l ush., J=8.5 Hz, 2H); to 7.84 (m, 2H); 8,86 (s, 1H).

Mass spectrum (IE): m/z = 48 (M+.); m/z = 327(M-C7H7SO2)+]; m/z = 91 (C7H7+) peak of the molecular ion.

Example 70

4-(1H-indol-5-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol

For 30 minutes in an inert atmosphere and at a temperature of about 70°C is stirred mixture of 0.5 g of 3-benzyloxy-4-(1H-indol-5-yl)-1-(2-piperidine-1-retil)-1H-pyrazole, 0.5 g of ammonium formate and 0.5 g of palladium-on-coal (10%) is 50 cm 3of ethanol. The reaction medium is then cooled to a temperature of about 20°C, filtered through celite®, washed with ethanol and concentrated to dryness under reduced pressure (3 kPa). The residue is purified on a column of silica (grain size distribution 20-40 µm), elwira a mixture of dichloromethane and 2 n solution of ammonia in methanol (90:10 by volume). Get 0,258 g of 4-(1H-indol-5-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol in the form of a flocculent solid white color.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1.33 to 1.55V (m, 6H); 2.40 a (m, 4H); to 2.66 (t, J=6.5 Hz, 2H); 4,00 (t, J=6.5 Hz, 2H); 6,39 (t ush., J=2.5 Hz, 1H); from 7,27 to 7.40 (m, 3H); 7,81 (m, 2H); of 10.05 (ush., 1H); 10,95 (m ush., 1H).

IR-spectrum (KBr): 3265; 2944; 1593; 1524; 1242; 1184; 1044; 891; 803; 762; 725 and 437 cm-1.

Mass spectrum (IE): m/z = 310 (M+.); m/z = 98 (C6H12N+) peak of the molecular ion.

3-benzyloxy-4-(1H-indol-5-yl)-1-(2-piperidine-1-retil)-1H-pyrazole

Follow the procedure of example 37, but using 3,39 g of 3-benzyloxy-4-bromo-1-(2-piperidine-1-retil)-1H-pyrazole, 3,14 g 5-undeliverable acid, a 3.87 g of potassium carbonate, 1.2 g tetrakis(triphenylphosphine)palladium 70 cm3toluene and 20 cm3of ethanol. After cleaning 2 times when using a column with silica (grain size distribution 20-40 µm), elwira a mixture of dichloromethane and methanol (95:5 by volume), thereby obtaining 2.17 g of 3-benzyloxy-4-(1H-indol-5-yl)-1-(2-piperidine-1-retil)-1H-feast of the ash in the form of oil beige which crystallizes.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1.33 to 1.55V (m, 6H); from 2.32 to 2.50 (m ush., 4H); 2,72 (m ush., 2H); 4,10 (t, J=6.5 Hz, 2H); 5,32 (s, 2H); 6,39 (t ush., J=2.5 Hz, 1H); 7.29 trend to 7.46 (m, 6H); 7,52 (d ush., J=8.5 Hz, 2H); 7,81 (ush., 1H); to 7.93 (s, 1H); 11.0 in (m ush., 1H).

Example 71

4-(5-bromothiophene-2-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol

Follow the procedure of example 38, but using 0,592 g of 3-benzyloxy-4-(5-bromothiophene-2-yl)-1-(2-piperidine-1-retil)-1H-pyrazoloquinoline, the 3.65 cm312 N. hydrochloric acid and 4 cm3of ethanol. The mixture is heated for 2 hours at a temperature of about 100°C. After cooling to a temperature of about 20°C. the reaction medium is treated with ethanol, concentrated to dryness under reduced pressure (2 kPa); the residue is precipitated in diisopropyl ether, and then purified by using a column of silica (grain size distribution 20-40 µm), elwira a mixture of dichloromethane and 2 n solution of ammonia in methanol (90:10 by volume). Get 0,068 g of 4-(5-bromothiophene-2-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol in the form of a yellow powder.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1.33 to of 1.53 (m, 6H); is 2.37 (m, 4H); 2,62 (t, J=6.5 Hz, 2H); 3,99 (t, J=6.5 Hz, 2H); 6,93 (d, J=3.5 Hz, 1H); 7,10 (d, J=3.5 Hz, 1H); a 7.85 (s, 1H); from 10,45 to 10.75 (m very ush., 1H).

IR-spectrum (KBr): 2938; 1593; 1536; 1471; 1173; 981; 798; 758 and 496 cm-1.

Mass spectrum (IE): m/z = 355 (M+.); m/z = 98 (C6H12N+) peak is molekulyarnogo ion.

3-benzyloxy-4-(5-bromothiophene-2-yl)-1-(2-piperidine-1-retil)-1H-personocall

Follow the procedure of example 15, but using 0,154 g of sodium hydride (75 wt.% dispersion in vaseline oil), 0,477 g of 1-(2-chloroethyl)piperidinedione and 0.62 g of 3-benzyloxy-4-(5-bromothiophene-2-yl)pyrazole 13 cm3of dimethylformamide. After stirring for 1 hour at a temperature of about 20°With the environment is treated with 50 cm3ethyl acetate and 50 cm3water; the organic phase is decanted, washed with 3 times 50 cm3aqueous saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). The residue is treated with 10 cm3acetone and 170 mg of oxalic acid in solution in 2 cm3of acetone. The precipitate is filtered using sintered glass filter, washed with acetone, dried, and then purified by using a column of silica (grain size distribution 20-40 µm), elwira a mixture of dichloromethane and methanol (95:5 then 90:10 by volume). So get 0,716 g of 3-benzyloxy-4-(5-bromothiophene-2-yl)-1-(2-piperidine-1-retil)-1H-pyrazoloquinoline in the form of a yellow powder.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): to 1.48 (m, 2H); of 1.65 (m, 4H); from 2,86 to 3.00 (m ush., 4H); 3.25 to (m ush., partially hidden, 2H); 4,30 (t ush., J=6.5 Hz, 2H); 5,32 (s, 2H); 7,01 (d, J=3.5 Hz, 1H); to 7.15 (d, J=3.5 Hz, 1H); from 732 to 7.54 (m, 5H); of 8.09 (s, 1H).

IR-spectrum (KBr): 2948; 2536; 1724; 1641; 1595; 1532; 1498; 1451; 1363; 1173; 1008; 795 and 702 cm-1.

Mass spectrum (IE): m/z = 445 (M+.); m/z = 98 (C6H12N+) peak of the molecular ion.

3-benzyloxy-4-(5-bromothiophene-2-yl)-1H-pyrazole

Follow the procedure of example 38, but using 1.1 g of 1-(toluene-4-sulfonyl)-3-benzyloxy-4-(5-bromothiophene-2-yl)-1H-pyrazole and 5 cm31 N. solution tetrabutylammonium in tetrahydrofuran and 40 cm3tetrahydrofuran (THF). After purification using a column with silica (grain size distribution 20-40 µm), elwira a mixture of dichloromethane and acetone (95:5 by volume), thereby obtaining the 0,624 g of 3-benzyloxy-4-(5-bromothiophene-2-yl)-1H-pyrazole in the form of a solid yellow color.

IR-spectrum (KBr): 3193; 1599; 1503; 1438; 1362; 1238; 1023; 795; 731; 694 and 496 cm-1.

Mass spectrum (IE): m/z = 334 (M+.); m/z = 91 (C7H7+) peak of the molecular ion.

1-(toluene-4-sulfonyl)-3-benzyloxy-4-(5-bromothiophene-2-yl)-1H-pyrazole

Follow the procedure of example 38, but using 1 g of 1-(toluene-4-sulfonyl)-3-benzyloxy-4-iodine-1H-pyrazole, 1,32 g 5-bromothiophene-2-Voronovo acid, 1.22 g of potassium carbonate and 309 mg dichlorobis(triphenylphosphine)palladium in 20 cm3toluene and 5 cm3of ethanol. After purification on a column of silica (grain size distribution 20-40 µm), elwira a mixture of ethyl acetate and cyclohexane (10:90 by volume), thereby obtaining 0.8 g of 1-(toluene-4-sulfonyl)-3-benzyloxy-4-(5-bromothiophene-2-yl)-1H-pyrazole in the form of retinoid substances orange color.

IR-spectrum (CCl4): 1597; 1527; 1494; 1391; 1190; 1179; 1096; 1081; 695; 671; 595 and 540 cm-1.

Mass spectrum (IC): m/z = 489 (MN+); m/z = 263 (HPPh3+) peak of the molecular ion.

Example 72

2-[1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzamide

0,373 g of 4-(4-cyanophenyl)-1-(2-piperidine-1-retil)-1H-pyrazoloquinoline and 11 cm30.1 G. of sodium hydroxide solution in 20 cm3dichloromethane is stirred at a temperature of about 20°C for 15 minutes. The organic phase is decanted, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). The residue is treated with 11 cm3of toluene. Add 0,287 g trimethylsilanol potassium and the reaction medium is heated at the boiling point under reflux of the solvent for 5 hours and 30 minutes. The mixture is cooled to a temperature of about 20°C, treated with 40 cm3ethyl acetate and 40 cm3water. The organic phase is decanted, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). The residue is purified on a column of silica (grain size distribution 20-40 µm), elwira a mixture of dichloromethane and 2 n solution of ammonia in methanol (95:5 by volume). Get of 0.081 g of 2-[1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzamide in the form of a solid white color, melting at a pace which the temperature of 168°C.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1.33 to 1.55V (m, 6H); 2.40 a (m, 4H); in 2.68 (t, J=6.5 Hz, 2H); 4,22 (t, J=6.5 Hz, 2H); from 7.23 percent to 7.45 (m, 4H); 7,50 (d ush., J=8.5 Hz, 1H); of 7.70 (d, J=1.0 Hz, 1H); to 7.75 (m ush., 1H); 7,98 (d, J=1.0 Hz, 1H).

IR-spectrum (KBr): 3380; 3162; 2921; 1646; 1402; 954; 858; 754 and 633 cm-1.

Mass spectrum (IC): m/z = 299 (MH+) peak of the molecular ion.

4-(4-cyanophenyl)-1-(2-piperidine-1-retil)-1H-personocall

Follow the procedure of example 15, but using 0,098 g of sodium hydride (75 wt.% dispersion in vaseline oil), 0,305 g of 1-(2-chloroethyl)piperidinedione and 0.2 g of 4-(4-cyanophenyl)-1H-pyrazole. So get 0,373 g of 4-(4-cyanophenyl)-1-(2-piperidine-1-retil)-1H-pyrazoloquinoline in the form of white powder.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): 1,50 (m, 2H); by 1.68 (m, 4H); 2,96 (m, 4H); 3,33 (t ush., J=6.5 Hz, 2H); 4,55 (t, J=6.5 Hz, 2H); 7,45 (m, 1H); 7,73 (m, 2H); 7,89 (m, 1H); of 8.06 (d, J=1.0 Hz, 1H); 8,42 (d, J=1.0 Hz, 1H).

IR-spectrum (KBr): 2949; 2223; 1747; 1641; 1600; 1225; 1207; 990; 952; 764; 705 and 504 cm-1.

Mass spectrum (IC): m/z = 281 (MH+) peak of the molecular ion.

4-(4-cyanophenyl)-1H-pyrazole:

Follow the procedure of example 38, but using 0,613 g of 1-(toluene-4-sulfonyl)-4-(4-cyanophenyl)-1H-pyrazole and 3.8 cm31 N. solution tetrabutylammonium in tetrahydrofuran and 30 cm3tetrahydrofuran (THF). After purification on a column of silica (grain size distribution 20-40 µm), elwira a mixture of dichloromethane and acetone (90:10 by volume), thus p is to obtain 0,202 g of 4-(4-cyanophenyl)-1H-pyrazole in the form of a solid white color.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): the 7.43 (m, 1H); from 7,69 to 7.80 (m, 2H); 7,88 (m, 1H); from 8.00 to 8.30 (m ush., 2H); 13,3 (m ush., 1H).

IR-spectrum (KBr): 3153; 2966; 2218; 1601; 1516; 1347; 1044; 949; 763; 656 and 501 cm-1.

Mass spectrum (S): m/z = 169 (M+.) peak of the molecular ion; m/z = 142 [(M-CHN)+]; m/z = 115 [(m/z = 142-CHN)+].

1-(toluene-4-sulfonyl)-4-(4-cyanophenyl)-1H-pyrazole

Follow the procedure of example 41 to obtain 3-benzyloxy-4-(5-chlorothiophene-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrazole, but based on 0,943 g of 1-(toluene-4-sulfonyl)-4-tributylstannyl-1H-pyrazole, of 0.43 g of 2-cyano-1-yogashala, 84 mg of Tris(dibenzylideneacetone)palladium and 77 mg of Tris(triphenyl)phosphine in 11 cm3dioxane. After purification on a column of silica (grain size distribution 20-40 µm), elwira with a mixture of cyclohexane and ethyl acetate (90:10 then 80:20, then 50:50 by volume), thereby obtaining the 0,613 g of 1-(toluene-4-sulfonyl)-4-(4-cyanophenyl)-1H-pyrazole in the form of a pasty solid yellow-orange color.

1H-NMR-spectrum (400 MHz, DMSO-d6, δ in ppm): to 2.42 (s, 3H); from 7.50 to 7.58 (m, 3H); 7,78 (dt, J=1, 5 and 8.0 Hz, 1H); 7,84 (l ush., J=8.0 Hz, 1H); from 7,93 to 7.98 (m, 3H); scored 8.38 (d, J=1.0 Hz, 1H); 8,98 (d, J=1.0 Hz, 1H).

IR-spectrum (KBr): 2225; 1382; 1192; 1176; 1091; 1051; 812; 761; 702; 679; 664; 593 and 541 cm-1.

Mass spectrum (S): m/z = 323 (M+.); m/z = 259(M-SO2)+.]; m/z = 91 (C7H7+) peak of the molecular ion.

1-(toluene-4-sulfonyl)-4-tributylstannyl the l-1H-pyrazole

Follow the procedure of example 41 to obtain 3-benzyloxy-1-(toluene-4-sulfonyl)-4-tributylstannyl-1H-pyrazole, but on the basis of 1.5 g of 1-(toluene-4-sulfonyl)-4-iodine-1H-pyrazole, 2.65 cm31,1,1,2,2,2-hexabutylditin, 58 mg of palladium diacetate and 136 mg of triphenylphosphine in 20 cm3of dimethylformamide. After 2 cleanings on a column of silica (grain size distribution 20-40 µm), elwira cyclohexane and then with a mixture of cyclohexane and ethyl acetate (95:5 by volume), thereby obtaining the 0,743 g of 1-(toluene-4-sulfonyl)-4-tributylstannyl-1H-pyrazole as a colourless oil.

IR-spectrum (CH2Cl2): 2959; 2925; 2873; 2854; 1378; 1175; 1064; 957; 673; 594 and 543 cm-1.

Mass spectrum (S): m/z = 511 (M+.); m/z = 455(M-C4H8)+.] the peak molecular ion; m/z = 399(m/z = 455-C4H8)+.]; m/z = 343 [m/z = 399-C4H8)+.]; m/z = 91 (C7H7+).

Example 73

4-(2-hydroxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazolidinone

Stir the solution 0,582 g of 4-(2-methoxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazoloquinoline 12 cm3dichloromethane under inert atmosphere cooled to a temperature of about -78°C. Add 4.3 cm3tribromide boron and continue stirring for 4 hours at a temperature of about -70°C., then for 15 hours at a temperature of about 20°C. the Reaction medium is treated with 10 cm3in the s. The organic phase is decanted and then washed with 1 N. a solution of sodium hydroxide up to pH 8-8,4 (paper Lyphan) and treated with 20 cm3water. The organic phase is decanted, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). The residue is precipitated in isopropyl ether; the residue purified on a column of silica (grain size distribution 20-40 µm), elwira a mixture of dichloromethane and methanol (90:10 by volume); the resulting resin like substance is treated with 1 N. solution of hydrogen chloride in diethyl ether. Get 0.172 g of 4-(2-hydroxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazolidinone in the form of a powder pink color.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1.30 to 1.82 (m ush., 6H); from 2,38 to 3.62 (m very ush., 6H); from 4,22 to 4.60 (m ush., 2H); PC 6.82 (dt, J=1, 5 and 8.0 Hz, 1H); 6,92 (l ush., J=8.0 Hz, 1H); 7.03 is (dt, J=1.5 and 8.0 Hz, 1H); rate of 7.54 (DD, J=1.5 and 8.0 Hz, 1H); 7,98 (ush., 1H); 8,23 (ush., 1H); from 9,05 up to 9.45 (m very ush., 1H); 9,76 (ush., 1H).

IR-spectrum (KBr): 3144; 2938; 2539; 1560; 1461; 1351; 1282; 1238; 1111; 954; 856; 747 and 478 cm-1.

Mass spectrum (S): m/z = 271 (M+.); m/z = 98 [C6H12N+] the peak molecular ion.

4-(2-methoxyphenyl)-1-(2-piperidine-1-retil)-1H-personocall

Follow the procedure of example 15, but using 0,22 g of sodium hydride (75 wt.% dispersion in vaseline oil), 0,681 g of 1-(2-chloroethyl)piperidinedione and 0.46 mg of 4-(2-methoxyphenyl)-1H-what irazola. So get 0,582 g of 4-(2-methoxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazoloquinoline in a solid white color.

1H-NMR spectrum (300 MHz, DMSO-d6for 50% of the mixture, δ in ppm): 1,50 (m, 2H); from 1.62 to 1.75 (m ush., 4H); from 2,88 up to 3.09 (m, 4H); 3.15 in (t, J=6.5 Hz, 2H); to 3.89 (s, 3H); to 4.52 (t, J=6.5 Hz, 2H); 6,99 (t ush., J=8.0 Hz, 1H); 7,10 (l ush., J=8.0 Hz, 1H); 7.23 percent (dt, J=1.5 and 8.0 Hz, 1H); 7,63 (DD, J=1.5 and 8.0 Hz, 1H); 8,01 (ush., 1H); 8,23 (ush., 1H).

IR-spectrum (KBr): 2948; 2537; 1719; 1635; 1493; 1246; 1184; 1028; 952; 756; 721; 704 and 497 cm-1.

Mass spectrum (IC): m/z = 281 (MH+) peak of the molecular ion; m/z = 148 (M H+).

4-(2-methoxyphenyl)-1H-pyrazole:

Follow the procedure of example 38, but using a 1.08 g of 1-(toluene-4-sulfonyl)-4-(2-methoxyphenyl)-1H-pyrazole and 7.3 cm31 N. solution tetrabutylammonium in tetrahydrofuran and 58 cm3tetrahydrofuran (THF). After purification on a column of silica (grain size distribution 20-40 µm), elwira a mixture of dichloromethane and methanol (90:10 by volume), thereby obtaining the 0,463 g of 4-(2-methoxyphenyl)-1H-pyrazole in the form of solids dirty white color.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): to 3.89 (s, 3H); 6,97 (dt, J=1.5 and 8.5 Hz, 1H); 7,06 (l ush., J=8.5 Hz, 1H); 7,21 (m, 1H); 7,63 (DD, J=1.5 and 8.5 Hz, 1H); from a 7.85 to 8.20 (m very ush., 2H); 12,9 (m ush., 1H).

IR-spectrum (KBr): 3156; 2936; 2832; 1569; 1488; 1466; 1263; 1247; 1148; 1027; 950; 753; 661 and 628 cm-1.

Mass spectrum (S): m/z = 174 (M+.) peak of the molecular ion; m/z = 159 [(M-CH3)+]; mz = 131 [(m/z = 159-CO) +].

1-(toluene-4-sulfonyl)-4-(2-methoxyphenyl)-1H-pyrazole

Follow the procedure of example 38, but using 1.5 g of 1-(toluene-4-sulfonyl)-4-iodine-1H-pyrazole, 1,31 g 2-methoxyphenylacetic acid, of 1.74 g of potassium carbonate and 0,605 g dichlorobis(triphenylphosphine)palladium in 30 cm3toluene and 7.5 cm3of ethanol. After purification on a column of silica (grain size distribution 20-40 µm), elwira a mixture of ethyl acetate and cyclohexane (20:80 by volume), thereby obtaining 1,081 g of 1-(toluene-4-sulfonyl)-4-(2-methoxyphenyl)-1H-pyrazole in the form of pasty substances orange color.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): to 2.41 (s, 3H); to 3.92 (s, 3H); 7,01 (dt, J=1.5 and 8.5 Hz, 1H); 7,13 (l ush., J=8.5 Hz, 1H); 7,33 (m, 1H); 7,50 (d ush., J=8.5 Hz, 2H); 7,73 (DD, J=1.5 and 8.5 Hz, 1H); to 7.93 (d ush., J=8.5 Hz, 2H); to 8.41 (ush., 1H); 8,72 (ush., 1H).

IR-spectrum (KBr): 2835; 1497; 1372; 1177; 1097; 1039; 1023; 950; 753; 681; 598 and 550 cm-1.

Mass spectrum (S): m/z = 328 (M+.) peak of the molecular ion; m/z = 264(M-SO2)+.]; m/z = 173 [(M-C7H7SO2)+]; m/z = 91 (C7H7+).

Example 74

4-(1H-indol-5-yl)-1-(2-piperidine-1-retil)-1H-pyrazole

Follow the procedure of example 38, but using 1.22 g of 4-iodine-1-(2-piperidine-1-retil)-1H-pyrazole, 1,93 g 1H-indole-5-Voronovo acid, 2,547 g tribalista, 0,421 g dichlorobis(triphenylphosphine)palladium 50 cm3dimethoxyethane. After purification by chromatography under a nitrogen pressure kA on a column of silica gel (grain size distribution 20-45 μm; diameter 3 cm; height 60 cm), elwira a mixture of ethyl acetate and methanol (95:5 then 90:10 by volume), fractions 18-30 unite, concentrate to dryness under reduced pressure (3 kPa). So get to 0.23 g of 4-(1H-indol-5-yl)-1-(2-piperidine-1-retil)-1H-pyrazole in the form of a whitish powder.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from to 1.34 to 1.56 (m, 6H); to 2.41 (m, 4H); of 2.72 (t, J=6.5 Hz, 2H); 4,22 (t, J=6.5 Hz, 2H); 6,41 (m, 1H); from 7,27 to 7.40 (m, 3H); 7,71 (m, 1H); 7,80 (d, J=1.0 Hz, 1H); 8,06 (ush., 1H); 11.0 in (m ush., 1H).

IR-spectrum (KBr): 2937; 1436; 1363; 1167; 1119; 994; 887; 792; 763; 614 and 430 cm-1.

Mass spectrum (S): m/z = 294 (M+.); m/z = 98 (C6H12N+) peak of the molecular ion.

4-iodine-1-(2-piperidine-1-retil)-1H-pyrazole

Follow the procedure of example 15, but using 4.94 g of sodium hydride (75 wt.% dispersion in vaseline oil), 19 g of 1-(2-chloroethyl)piperidinedione and 10 g of 4-iterate. After stirring for 15 hours at a temperature of about 20°C. the reaction medium is treated with 1000 cm3ethyl acetate and 1000 cm3water; the organic phase is decanted, washed 3 times in 1000 cm3water and 500 cm3aqueous saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). The residue is purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (grain size distribution 20-45 μm; diameter 6 cm; height 60 cm), luira a mixture of ethyl acetate and cyclohexane (30:70 by volume), then with ethyl acetate. Fractions 16-20 unite, concentrate to dryness under reduced pressure (3 kPa). So get of 8.2 g of 4-iodine-1-(2-piperidine-1-retil)-1H-pyrazole in the form of oil is light yellow in color.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1,34 through 1.52 (m, 6H); a 2.36 (m, 4H); of 2.64 (t, J=6.5 Hz, 2H); 4,22 (t, J=6.5 Hz, 2H); 7,51 (ush., 1H); 7,92 (ush., 1H).

Mass spectrum (IC): m/z = 306 (MN+) peak of the molecular ion.

Example 75

4-(4-were)-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebroid

Follow the procedure of example 38, but using 0,63 g of 3-benzyloxy-4-(4-were)-1-(2-piperidine-1-retil)-1H-pyrazoloquinoline, 4.8 cm312 N. hydrochloric acid and 4.8 cm3of ethanol. The mixture is heated for 4 hours at a temperature of about 100°C. After cooling to a temperature of about 20°C. the reaction medium is treated with ethanol, concentrated to dryness under reduced pressure (2 kPa); the residue is precipitated in diisopropyl ether. Get 0,385 g of 4-(4-were)-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebrabased in a solid white color.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): 1,40 (m, 1H); from 1.63 to to 1.87 (m, 5H); 2,30 (s, 3H); from 2,82 up to 3.02 (m ush., 2H); from 3,27 to 3.53 (m, 4H); to 4.38 (t ush., J=6.5 Hz, 2H); 7,15 (l ush., J=8.5 Hz, 2H); 7,54 (d ush., J=8.5 Hz, 2H); 7,98 (s, 1H); of 10.05 (m very ush., 1H); 10,4 (m ush., 1H).

IR-spectrum (KBr): 2941; 2646; 1597; 1534; 1447; 1179; 1010; 818; 627 and 515 cm-1.

Mass-Spa is Tr (S): m/z = 285 (M +.); m/z = 98 (C6H12N+) peak of the molecular ion.

3-benzyloxy-4-(4-were)-1-(2-piperidine-1-retil)-1H-personocall

Follow the procedure of example 15, but using 0,123 g of sodium hydride (75 wt.% dispersion in vaseline oil), of 0.38 g of 1-(2-chloroethyl)piperidinedione and 0.39 g of 3-benzyloxy-4-(4-were)-1H-pyrazole. So get 0,632 g of 3-benzyloxy-4-(4-were)-1-(2-piperidine-1-retil)-1H-pyrazoloquinoline in the form of white powder.

IR-spectrum (KBr): 2931; 2639; 2543; 1719; 1618; 1580; 1519; 1452; 1279; 1180; 818; 721 and 500 cm-1.

Mass spectrum (IC): m/z = 376 (MH+) peak of the molecular ion.

3-benzyloxy-4-(4-were)-1H-pyrazole

Follow the procedure of example 38, but using 0.8 g of 1-(toluene-4-sulfonyl)-3-benzyloxy-4-(4-were)-1H-pianzola and 4 cm31 N. solution tetrabutylammonium in tetrahydrofuran and 40 cm3tetrahydrofuran (THF). So get 0,397 g of 3-benzyloxy-4-(4-were)-1H-pyrazole in the form of white powder.

IR-spectrum (KBr): 3187; 2980; 1586; 1498; 1450; 1380; 1233; 1043; 814; 737; 695 and 514 cm-1.

Mass spectrum (S): m/z = 264 (M+.); m/z = 186 [(M-C6H6)+]; m/z = 91 (C7H7+) peak of the molecular ion.

3-benzyloxy-1-(toluene-4-sulfonyl)-4-(4-were)-1H-pyrazole

Follow the procedure of example 38, but using 1 g of 1-(toluene-4-sulfonyl)-3-benzyloxy-4-iodine-1H-pyrazole, 0,898 g 4-methylphenylimino the acid, 0,913 g of potassium carbonate and 0,331 g of tetrakis(triphenylphosphine)palladium in 13 cm3toluene, 3 cm3ethanol and 3.3 cm3water. So get 0,817 g of 3-benzyloxy-1-(toluene-4-sulfonyl)-4-(4-were)-1H-pyrazole in the form of vatoobraznye solids pinkish-beige color.

IR-spectrum (KBr): 1589; 1485; 1377; 1191; 1179; 1098; 813; 702; 672; 580 and 538 cm-1.

Mass spectrum (S): m/z = 418 (M+.); m/z = 263(M-C7H7SO2)+]; m/z = 91 (C7H7+) peak of the molecular ion.

Example 76

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(1H-indol-5-yl)-1H-pyrazole

Follow the procedure of example 38, but using 1 g of 1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-iodine-1H-pyrazole, 0,797 g 1H-indole-5-Voronovo acid, 1,026 g of potassium carbonate, 0,463 g dichlorobis(triphenylphosphine)palladium in 30 cm3toluene, 6 cm3ethanol and 3 cm3water. After purification by chromatography under a nitrogen pressure of 50 kPa on a column of aluminum oxide SVT, elwira with ethyl acetate, then with a mixture of ethyl acetate and methanol (95:5 then 90:10 then 80:20 by volume), fractions 97-110 unite, concentrate to dryness under reduced pressure (3 kPa). The residue is precipitated in a mixture of 5 cm3ethyl acetate and 25 cm3diisopropyl ether. Thus obtain 0.18 g of 1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(1H-indol-5-yl)-1H-pyrazole in the form of a yellow powder.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in d): of 1.34 (m, 1H); from 1.53 to 1.75 (m, 3H); 2.13 in (m, 1H); from 2.67 to of 2.81 (m, 3H); to 3.02 (m, 1H); 3,26 (m partially hidden, 1H); to 3.49 (m, 1H); of 4.44 (m, 1H); 6,40 (m, 1H); 7.29 trend to 7.41 (m, 3H); 7,75 (ush., 1H); 7,87 (ush., 1H); by 8.22 (ush., 1H); 11.0 in (m ush., 1H).

IR-spectrum (KBr): 3113; 2939; 1587; 1454; 1362; 1165; 1058; 976; 881; 792; 729; 619 and 435 cm-1.

Mass spectrum (ES): m/z = 293 (MN+) peak of the molecular ion.

The enantiomers separated by HPLC on a column of phase Chiralpak AD 20 μm using used as eluent a mixture of heptane, ethanol and butylamine (40:60:0.2 to by volume). Get 2 enantiomer a and b, which are cleaned by the following method.

Enantiomer And purified by extraction with ethyl acetate, then dissolved in 100 ml of water. The pH value of the solution is set to 10 using 0.1 G. of sodium hydroxide solution. The organic phase is extracted with 100 ml of ethyl acetate. The aqueous phase is treated with 2 times 50 ml of dichloromethane and decanted. The organic phase is dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure. The organic phase is monitored by HPLC with polarity reversed phase column (Thermo hypersil Hypurity C18, 250×4,6×5 μm; eluent: gradient 95/5: acetate buffer/acetonitrile in 50 minutes. Get of 42.6 mg (-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(1H-indol-5-yl)-1H-pyrazole; enantiomer ([α]20D= -37,3° (solvent: dimethylsulfoxide; concentration of 0.3)).

Enantiomer In about imaut by extraction with ethyl acetate, then dissolved in 100 ml of water. The pH value of the solution is set to 10 using 0.1 G. of sodium hydroxide solution. The organic phase is extracted with 100 ml of ethyl acetate. The aqueous phase is treated with 2 times 50 ml of dichloromethane and decanted. The organic phase is dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure. The organic phase is monitored by HPLC with polarity reversed phase column (Thermo hypersil Hypurity C18, 250×4,6×5 μm; eluent: gradient 95/5: acetate buffer/acetonitrile in 50 minutes. Get 56,3 mg (+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(1H-indol-5-yl)-1H-pyrazole; enantiomer ([α]20D= +36,2° (solvent: dimethylsulfoxide; concentration: 0,42)).

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-iodine-1H-pyrazole

Follow the procedure of example 5, but using of 0.48 g of sodium hydride (75 wt.% dispersion in vaseline oil), 3,079 g 1-azabicyclo[2,2,2]Oct-3-silt ester toluene-4-sulfonic acids and of 1.94 g of 4-iterate 30 cm3of dimethylformamide. The residue is purified by chromatography under a nitrogen pressure of 50 kPa on a column of aluminum oxide SVT, elwira with ethyl acetate, then with a mixture of ethyl acetate and methanol (95:5 then 90:10 by volume). Faction 29-30 unite, concentrate to dryness under reduced pressure (3 kPa). The oil obtained is again purified on a column of aluminum oxide SVT, elwira with ethyl acetate. Coat the AI 11-15 unite, concentrate to dryness under reduced pressure (3 kPa). Thus obtain 0.33 g of 1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-iodine-1H-pyrazole in the form of oil, which crystallizes.

1H-NMR-spectrum (400 MHz, DMSO-d6, δ in ppm): 1,30 (m, 1H); of 1.46 (m, 1H); of 1.66 (m, 2H); 2.05 is (m, 1H); from 2.65 to 2,78 (m, 4H); 2.91 in (m, 1H); 3,21 (m partially hidden, 1H); of 4.44 (m, 1H); 7,58 (ush., 1H); 8,06 (ush., 1H).

Mass spectrum (S): m/z = 303 (M+.); m/z = 220(M-C5H9N)+.]; m/z = 109 (C7H11N+.); m/z = 97 (C6H11N+.) peak of the molecular ion.

Example 77

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(5-chlorothiophene-2-yl)-1H-pyrazole-3-algebroid, isomer And

Follow the procedure of example 38, but using of 0.13 g of 1-(1-azabicyclo[2,2,2]Oct-3-yl)-3-benzyloxy-4-(5-chlorothiophene-2-yl)-1H-pyrazole, isomer A, 10 cm312 N. hydrochloric acid and 15 cm3of ethanol. The mixture is heated for 22 hours at a temperature of about 100°C., then cooled to a temperature of about 20°C; the reaction mixture is concentrated to dryness under reduced pressure (3 kPa), then treated 2 times with 20 cm3ethanol and concentrated to dryness under reduced pressure (2 kPa); the residue is precipitated in 20 cm3diisopropyl ether. Receive 80 mg of 1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(5-chlorothiophene-2-yl)-1H-pyrazole-3-algebrabased, isomer A, in the form of a grayish powder.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1.62 to 198 (m, 4H); a 2.36 (m, 1H); from 3,07 to 3,55 (m partially hidden, 4H); 3,71 (m, 2H); to 4.62 (m, 1H); 7.03 is (m, 2H); 8,10 (ush., 1H); 10,75 (m ush., 1H).

IR-spectrum (KBr): 1602, 1536; 1459; 1164; 1005; 795 and 502 cm-1.

Mass spectrum (ES): m/z = 310 (MH+) peak of the molecular ion.

[α]D= -14° (solvent: methanol; concentration: 0,1266)

Example 78

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(5-chlorothiophene-2-yl)-1H-pyrazole-3-algebroid, the isomer In

Follow the procedure of example 38, but using of 0.13 g of 1-(1-azabicyclo[2,2,2]Oct-3-yl)-3-benzyloxy-4-(5-chlorothiophene-2-yl)-1H-pyrazole, isomer, 5 cm312 N. hydrochloric acid and 10 cm3of ethanol. The mixture is heated for 15 hours at a temperature of about 100°C., then cooled to a temperature of about 20°C; the reaction mixture is concentrated to dryness under bonigen pressure (3 kPa), then treated 2 times with 20 cm3toluene and concentrated to dryness under reduced pressure (2 kPa); the residue is treated 3 times by 20 cm3ethanol and concentrated to dryness under reduced pressure (2 kPa). The thus obtained residue precipitated in 20 cm3diisopropyl ether. Receive 100 mg of 1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(5-chlorothiophene-2-yl)-1H-pyrazole-3-algebrabased, isomer, in the form of a grayish powder.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1.62 to 2.00 (m, 4H); of 2.38 (m, 1H); from 3,05 to 3.53 (m, 4H); to 3.73 (m, 2H); 4,63 (m, 1H); 7.03 is (m, 2H); 8,11 (ush., 1H); 10,75 (m ush., 1H).

The IR spectrum of the (KBr): 1601, 1536; 1457; 1163; 1004; 794 and 502 cm-1.

Mass spectrum (IC): m/z = 310 (MH+) peak of the molecular ion.

[α]D= -18° (solvent: methanol; concentration: 0, 2168)

1-(1-azabicyclo[2,2,2]Oct-3-yl)-3-benzyloxy-4-(5-chlorothiophene-2-yl)-1H-pyrazole, isomers a and b

Follow the procedure of example 5, but using 0,495 g of sodium hydride (75 wt.% dispersion in vaseline oil), 3,178 g complex 1-azabicyclo[2,2,2]Oct-3-silt ester toluene-4-sulfonic acids and of 1.94 g of 3-benzyloxy-4-(5-chlorothiophene-2-yl)pyrazole 70 cm3of dimethylformamide. The residue is purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (grain size distribution 20-45 μm; diameter 3 cm; height, 50 cm), elwira dichloromethane, then with a mixture of dichloromethane and methanol (95:5 then 90:10 then 80:20 by volume). Faction 52-74 unite, concentrate to dryness under reduced pressure (3 kPa). The oil obtained is again purified on a column of aluminum oxide SVT, elwira with ethyl acetate, then with a mixture of ethyl acetate and methanol (90:10 by volume). Fractions 22, 32 and 40-50 unite, concentrate to dryness under reduced pressure (3 kPa). Thus obtained 0.5 g of 1-(1-azabicyclo[2,2,2]Oct-3-yl)-3-benzyloxy-4-(5-chlorothiophene-2-yl)-1H-pyrazole in the form of oil green colors, which crystallizes, 2 enantiomer is divided by HPLC.

Mass spectrum (S): m/z = 399 (M+.); m/z = 308 [M-C7H7)+]; m/z = 110 (C7H12N+ ); m/z = 91 (C7H7+) peak of the molecular ion.

On the basis of 0.45 g of 1-(1-azabicyclo[2,2,2]Oct-3-yl)-3-benzyloxy-4-(5-chlorothiophene-2-yl)-1H-pyrazole enantiomers separated by HPLC on Chiralpak AD 20 μm, elwira a mixture of 70% heptane/15% ethanol/15% methanol/0.1% triethylamine. Obtain 138 mg of 1-(1-azabicyclo[2,2,2]Oct-3-yl)-3-benzyloxy-4-(5-chlorothiophene-2-yl)-1H-pyrazole, isomer A ([α]D= +28,2° (solvent: methanol; concentration: 0,5)), and 129 mg of 1-(1-azabicyclo[2,2,2]Oct-3-yl)-3-benzyloxy-4-(5-chlorothiophene-2-yl)-1H-pyrazole, isomer B ([α]D= -24,6° (solvent: methanol; concentration: 0,5)).

Mass spectrum (S): m/z = 399 (M+.); m/z = 308 [M-C7H7)+]; m/z = 110 (C7H12N+); m/z = 91 (C7H7+) peak of the molecular ion.

Example 79

1-(1-azabicyclo[2,2,2]Oct-2-ylmethyl)-4-phenyl-1H-pyrazole-3-algebroid

To a solution of 0.8 g of 2-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]octane in 20 cm3ethanol add 1.8 cm36 N. hydrochloric acid, stirred for 30 minutes at room temperature, then concentrated to dryness under reduced pressure (3 kPa). A suspension of the obtained residue and 114 mg of 10%palladium-on-coal 20 cm3ethanol is stirred in an autoclave at a hydrogen pressure of 100 kPa at 20°C for 8 hours. The reaction mixture was then filtered through celite®and the end of tryout to dryness under reduced pressure (3 kPa), getting pasty residue is again treated with 40 cm3acetone and RUB until complete crystallization. After filtering off the resulting solid and drying under vacuum (70 PA) at a temperature of 60°With a gain of 0.6 g of 1-(1-azabicyclo[2,2,2]Oct-2-ylmethyl-4-phenyl-1H-pyrazole-3-algebrabased in the form of beige crystals, melting at a temperature above 260°C.

1H-NMR spectrum (300 MHz, DMSO-d6(when standardized to 2.50 ppm), δ in ppm): 1.55V (m, 1H); 1.71 to 1,95 (m, 5H); of 2.08 (m, 1H); from 3,12 up to 3.35 (m partially hidden, 3H); 3,50 (m, 1H); 3,88 (m, 1H); 4,27 (DD, J=7,5 and 14.0 Hz, 1H); was 4.42 (DD, J=7,5 and 14.0 Hz, 1H); 7,12 (t ush., J=7.5 Hz, 1H); 7,32 (t ush., J=7.5 Hz, 2H); 7,63 (l ush., J=7.5 Hz, 2H); 8,01 (s, 1H); 9,80 (m ush., 1H); 10,45 (m ush., 1H).

Mass spectrum (S): m/z = 283 (M+.); m/z = 201(M-C5H8N)+.]; m/z = 173 [(M-C7H12N)+.]; m/z = 124 (C8H14N+) peak of the molecular ion; m/z = 82 (C5H8N+); m/z = 36 (HCl+.).

2-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]octane can be obtained as follows.

To a solution of 0.95 g of 3-benzyloxy-4-phenylpyrazol 20 cm3anhydrous DMF (dimethylformamide) gradually add in an argon atmosphere and at room temperature, 182 mg of sodium hydride (75 wt.% dispersion in vaseline oil). After stirring for 0.75 hour at a temperature of about 50°C. gradually add Rast is the PR of 1.25 g of 1-azabicyclo[2,2,2]Oct-2-ylmethylphosphonate 20 cm 3anhydrous DMF (dimethylformamide), and then heated for 24 hours at a temperature of about 110°C. the Mixture is cooled to room temperature, then slowly add 10 cm3water, and finally concentrated in a rotary evaporator. To the obtained residue, add 25 cm3water and extracted with 250 cm3ethyl acetate. The organic phase is washed with 3 times 25 cm3water, then filtered through a filter to separate (Whatman®; standard: 2200 185) and concentrated to dryness under reduced pressure (3 kPa). The obtained oily residue is purified by chromatography on aluminium oxide, elwira dichloromethane. After concentrating the fractions under reduced pressure to obtain 0.8 g of 2-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]octane in the form of an oil which slowly solidifies to amorphous solids.

Mass spectrum (S): m/z = 373 (M+.); m/z = 282(M-C7H7)+]; m/z = 124 (C8H14N+); m/z = 91 (C7H7+) peak of the molecular ion; m/z = 82 (C5H8N+).

1-azabicyclo[2,2,2]Oct-2-ylmethylphosphonate can be obtained as follows.

To a solution of 1 g (1-azabicyclo[2,2,2]Oct-2-yl)methanol at 40 cm3dichloromethane at a temperature of about 0°C in an argon atmosphere add to 0.69 cm3pyridine, then added dropwise to 0.66 cm3methanesulfonyl the reed. The suspension is stirred for 20 minutes at a temperature of about 0°C, then for 18 hours at room temperature. To the mixture then add 15 cm3aqueous saturated potassium carbonate solution and extracted with 3 times 50 cm3ethyl acetate. The combined organic phases are dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). The resulting residue is purified by chromatography on aluminium oxide, elwira with ethyl acetate. After concentrating the fractions under reduced pressure to obtain 1.1 g of 1-azabicyclo[2,2,2]Oct-2-ylmethylphosphonate in the form of a colorless oil.

Mass spectrum (S): m/z = 219 (M+.); m/z = 140 [(M-SO2CH3)+]; m/z = 124 (C8H14N+); molecular ion peak.

(1-azabicyclo[2,2,2]Oct-2-yl)methanol can be obtained according to the method described in patent DE 1938546.

Example 80

3-[4-(3,5-differenl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octahedrally

To a solution of 0.65 g of 4-(3,5-differenl)-1H-pyrazole in 30 cm3anhydrous DMF (dimethylformamide) gradually add in an argon atmosphere and at room temperature 0,173 g of sodium hydride (75 wt.% dispersion in vaseline oil). After stirring for 0.75 hour at a temperature of about 50°C is added dropwise a solution of 1.17 g of 3-[(methanesulfonyl)oxy]-1-azabicyclo[2,2,2]octane in 10 cm3besod the CSOs of dimethylformamide, then heated for 20 hours at a temperature of about 110°C. the Mixture is cooled to room temperature, then slowly add 5 cm3water and concentrate under reduced pressure (3 kPa). The residue is treated with 20 cm3water and extracted with 250 cm3ethyl acetate. The organic phase is washed 4 times with 20 cm3water, then dried, filtered and concentrated to dryness under reduced pressure (3 kPa). The resulting residue is purified by chromatography on aluminium oxide, elwira a mixture of dichloromethane and ethyl acetate (70:30 by volume). After concentrating the fractions under reduced pressure to obtain an oil which is dissolved in 35 cm3of acetone, and add 20 cm31 M solution of hydrogen chloride in diethyl ether. After stirring for 1 hour at room temperature, the formed precipitate was separated by filtration and dried under vacuum (70 kPa) at 40°C. are Thus obtained of 0.44 g of 3-[4-(3,5-differenl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octahedrally in the form of hygroscopic crystals white.

1H-NMR spectrum (300 MHz, DMSO-d6(when standardized to 2.50 ppm), δ in ppm): 1,71 (m, 2H); 2,00 (m, 2H); to 2.42 (m, 1H); from 3,20 up to 3.48 (m, 4H); from 3,75 to 3,95 (m, 2H); of 4.90 (m, 1H); 7,05 (TT, J=2.5 and 9.5 Hz, 1H); 7,40 (m, 2H); 8.17 and (ush., 1H); 8,60 (ush., 1H); 10,6 (m ush., 1H).

Mass spectrum (S): m/z = 289 (M+.) peak of the molecular ion; m/z 206 [M-C 5H8N)+.]; m/z = 109 (C7H11N+.); m/z = 36 (HCl+.).

4-(3,5-differenl)-1H-pyrazole can be obtained as follows.

To a solution of 2.1 g of 4-(3,5-differenl)-1-(toluene-4-sulfonyl)-1H-pyrazole 70 cm3tetrahydrofuran at room temperature add 15,7 cm31 M solution of tetrabutylammonium in tetrahydrofuran. The mixture is refluxed for 4.5 hours, then cooled to room temperature and concentrated to dryness under reduced pressure (3 kPa). To the residue are added 50 cm3water and extracted with 200 cm3ethyl acetate. The organic phase is washed with 50 cm3water, then 25 cm3aqueous saturated solution of sodium chloride and finally dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). The remainder proscout 40 cm3dichloromethane, then allocate by filtration under vacuum. Thus obtained 0.65 g of 4-(3,5-differenl)-1H-pyrazole as white crystals, melting at about 185°C.

Mass spectrum (S): m/z = 180 (M+.) peak of the molecular ion; m/z = 153 [(M-HCN)+]; m/z = 126 [(m/z = 153-HCN)+.].

4-(3,5-differenl)-1-(toluene-4-sulfonyl)-1H-pyrazole can be obtained as follows.

To a solution of 3.5 g of 4-iodine-1-(toluene-4-sulfonyl)-1H-pyrazole in 100 sup> 31,2-dimethoxyethane add in an argon atmosphere and at room temperature of 6.31 g of 3,5-diftorhinolonom acid. The reaction medium is heated to a temperature of 110°C and then add 8.5 g of finely ground tribalista and of 0.91 g of bis(triphenylphosphine)pallidiflora, then refluxed for 3.5 hours. The mixture is cooled to room temperature, filtered through celite®which is then washed with 500 cm3ethyl acetate. The organic phase is washed with 5 times 100 cm3water, then 2 times 100 cm3aqueous saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). The residue is purified by chromatography on silica, elwira cyclohexane, then dichloromethane. After concentrating the fractions under reduced pressure to obtain 2.2 g of 4-(3,5-differenl)-1-(toluene-4-sulfonyl)-1H-pyrazole in the form of white powder.

Mass spectrum (S): m/z = 334 (M+.); m/z = 270(M-SO2)+.]; m/z = 155 (C7H7SO2+); m/z = 91 (C7H7+) peak of the molecular ion.

Example 81

4-benzo[b]thiophene-2-yl-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebroid

To a solution of 930 mg of 1-[2-(4-benzo[b]thiophene-2-yl-3-benzyl-occipital-1-yl)ethyl]piperidine in 15 cm3ethanol in peremeci the years add 8 cm 312 N. hydrochloric acid. After heating for 7 hours at boiling temperature under reflux of the solvent, and then curing for 15 hours at a temperature of about 20°C, the reaction medium is evaporated to dryness under reduced pressure (2.7 kPa). The remainder, repeating three times, successively dissolved in ethanol and evaporated to dryness under reduced pressure (2.7 kPa), then proscout 20 cm3diisopropyl ether. The formed precipitate is filtered off and dried under vacuum (2.7 kPa)to give 790 mg of 4-benzo[b]thiophene-2-yl-1-(2-piperidine-1-retil)-1H-pyrazole-3-algebrabased in the form of a solid pale yellow color.

Mass spectrum (CI): 328(+) = (M+H)(+); the presence 36(+)/38(+) = HCl(+).

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): to 1.42 (m, 1H); from 1.65 to 1.89 (m, 5H); 2.95 and (m, 2H); from 3,38 up of 3.54 (m, 4H); of 4.44 (t, J=6.5 Hz, 2H); from 7.23 percent to 7.38 (m, 2H); to 7.50 (s, 1H); 7,78 (l ush., J=7.5 Hz, 1H); of 7.90 (d ush., J=7.5 Hz, 1H); 8,07 (s, 1H); from 10.05 to 10.2 (m very ush., 1H); 10,9 (m ush., 1H).

1-[2-(4-benzo[b]thiophene-2-yl-3-benzyloxyphenol-1-yl)ethyl]piperidine can be obtained as follows.

To a suspension of 225 mg of sodium hydride (75%dispersion in mineral oil) in 30 cm3of dimethylformamide in an argon atmosphere and with stirring portion 860 mg of 4-benzo[b]thiophene-2-yl-3-benzyloxy-1H-pyrazole. After heating for 30 minutes at a temperature of 50°C. the mixture is stirred is for 1 hour at a temperature of about 20°C, then add a portion 725 mg of 1-(2-chloroethyl)piperidinedione. The reaction mixture is stirred for 15 hours at a temperature of about 20°C, then bring in 100 cm3water. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed successively twice with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give yellow oil, which was purified by chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (95:5 by volume)]. After concentrating the fractions under reduced pressure to obtain 930 mg of 1-[2-(4-benzo[b]thiophene-2-yl-3-benzyloxyphenol-1-yl)ethyl]piperidine in the form of oil pale yellow color.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from to 1.34 to 1.54 (m, 6H); 2.40 a (m, 4H); 2,69 (t, J=6.5 Hz, 2H); 4,11 (t, J=6.5 Hz, 2H); lower than the 5.37 (s, 2H); from 7.23 to of 7.48 (m, 6H); 7,56 (l ush., J=8.5 Hz, 2H); 7,73 (l ush., J=7.5 Hz, 1H); of 7.90 (d ush., J=7.5 Hz, 1H); 8,10 (s, 1H).

4-benzo[b]thiophene-2-yl-3-benzyloxy-1H-pyrazole can be obtained as follows.

To a solution of 1.4 g of 4-benzo[b]thiophene-2-yl-3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazole in 30 cm3of tetrahydrofuran in an argon atmosphere and with stirring, dobavlat 7.6 cm31 N. solution tetrabutylammonium in tetrahydrofuran. After heating for 15 hours at t is mperature boiling under reflux of the solvent, the reaction mixture is evaporated under reduced pressure (2.7 kPa) and the residue is added ethyl acetate. The organic phase is washed successively twice with water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa). The resulting oil is pale yellow (0,98 g) purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (70:30 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 860 mg of 4-benzo[b]thiophene-2-yl-3-benzyloxy-1H-pyrazole in the form of a solid white color.

IR-spectrum (KBr): 3173; 2950; 1586; 1530; 1501; 1445; 1363; 1304; 1215; 1166; 1022; 818; 745; 736; 727; 693 and 564 cm-1.

4-benzo[b]thiophene-2-yl-3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazole can be obtained as follows.

To a solution of 2 g of 3-benzyloxy-4-iodine-1-(toluene-4-sulfonyl)-1H-pyrazole in 40 cm3toluene, to which was added 10 cm3ethanol in an argon atmosphere and with stirring, add 2.4 g of 2-benzothiazolinone acid, 6.6 cm32 N. an aqueous solution of potassium carbonate and 660 mg of tetrakis(triphenylphosphine)palladium. After heating for 5 hours at boiling temperature under reflux of the solvent and curing for 15 hours at a temperature of about 20°C. the reaction medium is evaporated under reduced giving the situation (2.7 kPa). To the residue is added ethyl acetate, water and activated charcoal and filtered through Supercel. The filtrate is decanted, then the organic phase is washed successively twice with water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa). The resulting orange oil (3.8 g) purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (90:10 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) obtained solid cream color proscout in diisopropyl ether. Get after filtration of 1.4 g of 4-benzo[b]thiophene-2-yl-3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazole in the form of a solid white color.

Mass spectrum (EI): 460(+) = M(+); 305(+) = M(+)-Ts.

Example 82

1-(2-piperidine-1-retil)-4-thiophene-3-yl-1H-pyrazole-3-algebroid

To a solution of 640 mg of 1-[2-(3-benzyloxy-4-thiophene-3-alprazol-1-yl)ethyl]piperidine in 10 cm3ethanol was added with stirring 6 cm312 N. hydrochloric acid. After heating for 7 hours at boiling temperature under reflux of the solvent, and then curing for 15 hours at a temperature of about 20°C. the reaction medium is evaporated to dryness under reduced pressure (2.7 kPa). The remainder with three consecutive repetitions is tion is dissolved in ethanol and evaporated to dryness under reduced pressure (2.7 kPa), then it proscout in diisopropyl ether. The formed precipitate is filtered off and dried under vacuum (2.7 kPa)to give 470 mg of 1-(2-piperidine-1-retil)-4-thiophene-3-yl-1H-pyrazole-3-algebrabased in a solid white color.

Mass spectrum (CI): 278(+) = (M+H)(+); the presence 36(+)/38(+) = HCl(+).

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): 1,40 (m, 1H); from 1.64 to a 1.88 (m, 5H); of 2.93 (m, 2H); from 3,35 to 3.52 (m, 4H); 4,39 (t, J=6.5 Hz, 2H); to 7.35 (DD, J=1.0 and 5.0 Hz, 1H); 7,49 (DD, J=1.0 and 3.0 Hz, 1H); at 7.55 (DD, J=3.0 and 5.0 Hz, 1H); 7,94 (s, 1H); 9,85 to 10.05 (m very ush., 1H); 10,4 (m ush., 1H).

1-[2-(3-benzyloxy-4-thiophene-3-alprazol-1-yl)ethyl]piperidine can be obtained as follows.

To a suspension of 200 mg of sodium hydride (75%dispersion in mineral oil) in 30 cm3of dimethylformamide in an argon atmosphere and with stirring, add a dose of 650 mg of 3-benzyloxy-4-thiophene-3-yl-1H-pyrazole. After heating for 30 minutes at a temperature of 50°C. the mixture is stirred for 30 minutes at a temperature of about 20°C, then to it was added portion 654 mg of 1-(2-chloroethyl)piperidinedione. The reaction medium is stirred for 15 hours at a temperature of about 20°C, then bring in 100 cm3water. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed successively twice with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filter the Ute and evaporated under reduced pressure (2.7 kPa), getting an orange oil, which was purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (95:5 by volume)]. After concentrating the fractions under reduced pressure to obtain 640 mg of 1-[2-(3-benzyloxy-4-thiophene-3-alprazol-1-yl)ethyl]piperidine in the form of a yellow oil.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1.32 to 1.54 (m, 6H); of 2.38 (m, 4H); to 2.67 (t, J=6.5 Hz, 2H); 4,06 (t, J=6.5 Hz, 2H); and 5.30 (s, 2H); from 7,30 to 7.55 (m, 8H); 7,98 (s, 1H).

3-benzyloxy-4-thiophene-3-yl-1H-pyrazole can be obtained as follows.

To a solution of 1.35 g of 3-benzyloxy-4-thiophene-3-yl-1-(toluene-4-sulfonyl)-1H-pyrazole in 30 cm3of tetrahydrofuran in an argon atmosphere and with stirring, add 8.5 cm31 N. solution tetrabutylammonium in tetrahydrofuran. After heating for 15 hours at boiling temperature under reflux of the solvent reaction medium is evaporated under reduced pressure (2.7 kPa) and the residue is added ethyl acetate. The organic phase is washed successively three times with water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa). The obtained residue (0.96 g) purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (70:30 by volume)]. After the end of the tiravanija fractions under reduced pressure (2.7 kPa) to obtain 650 mg of 3-benzyloxy-4-thiophene-3-yl-1H-pyrazole in the form of a cream solid color.

Mass spectrum (EI): 256(+) = M(+); 91(+) = C7H7(+).

3-benzyloxy-4-thiophene-3-yl-1-(toluene-4-sulfonyl)-1H-pyrazole can be obtained as follows.

To a solution of 2 g of 3-benzyloxy-4-iodine-1-(toluene-4-sulfonyl)-1H-pyrazole in 40 cm3toluene, to which was added 10 cm3ethanol in an argon atmosphere and with stirring, add 1.7 g of 3-thienylboronic acid, 6.6 cm32 N. an aqueous solution of potassium carbonate and 660 mg of tetrakis(triphenylphosphine)palladium. After heating for 5 hours at boiling temperature under reflux of the solvent and curing for 15 hours at a temperature of about 20°C. the reaction medium is evaporated under reduced pressure (2.7 kPa). To the residue is added ethyl acetate, water and activated charcoal and filtered through Supercel. The filtrate is decanted, then the organic phase is washed successively twice with water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa). The obtained solid substance proscout in diisopropyl ether, filtered off and crystallized from 10 cm3of ethanol. Thus obtain 1.35 g of 3-benzyloxy-4-thiophene-3-yl-1-(toluene-4-sulfonyl)-1H-pyrazole in the form of a solid beige color.

Mass spectrum (EI): 410(+) = M(+); 255(+) = M(+)-Ts.

Example 83

4-[3-hydroxy-1-(2-piperidine-1-retil)-1H-shall irsol-4-yl]benzenedithiol

To a solution of 442 mg of 4-[3-benzyloxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzamide in 20 cm3ethanol add 4 cm33 n solution of hydrogen chloride in diethyl ether. After stirring for 1 hour at a temperature of about 20°C. the solution is evaporated to dryness under reduced pressure (2.7 kPa). The residue is treated with 25 cm3of ethanol. The resulting solution was injected into the autoclave and added 52 mg of 10%palladium-on-charcoal, then placed in an atmosphere of hydrogen (10 bar). After stirring for 8 hours at a temperature of 22°C. the reaction medium is filtered through Supercel, the filtrate is evaporated and the residue proscout in diisopropyl ether. The obtained solid is filtered off, dried under vacuum (2.7 kPa)to give 118 mg of 4-[3-hydroxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzenedicarboxamide in the form of a cream solid color.

Mass spectrum (CI): 315(+) = (M+H)(+).

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): 1,41 (m, 1H); from 1.64 to 1.89 (m, 5H); to 2.94 (m, 2H); from 3.25 to 3.53 (m, 4H); to 4.41 (t, J=6.5 Hz, 2H); 7.23 percent (m ush., 1H); 7,73 (l ush., J=8.5 Hz, 2H); from 7,83 to 7.91 (m, 3H); to 8.14 (s, 1H); from 9,80 to 9.95 (m very ush., 1H); 10,65 (ush., 1H).

4-[3-benzyloxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzamide can be obtained as follows.

To a suspension 144 mg of sodium hydride (75%dispersion in mineral oil) in 30 cm3of dimethylformamide in an argon atmosphere and n and stirring portion 527 mg of 4-(3-benzyloxy-1H-pyrazole-4-yl)benzamide. After heating for 30 minutes at a temperature of 50°C. the mixture is stirred for 30 minutes at a temperature of about 20°C, then to it was added portion 465 mg of 1-(2-chloroethyl)piperidinedione. The reaction medium is stirred for 15 hours at a temperature of about 20°C, then bring in 100 cm3water. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed successively twice with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa). The obtained solid substance proscout in diisopropyl ether, filtered off and crystallized from acetone. So get 445 mg of 4-[3-benzyloxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzamide in the form of a solid white color.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1.32 to 1.54 (m, 6H); 2,39 (m, 4H); 2,69 (t, J=6.5 Hz, 2H); 4.09 to (t, J=6.5 Hz, 2H); 5,33 (s, 2H); from 7.24 (m ush., 1H); from 7,32 to 7.46 (m, 3H); 7,52 (d ush., J=8.5 Hz, 2H); 7,70 (l ush., J=7.5 Hz, 2H); from 7,81 to 7,88 (m, 3H); 8,17 (s, 1H).

4-(3-benzyloxy-1H-pyrazole-4-yl)benzamide can be obtained as follows.

To a solution of 1.1 g of 4-[3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazole-4-yl]benzamide 30 cm3tetrahydrofuran (THF) add 6.5 cm31 N. solution tetrabutylammonium in tetrahydrofuran. After heating for 15 hours at temperature the round boiling under reflux of the solvent reaction medium is cooled in a bath with ice. After filtration, and then drying the obtained crystals in vacuum (2.7 kPa) receive 527 mg of 4-(3-benzyloxy-1H-pyrazole-4-yl)benzamide in the form of a solid white color.

IR-spectrum (KBr): 3403; 3176; 1667; 1611; 1576; 1553; 1517; 1485; 1393; 1379; 1226; 1040; 1027 and 739 cm-1.

4-[3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazole-4-yl]benzamide can be obtained as follows.

To a solution of 2.5 g of 3-benzyloxy-4-iodine-1-(toluene-4-sulfonyl)-1H-pyrazole in 40 cm3toluene, to which was added 10 cm3ethanol in an argon atmosphere and with stirring, add 2,72 g of 4-aminocarbonylmethyl acid, 8.3 cm32 N. an aqueous solution of potassium carbonate and 830 mg of tetrakis(triphenylphosphine)palladium. After heating for 15 hours at boiling temperature under reflux of the solvent reaction medium is cooled to a temperature of about 20°C. and evaporated under reduced pressure (2.7 kPa). To the residue is added ethyl acetate, water and activated charcoal and filtered through Supercel. The filtrate is decanted, then the organic phase is washed successively twice with water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa). The resulting yellow oil (3.7 g) purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (50:0, then 20:80 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 1.1 g of 4-[3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazole-4-yl]benzamide in the form of a solid white color.

Mass spectrum (EI): 447(+) = M(+); 91(+) = C7H7(+).

Example 84

3-[3-hydroxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzenedithiol

To a solution of 690 mg of 3-[3-benzyloxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzamide in 20 cm3ethanol add 4 cm33 n solution of hydrogen chloride in diethyl ether. After stirring for 45 minutes at a temperature of about 20°C. the solution is evaporated to dryness under reduced pressure (2.7 kPa). The residue is treated with 25 cm3of ethanol. The resulting solution was injected into the autoclave and to it add 80 mg of 10%palladium-on-charcoal, then placed in an atmosphere of hydrogen (10 bar). After stirring for 8 hours at a temperature of 22°C. the reaction medium is filtered through Supercel, the filtrate is evaporated and the residue proscout in diisopropyl ether. The obtained solid is filtered off, dried under vacuum (2.7 kPa)to give 528 mg of 3-[3-hydroxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzenedicarboxamide in the form of a solid pale yellow color.

Mass spectrum (CI): 315(+) = (M+H)(+).

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): 1,40 (m, 1H); from 1.65 to a 1.88 (m, 5H); to 2.94 (m, 2H); about the 3,41 up of 3.54 (m, 4H); was 4.42 (t, J=6.5 Hz, 2H); 7,33 (m ush., 1H); 7,42 (t, J=8.0 Hz, 1H); to 7.64 (d ush., J=8.0 Hz, 1H); of 7.82 (d ush., J=8.0 Hz, 1H); 7,94 (m ush., 1H); 8,10 (s, 1H); 8,14 (ush., 1H); from 9,90 to 10.05 (m very ush., 1H); 10,55 (ush., 1H).

3-[3-benzyloxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzamide can be obtained as follows.

To a suspension 315 mg of sodium hydride (75%dispersion in mineral oil) in 30 cm3of dimethylformamide in an argon atmosphere and with stirring, add a portion of 1.16 g of 3-(3-benzyloxy-1H-pyrazole-4-yl)benzamide. After heating for 30 minutes at a temperature of 50°C. the mixture is stirred for 30 minutes at a temperature of about 20°C, then to it was added portion 1 g of 1-(2-chloroethyl)piperidinedione. The reaction medium is stirred for 15 hours at a temperature of about 20°C, then bring in 100 cm3water. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed successively twice with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give a yellow oil (1.6 g), which was purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: dichloromethane, then dichloromethane/methanol (98:2; 95:5 then 90:10 by volume)]. After concentrating the fractions under reduced pressure to obtain 700 mg of 3-[3-benzyloxy-1-(2-piperidine-1-retil)-1 is-pyrazole-4-yl]benzamide in the form of oil pale yellow color.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1.33 to 1.54 (m, 6H); 2.40 a (m, 4H); 2,70 (t, J=6.5 Hz, 2H); 4,10 (t, J=6.5 Hz, 2H); 5,33 (s, 2H); from 7,30 to 7,44 (m, 5H); 7,53 (l ush., J=8.5 Hz, 2H); 7,63 (l ush., J=8.0 Hz, 1H); 7,80 (l ush., J=8.0 Hz, 1H); 7,92 (m ush., 1H); 8,11 (s, 1H); 8,15 (ush., 1H).

3-(3-benzyloxy-1H-pyrazole-4-yl)benzamide can be obtained as follows.

To a solution of 2.1 g of 3-[3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazole-4-yl]benzamide 40 cm3of tetrahydrofuran in an argon atmosphere and with stirring, add 11.8 cm31 N. solution tetrabutylammonium in tetrahydrofuran. After heating for 15 hours at boiling temperature under reflux of the solvent reaction medium is evaporated under reduced pressure (2.7 kPa) and the residue is added ethyl acetate. The organic phase is washed successively twice with water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa). The remainder proscout in diisopropyl ether, filtered off and dried under vacuum (2.7 kPa), receiving of 1.16 g of 3-(3-benzyloxy-1H-pyrazole-4-yl)benzamide in the form of a cream solid color.

IR-spectrum (KBr): 3332; 3196; 2975; 1682; 1606; 1581; 1572; 1505; 1447; 1389; 1280; 1232; 1049; 732; 695; 672 and 637 cm-1.

3-[3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazole-4-yl]benzamide can be obtained as follows.

To a solution of 2.5 g of 3-benzyloxy-4-yo is-1-(toluene-4-sulfonyl)-1H-pyrazole in 40 cm 3toluene, to which was added 10 cm3ethanol in an argon atmosphere and with stirring of 2.72 g of 3-aminocarbonylmethyl acid, 8.3 cm32 N. an aqueous solution of potassium carbonate and 830 mg of tetrakis(triphenylphosphine)palladium. After heating for 15 hours at boiling temperature under reflux of the solvent reaction medium is cooled in a bath with ice. After filtration, and then drying the obtained crystals in vacuum (2.7 kPa) to obtain 2.1 g of 3-[3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazole-4-yl]benzamide in the form of a solid white color.

Mass spectrum (EI): 447(+) = M(+); 91(+) = C7H7(+).

Example 85

(-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-algebroid

To a solution of 1.44 g of (+)-3-(3-benzyloxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2,2,2]octane in 20 cm3ethanol was added with stirring 15 cm312 N. hydrochloric acid. After heating for 7 hours at boiling temperature under reflux of the solvent, and then curing for 15 hours at a temperature of about 20°C. the reaction medium is evaporated to dryness under reduced pressure (2.7 kPa). The remainder with three repetitions sequentially dissolved in ethanol and evaporated to dryness under reduced pressure (2.7 kPa), then it proscout 20 cm3diisopropyl ether. The image is vasica precipitate is filtered off and dried under vacuum (2.7 kPa), receiving 1.2 g of (-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-algebrabased in a solid white color.

Mass spectrum (EI): 269(+) = M(+); the presence 36(+)/38(+) = HCl(+).

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1,69 to 2.04 (m, 4H); 2,43 (m, 1H); from 3,22 to 3.47 (m, 4H); 3.72 points to 3.85 (m, 2H); of 4.67 (m, 1H); 7,15 (TT, J=1.5 and 7.5 Hz, 1H); 7,34 (t ush., J=7.5 Hz, 2H); to 7.67 (d ush., J=7.5 Hz, 2H); 8,18 (s, 1H); 10,2 (m ush., 1H); 10,4 (m ush., 1H).

[α]20D= -17,4° ± 0,6° (C = 0,5; methanol).

(+)-3-(3-benzyloxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2,2,2]octane and (-)-3-(3-benzyloxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2,2,2]octane can be obtained as follows.

The ethanol solution containing 1.5 g of 3-(3-benzyloxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2,2,2]octane injected into a column of diameter 6 cm, containing 800 g of chiral stationary phase Chiralpak ADTM. Elution is carried out using a mixture of 10% ethanol, 10% methanol, 0.1% triethylamine and 80% heptane. The flow rate of the mobile phase is 90 ml/min Programalso enantiomer elute in the first place, the solution is evaporated to dryness under reduced pressure (2.7 kPa)to give 0.66 g of oil.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): 1,30 (m, 1H); 1.50 to 1.71 (m, 3H); of 2.08 (m, 1H); from 2.65 to 2.79 (m, 3H); 2,99 (m, 1H); from 3.15 and $ 3.42 (m, 2H); 4,27 (m, 1H); 5,33 (s, 2H); 7,15 (TT, J=1.5 and 7.5 Hz, 1H); from 7,30 to 7,44 (m, 5H); 7,51 (l ush., J=7.5 Hz, 2H); 7,69 (l ush., J=7.5 Hz, 2H); to 8.20 (s, 1H).

[α]20D= +27,0° ± 0,8° (C = 0,5; methane is).

The solution containing levogyrate enantiomer, eluruumis in the second place, is evaporated to dryness under reduced pressure (2.7 kPa)to give 0.65 g of oil.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): 1,31 (m, 1H); 1.50 to 1.72 (m, 3H); of 2.09 (m, 1H); from 2,66 to 2.80 (m, 3H); 2,99 (m, 1H); from 3,16 to 3.43 (m, 2H); 4,29 (m, 1H); of 5.34 (s, 2H); 7,14 (TT, J=1.5 and 7.5 Hz, 1H); from 7,30 to 7,44 (m, 5H); 7,51 (l ush., J=7.5 Hz, 2H); 7,70 (l ush., J=7.5 Hz, 2H); to 8.20 (s, 1H).

[α]20D= -27,0° ± 0,8° (C = 0,5; methanol).

Example 86

(+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-algebroid

To a solution of 1.44 g of (-)-3-(3-benzyloxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2,2,2]octane in 20 cm3ethanol was added with stirring 15 cm312 N. hydrochloric acid. After heating for 7 hours at boiling temperature under reflux of the solvent, and then curing for 15 hours at a temperature of about 20°C. the reaction medium is evaporated to dryness under reduced pressure (2.7 kPa). The remainder with three repetitions sequentially dissolved in ethanol and evaporated to dryness under reduced pressure (2.7 kPa), then it proscout 20 cm3diisopropyl ether. The formed precipitate is filtered off and dried under vacuum (2.7 kPa)to give 1.2 g of (+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-algebrabased in a solid beige color.

Mass spectrum (EI): 269(+) = M(+); ricotta 36(+)/38(+) = HCl(+).

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1,70 to 2.03 (m, 4H); 2,43 (m, 1H); from 3,22 to 3.47 (m, 4H); 3.72 points to 3.86 (m, 2H); and 4.68 (m, 1H); 7,15 (TT, J=1.5 and 7.5 Hz, 1H); 7,34 (t ush., J=7.5 Hz, 2H); to 7.67 (d ush., J=7.5 Hz, 2H); 8,19 (s, 1H); 10,2 (m ush., 1H); 10.3 to 10.5 (m very ush., 1H).

[α]20D= +13,7° ± 0,6° (C = 0,5; methanol).

Example 87

(-)-1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-phenyl-1H-pyrazole-1-algebroid

To a solution of 825 mg of (-)-3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]octane in 10 cm3ethanol was added with stirring 10 cm312 N. hydrochloric acid. After heating for 7 hours at boiling temperature under reflux of the solvent, and then curing for 15 hours at a temperature of about 20°C. the reaction medium is evaporated to dryness under reduced pressure (2.7 kPa). The remainder with three repetitions sequentially dissolved in ethanol and evaporated to dryness under reduced pressure (2.7 kPa), then it proscout in diisopropyl ether. The formed precipitate is filtered off and dried under vacuum (2.7 kPa)to give 700 mg of (-)-1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-phenyl-1H-pyrazole-1-algebrabased in a solid white color.

Mass spectrum (EI): 283(+) = M(+).

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1.66 to of 1.93 (m, 4H); 2.05 is (m, 1H); 2,52 (m hidden, 1H); to 2.94 (m, 1H); from 3,12 to 3.40 (m, 5H); from 3,98 up of 4.12 (m, 2H); 7,13 (TT, J=1.5 and 7.5 Hz,1H); 7,33 (t ush., J=7.5 Hz, 2H); to 7.64 (d ush., J=7.5 Hz, 2H); to 7.99 (s, 1H); 10,1 (m ush., 1H).

[α]20D= -36,8° ± 0,8° (C = 0,5; methanol).

(-)-3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]octane and (+)-3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]octane can be obtained as follows.

To a suspension of 1.9 g of sodium hydride (75 wt.% dispersion in vaseline oil) in 50 cm3of dimethylformamide gradually add in an argon atmosphere and at a temperature of about 20°With a solution of 5 g of 3-benzyloxy-4-phenylpyrazol 30 cm3of dimethylformamide. After stirring for 1 hour at a temperature of about 50°C, add small portions of 5.8 g of 3-chloromethyl-1-azabicyclo[2,2,2]octahedrally, then heated for 15 hours at a temperature of about 90°C. the Mixture is cooled to a temperature of about 20°C, then bring in 400 cm3water. The aqueous phase is extracted 2 times with ethyl acetate. The combined organic phases are washed 2 times with water and aqueous saturated sodium chloride solution, then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The resulting orange oil purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (10:90 by volume), ethyl acetate, then ethyl acetate/methanol (95:5 by volume)]. After concentrating the fractions under reduced is the first pressure receiving 1.7 g oil pale yellow color.

Ethanol solution of this oil is introduced into a column with a diameter of 8 cm, containing 1180 g of chiral stationary phase Chiracel ODTM. Elution is carried out using a mixture of 50% ethanol, 0.1% triethylamine and 50% heptane. The flow rate of the mobile phase is 120 ml/min Levogyrate enantiomer elute in the first place, the solution is evaporated to dryness under reduced pressure (2.7 kPa), receiving of 0.82 g of oil.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1,24 up to 1.59 (m, 4H); of 1.78 (m, 1H); and 2.14 (m, 1H); is 2.37 (m, 1H); from 2,59 to 2,90 (m, 5H); to 3.89 (d, J=8.0 Hz, 2H); 5,31 (s, 2H); 7,14 (TT, J=1.5 and 7.5 Hz, 1H); from 7,30 to 7,44 (m, 5H); 7,50 (d ush., J=8.5 Hz, 2H); to 7.64 (d ush., J=8.5 Hz, 2H); of 8.09 (s, 1H).

[α]20D= -37,8° ± 0,8° (C = 0,5; methanol).

The solution containing programalso enantiomer, eluruumis in the second place, is evaporated to dryness under reduced pressure (2.7 kPa)to give 0.74 g of oil.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from to 1.24 to 1.60 (m, 4H); of 1.78 (m, 1H); and 2.14 (m, 1H); of 2.36 (m, 1H); from 2.60 to 2,90 (m, 5H); 4,00 (d, J=8.0 Hz, 2H); 5,31 (s, 2H); 7,14 (TT, J=1.5 and 7.5 Hz, 1H); from 7,30 to 7,44 (m, 5H); 7,50 (d ush., J=8.5 Hz, 2H); to 7.64 (d ush., J=8.5 Hz, 2H); of 8.09 (s, 1H).

[α]20D= +39,1° ± 0,9° (C = 0,5; methanol).

Example 88

(+)-1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-phenyl-1H-pyrazole-1-algebroid

To a solution of 740 mg (+)-3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]octane in 10 cm3ethanol was added with stirring 10 cm312 N. PI is estevadeordal acid. After heating for 7 hours at boiling temperature under reflux of the solvent, and then curing for 15 hours at a temperature of about 20°C. the reaction medium is evaporated to dryness under reduced pressure (2.7 kPa). The remainder with three repetitions sequentially dissolved in ethanol and evaporated to dryness under reduced pressure (2.7 kPa), then it proscout in diisopropyl ether. The formed precipitate is filtered off and dried under vacuum (2.7 kPa)to give 600 mg (+)-1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-phenyl-1H-pyrazole-1-algebrabased in a solid white color.

Mass spectrum (EI): 283(+) = M(+).

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1.67 to was 1.94 (m, 4H); to 2.06 (m, 1H); 2,52 (m hidden, 1H); to 2.94 (m, 1H); from 3,12 to 3.40 (m, 5H); from 3.99 to of 4.12 (m, 2H); 7,13 (TT, J=1.5 and 7.5 Hz, 1H); 7,33 (t ush., J=7.5 Hz, 2H); to 7.64 (d ush., J=7.5 Hz, 2H); to 7.99 (s, 1H); of 10.05 (m ush., 1H).

[α]20D= +36,5° ± 0,8° (C = 0,5; methanol).

Example 89

1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-(4-chlorophenyl)-1H-pyrazole-3-algebroid

To a solution of 430 mg of 3-[3-benzyloxy-4-(4-chlorophenyl)pyrazole-1-ylmethyl]-1-azabicyclo[2,2,2]Oceanborn 10 cm3ethanol was added with stirring 10 cm312 N. hydrochloric acid. After stirring for 15 hours at boiling temperature under reflux of the solvent, the reaction mixture is cooled to temperature is about 20°C and evaporated to dryness under reduced pressure (2.7 kPa). The residue is treated with water. The resulting solution was adjusted to a pH of about 8 with 1 n sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residual solid proscout in diisopropyl ether, filtered off and dried under reduced pressure (2.7 kPa)to give 137 mg of 1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-(4-chlorophenyl)-1H-pyrazole-3-algebrabased in a solid white color.

Mass spectrum (EI): 317(+)/... = M(+)/...(1 Cl).

1H-NMR-spectrum (400 MHz, DMSO-d6, δ in ppm): from 1.30 to 1.61 (m, 4H); of 1.78 (m, 1H); to 2.15 (m, 1H); of 2.38 (m, 1H); from 2,66 to of 2.81 (m, 4H); is 2.88 (m, 1H); 3,91 (d, J=8.0 Hz, 2H); 7,37 (l ush., J=8.5 Hz, 2H); to 7.67 (d ush., J=8.5 Hz, 2H); 8,00 (s, 1H); from 10,35 to 10, 5 (m very ush., 1H).

3-[3-benzyloxy-4-(4-chlorophenyl)pyrazole-1-ylmethyl]-1-azabicyclo[2,2,2]Oceanborn can be obtained as follows.

A solution of 3 g of 3-benzyloxy-4-(4-chlorophenyl)-1H-pyrazole and 3 g of potassium tert-butylate in 30 cm3of dimethylformamide in an inert atmosphere and with stirring, heated for 30 minutes at 50°C, then added 3.1 g of 3-chloromethyl-1-azabicyclo[2,2,2]octahedrally. After boiling under reflux for 15 hours, the reaction environment contribute in the water and the mixture extracted twice with ethyl acetate. The organic phase is washed with PEFC is therefore twice with water and aqueous saturated solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa). The resulting oil beige (5.3g) purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (20:80 by volume), ethyl acetate, then ethyl acetate/methanol (90:10 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) get a solid substance that is dissolved in 10 cm3of tetrahydrofuran in an inert atmosphere. To a stirred and cooled to -60°C. solution add 3 cm31 N. of a solution of borane in tetrahydrofuran. After reaction for 2.5 hours at a temperature of -60°C. to the reaction medium add 15 cm3water, stand to raise the temperature of the mixture to a temperature of about 20°C and the solution extracted with ethyl acetate. The organic phase is washed twice with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa)to give an oil (1 g), which was purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: ethyl acetate, ethyl acetate/methanol (90:10 by volume)and then dichloromethane/methanol (80:20 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 430 mg of 3-[3-benzyloxy-4-(4-chlorophenyl)pyrazole-1-ylmethyl]-1-azabicyclo[2,2,2]is cranborne in the form of oil, used without other purification for the continuation of the synthesis.

Example 90

(-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazole-3-algebroid

To a solution of 690 mg (+)-3-[3-benzyloxy-4-(4-chlorophenyl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane in 10 cm3ethanol was added with stirring to 7 cm312 N. hydrochloric acid. After heating for 7 hours at boiling temperature under reflux of the solvent, the reaction medium is cooled to a temperature of about 20°C and evaporated to dryness under reduced pressure (2.7 kPa). The remainder proscout in diisopropyl ether, filtered off and dried under reduced pressure (2.7 kPa)to give 580 mg of (-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazole-3-algebrabased in a solid beige color.

Mass spectrum (EI): 303(+)/... = M(+)/...(1 Cl).

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1,68 to 2.03 (m, 4H); to 2.42 (m, 1H); from 3,20 to 3,55 (m, 4H); of 3.78 (m, 2H); of 4.66 (m, 1H); 7,41 (l ush., J=8.5 Hz, 2H); 7,71 (l ush., J=8.5 Hz, 2H); of 8.25 (s, 1H); 10,35 (m ush., 1H); 10,65 (m ush., 1H).

[α]20D= -19,4° ± 0,7° (C = 0,5; methanol).

(+)-3-[3-benzyloxy-4-(4-chlorophenyl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane and (-)-3-[3-benzyloxy-4-(4-chlorophenyl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane can be obtained as follows.

The ethanol solution containing 0.29 grams (±)3-[3-benzyloxy-4-(4-chlorophenyl)pyrazole-1-yl]-1-azabicyclo[2,2,2]OCTA is a, enter in column 8 cm, containing 1180 g stationary chiral phase Chiralpak ADTM. Elution is carried out using a mixture of heptane, ethanol, methanol and triethylamine (80:10:10:0.1 volumes), and the flow rate of the mobile phase is 120 ml/min Programalso enantiomer elute in the first place, the solution is evaporated to dryness under reduced pressure (2.7 kPa), receiving 0,69 g (+)-3-[3-benzyloxy-4-(4-chlorophenyl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane in the form of oil.

Mass spectrum (EI): 393(+)/... = M(+)/...(1 Cl); 91(+) = C7H7(+).

[α]20D= +25,4° ± 0,8° (C = 0,5; methanol).

The solution containing levogyrate enantiomer, eluruumis in the second place, is evaporated to dryness under reduced pressure (2.7 kPa), receiving 0,69 g (-)-3-[3-benzyloxy-4-(4-chlorophenyl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane in the form of oil.

Mass spectrum (EI): 393(+)/... = M(+)/...(1 Cl); 91(+) = C7H7(+).

[α]20D= -26,2° ± 0,8° (C = 0,5; methanol).

Example 91

(+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazole-3-algebroid

To a solution of 690 mg (-)-3-[3-benzyloxy-4-(4-chlorophenyl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane in 10 cm3ethanol was added with stirring to 7 cm312 N. hydrochloric acid. After heating for 7 hours at boiling temperature under reflux of the solvent reaction medium is cooled to a temperature OK the lo 20°C and evaporated to dryness under reduced pressure (2.7 kPa). The remainder proscout in diisopropyl ether, filtered off and dried under reduced pressure (2.7 kPa)to give 580 mg of (+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazole-3-algebrabased in a solid beige color.

Mass spectrum (EI): 303(+)/... = M(+)/...(1 Cl).

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1.67 to 2.02 (m, 4H); to 2.42 (m, 1H); from 3,22-3.50 (m, 4H); with 3.79 (m, 2H); of 4.66 (m, 1H); 7,41 (l ush., J=8.5 Hz, 2H); 7,71 (l ush., J=8.5 Hz, 2H); of 8.25 (s, 1H); from 10.2 to 10.3 (m very ush., 1H); 10,65 (m ush., 1H).

[α]20D= +17,7° ± 0,6° (C = 0,5; methanol).

Example 92

(-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-forfinal)-1H-pyrazole-3-algebroid

To a solution of 135 mg (+)-3-[3-benzyloxy-4-(4-forfinal)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane in 5 cm3ethanol was added with stirring 5 cm312 N. hydrochloric acid. After heating for 7 hours at boiling temperature under reflux of the solvent reaction medium is cooled to a temperature of about 20°C and evaporated to dryness under reduced pressure (2.7 kPa). The remainder proscout in diisopropyl ether, filtered off and dried under reduced pressure (2.7 kPa)to give 91 mg of (-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-forfinal)-1H-pyrazole-3-algebrabased in a solid white color.

Mass spectrum (EI): 287(+) = M(+).

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1.66 to 2.03 (m, 4); to 2.42 (m, 1H); from 3,20 to 3.49 (m, 4H); with 3.79 (m, 2H); of 4.66 (m, 1H); 7,19 (t ush., J=9.0 Hz, 2H); 7,71 (DD ush., J=6.0 and 9.0 Hz, 2H); 8,17 (s, 1H); 10,15 (m ush., 1H); and 10.5 (s, 1H).

[α]20D= -14,9° ± 0,7° (C = 0,5; methanol).

(+)-3-[3-Benzyloxy-4-(4-forfinal)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane and (-)-3-[3-benzyloxy-4-(4-forfinal)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane can be obtained as follows.

A solution of 2 g of 3-benzyloxy-4-(4-forfinal)-1H-pyrazole and 1 g of potassium tert-butylate in 20 cm3of dimethylformamide in an inert atmosphere is stirred for 1.5 hours at a temperature of about 20°C, then added a solution of 2.3 g complex 1-azabicyclo[2,2,2]Oct-3-silt ester toluene-4-sulfonic 25 cm3of dimethylformamide. After heating for 15 hours at a temperature of 100°C. the reaction environment contribute in the water and the mixture extracted twice with ethyl acetate. The combined organic phases are washed successively twice with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa). The resulting orange oil purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: ethyl acetate, then ethyl acetate/methanol (98:2 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) get an orange oil (1.5 g), which was purified flash chromatography on doxydycline under pressure of argon (50 kPa) [eluent: ethyl acetate/methanol (95:5 by volume), then dichloromethane/methanol (98:2, 95:5 then 90:10 by volume)]. Concentration of the appropriate fractions under reduced pressure (2.7 kPa) leads to an orange oil (500 mg), which is again purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (10:90 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 290 mg of (R,S)-3-[3-benzyloxy-4-(4-forfinal)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane in the form of oil pale yellow color.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): 1.28 (in m, 1H); from 1.49 to 1.71 (m, 3H); of 2.08 (m, 1H); from 2.65 to 2.79 (m, 3H); 2,98 (m, 1H); from 3,14 to 3.44 (m, 2H); 4.25 in (m, 1H); 5,33 (m, 2H); 7.18 in (t ush., J=9.0 Hz, 2H); from 7,30 to 7,44 (m, 3H); 7,50 (d ush., J=7.5 Hz, 2H); 7,71 (DD ush., J=6.0 and 9.0 Hz, 2H); to 8.20 (s, 1H).

The ethanol solution containing 0.29 grams (±)-3-[3-benzyloxy-4-(4-forfinal)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane, is introduced into a column with a diameter of 8 cm, containing 1180 g stationary chiral phase Chiralpak ADTM. Elution is carried out using a mixture of heptane, ethanol, methanol and triethylamine (80:10:10:0.1 volumes), and the flow rate of the mobile phase is 120 ml/min Programalso enantiomer elute in the first place, the solution is evaporated to dryness under reduced pressure (2.7 kPa), receiving is 0.135 g of (+)-3-[3-benzyloxy-4-(4-forfinal)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane in the form of oil.

1H-NMR spectrum (300 MHz, D IS the CO-d 6, δ in ppm): 1,30 (m, 1H); 1.50 to 1.71 (m, 3H); of 2.08 (m, 1H); from 2,64 to 2.80 (m, 3H); 2,99 (m, 1H); from 3,16 to 3.43 (m, 2H); 4.26 deaths (m, 1H); 5,33 (m, 2H); 7,17 (t ush., J=9.0 Hz, 2H); from 7,30 to 7,44 (m, 3H); 7,50 (d ush., J=7.5 Hz, 2H); 7,71 (DD ush., J=6.0 and 9.0 Hz, 2H); to 8.20 (s, 1H).

[α]20D= +21,5° ± 0,5° (C = 0,5; methanol).

The solution containing levogyrate enantiomer, eluruumis in the second place, is evaporated to dryness under reduced pressure (2.7 kPa), receiving 0,137 g (-)-3-[3-benzyloxy-4-(4-forfinal)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane in the form of oil.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): 1,30 (m, 1H); from 1.49 to 1.71 (m, 3H); of 2.08 (m, 1H); from 2.65 to 2.80 (m, 3H); 2,98 (m, 1H); from 3.15 and $ 3.42 (m, 2H); 4.25 in (m, 1H); 5,33 (m, 2H); 7.18 in (t ush., J=9.0 Hz, 2H); from 7,30 to 7,44 (m, 3H); 7,50 (d ush., J=7.5 Hz, 2H); 7,71 (DD ush., J=6.0 and 9.0 Hz, 2H); to 8.20 (s, 1H).

[α]20D= -20,2° ± 0,6° (C = 0,5; methanol).

3-benzyloxy-4-(4-forfinal)-1H-pyrazole can be obtained as follows.

To a solution of 3.5 g of 3-benzyloxy-4-(4-forfinal)-1-(toluene-4-sulfonyl)-1H-pyrazole in 50 cm3of tetrahydrofuran in an argon atmosphere and with stirring, add 20 cm31 N. solution tetrabutylammonium in tetrahydrofuran. After heating for 15 hours at boiling temperature under reflux of the solvent reaction medium is evaporated under reduced pressure (2.7 kPa) and the residue is added ethyl acetate. The organic phase is washed successively twice with water and water is a saturated solution of sodium chloride; it is dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa). The obtained solid yellow (2.3 g) purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (70:30 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) receive 2 g of 3-benzyloxy-4-(4-forfinal)-1H-pyrazole in the form of a solid white color.

Mass spectrum (EI): 268(+) = M(+).

3-benzyloxy-4-(4-forfinal)-1-(toluene-4-sulfonyl)-1H-pyrazole can be obtained as follows.

To a solution of 4.8 g of 3-benzyloxy-4-iodine-1-(toluene-4-sulfonyl)-1H-pyrazole in 40 cm3toluene, to which was added 10 cm3ethanol in an argon atmosphere and with stirring, add 4.5 g 4-ftorhinolonovy acid, 15 cm32 N. an aqueous solution of potassium carbonate and 1.6 g of tetrakis(triphenylphosphine)palladium. After heating for 5 hours at a temperature of 100°C and incubation for 15 hours at a temperature of about 20°C. the reaction medium is evaporated under reduced pressure (2.7 kPa). To the residue is added ethyl acetate, water and activated charcoal and filtered through Supercel. The filtrate is decanted, then the organic phase is washed successively three times with water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa). Floor the obtained solid yellow (9 g) purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (95:5 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 3.5 g of 3-benzyloxy-4-(4-forfinal)-1-(toluene-4-sulfonyl)-1H-pyrazole in the form of a solid yellow color.

Mass spectrum (EI): 422(+) = M(+); 267(+) = 422(+)-Ts; 91(+) = C7H7(+).

Example 93

(+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-forfinal)-1H-pyrazole-3-algebroid

To a solution of 137 mg (-)-3-[3-benzyloxy-4-(4-forfinal)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane in 5 cm3ethanol was added with stirring 5 cm312 N. hydrochloric acid. After heating for 7 hours at boiling temperature under reflux of the solvent reaction medium is cooled to a temperature of about 20°C and evaporated to dryness under reduced pressure (2.7 kPa). The remainder proscout in diisopropyl ether, filtered off and dried under reduced pressure (2.7 kPa)to give 99 mg of (+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-forfinal)-1H-pyrazole-3-algebrabased in a solid white color.

Mass spectrum (EI): 287(+) = M(+).

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1,69 to 2.03 (m, 4H); to 2.41 (m, 1H); from 3,19-3.50 (m, 4H); with 3.79 (m, 2H); with 4.65 (m, 1H); 7,19 (t ush., J=9.0 Hz, 2H); 7,71 (DD ush., J=6.0 and 9.0 Hz, 2H); 8,17 (s, 1H); from 10.1 to 10.3 (m very ush., 1H); and 10.5 (s, 1H).

[α]20D= +15,3° ± 0,6° (C = 0,5; methanol).

Example 94

3-[4-(4-chlorophenyl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octahedrally

R is the target of 600 mg of 4-(4-chlorophenyl)-1H-pyrazole and 420 mg of potassium tert-butylate in 20 cm 3of dimethylformamide in an inert atmosphere is stirred for 2 hours at a temperature of about 20°C, then added a solution of 1.1 g of complex 1-azabicyclo[2,2,2]Oct-3-silt ester toluene-4-sulfonic 20 cm3of dimethylformamide. After heating for 15 hours at a temperature of 100°C. the reaction environment contribute in the water and the mixture extracted twice with ethyl acetate. The combined organic phases are washed successively twice with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa). The resulting orange oil (1 g) and purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: ethyl acetate, then ethyl acetate/methanol (95:5 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) get an orange oil (840 mg), which was purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: ethyl acetate, ethyl acetate/methanol (80:20 by volume)and then dichloromethane/methanol (80:20 by volume)]. Concentration of the appropriate fractions under reduced pressure (2.7 kPa) leads to solid substance creamy (250 mg)which was dissolved in ethyl acetate. To the solution add 0,85 cm31 n solution of hydrogen chloride in diethyl ether, then evaporated to dryness at ponie nom pressure (2.7 kPa). The remainder proscout in diisopropyl ether and the resulting solid is filtered off, then dried under reduced pressure (2.7 kPa)to give 239 mg of 3-[4-(4-chlorophenyl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octahedrally in the form of a cream solid color.

Mass spectrum (EI): 287(+)/... = M(+)/...(1 Cl); 36(+)/38(+) = HCl(+) = salt formation with HCl.

1H-NMR-spectrum (400 MHz, DMSO-d6, δ in ppm): 1,71 (m, 2H); to 1.98 (m, 2H); to 2.41 (m, 1H); from 3,20 to 3.46 (m, 4H); of 3.78 (m, 1H); to 3.92 (m, 1H); 4,89 (m, 1H); 7,44 (l ush., J=8.5 Hz, 2H); to 7.64 (d ush., J=8.5 Hz, 2H); with 8.05 (s, 1H); 8,46 (s, 1H); from 10.05 to 10,35 (m very ush., 1H).

4-(4-chlorophenyl)-1H-pyrazole can be obtained as follows.

To a solution of 2,8 4-(4-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in 30 cm3of tetrahydrofuran in an argon atmosphere and with stirring, add 21 cm31 N. solution tetrabutylammonium in tetrahydrofuran. After heating for 8 hours at boiling temperature under reflux of the solvent reaction medium is evaporated under reduced pressure (2.7 kPa) and the residue is added ethyl acetate. The organic phase is washed successively twice with water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa). The obtained solid yellow (2.1 g) purified flash chromatography on silica under pressure of argon (50 kPa) eluent: cyclohexane/ethyl acetate (50:50 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 1.2 g of 4-(4-chlorophenyl)-1H-pyrazole in the form of a solid white color.

Mass spectrum (S): m/z = 178 (M+.) peak of the molecular ion; m/z = 151 [(M-HCN)+.]; m/z = 116 [(m/z = 151-Cl)+]; m/z = 89 [(m/z = 116-HCN)+].

4-(4-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole can be obtained as follows.

To a solution of 5 g of 4-iodine-1-(toluene-4-sulfonyl)-1H-pyrazole in 60 cm3toluene, to which was added 15 cm3ethanol in an argon atmosphere and with stirring of 6.1 g of 4-Chlorfenvinphos acid, 20 cm32 N. an aqueous solution of potassium carbonate and 2.1 g of tetrakis(triphenylphosphine)palladium. After heating for 3 hours at a temperature of 100°C and incubation for 15 hours at a temperature of about 20°C. the reaction medium is evaporated under reduced pressure (2.7 kPa). To the residue is added ethyl acetate, water and activated charcoal and filtered through Supercel. The filtrate is decanted, then the organic phase is washed successively twice with water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa). The obtained oil (10.7 g) purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (90:10 by volume)]. After concentrating the fractions under bonigen the m pressure (2.7 kPa) obtained residue proscout in diisopropyl ether. After filtering off and drying under reduced pressure (2.7 kPa) to obtain 2.8 g of 4-(4-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in the form of a solid orange color.

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): to 2.41 (s, 3H); from 7,44 to 7,53 (m, 4H); 7,80 (l ush., J=9.0 Hz, 2H); 7,92 (l ush., J=9.0 Hz, 2H); 8,42 (s, 1H); 9,04 (s, 1H).

Example 95

3-[4-(4-chlorophenyl)pyrazole-1-ylmethyl]-1-azabicyclo[2,2,2]octahedrally

To a suspension of 345 mg of sodium hydride (75 wt.% dispersion in vaseline oil) in 15 cm3of dimethylformamide gradually add in an argon atmosphere and at a temperature of about 20°With a solution of 640 mg of 4-(4-chlorophenyl)-1H-pyrazole in 25 cm3of dimethylformamide. After stirring for 45 minutes at a temperature of about 50°C, add small portions of 1.4 g of 3-chloromethyl-1-azabicyclo[2,2,2]octahedrally, then heated for 15 hours at a temperature of about 100°C. the Mixture is cooled to a temperature of about 20°C, then bring in the water. The aqueous phase is extracted 2 times with ethyl acetate. The combined organic phases are washed 2 times with water and aqueous saturated sodium chloride solution, then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The resulting orange oil (1.3 g) purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: ethyl acetate, then ethyl shall zitat/methanol (99:1, then 97:3 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) receive oil (520 mg), which was purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: dichloromethane/7 n ammonia solution in methanol (97:3 by volume)]. Concentration of the appropriate fractions under reduced pressure (2.7 kPa) leads to the oil pale yellow (330 mg), which was dissolved in ethyl acetate. To the solution add 0,985 cm31 n solution of hydrogen chloride in diethyl ether, then evaporated to dryness under reduced pressure (2.7 kPa). The remainder proscout in diisopropyl ether and the resulting solid is filtered off, then dried under reduced pressure (2.7 kPa)to give 353 mg of 3-[4-(4-chlorophenyl)pyrazole-1-ylmethyl]-1-azabicyclo[2,2,2]octahedrally in a solid white color.

Mass spectrum (EI): 301(+)/... = M(+)/...(1 Cl).

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1.65-2.13 (m, 5H); of 2.58 (m, 1H); of 2.93 (m, 1H); from 3.09 to 3,63 (m, 5H); from 4,22 to 4,34 (m, 2H); 7,42 (l ush., J=9.0 Hz, 2H); 7,62 (l ush., J=9.0 Hz, 2H); to 7.95 (s, 1H); of 8.28 (s, 1H); from 9,90 to 10.2 (m very ush., 1H).

Example 96

3-[4-(3-chloro-4-methoxyphenyl)pyrazole-1-ylmethyl]-1-azabicyclo[2,2,2]octane

To a suspension of 530 mg of sodium hydride (75 wt.% dispersion in vaseline oil) in 15 cm3of dimethylformamide gradually add in an argon atmosphere and at a temperature of approximately is 20°C. a solution of 1.1 g of 4-(3-chloro-4-methoxyphenyl)-1H-pyrazole in 25 cm 3of dimethylformamide. After stirring for 1 hour at a temperature of about 50°C, add small portions 2,07 g of 3-chloromethyl-1-azabicyclo[2,2,2]octahedrally, then heated for 15 hours at a temperature of about 100°C. the Mixture is cooled to a temperature of about 20°C, then bring in the water. The aqueous phase is extracted 2 times with ethyl acetate. The combined organic phases are washed 2 times with water and aqueous saturated sodium chloride solution, then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The resulting orange oil (1.8 g) purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: ethyl acetate, then ethyl acetate/methanol (98:2 then 95:5 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) receive oil (550 mg), which was purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: dichloromethane/7 n ammonia solution in methanol (98:2 by volume)]. Concentration of the appropriate fractions under reduced pressure (2.7 kPa) leads to the oil pale yellow (400 mg), which is again purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa)[eluent: ethyl acetate/methanol (95:5 by volume)and then dichloromethane/methanol (80:20 by volume)]. After concentrating the fractions under below the nom pressure (2.7 kPa) to obtain 140 mg of 3-[4-(3-chloro-4-methoxyphenyl)pyrazole-1-ylmethyl]-1-azabicyclo[2,2,2]octane in the form of a solid white color.

Mass spectrum (CI): 332(+)/... = (M+N)(+)/...(1 Cl); 349(+) = (M+NH4)(+)/....

1H-NMR-spectrum (400 MHz, DMSO-d6, δ in ppm): from 1,28 to 1.57 (m, 4H); or 1.77 (m, 1H); to 2.15 (m, 1H); of 2.36 (m, 1H); from 2,58 to 2.88 (m, 5H); 3,85 (s, 3H); 4,10 (d, J=8.0 Hz, 2H); for 7.12 (d, J=8.0 Hz, 1H); to 7.50 (DD, J=2.0 and 8.0 Hz, 1H); to 7.64 (d, J=2.0 Hz, 1H); a 7.85 (s, 1H); 8,08 (s, 1H).

4-(3-chloro-4-methoxyphenyl)-1H-pyrazole can be obtained as follows.

To a solution of 5.2 g of 4-(3-chloro-4-methoxyphenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in 50 cm3of tetrahydrofuran in an argon atmosphere and with stirring, add 35 cm31 N. solution tetrabutylammonium in tetrahydrofuran. After heating for 5 hours at boiling temperature under reflux of the solvent reaction medium is evaporated under reduced pressure (2.7 kPa) and the residue is added ethyl acetate. The organic phase is washed successively twice with water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa). The obtained solid orange (5,1 g) purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (50:50 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 1.84 g of 4-(3-chloro-4-methoxyphenyl)-1H-pyrazole in the form of a solid pale yellow color.

Mass spectrum (EI): 208(+)/... = M(+)/...(1 Cl); 13(+)/... = M(+)/...-CH 3.

4-(3-chloro-4-methoxyphenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole can be obtained as follows.

To a solution of 5.6 g of 4-iodine-1-(toluene-4-sulfonyl)-1H-pyrazole in 60 cm3toluene, to which was added 15 cm3ethanol in an argon atmosphere and with stirring, add 9 g of 4-chloro-3-methoxyphenylacetic acid, 24 cm32 N. an aqueous solution of potassium carbonate and 2.45 g of tetrakis(triphenylphosphine)palladium. After heating for 3 hours at a temperature of 100°C and incubation for 15 hours at a temperature of about 20°C. the reaction medium is evaporated under reduced pressure (2.7 kPa). To the residue is added ethyl acetate, water and activated charcoal and filtered through Supercel. The filtrate is decanted, then the organic phase is washed successively twice with water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa). The obtained solid substance proscout in ethyl acetate, filtered and dried under reduced pressure (2.7 kPa)to give 5.2 g of 4-(3-chloro-4-methoxyphenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in the form of a solid beige color that is used without other purification in the next stage.

1H-NMR spectrum (300 MHz, DMSO-d6for 70% of the mixture, δ in ppm): 2.40 a (m, 3H); 3,88 (ush., 3H); 7,19 (d, J=8.5 Hz, 1H); 7,50 (d ush., J=8.5 Hz, 2H); 7,71 (DD, J=2.0 and 8.5 Hz, 1H); from 7.88 to 7.93 (m, 3H); 8,1 (s, 1H); 8,99 (s, 1H) (purity, estimated as 70%1H-NMR, + source baronova acid).

Example 97

4-[1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-1H-pyrazole-4-yl]-2-chlorophenylhydrazone

A solution of 470 mg of 3-[4-(3-chloro-4-methoxyphenyl)pyrazole-1-ylmethyl]-1-azabicyclo[2,2,2]octane in 20 cm3dichloromethane is cooled in a bath with ice, then add to it 12 cm31 N. solution tribromide boron in dichloromethane. After keeping for returning the reaction mixture to a temperature of about 20°C. the reaction continued for 15 hours at this temperature, the mixture is then bring the water, to which was added dichloromethane. The solution is brought to a pH of about 8 by adding 1 n sodium hydroxide solution. The formed precipitate is filtered off, treated with ethanol under heating. After filtration of the suspension in a hot state to the filtrate add water and activated charcoal, filtered through Wattman paper®and evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid beige (330 mg) was dissolved in 10 cm3ethanol and 10 cm312 N. hydrochloric acid. After heating for 12 hours at boiling temperature under reflux of the solvent, the mixture is cooled to a temperature of about 20°C, evaporated to dryness under reduced pressure (2.7 kPa). The obtained solid substance with the requirements of the I iterations sequentially dissolved in ethanol and evaporated to dryness under reduced pressure (2.7 kPa), then it proscout in diisopropyl ether, filtered off and dried under vacuum (2.7 kPa)to give 370 mg of 4-[1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-1H-pyrazole-4-yl]-2-chlorophenylhydrazone in the form of a cream solid color.

Mass spectrum (ESP) (electronic ionization sputtering with the formation of positive ions): 318(+)/... = (M+N)(+).

1H-NMR spectrum (300 MHz, DMSO-d6, δ in ppm): from 1.66 to 1.92 (m, 4H); 2,07 (m, 1H); 2,60 (m, 1H); to 2.94 (m, 1H); from 3,10 to 3.39 (m, 5H); from 4,15 to 4.32 (m, 2H); 7,00 (d, J=8.5 Hz, 1H); 7,34 (DD, J=2.5 and 8.5 Hz, 1H); 7,56 (d, J=2.5 Hz, 1H); a 7.85 (s, 1H); is 8.16 (s, 1H); from 9,80 to 10.3 (m very ush., 2H).

Example 98

4-[1-(1-azabicyclo[2,2,2]Oct-3-yl)-1H-pyrazole-4-yl]-2-chlorophenol

A solution of 750 mg of 3-[4-(3-chloro-4-methoxyphenyl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane in 25 cm3dichloromethane in an argon atmosphere and with stirring, cooled in a bath with ice, then add to it 11 cm31 N. solution tribromide boron in dichloromethane. After keeping the reaction mixture for 30 minutes at a temperature of about 0°C., heating for 3 hours at 40°C, then standing for 15 hours at a temperature of about 20°C. the reaction mixture was making in water, to which was added dichloromethane. The resulting suspension is filtered and the solid is treated with water. The mixture is brought to pH 8, then extracted with ethyl acetate. The organic phase is washed placenta is therefore twice with water and aqueous saturated solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa). The obtained solid beige (800 mg) purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: dichloromethane/methanol (80:20 by volume)]. Concentration of the appropriate fractions under reduced pressure (2.7 kPa) leads to the residue, which proscout in diisopropyl ether, filtered off and dried under reduced pressure (2.7 kPa)to give 240 mg of 4-[1-(1-azabicyclo[2,2,2]Oct-3-yl)-1H-pyrazole-4-yl]-2-chlorophenol in the form of a solid white color.

Mass spectrum (EI): 303(+)/... = M(+)/...(1 Cl).

1H-NMR-spectrum (400 MHz, DMSO-d6, δ in ppm): 1,32 (m, 1H); and 1.54 (m, 1H); to 1.70 (m, 2H); 2,02 (m, 1H) 2,77 (m, 3H); 2,98 (m, 1H); from 3,20 to 3.50 (m, 2H); was 4.42 (m, 1H); 6,98 (d, J=9.0 Hz, 1H); 7,40 (DD, J=2.0 and 9.0 Hz, 1H); a 7.62 (d, J=2.0 Hz, 1H); 7,87 (s, 1H); of 8.28 (s, 1H); of 10.05 (m ush., 1H).

3-[4-(3-chloro-4-methoxyphenyl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane can be obtained as follows.

A solution of 1.35 g of 4-(3-chloro-4-methoxyphenyl)-1H-pyrazole and 800 mg of potassium tert-butylate in 20 cm3of dimethylformamide in an inert atmosphere is stirred for 1 hour at a temperature of about 20°C, then added a solution of 2 g complex 1-azabicyclo[2,2,2]Oct-3-silt ester toluene-4-sulfonic 20 cm3of dimethylformamide. After heating for 18 hours at a temperature of 100°C. the reaction environment contribute in the water and the mixture is xtraceroute twice with ethyl acetate. The combined organic phases are washed successively twice with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa). The resulting orange oil (2 g) is purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: ethyl acetate, ethyl acetate/methanol (80:20 by volume)and then dichloromethane/methanol (80:20 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 480 mg of 3-[4-(3-chloro-4-methoxyphenyl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane in the form of an orange oil.

Mass spectrum (S): m/z = 317 (M+.); m/z = 234(M-C5H9N)+.]; m/z = 109 [C7H11N+.]; m/z = 97 [C6H11N+.] the peak molecular ion.

Examples 99 and 100

(-)-4-[1-(1-azabicyclo[2,2,2]Oct-3-yl)-1H-pyrazole-4-yl]-2-chlorophenol and (+)-4-[1-(1-azabicyclo[2,2,2]Oct-3-yl)-1H-pyrazole-4-yl]-2-chlorophenol

The ethanol solution containing 0,173 g of 4-[1-(1-azabicyclo[2,2,2]Oct-3-yl)-1H-pyrazole-4-yl]-2-chlorophenol, is introduced into a column with a diameter of 8 cm, containing 1180 g stationary chiral phase Chiralpak ADTM. Elution is carried out using a mixture of heptane, ethanol, methanol and triethylamine (80:10:10:0.1 volumes), and the flow rate of the mobile phase is 120 ml/min Levogyrate enantiomer elute in the first place, the solution is evaporated to dryness at Pont the leaders introduce pressure (2.7 kPa), getting 0,093 g (-)-4-[1-(1-azabicyclo[2,2,2]Oct-3-yl)-1H-pyrazole-4-yl]-2-chlorophenol in the form of oil.

Mass spectrum (EI): 303(+)/... = M(+)/...(1 Cl).

1H-NMR-spectrum (400 MHz, DMSO-d6, δ in ppm): 1,31 (m, 1H); 1,53 (m, 1H); by 1.68 (m, 2H); of 2.09 (m, 1H); from 2.67 to 2.80 (m, 3H); of 2.97 (m, 1H); from 3,18 up to 3.48 (m, 2H); 4,39 (m, 1H); to 6.95 (d, J=8.5 Hz, 1H); 7,38 (DD, J=2.5 and 8.5 Hz, 1H); of 7.60 (d, J=the 2.5 Hz, 1H); a 7.85 (s, 1H); 8,23 (s, 1H); from 9,98 to 10.15 (m very ush., 1H).

[α]20D= -4,1° ± 0,6° (C = 0,5; methanol).

The solution containing programalso enantiomer, eluruumis in the second place, is evaporated to dryness under reduced pressure (2.7 kPa), receiving is 0.102 g of (+)-4-[1-(1-azabicyclo[2,2,2]Oct-3-yl)-1H-pyrazole-4-yl]-2-chlorophenol in the form of oil.

Mass spectrum (EI): 303(+)/... = M(+)/...(1 Cl).

1H-NMR-spectrum (400 MHz, DMSO-d6, δ in ppm): 1,35 (m, 1H); and 1.54 (m, 1H); to 1.70 (m, 2H); 2,12 (m, 1H); from 2.70 to 2.83 (m, 3H); 3,00 (m, 1H); from 3,21 up 3,51 (m, 2H); 4,43 (m, 1H); to 6.95 (d, J=8.5 Hz, 1H); 7,38 (DD, J=2.5 and 8.5 Hz, 1H); to 7.61 (d, J=the 2.5 Hz, 1H); 7,87 (s, 1H); of 8.27 (s, 1H); of 10.05 (m ush., 1H).

[α]20D= +5,3° ± 0,4° (C = 0,5; methanol).

Examples 101 and 102

(+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-pyridin-2-yl-1H-pyrazole-3-ol and (-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-pyridin-2-yl-1H-pyrazole-3-ol

The ethanol solution containing 0.3 g of (±)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-pyridin-2-yl-1H-pyrazole-3-ol, is introduced into a column with a diameter of 8 cm, containing 1180 g stationary chiral phase Chiralpak ADTM, 20 μm. Elution is carried out using a mixture of heptane, ethanol, m is canola and triethylamine (70:15:15:0,2 by volume), moreover, the flow rate of the mobile phase is 120 ml/min Levogyrate enantiomer elute in the first place, the solution is evaporated to dryness under reduced pressure (2.7 kPa), receiving 0,109 g (-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-pyridin-2-yl-1H-pyrazole-3-ol in the form of oil.

Mass spectrum (S): m/z = 270 (M+.); m/z = 187 [(M-C5H9N)+] the peak molecular ion.

1H-NMR-spectrum (400 MHz, DMSO-d6(when standardized to 2.50 ppm), δ in ppm): 1,31 (m, 1H); from of 1.55 to 1.70 (m, 3H); 2,07 (m, 1H); from 2.65 to 2.75 (m, 2H); 2,90 (m, 1H); from 3,14 to 3.39 (m partially hidden, 3H); is 4.21 (m, 1H); 7,14 (m, 1H); 7,72 (l ush., J=7.5 Hz, 1H); for 7.78 (m, 1H); compared to 8.26 (s, 1H); 8,45 (l ush., J=5.0 Hz, 1H); from 10.9 to 11.1 (m ush., 1H).

[α]20D= -40,7° ± 0,8° (C = 0,5; dimethylformamide).

The solution containing programalso enantiomer, eluruumis in the second place, is evaporated to dryness under reduced pressure (2.7 kPa), receiving 0,113 g (+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-pyridin-2-yl-1H-pyrazole-3-ol in the form of oil.

Mass spectrum (IE): m/z = 270 (M+.); m/z = 187 [(M-C5H9N)+] the peak molecular ion.

1H-NMR-spectrum (400 MHz, DMSO-d6(when standardized to 2.50 ppm), δ in ppm): 1,32 (m, 1H); from 1.56 to 1.68 (m, 3H); of 2.08 (m, 1H); from 2,66 to was 2.76 (m, 2H); 2,92 (m, 1H); from 3,14 $ 3.42 (m partially hidden, 3H); 4,22 (m, 1H); 7,14 (m, 1H); 7,71 (l ush., J=7.5 Hz, 1H); for 7.78 (m, 1H); of 8.27 (s, 1H); of 8.47 (d ush., J=5.0 Hz, 1H); 10.8 and of 11.15 (m ush., 1H).

[α]20D= +35,4° ± 0,8° (C = 0,5; dimethylformamide).

(±)-1-(1-azabicyclo,2,2]Oct-3-yl)-4-pyridin-2-yl-1H-pyrazole-3-algebroid can be obtained as follows.

To a solution of 330 mg of 3-[3-(cyclohex-2-enyloxy)-4-pyridin-2-alprazol-1-yl]-1-azabicyclo[2,2,2]octane 7 cm3dioxane add 7 cm34 n solution of hydrogen chloride in dioxane. After stirring for 15 hours at a temperature of about 20°C. the formed insoluble part is filtered off, washed with diisopropyl ether and dried under reduced pressure (2.7 kPa)to give 300 mg (±)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-pyridin-2-yl-1H-pyrazole-3-algebrabased in a solid white color.

Mass spectrum (IE): m/z = 270 (M+.); m/z = 187 [(M-C5H9N)+] the peak molecular ion; m/z = 36 (HCl+.).

3-[3-(cyclohex-2-enyloxy)-4-pyridin-2-alprazol-1-yl]-1-azabicyclo[2,2,2]octane can be obtained as follows.

A solution of 2.5 g of 2-[3-(cyclohex-2-enyloxy)-1H-pyrazole-4-yl]pyridine and 1.4 g of potassium tert-butylate in 20 cm3of dimethylformamide in an inert atmosphere is stirred for 1 hour at 50°C, then added a solution of 4 g of complex 1-azabicyclo[2,2,2]Oct-3-silt ester toluene-4-sulfonic 20 cm3of dimethylformamide. After heating for 15 hours at a temperature of 100°C. the reaction environment contribute in the water and the mixture extracted twice with ethyl acetate. The combined organic phases are washed successively twice with water and aqueous saturated sodium chloride solution, dried over Sul is blockhead magnesium and evaporated under reduced pressure (2.7 kPa). The resulting orange oil (5.3g) purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (60:40 by volume), ethyl acetate, then ethyl acetate/methanol (95:5 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) receive oil, which is purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: dichloromethane/methanol (95:5, then 70:30 by volume)]. Concentration of the appropriate fractions under reduced pressure (2.7 kPa) leads to 370 mg of 3-[3-(cyclohex-2-enyloxy)-4-pyridin-2-alprazol-1-yl]-1-azabicyclo[2,2,2]octane in the form of oil pale yellow color.

1H-NMR-spectrum (400 MHz, DMSO-d6(when standardized to 2.50 ppm), δ in ppm): 1,35 (m, 1H); from of 1.59 to 1.70 (m, 4H); of 1.78 (m, 1H); from 1.86GHz to 2.17 (m, 5H); from 2.67 to 2,78 (m, 3H); 2,96 (m, 1H); 3,19 (m, 1H); from 3,27 to 3.37 (m hidden, 1H); 4,30 (m, 1H); 5,20 (m, 1H); from 5,95 to 6.04 (m, 2H); 7,10 (m, 1H); 7,74 (m, 2H); 8,18 (s, 1H); of 8.47 (d ush., J=5.0 Hz, 1H).

Examples 103 and 104

(+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-ylamine and (-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-ylamine

The ethanol solution containing of 0.13 g of (±)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-ylamine injected into a column with a diameter of 8 cm, containing 1180 g stationary chiral phase Chiralpak ADTM, 20 μm. Elution is carried out using a mixture of heptane, ethanol and triethylamine(50:50:0.1 volumes), moreover, the flow rate of the mobile phase is 120 ml/min Levogyrate enantiomer elute in the first place, the solution is evaporated to dryness under reduced pressure (2.7 kPa)to give 0.035 g of (-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-ylamine in the form of oil.

Mass spectrum (S): m/z = 268 (M+.) peak of the molecular ion; m/z = 185 [(M-C5H9N)+]; m/z = 109 (C7H11N+.).

1H-NMR spectrum (300 MHz, DMSO-d6(when standardized to 2.50 ppm), δ in ppm): to 1.37 (m, 1H); from 1,61 to total 1.74 (m, 3H); 2,11 (m, 1H); from 2.71 to 2.85 (m, 3H); 3,00 (m, 1H); from 3,12 to 3.53 (m partially hidden, 2H); is 4.21 (m, 1H); 4,65 (m ush., 2H); 7,13 (TT, J=1.5 and 7.5 Hz, 1H); 7,32 (t ush., J=7.5 Hz, 2H); 7,52 (d ush., J=7.5 Hz, 2H); of 7.90 (s, 1H).

[α]20D= -... (dimethylformamide).

The solution containing programalso enantiomer, eluruumis in the second place, is evaporated to dryness under reduced pressure (2.7 kPa), receiving 0,039 g (+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-ylamine in the form of oil.

Mass spectrum (IE): m/z = 268 (M+.); m/z = 185 [(M-C5H9N)+]; m/z = 109 (C7H11N+.) peak of the molecular ion.

1H-NMR spectrum (300 MHz, DMSO-d6(when standardized to 2.50 ppm), δ in ppm): of 1.34 (m, 1H); from 1,60 to 1.73 (m, 3H); of 2.09 (m, 1H); from 2,68 to 2,82 (m, 3H); from 2,90 to 3.53 (m partially hidden, 3H); 4,19 (m, 1H); 4,63 (m ush., 2H); 7,12 (t ush., J=7.5 Hz, 1H); 7,32 (t ush., J=7.5 Hz, 2H); 7,51 (l ush., J=7.5 Hz, 2H); 7,89 (s, 1H).

[α]20D= +... (dimethylformamide).

p> (±)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-ylamine can be obtained as follows.

To a solution of 280 mg diallyl[1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-yl]amine in 10 cm3dichloromethane in an argon atmosphere and with stirring, add 1.1 g of 1,3-dimethylbarbituric acid and 50 mg of tetrakis(triphenylphosphine)palladium. After boiling under reflux the reaction medium for 15 hours the mixture is evaporated to dryness under reduced pressure (2.7 kPa). The residue is treated with 1 N. hydrochloric acid and the solution is washed 2 times with ethyl acetate. The resulting aqueous phase is alkalinized 1 N. a solution of sodium hydroxide and extracted 2 times with ethyl acetate. The combined organic phases are washed with aqueous saturated solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa). The residue is treated with dichloromethane and the solution is treated with activated charcoal, filtered through Supercel and evaporated under reduced pressure (2.7 kPa)to give 130 mg of (±)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-ylamine in the form of an orange oil.

1H-NMR spectrum (300 MHz, DMSO-d6(when standardized to 2.50 ppm), δ in ppm): from 1.20 up to 1.38 (m, 1H); from 1.58 to 1.71 (m, 3H); 2,07 (m, 1H); from 2,62 to 2.79 (m, 3H); from 2,88 to 3,63 (m partially hidden, 3H); to 4.16 (m, 1H); 4,63 (ush., 2H); 7,13 (t ush., J=7.5 Hz, 1H); 7,32 (t ush., J=7.5 Hz, 2H); 7,52 (d ush., J=7,5 Hz, 2H); 7,89 (s, 1H).

Diallyl[1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-yl]amine can be obtained as follows.

A solution of 1.3 g of diallyl(4-phenyl-1H-pyrazole-3-yl]amine and 730 mg of potassium tert-butylate in 20 cm3of dimethylformamide in an argon atmosphere is stirred for 45 minutes at a temperature of 45°C, then added a solution of 2.3 g complex 1-azabicyclo[2,2,2]Oct-3-silt ester toluene-4-sulfonic 15 cm3of dimethylformamide. After heating for 15 hours at a temperature of 100°C. the reaction environment contribute in the water and the mixture extracted twice with ethyl acetate. The combined organic phases are washed successively twice with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa). The resulting orange oil (1.8 g) purified flash chromatography on aluminium oxide STV1 under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (60:40 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) receive oil, which is purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: dichloromethane/methanol (50:50 by volume)]. Concentration of the appropriate fractions under reduced pressure (2.7 kPa) leads to 280 mg diallyl[1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-yl]amine (containing 20% (the definition is on on 1H-NMR) diallyl(4-phenyl-1H-pyrazole-3-yl)amine) in the form of oil pale yellow color.

1H-NMR spectrum (300 MHz, DMSO-d6(when standardized to 2.50 ppm), δ in ppm): 1,29 (m, 1H); from 1.53 to 1.69 in (m, 3H); 2,03 (m, 1H); from 2,62 to 2.80 (m, 3H); of 2.97 (m, 1H); 3,17 (m, 1H); 2,39 (m, 1H); from 3,52 to 3.52 (m, 4H); 4,24 (m, 1H); from 4,98 up to 5.17 (m, 4H); from 5,75 to 5,91 (m, 2H); 7,17 (TT, J=1.5 and 7.5 Hz, 1H); 7,33 (t ush., J=7.5 Hz, 2H); to 7.61 (d ush., J=7.5 Hz, 2H); to 7.93 (s, 1H).

Diallyl(4-phenyl-1H-pyrazole-3-yl)amine can be obtained as follows.

To a solution of 2.9 g of diallyl[4-phenyl-1-(2-trimethylsilylethynyl)-1H-pyrazole-3-yl]amine in 25 cm3of tetrahydrofuran in an argon atmosphere and with stirring, add 22 cm31 N. solution tetrabutylammonium in tetrahydrofuran. After heating for 18 hours at boiling temperature under reflux of the solvent type 6.3 cm31 N. solution tetrabutylammonium and continue heating for 4 hours. After evaporation to dryness of the reaction medium under reduced pressure (2.7 kPa) to the residue is added ethyl acetate and the organic phase is washed successively twice with water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa). The resulting brown oil (1.8 g) purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: cyclohexane/those who acetate (70:30 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 1.3 g diallyl(4-phenyl-1H-pyrazole-3-yl)amine in the form of an orange oil.

Mass spectrum (IE): m/z = 239 (M+.) peak of the molecular ion; m/z = 198(M-C3H5)+]; m/z = 41 (C3H5+).

Diallyl[4-phenyl-1-(2-trimethylsilylethynyl)-1H-pyrazole-3-yl)amine can be obtained as follows.

To a solution of 2.9 g of 4-phenyl-1-(2-trimethylsilylethynyl)-1H-pyrazole-3-ylamine 60 cm3acetonitrile in an argon atmosphere and with stirring, add 8,17 g of cesium carbonate and 4.35 cm3allylbromide. After heating for 15 hours at boiling temperature under reflux of the solvent reaction medium is evaporated to dryness under reduced pressure (2.7 kPa) and the residue treated with ethyl acetate. The organic solution is washed successively twice with water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa). The resulting orange oil (4 g) purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (93:7 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa) to obtain 2.9 g of diallyl[4-phenyl-1-(2-trimethylsilylethynyl)-1H-pyrazole-3-yl]amine in the form of oil orange color is the same.

1H-NMR spectrum (300 MHz, DMSO-d6(when standardized to 2.50 ppm), δ in ppm): -0,03 (s, 9H); or 0.83 (m, 2H); from 3,52 up 3,63 (m, 6H); from 5,04 to 5.15 (m, 4H); of 5.24 (s, 2H); from 5.74 to 5.90 (m, 2H); 7,21 (TT, J=1.5 and 7.5 Hz, 1H); of 7.36 (t ush., J=7.5 Hz, 2H); 7,58 (l ush., J=7.5 Hz, 2H); of 7.96 (s, 1H).

4-phenyl-1-(2-trimethylsilylethynyl)-1H-pyrazole-3-ylamine can be obtained as follows.

To a mixture of 50 cm3ethanol and 50 cm3water is added 3.7 g of iron, 1.8 g of ammonium chloride, then a solution of 3.5 g of 3-nitro-4-phenyl-1-(2-trimethylsilylethynyl)-1H-pyrazole in 50 cm3of ethanol. After heating for 8 hours at boiling temperature under reflux of the solvent and under stirring and incubation for 15 hours at a temperature of about 20°C. the reaction medium is filtered through Supercel and the filtrate is evaporated to dryness under reduced pressure (2.7 kPa). The residue is treated with ethyl acetate and the organic solution is washed successively twice with water and aqueous saturated solution of sodium chloride, after which it is dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa)to give 2.9 g of 4-phenyl-1-(2-trimethylsilylethynyl)-1H-pyrazole-3-ylamine in the form of an orange oil.

1H-NMR-spectrum (400 MHz, DMSO-d6(when standardized to 2.50 ppm), δ in ppm): -0,01 (s, 9H); 0,86 (m, 2H); of 3.56 (m, 2H); 4.75 in (ush., 2H); to 5.17 (s, 2H); 7.18 in (t ush., J=7.5 Hz, 1H); 7,35 (t ush., J=7.5 Hz, 2H); 7,50 (d ush., J=7.5 Hz, 2H); 7,88 (s,1H).

3-nitro-4-phenyl-1-(2-trimethylsilylethynyl)-1H-pyrazole can be obtained as follows.

To a solution of 7.8 g of 4-iodine-3-nitro-1-(2-trimethylsilylethynyl)-1H-pyrazole 120 cm3toluene, to which was added 30 cm3ethanol, added 8.8 g phenylboronic acid, 36 cm32 N. an aqueous solution of potassium carbonate and 3.6 g of tetrakis(triphenylphosphine)palladium. After heating for 15 hours at a temperature of 100°C. the reaction medium is cooled to a temperature of about 20°C, then it is evaporated under reduced pressure (2.7 kPa). The residue is treated with ethyl acetate and the organic solution is washed successively twice with water and aqueous saturated sodium chloride solution; it is dried over magnesium sulfate and evaporated under reduced pressure (2.7 kPa)to give 14.3 g of brown oil, which was purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (90:10, then 70:30 by volume)]. Concentration of the appropriate fractions under reduced pressure (2.7 kPa) leads to 4.5 g 3-nitro-4-phenyl-1-(2-trimethylsilylethynyl)-1H-pyrazole in the form of a yellow oil.

Mass spectrum (IE): m/z = 319 (M+.); m/z = 246(M-C3H9Si)+] the peak molecular ion; m/z = 73 (C3H9Si+).

4-iodine-3-nitro-1-(2-trimethylsilylethynyl)-1H-pyrazole can be recip is n, as follows.

To a suspension of 1.7 g of sodium hydride (75%dispersion in liquid paraffin) in 120 cm3of dimethylformamide in an argon atmosphere and with stirring, add a portion of 10 g of 3-nitro-4-phenyl-1H-pyrazole. The mixture is stirred for 45 minutes at a temperature of about 20°C., then slowly add 14 cm32-trimethylsilylamodimethicone. After stirring for 15 hours at a temperature of about 20°C. the reaction environment contribute 500 cm3water and the mixture extracted three times with 500 cm3ethyl acetate. The combined organic phases are washed successively twice with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa)to give orange oil (22 g), which was purified flash chromatography on silica under pressure of argon (50 kPa) [eluent: cyclohexane/ethyl acetate (85:15 by volume)]. After concentrating the fractions under reduced pressure gain of 7.8 g of 4-iodine-3-nitro-1-(2-trimethylsilylethynyl)-1H-pyrazole in the form of oil pale yellow color.

1H-NMR spectrum (300 MHz, DMSO-d6(when standardized to 2.50 ppm), δ in ppm): -0,03 (s, 9H); 0.87 (m, 2H); 3,61 (m, 2H); 5,51 (s, 2H); charged 8.52 (s, 1H).

Examples 105 and 106

1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(1H-indol-4-yl)-1H-pyrazolidinone, enantiomers a and b

Follow the procedure of example 38, but IP is by using 0,78 g of 1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-iodine-1H-pyrazole, 0.51 g of complex pinacoline ester 1H-indol-4-Voronovo acid value (0.475) g of sodium carbonate, with 0.13 g of dichloro-1,1'-bis(diphenylphosphinite)palladium 35 cm3dioxane and 5 cm3water. After purification by chromatography under a nitrogen pressure of 50 kPa when using speakers with basic aluminum oxide (Merck), elwira with a mixture of cyclohexane and ethyl acetate (50:50, then 25:75, 10:90 by volume), then a mixture of ethyl acetate and methanol (95:5 by volume) fraction 49-120 unite, concentrate to dryness under reduced pressure (3 kPa). Faction 192-205 unite, washed with 5 cm3water and concentrated to dryness under reduced pressure (3 kPa). 2 party matter, in powder form orange unite (266 mg) and purified by HPLC to separate the enantiomers on a column with phase Chiralcel OD, 20 μm, using as eluent a mixture of heptane, methanol, ethanol and triethylamine (60:10:30:0,2 volumes); each enantiomer is then treated with 10 cm3dichloromethane and 5 cm3water. The organic phase is washed with aqueous saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (3 kPa). Each of the thus obtained white powder is then treated with 20 cm3absolute ethanol, then for 20 minutes, heated at boiling temperature with bratim refrigerator solvent. Each solution is filtered, washed with 5 cm3absolute ethanol, add 1 cm31 n solution of hydrogen chloride in diethyl ether. The fluid is concentrated to dryness under reduced pressure, treated with 5 cm3ethanol and again concentrated to dryness under reduced pressure; the remains of the precipitated 5 cm3diisopropyl ether, and then filtered using sintered glass filter. Thus receive 45 mg (+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(1H-indol-4-yl)-1H-pyrazolidinone, enantiomer A, in the form of a powder beige ([α]20D= +21,0°C; solvent: dimethylsulfoxide; concentration: 0.5) and 39 mg of (-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(1H-indol-4-yl)-1H-pyrazolidinone, enantiomer, in the form of a powder beige ([α]20D= -22,7°C; solvent: dimethylsulfoxide; concentration: 0,5).

The pharmaceutical compositions according to the invention is formed by a compound of the formula (I) or the salt of such compounds in pure form or in the form of a composition in which it is associated (associated) with any other pharmaceutically acceptable product, which can be inert or physiologically active. Medicinal product according to the invention can be used orally, parenterally, rectally or locally.

As solid compositions of the La oral administration may be tablets used, pills, powders (gelatin capsules, pills or granules. In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, in an argon atmosphere. These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a vehicle for protective coatings (pills) or lacquer.

As liquid compositions for oral administration can be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. These compositions can comprise substances other than diluents, for example wetting, sweetening means, thickeners, flavoring agents or stabilizers.

Sterile compositions for parenteral administration can preferably be an aqueous or nonaqueous solutions, suspensions or emulsions. As a diluent or excipient you can use water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable complex organic esters, for example etiloleat, or other suitable organic is their solvents. These compositions can also contain auxiliary funds, in particular wetting, isotonic agents, emulsifiers, dispersing means and stabilizers. Sterilization can be done in several ways, for example by asamisimasa filtration, by incorporating in the composition of sterilizing agents, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Compositions for rectal injection are suppositories or rectal capsules which contain, besides the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

Compositions for point of introduction may constitute, for example, creams, lotions, lotions for the eyes, the liquid for rinsing the mouth and appliques on the gums, nasal drops or aerosols.

Doses depend on the desired effect, the duration of treatment and the route of administration; they typically range from 5 mg to 1000 mg per day orally for an adult at single doses of 1 mg to 250 mg of active substance.

Typically, the physician determines the appropriate dosage depending on the age, weight and all other factors inherent to the patient.

The compounds of formula (I) according to the invention will be useful as a drug for treatment of diseases resulting from the dysfunction of the nicotinic receptor alpha 7 or positively respond to their modulation; in the treatment, prevention, diagnosis and/or monitoring the development of psychiatric or neurological disorders or diseases of the Central nervous system in which there is a deterioration of cognitive functions or processing sensory information.

More specifically subjected to the treatment of diseases or disorders affect cognitive abilities, attention, ability to concentrate, learning and/or memory, Alzheimer's disease and associated cognitive disorders, senile dementia, vascular dementia, lung deterioration of cognitive functions associated with age mnesticheskih deficits; cognitive impairments associated with bacterial or viral infections; attention deficits associated with the disorder; schizophrenia; treatment of inflammatory syndromes, ulcerative colitis, Crohn's disease, syndrome of irritation of the colon, arthritis; treatment of acute or chronic pain, fibromyalgia; subsequent treatment for acute injuries of neural degenerations, violations cerebral blood flow to cerebral ischemia or what hypoxia; treatment of chronic neural degenerations observed during Parkinson's disease, horii's disease, multiinstitutional atrophy, progressive pseudobulbar palsy, amyotrophic lateral sclerosis; treatment of epilepsy, depression, anxiety, manic-depressive psychosis, obsessive compulsive disorders, phobias, post traumatic stress disorder syndrome, panic attacks, syndrome Gilles de La Tourette, anorexia and bulimia, sleep disorders.

The compounds of formula (I) can also be used to reduce drug consumption, to facilitate maintaining Asistencia against them or alleviate their symptoms of deprivation.

The compounds of formula (I) can also be used as a diagnostic agent.

The following examples illustrate compositions according to the invention.

An example of a

Receive, in the usual manner, gelatin capsules with doses of 50 mg of active product having the following composition mg:

the compound of formula (I)50
cellulose18
lactose55
gel Kremnev the th acid 1
natrocarbonatite10
talc10
magnesium stearate1

The EXAMPLE IN

Get in the usual manner tablet with doses of 50 mg of active product having the following composition mg:

the compound of formula (I)50
lactose104
cellulose40
polyvidone10
natrocarbonatite22
talc10
magnesium stearate2
the gel of silicic acid2
a mixture of hydroxymethylcellulose, glycerol, titanium dioxide (72-3,5-24,5) to the total mass of the final film-coated tablets245

EXAMPLE WITH

Get solution for injection containing 1 mg of active product, having the following composition mg:

the compound of formula (I)10
benzoic acid80
benzyl alcohol : 0,06
sodium benzoate80
ethanol, 95%0,4
sodium hydroxide24
propylene glycol1,6
water to total amount4

1. The compound of formula (I)

in which A, if present, means (C1-C6)-alkyl;
R1 means a group NR6R7, (C4-C7-azacyclonol, (C5-C9-azabicycloalkanes, and these groups are optionally substituted by one or more substituents selected from (C1-C5)-alkyl or halogen;
A-R1 is such that the nitrogen radical R1 and the nitrogen in position 1 of the pyrazole are necessarily separated by at least two carbon atoms;
R3 means a radical of H, HE, NH2, ORc, NHC(O)Ra or NHSO2Ra;
R4 denotes phenyl or hetero is the Rila, optionally, substituted by one or more substituents selected from halogen, CN, NH2HE, ORc, C(O)NH2, phenyl, polyfluoroankyl, linear or branched (C1-C6)-alkyl, and these substituents optionally substituted with halogen, and heteroaryl radicals are 3-10-membered containing one or more heteroatoms selected from sulfur and nitrogen;
R5 means a radical of H, linear or branched (C1-Cb)-alkyl;
Ra means a linear or branched (C1-C6)-alkyl;
Rc means a linear or branched (C1-C6)-alkyl, (poly)foralkyl or phenyl;
R6 and R7, independently of one another, mean hydrogen, (C1-C6)-alkyl;
R6 and R7 may form a 5-, 6 - or 7-membered saturated or unsaturated cycle which includes one heteroatom, such as N and which is optionally substituted by one or more halogen atoms;
its racemates, the enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts, with the exception of 3-(3-pyridinyl)-1H-pyrazole-1-butanamine, 4-(3-pyridinyl)-1H-pyrazole-1-butanamine and N-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine.

2. The compound of formula (I) according to claim 1

in which A, if present, means (C1-C6)-alkyl;
R1 means a group NR6R7, (C4-C7)-Azazello the keel, (C5-C9-azabicycloalkanes, and these groups are optionally substituted by one or more substituents selected from (C1-C5)-alkyl or halogen;
A-R1 is such that the nitrogen radical R1 and the nitrogen in position 1 of the pyrazole are necessarily separated by at least two carbon atoms;
R3 means a radical, HE, NH2, OMe, H;
R4 denotes phenyl or heteroaryl optionally substituted by one or more substituents selected from halogen, CN, NH2HE, ORc, C(O)NH2, phenyl, polyfluoroankyl, linear or branched (C1-C6)-alkyl, and these substituents optionally substituted with halogen, and heteroaryl radicals are 3-10-membered containing one or more heteroatoms selected from sulfur and nitrogen;
R5 means a radical H or Me;
Ra means a linear or branched (C1-C6)-alkyl;
Rc means a linear or branched (C1-C6)-alkyl, (poly)foralkyl or phenyl;
R6 and R7, independently of one another, mean hydrogen, (C1-C6)-alkyl;
R6 and R7 may form a 5-, 6 - or 7-membered saturated or unsaturated cycle which includes one heteroatom, such as N and which is optionally substituted by one or more halogen atoms;
its racemates, the enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable the E. salt, with the exception of 3-(3-pyridinyl)-1H-pyrazole-1-butanamine, 4-(3-pyridinyl)-1H-pyrazole-1-butanamine and N-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine.

3. The compound of formula (I) according to claim 1

in which A, if present, means (C1-C6)-alkyl;
R1 means a group NR6R7, (C4-C7-azacyclonol, (C5-C9-azabicycloalkanes, and these groups are optionally substituted by one or more substituents selected from (C1-C5)-alkyl or halogen;
A-R1 is such that the nitrogen radical R1 and the nitrogen in position 1 of the pyrazole are necessarily separated by at least two carbon atoms;
R3 means a radical, HE, NH2, OMe, H;
R4 denotes phenyl or heteroaryl optionally substituted by one or more substituents selected from halogen, CN, NH2HE, ORc, phenyl, polyfluoroankyl, C(O)NH2linear or branched (C1-C6)-alkyl and these substituents optionally substituted with halogen, and heteroaryl radicals are 3-10-membered containing one or more heteroatoms selected from sulfur and nitrogen;
R5 means hydrogen;
Ra means a linear or branched (C1-C6)-alkyl;
Rc means a linear or branched (C1-C6)-alkyl, (poly)foralkyl or phenyl;
R6 and R7, independently of one another, denote bodoro is, (C1-C6)-alkyl;
R6 and R7 may form a 5-, 6 - or 7-membered saturated or unsaturated cycle which includes one heteroatom, such as N and which is optionally substituted by one or more halogen atoms;
its racemates, the enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts, with the exception of 3-(3-pyridinyl)-1H-pyrazole-1-butanamine, 4-(3-pyridinyl)-1H-pyrazole-1-butanamine and N-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine.

4. The compound according to claim 1, characterized in that it is chosen from the group consisting of:
1-[2-(3-methoxy-4-phenylpyrazol-1-yl)ethyl]piperidine;
1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-phenyl-1H-pyrazole-1-ol;
3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]octane;
3-(3-methoxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]octane;
1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-ol;
1-(2-peligrosas-1-retil)-4-phenyl-1H-pyrazole-3-ol;
1-[2-(2-methylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;
1-[2-(4-foreperiod-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;
1-[2-(3-methylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;
1-[2-(3,6-dihydro-2H-pyridine-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;
1-[2-(7-azabicyclo[2,2,1]hept-7-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;
1-[2-(2-azabicyclo[2,2,2]Oct-2-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;
1-[2-(2-azabicyclo[2,2,1]hept-2-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;
1-[2-dimethylaminoethyl]-4-phenyl-1H-piraso the-3-ol;
1-[3-dimethylaminopropyl]-4-phenyl-1H-pyrazole-3-ol;
1-[2-((2S,6R)-2,6-dimethylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;
1-[2-diethylaminoethyl]-4-phenyl-1H-pyrazole-3-ol;
1-(2-diisopropylaminoethyl)-4-phenyl-1H-pyrazole-3-ol;
4-phenyl-1-(2-pyrrolidin-1-retil)-1H-pyrazole-3-ol;
3-(3-methoxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2,2,2]octane;
1-[2-(3-deformedarse-4-phenylpyrazol-1-yl)ethyl]piperidine;
4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-ylamine;
4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-ylamine;
N-[4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-yl]ndimethylacetamide;
N-[4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-yl]methanesulfonamide;
1-(2-dimethylaminopropyl)-4-phenyl-1H-pyrazole-3-ol;
1-(1-methylpiperidin-3-ylmethyl)-4-phenyl-1H-pyrazole-3-ol;
5-methyl-4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;
4-(3-AMINOPHENYL)-1-(2-dimethylaminoethyl)-1H-pyrazole-3-ol;
N-{3-[3-hydroxy-1-(2-dimethylaminoethyl)-1H-pyrazole-4-yl]phenyl}ndimethylacetamide;
4-(4-AMINOPHENYL)-1-(2-dimethylaminoethyl)-1H-pyrazole-3-ol;
1-(2-dimethylaminoethyl)-4-(4'-forbiden-3-yl)-1H-pyrazole-3-ol;
4-biphenyl-3-yl-1-(2-dimethylaminoethyl)-1H-pyrazole-3-ol;
1-(2-dimethylaminoethyl)-4-(4'-forbiden-4-yl)-1H-pyrazole-3-ol;
1-(2-piperidine-1-retil)-4-pyridin-2-yl-1H-pyrazole-3-ol;
1-(2-piperidine-1-retil)-4-pyridin-4-yl-1H-pyrazole-3-ol;
4-(4-forfinal)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;
4-(4-trifloromethyl)-1-(2-piperid the n-1-retil)-1H-pyrazole-3-ol;
4-phenyl-1-(2-piperidine-1-ylpropyl)-1H-pyrazole-3-ol;
3-(4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2,2,2]octane;
4-(5-chlorothiophene-2-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;
4-(3-methoxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;
4-(2-methoxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;
4-(3-hydroxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;
4-(4-hydroxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;
4-(4-methoxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;
4-(3-forfinal)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;
1-(2-piperidine-1-retil)-4-(3-triptoreline)-1H-pyrazole-3-ol;
1-(2-piperidine-1-retil)-4-pyridin-3-yl-1H-pyrazole-3-ol;
4-(4-chlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;
4-(3-chlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;
4-(2-forfinal)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;
4-(2-chlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;
1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazole-3-ol;
1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(3-chlorophenyl)-1H-pyrazole-3-ol;
1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(3-forfinal)-1H-pyrazole-3-ol;
1-(1-methylpyrrolidine-3-yl)-4-phenyl-1H-pyrazole-3-ol;
1-[2-(1-methylpyrrolidine-2-yl)ethyl]-4-phenyl-1H-pyrazole-3-ol;
1-(pyrrolidin-3-yl)-4-phenyl-1H-pyrazole-3-ol;
1-[(1-methylpyrrolidine-2-(S)-yl)methyl]-4-phenyl-1H-pyrazole-3-ol;
4-phenyl-1-pyrrolidin-3-ylmethyl-1H-pyrazole-3-ol;
1-((2R)-1-methylpyrrolidine-2-ylmethyl)-4-phenyl-1H-shall irsol-3-ol;
4-phenyl-1-(piperidine-3-yl)-1H-pyrazole-3-ol;
1-(1-methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazole-3-ol;
1-(1-mutilation-3-yl)-4-phenyl-1H-pyrazole-3-ol;
4-phenyl-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;
4-(thiophene-2-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;
4-(3,4-dichlorophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;
4-(4-bromophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;
4-(1H-indol-5-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;
4-(5-bromothiophene-2-yl)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;
2-[1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzamide;
4-(4-cyanophenyl)-1-(2-piperidine-1-retil)-1H-pyrazole oxalate;
4-(2-hydroxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole;
4-(2-methoxyphenyl)-1-(2-piperidine-1-retil)-1H-pyrazole oxalate;
4-(1H-indol-5-yl)-1-(2-piperidine-1-retil)-1H-pyrazole;
4-(4-were)-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;
1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(1H-indol-5-yl)-1H-pyrazole;
(+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(1H-indol-5-yl)-1H-pyrazole;
(-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(1H-indol-5-yl)-1H-pyrazole;
1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(5-chlorothiophene-2-yl)-1H-pyrazole-3-ol;
1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(5-chlorothiophene-2-yl)-1H-pyrazole-3-ol HCl;
1-(1-azabicyclo[2,2,2]Oct-2-ylmethyl)-4-phenyl-1H-pyrazole-3-ol;
3-[4-(3,5-differenl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane;
4-benzo[b]thiophene-2-yl-1-(2-piperidine-1-retil)-1H-pyrazole-3-ol;
4-benzo[b]thiophene-2-yl-1-(2-piperidine-1-retil)1H-pyrazole-3-ol hydrochloride;
1-(2-piperidine-1-retil)-4-thiophene-3-yl-1H-pyrazole-3-ol;
4-[3-hydroxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzamide;
3-[3-hydroxy-1-(2-piperidine-1-retil)-1H-pyrazole-4-yl]benzamide;
(-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-ol;
(+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-ol;
(-)-1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-phenyl-1H-pyrazole-1-ol;
(+)-1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-phenyl-1H-pyrazole-1-ol;
1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-4-(4-chlorophenyl)-1H-pyrazole-3-ol;
(-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazole-3-ol;
(+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazole-3-ol;
(-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-forfinal)-1H-pyrazole-3-ol;
(+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(4-forfinal)-1H-pyrazole-3-ol;
3-[4-(4-chlorophenyl)pyrazole-1-yl]-1-azabicyclo[2,2,2]octane;
3-[4-(4-chlorophenyl)pyrazole-1-ylmethyl]-1-azabicyclo[2,2,2]octane;
3-[4-(3-chloro-4-methoxyphenyl)pyrazole-1-ylmethyl]-1-azabicyclo[2,2,2]octane;
4-[1-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-1H-pyrazole-4-yl]-2-chlorophenol;
4-[1-(1-azabicyclo[2,2,2]Oct-3-yl)-1H-pyrazole-4-yl]-2-chlorophenol;
(-)-4-[1-(1-azabicyclo[2,2,2]Oct-3-yl)-1H-pyrazole-4-yl]-2-chlorophenol;
(+)-4-[1-(1-azabicyclo[2,2,2]Oct-3-yl)-1H-pyrazole-4-yl]-2-chlorophenol;
(+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-pyridin-2-yl-1H-pyrazole-3-ol;
(-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-pyridin-2-yl-1H-pyrazole-3-ol;
(+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-ylamine;
(-)-1-(1-and bicyclo[2,2,2]Oct-3-yl)-4-phenyl-1H-pyrazole-3-ylamine;
(+)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(1H-indol-4-yl)-1H-pyrazole;
(-)-1-(1-azabicyclo[2,2,2]Oct-3-yl)-4-(1H-indol-4-yl)-1H-pyrazole;
their racemates, enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts.

5. The method of obtaining the compounds of formula (I) according to claim 1 and in which R3 means IT is based on the compounds of formula (II):

where GP denotes a protective group of hydroxyl group, characterized in that the compounds of formula (II) removing the protective group, and then, if necessary, turn it into a pharmaceutically acceptable salt.

6. The method of obtaining the compounds of formula (I) according to claim 1 and in which R3 means ORc, H, NH2by alkylation of pyrazoles of the formula (III):

where GP denotes a protective group, group IT using the compounds of formula (IV) R1-A-X, in which X represents Cl, Br, I, OTs, OMs, OTf, in alkaline medium, in an aprotic solvent, and, if necessary, removing the protective group and, if necessary, the resulting product is converted into pharmaceutically acceptable salt.

7. The pharmaceutical composition intended for the treatment of diseases resulting from the dysfunction of the nicotinic receptor α7 or positively respond to their modulation, comprising at least one compound according to any one of claims 1 to 4 in a pharmaceutically p is yimlamai environment.

8. The use of the compounds of formula (I):

in which A, if present, means (C1-C6)-alkyl;
R1 means a group NR6R7, (C4-C7-azacyclonol, (C5-C9-azabicycloalkanes, and these groups are optionally substituted by one or more substituents selected from (C1-C5)-alkyl or halogen;
A-R1 is such that the nitrogen radical R1 and the nitrogen in position 1 of the pyrazole are necessarily separated by at least two carbon atoms;
R3 means a radical of H, HE, NH2, ORc, NHC(O)Ra or NHSO2Ra;
R4 denotes phenyl or heteroaryl optionally substituted by one or more substituents selected from halogen, CN, NH2HE, ORc, C(O)NH2, phenyl, polyfluoroankyl, linear or branched (C1-C6)-alkyl, and these substituents optionally substituted with halogen, and heteroaryl radicals are 3-10-membered containing one or more heteroatoms selected from sulfur and nitrogen;
R5 means a radical of H, linear or branched (C1-C6)-alkyl;
Ra means a linear or branched (C1-C6)-alkyl;
Rc means a linear or branched (C1-C6)-alkyl, (poly)foralkyl or phenyl;
R6 and R7, independently of one another, mean hydrogen, (C1-C6)-alkyl;
R6 and R7 may make obyvaci 5-, 6 - or 7-membered saturated or unsaturated cycle which includes one heteroatom, such as N and which is optionally substituted by one or more halogen atoms;
with the exception of N-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine as a medicinal product intended for the treatment of diseases resulting from the dysfunction of the nicotinic receptor α7 or positively respond to their modulation.

9. The use of claim 8 compounds of formula (I):

in which A, if present, means (C1-C6)-alkyl;
R1 means a group NR6R7, (C4-C7-azacyclonol, (C5-C9-azabicycloalkanes, and these groups are optionally substituted by one or more substituents selected from (C1-C5)-alkyl or halogen;
A-R1 is such that the nitrogen radical R1 and the nitrogen in position 1 of the pyrazole are necessarily separated by at least two carbon atoms;
R3 means a radical, HE, NH2, OMe, H;
R4 denotes phenyl or heteroaryl optionally substituted by one or more substituents selected from halogen, CN, NH2HE, ORc, C(O)NH2, phenyl, polyfluoroankyl, linear or branched (C1-C6)-alkyl, and these substituents optionally substituted with halogen, and heteroaryl radicals are 3-10-membered containing one and the or more heteroatoms, selected from sulfur and nitrogen;
R5 means hydrogen or Me;
Ra means a linear or branched (C1-C6)-alkyl;
Re means a linear or branched (C1-C6)-alkyl, (poly)foralkyl or phenyl;
R6 and R7, independently of one another, mean hydrogen, (C1-C6)-alkyl;
R6 and R7 may form a 5-, 6 - or 7-membered saturated or unsaturated
the loop including one heteroatom, such as N and which is optionally substituted by one or more halogen atoms;
with the exception of N-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine as a medicinal product intended for the treatment of diseases resulting from the dysfunction of the nicotinic receptor α7 or positively respond to their modulation.

10. The use of claim 8 compounds of formula (I):

in which A, if present, means (C1-C6)-alkyl;
R1 means a group NR6R7, (C4-C7-azacyclonol, (C5-C9-azabicycloalkanes, and these groups are optionally substituted by one or more substituents selected from (C1-C5)-alkyl or halogen;
A-R1 is such that the nitrogen radical R1 and the nitrogen in position 1 of the pyrazole are necessarily separated by at least two carbon atoms;
R3 means a radical, HE, NH2, OMe, H;
R4 denotes phenyl or heteroaryl, n is necessarily substituted by one or more substituents selected from halogen, CN, NH2HE, ORc, phenyl, polyfluoroankyl, C(O)NH2linear or branched (C1-C6)-alkyl, and these substituents optionally substituted with halogen, and heteroaryl radicals are 3-10-membered containing one or more heteroatoms selected from sulfur and nitrogen;
R5 means hydrogen;
Ra means a linear or branched (C1-C6)-alkyl;
Rc means a linear or branched (C1-C6)-alkyl, (poly)foralkyl or phenyl;
R6 and R7, independently of one another, mean hydrogen, (C1-C6)-alkyl;
R6 and R7 may form a 5-, 6 - or 7-membered saturated or unsaturated cycle which includes one heteroatom, such as N and which is optionally substituted by one or more halogen atoms;
with the exception of N-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine as a medicinal product intended for the treatment of diseases resulting from the dysfunction of the nicotinic receptor α7 or positively respond to their modulation.

11. The use of at least one compound according to any one of claims 1 to 4 for obtaining a medicinal product intended for the treatment of diseases resulting from the dysfunction of the nicotinic A7 receptors or positively respond to their modules the Y.

12. The use of at least one compound according to any one of claims 1 to 4 for obtaining a medicinal product intended to treat, prevent, diagnose and/or monitor the development of psychiatric or neurological disorders or diseases of the Central nervous system in which there is a deterioration of cognitive functions or processing sensory information.

13. The application of claim 11, wherein the disease or disorder refers to cognitive abilities, attention, ability to concentrate, learning and/or memory.

14. The application of claim 11, wherein the disease is Alzheimer's disease and related cognitive disorders.

15. The application of claim 11, wherein the disease is schizophrenia.

16. The use of at least one compound according to any one of claims 1 to 4 for obtaining a medicinal product intended to reduce drug consumption, to facilitate maintaining Asistencia against them or alleviate withdrawal symptoms, and for its therapeutic use in the treatment of acute or chronic neuronal degenerations.



 

Same patents:

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to new biarylcarboxamides of the general formula (I): wherein A means compound of the formula (II): ; D means oxygen atom (O) or sulfur atom (S); E means a simple bond, oxygen atom, sulfur atom or NH; Ar1 means 5-membered heteroaromatic ring comprising one nitrogen atom (N) and one sulfur atom (S) or one oxygen atom (O), or one S atom, or one N atom; or 6-membered aromatic ring, or heteroaromatic ring comprising one N atom; Ar2 means 5-membered heteroaromatic ring comprising one S atom or on O atom, or one N atom and one O atom, or one N atom; or 6-membered aromatic ring or heteroaromatic ring comprising one N atom; or 9-membered condensed heteroaromatic ring system comprising one O atom, or 10-membered condensed aromatic ring system, or heteroaromatic ring system comprising one N atom wherein aromatic ring Ar2 is possibly substituted with one or two substitutes taken among halogen atom, (C1-C4)-alkyl, cyano-group (-CN), nitro group (-NO2), NR1R2, OR3, trihalogen-(C1-C4)-alkyl, (C1-C4)-acylamino-, hydroxy-, morpholino-, amino-, methylamino-group, amino-(C1-C4)-alkyl and hydroxymethyl but if Ar1-phenyl and Ar2 represent quinolinyl group then Ar2 is substituted with one or two (C1-C4)-alkyls, -CN, -NO2, NR1R2, OR3 wherein R1, R2 and R3 mean (C1-C4)-alkyl and compound of the formula (III) doesn't represent .

EFFECT: improved preparing and treatment methods.

33 cl, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with formula I: , where D is O; E is CH2 or O; n equals 1 or 2, and R1 is chosen from hydrogen, halogen or substituted or unsubstituted 5- or 6-member aromatic or heteroaromatic ring with 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atom, or is chosen from substituted or unsubstituted 8-, 9- or 10-member condensed heteroaromatic ring system with 0 or 1 nitrogen atom, 0 or 1 oxygen atom, where the said aromatic or heteroaromatic rings or ring systems, when they are substituted, have substitutes which are chosen from -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, halogen, -CF3, -S(O)mR2, where m equals 0, 1 or 2, -NR2R3, -NR2C(O)R3 or -C(O)NR2R3; R2 and R3 are in each case independently chosen from hydrogen, -C1-C4alkyl, -C3-C6cycloalkyl, aryl; or its stereoisomers, enantiomers or pharmaceutically acceptable salts; under the condition that the given compound is not 2-(1-aza-bicyclo[2.2.2]oct-3-yl)-2,3-dihydroisoindol-1-one. The invention also relates to compounds with formulae II or III, to a pharmaceutical composition, as well as to use of compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds with activity towards alpha 7 nicotinic acetylcholine receptors (α7 nAChRs).

8 cl, 72 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the new compounds of formula I in the form of the salt or zwitter-ion, wherein R1 and R3 are independently phenyl, C3-C8 cycloalkyl or thienyl group, R2 is haloid or hydroxyl group; R4 is C1-C8 alkyl substituted with -NR5-CO-R6 or -CO-NR9R10; R5 is hydrogen ; R6 is C1-C8alkyl or C1-C8 alkoxy, each of them is optionally substituted with 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or R6 is 5-10-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur; R9 is hydrogen or C1-C8alkyl; R10 is C1-C8alkyl, optionally substituted with cyano group, C1-C8 alkoxy group or with 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or R10 is 5-9-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur. The invention refers also to the pharmaceutic composition, to the application of compound of any of claims 1-5 as well as to the preparation method of compound of formula I of claim 1.

EFFECT: preparation of the new biologically active compounds taking the effect of muscarin receptor M3.

9 cl, 247 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns medical products and concerns the method of obtaining of a Solifenacin composition or its salts for use in a solid preparation which includes at least one stage chosen of the group consisting of (i) stage of wet granulation with use of a dissolvent for Solifenacin or its salts, thereat quantity of Solifenacin or its salts which should be dissolved in 1 ml of a dissolvent makes less than 0.1 mg, (ii) stage of dicrease of quantity or rate of addition of a dissolvent if the dissolvent moves Solifenacin or its salt in an amorphous condition, and quantity of Solifenacin or its salts which should be dissolved in 1 ml of a dissolvent 10 mg or more and (iii) stage of activisation of process of crystallisation of a composition of the wet granulation received by means of a usual way. Also the pharmaceutical composition for use in the solid preparation, showing selective opposing action against muscarinic M3 receptors is revealed.

EFFECT: rising of stability of the compositions containing Solifenacin or its salt.

12 cl, 3 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1-azabicycloalkyl of general formula I, , in which X represents CH2 or simple bond; Y represents group of formula or and, where R has values given in description, which are agonists of alpha 7 nicotine acetylcholine receptor (nAChR).

EFFECT: possibility of using as pharmaceutical preparations.

18 cl

FIELD: chemistry.

SUBSTANCE: present invention pertains to a new derivative of cyclic amine or its salts with the following formula (I): (where symbols stand for the following: A: 5-8-member cyclic amine, which may contain a double bond, a bridged structure and may contain substitutes R7-R11 in the ring, or -NH2, -NH(inferior alkyl), -N(inferior alkyl)2 or ) morpholin-1-yl; ring B: benzole, thiophene, furane, pyrrole, 5-7-member cycloalkane or 5-7-member cycloalkene; X1: a bond or inferior alkylene; X2: -(CR12R13)n-, -N(R14)-, -N(R14)CO-, -CON(R14)-, -CO-, -CH(OH)-, -N(R14)- (CR12R13)n-, (CR12R13)n-N(R14)-, -CON(R14)-(CR12R13)n-, -n(R14)CO-(CR12R13)n-, -(CR12R13)n-N(R14)CO-, -(CR12R13)n-CON(R14)-, -CO-(CR12R13)n- or -(CR12R13)n-CO-; Y1: -OH, -O-inferior alkyl, NH2 or -N3; R1 and R2: are identical or different and stand for a halogen atom, inferior alkyl or inferior alkylene-OH; R3-R6: are identical or different and stand for a hydrogen atom, a halogen atom, inferior alkyl, inferior alkenyl, inferior alkynyl, -O-inferior alkyl, -OH, -NH2, -NH(inferior alkyl), -N(inferior alkyl)2, -NH-CO- inferior alkyl, -N(inferior alkyl)-CO- inferior alkyl, -CN-, -NO2, -CF3, -O-inferior alkylene-OH, -inferior alkylene-OH, -inferior alkylene-halogen, -inferior alkylene-O-inferior alkyl, -CO-5-8-member cyclic amine, -COOH-inferior alkyl, -COO-inferior alkylene-aryl, pyridine, thiophene, -inferior alkylene-morpholine, aryl, which may contain a substitute: -O-inferior alkyl or -CF3; R7: hydrogen atom, inferior alkyl, -inferior alkylene-aryl or -inferior alkylene-pyridine: R7 is substitute on the nitrogen atom of the cyclic amine; R8-R14: are identical or different and stand for a hydrogen atom or inferior alkyl; n: is an integer, equal to 1, 2 or 3; where R5 and R6, R4 and R5 or R3 and R4 can form an inferior alkylene together, -O-inferior alkylene-O-, -O-inferior alkylene-, -inferior alkylene-O-, -C(R15)=C(R16)-O-, -O-C(R15)=C(R16)-, -C(R15)=C(R16)-C(R17)=C(R18)-; R3 and Y1 together can form -O-inferior alkylene-O- or -inferior alkylene-O-; R1 and Y1 together can form -inferior alkylene-O-; and Y1 and a branch on - X1-A together can form -O- or -O-inferior alkylene; R15-R18 stand for a hydrogen atom, under the condition that, 6-chloro-2,2-dimethyl-1-(1-methyl-4-piperidinyl)indan-1-ol is not included in the group of compounds). The invention also pertains to a derivative of cyclic amine or its salts with formula (II), to a derivative of cyclic amine or its salts with formula (III), to pharmaceutical composition, as well as their use.

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on these compounds, with antagonist effect on NMDA receptors NMDA.

7 cl, 160 ex, 45 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula I: , where: a is 0 or whole number of 1 to 3; each R1 is selected independently out of the halogens; b is 0 or whole number of 1 to 3; each R2 is selected independently out of the halogens; W is linked in 3 or 4 position against the nitrogen atom in piperidine ring and is O; c is 0 or whole number of 1 to 4; each R3 is selected independently out of (1-4C)alkyls; or two groups of R3 are linked together forming (1-3C)alkylene or oxyrane-2,3-diyl; R4 is a bivalent group of the formula: -(R4a)d-(A1)e-(R4b)t-Q-(R4c)g-(A2)h-(R4d)i-, where each of d, e, f, g, h and i is selected independently out of 0 or 1; each of R4a, R4b, R4c and R4d is selected independently out of (1-10C)alkylene, where each alkylene group is unsubstituted or substituted by 1-5 substitutes selected independently out of (1-4C)alkyl, fluorine and hydroxy-; each of A1 and A2 is selected independently out of (3-7C)cycloalkylene, (6-10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene and (3-6C)heterocyclene where each cycloalkylene is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogens, (1-4C)alkyl, (1-4C)alkoxy-, -S(O)2-(1-4C)alkyl, hydroxy-, nitro- and trifluormethoxy; Q is selected out of -O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-; -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and -N(Qk) links; each of Qa, Qb, Qc, Qd, Qe, Qf and Qk is selected independently out of hydrogen, (1-6C)alkyl and A3, where alkyl group is unsubstituted or substituted by 1-3 substitutes selected independently out of fluorine, hydroxy- and (1-4C)alkoxy-; or together with nitrogen atom and R4b or R4c group to which they are linked they form 4-6-membered azacycloalkylene group; A3 is selected independently out of (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroalkyl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogen, (1-4C)alkyl and (1-4C)alkoxy-, if the number of adjacent atoms in the shortest chain between two nitrogen atoms, to which R4 is linked, lies within 4 to 16; R5 is hydrogen or (1-4C)alkyl; R6 is -NR6aCR6b(O), and R7 is hydrogen; either R6 and R7 together form -NR7aC(O)-CR7b=CR7c-; each of R6a and R6b is hydrogen or (1-4C)alkyl independently; and each of R7a, R7b and R7c is hydrogen or (1-4C)alkyl independently; or the pharmaceutically acceptable salts, solvates or stereoisomers of the claimed compounds. The invention also concerns compounds of the formula I, 1-[2-(2-chlor-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxuphenylcarbamoyl)ethyl] piperidine-4-yl ether of biphenyl-2-ylcarbamine acid or its pharmaceutically acceptable salt or solvate, pharmaceutical composition, method of pulmonary disease treatment, method of bronchial lumen dilation for a patient, method of treatment of chronic obstructive pulmonary disease or asthma, method of obtaining the compound of the formula I, medicine based on it, and application of compounds described in any of the paragraphs 1, 13, 14, 24, 25, 26, 27 or 28.

EFFECT: obtaining of new biologically active compounds with high activity rate of both antagonist of muscarine receptors and β2 agonist of adrenergic receptors.

42 cl, 186 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel quinuclidine derivatives and their using as pharmaceutical agents. Based on their pharmacological pattern proposed compounds can be useful in treatment of different diseases and disorders associated with cholinergic system of the central nervous system, peripheral nervous system, diseases and disorders associated with contraction of smooth muscle, endocrine diseases or disorders, diseases or disorders associated with neurodegeneration, diseases or disorders associated with inflammation, pain and abstinence syndrome caused by ceasing use of chemical substances.

EFFECT: valuable medicinal properties of compounds.

11 cl, 1 tbl, 46 ex

FIELD: organic chemistry, medicine, chemical technology.

SUBSTANCE: invention describes a method for synthesis of 1-hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane bromide represented by the formula: . Method involves interaction of 1-hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane with hydrobromic acid or its inorganic salt (for example, sodium bromide or potassium bromide) in water in the ionic exchange reaction. 1-Hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane bromide represents an immunotropic agent that shows versatile effect on human immune status and elicits antitumor, bacteriostatic and anti-aggregate effects. Invention proposes a method for synthesis of a novel synthetic low-molecular preparation possessing the expressed stimulating effect on the antitumor immunity system that is equal or exceeding by effectiveness effect of the modern domestic and foreign preparation - immunomodulators that represent natural high-molecular biologically active substances prepared by methods of genetic engineering.

EFFECT: improved method of synthesis, valuable medicinal and biological properties of substance.

1 cl, 6 tbl, 21 dwg, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds that represent quaternary ammonium salt of the formula (II): wherein R1 means group chosen from phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl; R2 means group chosen from (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, saturated or unsaturated (C3-C7)-cycloalkyl, saturated or unsaturated (C3-C7)-cycloalkylmethyl, phenyl, benzyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, pyridyl and pyridylmethyl; cyclic groups in R1 and R2 are optionally substituted with one, two or three substitutes chosen from halogen atom, linear or branched (C1-C8)-alkyl, hydroxy, linear or branched (C1-C8)-alkoxy wherein (C1-C8)-alkyl groups are unsubstituted or substituted with one or more halogen atoms, hydroxy or (C1-C8)-alkoxy groups, and (C1-C8)-alkoxy group is unsubstituted or substituted with one or more halogen atoms or hydroxy groups; p means 1 or 2, and carbamate group is joined at positions 2, 3 or 4 of azoniabobicyclic ring system; m means a whole number from 1 to 6; n means 0 or 1; A represents -CH2-, -CH=CH-, -C(O)-, -O-, -S- and -NMe-group; B represents hydrogen atom or group chosen from linear or branched (C1-C8)-alkyl, hydroxy, linear or branched (C1-C8)-alkoxy, cyano, nitro, -CH=CR'R'', -C(O)OR', -OC(O)R', (C3-C7)-cycloalkyl, phenyl, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl, benzo[1.3]dioxolyl, 5-10-membered heteroaryl or heterocyclyl group wherein each R' and R'' represents independently hydrogen atom or linear or branched (C1-C8)-alkyl group, and wherein cyclic groups represented as B are substituted optionally with one, two or three substitutes chosen from halogen atom, hydroxy, linear or branched (C1-C8)-alkyl, -OR', -CONR'R'', -CN, and -COOR'; R' and R'' are given above and wherein (C1-C8)-alkyl groups are unsubstituted or substituted with one or more halogen atoms, hydroxy or (C1-C8)-alkoxy groups, and (C1-C8)-alkoxy groups are unsubstituted or substituted with one or more halogen atoms or hydroxy groups; X- represents a pharmaceutically acceptable anion of mono- or polyvalent acid, and involving all individual stereoisomers of compound of the formula (II) and their mixtures. Also, invention relates to a method for inhibition, pharmaceutical composition, combined product and their using in therapeutic treatment as antagonists of M3 muscarinic receptors. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 187 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 1-(2S,3S)-2-benzhyryl-N-(5-tert.-butyl-2-methoxybenzyl)quinuclidin-3-amine (further named in the claim as "compound of the formula (I)" ) and its pharmaceutically acceptable salts. Invention relates to an improved method of synthesis of citrate monohydrate salt of compound of the formula (Ia):

EFFECT: improved method of synthesis.

10 cl, 2 sch,

FIELD: medicine.

SUBSTANCE: invention is related to compound of formula (I), (values of radicals are described in formula of invention) or its pharmaceutically acceptable salts, to methods of its production, pharmaceutical composition, which contains it. Application of invention is described for manufacturing of medicinal agent intended for provision of inhibiting action in respect to HDAC in warm-blooded animal, in production of agent used for treatment of malignant tumor. Method is also described for provision of inhibiting action in warm-blooded animal.

EFFECT: compounds have inhibiting activity in respect to HDAC.

15 cl, 17 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to use of compounds of formula (I) where R1 is lower alkyl or halogen; R2 is hydrogen or halogen; R3 is (CHR')nOH, phenyl, possibly substituted with a -(CHR')nOH group, or is a saturated, partially saturated or aromatic 5- or 6-member heterocyclic ring with one heteroatom, selected from a group which consists of -N(R4)-, -N=, -S- or -S(O)2, where the rings are possibly substituted with a -(CHR')nOH group; R' is hydrogen or a -(CH2)nOH, independent of the value of n; R4 is hydrogen, -S(O2)-lower alkyl group or -C(O)-lower alkyl; X is -O-, -CH2O-, -S- or a bond; n equals 1 or 2; or their pharmaceutically active acid addition salts for making medicine for treating schizophrenia, as well as to compounds of formula (I).

EFFECT: description is given of compounds which can be used in medicine.

8 cl, 16 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: new 5-sulphanyl-4H-1,2,4-triazole derivatives of general formula I (meaning of radicals R1-R3 are indicated in the description of the invention), methods of their preparation by liquid-phase parallel synthesis and pharmaceutical composition are claimed.

EFFECT: claimed compounds display high affinity to some subtypes of somostatin receptors of the SST2 and SST5 subtypes and possibility of their usage for treatment of pathological states or diseases involving one or more of the given somostatin receptors

9 cl, 708 ex

FIELD: chemistry; medicine.

SUBSTANCE: in novel triazole derivatives of general formula I or their pharmaceutically acceptable salts R4 is hydrogen; X is selected from group, consisting of single bond, NH- and groups: , values of R1-R3 radicals are given in description, pharmaceutical composition containing them, and application of novel compounds for obtaining medication for treating hyperglycemia, insulin-resistance, type 2 diabetes, fat exchange derangements, obesity, atheroslerosis and metabolic syndrome.

EFFECT: medications possess higher efficiency.

26 cl, 8 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula (I), their obtaining and application as elastase inhibitors, and can be applied in medicine, where Y = CH; R№ represents H or alkyl; RІ represents phenyl or 5-6-memner heteroaryl, G1 represents phenyl; R5 represents H, halogen, alkyl, CN or fluorinated alkyl; n=1-3; R4 = H; L represents bond, O, NR29 or alkyl; or R4 and L are bound together in such way that group -NR4L- represents 5-7-member asacyclic ring; G2 represents phenyl, 5-6-member heteroaryl, cycloalkyl, C4-7-heterocycle, bicycle from two condensed, bound with direct bond or separated with O atom rings, selected from phenyl, 5-6-member heteroaryl, cycloalkyl or C4-7-heterocycle; or when L does not represent bond, G2 represents H; s = 0-2; R25 represents H, alkyl or cycloalkyl; R29 represents H or alkyl.

EFFECT: obtaining novel biologically active compounds.

10 cl, 95 ex, 1 tbl

FIELD: chemistry; pharmacology.

SUBSTANCE: invention refers to new benzofuran and benzothiophen derivatives of general formula I, , wherein X is chosen from O and S; R1 is chosen from H, (C1-C6)alkyl, C(O)(C1-C6) alkyl and benzoyl; R2 is chosen from phenyl optionally substituted with 1 or 2 substitutes, each independently chosen from CN, NO2, (C1-C6)alkyl, (C1-C6)alkoxy, halogen, halogen(C1-C6)alkyl, pyridyl or benzo[1,3]dioxolyl optionally substituted with (C1-C6)alkyl. There are disclosed pharmaceutical composition based on compounds I and method of treatment.

EFFECT: compounds can be used to treat or prevent diseases associated with malignant cell proliferation.

26 cl, 7 tbl, 365 ex

FIELD: chemistry.

SUBSTANCE: invention concerns method of treatment, alleviation and/or prevention of neurological state, particularly neurodegenerative disorders, involving administration of effective quantity of compound with formula I: . Also invention concerns application of compound of the formula I as neurotherapeutical, neuroprotective or antimyloid agent, pharmaceutical or veterinary composition for treatment, alleviation and/or prevention of neurological states, and compounds of the formula I on the following additional terms: (b) if R3, R and R' are H, and R2 is (CH2)2NR9R10, then both R9 and R10 are not ethyl or methyl; (c) if R3, R and R' are H, and R2 is (CH2)2NR9R10, then both R9 and R10 are not hydrogen or ethyl; (d) if R3, R and R' are H, and R2 is NR11R12, then both R11 and R12 are not hydrogen; (e) if R3, R and R' are H, and R2 is COR6, then R6 is not H, OH or CH2Cl; (f) if R3, R and R' are H, and R2 is not CH3 or CH2Cl; (g) if R3, R and R' are H, and R2 is HCNN R9R10, then both R9 and R10 are not H.

EFFECT: efficient treatment, alleviation and prevention of neurological state.

24 cl, 14 tbl, 21 ex, 14 dwg

FIELD: chemistry.

SUBSTANCE: present invention pertains to a new derivative of cyclic amine or its salts with the following formula (I): (where symbols stand for the following: A: 5-8-member cyclic amine, which may contain a double bond, a bridged structure and may contain substitutes R7-R11 in the ring, or -NH2, -NH(inferior alkyl), -N(inferior alkyl)2 or ) morpholin-1-yl; ring B: benzole, thiophene, furane, pyrrole, 5-7-member cycloalkane or 5-7-member cycloalkene; X1: a bond or inferior alkylene; X2: -(CR12R13)n-, -N(R14)-, -N(R14)CO-, -CON(R14)-, -CO-, -CH(OH)-, -N(R14)- (CR12R13)n-, (CR12R13)n-N(R14)-, -CON(R14)-(CR12R13)n-, -n(R14)CO-(CR12R13)n-, -(CR12R13)n-N(R14)CO-, -(CR12R13)n-CON(R14)-, -CO-(CR12R13)n- or -(CR12R13)n-CO-; Y1: -OH, -O-inferior alkyl, NH2 or -N3; R1 and R2: are identical or different and stand for a halogen atom, inferior alkyl or inferior alkylene-OH; R3-R6: are identical or different and stand for a hydrogen atom, a halogen atom, inferior alkyl, inferior alkenyl, inferior alkynyl, -O-inferior alkyl, -OH, -NH2, -NH(inferior alkyl), -N(inferior alkyl)2, -NH-CO- inferior alkyl, -N(inferior alkyl)-CO- inferior alkyl, -CN-, -NO2, -CF3, -O-inferior alkylene-OH, -inferior alkylene-OH, -inferior alkylene-halogen, -inferior alkylene-O-inferior alkyl, -CO-5-8-member cyclic amine, -COOH-inferior alkyl, -COO-inferior alkylene-aryl, pyridine, thiophene, -inferior alkylene-morpholine, aryl, which may contain a substitute: -O-inferior alkyl or -CF3; R7: hydrogen atom, inferior alkyl, -inferior alkylene-aryl or -inferior alkylene-pyridine: R7 is substitute on the nitrogen atom of the cyclic amine; R8-R14: are identical or different and stand for a hydrogen atom or inferior alkyl; n: is an integer, equal to 1, 2 or 3; where R5 and R6, R4 and R5 or R3 and R4 can form an inferior alkylene together, -O-inferior alkylene-O-, -O-inferior alkylene-, -inferior alkylene-O-, -C(R15)=C(R16)-O-, -O-C(R15)=C(R16)-, -C(R15)=C(R16)-C(R17)=C(R18)-; R3 and Y1 together can form -O-inferior alkylene-O- or -inferior alkylene-O-; R1 and Y1 together can form -inferior alkylene-O-; and Y1 and a branch on - X1-A together can form -O- or -O-inferior alkylene; R15-R18 stand for a hydrogen atom, under the condition that, 6-chloro-2,2-dimethyl-1-(1-methyl-4-piperidinyl)indan-1-ol is not included in the group of compounds). The invention also pertains to a derivative of cyclic amine or its salts with formula (II), to a derivative of cyclic amine or its salts with formula (III), to pharmaceutical composition, as well as their use.

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on these compounds, with antagonist effect on NMDA receptors NMDA.

7 cl, 160 ex, 45 tbl

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of pyridazin-3(2H)-one of formula (I), where R1, R2 and R4 are organic radicals described in the claim 1, R3 is cyclic group described in the claim, and R5 is phenyl or heteroaryl group described in the claim. Compounds of formula (I) inhibit phosphodiesterase 4 (PDE-4) and can be applied in treatment of various diseases or pathological states alleviated by PDE-4 inhibition, and in medicine production for treatment of aforesaid diseases. Also invention claims method of obtaining these compounds and intermediate compounds for their obtainment.

EFFECT: obtaining compounds which can be used in treatment of various diseases or pathological states and in medicine production for treatment of aforesaid diseases.

25 cl, 28 tbl, 243 ex

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