Diazaspiropiperidine derivatives

FIELD: chemistry.

SUBSTANCE: invention concerns novel derivatives of diazaspiropiperidine of the formula I: , where A-B is -CH2-CH2-, -CH2-O- or -O-CH2-; X is hydrogen or hydroxy; R1 is aryl optionally substituted by one or more substitutes selected out of group including haloid, (lower) alkyl, cyano, CF3, -OCF3, (lower) alkoxy, -SO2-(lower)alkyl, or heteroaryl with two nitrogen atoms; R2 is phenyl optionally substituted by one or more substitutes selected out of group including haloid, (lower) alkyl, CF3 or (lower) alkoxy; R3 is hydrogen or (lower)alkyl; n is 0, 1 or 2; and their pharmaceutically acceptable salts.

EFFECT: medicine based on compounds of the formula 1 and their application in obtaining medicine for neuropathological and neuropsychiatric disease treatment.

12 cl, 1 tbl, 29 ex

 

The present invention relates to compounds of formula I

where a-b means-CH2-CH2-, -CH2-O - or-O-CH2-;

X is hydrogen or hydroxy;

R1means aryl, optionally substituted by one or two substituents selected from the group consisting of halogen, (ness.)of alkyl, cyano, CF3, -OCF3, (ness.)alkoxy, -SO2-(ness.)the alkyl, or heteroaryl;

R2means aryl, optionally substituted by one or two substituents selected from the group consisting of halogen, (ness.)of alkyl, CF3or (ness.)alkoxy;

R3means hydrogen or (ness.)alkyl;

n means 0, 1 or 2,

and to their pharmaceutically active salts.

The present invention relates to compounds of General formula I, containing their pharmaceutical compositions and their use in the treatment of neurological and neuropsychiatrically disorders.

It has been unexpectedly found that compounds of General formula I are effective inhibitors of glycine vector 1 (GlyT-1) and have significant selectivity towards inhibitors of glycine vector 2 (GlyT-2).

Schizophrenia is a progressive and devastating neurological disorder characterized by episodic positive symptoms such as delusions, hallucinate is, thought disorder and psychosis, and persistent negative symptoms such as sluggish emotional reaction, impaired attention and social care, and violations of cognitive abilities (D.A.Lewis and J.A.Lieberman, Neuron, 2000, 28: 325-33). For decades, research has focused on the hypothesis that dopaminergic hyperresponsiveness", which led to therapeutic interventions, including the blockade of the dopaminergic system (R.J.Vandenberg and K.R.Aubrey, Exp. Opin. Ther. Targets, 2001, 5 (4): 507-518; A.Nakazato and S.Okuyama and others, 2000, Exp. Opin. Ther. Patents, 10 (1): 75-98). This pharmacological approach does not apply to negative symptoms and symptom of impaired cognitive abilities, which are the best predictors of functional outcome (.Sharma, Br.J. Psychiatry, 1999, 174 (DOP): 44-51).

Additional model of schizophrenia was proposed in the mid-sixties, based on psychotomimetics action caused by blockade of glutamate system compounds such as phencyclidine (PCP) and related agents (ketamine), which are non-competitive antagonists of the receptor N-methyl-D-aspartate (NMDA). Interestingly, in healthy volunteers psychotomimetics action induced by PCP, includes positive and negative symptoms and cognitive dysfunction, so closely resembling schizophrenia in the of patients (D.C.Javitt and others, 1999, Biol. Psychiatry, 45: 668-679 and links in the context). In addition, transgenic mice expressing reduced levels of receptor subunit NMDAR1, show behavioral abnormalities similar to those observed in induced pharmacological way models of schizophrenia, supporting a model in which reduced activity of the NMDA receptor leads to similar schizophrenia behavior (A.R.Mohn and others, 1999, Cell 98: 427-236).

Glutamic neurotransmission, in particular the activity of the NMDA receptor, plays a crucial role in the plasticity of synapses, learning and remembering, such receptors, as NMDA, apparently, serve as a differential switch for synchronization threshold synaptic plasticity and memory formation (D.O.Hebb, 1949 The organization of behavior, Wiley, NY; T.V.Bliss and G.L.Collingridge, 1993, Nature, 361: 31-39). Transgenic mouse sverkhekspressiya the NR2B subunit of the NMDA receptor, have increased synaptic plasticity and excellent ability to learn and remember (J.P.Tang and others, 1999, Nature, 401 - 63-69).

So, if there is a deficiency of glutamate are involved in the pathophysiology of schizophrenia, increased transmission of glutamate, in particular through activation of the NMDA receptor, predicted would receive as antipsychotic effects and manifestations enhance cognitive abilities.

It is known that the amino acid glycine has on men is her least two important functions in the CNS. It acts as an inhibitory amino acid, binding is sensitive to strychnine glycine receptors, and also affects the exciting activity, acting as an essential co-agonist with glutamate to the receptor N-methyl-D-aspartate (NMDA). While glutamate released from synaptic endings dependent on the activity method, glycine, apparently, is present at a more constant level and, apparently, modulating/controlling receptor to its response to glutamate.

One of the most effective ways to control synaptic concentrations of the neurotransmitter is the effect on re-uptake at the synapse. Neurotransmitter vectors by removing neurotransmitters from the extracellular space can control their extracellular lifetime and thereby modulate the intensity of synaptic transmission (R.R.Gainetdinov and others, 2002, Trends in Pharm. Sci., 23 (8): 367-373).

Vectors glycine, which form a part of the family of sodium and chloride neurotransmitter vectors play an important role in ending glycinergic action and maintaining the concentration of vnekletochnogo glycine by re-absorption in precipitiously nerve endings and passing outside a thin glial processes.

Two different gene glycine vector were cloned (lyT-1 and GlyT-2) from the brain of a mammal, which give rise to two vectors with approximately 50% homology of amino acid sequences. A Transporter GlyT-1 is a four isoforms (1a, 1b, 1C and 1d), resulting from alternative splicing and alternative use of promoters. Only two of these isoforms were found in the brain of rodents (GlyT-1A, GlyT-1b). A Transporter GlyT-2 is also somewhat heterogeneous. In the brain of rodents were identified two isoforms GlyT-2 (2A and 2b). It is known that GlyT-1 is localized in the CNS and in peripheral tissues, whereas GlyT-2 is specific to the CNS. GlyT-1 is mainly distributed in glial cells and is found not only in areas relevant sensitive to strychnine glycine receptors, but also outside these areas, where it has been suggested, included in the modulation of receptor function of NMDA (.Lopez-Corcuera and others, 2001, Mol. Mem. Biol., 18: 13-20). Thus, one strategy to enhance receptor activity of NMDA receptors is to increase the concentration of glycine in the local microenvironment of synaptic NMDA receptors by inhibiting carrier GlyT-1 (R.Bergereon and others, 1998, Proc. Natl. Acad. Sci. USA, 95: 15730-15734; L. Chen et al, 2003, J. Neurophysiol., 89 (2): 691-703).

Inhibitors vectors glycine suitable for treatment of neurological and neuropsychiatric disorders. Most implied painful conditions are psychosis, shiz is phrenia (R.E.Armer and D.J.Miller DJ, 2001, Exp. Opin. Ther. Patents, 11 (4): 563-572), psychotic mood disorders such as acute major depression, mood disorders associated with psychotic disorders such as acute mania and depression associated with bipolar disorders, and mood disorders associated with schizophrenia (..Pralong and others, 2002, Prog. Neurobiol., 67: 173-202), autistic disorder (M.L.Carlsson, 1998, J. Neural Transm. 105: 525-535), disorders of cognitive abilities, such as dementia, including age-related dementia and senile dementia type Alzheimer's disease, memory disorders in mammals, including humans, attention deficit disorder and pain (R.E.Armer and D.J.Miller, 2001, Exp. Opin. Ther. Patents, 11 (4): 563-572).

Thus, increased activation of NMDA receptors by inhibiting carrier GlyT-1 can lead to the creation of drugs that treat psychosis, schizophrenia, dementia and other diseases in which the disturbed cognitive processes such as attention deficit disorder, or Alzheimer's disease.

Objects of the present invention are the compounds of formula I as such, the use of compounds of the formula I and their pharmaceutically acceptable salts for the preparation of drugs for the treatment of diseases associated with activation of NMDA receptors by inhibiting carrier GlyT-, cooking, medicines, based on the connection according to the invention and the reception, as well as the use of compounds of formula I in the control and prevention of illnesses such as psychoses, dysfunction in memory and learning, schizophrenia, dementia and other diseases in which the disturbed cognitive processes such as attention deficit disorder, or Alzheimer's disease.

Preferred indications for the use of the compounds of the present invention are schizophrenia, impaired cognitive ability and Alzheimer's disease.

Moreover, the invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers.

The term "(ness.)alkyl", as used in the context, means a group with a saturated linear or branched chain containing from 1 to 7 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl and the like. Preferred alkyl groups are groups with 1-4 carbon atoms.

The term "halogen" means chlorine, iodine, fluorine or bromine.

The term "aryl" means a monovalent cyclic aromatic hydrocarbon radical consisting of one or multiple condensed rings, from which at least one ring is aromatic in nature, for example phenyl is whether naphthyl.

The term "heteroaryl" means a cyclic aromatic hydrocarbon moiety containing one, two or three heteroatoms selected from the group consisting of oxygen, sulfur or nitrogen, for example pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isothiazole or isoxazolyl.

The term "pharmaceutically acceptable acid additive salts" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, n-toluensulfonate acid and the like.

Preferred compounds of formula I are the compounds of formula

where a-b means-CH2-CH2- or-CH2-O-;

X is hydrogen or hydroxy;

R1means phenyl, optionally substituted by one or two substituents selected from the group consisting of halogen (ness.)of alkyl, cyano, CF3, -OCF3, (ness.)alkoxy, -SO2-(ness.)the alkyl, or heteroaryl;

R2means phenyl, optionally substituted by one or two substituents selected from the group which, consisting of halogen or (ness.)alkoxy;

R3means hydrogen;

n means 1

and their pharmaceutically active salts.

Most preferred are compounds where n is 1, and a-means-CH2-CH2-. Particularly preferred compounds from this group are those in which R1and R2mean both phenyl, optionally substituted (ness.)by alkyl, halogen or CF3for example, the following connections:

CIS-rat-4-phenyl-8-(2-phenylcyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he,

CIS-rat-4-phenyl-8-(2-n-toolstorage)-2,8-diazaspiro[4.5]Decan-1-he,

CIS-rat-8-[2-(4-forfinal)cyclohexyl]-4-phenyl-2,8-diazaspiro[4.5]Decan-1-he,

CIS-rat-4-(4-forfinal)-8-[2-(4-forfinal)cyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he,

CIS-rat-4-(4-forfinal)-8-[2-(4-triptoreline)cyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he,

8-[2-(4-forfinal)-2-hydroxycyclohexyl]-4-phenyl-2,8-diazaspiro[4.5]Decan-1-he,

4-(4-forfinal)-8-[2-(3-forfinal)-2-hydroxycyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he,

4-(4-forfinal)-8-[2-(2-forfinal)-2-hydroxycyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he,

8-[2-(3-chlorophenyl)-2-hydroxycyclohexyl]-4-(4-forfinal)-2,8-diazaspiro[4.5]Decan-1-he /

4-(4-forfinal)-8-TRANS-(4-hydroxy-4-vinyltetrahydrofuran-3-yl)-2,8-diazaspiro[4.5]Decan-1-it.

Also preferred are compounds in which X OSN which comprises hydrogen.

The invention relates also to compounds in which X is hydroxy.

Objects of the present invention are, in addition, compounds in which n stands for 1 and A-In means-CH2-O-.

These compounds of formula I and their pharmaceutically acceptable salts can be obtained by methods known in this field, for example by the methods described below, which include

a) interaction of the compounds of formula

with the compound of the formula

with the formation of connections

where the substituents have the meanings given above, or

b) interaction of the compounds of formula

with the compound of the formula

with the formation of the compounds of formula

where the substituents have the meanings given above, or

C) if necessary, separation of the racemic forms to the corresponding enantiomers and

if necessary, the conversion of the compounds obtained into pharmaceutically acceptable acid additive salt.

The compounds of formula I can be obtained in accordance with the variants of the method (a), b) or C) and with the following schemes 1, 2 and 3.

Used the following abbreviations:

LDA - diisopropylamide lithium

DHM - dichloromethane

THF - tetrahydrofuran

PMGS - polymethylhydrosiloxane

DMSO - dimethyl sulfoxide

On the basis of the appropriate 1-substituted piperidine-4-alkylcarboxylic 2, treatment with a suitable base, typically LDA, then treatment with an appropriately substituted nitroalkenes 3 leads to nitroalkane 4. Restoration of an amino group, facilitated by the use of Ni-Raney and hydrogen, typically at a pressure of 60 bar and 55°C in ethanol as a solvent leads to the formation of compound 5. Subsequent cyclization by heating in toluene at boiling gives amide 6. The removal of the protective group under standard conditions (treatment with TFA in DHM protective group R = tert-butyloxycarbonyl (Boc) or hydrogenolysis with Pd/C in CHM and methanol for the protective group R = benzyl (Bn)) gives diazepamoverdose 7 (scheme 1).

Scheme 1

Further interaction of the compounds of formula 7 with the corresponding compounds of formula 11 (which can be obtained by the reaction of arylhalides formula 8 with butyllithium and subsequent reaction with the epoxide of formula 9 to obtain the alcohol of formula 10, which are oxidized to the corresponding ketones of formula 11 with periodinane dessa-Martin) in the presence of tetraisopropoxide and triacetoxyborohydride sodium network connection f is rmula I (scheme 2). Alternative reaction of compounds of formulas 7 and 11 in the presence of tetraisopropoxide and triacetoxyborohydride sodium (in the presence or without PMGS) also gives the products of formula I. an Alternative strategy in which a full recovery amination of ketones of formula 11 with compounds of formula 12 in the device with trap Dean-stark gives the intermediate enamine, which can be recovered in situ in the compound of formula 13. The following stages 1-3, which are described in scheme 1, to give a compound of formula I.

Scheme 2

The compounds of formula I when X=IT is produced by interaction of the compounds of formula 7 with oxides of the formula 9 in boiling ethanol. The resulting β-amerosport formula 14 can then be oxidized to the ketone, preferably with a complex of pyridine-SO3in the presence of triethylamine in DMSO, giving the compounds of formula 15, which is then treated allithiamine reagents (formed by the exchange of halogen to metal)to ensure that the approach to the desired products of formula I (scheme 3).

All compounds of the formula 1, 4, 5, 6, 7, 11, 10, 13, 14, 15 usually formed during sequential reactions in an equal mixture of (R,R,S)-, (S,S,R)-, (R,R,R)- and (S,S,S)-enantiomers (racemic form) according to the procedures described below. They can be separated on chiral nerezisca enantiomers preparative who ASH using column Chiralpak OD or AD (5×50 cm) at room temperature using a mobile phase of ethanol-heptane, and UV detection at 220 nm.

Acid additive salts of basic compounds of formula I can be converted into the corresponding free base by treating at least a stoichiometric equivalent of a suitable base such as sodium hydroxide or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia and the like.

The compounds of formula I and their pharmaceutically applicable acid additive salts have valuable pharmacological properties. Specifically it was found that the compounds of the present invention are effective inhibitors of glycine carrier-1 (GlyT-1).

Compounds investigated in accordance with the test below.

Solutions and materials

Complete DMEM: nutrient mixture F-12 (Gibco Life Technologies), 5% fetal bovine serum (FBS) (Gibco Life Technologies), 1% penicillin/streptomycin (Gibco Life Technologies), 0.6 mg/ml hygromycin (Gibco Life Technologies), 1 mm glutamine (Gibco Life Technologies).

Buffer absorption (UB): 150 mm NaCl, 10 mm Hepes-Tris, pH 7.4, 1 mm CaCl2, 2.5 mm KCl, 2.5 mm MgSO4, 10 mm (+)-D-glucose.

Cells Flp-in™-CHO (Invitrogen catalog No. R758-07), steadily transfetsirovannyh cDNA mGlyT-1b.

Analysis of the inhibition of the absorption of glycine (mGlyT-1b)

Day 1 mammalian cells (Flp-in™-CHO), transfetsirovannyh cDNA mGlyT-1b, were placed at a density of 40,000 cells/well in complete medium F-12 without hygromycin in 96-well culture Board the s. On day 2 the medium aspirated and cells were washed twice with buffer absorption (UB). Then cells were incubated for 20 min at 22°C with each of the following: (i) no potential competitor, (ii) 10 mm non-radioactive glycine, (iii) one potential concentration of inhibitor. Used a range of concentrations of the potential inhibitor to obtain data for calculating the concentration of inhibitor causing 50% effect (e.g., IC50- the concentration of competitor that inhibits the uptake of glycine by 50%). Then immediately added a solution containing 60 nm of [3H]-glycine (11-16 CI/mmol) and 25 μm non-radioactive glycine. The plates were incubated with gentle shaking, the reaction was stopped by aspiration of the mixture and washing (three times) ice buffer UB. Cells were literally with scintillation liquid was dissolved in 1 h and the radioactivity in the cells was counted using a scintillation counter.

The potency of the compound as an inhibitor of glycine vector 1 (GlyT-1) depends on its racemic or enantiomeric form.

Preferred compounds exhibit IC50(nm) in respect of GlyT-1 is less than 100.

Example No.IC50(nm) of some enantiomers
61
2105
648
736,43
1091
1170
1595,77
1669
1773
2991

The compounds of formula I and pharmaceutically acceptable salts of compounds of formula I can be used as medicines, for example, in the form of pharmaceutical compositions. The pharmaceutical compositions can be administered orally, for example in the form of tablets, coated tablets, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the introduction can also be carried out rectally, for example in the form of suppositories, parenterally, e.g. in the form of injection solutions.

The compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for preparation of pharmaceutical compositions. For example, lactose, corn cu is hmal or their derivatives, talc, stearic acid or its salts etc can be used as such carriers for tablets, coated tablets coated tablets and hard gelatin capsules. Appropriate carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, not required in the case of soft gelatin capsules. Appropriate media for the preparation of solutions and syrups are, for example, water, polyols, glycerine, vegetable oil, and the like. Appropriate carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

Moreover, the pharmaceutical compositions can contain preservatives, soljubilizatory, stabilizers, slip agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for modifying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

Drugs, containing a compound of formula I or its pharmaceutically acceptable salt and a therapeutically inert carrier are also an object of the present invention, as the way to the floor is to be placed, which comprises bringing one or more compounds of the formula I and/or their pharmaceutically acceptable acid additive salts and, if required, one or more therapeutically valuable substances in Galanova the form of the introduction together with one or more therapeutically inert carriers.

The most preferred indications in the present invention are those which include disorders of the Central nervous system, for example, the treatment or prevention of schizophrenia, damage to cognitive abilities and Alzheimer's disease.

The dose can vary within wide limits and, of course, must be given to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to 1000 mg per day of the compounds of General formula I or the corresponding number of its pharmaceutically acceptable salts. The daily dose can be administered as a single dose or in divided doses, and, in addition, the upper limit can also be exceeded when this is required according to the testimony.

The following examples illustrate the present invention without its limitations. All temperatures are given in degrees Celsius.

Obtaining structural elements 11

rat-2-(4-Forfinal)cyclohexanone

rat-2-(4-Forfinal)cyclohexanol

(a) RA is Toro 1-bromo-4-fervently (12.5 ml, 114 mmol) in diethyl ether (250 ml) at -78°C was added utility (1.6 M, 68 ml, 109 mmol) in argon atmosphere. After 5 min at this temperature were added cyclohexanone (11,0 ml, 109 mmol), then diethylether boron TRIFLUORIDE (13, 8 ml, 109 mmol), the temperature was increased to about -50°C. After 4 h at this temperature the reaction was stopped by addition of ammonium chloride (saturated solution, 200 ml) and was diluted with water (50 ml). Then the product was extracted with diethyl ether (3×100 ml) and the combined organic extracts were dried over sodium sulfate. Filtration and evaporation gave given the title compound (11.9 g, 56%) as white crystals after trituration in hexane. MS (m/z): 194,1 (M+).

rat-2-(4-Forfinal)cyclohexanone

bi) To a solution of rat-2-(4-forfinal)cyclohexanol (3.8 g, 20 mmol) in DHM (320 ml) was added periodinane dessa-Martin [1,1,1-Tris(atomic charges)-1,1-dihydro-1,2-benzodioxol-3(1H)-he] (10 g, 24 mmole) at room temperature and after 2 h the reaction mixture was washed with sodium bicarbonate solution (10%, 150 ml). Then the organic phase was separated and washed with a solution of thiosulfate sodium (10%, 150 ml), then dried over sodium sulfate, filtered and evaporated. Purification by chromatography on silica gel, elution with a mixture of ethyl acetate-hexane (1:4) gave mentioned in the title compound (3.4 g, 89%) as Krista is catching white color. MS (m/z): USD 192.1 (M+).

rat-2-(4-Forfinal)cyclohexanone

bii) Alternative to the solution of rat-2-(4-forfinal)cyclohexanol (7.5 g, 39 mmol) in anhydrous DMSO (67 ml) were added triethylamine (27 ml, 190 mmol) in an argon atmosphere, the resulting mixture was cooled to 0°C. and then was added dropwise over 15 min a solution of a complex of a sulfur trioxide-pyridine (18,4 g, 116 mmol) in anhydrous DMSO. After 1 h the mixture was diluted with water (200 ml) and the product was extracted with DHM (2×100 ml). Then the combined organic extracts were dried over sodium sulfate, then filtered and evaporated. Purification by filtration through a layer of silica gel, elution with a mixture of ethyl acetate-hexane (1:4) gave mentioned in the title compound (7,1 g, 95%) as white crystals. MS (m/z): USD 192.1 (M+).

rat-2-n-Tollcollection

rat-2-n-Taillecavat

a) To a solution of n-tribromide (17.1 g, 100 mmol) in anhydrous TTF (100 ml) was added magnesium (2,43 g, 100 mmol) and then the resulting mixture was cooled to -20°C, was added CuBr complex-dimethyl sulfide (2.0 g, 10 mmol) and the mixture was stirred at -20°C for 10 minutes and Then was added dropwise a solution of cyclohexanone (10 ml, 100 mmol) in anhydrous THF (10 ml) and the reaction mixture was heated to a temperature of 0°C, which began exothermic reaction. Upon cooling bath of ice temperature can be maintained below 25°C. For the eat the reaction mixture was stirred at 0-5°C for additional 2 h, then "extinguished" by a solution of ammonium chloride (saturated, 30 ml) and the product was extracted with tert-butylmethylamine ether. Then the combined organic extracts were washed with water, dried over sodium sulfate, filtered and evaporated. Recrystallization from hexane gave mentioned in the title compound (9,9 g, 52%) as white crystals. MS (m/z): 190,1 (M+).

rat-2-n-Tollcollection

b) As described for the structural element 11, the stage bi), rat-2-n-taillecavat (a 4.86 g, 26 mmol) was converted into compound indicated in the title (4.68 g, 97%)which was obtained as white crystals. MS (m/z): 188,1 (M+).

rat-2-(4-Triptoreline)cyclohexanol

a) As described for the structural element 11, stage a), 4-bromobenzonitrile (10.0 g, 44 mmole) was transformed into the connection specified in the title (5,64 g, 52%)which was obtained in the form of a solid white color. MS (m/z): to 244.1 (M+).

rat-2-(4-Triptoreline)cyclohexanone

b) As described for the structural element 11, the stage bi), rat-2-(4-triptoreline)cyclohexanol (5.5 g, 23 mmole) was converted to the specified in the title compound (5,26 g, 96%)which was obtained in the form of a solid white color. MS (m/z): 242,1 (M+).

rat-2-(4-Cryptomailer)cyclohexanone

rat-2-(4-Triptoreline)cyclohexanol

a) As described for the structural element 11 stage a), 1-bromo-4-(triptoreline)benzene (10.3 g, 43 mmole) was converted to the specified in the title compound (6.7 g, 60%), which was received in the form of a solid white color. MS (m/z): 260,1 (M+).

rat-2-(4-Cryptomailer)cyclohexanone

b) As described for the structural element 11, the stage bi), rat-2-(4-cryptomailer)cyclohexanol (6.6 g, 25 mmol) was converted to the specified in the title compound (are 5.36 g, 82%)which was obtained in the form of a solid white color. MS (m/z): 258,2 (M+).

rat-2-(3-Forfinal)cyclohexanone

rat-2-(3-Forfinal)cyclohexanol

a) As described for the structural element 11, stage a), 1-bromo-3-torbenson (10.0 g, 57 mmol) was converted to the specified in the title compound (5.1 g, 46%)which was obtained in the form of a solid white color. MS (m/z): 194,1 (M+).

rat-2-(3-Forfinal)cyclohexanone

As described for the structural element 11, the stage bi), rat-2-(3-forfinal)cyclohexanol (5.0 g, 26 mmol) was converted to the specified in the title compound (3.9 g, 80%)which was obtained in the form of a solid white color. MS (m/z): USD 192.1 (M+).

rat-2-(3-Triptoreline)cyclohexanone

rat-2-(3-Triptoreline)cyclohexanol

a) As described for the structural element 11, stage a), 3-bromobenzonitrile (10.0 g, 44 mmole) was converted to the specified in the title compound (4,87 g, 45%)which was obtained as a solid substance b the logo color. MS (m/z): to 244.1 (M+).

rat-2-(3-Triptoreline)cyclohexanone

b) As described for the structural element 11, the stage bi), rat-2-(3-triptoreline)cyclohexanol (4.7 g, 19 mmol) was converted to the specified in the title compound (4,34 g, 93%)which was obtained in the form of oil is light yellow in color. MS (m/z): 242,1 (M+).

rat-2-(3-Fluoro-4-were)cyclohexanone

rat-2-(3-Fluoro-4-were)cyclohexanol

a) As described for the structural element 11, stage a), 4-bromo-2-vtortola (10.0 g, 53 mmole) was converted to the specified in the title compound (6,35 g, 58%)which was obtained in the form of a solid white color. MS (m/z): of 208.3 (M+).

rat-2-(3-Fluoro-4-were)cyclohexanone

b) As described for the structural element 11, the stage bi), rat-2-(3-fluoro-4-were)cyclohexanol (6.2 g, 30 mmol) was converted to the specified in the title compound (5.53 g, 91%)which was obtained in the form of a solid white color. MS (m/z): 206,1 (M+).

rat-2-(4-Methyl-3-triptoreline)cyclohexanone

rat-2-(4-Methyl-3-triptoreline)cyclohexanol

a) As described for the structural element 11, stage a), 4-methyl-3-(trifluoromethyl)brobinson (4,2 g, 18 mmol) was converted to the specified in the title compound (1,95 g, 43%)which was obtained in the form of a solid white color. MS (m/z): of 208.3 (M+).

rat-2-(4-Methyl-3-triptoreline)cyclohexanone

b) As described for ructures element 11, stage bi), rat-2-(4-methyl-3-triptoreline)cyclohexanol (1,91 g, 7 mmol) was converted to the specified in the title compound (1.8 g, 95%)which was obtained in the form of a solid white color. MS (m/z): 256,1 (M+).

rat-2-(4-Fluoro-3-were)cyclohexanone

rat-2-(4-Fluoro-3-were)cyclohexanol

a) As described for the structural element 11, stage a)5-bromo-2-vtortola (10.0 g, 53 mmole) was converted to the specified in the title compound (5,47 g, 50%), which was received in the form of a solid white color. MS (m/z): 208,2 (M+).

rat-2-(4-Fluoro-3-were)cyclohexanone

b) As described for the structural element 11, the stage bi), rat-2-(4-fluoro-3-were)cyclohexanol (5,4 g, 26 mmol) was converted to the specified in the title compound (14,7 g, 88%)which was obtained in the form of oil is light yellow in color. MS (m/z): 206,1 (M+).

rat-2-(4-Chloro-3-triptoreline)cyclohexanone

rat-2-(4-Chloro-3-triptoreline)cyclohexanol

a) As described for the structural element 11, stage a)5-bromo-2-chlorobenzotrifluoride (8,32 g, 30 mmol) was converted to the specified in the title compound (4.4 g, 52%)which was obtained in the form of a solid white color. MS (m/z): 278,1 (M+).

rat-2-(4-Chloro-3-triptoreline)cyclohexanone

b) As described for the structural element 11, the stage bi), rat-2-(4-chloro-3-triptoreline)cyclohexanol (4.3 g, 15 mmol) were converted into listed is in the title compound (4,13 g, 97%), which was received in the form of a solid white color. MS (m/z): 276,1 (M+).

Obtaining structural elements 7

rat-4-Phenyl-2,8-diazaspiro[4.5]Decan-1-he

Ethyl ester of rat-1-benzyl-4-(2-nitro-1-phenylethyl)piperidine-4-carboxylic acid

a) a Solution diisopropylate (14 mmol) was obtained by processing Diisopropylamine (1,37 g, 14 mmol) butyllithium (1.6 M, 8.5 ml, 14 mmol) at -78°C in anhydrous THF (10 ml) in an argon atmosphere and allowed to warm to -20°C. Then the solution was cooled to -60°C, was added to a solution of 1-benzylpiperidine-4-ethylcarboxylate (3,05 g, 12 mmol) in THF (8 ml) at -60°C and allowed to warm to -40°C for 1 h, after which dropwise added a solution of TRANS-β-nitrostyrene (1,93 g, 13 mmol) in THF (8 ml). The reaction mixture was allowed to warm to room temperature over 1 h, and then stopped the reaction by adding a solution of ammonium chloride (saturated, 40 ml) and the product was extracted with ethyl acetate (2×40 ml). The combined organic extracts were then washed with a saturated saline solution, dried over sodium sulfate and evaporated. Purification by chromatography on silica gel with elution with a mixture of dichloromethane-methanol (9:1) gave specified in the title compound (4.1 g, 84%) as a resin light yellow color. MS (m/z): 397,4 (M+N)+.

Ethyl ester rat-4-(2-amino-1-phenylethyl)-1-benzylpiperidine-4-carboxylic acid

b) R is the target ethyl ester rat-1-benzyl-4-(2-nitro-1-phenylethyl)piperidine-4-carboxylic acid (3,18 g, 8 mmol) in anhydrous ethanol (240 ml) was first made in the presence of Ni-Raney (3 g) at a pressure of 60 bar and a temperature of 55°C for 3 hours After cooling and reducing the pressure in the reaction vessel and the mixture was filtered through a layer of celite and the filtrate was evaporated, getting the balance specified in the title compound (2.9 g, 99%) as a clear oil. MS (m/z): 367,4 (M+N)+.

rat-Benzyl-4-phenyl-2,8-diazaspiro[4.5]Decan-1-he

c) a Solution of ethyl ester rat-4-(2-amino-1-phenylethyl)-1-benzylpiperidine-4-carboxylic acid (2.9 g, 8 mmol) in toluene (30 ml) was heated at boiling for 4 hours After cooling to room temperature and evaporation, the mixture was purified by chromatography on silica gel, elwira a mixture of dichloromethane-methanol-ammonium hydroxide (95:4,5:0,5), to obtain specified in the title compound (1.47 g, 58%) as a solid white color. MS (m/z): 321,4 (M+N)+.

rat-4-Phenyl-2,8-diazaspiro[4.5]Decan-1-he

d) a Suspension of rat-benzyl-4-phenyl-2,8-diazaspiro[4.5]Decan-1-it (28.8 g, 90 mmol) in a mixture of methanol-dichloromethane (4:1, 500 ml) was first made in the presence of Pd (10% on charcoal, 14 g, 132 mmole) at a pressure of 2 bars for 48 h at room temperature. After filtration through a layer of celite the reaction mixture was evaporated and the residue was dissolved in sodium hydroxide solution (2 N., 200 ml). The product was extracted with dichloromethane (3×150 ml) and the combined organic extracts who left the house taking over sodium sulfate. Filtration and evaporation gave specified in the title compound (13.1 g, 63%) as a solid white color after trituration in diethyl ether. MS (m/z): 231,4 (M+H)+.

Scheme 1, stage 1: ftoroproizvodnykh of connection with the BOC-protecting group rat-4-(4-Forfinal)-2,8-diazaspiro[4.5]Decan-1-he

4-Ethyl ester 1-tert-butyl ether piperidine-1,4-dicarboxylic acid

To a solution of ethyl ester of 4-piperidinecarboxylic acid (20 g, 127 mmol) in a mixture of dioxane-water (1:1, 120 ml) were added triethylamine (12,87 g, 127 mmol) at 0°C, then di-tert-BUTYLCARBAMATE (35.2 g, 161 mmol) and the resulting mixture is kept at this temperature for 2 hours the Product was then extracted with ethyl acetate (3×100 ml) and the combined organic extracts were washed with hydrochloric acid (1 N., 100 ml), saturated brine (100 ml), dried over sodium sulfate, filtered and evaporated. Purification by distillation in high vacuum (Cuellar) gave specified in the title compound (29.0 g, 89%) as a colorless liquid, BP. 140°C at 0.13 mbar. MS (m/z): 275,2 (M+NH4)+.

4-Ethyl ester 1-tert-butyl ether rat-4-[1-(4-forfinal)-2-nitroethyl]piperidine

1,4-dicarboxylic acid

b) a Solution diisopropylate was obtained by processing Diisopropylamine (6,98 g, 69 mmol) butyllithium (1.6 M, a 41.3 ml, 66 mmol) at -78°C in anhydrous THF (45 ml) in an atmosphere of ar is she was allowed to warm to -20°C. Then this solution was cooled to -60°C, was added to a solution of 4-ethyl ester 1-tert-bouteloua ether piperidine-1,4-dicarboxylic acid (15,44 g, 60 mmol) in anhydrous THF (45 ml) at -60°C and allowed to warm to -40°C for 1 h, then was added dropwise a solution of 4-fluoro-TRANS-β-nitrostyrene (10,02 g, 60 mmol) in anhydrous THF (40 ml). The reaction mixture was allowed to warm to room temperature over 1 h and then stopped the reaction by adding a solution of ammonium chloride (saturated, 250 ml), the product was extracted with diethyl ether (3×100 ml). The combined organic extracts were then washed with a saturated saline solution, dried over sodium sulfate, filtered and evaporated, getting mentioned in the title compound (26.7 g, 99%) as a resin light yellow color. MS (m/z): 442,4 (M+NH4)+.

Ethyl ester rat-4-(2-amino-1-phenylethyl)-1-tert-butylpiperazine-1,4-dicarboxylic acid

c) a Solution of 4-ethyl ester 1-tert-butyl ether rat-4-[1-(4-forfinal)-2-nitroethyl]piperidine-1,4-dicarboxylic acid (26,6 g, 60 mmol) in anhydrous ethanol (600 ml) was first made in the presence of Ni-Raney (25 g) at 50 pressure bar and a temperature of 50°C for 20 hours, After cooling and reducing the pressure in the reaction vessel and the mixture was filtered through a layer of celite and the filtrate was evaporated, leaving specified in the header connection (23,4 g, 99%) as transparent the CSOs oil, which was used directly in the next stage.

tert-Butyl ether rat-4-(4-forfinal)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylic acid

d) a Solution of ethyl ester rat-4-(2-amino-1-phenylethyl)-1-tert-butylpiperazine-1,4-dicarboxylic acid (23,4 g, 60 mmol) in toluene (200 ml) was heated at boiling for 18 hours After cooling to room temperature, evaporation gave specified in the title compound (17,17 g, 83%) as a solid white color after trituration in hot pentane. MS (m/z): 349,3 (M+N)+.

rat-4-(4-Forfinal)-2,8-diazaspiro[4.5]Decan-1-he

e) a Solution of tert-butyl methyl ether rat-4-(4-forfinal)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylic acid (46,0 g, 132 mmole) in dichloromethane (260 ml)containing triperoxonane acid (150 ml, of 1.32 mol), vigorously stirred at 0°C for 15 minutes the Reaction mixture was then poured into a solution of sodium hydroxide (3 N., 200 ml) and the product was extracted with dichloromethane (3×100 ml). Then the combined organic extracts were washed with water (100 ml), saturated brine (100 ml) and then dried over sodium sulfate. Filtration and evaporation of the solution gave specified in the header connection (22,14 g, 68%) as a solid white after mashing in ethyl acetate. MS (m/z): 249,2 (M+N)+.

Example 1

CIS-rat-4-Phenyl-8-(2-phenylcyclohexyl)-2,8-diazaspiro[4.5]decane-on

Ethyl ester of CIS-rat-1-(2-phenylcyclohexyl)piperidine-4-carboxylic acid

a) a Solution of ethyl ester of 4-piperidinecarboxylic acid (3.7 g, 24 mmole), 2-phenylcyclohexanone (5.0 g, 29 mmol) in toluene containing n-toluensulfonate (446 mg, 2 mmole)was heated at boiling in the device with a nozzle Dean-stark for 13 hours After cooling to room temperature the mixture was evaporated, leaving about 15 ml, and then diluted with 1,2-dichloroethane (120 ml), then was added acetic acid (0.95 ml) followed by addition of portions of triacetoxyborohydride sodium (7,3 g, 33 mmole). After 3.5 h the mixture is "extinguished" by the sodium hydroxide solution (3 N., 50 ml), diluted with water (50 ml) and the organic layer was separated. Then the organic layer was dried and evaporated, leaving a residue that was purified by chromatography on silica gel, elwira a mixture of heptane-ethyl acetate (9:1) to (4:1) and (3:2), receiving specified in the title compound in the form of oil is light yellow in color (5.5 g, 75%). MS (m/z): 316,2 (M+N)+.

Ethyl ester of CIS-rat-4-(2-nitro-1-phenylethyl)-1-(2-phenylcyclohexyl)piperidine-4-carboxylic acid

b) As described for the structural element 7, step a)ethyl ester of 1-(2-phenylcyclohexyl)piperidine-4-carboxylic acid (1.0 g, 3 mmole) was converted to the specified in the title compound (1.1 g, 73%)which was obtained in the form of not-quite-white solid MS (m/z): 465,4 (M+N) +.

CIS-rat-4-Phenyl-8-(2-phenylcyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he

c) As described for the structural element 7, stage b), ethyl ester of 4-(2-nitro-1-phenylcyclohexyl)piperidine-4-carboxylic acid (1.0 g, 2 mmole) was converted into the amino derivatives (810 mg, 87%)which was obtained in the form of oil is light yellow in color and used directly in the next stage. MS (m/z): 435,4 (M+N)+.

d) As described for the structural element 7, stage C), amino (810 mg, 2 mmole) was converted to the specified in the title compound (607 mg, 93%)which was obtained in the form of a solid white color. MS (m/z): 389,4 (M+H)+.

Example 2

CIS-rat-4-Phenyl-8-(2-n-tollcollect)-2,8-diazaspiro[4.5]Decan-1-he

A mixture of rat-2-n-taillecavat (410 mg, 2 mmole), rat-4-phenyl-2,8-diazaspiro[4.5]Decan-1-she (502 mg, 2 mmole) and tetraisopropoxide (810 μl, 3 mmole) was stirred at room temperature for 3 hours the Mixture then was diluted with tetrahydrofuran (5 ml) and then was added a solution of polymethylhydrosiloxane (261 mg, 4 mmole) in tetrahydrofuran (5 ml), the resulting solution was stirred over night. To this solution were added cyanoborohydride sodium (245 mg) and the resulting mixture was stirred at room temperature for 3 hours Then was added a solution of sodium hydroxide (3 M, 10 ml) and the mixture was stirred for 1 h the precipitate p which is separated by filtration through a layer of celite, the filtrate was washed with saturated saline solution, dried and evaporated, leaving the foam is light yellow in color. Purification by chromatography on silica gel, elution with a mixture of dichloromethane-methanol-aqueous ammonia(25%) (98:2:0,1 to 95:4,5:0,5) were specified in the title compound (250 mg, 29%)which was obtained in the form of a solid white color. MS (m/z): 403,6 (M+N)+.

Example 3

CIS-rat-4-(4-Forfinal)-8-(2-n-tollcollect)-2,8-diazaspiro[4.5]Decan-1-he

Ethyl ester of CIS-rat-1-(2-n-tollcollect)piperidine-4-carboxylic acid

a) As described for example 1A, rat-2-n-tollcollection (4,2 g, 22 mmole) was converted to the specified in the title compound (3.7 g, 48%)which was obtained in the form of oil is light yellow in color. MS (m/z): 330,4 (M+N)+.

Ethyl ester of CIS-rat-4-[1-(4-forfinal)-2-nitroethyl]-1-(2-n-tollcollect)piperidine-4-carboxylic acid

b) As described for example 1b, ethyl ester, CIS-rat-1-(1-n-tollcollect)piperidine-4-carboxylic acid (700 mg, 2 mmole) was converted to the specified in the title compound (880 mg, 83%)which was obtained in the form of a yellow resin. MS (m/z): 497,3 (M+N)+.

CIS-rat-4-(4-Forfinal)-8-(2-n-tollcollect)-2,8-diazaspiro[4.5]Decan-1-he

c) As described for example 1C, ethyl ester, CIS-rat-4-[1-(4-forfinal)-2-nitroethyl]-1-(2-n-tollcollect)piperidine-4-carboxylic acid (880 mg, 2 mmole) was transformed into aminopropane the (670 mg, 81%), which was received in the form of a yellow resin and used directly in the next stage. MS (m/z): 467,3 (M+N)+.

d) As described for example 1d, amino (665 mg, 1 mmol) was converted to the specified in the title compound (130 mg, 22%), which was received in the form of a solid of light yellow color. MS (m/z): UAH 421,2 (M+N)+.

Example 4

CIS-rat-4-(3,4-Dichlorophenyl)-8-(2-n-tollcollect)-2,8-diazaspiro[4.5]Decan-1-he

Ethyl ester of CIS-rat-4-[1-(3,4-dichlorophenyl)-2-nitroethyl]-1-(2-n-tollcollect)piperidine-4-carboxylic acid

a) As described for example 1b, ethyl ester rat-1-(2-n-tollcollect)piperidine-4-carboxylic acid (700 mg, 2 mmole) was converted to the specified in the title compound (772 mg, 66%)which was obtained in the form of a solid yellow color. MS (m/z): 547,2 (M)+.

b) As described for example 1C, ethyl ester, CIS-rat-4-[1-(3,4-dichlorophenyl)-2-nitroethyl]-1-(2-n-tollcollect)piperidine-4-carboxylic acid (772 mg, 1 mmol) was converted to the specified in the title compound (43 mg, 6%), which was received in the form of a yellow resin. MS (m/z): 471,3 (M)+.

Example 5

CIS-rat-4-(4-Methoxyphenyl)-8-(2-n-tollcollect)-2,8-diazaspiro[4.5]Decan-1-he

Ethyl ester of CIS-rat-4-[1-(4-methoxyphenyl)-2-nitroethyl]-1-(2-n-tollcollect)piperidine-4-carboxylic acid

a) As described for example 1b, ethyl ester rat-1-(2-n-talili logical)piperidine-4-carboxylic acid (700 mg, 2 mmole) was converted to the specified in the title compound (620 mg, 57%)which was obtained in the form of a yellow resin. MS (m/z): 509,4 (M+N)+.

CIS-rat-4-(4-Methoxyphenyl)-8-(2-n-tollcollect)-2,8-diazaspiro[4.5]Decan-1-he

b) As described for example 1C, ethyl ester, CIS-rat-4-[1-(4-methoxyphenyl)-2-nitroethyl]-1-(2-n-tollcollect)piperidine-4-carboxylic acid (620 mg, 1 mmol) was converted to the specified in the title compound (410 mg, 70%)which was obtained in the form of a yellow resin. MS (m/z): 433,5 (M+N)+.

Example 6

CIS-rat-8-[2-(4-forfinal)cyclohexyl]-4-phenyl-2,8-diazaspiro[4.5]Decan-1-he

As described for example 2, rat-2-(4-forfinal)cyclohexanone (417 mg, 2 mmole) was converted to the specified in the title compound (150 mg, 17%) (using 4-phenyl-2,8-diazaspiro[4.5]Decan-1-he instead of 4-(4-forfinal)-2,8-diazaspiro[4.5]Decan-1-it), which was received in the form of a solid white color. MS (m/z): of 407.5 (M+N)+.

Alternatively,

CIS-rat-8-[2-(4-Forfinal)cyclohexyl]-4-phenyl-2,8-diazaspiro[4.5]Decan-1-he

Ethyl ester of CIS-rat-1-[2-(4-forfinal)cyclohexyl]-4-(2-nitro-1-phenylethyl)piperidine-4-carboxylic acid

a) As described for example 1b, ethyl ester, CIS-rat-1-[2-(4-forfinal)cyclohexyl]piperidine-4-carboxylic acid (800 mg, 2.4 mmole) was converted to the specified in the title compound (677 mg, 59%)which was obtained in the form of a resin light yellow color. M is (m/z): 483,3 (M) +.

CIS-rat-8-[2-(4-Forfinal)cyclohexyl]-4-phenyl-2,8-diazaspiro[4.5]Decan-1-he

b) As described for example 1C, ethyl ester 1-[2-(4-forfinal)cyclohexyl]-4-(2-nitro-1-phenylethyl)piperidine-4-carboxylic acid (627 mg, 1.3 mmole) was converted into the amino derivatives (497 mg, 85%)which was obtained in the form of oil is light yellow in color and used directly in the next stage. MS (m/z): 453,6 (M)+.

c) As described for example 1d, amino (497 mg, 1.1 mmole) was converted to the specified in the title compound (197 mg, 44%)which was obtained as a solid not quite white matter. MS (m/z): 407,3 (M+N)+.

Example 7

CIS-rat-4-(4-Forfinal)-8-[2-(4-forfinal)cyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he

Ethyl ester of CIS-rat-1-[2-(4-forfinal)cyclohexyl]piperidine-4-carboxylic acid

a) As described for example 1A, rat-2-(4-forfinal)cyclohexanone (7.0 g, 36 mmol) was converted to the specified in the title compound (4.5 g, 38%)which was obtained in the form of oil is light yellow in color. MS (m/z): 334,3 (M+N)+.

Ethyl ester of CIS-rat-1-[2-(4-forfinal)cyclohexyl]-4-[1-(4-forfinal-2-nitroethyl]piperidine-4-carboxylic acid

b) As described for example 1b, ethyl ester, CIS-rat-1-[2-(4-forfinal)cyclohexyl]piperidine-4-carboxylic acid (1.0 g, 3 mmole) (using 4-fluoro-TRANS-β-nitrosothiol instead of TRANS-β-nitrostyrene) were converted into listed in the title of soy is inania (1.2 g, 77%), which was received in the form of a solid white color. MS (m/z): 501,4 (M+N)+.

CIS-rat-4-(4-Forfinal)-8-[2-(4-forfinal)cyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he

c) As described for example 1C, ethyl ester, CIS-rat-1-[2-(4-forfinal)cyclohexyl]-4-[1-(4-forfinal)-2-nitroethyl]piperidine-4-carboxylic acid (1.1 g, 2 mmole) was converted into the amino derivatives (1.0 g, 99%)which was obtained in the form of oil is light yellow in color and used directly in the next stage. MS (m/z): 471,3 (M+N)+.

d) As described for example 1d, amino (1,05 g, 2 mmole) was converted to the specified in the title compound (670 mg, 71%)which was obtained in the form of a solid white color. MS (m/z): 425,2 (M+N)+.

CIS-rat-4-(4-Forfinal)-8-[2-(4-forfinal)cyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he

e) Alternatively, a mixture of rat-2-(4-forfinal)cyclohexanone (775 mg, 3 mmole), RAC-4-(4-forfinal)-2,8-diazaspiro[4.5]Decan-1-she (500 mg, 3 mmole) and tetraisopropoxide (887 μl, 3 mmole) was stirred at 60°C over night. The resulting solution is then cooled to room temperature, were added cyanoborohydride sodium (245 mg, 4 mmole) and the resulting mixture was stirred at 50°C for 3 h and Then was added a solution of sodium hydroxide (6 M, 15 ml) and the mixture was stirred for 1 h Then the mixture was filtered through a layer of celite, the filtrate was washed with saturated sole is the first solution, was dried and evaporated, resulting in the remainder of the foam is light yellow in color. Purification by chromatography on silica gel, elution with a mixture of dichloromethane-methanol-aqueous ammonia(25%) (98:2:0,1 to 95:4,5:0,5) were specified in the title compound in the form of a solid white color. MS (m/z): 425,2 (M+N)+.

CIS-rat-4-(4-Forfinal)-8-[2-(4-forfinal)cyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he

f) Alternatively, as described for example 2, rat-2-(4-forfinal)cyclohexanone (500 mg, 3 mmole) was converted to the specified in the title compound (219 mg, 20%), which was received in the form of a solid white color. MS (m/z): 425,2 (M+N)+.

Example 8

CIS-rat-4-(3,4-Dichlorophenyl)-8-[2-(4-forfinal)cyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he

Ethyl ester of CIS-rat-4-[1-(3,4-dichlorophenyl)-2-nitroethyl]-1-[2-(4-forfinal)cyclohexyl]piperidine-4-carboxylic acid

a) As described for example 1b, ethyl ester, CIS-rat-1-[2-(4-forfinal)cyclohexyl]piperidine-4-carboxylic acid (800 mg, 2.4 mmole) (using 3,4-dichloro-ω-nitrosothiol instead of TRANS-β-nitrostyrene) turned on the specified title compound (779 mg, 59%)which was obtained in the form of foam a light yellow color. MS (m/z): of 551.3 (M)+.

CIS-rat-4-(3,4-Dichlorophenyl)-8-[2-(4-forfinal)cyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he

b) As described for example 1C, ethyl ester, CIS-rat-4-[1-(3,4-dichlorophenyl)-2-nitroethyl]-1-[2-(4-forfinal)cyclohexyl]piperid is n-4-carboxylic acid (729 mg, 1.3 mmole) was converted into the amino derivatives (646 mg, 93%)which was obtained in the form of oil is light yellow in color and used directly in the next stage.

c) As described for example 1d, amino (646 mg, 1.2 mmole) was converted to the specified in the title compound (270 mg, 46%)which was obtained in the form of not-quite-white solid. MS (m/z): 475,2 (M)+.

Example 9

CIS-rat-8-[2-(4-Forfinal)cyclohexyl]-4-(4-methoxyphenyl)-2,8-diazaspiro[4.5]Decan-1-he

Ethyl ester of CIS-rat-1-[2-(4-forfinal)cyclohexyl]-4-[1-(4-methoxyphenyl)-2-nitroethyl]piperidine-4-carboxylic acid

a) As described for example 1b, ethyl ester, CIS-rat-1-[2-(4-forfinal)cyclohexyl]piperidine-4-carboxylic acid (800 mg, 2.4 mmole) (using 4-methoxy-β-nitrosothiol instead of TRANS-β-nitrostyrene) were converted into listed in the title compound (642 mg, 52%)which was obtained in the form of foam a light yellow color. MS (m/z): 513,4 (M+N)+.

CIS-rat-4-(3,4-Dichlorophenyl)-8-[2-(4-forfinal)cyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he

b) As described for example 1C, ethyl ester, CIS-rat-1-[2-(4-forfinal)cyclohexyl]-4-[1-(4-methoxyphenyl)-2-nitroethyl] piperidine-4-carboxylic acid (601 mg, 1.2 mmole) was converted into the amino derivatives (523 mg, 92%)which was obtained in the form of oil is light yellow in color and used directly in the next stage. MS (m/z): 483,5 (M+N)+.

c) As described in the La example 1d, amino derivatives (523 mg, 1.1 mmole) was converted to the specified in the title compound (216 mg, 46%)which was obtained in the form of a white foam. MS (m/z): 437,3 (M+N)+.

Example 10

CIS-rat-4-(4-Forfinal)-8-[2-(4-triptoreline)cyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he

Ethyl ester of CIS-rat-1-[2-(4-triptoreline)cyclohexyl]piperidine-4-carboxylic acid

a) As described for example 1A, rat-2-(4-triptoreline)cyclohexanone (5.0 g, 21 mmol) was converted to the specified in the title compound (2.7 g, 34%)which was obtained in the form of oil is light yellow in color. MS (m/z): 384,2 (M+N)+.

Ethyl ester of CIS-rat-4-[1-(4-forfinal)-2-nitroethyl]-1-[2-(4-triptoreline)cyclohexyl]piperidine-4-carboxylic acid

b) As described for example 1b, ethyl ester 1-[2-(4-triptoreline)cyclohexyl]piperidine-4-carboxylic acid (1.0 g, 3 mmole) was converted to the specified in the title compound (610 mg, 43%)which was obtained in the form of oil is light yellow in color. MS (m/z): of 551.3 (M+N)+.

CIS-rat-4-(4-Forfinal)-8-[2-(4-triptoreline)cyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he

c) As described for example 1C, ethyl ester 4-[1-(4-forfinal)-2-nitroethyl]-1-[2-(4-triptoreline)cyclohexyl]piperidine-4-carboxylic acid (610 mg, 1 mmol) was converted into the amino derivatives (345 mg, 60%), which was received in the form of oil is light yellow in color and used directly for CL, the blowing stage. MS (m/z): 521,4 (M+N)+.

d) As described for example 1d, amino (345 mg, 1 mmol) was converted to the specified in the title compound (268 mg, 85%)which was obtained in the form of a solid white color. MS (m/z): 475,4 (M+N)+.

Obtaining structural elements 15

rat-8-(2-Oxocyclohexyl)-4-phenyl-2,8-diazaspiro[4.5]Decan-1-he

rat-8-(2-Hydroxycyclohexyl)-4-phenyl-2,8-diazaspiro[4.5]Decan-1-he

a) a Suspension of rat-4-phenyl-2,8-diazaspiro[4.5]Decan-1-it (13,10 g, 56,9 mmole) and 7-oxabicyclo[4.1.0]heptane (5,58 g, 56,9 mmole) in ethanol (250 ml) was heated at boiling for 3 days. After cooling to room temperature the mixture was filtered and the filtrate was evaporated, highlighting specified in the title compound (18,14 g, 97%)which was obtained in the form of not-quite-white solid. MS (m/z): 329,3 (M+N)+.

rat-8-(2-Oxocyclohexyl)-4-phenyl-2,8-diazaspiro[4.5]Decan-1-he

b) As described for the structural element 11, the stage bi)8-(2-hydroxycyclohexyl)-4-phenyl-2,8-diazaspiro[4.5]Decan-1-he (18,10 g, 55,0 mmol) was converted to the specified in the title compound (15,26 g, 76%)which was obtained in the form of a solid of light yellow color after trituration in hot diethyl ether. MS (m/z): 327,2 (M+N)+.

rat-4-(4-Forfinal)-8-(2-oxocyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he

rat-4-(4-Forfinal)-8-(2-hydroxycyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he

a) As described for article is alternova element 15, stage a), RAC-4-(4-forfinal)-2,8-diazaspiro[4.5]Decan-1-he (8,45 g 34,0 mmole) was converted to the specified in the title compound (11,63 g, 99%)which was obtained in the form of not-quite-white solid MS (m/z): 347,0 (M+N)+.

rat-4-(4-Forfinal)-8-(2-oxocyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he

b) As described for the structural element 15, stage b), 4-(4-forfinal)-8-(2-hydroxycyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he (to 2.06 g, 6.0 mmol) was converted to the specified in the title compound (1.26 g, 59%)which was obtained in the form of a solid of light yellow color after purification by chromatography on silica gel with elution with a mixture of dichloromethane-methanol (95:5 to 85:15). MS (m/z): 345,2 (M+N)+.

Example 11

8-[2-(4-Forfinal)-2-hydroxycyclohexyl]-4-phenyl-2,8-diazaspiro[4.5]Decan-1-he

To a solution of 1-bromo-4-fervently (1.4 g, 8 mmol) in anhydrous THF (5 ml) in an argon atmosphere at -78°C was added a solution of utility (1.6 M in hexane, 5 ml, 8 mmol) and the mixture was maintained at this temperature for 1 h To this solution was added a solution of 8-(2-oxocyclohexyl)-4-phenyl-2,8-diazaspiro[4.5]Decan-1-it (687 mg, 2 mmole) in anhydrous THF (15 ml) and the reaction mixture was allowed to warm to -20°C for 2 h before addition of a solution of ammonium chloride (saturated, 20 ml). Then the reaction mixture was evaporated, water was added (20 ml). The product was extracted with ethyl acetate (3×15 ml), obyedinenny the organic extracts were washed with saturated brine (10 ml), was dried over sodium sulfate, filtered and evaporated, resulting in residue solid light brown color. Purification by chromatography on silica gel with elution with a mixture of dichloromethane-methanol-aqueous ammonia (0,5%) (95:5 to 4:1) gave specified in the title compound (380 mg, 45%), which was received in the form of a solid white color. MS (m/z): 423,5 (M+N)+.

Example 12

8-[2-(3-Forfinal)-2-hydroxycyclohexyl]-4-phenyl-2,8-diazaspiro[4.5]Decan-1-he

As described in example 11, 8-(2-oxocyclohexyl)-4-phenyl-2,8-diazaspiro[4.5]Decan-1-he (500 mg, of 1.53 mmole) was converted to the specified in the title compound (348 mg, 50%) (using 3-bramptonbest instead of 1-bromo-4-fervently), which was received in the form of a solid white color. MS (m/z): 423,5 (M+N)+.

Example 13

8-[2-Hydroxy-2-(4-methoxyphenyl)cyclohexyl]-4-phenyl-2,8-diazaspiro[4.5]Decan-1-he

As described for example 11, 8-(2-oxocyclohexyl)-4-phenyl-2,8-diazaspiro[4.5]Decan-1-he (500 mg, of 1.53 mmole) was converted to the specified in the title compound (88 mg, 15%) (using 4-bromoanisole instead of 1-bromo-4-fervently), which was received in the form of a solid white color. MS (m/z): 435,6 (M+N)+.

Example 14

8-[2-Hydroxy-2-(3-methoxyphenyl)cyclohexyl]-4-phenyl-2,8-diazaspiro[4.5]Decan-1-he

As described for example 11, 8-(2-oxocyclohexyl)-4-phenyl-2,8-diazaspiro[4.5]Decan-1-he (500 mg, of 1.53 mmole) was converted into pointed to by the e in the title compound (411 mg, 69%) (using 3-bromoanisole instead of 1-bromo-4-fervently), which was received in the form of a solid white color. MS (m/z): 435,4 (M+N)+.

Example 15

4-(4-Forfinal)-8-[2-(3-forfinal)-2-hydroxycyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he

As described for example 11, 4-(4-forfinal)-8-(2-oxocyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he (200 mg, 1 mmol) was converted to the specified in the title compound (195 mg, 76%) (using 1-bromo-3-torbenson instead of 1-bromo-4-fervently), which was received in the form of a solid white color.

Example 16

4-(4-Forfinal)-8-[2-(2-forfinal)-2-hydroxycyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he

As described for example 11, 4-(4-forfinal)-8-(2-oxocyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he (200 mg, 1 mmol) was converted to the specified in the title compound (178 mg, 70%) (using 2-bramptonbest instead of 1-bromo-4-fervently), which was received in the form of a solid white color. MS (m/z):441,2 (M+H)+.

Example 17

8-[2-(3-(Chlorophenyl)-2-hydroxycyclohexyl]-4-(4-forfinal)-2,8-diazaspiro[4.5]Decan-1-he

As described for example 11, 4-(4-forfinal)-8-(2-oxocyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he (200 mg, 1 mmol) was converted to the specified in the title compound (205 mg, 77%) (using 1-bromo-3-chlorobenzene instead of 1-bromo-4-fervently), which was received in the form of a solid white color. MS (m/z): 457,3 (M)+.

Example 18

4-{2-[4-(4-Forfinal)-1-about the co-2,8-diazaspiro[4.5]Dec-8-yl]-1-hydroxycyclohexyl} benzonitrile

As described for example 11, 4-(4-forfinal)-8-(2-oxocyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he (200 mg, 1 mmol) was converted to the specified in the title compound (118 mg, 45%) (using 4-bromobenzonitrile instead of 1-bromo-4-fervently), which was received in the form of a solid white color. MS (m/z): USD 448,2 (M+N)+.

Example 19

4-(4-Forfinal)-8-[2-hydroxy-2-(4-triptoreline)cyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he

As described for example 11, 4-(4-forfinal)-8-(2-oxocyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he (200 mg, 1 mmol) was converted to the specified in the title compound (271 mg, 95%) (using 4-bromobenzonitrile instead of 1-bromo-4-fervently), which was received in the form of a solid white color. MS (m/z): 491,2 (M+H)+.

Example 20

4-(4-Forfinal)-8-[2-hydroxy-2-(4-methanesulfonyl)cyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he

As described for example 11, 4-(4-forfinal)-8-(2-oxocyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he (200 mg, 1 mmol) was converted to the specified in the title compound (16 mg, 6%) (using 4-bromophenylacetate instead of 1-bromo-4-fervently), which was received in the form of a solid white color. MS (m/z): 501,5 (M+N)+.

Example 21

4-(4-Forfinal)-8-(2-hydroxy-2-n-tollcollect)-2,8-diazaspiro[4.5]Decan-1-he

As described for example 11, 4-(4-forfinal)-8-(2-oxocyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he (200 mg, 1 mmol) was transformed specified in the OU in the title compound (178 mg, 70%) (using 4-bromthymol instead of 1-bromo-4-fervently), which was received in the form of a solid white color. MS (m/z): 437,4 (M+N)+.

Example 22

4-(4-Forfinal)-8-(2-hydroxy-m-tollcollect)-2,8-diazaspiro[4.5]Decan-1-he

As described for example 11, 4-(4-forfinal)-8-(2-oxocyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he (200 mg, 1 mmol) was converted to the specified in the title compound (229 mg, 90%) (using 3-bromthymol instead of 1-bromo-4-fervently), which was received in the form of a solid white color. MS (m/z): 437,3 (M+H)+.

Example 23

4-(4-Forfinal)-8-(2-hydroxy-o-tollcollect)-2,8-diazaspiro[4.5]Decan-1-he

As described for example 11, 4-(4-forfinal)-8-(2-oxocyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he (200 mg, 1 mmol) was converted to the specified in the title compound (158 mg, 62%) (using 2-bromthymol instead of 1-bromo-4-fervently), which was received in the form of a solid white color. MS (m/z): 437,4 (M+N)+.

Example 24

8-[2-(4-tert-Butylphenyl)-2-hydroxycyclohexyl]-4-(4-forfinal)-2,8-diazaspiro[4.5]Decan-1-he

As described for example 11, 4-(4-forfinal)-8-(2-oxocyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he (200 mg, 1 mmol) was converted to the specified in the title compound (192 mg, 69%) (using 1-bromo-4-tert-butylbenzoyl instead of 1-bromo-1-fervently), which was received in the form of a solid white color. MS (m/z): 479,6 (M+N)+.

Example 25

4-(4-CFT is henyl)-8-[2-hydroxy-2-(2-trifloromethyl)cyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he

As described for example 11, 4-(4-forfinal)-8-(2-oxocyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he (216 mg, 0,63 mmol) was converted to the specified in the title compound (209 mg, 66%) (using 1-bromo-2-(triptoreline)benzene instead of 1-bromo-4-fervently), which was received in the form of a solid white color. MS (m/z): 507,3 (M+N)+.

Example 26

4-(4-Forfinal)-8-[2-hydroxy-2-(4-imidazol-1-ylphenyl)cyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he

As described for example 11, 4-(4-forfinal)-8-(2-oxocyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he (344 mg, 1.0 mmol) was converted to the specified in the title compound (231 mg, 47%) (using 1-(4-bromophenyl)imidazole instead of 1-bromo-1-fervently), which was received in the form of a solid white color. MS (m/z): 489,3 (M+N)+.

Example 27

4-(4-Forfinal)-8-[2-hydroxy-2-(4-methoxyphenyl)cyclohexyl]-2,8-diazaspiro[4.5] Decan-1-he

As described for example 11, 4-(4-forfinal)-8-(2-oxocyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he (517 mg, 1.5 mmol) was converted to the specified in the title compound (568 mg, 84%) (using 4-bromoanisole instead of 1-bromo-4-fervently), which was received in the form of a solid white color. MS (m/z): 453,3 (M+N)+.

Example 28

4-(4-Forfinal)-8-[2-hydroxy-2-(4-methoxyphenyl)cyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he

As described for example 11, 4-(4-forfinal)-8-(2-oxocyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he (200 mg, 1 mmol) was converted is specified in the title compound (199 mg, 76%) (using 3-bromoanisole instead of 1-bromo-4-fervently), which was received in the form of a solid white color. MS (m/z): 453,3 (M+N)+.

Example 29

4-(4-Forfinal)-8-TRANS-(4-hydroxy-4-vinyltetrahydrofuran-3-yl)-2,8-diazaspiro[4.5] Decan-1-he

4-(4-Forfinal)-8-TRANS-(4-hydroxyethylamino-3-yl)-2,8-diazaspiro[4.5]Decan-1-he

a) As described for example 12A, (R)-4-(4-forfinal)-8-(2-oxocyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he (100 mg, 0.4 mmole) was converted to the specified in the title compound (57 mg, 41%) (using 3,5-epoxytetradecane instead oxabicyclo[4.1.0]heptane), which was received in the form of a solid white color after purification by chromatography on silica gel, elwira a mixture of dichloromethane-methanol (9:1). MS (m/z): 349,2 (M+N)+.

4-(4-Forfinal)-8-(4-oxitetraciclina-3-yl)-2,8-diazaspiro[4.5]Decan-1-he

b) As described for the structural element 11, the stage bi), 4-(4-forfinal)-8-TRANS-(4-hydroxyethylamino-3-yl)-2,8-diazaspiro[4.5]Decan-1-he (128 mg, 0.37 mmole) was converted to the specified in the title compound (100 mg, 79%)which was obtained in the form of a solid white color after purification by chromatography on silica gel, elwira a mixture of dichloromethane-methanol (9:1). MS (m/z): 347,4 (M+N)+.

4-(4-Forfinal)-8-TRANS-(4-hydroxy-4-vinyltetrahydrofuran-3-yl)-2,8-diazaspiro[4.5]Decan-1-he

(C) As described for example 11, 4-(4-forfinal)-8-(4-exoterikoy the EN-3-yl)-2,8-diazaspiro[4.5]Decan-1-he (90 mg, of 0.26 mmole) was converted to the specified in the title compound (65 mg, 59%) (using finality instead of 1-bromo-4-fervently), which was received in the form of a solid white color. MS (m/z): 425,4 (M+N)+.

nXAs-InR1R3R2Example
1NCH2CH2H1
1NCH2CH2H2
1NCH2CH2H3
1NCH2CH2H4
1NCH2CH2H5
1NCH2CH2H6
1NCH2CH2H7
1NCH2CH2H 8
1NCH2CH2H9
1NCH2CH2H10
1OHCH2CH2H11
1OHCH2CH2H12
1OHCH2CH2 H13
1OHCH2CH2H14
1OHCH2CH2H15
1OHCH2CH2H16
1OHCH2CH2H17

nX As-InR1R3R2Example
1HECH2CH2H18
1OHCH2CH2H19
1OHCH2CH2H20
1OHCH2CH2H21
1OH CH2CH2H22
1OHCH2CH2H23
1OHCH2CH2H24
1OHCH2CH2H25
1OHCH2CH226
1OHCH2CH2H27
1OHCH2CH2H28
1OHCH2OH29

The composition of the tablets (wet granulation)

ItemIngredientsmg tablet
5 mg25 mg100 mg500 mg
1.The compound of the formula I5 25100500
2.Anhydrous lactose
on differential
the DTG thermogram12510530150
3.Pre generowanie starch Sta-Rx 150066630
4.Microcrystalline cellulose303030150
5.Magnesium stearate1111
Everything about 167167167831

Method get

1. Mix the substances according to paragraphs 1, 2, 3 and 4 and pelletized with purified water.

2. Dry the granules at 50°C.

3. Skip granules through the appropriate grinding equipment.

4. To add substance to paragraph 5 and mix for three minutes; to compress on the appropriate media.

The capsules composition

ItemIngredientsmg/capsule
5 mg25 mg100 mg500 mg
1.The compound of the formula I525100500
2.Water lactose159123148-
3.Corn starch 25354070
4.Talc10151025
5.Magnesium stearate1225
Only200200300600

The method of cooking

1. Mix substances in paragraphs 1, 2 and 3 in an appropriate mixer for 30 minutes

2. To add substance to paragraphs 4 and 5 and mix for 3 minutes

3. Download the appropriate capsule.

1. Compounds of General formula I

where a-b means-CH2-CH2-, -CH2-O - or-O-CH2-;
X is hydrogen or hydroxy;
R1means aryl, optionally substituted by one or two substituents selected from the group consisting of halogen, (ness.)of alkyl, cyano, CF3, -OCF3, (ness.)alkoxy, -SO2-(ness.)the alkyl, or heteroaryl containing two nitrogen atom;
R2oz ACHAT phenyl, optionally substituted by one or two substituents selected from the group consisting of halogen, (ness.)of alkyl, CF3or (ness.)alkoxy;
R3means hydrogen or (ness.)alkyl;
n means 0, 1 or 2,
and their pharmaceutically active salts.

2. The compounds of formula I according to claim 1

where a-b means-CH2-CH2- or-CH2-O-;
X is hydrogen or hydroxy;
R1means phenyl, optionally substituted by one or two substituents selected from the group consisting of halogen (ness.)of alkyl, cyano, CF3, -OCF3, (ness.)alkoxy, -SO2-(ness.)the alkyl, or heteroaryl containing two nitrogen atom;
R2means phenyl, optionally substituted by one or two substituents selected from the group consisting of halogen or (ness.)alkoxy;
R3means hydrogen;
n means 1,
and their pharmaceutically active salts.

3. The compounds of formula I according to claim 2, where a-b means-CH2-CH2-.

4. The compounds of formula I according to claim 3, where R1and R2mean both phenyl, optionally substituted (ness.)by alkyl, halogen or CF3.

5. The compounds of formula I according to claim 4, where the connection means
CIS-rat-4-phenyl-8-(2-phenylcyclohexyl)-2,8-diazaspiro[4.5]Decan-1-he,
CIS-rat-4-phenyl-8-(2-n-toolstorage)-2,8-diazaspiro[4.5]Decan-1-he,
CIS-rat-8-[2-(4-forfinal)cyclohexyl]-4-phenyl-2,8-diazaspiro[4.5]Decan-1-he,
CIS-rat-4-(4-forfinal)-8-[2-(4-forfinal)cyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he,
CIS-rat-4-(4-forfinal)-8-[2-(4-triptoreline)cyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he,
8-[2-(4-forfinal)-2-hydroxycyclohexyl]-4-phenyl-2,8-diazaspiro[4.5]Decan-1-he,
4-(4-forfinal)-8-[2-(3-forfinal)-2-hydroxycyclohexyl]-2,8-diazaspiro[4.5]Decan-1-he,
4-(4-forfinal)-8-[2-(2-forfinal)-2-hydroxycyclohexyl]-2,8-diazaspiro[4,5]decane-1-he,
8-[2-(3-chlorophenyl)-2-hydroxycyclohexyl]-4-(4-forfinal)-2,8-diazaspiro[4.5]Decan-1-one or
4-(4-forfinal)-8-TRANS-(4-hydroxy-4-vinyltetrahydrofuran-3-yl)-2,8-diazaspiro[4.5]Decan-1-it.

6. The compounds of formula I according to claim 1, where X means hydrogen.

7. The compounds of formula I according to claim 1, where X denotes a hydroxy-group.

8. The compounds of formula I according to claim 2, where a-b means-CH2-O-.

9. Drug, inhibiting the absorption of glycine containing one or more compounds according to claim 1, and pharmaceutically acceptable excipients.

10. The drug according to claim 9 for the treatment of diseases which can be useful in the inhibition of the absorption of glycine.

11. Drug for PP and 10, where diseases are psychoses, pain, dysfunction in memory and learning, schizophrenia, dementia and other diseases in which violated the ducational ability, such as attention deficit disorder, or Alzheimer's disease.

12. The use of compounds according to claim 1 for obtaining a medicinal product intended for the treatment of psychoses, pain, neurodegenerative dysfunction in memory and learning, schizophrenia, dementia and other diseases in which impaired cognitive ability, such as attention deficit disorder, or Alzheimer's disease.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (1) where: R1 represents hydrogen atom, halogen, CP3, (1-3C)alkoxy group, m is an integer within 1 to 4, provided when m is equal to 2, 3 or 4, R1 substitutes can be either identical or different, R2 represents hydrogen atom, alkyl (1-6C) group optionally substituted with alkoxy group, cycloalkyl (3-6C) group, -CH2OH, -CH2OCH3, acetyl group, benzyl group optionally substituted with amino group, or group Q of the following composition (2): were: [ ]n symbolically represents -(CH2)n-, where n is an integer within 0 to 7, R3 represents hydrogen atom or alkyl (1-3C) group, R4 represents hydrogen atom, alkyl (1-6C) group optionally substituted with one or more groups, chosen of alkyl group, aryl group, fluorine, chlorine, bromine, hydroxyl group, alkoxy group, aryloxy group, acyloxy group, amino group, alkylamino group, dialkylamino group, arylamino group, thio group, alkylthio group, arylthio group, cyano group, oxo group, nitro group, acyl group, amido group, alkylamido group, amido group dialkyl, carboxyl group, saturated, unsaturated or partially saturated mono- or dicyclic 5-10-meroud ring optionally substituted with one or more groups, chosen of alkyl group, aryl group, fluorine, chlorine, bromine, hydroxyl group, alkyloxy group, aryloxy group, acyloxy group, amino group, alkylamino group, dialkylamino group, arylamino group, thio group, alkylthio group, arylthio group, cyano group, oxo group, nitro group, acyl group, amido group, alkylamido group, dialkylamido group, carboxyl group, or alkyl (1-3C) group substituted with saturated, unsaturated or partially saturated five- or hexamerous ring optionally containing one or more heteroatoms, such as nitrogen atom, oxygen atom or sulphur atom, optionally substituted with one or more groups chosen from alkyl group, aryl group, fluorine, chlorine, bromine, hydroxyl group, alkyloxy group, aryloxy group, acyloxy group, amino group, alkylamino group, dialkylamino group, arylamino group, thio group, alkylthio group, arylthio group, cyano group, oxo group, nitro group, acyl group, amido group, alkylamido group, dialkylamido group, carboxyl group, or (R3+R4) together with nitrogen atom, they are attached to, represent saturated, unsaturated or partially saturated mono- or dicyclic five- or hexamerous ring optionally containing one or more heteroatoms, such as nitrogen atom, oxygen atom or sulphur atom, optionally substituted with one or more groups chosen of alkyl group, aryl group, fluorine, chlorine, bromine, hydroxyl group, alkyloxy group, aryloxy group, acyloxy group, amino group, alkylamino group, dialkylamino group, arylamino group, thio group, alkylthio group, arylthio group, cyano group, oxo group, nitro group, acyl group, amido group, alkylamido group, dialkylamido group, carboxyl groups, as well as to all stereoisomers, to pharmaceutically acceptable salts. Additionally, the invention concerns pharmaceutical compositions and application of compounds.

EFFECT: production of new biologically active compounds with agonist activity to ORL1 receptors.

9 cl, 488 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula where A-B stands for CH2-CH2, -CH2-O-, -O-CH2-, -CH2-S-, -S-CH2-, -N(R4)-CH2- or -CH2-N(R4)-; R1 stands for (lower)alkyl, (lower)alkenyl, cycloalkyl or stands for aryl, optionally substituted with one or two substitutes chosen from the group consisting of haloid, cyano, (lower)alkyl, CF3, OCF3 or (lower)alkoxy, or stands for heteroaryl representing cyclic aromatic hydrocarbon radical containing one or two heteroatoms chosen of the group consisting of sulphur or nitrogen, e.g. thiazolyl or thienyl, optionally substituted with one or two substitutes chosen from (lower)alkyl; R2 stands for (lower)alkyl, cycloalkyl or stands for aryl, optionally substituted with one or two substitutes chosen from the group consisting of haloid, (lower)alkyl, CF3, (lower)alkoxy, or stands for heteroaryl representing cyclic aromatic hydrocarbon radical containing one sulphur heteroatom, e.g. thienyl; R3 stands for hydrogen; R4 stands for hydrogen or benzyl; n stands for 0, 1 or 2; and to their pharmaceutically acceptable salts. Besides, the invention concerns a medical product.

EFFECT: production of new biologically active compounds inhibiting glycine carrier 1 (GlyT-1).

19 cl, 59 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): their using (variants) for preparing a drug used in treatment of diseases modulation of activity of chemokine receptors is useful, and to a pharmaceutical composition modulating chemokine receptors and comprising abovementioned compound. In compound of the formula (I) m = 0 or 1; R1 means halogen atom; X, Y and Z represent independently a bond, -CH2- or -O-, or X and Y form in common -CH=C(CH3)- or -C(CH3)=CH- under condition that only one radical among X, Y and Z can represents a bond, and under condition that X and Y both don't represent -O- simultaneously; n = 0, 1 or 2; R2 represents halogen atom, or (C1-C6)-alkyl; q = 0 or 1; R3 represents -NHC(O)R10, -C(O)NR11R12 or -COOR12a; each radical among R4, R5, R6, R7 and R8 represents independently hydrogen atom (H) or (C1-C6)-alkyl; t = 0, 1 or 2; R9 represents halogen atom, -OH, -COOH, (C1-C6)-alkoxy group, (C1-C6)-alkoxycarbonyl; R10 represents group (C1-C6)-alkyl, (C3-C6)-cycloalkyl, or R10 represents -NR14R15; each R11 and R12 represents independently (1) H; (2) 3-6-membered saturated cycloalkyl or phenyl or 5-membered unsaturated heterocyclyl comprising from 1 to 4 heteroatoms N wherein indicated cycloalkyl, phenyl and heterocyclyl are substituted possibly with one or two substitutes chosen from -OH, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl; (3) (C1-C6)-alkyl substituted possibly at least with one substitute chosen from halogen atom, -OH, -COOH, (C1-C6)-alkylcarbonylamino group, phenyl, 5-membered unsaturated heterocyclyl comprising oxygen atom (O), or from 1 to 2 N atoms, bicycloheptyl wherein this phenyl, heterocyclyl or bicycloheptyl is substituted possibly at least with one substitute chosen from halogen atom, -OH, =O, or (4) (C1-C6)-alkylsulfonyl, or R11 and R12 in common with N atoms to which they are bound form 5-membered unsaturated heterocyclyl comprising one N atom or 5-6-membered heterocyclyl comprising from 1 to 2 heteroatoms, such as S, O and N, or 5-6-membered saturated heterocyclyl, ortho-condensed with benzene ring and comprising one N atom and wherein indicated heterocyclic systems are substituted possibly with one or two substitutes chosen from halogen atom, (C1-C6)-alkyl, (C1-C6)-hyroxyalkyl, (C1-C6)-halogenalkyl, (C1-C6)-alkylamino, di-(C1-C6)-alkylamino group, phenyl, halogenphenyl and hydroxydiphenylmethyl; R12a represents H or (C1-C6)-alkyl; each radical among R14 and R15 represents independently H or (C1-C6)-alkylsulfonyl, or R14 and R15 in common with N atom to which they are bound form 5-membered saturated heterocyclyl comprising one N atom and substituted possibly with one -OH, or its pharmaceutically acceptable salt or solvate. Also, invention relates to a method (variants) for synthesis of compound of the formula (I) according to one of the following method: by one variant, compound of the formula (II): is subjected for interaction with compound of the formula (III): by other variant, compound of the formula (IV): is subjected for interaction with compound of the formula (V): by other variant, compound of the formula (VI): wherein R3 represents -NHC(O)R10 and L1 represents a leaving group is subjected for interaction with L1C(O)R10; by other variant, compound of the formula (VIII): wherein R3 represents -C(O)NR11R12 and L2 represents a leaving group is subjected for interaction with compound of the formula (IX) given in the invention description. Also, invention relates to an intermediate compound of the formula (IIA): (wherein R1a is chosen from F, Cl, -CH3 and -CF3; s = 1 or 2; q = 0 or 1; w = 0 or 1; R2a represents F, and when q and s = 1 and w = 0 then R1a can't represent chlorine atom), and to a method for synthesis of compound of the formula (IIA) (wherein s = 1) and wherein compound of the formula (XX): is subjected for interaction with compound of the formula (XXII): (wherein R20 represent a protective group) before formation of compound of the formula (XXIV): followed by carrying out the cyclization reaction and removing the protective group R20.

EFFECT: improved methods of synthesis.

25 cl, 236 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel compounds of class quinoxalin-2-spiropyrroles of the general formula (I): wherein R1 = R2 mean hydrogen atom (H) (I); R1 means H; R2 means CH3 (II); R1 = R2 mean CH3 (III). Compound can be used as parent substances for synthesis of novel heterocyclic systems, and in medicine as antibacterial agents. Also, invention describes a method for synthesis of these compounds.

EFFECT: improved method of synthesis, valuable properties of compounds.

3 cl, 4 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes novel spiroazacyclic compounds of the general formula: wherein X means -CH2, -CH2O, -OCH2 or oxygen atom (O); Y represents O; Z means -CH or nitrogen atom (N); R1 means (C1-C6)-alkyl optionally substituted with morpholinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, 2-oxoimidazolidinyl, imidazolidinyl, 2-oxooxazolidinyl, oxazalidinyl or (C3-C6)-cycloalkyl, (C2-C8)-alkyl ester or benzyl ester; m is chosen from group comprising 0 or 1; R4 means hydrogen atom or benzyl optionally substituted with halogen atom or (C1-C4)-alkyl; R5 means hydrogen atom or benzyl optionally substituted with halogen atom, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; R6 means hydrogen atom or benzyl optionally substituted with (C1-C4)-alkoxy-, cycloalkyl-(C1-C4-alkoxy)- or halogen-(C1-C4-alkoxy)-group; R2 and R3 mean hydrogen atom and at least two radicals among R4, R5 and R6 mean optionally substituted benzyl. Also, invention relates to a method for inhibition of activity of serotonin 5-HT2A receptors, a method for treatment of state mediated by serotonin 5-HT2A receptors, and using spiroazacyclic compounds proposed.

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

35 cl, 3 tbl, 2 dwg, 45 ex

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

SUBSTANCE: invention describes novel spiropyrazole compounds of the general formula (I): wherein W means hydrogen atom, (C1-C10)-alkyl, (C3-C7)-cycloalkyl, cyano-(C1-C10)-alkyl, -(C1-C4)-alkyl-COOV1 wherein V1 means hydrogen atom (H) or (C1-C6)-alkyl, -(C1-C5)-alkyl-C(=O)-W1 wherein W1 means amino-group, or -(C1-C5)-alkyl-NHS(=O)2-W1 wherein W1 means -(C1-C10)-alkyl; Q means phenyl; n mean a whole number 0 or 1; A, B and C mean hydrogen atom; Z means a simple bond, methylene or ethylene group; R1 means (C3-C12)-cycloalkyl substituted optionally with (C1-C10)-alkyl, naphthyl, tetrahydronaphthyl, decahydronaphthyl, indenyl, norbornyl, dibenzocycloheptyl, 9-acenaphthyl, phenyl substituted optionally with benzyloxy-group, biphenyl or (C1-C10)-alkyl substituted optionally with 1-3 substitutes chosen from phenyl, cyano-group, -COOV1 wherein V1 means (C1-C6)-alkyl and -(C1-C5)-alkyl-C(=O)-W1 wherein W1 means amino-, (C1-C4)-alkylamino- or di-(C1-C4)-alkylamino-group; R2 means (C1-C10)-alkyl, (C3-C7)-cycloalkyl or halogen atom. Also, invention to their pharmaceutically acceptable salts, solvates, pharmaceutical composition containing thereof, a method for treatment of pain and a method for modulation of pharmacological response of described ORL-1- or μ-receptors. Invention can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 3 tbl, 5 ex

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

SUBSTANCE: invention relates to novel 3-phenyl-3,7-diazabicyclo[3,3,1]nonane compounds of the formula (I): wherein R1 means (C1-C6)-alkyl, (C4-C7)-cycloalkyl; R2 means (lower)-alkyl; R3 means (lower)-alkyl, or R2 and R3 form in common (C3-C6)-alkylene chain; R4 means phenyl monosubstituted at ortho- or para-position with nitro-, cyano-group or (lower)-alkanoyl, or disubstituted at ortho- and para-position with nitro-group, and their physiologically acceptable acid-additive salts. Compounds of the formula (I) possess anti-arrhythmic activity and therefore they can be used in pharmaceutical composition used in treatment and/or prophylaxis of cardiac rhythm disorders. Also, invention describes a method for synthesis of these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

8 cl, 6 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of triazaspiro[5,5]undecane of the formula (I):

wherein values of radicals R1-R5 are given in the invention claim, ort o their quaternary ammonium salts, N-oxides or nontoxic salts. Proposed compounds possess inhibitory and regulating activity with respect to chemokine/chemokine receptors and can be useful in prophylaxis and treatment of different inflammatory diseases, such as asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis or proliferative arthritis and other similar diseases. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I).

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

9 cl, 5 sch, 36 tbl, 70 ex

FIELD: chemistry.

SUBSTANCE: invention concerns novel pyrazole derivatives of the formula (IIIa) , where R1 is T-(ring D), where ring D is naphthyl or phenyl optionally substituted by -R5; Rx, Ry, R2, R2' and R5 are as defined in the claim; and pharmaceutical composition containing claimed compounds. Compounds inhibit protein kinases such as Aurora-2, GSK-3 or Src and can be applied in treatment methods for diseases mediated by the indicated protein kinases, such as cancer, diabetes and Alzheimer's disease.

EFFECT: compounds also applicable in methods of hyperphosphorylated protein Tau products inhibition and β-catenin phosphorylation inhibition.

24 cl, 12 tbl, 292 ex

FIELD: medicine.

SUBSTANCE: inventions relate to medicine, in particular to psychiatry and can be used for treatment or prevention of anxiety state or anxiety state episode. Pharmaceutical composition includes efficient amount of ELB 139 (1-(4-chlorphenyl)-4-pyperidinoimidazolin-2-on) or 1-(4-methoxyphenyl)-4-pyperidinoimidazolin-2-on, and method includes introduction to patient of efficient amount of ELB 139 (1-(4-chlorphenyl)-4-pyperidinoimidazolin-2-one) or 1-(4-methoxyphenyl)-4-pyperidino imidazolin-2-one.

EFFECT: introduction of ELB 139 (1-(4-chlorphenyl)-4-pyperidinoimidazolin-2-one) or 1-(4-methoxyphenyl)-4-pyperidinoimidazolin-2-one for treatment or prevention of anxiety state or anxiety state episode has stronger effect in comparison with other compounds of similar chemical formula.

8 cl, 7 ex, 10 dwg

FIELD: medicine.

SUBSTANCE: there is disclosed application of glycosaminoglycan fraction of apparent molecular weight 2400 (±200)D depolymerised from glycosaminoglycan chosen from heparan sulphate and heparin for preparation of pharmaceutical compositions for treating the emotional insanities chosen from depressive disorder, qualm, anxiety neurosis, agitation, mental confusion. Additionally there is disclosed emotional insanity treatment method with no excitory influence depressing effect on central nervous system.

EFFECT: it is revealed that the claimed compounds both reduced emotional reactions and improved exploratory behaviour, ensured better environmental and potential hostility adaptation.

6 cl, 4 tbl

FIELD: medicine.

SUBSTANCE: present group of inventions concerns medicine, namely, psychiatry, and includes methods of treatment of schizophrenia at patients with superfluous mass of a body and application of azenapin for manufacturing of the medicine for treatment of this pathological condition.

EFFECT: effective treatment of schizophrenia in the absence of characteristic for other antipsychotic preparations of augmentation of mass of a body.

12 cl, 1 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely to psychiatry, and can be used at treatment of patients with a neurosis of obsessional conditions. For this purpose within 20 days pharmacotherapy is performed, including Diazepamum introduction, Mexidol and Tymogene. Thus Tymogene is administered intramusculary in a dose of 0.1-0.125 mg once in two days in amount of 10 injections. Simultaneously with pharmacotherapy within the first 15 days hyperbaric oxygenation is performed.

EFFECT: method provides appreciable reduction of the undesirable effects arising owing to administration of benzodiazepine anxiolytics, namely muscle relaxing activity, and also prevents possibility of medicinal dependence to the given group of preparations.

1 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely psychiatry, and can be used at treatment of patients with a hysterical neurosis. For this purpose pharmacotherapy is performed within 20 days including administration of 0.5% solution of Diazepamum intramusculary, 2-3 ml a day, Mexidol, 0.01% of T-activin solution 1-1.2 ml intramusculary, ten injections in a day. Thus Mexidol during the first 10 days is administered in the form of 5% solution of 2-3 ml a day intravenously driply, and the next 10 days in tablets in a daily dose of 100-125 mg. Simultaneously with pharmacotherapy within the first 10 days of 1 times a day perform hyperbaric oxygenation with an overpressure of 0.8-1.0 atmosphere at rate of a compression and decompression of 0.1 atmospheres in a minute, the isopressure period makes 40 minutes.

EFFECT: method allows providing a fast and full reduction of psychopathologic symptoms with the subsequent long remission at the expense of complex influence on neurohomeostasis and potentiations of therapeutic effect of anxiolytics.

1 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new ester derivatives of 2-amino-bicyclo[3,1,0]hexane-2,6-dicarboxylic acid, with formula [I] or [II] and their pharmaceutical salts, with antagonistic properties towards II group metabotropic glutamate receptors. In general formulae [I] or [II] R1 and R2 are identical or different, and each stands for a C1-10alkyl group, or one of R1 or R2 is a hydrogen atom, and the other is a C1-10alkyl group, C2-10alkenyl group, C2-10alkynyl group, C1-10alkyl group, substituted with a phenyl group, possibly substituted with halogen atoms, C1-4alkyl group, C1-4 alkoxyl group; hydroxyC2-10alkyl group, halogenC1-10alkyl group, azidoC1-10alkyl, aminoC2-10alkyl, C1-10alkoxycarbonylC1-10alkyl group, farnesyl group, 4-morpholinyl-C1-10alkyl group, C1-10alkyl group, substituted with a group with formula -C(O)NRaRb (where Ra and Rb are identical or different and each represents a hydrogen atom or a C1-10alkyl group), or with a group with formula -CHRcOC(O)ZRd (where Z is an oxygen atom or a single bond; Rc represents a hydrogen atom, C1-10alkyl group or aryl group, chosen from phenyl and naphthyl, which can be substituted with a C1-4alkyl group or C1-4alkoxyl group), or substituted with a group with formula [i] [ii], (where Rd denotes the same as described above), or by a group with formula [ii]; X is a fluorine atom; and Y represents -OCHR3R4, -SR3, -S(O)nR5, -SCHR3R4, -NHCHR3R4, -N(CHR3R4)(CHR3'R4'), -NHCOR3 or -OCOR5 (where R3, R3', R4 and R4' are identical or different, and each represents a hydrogen atom, C1-10alkyl group, phenyl group, naphthyl group, phenyl group substituted with one-five substitutes, chosen from a group, consisting of a halogen atom, R5 represents a phenyl group, or a phenyl group substituted with one-five substitutes, chosen from a group, consisting of a halogen atom, and n is 1 or 2).

EFFECT: invented compounds can be used in treating and preventing mental illnesses, such as schizophrenia, anxiety and anxiety related diseases, depression, bipolar disorders and epilepsy, invention also pertains to a medicinal preparation.

30 cl, 5 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention concerns stable pharmaceutical compositions include azetidine derivatives, particularly N-{1-[bis(4-chlorophenyl)methyl]azetidine-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, and method of its obtainment. Invention can be applied in medicine.

EFFECT: obtaining new stable pharmaceutical composition based on azetidine derivative.

5 cl, 6 dwg, 6 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to compounds with formula (I) in which radicals and symbols assume values, defined in paragraph of the formula of invention. Formula (I) compounds have affinity to bonding with serotonin 5-HT6 receptor and can be used in therapeutic treatment of disorders, related to the 5-HT6 receptor or mediated by them.

EFFECT: design of a method of treating central nervous system disorders.

17 cl, 5 tbl, 128 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns novel pyrazole derivatives of the formula (IIIa) , where R1 is T-(ring D), where ring D is naphthyl or phenyl optionally substituted by -R5; Rx, Ry, R2, R2' and R5 are as defined in the claim; and pharmaceutical composition containing claimed compounds. Compounds inhibit protein kinases such as Aurora-2, GSK-3 or Src and can be applied in treatment methods for diseases mediated by the indicated protein kinases, such as cancer, diabetes and Alzheimer's disease.

EFFECT: compounds also applicable in methods of hyperphosphorylated protein Tau products inhibition and β-catenin phosphorylation inhibition.

24 cl, 12 tbl, 292 ex

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