Piperidinbenzolsulfamide derivatives

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the general formula: , where R1 is an inferior alkyl, -(CH2)n-aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluormethyl, or pyridine; R2 is an inferior alkyl, -(CH2)n- aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluoromethyl, nitro-, cyano-, -NR'R", hydroxy-, or heteroaryl group that is a monovalent heterocyclic 5- or 6-membered aromatic radical with N atoms, either R2 is a heteroaryl that is monovalent heterocyclic 5- or 6-membered aromatic radical where heteroatoms are chosen from N, O or S group, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl or halogen; R3 is pyridine or aryl, unsubstituted or substituted by a halogen or inferior alkyl; R4 is hydrogen or hydroxy-. A is -S(O)2- or -C(O)-; X, Y are -CH2- or -O- independently from each other, though both X and Y should not be -O- at the same time; R'R" are hydrogen or inferior alkyl independently from each other; n is 0, 1 or 2. Also the invention concerns pharmaceutically acceptable additive salts and acids of the compounds, and a medicine based on it.

EFFECT: new biologically active compounds show inhibition effect in glycine absorption.

21 cl, 214 ex, 1 tbl

 

The present invention relates to compounds of General formula

in which R1represents a lower alkyl, -(CH2)naryl, unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, -OCF3, halogen, -NR'r R" or trifluoromethyl, or represents heteroaryl;

R2represents a lower alkyl, -(CH2)naryl, unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, trifloromethyl, nitro, cyano, -NR'r R', hydroxy, or heteroaryl group, or represents heteroaryl, unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl or halogen;

R3is heteroaryl or represents aryl, unsubstituted or substituted with halogen or lower alkyl;

R4represents hydrogen or hydroxy;

And represents-S(O)2- or-C(O)-;

X, Y independently of one another represent-CH2- or-O -, provided that X and Y are not simultaneously mean-O-;

R R" independently of one another represent hydrogen, lower alkyl or-C(O)-lower alkyl;

n means 0, 1 or 2,

and also from OSISA to their pharmaceutically acceptable additive salts with acid (salts - the addition products of acids).

In addition, the present invention includes all of their racemic mixtures, their corresponding enantiomers and/or optical isomers.

The present invention relates to compounds of General formula I, to contain their pharmaceutical compositions and to their use in the treatment of neurological or neuropsychiatric disorders and disorders. It has been unexpectedly found that compounds of General formula I are effective inhibitors of the glycine Transporter 1 (GlyT-1), the vector of glycine, and that these compounds exhibit good selectivity for inhibitors of the glycine Transporter 2 (GlyT-2).

Schizophrenia is a progressive and devastating neurological disease characterized by episodic positive symptoms such as delusions, hallucinations, disturbances of mental activity and psychosis, and persistent negative symptoms, such as sluggish affect, decreased attention and social isolation, and reduced cognitive ability (Lewis D.A., J.A. Lieberman, Neuron, 28: 325-33, 2000). In the last decade of research focused on the hypothesis of the so-called "dopamine hyperactivity disorder", which has led to therapeutic interventions associated with blocking dopaminergic system (R.J. Vandenberg, Aubrey K.R., Exp. Opin. Ther. Targets, 5 (4):507-518, 2001; Nakazato, A., S. Okuyama et al., Exp. Opin. Ther. Patents, 10 (1): 75-98, 2000). This therapeutic approach will have little effect on negative and cognitive symptoms, which are the most prominent indicators of prognosis of functional outcome (Sharma T., Br. J. Psychiatry, 174 (suppl. 28): 44-51,1999).

Complementary model of schizophrenia proposed in the mid-1960s, based on psychotomimetics action caused by blockade of the glutamate system in the effects of compounds such as phencyclidine (PCP -). from the English. phencyclidine and related agents (ketamine), which are non-competitive antagonists of the NMDA receptor. Interestingly, in healthy volunteers PCP-induced psychotomimetic action includes positive and negative symptoms and cognitive dysfunction, and thus, it is very similar to schizophrenia patients (Javitt D.C. et al., Biol. Psychiatry, 45: 668-679, 1999). In addition, transgenic mice expressing reduced NMDAR1-subunits, exhibit behavioural abnormalities, similar to the deviations observed in pharmacologically induced models that testify in support of the model, according to which lower the activity of the NMDA receptor leads to behavior that is similar to schizophrenia (Mohn A.R. et al., Cell 98: 427-236, 1999).

Glutamic neurotransmission, in particular the activity of the NMDA receptor, the game is t critical role in the processes of synaptic plasticity, learning and remembering, so, apparently, NMDA receptor serve as a sort of switch to pass the threshold of synaptic plasticity and memory formation (Wiley NY, Bliss, T.V., G.L. Collingridge, Nature 361: 31-39, 1993). Transgenic mouse excessively expressing NMDA NR2B-subunit, show increased synaptic plasticity and better ability to learn and remember (J.P. Tang et al., Natur, 401-63-69, 1999).

Thus, if there is a deficiency of glutamate is associated with the pathophysiology of schizophrenia, increased glutamate transmission, in particular by activation of the NMDA receptor could lead to production as antipsychotic and enhance cognitive ability effects.

The amino acid glycine is known to have at least two important functions in the CNS (Central nervous system). It acts as an inhibitory amino acid, by binding to the strychnine-sensitive glycine receptors and it also affects the exciting activity, acting as an important coagonist with glutamate in relation to the operation of N-methyl-D-aspartate receptors (NMDA). from the English. N-methyl-D-aspartate-N-methyl-D-aspartate). Although glutamate released from synaptic terminals-dependent activity by the way, glycine, apparently, is present in more than a constant number and, apparently, modulating/controlling eceptor in respect of their response to glutamate.

One of the most effective ways to control synaptic concentration of neurotransmitter is based on the effect on re-uptake at the synapse. Neurotransmitter during transportation by removing neurotransmitters from the extracellular space can control the lifetime outside the cell and thus to modulate the magnitude of synaptic transmission (Gainetdinov R.R. et al, Trends in Pharm. Sci., 23 (8): 367-373, 2002).

Glycotransferase (vector glycine), which form a part of sodium chloride and family of neurotransmitter transporters play an important role in the termination of postsynaptic glycinergic impact and the maintenance of low extracellular concentration of glycine through re-absorption of glycine in presynaptic nerve terminals and when the next thin glial processes.

Have been cloned from mammalian brain, two different gene glycine Transporter (GlyT-1 and GlyT-2), which lead to the two conveyors ˜50%homologically amino acid sequence. GlyT-1 is represented by four isoforms arising from alternative splicing and alternative use of the promoter (1A, 1b, 1C and Id). Only two isoforms were detected in the brain of rodents (GlyT-1A, GlyT-lb). GlyT-2 also has a certain degree of heterogeneity. Two itfor the s GlyT-2 (2A and 2b) identified in the brain of rodents. GlyT-1, known to be localized in the Central nervous system (CNS) and in peripheral tissues, while the GlyT-2 is specific to the CNS. GlyT-1 is predominantly glial distribution and is found not only in the areas corresponding to the strychnine-sensitive glycine receptors, but also outside these areas, where it is believed that it is associated with modulation of the function of the NMDA receptor (Lopez-Corcuera C. et al., Mol. Mem. Biol., 18: 13-20, 2001). Thus, one strategy to enhance the activity of the NMDA receptor is to increase the concentration of glycine in the local microenvironment of synaptic NMDA receptors by inhibition of GlyT-1 Transporter (Bergereon R. et al., Proc. Natl. Acad. Sci. USA, 95: 15730-15734, 1998).

Inhibitors of the glycine transporters are suitable for the treatment of neurological or neuropsychiatric disorders and disorders. A large part of the relevant diseases are mental illness, schizophrenia (Armer R.E., Miller D.J., Exp. Opin. Ther. Patents, 11 (4): 563-572, 2001), psychotic mood disorders such as expressed depressive disorder; mood disorders associated with psychotic disorders such as mania or depression associated with bipolar disorders, and mood disorders associated with schizophrenia (Pralong ET et al., Prog. Neurobiol, 67: 173-202, 2002), autistic disorder (Carlsson M.L., J. Neural Trans. 105: 525-53, 1998), cognitive impairment or disorder, such as dementia (dementia), including age-related dementia and senile dementia type Alzheimer's disease, memory disorders in mammals, including humans, disorders related to attention deficit and pain (Armer R.E., Miller D.J., Exp. Opin. Ther. Patents, 11 (4): 563-572, 2001).

Thus, increased activation of NMDA receptors via inhibition of GlyT-1 can lead to agents that are suitable for the treatment of psychosis, schizophrenia, dementia (dementia) and other diseases related to cognitive processes, such as disorders associated with attention deficit or Alzheimer's disease.

The object of the present invention are the compounds of formula I themselves, the use of compounds of the formula I and their pharmaceutically acceptable salts to obtain drugs for the treatment of diseases related to activation of NMDA receptors via inhibition of Glyt-1, receipt, medicines based on compounds according to the present invention, and receipt of them, and also the use of compounds of formula I for the control or prevention of diseases, such as mental illness, disorders of memory and learning ability, schizophrenia, dementia (dementia) and other diseases associated with cognitive processes, for example, is zabolevaniya, associated with attention deficit or Alzheimer's disease.

Preferred indications for the use of the compounds according to the present invention are schizophrenia, cognitive disorders and disorders and Alzheimer's disease.

When used in the text of this application, the term "lower alkyl" means a saturated alkyl group with a linear or branched chain containing from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl and the like groups. Preferred lower alkyl groups are groups containing 1-4 carbon atoms.

The term "halogen" denotes chlorine, iodine, fluorine and bromine.

The term "lower alkoxy" denotes a group in which the alkyl residues are as defined above, and which is attached via an oxygen atom.

The term "aryl" denotes a monovalent cyclic aromatic radical consisting of one or more condensed ring systems, where at least one ring system is aromatic in nature, for example, such a radical as phenyl or naphthyl.

The term "heteroaryl" denotes a monovalent heterocyclic 5 - or 6-membered aromatic radicals, where the heteroatoms are selected from N, O or S, for example, such a radical, as thiophenyl, pyrid the Nile, pyrimidinyl, imidazolyl, piperidinyl, furanyl, pyrrolyl, isoxazolyl, pyrazolyl, pyrazinyl, benzo[1,3]dioxole, benzo{b}thiophenyl or benzotriazolyl.

The term "pharmaceutically acceptable additive salts with acids (salt - addition products of acids)include salts formed with inorganic and organic acids, such as chloromethane 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 similar acids.

Preferred are the compounds of formula

in which R1represents lower alkyl, benzyl or represents phenyl, unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen or trifloromethyl;

R2represents lower alkyl, benzyl, thiophenyl or represents phenyl, unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen or trifloromethyl, nitro, amino, hydroxy or the group-NHC(O)- lower alkyl;

R3represents the t of a pyridine-3-yl, pyridine-4-yl or represents phenyl, unsubstituted or substituted with halogen or lower alkyl;

R4represents hydrogen or hydroxy;

And represents-S(O)2- or-C(O)-;

X, Y independently of one another represent-CH2- or-O-, provided that X and Y are not simultaneously denote-O-,

and their pharmaceutically acceptable additive salts with acids (salt - addition products of acids).

Particularly preferred compounds according to the present invention are those compounds of formula I, in which X and Y both represent-CH2-And represents-S(O)2-, R3represents unsubstituted phenyl and R4represents hydrogen, for example, the following connections:

(+/-)-3,4-dichloro-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide,

(+/-)-4-methoxy-N-(3-methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide,

(+/-)-4-methoxy-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide,

(+/-)-N-(4-forfinal)-4-methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide,

(+/-)-N-(4-forfinal)-4-methoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide,

(+/-)-4-methoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-(3-triptoreline)benzosulfimide or

(+)-4-methoxy-N-'is-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide.

Also preferred are compounds in which X and Y both represent-CH2-And means-C(O)-, R3means unsubstituted phenyl and R4means hydrogen, for example, the following connections:

(+/-)-3-methoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-n-toolbarname,

(+/-)-4-fluoro-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-n-toolbarname,

(+/-)-N-(4-chlorophenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-3-cryptomelane or

(+/-)-N-(4-chlorophenyl)-3-methoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide.

In addition, another preferred group of compounds are those compounds in which X and Y both represent-CH2-And means-C(O)-, R3means unsubstituted phenyl and R4means hydroxy, for example, the following connections:

(+/-)-N-(4-forfinal)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-3-methoxybenzamide,

(+/-)-N-(4-chlorophenyl)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-3-methoxybenzamide,

(+/-)-4-fluoro-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-N-n-toolbarname,

(+/-)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-N-(3-methoxyphenyl)benzamide or

(+/-)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-3-methoxy-N-n-toolbarname.

Also preferred are compounds in which X and Y both represent the keys a-CH 2-And means-S(O)2-, R3represents unsubstituted phenyl or phenyl substituted by chlorine, fluorine or stands, and R4means hydroxy, for example, the following connections:

(+/-)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic,

(+)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxy-N - vinylbenzenesulfonic,

(+/-)-N-(4-chlorophenyl)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxybenzenesulfonamide,

(+/-)-N-{CIS-1-[2-(4-chlorophenyl)-2-hydroxycyclohexyl]piperidine-4-yl}-4-methoxy-N-vinylbenzenesulfonic,

(+/-)-N-{CIS-1-[2-(4-forfinal)-2-hydroxycyclohexyl]piperidine-4-yl}-4-methoxy-N-vinylbenzenesulfonic,

(+/-)-N-[CIS-1-(2-hydroxy-2-o-tollcollect)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic,

(+/-)-N-(4-forfinal)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxybenzenesulfonamide,

(+/-)-N-(4-forfinal)-N-{CIS-1-[2-(4-forfinal)-2-hydroxycyclohexyl]piperidine-4-yl}-4-methoxybenzenesulfonamide,

(+/-)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxy-N-(3-methoxyphenyl)benzosulfimide,

(+/-)-N-{CIS-1-[2-(4-forfinal)-2-hydroxycyclohexyl]piperidine-4-yl}-4-methoxy-N-(3-methoxyphenyl)benzosulfimide or

(+/-)-N-[TRANS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic.

In addition to t the th, preferred are compounds in which X and Y both represent-CH2-And means-S(O)2-, R3means pyridin-3-yl or pyridin-4-yl and R4means hydroxy, for example, the following connections:

(+/-)-N-(4-chlorophenyl)-N-[CIS-1-(2-hydroxy-2-pyridine-3-illlogical)piperidine-4-yl]-4-methoxybenzenesulfonamide,

(+/-)-N-[CIS-1-(2-hydroxy-2-pyridine-4-illlogical)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic,

(+/-)-N-[CIS-1-(2-hydroxy-2-pyridine-3-illlogical)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic,

(+/-)-N-(4-forfinal)-N-[CIS-1-(2-hydroxy-2-pyridine-4-illlogical)piperidine-4-yl]-4-methoxybenzenesulfonamide,

(+/-)-N-[CIS-1-(2-hydroxy-2-pyridine-4-illlogical)piperidine-4-yl]-4-methoxy-N-(3-triptoreline)benzosulfimide or

(+/-)-N-[CIS-1-(2-hydroxy-2-pyridine-3-illlogical)piperidine-4-yl]-4-methoxy-N-(3-triptoreline)benzosulfimide.

Also preferred are compounds in which X is-CH2-, Y represents-O-, And means-S(O)2-, R3means unsubstituted phenyl and R4means hydroxy, for example, the following connection:

(+/-)-N-(4-forfinal)-N-[CIS-1-(4-hydroxy-4-vinyltetrahydrofuran-3-yl)piperidine-4-yl]-4-methoxybenzenesulfonamide.

Also preferred are compounds in which X is-CH2-, Y represents-O-, And about the means-C(O)-, R3means unsubstituted phenyl and R4means hydroxy, for example, the following connection:

(+/-)-N-(4-forfinal)-N-[CIS-1-(4-hydroxy-4-vinyltetrahydrofuran-3-yl)piperidine-4-yl]-3-methoxybenzamide.

Also preferred are compounds in which X and Y both represent-CH2-And means-C(O)- and R3means heteroaryl, unsubstituted or substituted with halogen or lower alkyl, or compounds in which X and Y both represent-CH2-And means-C(O)-, R3means heteroaryl, unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl or halogen, and R4means hydrogen.

The compounds of formula I and their pharmaceutically acceptable salts according to the present invention can be obtained using methods known from the prior art, for example, using the method described below, this method includes

a) interaction of the compounds of formula

with the compound of the formula

R2SO2Cl

in the presence of a base and/or acceptor of the proton with obtaining thus the compounds of formula

in which X, Y, R1, R2and R3are as defined above, or

b) interactions link the formula

with the compound of the formula

R2COCl

in the presence of a base and/or acceptor of the proton with obtaining thus the compounds of formula

in which X, Y, R1, R2and R3are as defined above, or

C) the interaction of the compounds of formula

with the compound of the formula

R3Li

obtaining thus the compounds of formula

in which A, X, Y, R1, R2and R3are as defined above, or

g) the interaction of the compounds of formula

with the compound of the formula

obtaining thus the compounds of formula

in which A, X, Y, R1, R2and R3are as defined above, and,

if necessary, the conversion of the compounds obtained into pharmaceutically acceptable additive salts with acids (addition products of acids).

The compounds of formula I can be obtained in accordance with the variants of the method (a)-g) and according to the following schemes 1-7.

1. Obtaining compounds of the formula I, in which R4means hydrogen (scheme 1)

Compounds according to the present invention can be floor is obtained by the methods similar to the methods known from the prior art.

Scheme 1

The compounds of formula I in which R4means of hydrogen and a represents a group-S(O)2-it is easy to get through sulfonylamine corresponding secondary amines using methods known from the prior art, for example, by processing the amine sulphonylchloride in the presence of a suitable base or proton acceptor (scheme 1, stage b). Suitable amines include diisopropylethylamine, 4-dimethylaminopyridine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene and other amines. The acceptors of protons include, for example, 1-methoxy-2-methyl-1-trimethylsilylpropyne.

The compounds of formula I in which R4means hydrogen, and a represents a group-C(O)-, it is easy to get by acylation of the corresponding secondary amines using methods known from the prior art, such as treatment of the amine acylchlorides in the presence of a suitable base or proton acceptor (scheme 1, step G). Suitable amines include diisopropylethylamine, dimethylaminopyridine, triethylamine, etc. Acceptors of protons include, for example, 1-methoxy-2-methyl-1-trimethylsilylpropyne.

Predecessors - secondary amines get pausedstateentered amination of the ketone, the interaction of the obtained amine with the appropriate piperidine at 60°in ethanol in the presence of stoichiometric amount of tetraisopropoxide titanium, with subsequent interaction with sodium borohydride or cyanoborohydride sodium at room temperature (scheme 1, stage B), or the interaction of the obtained amine with the appropriate piperidone in the presence of acid, such as acetic acid, and triacetoxyborohydride sodium. Can also be used other methods of restoration amination, known from the prior art.

Predecessor - ketone - get through reductive amination of the corresponding cycloalkanones using 1,4-dioxa-8 azaspiro[4.5]decane, followed by hydrolysis of the acetal in acidic conditions as shown in scheme 1, step A. Can be used as promoted by titanium and acid catalyzed reductive amination. Get only the CIS-isomers. Remove protective acetaldol grouping is carried out, for example, by treatment with concentrated chloroethanol acid in dioxane by boiling the mixture under reflux.

Compounds according to the present invention can also be obtained in accordance with one of the above on the moves using the methods and techniques of parallel synthesis in solution.

2. Obtaining compounds of the formula I, in which R4means a hydroxy-group (scheme 2-6)

Scheme 2

The compounds of formula I in which R4means a hydroxy-group and a represents-S(O)2- or-C(O)-, can be obtained by the interaction of N-[1-(2-oxocyclohexyl)piperidine-4-yl]-N-aryl-arylsulfonamides or N-[1-(2-oxocyclohexyl)piperidine-4-yl]-N-aryl-arylamido at -78°C in THF with one of abillities reagents R3-Li, which are either commercially available or can be obtained from the corresponding aryl halides, according to one of the many methods known from the prior art (scheme 2, step E). In this procedure receive only the CIS-form.

Scheme 3

Predecessors - N-[1-(2-oxocyclohexyl)piperidine-4-yl]-N-aryl-arylsulfonamides - produced by oxidation of N-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-N-aryl-arylsulfonamides in accordance with one of the many methods known from the prior art, for example, with the use of a complex of pyridine-sulfur trioxide in the presence of triethylamine and dimethyl sulfoxide at room temperature. The same technique is used for the synthesis of N-[1-(2-oxocyclohexyl)piperidine-4-yl]-N-aryl-arylamido (scheme 3, step D).

Predecessor - cyclic secondary is hydrated alcohol - can be obtained by the interaction of the appropriately functionalized amine with a cyclic epoxide (scheme 3, step D), for example, by mixing such amine and epoxide in ethanol at a temperature of education phlegmy solvent.

Appropriately functionalityand amines can be obtained by the interaction of N-tert-butoxycarbonyl-4-piperidone or N-benzyl-4-piperidinol with the amine R1NH2(scheme 3, step A), followed by sulfonylamine or acylation, as described above (scheme 3, step B). The protective group is then removed by acid hydrolysis or hydrogenation in accordance with the methods known from the prior art (scheme 3, step B).

Scheme 4

Alternatively, to obtain N-[1-(2-oxocyclohexyl)piperidine-4-yl]-N-aryl-arylsulfonamides or N-[1-(2-oxocyclohexyl)piperidine-4-yl]-N-aryl-arylamido can be used another synthetic approach, as shown in figure 4. 1-(2-Hydroxycyclohexyl)piperidine-4-one is treated with the amine R1NH2in the presence of tetraisopropoxide titanium and cyanoborohydride sodium (scheme 4, step B). Obtained 2-(4-killinarden-1-yl)cyclohexanol oxidize with use of a complex of pyridine-sulfur trioxide, while receiving the corresponding 2-(4-aalami piperidin-1-yl)cyclohexanone (scheme 4, stage b). This connection or sulfonylurea or acelerou on the secondary amino group as described above, thus obtaining N-[1-(2-oxocyclohexyl)piperidine-4-yl]-N-aryl-arylsulfonamides or N-[1-(2-oxocyclohexyl)piperidine-4-yl]-N-aryl-arylamide (scheme 4, step G).

1-(2-Hydroxycyclohexyl)piperidine-4-one is obtained by interaction of 1,4-dioxa-8 azaspiro[4.5]decane with cyclohexanediol with subsequent hydrolysis of the acetal in acidic conditions as shown in scheme 4, step A.

Scheme 5

Appropriately functionalityand piperidine, for example, such as shown in scheme 3, can also interact with 1-arylcyclohexylamine, as shown in scheme 5, to obtain the compounds according to the present invention, in which the position of the substituents in cycloalkanones ring is a TRANS-position.

Scheme 6

In addition, appropriate functionalityand piperidine for example, such as shown in scheme 3, can also interact with (+/-)was 3.7-dioxabicyclo[4.1.0]heptane (receive, as described in Tchelitcheff P.; C.R. Hebd. Seances Acad. Sci.; 224; 1947; 1722) (scheme 6, step A), and then the resulting alcohols are oxidized to the corresponding ketones, as described above (scheme 6, step B). The interaction of these ketones with allithiamine R the agents (by analogy with scheme 2, stage E), allows to obtain compounds according to the present invention, in which X or Y represents-O-.

3. The formation of compounds in which R2-R4, X and Y have values such as described above, and R1means heteroaryl

The compounds of formula I in which R1means heteroaromatic ring system, get through acylation of the corresponding heteroaromatic amine suitable acylchlorides in the presence of a strong Protic bases, such as 2-tert-Butylimino-2-diethylamino-1,3-dimethylpyridine-1,3,2-datafactory (BEMP). To facilitate purification of the reaction mixture can also be used associated with resin aprotic base such as polystyrene-bound Ben. Secondary heteroaromatic amines according to the present invention, in which R1means heteroaromatic ring system, in particular asenovo ring system, produced by interaction of the corresponding primary amine with heteroarylboronic, preferably with heteroaromatic or bromide in the presence of a base and catalytic amounts of a suitable palladium complex. The precursor primary amine can be obtained by reductive amination of the corresponding 4-piperidone source NH3for example, what redstem interaction with ammonium formate in the presence of Pd(0), or using other methods known from the prior art (scheme 7).

Scheme 7

The transformation of compounds of formula I in salt shall be implemented by processing at least a stoichiometric amount of a suitable acid, such as chloromethane acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or a similar acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, n-toluensulfonate acid, salicylic acid, and the like. Usually the free base is dissolved in an inert organic solvent, such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol, or other solvent, and adding the acid in the same solvent. The temperature of the support between 0 and 50°C. the Obtained salt precipitates spontaneously or can be isolated from solution using a less polar solvent.

dditive salts with acids (addition products of acids) to the main compound of the formula I can be converted into the corresponding free base by treatment using at least a stoichiometric equivalent of a suitable base, such as sodium hydroxide or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia and similar reasons.

The compounds of formula I and their pharmaceutically acceptable additive salts have valuable pharmacological properties. In particular, it was found that the compounds according to the present invention are effective inhibitors of the glycine Transporter I (GlyT-1).

Compounds investigated using tests below.

Solutions and substances

Complete DMEM (modified Eagle medium of Dulbecco): DMEM ("Gibco Life technologies), glucose, fetal bovine serum (FBS) 5%, ("Gibco life technologies), penicillin/streptomycin 1% ("Gibco life technologies), geneticin 1 mg/ml ("Gibco life technologies"), a Proline to 19.8 mg/0.5 l medium (Sigma).

Buffer to absorb (PB): 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.

Cho cells (Cho). from the English. Chinese Hamster Ovary - cells of the ovaries of Chinese hamsters) stable transfection with hglyT1b cDNA, clone A-47.

Study of the inhibition of the absorption of glycine (hGlyT-1b)

Day 1 mammalian cells (Cho), transfection with hGlyT-1b cDNA (clone A-47), were placed at a density of 50,000 cells/well in complete DMEM in 96-well culture plates. On day 2 the medium is removed and cells prom the live double-buffer to absorb (PB). The cells are then incubated for 30 min at 22°in accordance with one of the following: (i) no potential competing compounds (ii) with 10 mm non-radioactive glycine, (iii) with the potential inhibitor in certain concentrations. To obtain the data necessary to calculate the concentration of inhibitor resulting in 50%increase effect (e.g., IC50for competitive inhibition of the uptake of glycine) use a range of concentrations of potential inhibitors. Then immediately add the solution containing [3H]-glycine 60 nm (11-16 Curie/mmol) and 25 μm non-radioactive glycine. After that, cells incubated with mild shaking for 30 min at 22-24°C, after which the reaction is stopped by removing the mixture and washing (three times) using chilled on ice PSU. Cells are lysed using a scintillation liquid, shaken for 3 hours and measure the radioactivity of the cells using a scintillation counter.

Preferred compounds are characterized by the value of the IC50(μm) in respect of GlyT-1 in the range of 0.015-0,100, as shown in the table below.

ExampleIC50(µm)ExampleIC50(µm)
10,048108 0,04
30,0941090,073
110,0561100,076
170,0491110,068
220,0831120,061
340,098114of 0.066
35of 0.0661150,071
670,0991200,091
690,0291210,071
750,0681230,095
960,0491250,096
980,0331390,044
990,0281410,1
1000,0151420,063
1020,0921440,082
1050,0841590,068
1070,0831630,085

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 a farm is sitechecker drugs. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. In addition, the introduction can be effectively carried out rectally, for example in the form of suppositories, parenterally, e.g. in the form of solutions for injection.

The compounds of formula I can be used together with pharmaceutically inert, inorganic or organic carriers for pharmaceutical compositions. As carriers for tablets, coated tablets, dragées and hard gelatin capsules can be used, for example, lactose, corn starch or its derivatives, talc, stearic acid or their salts and similar compounds. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like compounds. However, depending on the nature of the active compounds in the case of soft gelatin capsules the media may not be used. Suitable carrier materials for obtaining of solutions and syrups are, for example, water, polyols, glycerine, vegetable oil, and the like compounds. Suitable carriers for suppositories are, for example, natural or otverzhdennyh the oil, waxes, fats, semi-liquid or liquid polyols and the like compounds.

Pharmaceutical compositions can also contain preservatives, soljubilizatory, stabilizers, improves wetting agents, emulsifiers, sweeteners, tinted agents, agents for improving taste and smell, salts for regulating the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically important compounds.

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 well as the way they are received, which includes the introduction of one or more compounds of formula I and/or pharmaceutically acceptable additive salts with an acid and, if necessary, one or more therapeutic substances in the composition of a medicinal product, together with one or more therapeutically inert carrier.

The most appropriate evidence in accordance with the present invention are indications, which include disorders or disorders of the Central nervous system, for example, such evidence as the treatment or prevention of schizophrenia, cognitive impairment and Alzheimer's disease.

The dosage may vary within wide limits and Bud is t, of course, be adjusted depending on 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 about 1000 mg per day of the compounds of General formula I or the corresponding number of its pharmaceutically acceptable salts. The daily dosage may be entered as a single dose or divided into multiple doses and, in addition, may be exceeded, if it is found that it is necessary according to the testimony.

Manufacturing of tablets (wet granulation)

PositionIngredientsmg tablet
5 mg25 mg100 mg500 mg
1The compound of the formula I525100500
2Anhydrous lactose DTG12510530150
3Sta-Rx 150066630
4Microcrystalline cellulose303030150
5 Magnesium stearate1111
The total number of167167167831

Method get

1. Mixed connection positions 1, 2, 3 and 4 and carry out granulation, using purified water.

2. Dry the granules at 50°C.

3. Place granules in a suitable device for grinding.

4. Add substance according to the position 5 and stirred for three minutes, then pressed, using a suitable press.

Getting capsules

PositionIngredientsmg/capsule
5 mg25 mg100 mg500 mg
1The compound of the formula I525100500
2Water lactose159123148-
3Corn starch25354070
4Talc10151025
5Magnesium stearate 1225
The total number of200200300600

The method of cooking

1. Mixed connection positions 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add connection according to the positions 4 and 5 and mix for 3 minutes.

3. Placed in a suitable capsule.

Example 1

(+/-)-3,4-Dichloro-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the header of the get connection, as shown in figure 1.

(A) Receive (+/-)-CIS-1-(2-phenylcyclohexyl)piperidine-4-it. To a solution of 2-phenylcyclohexanone (46,0 g, 264 mmol) and 1,4-dioxa-8 azaspiro[4.5]decane (31,5 g, 220 mmol) in toluene (380 ml), add n-toluensulfonate acid monohydrate (4,18 g of 22.0 mmol) and then the resulting mixture was refluxed in an apparatus equipped with a trap Dean-stark within 24 hours. Then the reaction mixture was evaporated and the crude enamine was dissolved in 1,2-dichloroethane (900 ml) and acetic acid (8,00 ml). To this solution add portions triacetoxyborohydride sodium (69,0 g, 308 mmol). After a total time of reaction time of 2.5 hours, the reaction mixture is treated using 2 n NaOH solution (250 ml) and extracted with dichloromethane. Volume of the United organic extracts washed with saturated salt solution, dried over magnesium sulfate, filtered and evaporated. Purification of the crude product is performed with the use of layer ("cushions") of silica gel (10:1)using a mixture of n-heptane/ethyl acetate in a ratio of 10:1, then a mixture of n-heptane/ethyl acetate in a ratio of 9:1 and finally as the eluent ethyl acetate, thus obtaining (+/-)-8-(CIS-2-phenylcyclohexyl)-1,4-dioxa-8 azaspiro[4.5]decane (44,8 g, yield 68%) as a yellow oily substance, mass spectrum (ISP): m/e=302,4 (M+N+).

A solution of (+/-)-8-(CIS-2-phenylcyclohexyl)-1,4-dioxa-8 azaspiro[4.5]decane (44,8 g) in the Meon (100 ml) and 6 N. HCl (445 ml) is refluxed for 16 hours. Then the reaction mixture was alkalinized using solid sodium carbonate, extracted with dichloromethane, dried over sodium sulfate, filtered and evaporated. The crude product is purified rapid chromatography on silica gel using as eluent n-heptane. (+/-)-1-(CIS-2-Phenylcyclohexyl)piperidine-4-one (28.8 g, 75%yield) are obtained in the form of a viscous yellow oily substance, mass spectrum (ISP): m/e=258,3 (M+N+).

(B) Reductive amination of obtaining at the same time (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine. A solution of (+/-)-CIS-1-(2-phenylcyclohexyl)piperidine-4-it (0,500 g, 1.94 mmol) and aniline (0,360 g, 3.88 mmol) in technical ethanol (3 ml) is treated using Ti(OiPr)4(1.10 g, 1,15ml, 3.88 mmol). The resulting solution was heated to 60°C and stirred for 2.5 hours. After cooling to room temperature, add cyanoborohydride sodium (0,244 g, 3.88 mmol) and then the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane (40 ml) and treated with vigorous stirring, 5 N. NaOH solution (2 ml) and sodium sulfate (3.0 g). After 15 minutes of transparent solution stands out white solid, which is filtered and evaporated, thus obtaining the crude oily substance. Cleaning is performed rapid chromatography (20-70% ether in dichloromethane). Specified in the header connection - amine (0,460 g, yield 70%) are obtained in the form of deliquescent white solid, mass spectrum (ISP): m/e=335,2 (M+N+).

(C) Sulfonylurea and receive at the same time (+/-)-3,4-dichloro-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide. A solution of (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine (0,105 mg, 0,310 mmol) in dry pyridine (1.5 ml) and dichloromethane (1.0 ml) is treated with a solution of 3,4-dichlorobenzenesulfonate (0,131 mg, 0,530 mmol) in dichloromethane (1.0 ml) and stirred at room temperature for 24 hours. Then the resulting mixture was diluted with dichloromethane and stop the reaction by adding to the reaction mixture water and hydrox is Yes sodium 1 N. (1.0 ml). The phases are separated and the aqueous phase is extracted twice with dichloromethane. The combined organic phases are dried using anhydrous sodium sulfate, then concentrated, thus obtaining the crude residue. The residue is purified rapid chromatography on silica gel, elwira with ethyl acetate, 10-30% in heptane. The connection specified in the header of the example (0,158 g, yield 92%)are in the form of not-quite-white solid, mass spectrum (ISP): m/e=543,3 and 545,3 (M+N+).

Example 2

(+/-)-3,4-Dichloro-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

The connection specified in the header of example, get that way as indicated in example 1, stage (A), (B). Stage (C) replace the following procedure.

(B) Acylation with obtaining (+/-)-3,4-dichloro-N-phenyl-N-[CIS-1 -(2-phenylcyclohexyl)piperidine-4-yl]benzamide. A solution of (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine (0,017 g 0,050 mmol), dimethylaminopyridine (0,012 g 0,010 mmol) and 1-methoxy-2-methyl-1-trimethylsilylpropyne (0,020 ml, 0.10 mmol) in dry tetrahydrofuran (0.5 ml) is treated with a solution of 3,4-dichlorobenzotrifluoride (16 mg, of 0.075 mmol) in dry tetrahydrofuran (0,37 ml). The resulting mixture was stirred using a mixer "Syncore Shaker" for 20 hours, then stop the reaction by adding water (0.15 ml). After that the reaction mixture in the W ill result directly in preparative column for liquid chromatography high resolution (IHVR) ("YMC ODS-AQ"; 50×20 mm; 5 μm; flow rate 30 ml/min; run time 5 min; gradient: 20-80% acetonitrile in water; detection: light scattering). Specified in the title compound (7.0 mg, yield 28%) gain in the form of a white solid, mass spectrum (ISP): m/e=507,30 (M+N+).

Example 3

(+/-)-4-Methoxy-N-(3-methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=535,5 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using a 3-methoxyaniline, and receive (+/-)-(3-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 4-methoxybenzenesulfonamide.

Example 4

(+/-)-N-Phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]isobutyramide

Specified in the title compound, mass spectrum (ISP): m/e=405,6 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is performed using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 2-methylpropanoate.

Example 5

(+/-)-3-Methoxy-N-(3-methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=499,3 (M+N+receive by methods which, described in example 2, steps (A)-(C). Stage (B) is conducted using a 3-methoxyaniline, and receive (+/-)-(3-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 3-methoxybenzylamine.

Example 6

(+/-)-N-(3-Methoxyphenyl)-2-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]ndimethylacetamide

Specified in the title compound, mass spectrum (ISP): m/e=483,5 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using a 3-methoxyaniline, and receive (+/-)-(3-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 2-phenylacetylcarbinol.

Example 7

(+/-)-N-Phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl] benzamide

Specified in the title compound, mass spectrum (ISP): m/e=439,5 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is performed using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with benzoyl chloride.

Example 8

(+/-)-N-(3-Methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=469,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using a 3-metocean is in, and receive (+/-)-(3-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with benzoyl chloride.

Example 9

(+/-)-N-Benzyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=453,6 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using benzylamine, and receiving at the same time (+/-)-benzyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with benzoyl chloride.

Example 10

(+/-)-N-Phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=475,3 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is performed using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with benzosulphochloride.

Example 11

(+/-)-4-Methoxy-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=505,3 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is performed using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which will overhaul interaction with 4-methoxybenzenesulfonamide on stage (In).

Example 12

(+/-)-N-(3-Methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=505,4 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using a 3-methoxyaniline, and receive (+/-)-(3-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is subjected to interaction with benzosulphochloride on stage (In).

Example 13

(+/-)-N-Benzyl-4-methoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=519,3 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using benzylamine, while receiving (+/-)-benzyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is subjected to interaction with 4-methoxybenzenesulfonamide on stage (In).

Example 14

(+/-)-N-[CIS-1-(2-Phenylcyclohexyl)piperidine-4-yl]-N-n-toolbarname

Specified in the title compound, mass spectrum (ISP): m/e=453,6 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using n-tolylamino, while receiving [CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-n-tolylamino, which is then at the stage (C) is subjected to interaction with benzoyl chloride.

Example 15

(+/-)-2-Methyl-N-[CIS-1-(2-phenylcyclohexyl)is piperidin-4-yl]-N-n-toolbarname

Specified in the title compound, mass spectrum (ISP): m/e=467,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using n-tolylamino, while receiving [CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-p-tolylamino, which is then subjected to stage (C) interaction with 2-methylbenzothiazol

Example 16

(+/-)-N-[CIS-1-(2-Phenylcyclohexyl)piperidine-4-yl]-N-n-tolyl-3-cryptomelane

Specified in the title compound, mass spectrum (ISP): m/e=521,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using n-tolylamino, while receiving [CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-n-tolylamino, which is then at the stage (C) is subjected to interaction with 3-triftoratsetilatsetonom

Example 17

(+/-)-3-Methoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-n-toolbarname

Specified in the title compound, mass spectrum (ISP): m/e=483,5 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using n-tolylamino, while receiving [CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-n-tolylamino, which is then at the stage (C) is subjected to interaction with 3-methoxybenzylamine.

Example 18

(+/-)-4-Methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-n-toolbarname

Specified in the title compound, mass spectrum (ISP): m/e=467,4 (M+N+, receive the procedure described in example 2, steps (A)-(C). Stage (B) is conducted using n-tolylamino, while receiving [CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-n-tolylamino, which is then at the stage (C) is subjected to interaction with 4-methylbenzothiazol.

Example 19

(+/-)-4-Chloro-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-n-toolbarname

Specified in the title compound, mass spectrum (ISP): m/e=487,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using n-tolylamino, while receiving [CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-n-tolylamino, which is then at the stage (C) is subjected to interaction with 4-chlorobenzylchloride.

Example 20

(+/-)-4-Methoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-n-toolbarname

Specified in the title compound, mass spectrum (ISP): m/e=483,6 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using n-tolylamino, while receiving [CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-n-tolylamino, which is then at the stage (C) is subjected to interaction with 4-methoxybenzylamine.

Example 21

(+/-)-3,4-Dichloro-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-n-toolbarname

Specified in the title compound, mass spectrum (ISP): m/e=521,4, of 523.4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using the n-tolylamino, while receiving [CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-n-tolylamino, which is then at the stage (C) is subjected to interaction with 3,4-dichlorobenzotrifluoride.

Example 22

(+/-)-4-Fluoro-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-n-toolbarname

Specified in the title compound, mass spectrum (ISP): m/e=471,3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using n-tolylamino, while receiving [CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-n-tolylamino, which is then at the stage (C) is subjected to interaction with 4-tormentilla.

Example 23

(+/-)-N-(4-Methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=469,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-methoxyaniline, and receive (+/-)-(4-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with benzoyl chloride.

Example 24

(+/-)-N-(4-Methoxyphenyl)-2-methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=483,5 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-methoxyaniline, and receive (+/-)-(4-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)PI is uridin-4-yl]amine, then at stage (C) is subjected to interaction with 2-methylbenzothiazol.

Example 25

(+/-)-N-(4-Methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-3-cryptomelane

Specified in the title compound, mass spectrum (ISP): m/e=537,5 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-methoxyaniline, and receive (+/-)-(4-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 3-triftoratsetilatsetonom).

Example 26

(+/-)-3-Methoxy-N-(4-methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=499,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-methoxyaniline, and receive (+/-)-(4-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 3-methoxybenzylamine.

Example 27

(+/-)-N-(4-Methoxyphenyl)-4-methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=483,60 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-methoxyaniline, and receive (+/-)-(4-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidin the-4-yl]amine, then at stage (C) is subjected to interaction with 4-methylbenzothiazol.

Example 28

(+/-)-4-Chloro-N-(4-methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=503,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-methoxyaniline, and receive (+/-)-(4-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 4-chlorobenzylchloride.

Example 29

(+/-)-3,4-Dichloro-N-(4-methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=537,4, 539,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-methoxyaniline, and receive (+/-)-(4-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 3,4-dichlorobenzotrifluoride.

Example 30

(+/-)-4-Fluoro-N-(4-methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=487,40 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-methoxyaniline, and receive (+/-)-(4-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is th then subjected to interaction with 4-tormentilla on stage (In).

Example 31

(4-Methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amide (+/-)-thiophene-2-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=475,40 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-methoxyaniline, and receive (+/-)-(4-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 2-thiophenecarbonitrile.

Example 32

(+/-)-N-(4-Chlorophenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=473,3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-Chloroaniline, and receive (+/-)-(4-chlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with benzoyl chloride.

Example 33

(+/-)-N-(4-Chlorophenyl)-2-methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=487,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-Chloroaniline, and receive (+/-)-(4-chlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 2-methylbenzothiazol.

Example 34

(+/-)-N-(4-Chloro who enyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-3-cryptomelane

Specified in the title compound, mass spectrum (ISP): m/e=541,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-Chloroaniline, and receive (+/-)-(4-chlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 3-triftoratsetilatsetonom.

Example 35

(+/-)-N-(4-Chlorophenyl)-3-methoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=503,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-Chloroaniline, and receive (+/-)-(4-chlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 3-methoxybenzylamine.

Example 36

(+/-)-4-Chloro-N-(4-chlorophenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=are 507, 5, 509,5 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-Chloroaniline, and receive (+/-)-(4-chlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 4-chlorobenzylchloride.

Example 37

(+/-)-N-(4-Chlorophenyl)-4-methoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the header is the connection, mass spectrum (ISP): m/e=503,5 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-Chloroaniline, and receive (+/-)-(4-chlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 4-methoxybenzylamine.

Example 38

(+/-)-3,4-Dichloro-N-(4-chlorophenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=are 507, 5, 509,5 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-Chloroaniline, and receive (+/-)-(4-chlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 3,4-dichlorobenzotrifluoride.

Example 39

(+/-)-N-(4-Chlorophenyl)-4-fluoro-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=491,30 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-Chloroaniline, and receive (+/-)-(4-chlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 4-tormentilla.

Example 40

(+/-)-Thiophene-2-carboxylic acid (4-chlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amide

Specified in the title compound, mass spectrum (ISP): me=479,4 (M+N +receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-Chloroaniline, and receive (+/-)-(4-chlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 2-thiophenecarbonitrile.

Example 41

(+/-)-3-Methoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-n-talibancontrolled

Specified in the title compound, mass spectrum (ISP): m/e=519,4 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using n-tolylamino, while receiving (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-n-tolylamino that at the stage (C) is subjected to interaction with 3-methoxybenzenesulfonamide.

Example 42

(+/-)-4-Chloro-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-n-talibancontrolled

Specified in the title compound, mass spectrum (ISP): m/e=523,3 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using n-tolylamino, while receiving (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-n-tolylamino that at the stage (C) is subjected to interaction with 4-chlorobenzenesulfonamide.

Example 43

(+/-)-3,4-Dichloro-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-n-talibancontrolled

Specified in the title compound, mass spectrum (ISP): m/e=557,3, 559,3 (M+N+receive so what Braz, as indicated in example 1, stage (A) - (C). Stage (B) is conducted using n-tolylamino, while receiving (+1-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-n-tolylamino, which is subjected to interaction with 3,4-dichlorobenzenesulfonate on stage (In).

Example 44

(+/-)-3,4-Dichloro-N-(4-methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=573,3, 575,3 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using 4-methoxyaniline, and receive (+/-)-(4-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 3,4-dichlorobenzenesulfonate.

Example 45

(+/-)-4-Chloro-N-(4-chlorophenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=543,3, 545,3 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using 4-Chloroaniline, and receive (+/-)-(4-chlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 4-chlorobenzenesulfonamide.

Example 46

(+/-)-N-(4-Chlorophenyl)-4-methoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=539,5 (M+N+, get that way as indicated in example 1, stage (A)-(C). Stage (B) is conducted using 4-Chloroaniline, and receive (+/-)-(4-chlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 4-methoxybenzenesulfonamide.

Example 47

[CIS-1-(2-Phenylcyclohexyl)piperidine-4-yl]-n-toolame (+/-)-thiophene-2-sulfonic acid

Specified in the title compound, mass spectrum (ISP): m/e=495,3 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using n-tolylamino, while receiving (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-n-tolylamino that at the stage (C) is subjected to interaction with 2-thiophenesulfonyl.

Example 48

(+/-)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-n-talibancontrolled

Specified in the title compound, mass spectrum (ISP): m/e=489,4 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using n-tolylamino, while receiving (+1-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-n-tolylamino that at the stage (C) is subjected to interaction with benzosulphochloride.

Example 49

(+/-)-2-Methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-n-talibancontrolled

Specified in the title compound, mass spectrum (ISP): m/e=503,5 (M+N+receive such manner as is specified is shown in example 1, stage (A)-(C). Stage (B) is conducted using n-tolylamino, while receiving (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-n-tolylamino that at the stage (C) is subjected to interaction with 2-methylbenzenesulfonamide.

Example 50

(+/-)-4-Methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-n-talibancontrolled

Specified in the title compound, mass spectrum (ISP): m/e=503,5 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using n-tolylamino, while receiving (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-n-tolylamino that at the stage (C) is subjected to interaction with 4-methylbenzenesulfonamide.

Example 51

(+/-)-N-(4-Chlorophenyl)-2-methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=523,3 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using 4-Chloroaniline, and receive (+/-)-(4-chlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 2-methylbenzenesulfonamide.

Example 52

(+/-)-N-(4-Chlorophenyl)-3-methoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=539,5 (M+N+receive therefore, as described in example 1, stage (A)-(C) Stage (B) is conducted, using 4-Chloroaniline, and receive (+/-)-(4-chlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 3-methoxybenzenesulfonamide.

Example 53

(+/-)-N-(4-Chlorophenyl)-4-methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=523,3 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using 4-Chloroaniline, and receive (+/-)-(4-chlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 4-methylbenzenesulfonamide.

Example 54

(+/-)-3,4-Dichloro-N-(4-chlorophenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=577,1, 579,1 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using 4-Chloroaniline, and receive (+/-)-(4-chlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 3,4-dichlorobenzenesulfonate.

Example 55

(+/-)-N-[CIS-1-(2-Phenylcyclohexyl)piperidine-4-yl]-N-n-tolyl-3-triftoratsetilatsetonom

Specified in the title compound, mass spectrum (ISP): m/e=557,5 (M+N+receive therefore, as described in example 1, stage (a)-C). Stage (B) is conducted using n-tolylamino, while receiving (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-n-tolylamino that at the stage (C) is subjected to interaction with 3-triftoratsetilatsetonom.

Example 56

(+/-)-N-(4-Methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=505,4 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using 4-methoxyaniline, and receive (+/-)-(4-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with benzosulphochloride.

Example 57

(+/-)-N-(4-Methoxyphenyl)-2-methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=519,5 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using 4-methoxyaniline, and receive (+/-)-(4-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 2-methylbenzenesulfonamide.

Example 58

(+/-)-N-(4-Methoxyphenyl)-4-methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=519,4 (M+N+receive therefore, as stated in the application is e 1, stage (A)-(C). Stage (B) is conducted using 4-methoxyaniline, and receive (+/-)-(4-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl] amine, which is at the stage (C) is subjected to interaction with 4-methylbenzenesulfonamide.

Example 59

(+/-)-4-Chloro-N-(4-methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=539,4 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using 4-methoxyaniline, and receive (+/-)-(4-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 4-chlorobenzenesulfonamide.

Example 60

(+/-)-N-(3,4-Dichlorophenyl)-4-methoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=573,3, 575,3 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using 3,4-dichloraniline, and receive (+/-)-(3,4-dichlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 4-methoxybenzenesulfonamide.

Example 61

(+/-)-4-Chloro-N-(3-methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=539,5 (M+N+), ucaut thus, as indicated in example 1, stage (A)-(C). Stage (B) is conducted using a 3-methoxyaniline, and receive (+/-)-(3-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 4-chlorobenzenesulfonamide.

Example 62

(+/-)-N-(3-Methoxyphenyl)-4-methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=519,5 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using a 3-methoxyaniline, and receive (+/-)-(3-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 4-methylbenzenesulfonamide.

Example 63

(+/-)-3,4-Dichloro-N-(3-methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=573,3, 575,3 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using a 3-methoxyaniline, and receive (+/-)-(3-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 3,4-dichlorobenzenesulfonate.

Example 64

(+/-)-4-Fluoro-N-(3-methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (SP): m/e=523,3 (M+N +receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using a 3-methoxyaniline, and receive (+/-)-(3-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 4-forbindelsesfanebladet.

Example 65

(+/-)-N-(3-Methoxyphenyl)-2-methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=519,4 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using a 3-methoxyaniline, and receive (+/-)-(3-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 2-methylbenzenesulfonamide.

Example 66

(+/-)-4-Chloro-N-(4-forfinal)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=527,3 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using 4-ftoranila, and receive (+/-)-(4-forfinal)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 4-chlorobenzenesulfonamide.

Example 67

(+/-)-N-(4-Forfinal)-4-methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass is the range (ISP): m/e=are 507, 5 (M+N +receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using 4-ftoranila, and receive (+/-)-(4-forfinal)- [CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 4-methylbenzenesulfonamide.

Example 68

(+/-)-3,4-Dichloro-N-(4-forfinal)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=561,4, 563,4 (M+N+receive therefore, as described in example 1, stage (A) - (C). Stage (B) is conducted using 4-ftoranila, and receive (+/-)-(4-forfinal)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 3,4-dichlorobenzenesulfonate.

Example 69

(+/-)-N-(4-Forfinal)-4-methoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=523,3 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using 4-ftoranila, and receive (+/-)-(4-forfinal)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 4-methoxybenzenesulfonamide.

Example 70

(+/-)-4-Fluoro-N-(4-forfinal)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass is the range (ISP): m/e=511,4 (M+N +receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using 4-ftoranila, and receive (+/-)-(4-forfinal)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 4-forbindelsesfanebladet.

Example 71

(+/-)-N-(4-Forfinal)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=493,3 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using 4-ftoranila, and receive (+/-)-(4-forfinal)- [CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with benzosulphochloride.

Example 72

(+/-)-N-(4-Forfinal)-2-methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=are 507, 5 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using 4-ftoranila, and receive (+/-)-(4-forfinal)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 2-methylbenzenesulfonamide.

Example 73

(+/-)-4-Chloro-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-(3-triptoreline)benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=577,3 (M+sup> +receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using a 3-triptorelin, and receive (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-(3-triptoreline)amine, which is at the stage (C) is subjected to interaction with 4-chlorobenzenesulfonamide.

Example 74

(+/-)-4-Methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-(3-triptoreline)benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=557,4 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using a 3-triptorelin, and receive (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-(3-triptoreline)amine, which is at the stage (C) is subjected to interaction with 4-methylbenzenesulfonamide.

Example 75

(+/-)-4-Methoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-(3-triptoreline)benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=RUB 573.4 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using a 3-triptorelin, and receive (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-(3-triptoreline)amine, which is at the stage (C) is subjected to interaction with 4-methoxybenzenesulfonamide.

Example 76

(+/-)-4-Fluoro-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-(3-trifloromethyl the Nile)benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=561,5 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using a 3-triptorelin, and receive (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-(3-triptoreline)amine, which is at the stage (C) is subjected to interaction with 4-forbindelsesfanebladet.

Example 77

(+/-)-N-[CIS-1-(2-Phenylcyclohexyl)piperidine-4-yl]-N-(3-triptoreline)benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=543,4 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using a 3-triptorelin, and receive (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-(3-triptoreline)amine, which is at the stage (C) is subjected to interaction with benzosulphochloride.

Example 78

(+/-)-2-Methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-(3-triptoreline)benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=557,5 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using a 3-triptorelin, and receive (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-(3-triptoreline)amine, which is at the stage (C) is subjected to interaction with 2-methylbenzenesulfonamide.

Example 79

(+/-)-4-Chloro-N-[CIS-1-(2-Fe is illlogical)piperidine-4-yl]-N-o-talibancontrolled

Specified in the title compound, mass spectrum (ISP): m/e=523,3 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using o-tolylamino, while receiving (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-o-tolylamino that at the stage (C) is subjected to interaction with 4-chlorobenzenesulfonamide.

Example 80

(+/-)-4-Methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-o-talibancontrolled

Specified in the title compound, mass spectrum (ISP): m/e=503,5 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using o-tolylamino, while receiving (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-o-tolylamino that at the stage (C) is subjected to interaction with 4-methylbenzenesulfonamide.

Example 81

(+/-)-3,4-Dichloro-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-o-talibancontrolled

Specified in the title compound, mass spectrum (ISP): m/e=557,4, 559,4 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using o-tolylamino, while receiving (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-o-tolylamino that at the stage (C) is subjected to interaction with 3,4-dichlorobenzenesulfonate.

Example 82

(+/-)-4-Methoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-o-talibancontrolled

Specified in the header is VCE connection, mass spectrum (ISP): m/e=519,5 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using o-tolylamino, while receiving (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-o-tolylamino that at the stage (C) is subjected to interaction with 4-methoxybenzenesulfonamide.

Example 83

(+/-)-4-Fluoro-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-o-talibancontrolled

Specified in the title compound, mass spectrum (ISP): m/e=are 507, 5 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using o-tolylamino, while receiving (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-o-tolylamino that at the stage (C) is subjected to interaction with 4-forbindelsesfanebladet.

Example 84

(+/-)-N-[CIS-1-(2-Phenylcyclohexyl)piperidine-4-yl]-N-o-talibancontrolled

Specified in the title compound, mass spectrum (ISP): m/e=489,5 (M+H+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using o-tolylamino, while receiving (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-o-tolylamino that at the stage (C) is subjected to interaction with benzosulphochloride.

Example 85

(+/-)-2-Methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-o-talibancontrolled

Specified in the title compound, mass spectrum (ISP): m/e=503,5 (M+N+receive t is thus, as indicated in example 1, stage (A)-(C). Stage (B) is conducted using o-tolylamino, while receiving (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-o-tolylamino that at the stage (C) is subjected to interaction with 2-methylbenzenesulfonamide.

Example 86

(+/-)-4-Chloro-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=509,5 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is performed using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is subjected to stage (C) interaction with 4-chlorobenzenesulfonamide.

Example 87

(+/-)-4-Methyl-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=489,4 (M+H+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is performed using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 4-methylbenzenesulfonamide.

Example 88

(+/-)-4-Fluoro-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=493,3 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B)is conducted, using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 4-forbindelsesfanebladet.

Example 89

(+/-)-2-Methyl-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=489,5 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is performed using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 2-methylbenzenesulfonamide.

Example 90

(+/-)-N-Benzyl-4-chloro-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=523,3 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using benzylamine, while receiving (+/-)-benzyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 4-chlorobenzenesulfonamide.

Example 91

(+/-)-N-Benzyl-4-methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=503,5 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using benzylamine, while receiving (+/-)-b is nil-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which stage (B) is subjected to interaction with 4-methylbenzenesulfonamide.

Example 92

(+/-)-N-(3,4-Dichlorophenyl)-2-methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=557,4, 559,4 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using 3,4-dichloraniline, and receive (+/-)-(3,4-dichlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 2-methylbenzenesulfonamide.

Example 93

(+/-)-4-Chloro-N-(3,4-dichlorophenyl)-N-[CIS-1-(2-phenylcyclohexyl)-piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=577,2, 579,2 (M+N+receive therefore, as described in example 1, stage (A) - (C). Stage (B) is conducted using 3,4-dichloraniline, and receive (+/-)-(3,4-dichlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 4-chlorobenzenesulfonamide.

Example 94

(+/-)-4-Nitro-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=520,3 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is performed using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)p is peridin-4-yl]amine, which stage (B) is subjected to interaction with 4-nitrobenzenesulfonamide.

Example 95

(+/-)-4-Amino-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=490,3 (M+N+receive by hydrogenation of (+/-)-4-nitro-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide in accordance with the following method.

(+/-)-4-Nitro-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide (0.05 g, 0,096 mmol) is suspended in isopropanol (3 ml) and the resulting mixture is blown with argon. Add to the suspension of palladium hydroxide on charcoal, and then the suspension is placed in an atmosphere of hydrogen and stirred at room temperature for 20 hours. The catalyst is filtered off and the solvent is evaporated, thus obtaining specified in the title compound as a white foam solid (0,039 g, yield 82%).

Example 96

(+)-4-Methoxy-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=505,5 (M+N+receive by chromatographic separation of (+/-)-4-methoxy-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide on a chiral column ["Chiralpak AD", mortar: a mixture of ethanol (2 ml)/heptane (3 ml), elution: 5% isopropanol is in heptane, the flow rate 35 ml/min, wavelength 245 nm, retention time 26,73 min].

Example 97

(-)-4-Methoxy-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=505,5 (M+N+receive by chromatographic separation of (+/-)-4-methoxy-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide on a chiral column ["Chiralpak AD", mortar: a mixture of ethanol (2 ml)/heptane (3 ml), elution: 5% isopropanol in heptane, flow rate 35 ml/min, wavelength 245 nm, retention time of 32.5 min].

Example 98

(+/-)-N-(4-Forfinal)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-3-methoxybenzamide

Specified in the header of the get connection, as shown in schemes 2 and 3.

(A) Reductive amination with getting this tert-butyl ester 4-(4-forgenerating)piperidine-1-carboxylic acid. To a solution of 1-Boc-4-piperidone (10.0 g, 50.0 mmol) in 1,2-dichloroethane (100 ml) is added 4-ftoranila (the ceiling of 5.60 g, 50.0 mmol), acetic acid (6,20 ml, 103 mmol) and triacetoxyborohydride sodium (16,8 g, 75,3 mmol). After stirring at room temperature for 18 hours the reaction is stopped by adding to the reaction mixture of 1 n sodium hydroxide solution (200 ml). The aqueous phase is extracted with dichloromethane, the combined organic layers dried over anhydrous sulfate is m sodium filtered and concentrated in vacuo. The resulting residue is transferred into the ether, thus obtaining a residue. After filtration obtain tert-butyl ester 4-(4-forgenerating)piperidine-1-carboxylic acid (11.1 g, 75%yield) as not quite white solid, mass spectrum (ISP): m/e=295,3 (M+N+).

(B) Acylation with getting this tert-butyl ester 4-[(4-forfinal)-(3-methoxybenzoyl)amino]piperidine-1-carboxylic acid. To a solution of tert-butyl ester 4-(4-forgenerating)piperidine-1-carboxylic acid (5.0 g, 17 mmol) in dichloromethane (60 ml), add triethylamine (of 5.9 ml, 42 mmol), 4-dimethylaminopyridine (0.21 g, 1.7 mmol) and 3-methoxybenzylamine (3.5 g, 20 mmol). After stirring at room temperature for 20 hours the reaction is stopped by adding to the reaction mixture of sodium bicarbonate (50 ml). The aqueous phase is extracted with dichloromethane, the combined organic layers dried over without form sodium sulfate, filtered and concentrated in vacuo. The resulting residue is transferred into the ether with the receipt of this Deposit. After filtration obtain tert-butyl ester 4-[(4-forfinal)-(3-methoxybenzoyl)amino]piperidine-1-carboxylic acid (6.2 g, yield 84%) as a white solid, mass spectrum (ISP): m/e=429,3 (M+N+).

(C) removing the protection and obtain tert-butyl ether N-(4-forfinal)-3-methoxy-N-piperidine-4-benzamide. To a cooled to 0°With a solution of tert-butyl ester 4-[(4-forfinal)-(3-methoxybenzoyl)amino]piperidine-1-carboxylic acid (6.0 g, 14 mmol) in dichloromethane (60 ml) is added triperoxonane acid (11 ml, 141 mmol). After stirring for 1.5 hours at room temperature the reaction mixture was concentrated in vacuo. The resulting residue is transferred in dichloromethane and sodium hydroxide (1 BC). The aqueous phase is extracted with dichloromethane, the combined organic layers dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue is transferred into the ether, thus obtaining a residue. After filtration of receive N-(4-forfinal)-3-methoxy-N-piperidine-4-ylbenzene (4,2 g, yield 90%) as a pale yellow solid, mass spectrum (ISP): m/e=329,3 (M+N+).

(G) Receive (+/-)-N-(4-forfinal)-N-[TRANS-1-(2-hydroxycyclohexyl)piperidine-4-yl]-3-methoxybenzamide. To a solution of N-(4-forfinal)-3-methoxy-N-piperidine-4-ilasamaja (3.0 g, 9.1 mmol) in ethanol (30 ml) add cyclohexenone (0,90 ml, 9.1 mmol). The reaction mixture was refluxed for 44 hours, then cooled to room temperature and concentrate. The resulting residue is boiled in ether for 1 hour, then cooled to room temperature, thus obtaining a residue. After filtration of gain (+/-)-N-(4-forfinal)-N-[TRANS-1-(2-hydroc illogical)piperidine-4-yl]-3-methoxybenzamide (3.5 g, yield 90%) as a pale yellow solid, mass spectrum (ISP): m/e=427,3 (M+N+).

(D) Oxidation to (+/-)-N-(4-forfinal)-3-methoxy-N-[1-(2-oxocyclohexyl)piperidine-4-yl]benzamide. To a solution of (+/-)-N-(4-forfinal)-N-[TRANS-1-(2-hydroxycyclohexyl)piperidine-4-yl]-3-methoxybenzamide (1.0 g, 2.3 mmol) in dichloromethane (6.0 ml) and DMSO (6.0 ml) is added triethylamine (1.6 ml, 12 mmol). The reaction mixture was cooled to 0°and then added dropwise to the solution of a complex of a sulfur trioxide-pyridine (1.1 g, 7.0 mmol) in dimethyl sulfoxide. After stirring for 2 hours at room temperature the reaction mixture was poured into water and dichloromethane. The aqueous phase is extracted with dichloromethane, the combined organic layers dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained residue chromatographic on silica gel (CH2Cl2-Meon in the ratio 97:3)to give (+/-)-N-(4-forfinal)-3-methoxy-N-[1-(2-oxocyclohexyl)piperidine-4-yl]benzamide (0,82 g, yield 83%) as a white solid, mass spectrum (ISP): m/e=425,3 (M+N+).

(E) Receive (+/-)-N-(4-forfinal)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-3-methoxybenzamide. To a cooled to -78°With a solution of (+/-)-N-(4-forfinal)-3-methoxy-N-[1-(2-oxocyclohexyl)piperidine-4-yl]benzamide (of 0.13 g, 0.30 mmol) in tetrahydrofuran (2.5 ml) is added Fe is illite (1.7 M solution in a mixture of cyclohexane/ether, of 0.18 ml, 0.30 mmol). After stirring for 40 min at -78°the reaction is stopped by adding to the reaction mixture saturated solution of ammonium chloride (5 ml) and then the aqueous phase is extracted with ethyl acetate. The combined organic layers dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained residue chromatographic on silica gel (CH2Cl2/Meon in the ratio 99:1)to give (+/-)-N-(4-forfinal)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-3-methoxybenzamide (0,050 g, yield 34%) as a white foam substance, mass spectrum (ISP): m/e=503,4 (M+N+).

Example 99

(+/-)-N-[CIS-1-(2-Hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic

Specified in the header connection receive in accordance with the methods shown in schemes 2 and 4.

(A) Receive (+/-)-TRANS-1-(2-hydroxycyclohexyl)piperidine-4-it. To a solution of 1,4-dioxa-8 azaspiro[4,5]decane (14,7 g, 100 mmol) in ethanol (75 ml) add cyclohexanone (10.0 g, 100 mmol). The reaction mixture is refluxed for 40 hours, then cooled to room temperature and concentrate. The obtained residue chromatographic on silica gel (hexane/ethyl acetate in the ratio 4:1), thus obtaining (+/-)-TRANS-2-(1,4-dioxa-8 azaspiro[4,5]Dec-8-yl)cyclohexanol (22.1 g, yield 91%) as white is on solids, mass spectrum (ISP): m/e=241,2 (M+).

A solution of (+/-)-TRANS-2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)cyclohexanol (1.50 g, and 6.25 mmol) in dioxane (45 ml) is treated with 5 N. solution chloroethanol acid (10 ml). The resulting mixture was heated to 105°C and stirred for 4 hours. After cooling to room temperature, add water to the mixture (9 ml), then the mixture is alkalinized to pH 14 by the slow addition of 5 n sodium hydroxide solution. The mixture is then extracted three times with ethyl acetate and the combined organic extracts dried with anhydrous sodium sulfate, and then concentrated. The remaining oily substance cleanse rapid chromatography on silica gel, elwira methanol (0-5%) in dichloromethane. (+/-)-TRANS-1-(2-Hydroxycyclohexyl)piperidine-4-one (0,830 g, yield 68%) was obtained as a white solid, mass spectrum (ISP): m/e=198,3 (M+N+).

(B) Reductive amination of obtaining at the same time (+/-)-TRANS-2-(4-phenylaminopyrimidine-1-yl)cyclohexanol. A solution of (+1-)-TRANS-1-(2-hydroxycyclohexyl)piperidine-4-it (0,68, 3.4 mmol) in ethanol (4 ml) is treated using aniline (0.32 g, 3.4 mmol) and tetraisopropoxide titanium (1.2 g, 4.1 mmol). The resulting mixture was heated to 38°C and stirred for 15 hours. After cooling to 0°in a bath with a mixture of ice/water add portions of borohydride sodium (0,19 g, 5.1 mm is l), thus there is a vigorous evolution of hydrogen. The resulting suspension was diluted with ethanol (4 ml) and stirred at room temperature for 3 hours. The reaction mixture was then further diluted with ethanol to stop the reaction, using 1 n sodium hydroxide solution. The two phases are separated and then the aqueous phase is extracted with dichloromethane. The combined organic extracts dried with anhydrous sodium sulfate and concentrated. The resulting residue is purified rapid chromatography on a column of silica gel, elwira methanol (0-10%) in dichloromethane. (+/-)-TRANS-2-(4-Phenylaminopyrimidine-1-yl)cyclohexanol (0.50 g, yield 53%) was obtained as a white solid, mass spectrum (ISP): m/e=of 275.4 (M+N+).

(B) Oxidation to (+/-)-2-(4-phenylaminopyrimidine-1-yl)cyclohexanone. A solution of (+/-)-TRANS-2-(4-phenylaminopyrimidine-1-yl)cyclohexanol (0,22 g, 0.81 mmol) in dry dimethylsulfoxide (4.8 ml) is treated using triethylamine (0,41 g, 4.1 mmol). The solution of a complex of pyridine-sulfur trioxide (0.39 g, 2.4 mmol), dried for one night using a vacuum pump, in dry dimethylsulfoxide (1.9 ml) is added dropwise to the mixture for 3 minutes the resulting solution was stirred at room temperature for 1 hour, then stop the reaction by adding water (50 ml). The resulting mixture was extracted four times what acetate (4× 20 ml). The combined organic phases are washed twice with water (2×20 ml), then dried with anhydrous sodium sulfate and concentrated to obtain a colorless oily substance. Cleaning is carried out by chromatography on silica gel, elwira methanol (0-10%) in dichloromethane.

(+/-)-2-(4-Phenylaminopyrimidine-1-yl)cyclohexanone (0.12 g, yield 53%) are obtained in the form of not-quite-white solid, mass spectrum (ISP): m/e=273,4 (M+N+).

(D) Sulfonylamine obtaining at the same time (+/-)-4-methoxy-N-[1-(2-oxocyclohexyl)piperidine-4-yl]-N-vinylbenzenesulfonic. (+/-)-2-(4-Phenylaminopyrimidine-1-yl)cyclohexanone sulfonylureas using 4-methoxybenzenesulfonamide thus, as in example 1, stage (B). (+/-)-4-Methoxy-N-[1-(2-oxocyclohexyl)piperidine-4-yl]-N-vinylbenzenesulfonic, mass spectrum (ISP): m/e 443,5 (M+N+receive in the form of a white foam solid.

(E) Receive (+/-)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic. A solution of bromine benzol (0.16 g, 1.0 mmol) in dry tetrahydrofuran (2.1 ml) is cooled to -70°With, then add dropwise a solution of utility (1.6 M) in hexane (0,65 ml, 1.0 mmol). The resulting solution was stirred at -70°C for 1 hour, then treated with a solution of (+/-)-4-methoxy-N-[1-(2-oxocyclohexyl)piperidine-4-yl]-N-vinylbenzenesulfonic (0,12 mg, 0,26 mm is l) in dry tetrahydrofuran (2.1 ml). The reaction mixture was stirred at -70°C for 1 hour, then allow to slowly warm to room temperature and stirred for 10 min. After cooling to -78°the reaction is stopped by adding to the reaction mixture of 20%aqueous ammonium chloride (3.4 ml). The two phases are separated and then the aqueous phase is extracted twice with ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate and concentrated. The resulting residue is purified rapid chromatography on silica gel, elwira methanol (0-5%) in dichloromethane. (+/-)-N-[CIS-1-(2-Hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic, mass spectrum (ISP): m/e 521,5 (M+N+receive in the form of a white foam solid (0,093 g, yield 69%).

Example 100

(+)-N-[CIS-1-(2-Hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic

Specified in the title compound, mass spectrum (ISP): m/e=521,5 (M+N+receive by chromatographic separation of (+/-)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic on a chiral column ["Chiralpak AD", solution: ethanol (2 ml)/heptane (3 ml), elution: 10% ethanol in heptane, flow rate 35 ml/min, wavelength 245 nm, retention time 29,64 min].

Example 101

(-)-N-[CIS-1-(2-Hydroxy-2-phenylcyclohexyl)piperidine-4-and the]-4-methoxy-N-vinylbenzenesulfonic

Specified in the title compound, mass spectrum (ISP): m/e=521,5 (M+N+receive by chromatographic separation of (+/-)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic on a chiral column ["Chiralpak AD", solution: ethanol (2 ml)/heptane (3 ml), elution: 10% ethanol in heptane, flow rate 35 ml/min, wavelength 245 nm, retention time 39,56 min].

Example 102

(+/-)-N-(4-Chlorophenyl)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxybenzenesulfonamide

Specified in the title compound, mass spectrum (ISP): m/e=555,3 (M+N+receive therefore, as described in example 99, stage (A)-(E). Stage (B) is conducted using 4-Chloroaniline, and receive (+/-)-TRANS-2-[4-(4-chlorpheniramine)piperidine-1-yl]cyclohexanol, which is oxidized to (+/-)-2-[4-(4-chlorpheniramine)piperidine-1-yl]cyclohexanone on stage (In). This compound is then subjected to interaction with 4-methoxybenzenesulfonamide on stage (G), thus obtaining (+/-)-N-(4-chlorophenyl)-4-methoxy-N-[1-(2-oxocyclohexyl)piperidine-4-yl]benzosulfimide. Final stage (E) is carried out using bromine benzol.

Example 103

(+/-)-N-(4-Chlorophenyl)-N-{CIS-1-[2-(4-chlorophenyl)-2-hydroxycyclohexyl]piperidine-4-yl}-4-methoxybenzenesulfonamide

Specified in the title compound, mass spectrum (ISP): m/e=589,3 (M+N+receive so about the time, as described in example 102, stages (A)-(E). Final stage (E) is conducted using 4-bromchlorenone.

Example 104

(+/-)-N-(4-Chlorophenyl)-N-{CIS-1-[2-(4-forfinal)-2-hydroxycyclohexyl]piperidine-4-yl}-4-methoxybenzenesulfonamide

Specified in the title compound, mass spectrum (ISP): m/e=573,3 (M+N+receive therefore, as described in example 102, stages (A)-(E). Final stage (E) is conducted using 4-bromptonville.

Example 105

(+/-)-N-(4-Chlorophenyl)-N-[CIS-1-(2-hydroxy-2-pyridine-3-illlogical)piperidine-4-yl]-4-methoxybenzenesulfonamide

Specified in the title compound, mass spectrum (ISP): m/e=556,3 (M+N), get that way as indicated in example 102, stages (A)-(E). Final stage (E) is conducted using 3-bromopyridine.

Example 106

(+/-)-N-(4-Chlorophenyl)-N-[CIS-1-(2-hydroxy-2-o-tollcollect)piperidine-4-yl]-4-methoxybenzenesulfonamide

Specified in the title compound, mass spectrum (ISP): m/e=569,4 (M+N+receive therefore, as described in example 102, stages (A)-(E). Final stage (E) is conducted using a 2-bromthymol.

Example 107

(+/-)-N-{CIS-1-[2-(4-Chlorophenyl)-2-hydroxycyclohexyl]piperidine-4-yl}-4-methoxy-N-vinylbenzenesulfonic

Specified in the title compound, mass spectrum (ISP): m/e=555,3 (M+N+receive therefore, as described in example 99, stage (a)to (E). Final stage (E) is conducted using 4-bromchlorenone.

Example 108

(+/-)-N-{CIS-1-[2-(4-Forfinal)-2-hydroxycyclohexyl]piperidine-4-yl}-4-methoxy-N-vinylbenzenesulfonic

Specified in the title compound, mass spectrum (ISP); m/e=539,4 (M+N+receive therefore, as described in example 99, step (a) to (E). Final stage (E) is conducted using 4-bromptonville.

Example 109

(+/-)-N-[CIS-1-(2-Hydroxy-2-pyridine-4-illlogical)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic

Specified in the title compound, mass spectrum (ISP): m/e=522,4 (M+N+receive therefore, as described in example 99, stage (A)-(E). Final stage (E) is conducted using 4-bromopyridine.

Example 110

(+/-)-N-[CIS-1-(2-Hydroxy-2-pyridine-3-illlogical)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic

Specified in the title compound, mass spectrum (ISP): m/e=522,4 (M+N+receive therefore, as described in example 99, stage (A)-(E). Final stage (E) is conducted using 3-bromopyridine.

Example 111

(+/-)-N-[CIS-1-(2-Hydroxy-2-o-tollcollect)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic

Specified in the title compound, mass spectrum (ISP): m/e=535,4 (M+N+receive therefore, as described in example 99, stage (A)-(E). Final stage (E) is carried out with use of the cation of 2-bromthymol.

Example 112

(+/-)-N-(4-Forfinal)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxybenzenesulfonamide

Specified in the title compound, mass spectrum (ISP): m/e=539,4 (M+N+receive therefore, as described in example 99, stage (A)-(E). Stage (B) is conducted using 4-ftoranila, and receive (+/-)-TRANS-2-[4-(4-forgenerating)piperidine-1-yl]cyclohexanol, which is oxidized to (+/-)-2-[4-(4-forgenerating)piperidine-1-yl]cyclohexanone on stage (In). This compound is then subjected to interaction with 4-methoxybenzenesulfonamide on stage (G), thus obtaining (+/-)-N-(4-forfinal)-4-methoxy-N-[1-(2-oxocyclohexyl)piperidine-4-yl]benzosulfimide. Final stage (E) is carried out using bromine benzol.

Example 113

(+/-)-N-{CIS-1-[2-(4-Chlorophenyl)-2-hydroxycyclohexyl]piperidine-4-yl}-N-(4-forfinal)-4-methoxybenzenesulfonamide

Specified in the title compound, mass spectrum (ISP): m/e=573,3 (M+N+receive therefore, as described in example 112, steps (A)-(E). Final stage (E) is conducted using 4-bromchlorenone.

Example 114

(+/-)-N-(4-Forfinal)-N-[CIS-1-[2-(4-forfinal)-2-hydroxycyclohexyl]piperidine-4-yl}-4-methoxybenzenesulfonamide

Specified in the title compound, mass spectrum (ISP): m/e=557,3 (M+N+receive therefore, as described in example 112, steps (A)-(E). Zakluchitel the Dalet (E) is conducted using 4-bromptonville.

Example 115

(+/-)-N-(4-Forfinal)-N-[CIS-1-(2-hydroxy-2-pyridine-4-illlogical)piperidine-4-yl]-4-methoxybenzenesulfonamide

Specified in the title compound, mass spectrum (ISP): m/e=540,4 (M+N+receive therefore, as described in example 112, steps (A)-(E). Final stage (E) is conducted using 4-bromopyridine.

Example 116

(+/-)-N-(4-Forfinal)-N-[CIS-1-(2-hydroxy-2-pyridine-3-illlogical)piperidine-4-yl]-4-methoxybenzenesulfonamide

Specified in the title compound, mass spectrum (ISP): m/e=540,4 (M+N+receive therefore, as described in example 112, steps (A)-(E). Final stage (E) is conducted using 3-bromopyridine.

Example 117

(+/-)-N-[CIS-1-(2-Hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxy-N-(3-triptoreline)benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=589,4 (M+N+receive therefore, as described in example 99, stage (A)-(E). Stage (B) is conducted using 4-triptorelin, and receive (+/-)-TRANS-2-[4-(4-triptoreline)piperidine-1-yl]cyclohexanol, which is oxidized to (+/-)-2-[4-(4-triptoreline)piperidine-1-yl]cyclohexanone on stage (In). This compound is then subjected to interaction with 4-methoxybenzenesulfonamide on stage (G), thus obtaining (+/-)-N-(4-triptoreline)-4-methoxy-N-[1-(2-oxo-cyclohexyl)Pipa is one-4-yl]benzosulfimide. Final stage (E) is carried out using bromine benzol.

Example 118

(+/-)-N-{CIS-1-[2-(4-Chlorophenyl)-2-hydroxycyclohexyl]piperidine-4-yl}-4-methoxy-N-(3-triptoreline)benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=623,4 (M+N+receive therefore, as described in example 117, stage (A)-(E). Final stage (E) is conducted using 4-bromchlorenone.

Example 119

(+/-)-N-{CIS-1-[2-(4-Forfinal)-2-hydroxycyclohexyl]piperidine-4-yl}-4-methoxy-N-(3-triptoreline)benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=607,3 (M+N+receive therefore, as described in example 117, stage (A)-(E). Final stage (E) is conducted using 4-bromptonville.

Example 120

(+/-)-N-[CIS-1-(2-Hydroxy-2-pyridine-4-illlogical)piperidine-4-yl]-4-methoxy-N-(3-triptoreline)benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=590,40 (M+N+receive therefore, as described in example 117, stage (A)-(E). Final stage (E) is conducted using 4-bromopyridine.

Example 121

(+/-)-N-[CIS-1-(2-Hydroxy-2-pyridine-3-illlogical)piperidine-4-yl]-4-methoxy-N-(3-triptoreline)benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=590,40 (M+N+receive therefore, as indicated in note the re 117, stage (A)-(E). Final stage (E) is conducted using 3-bromopyridine.

Example 122

(+/-)-N-[CIS-1-(2-Hydroxy-2-o-tollcollect)piperidine-4-yl]-4-methoxy-N-(3-triptoreline)benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=603,4 (M+N+receive therefore, as described in example 117, stage (A)-(E). Final stage (E) is conducted using a 2-bromthymol.

Example 123

(+/-)-N-[CIS-1-(2-Hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxy-N-(3-methoxyphenyl)benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=551,4 (M+N+receive therefore, as described in example 99, stage (A)-(E). Stage (B) is conducted using a 3-methoxyaniline, and receive (+/-)-TRANS-2-[4-(3-methoxybenzylamine)piperidine-1-yl]cyclohexanol, which is oxidized to (+/-)-2-[4-(3-methoxybenzylamine)piperidine-1-yl]cyclohexanone on stage (In). This compound is then subjected to interaction with 4-methoxybenzenesulfonamide on stage (G), thus obtaining (+/-)-N-(3-methoxyphenyl)-4-methoxy-N-[1-(2-oxocyclohexyl)piperidine-4-yl]benzosulfimide. Final stage (E) is carried out using bromine benzol.

Example 124

(+/-)-N-{CIS-1-[2-(4-Chlorophenyl)-2-hydroxycyclohexyl]piperidine-4-yl}-4-methoxy-N-(3-methoxyphenyl)benzosulfimide

Specified in the title compound, mass-SP the KTR (ISP): m/e=585,3 (M+N +receive therefore, as described in example 123, stage (A)-(E). Final stage (E) is conducted using 4-chlorpromazine.

Example 125

(+/-)-N-{CIS-1-[2-(4-Forfinal)-2-hydroxycyclohexyl]piperidine-4-yl}-4-methoxy-N-(3-methoxyphenyl)benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=569,4 (M+N+receive therefore, as described in example 123, stage (A)-(E). Final stage (E) is conducted using 4-ferramenta.

Example 126

(+/-)-N-[CIS-1-(2-Hydroxy-2-pyridine-4-illlogical)piperidine-4-yl]-4-methoxy-N-(3-methoxyphenyl)benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=552,4 (M+N+receive therefore, as described in example 123, stage (A)-(E). Final stage (E) is conducted using 4-bromopyridine.

Example 127

(+/-)-N-[CIS-1-(2-Hydroxy-2-pyridine-3-illlogical)piperidine-4-yl]-4-methoxy-N-(3-methoxyphenyl)benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=552,4 (M+N+receive therefore, as described in example 124, stage (A)-(E). Final stage (E) is conducted using 3-bromopyridine.

Example 128

(+/-)-4-Chloro-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-N-vinylbenzenesulfonic

Specified in the title compound, mass spectrum (ISP): m/e=525,3 (M+N+receive thisway, as described in example 99, stage (A)-(E). Stage (D) is performed using 4-chlorobenzenesulfonamide, while receiving (+/-)-4-chloro-N-[1-(2-oxocyclohexyl)piperidine-4-yl]-N-vinylbenzenesulfonic. Final stage (E) is carried out using bromine benzol.

Example 129

(+/-)-4-Chloro-N-[CIS-1-[2-(4-chlorophenyl)-2-hydroxycyclohexyl]piperidine-4-yl}-N-vinylbenzenesulfonic

Specified in the title compound, mass spectrum (ISP): m/e=559,30 (M+N+receive therefore, as described in example 128, steps (A)-(E). Final stage (E) is conducted using 4-chlorpromazine.

Example 130

(+/-)-4-Chloro-N-{CIS-1-[2-(4-forfinal)-2-hydroxycyclohexyl]piperidine-4-yl}-N-vinylbenzenesulfonic

Specified in the title compound, mass spectrum (ISP): m/e=543,4 (M+N+receive therefore, as described in example 128, steps (A)-(E). Final stage (E) is conducted using 4-ferramenta.

Example 131

(+/-)-4-Chloro-N-[CIS-1-(2-hydroxy-2-pyridine-4-illlogical)piperidine-4-yl]-N-vinylbenzenesulfonic

Specified in the title compound, mass spectrum (ISP): m/e=526,3 (M+N+receive therefore, as described in example 128, steps (A)-(E). Final stage (E) is conducted using 4-bromopyridine.

Example 132

(+/-)-4-Chloro-N-[CIS-1-(2-hydroxy-2-pyridine-3-illlogical)piperidine-4-yl]-N-vinylbenzenesulfonic the ID

Specified in the title compound, mass spectrum (ISP): m/e=526,3 (M+N+receive therefore, as described in example 128, steps (A)-(E). Final stage (E) is conducted using 3-bromopyridine.

Example 133

(+/-)-4-Chloro-N-[CIS-1-(2-hydroxy-2-o-tollcollect)piperidine-4-yl]-N - vinylbenzenesulfonic

Specified in the title compound, mass spectrum (ISP): m/e=539,4 (M+N+receive therefore, as described in example 128, steps (A)-(E). Final stage (E) is conducted using a 2-bromthymol.

Example 134

(+/-)-3,4-Dichloro-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-N-vinylbenzenesulfonic

Specified in the title compound, mass spectrum (ISP): m/e=559,3 (M+N+receive therefore, as described in example 99, stage (A)-(E). Stage (D) is conducted using 3,4-dichlorobenzenesulfonate, while receiving (+/-)-3,4-dichloro-N-[1-(2-oxocyclohexyl)piperidine-4-yl]-N-vinylbenzenesulfonic. Final stage (E) is carried out using bromine benzol.

Example 135

(+/-)-3,4-Dichloro-N-{CIS-1-[2-(4-chlorophenyl)-2-hydroxycyclohexyl]piperidine-4-yl}-N-vinylbenzenesulfonic

Specified in the title compound, mass spectrum (ISP): m/e=593,3 (M+N+receive therefore, as described in example 134, stage (A)-(E). Final stage (E) is conducted using 4-chlorpromazine.

Example 136

(+/-)-3,4-Dichloro-N-{CIS-1-[2-(4-forfinal)-2-hydroxycyclohexyl]piperidine-4-yl}-N-vinylbenzenesulfonic

Specified in the title compound, mass spectrum (ISP): m/e=577,3 (M+N+receive therefore, as described in example 134, stage (A)-(E). Final stage (E) is conducted using 4-ferramenta.

Example 137

(+/-)-3,4-Dichloro-N-[CIS-1-(2-hydroxy-2-pyridine-3-illlogical)piperidine-4-yl]-N-vinylbenzenesulfonic

Specified in the title compound, mass spectrum (ISP): m/e=560,2 (M+N+receive therefore, as described in example 135, stage (A)-(E). Final stage (E) is conducted using 3-bromopyridine.

Example 138

(+/-)-3,4-Dichloro-N-[CIS-1-(2-hydroxy-2-o-tollcollect)piperidine-4-yl]-N-vinylbenzenesulfonic

Specified in the title compound, mass spectrum (ISP): m/e=573,2 (M+N+receive therefore, as described in example 134, stage (A)-(E). Final stage (E) is conducted using a 2-bromthymol.

Example 139

(+/-)-N-(4-Chlorophenyl)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-3-methoxybenzamide

Specified in the title compound, mass spectrum (ISP): m/e=519,4 (M+N+), white foamed substance thus, as described in example 98, steps (A)-(E). Stage (A) is conducted using 4-Chloroaniline, while receiving tert-butyl ester 4-(4-chlorpheniramine)piperidin the-1-carboxylic acid, which stage (B) acelerou up tert-butyl ester 4-[(4-chlorophenyl)-(3-methoxybenzoyl)amino]piperidine-1-carboxylic acid. Then, the compound obtained is subjected to removal of the protective group, thus obtaining N-(4-chlorophenyl)-3-methoxy-N-piperidine-4-ylbenzene (In), and after interaction with cyclohexanediol receive (+/-)-N-(4-chlorophenyl)-N-[TRANS-1-(2-hydroxycyclohexyl)piperidine-4-yl]-3-methoxybenzamide [stage (G)]. Oxidation to (+/-)-N-(4-chlorophenyl)-3-methoxy-N-[1-(2-oxocyclohexyl)piperidine-4-yl]benzamide in stage (D) and interaction with phenyllithium [stage (E)] allows to obtain the connection specified in the header.

Example 140

(+/-)-N-[CIS-1-(2-Hydroxy-2-o-tollcollect)piperidine-4-yl]-4-methoxy-N-(3-methoxyphenyl)benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=565,4 (M+N+receive therefore, as described in example 123, stage (A)-(E). Final stage (E) is conducted using a 2-bromthymol.

Example 141

(+/-)-4-Fluoro-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-N-n-toolbarname

Specified in the title compound, mass spectrum (ISP): m/e=487,4 (M+N+receive therefore, as described in example 98, steps (A)-(E). Stage (A) is conducted using 4-tolylamino, while receiving tert-butyl ether 4-n-triaminopyrimidine-1-carboxylic acid, which is subjected is zolirovany, using 4-perbenzoate and get on the stage (B) tert-butyl ether 4-[(4-perbenzoic)-n-tolylamino]piperidine-1-carboxylic acid. Then this compound is subjected to removal of the protective group, while receiving 4-fluoro-N-piperidine-4-yl-N-n-toolbarname (In), and after interaction with cyclohexanediol receive (+/-)-4-fluoro-N-[TRANS-1-(2-hydroxycyclohexyl)piperidine-4-yl]-N-n-toolbarname [stage (G)]. Oxidation to (+/-)-4-fluoro-N-[1-(2-oxocyclohexyl)piperidine-4-yl]-N-n-toolbased on stage (D) and interaction with phenyllithium [stage (E)] allows to obtain the connection specified in the header.

Example 142

(+/-)-N-[CIS-1-(2-Hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-N-(3-methoxyphenyl)benzamide

Specified in the title compound, mass spectrum (ISP): m/e=485,4 (M+N+receive such manner as in example 98, steps (A)-(E). Stage (A) is carried out with the use of 3-methoxyaniline and receive tert-butyl ester 4-(3-methoxybenzylamine)piperidine-1-carboxylic acid, which is subjected to acylation, using benzoyl chloride and receive tert-butyl ester 4-[benzoyl-(3-methoxyphenyl)amino]piperidine-1-carboxylic acid (B). This compound is then subjected to removal of protection, receiving N-(3-methoxyphenyl)-N-piperidine-4-ylbenzene (In), and after interaction with cyclohexanediol receive (+/-)-N-[TRANS-1-(2-hydroxyzin the hexyl)piperidine-4-yl]-N-(3-methoxyphenyl)benzamide [stage (G)]. Oxidation to (+/-)-N-(3-methoxyphenyl)-N-[1-(2-oxocyclohexyl)piperidine-4-yl]benzamide in stage (D) and interaction with phenyllithium [stage (E)] results in the connection specified in the header.

Example 143

(+/-)-3-Methoxy-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=469,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is performed using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 3-methoxybenzylamine.

Example 144

(+/-)-N-[CIS-1-(2-Hydroxy-2-phenylcyclohexyl)piperidine-4-yl] -3-methoxy-N-n-toolbarname

Specified in the title compound, mass spectrum (ISP): m/e=499,0 (M+H+receive therefore, as indicated in premise 141, stage (A)-(E). Stage (B) is conducted using a 3-methoxybenzoate, obtaining thus tert-butyl ester 4-[(3-methoxybenzoyl)-n-tolylamino]piperidine-1-carboxylic acid. Then this compound is subjected to removal of the protective group, while receiving 3-methoxy-N-piperidine-4-yl-N-n-toolbarname (stage b), and after interaction with cyclohexanediol receive (+/-)-N-{TRANS-1-(2-hydroxycyclohexyl)piperidine-4-yl]-3-methoxy-N-n-toolbarname [stage (G)]. Oxidation to (+/-)-3-methoxy-N-[1-(2-oxaz clohessy)piperidine - 4-yl]-N-n-Talibanization, stage (D), and interaction with phenyllithium [stage (E)] lead to the connection specified in the header.

Example 145

(+/-)-4-Fluoro-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=457,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is performed using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 4-tormentilla.

Example 146

(+/-)-N-Phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-3-cryptomelane

Specified in the title compound, mass spectrum (ISP): m/e=507,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is performed using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then subjected to interaction with 3-triterpenoids on stage (In).

Example 147

(+/-)-3-Methoxy-N-(3-methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=499,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using a 3-methoxyaniline, and receive (+/-)-(3-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then n the stage (C) is subjected to interaction with 3-methoxybenzylamine.

Example 148

(+/-)-4-Fluoro-N-(3-methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl] benzamide

Specified in the title compound, mass spectrum (ISP): m/e=487,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using a 3-methoxyaniline, and receive (+/-)- (3-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 4-tormentilla

Example 149

(+/-)-N-(3-Methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-3-cryptomelane

Specified in the title compound, mass spectrum (ISP): m/e=537,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using a 3-methoxyaniline, and receive (+/-)-(3-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 3-triterpenoids.

Example 150

(+/-)-3,4-Dichloro-N-(3-methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=537,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using a 3-methoxyaniline, and receive (+/-)-(3-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 3,4-dichlorobenzophenone the M.

Example 151

(+/-)-N-(4-Forfinal)-3-methoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl] benzamide

Specified in the title compound, mass spectrum (ISP): m/e=487,5 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-ftoranila, and receive (+/-)-(4-forfinal)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 3-methoxybenzylamine.

Example 152

(+/-)-4-Fluoro-N-(4-forfinal)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=475,3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-ftoranila, and receive (+/-)-(4-forfinal)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 4-tormentilla.

Example 153

(+/-)-N-(4-Forfinal)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-3-cryptomelane

Specified in the title compound, mass spectrum (ISP): m/e=525,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-ftoranila, and receive (+/-)-(4-forfinal)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 3-Cryptor-benzoyl chloride.

Example 154

(+/-)-3,4-Di the ENT-N-(4-forfinal)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=525,3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-ftoranila, and receive (+/-)-(4-forfinal)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 3,4-dichlorobenzotrifluoride.

Example 155

(+/-)-4-Fluoro-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-(3-triptoreline)benzamid

Specified in the title compound, mass spectrum (ISP): m/e=525,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using a 3-triptorelin, and receive (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-(3-triptoreline)amine, which is then at the stage (C) is subjected to interaction with 4-tormentilla.

Example 156

(+/-)-N-[CIS-1-(2-Phenylcyclohexyl)piperidine-4-yl]-3-trifluoromethyl-N-(3-triptoreline)benzamid

Specified in the title compound, mass spectrum (ISP): m/e=575,3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using a 3-triptorelin, and receive (+/-)-[CIS - 1-(2-phenylcyclohexyl)piperidine-4-yl]-(3-triptoreline)amine, which is then at the stage (C) is subjected to interaction with 3-triterpenoids.

Example 157

(+/-)-4-Hydroxy-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-albenzaalbenza

A solution of (+/-)-4-methoxy-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide (0,047 g 0,090 mmol) in dichloromethane (2 ml) cooled to -78°C. is Added dropwise at this temperature tribromide boron, 1 M in dichloromethane (of 0.30 ml, 0.30 mmol). The resulting mixture was then warmed up to room temperature and stirred for 5 hours. The reaction is stopped by adding to the reaction mixture of 1 n sodium hydroxide solution, then extracted three times with dichloromethane. The combined organic phases are dried with sodium sulfate and concentrated. The resulting residue is purified by rapid chromatography on silica gel (mixture of dichloromethane/methanol/ammonia in the ratio of 110:10:1), while receiving specified in the header connection (0,029 mg, yield 63%) as not quite white solid, mass spectrum (ISP): m/e=491,3 (M+H+).

Example 158

(+/-)-N-(4-{Phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]sulfamoyl}phenyl)ndimethylacetamide

A solution of (+/-)-4-amino-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl] benzene sulfonamida (0.1 g, 0.2 mmol) in acetic acid (5 ml) is treated using acetic anhydride (1 ml) and then stirred at room temperature for 1 hour. Volatiles evaporated, after which the resulting residue is purified rapid chromatography on silica gel, elwira a mixture of dichloromethane/methanol/ammonia in sootnoshenie is 110:10:1. The resulting product is recrystallized from a mixture of hexane/ether, thus obtaining specified in the title compound (0.06 g, yield 59%) as a white solid, mass spectrum (ISP): m/e=532,5 (M+N+).

Example 159

(+/-)-N-[TRANS-1-(2-Hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic

The connection specified in the header of example, get thus, as shown in figure 5.

To a solution of 4-methoxy-N-phenyl-N-piperidine-4-albenzaalbenza (1.1 g, 3.2 mmol) in ethanol (3.5 ml) is added (+/-)-1-phenyl-7-oxabicyclo[4.1.0]heptane (0,180 g, 1.06 mmol). The reaction mixture is refluxed for 48 hours, then cooled to room temperature and concentrate. The obtained residue chromatographic on silica gel (CH2Cl2/Meon in the ratio 49:1), thus obtaining (+/-)-N-[TRANS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic (65 mg, yield 6%) as a white foam substance, mass spectrum (ISP): m/e=521,4 (M+N+).

Example 160

(+/-)-N-(4-Methoxy)-N-[TRANS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-3-methoxybenzamide

Specified in the title compound, mass spectrum (ISP): m/e=519,3 (M+N+), white foamed substance thus, as described in example 159, using as starting compound N-(4-chlorophenyl)-3-methoxy-N-piperidine-4-even the amide.

Example 161

(+/-)-3-Methoxy-N-(3-methylbutyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=463,5 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using a 3-methylbutylamine, while receiving (+/-)-(3-methylbutyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is then at the stage (C) is subjected to interaction with 3-methoxybenzylamine.

Example 162

(+/-)-4-Methoxy-N-(3-methylbutyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide

Specified in the title compound, mass spectrum (ISP): m/e=499,5 (M+N+receive therefore, as described in example 1, stage (A)-(C). Stage (B) is conducted using a 3-methylbutylamine, while receiving (+/-)-(3-methylbutyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is subjected to stage (C) interaction with 4-methoxybenzenesulfonamide.

Example 163

(+/-)-N-(4-Forfinal)-N-[CIS-1-(4-hydroxy-4-vinyltetrahydrofuran-3-yl)piperidine-4-yl]-4-methoxybenzenesulfonamide

The connection specified in the header of example, get thus, as shown in schemes 2 and 6.

Obtain N-(4-forfinal)-4-methoxy-N-piperidine-4-albenzaalbenza. This connection get that way as in example 98, steps (A)-(C). Stage (B) (acylation) replace the following procedure sulfanilic the cation. To a solution of tert-butyl ester 4-(4-forgenerating)piperidine-1-carboxylic acid (4,00 g of 13.6 mmol) in dichloromethane (60 ml) and pyridine (32 ml) is added 4-methoxybenzenesulfonamide (3,40 g, 16.3 mmol). After stirring for 40 hours at room temperature, the reaction mixture was diluted with ethyl acetate (80 ml), washed with a solution chloroethanol acid (2×50 ml of 0.5 N.) and a saturated solution of sodium bicarbonate (50 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue is transferred into the ether, thus obtaining a residue. After filtration obtain tert-butyl ester 4-[(4-forfinal)-(4-methoxybenzenesulfonyl)amino]piperidine-1-carboxylic acid (4,70 g, yield 74%) as not quite white solid, mass spectrum (ISP): m/e=465,2 (M+N+).

(A and B) Receive (+/-)-N-(4-forfinal)-4-methoxy-N-[1-(4-oxo-tetrahydropyran-3-yl)piperidine-4-yl]benzosulfimide and (+/-)-N-(4-forfinal)-4-methoxy-N-[1-(3-oxitetraciclina-4-yl)piperidine-4-yl]benzosulfimide. To a solution of N-(4-forfinal)-4-methoxy-N-piperidine-4-albenzaalbenza (7,60 g of 20.8 mmol) in ethanol (30 ml) add rat-3,7-dioxabicyclo[4.1.0]heptane (2.50 g, 25,0 mmol). The reaction mixture was refluxed overnight, concentrated in vacuo and dissolved in dichloromethane (60 ml), dimethyl sulfoxide (30 ml) and triethylamine (4,93 ml). Satelections the mixture is cooled to 0° C and added dropwise the solution of a complex of a sulfur trioxide-pyridine (7.47 g, 21.1 mmol) in dimethyl sulfoxide (30 ml). After stirring for 2.5 hours at room temperature the reaction mixture was poured into water and dichloromethane. The aqueous phase is extracted with dichloromethane, the combined organic layers dried over sodium sulfate, filtered and concentrated in vacuo. The obtained residue chromatographic on silica gel (heptane-ethyl acetate in the ratio 1:1), obtaining (N-(4-forfinal)-4-methoxy-N-[1-(4-oxitetraciclina-3-yl)piperidine-4-yl]benzosulfimide (1.45 g, yield 15%, the first erwerbende connection) as a yellow oily substance, mass spectrum (ISP): m/e=463,2 (M+N+) and N-(4-forfinal)-4-methoxy-N-[1-(3-oxitetraciclina-4-yl)piperidine-4-yl]benzosulfimide (0,120 g, yield of 1.2%, the second erwerbende connection) as a yellow oily substance, mass spectrum (ISP): m/e=463,2 (M+N+).

(E) Receive (+/-)-N-(4-forfinal)-N-[CIS-1-(4-hydroxy-4-vinyltetrahydrofuran-3-yl)piperidine-4-yl]-4-methoxybenzenesulfonamide. To a cooled to -78°With a solution of (+/-)-N-(4-forfinal)-4-methoxy-N-[1-(4-oxitetraciclina-3-yl)piperidine-4-yl]benzosulfimide (0,30 g of 0.65 mmol) in tetrahydrofuran (5 ml) is added finality (1.7 M solution in a mixture of cyclohexane/ether, from 0.84 ml, 1.4 mmol). After stirring for 90 min at -78°reaction stopping the pad from sliding is more of adding to the reaction mixture saturated solution of ammonium chloride (5 ml), then the aqueous phase is extracted with ethyl acetate. The combined organic layers dried over sodium sulfate, filtered and concentrated in vacuo. The obtained residue chromatographic on silica gel (mixture of heptane/ethyl acetate in the ratio 7:3)to give (+/-)-N-(4-forfinal)-N-[CIS-1-(4-hydroxy-4-vinyltetrahydrofuran-3-yl)piperidine-4-yl]-4-methoxybenzenesulfonamide (0,040 g, yield 12%) as a pale yellow solid, mass spectrum (ISP): m/e=to 541.3 (M+N+).

Example 164

(+/-)-N-(4-Forfinal)-N-[CIS-1-(3-hydroxy-3-vinyltetrahydrofuran-4-yl)piperidine-4-yl]-4-methoxybenzenesulfonamide

The connection specified in the header of the example, the mass spectrum (ISP): m/e=to 541.3 (M+N+), yellow solid substance thus, as described in example 163, step (B), using as starting compound N-(4-forfinal)-4-methoxy-N-[1-(3-oxitetraciclina-4-yl)piperidine-4-yl]benzosulfimide.

Example 165

(+/-)-N-(4-Forfinal)-N-[CIS-1-(4-hydroxy-4-vinyltetrahydrofuran-3-yl)piperidine-4-yl]-3-methoxybenzamide

The connection specified in the header of the example, the mass spectrum (ISP): m/e=505,3 (M+N+), white foamed substance in such a way as described in example 163, steps (A)-(E). N-(4-Forfinal)-3-methoxy-N-piperidine-4-ylbenzene used in stage (A): oxidation allows to obtain (+/-)-N-(4-forfinal)-3-methoxy-N-[1-(4-oxitetraciclina the-3-yl)piperidine-4-yl]benzamide, which is subjected to interaction with phenyllithium on stage (E).

Example 166

(+/-)-N-Phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]nicotinamide

Specified in the title compound, mass spectrum (ISP): m/e=440,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is performed using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is subjected to interaction with nicotinanilide on stage (In).

Example 167

Phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amide (+/-)-furan-2-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=429,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is performed using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is subjected to stage (C) interaction with furan-2-carbonylchloride.

Example 168

Phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amide (+/-)-thiophene-2-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=445,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is performed using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with thiophene-2-carbonylchloride.

Example 169

Phenyl-CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amide (+/-)-thiophene-3-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=445,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is performed using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with thiophene-3-carbonylchloride.

Example 170

Phenyl-[CIS-1 -(2-phenylcyclohexyl)piperidine-4-yl]amide (+/-)-isoxazol-5-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=430,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is performed using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with the isoxazol-5-carbonylchloride.

Example 171

Phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amide (+/-)-5-methylisoxazol-3-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=444,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is performed using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 5-methylisoxazol-3-carbonylchloride.

Example 172

Phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amide (+/-)-2,5-dimethyl-2H-pyrazole-3-carboxylic acid

Specified in the header is VCE connection, mass spectrum (ISP): m/e=rate of 457.5 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is performed using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 2,5-dimethyl-2H-pyrazole-3-carbonylchloride.

Example 173

Phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amide (+/-)-pyrazin-2-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=441,7 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is performed using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with pyrazin-2-carbonylchloride.

Example 174

(+/-)-2-Methyl-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=453,8 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is performed using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 2-methylbenzothiazol.

Example 175

Phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amide (+/-)-benzo[1,3]dioxol-5-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=483,8 (M+N+), get methods is e, described in example 2, steps (A)-(C). Stage (B) is performed using aniline, and receive (+/-)-phenyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with benzo[1,3]dioxol-5-carbonylchloride.

Example 176

(+/-)-N-(3, 5dimethylphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=467,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 3,5-dimethylaniline, and receive (+/-)-(3, 5dimethylphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with benzoyl chloride.

Example 177

(+/-)-4-Dimethylamino-N-(3, 5dimethylphenyl)]-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl] benzamide

Specified in the title compound, mass spectrum (ISP): m/e=510,3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 3,5-dimethylaniline, and receive (+/-)-(3, 5dimethylphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 4-dimethylaminobenzaldehyde.

Example 178

(+/-)-3-Methoxy-N-phenethyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=497.4 m (M+N+receive according to the method described in example 2, stage A)-(C). Stage (B) is conducted using phenethylamine, while receiving (+/-)-phenethyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 3-methoxybenzylamine.

Example 179

(+/-)-3,4-Dimethoxy-N-phenethyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=527,3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using phenethylamine, while receiving (+/-)-phenethyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 3,4-dimethoxybenzaldehyde.

Example 180

(+/-)-N-Benzyl-4-dimethylamino-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=496,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using benzylamine, while receiving (+/-)-benzyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 4-dimethylaminobenzaldehyde.

Example 181

(+/-)-N-Benzyl-3,4-dimethoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=was 513.3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using benzylamine, while receiving (+/)-benzyl-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which stage (B) is subjected to interaction with 3,4-dimethoxybenzaldehyde.

Example 182

(+/-)-N-(3,5-Differenl)-2,5-debtor-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=511,2 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 3.5-diptiranjan, and receive (+/-)-(3,5-differenl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 2.5-differentiaion.

Example 183

N-(3,5-Differenl)-2-methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=489,3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 3.5-diptiranjan, and receive (+/-)-(3,5-differenl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 2-methylbenzothiazol.

Example 184

(+/-)-2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid (3,5-differenl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amide

Specified in the title compound, mass spectrum (ISP): m/e=507,2 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 3.5-diptiranjan, and receive (+/-)-(3,5-differenl)-[CIS-1-(2-phenylcyclohexyl)piperidin the-4-yl]amine, which stage (B) is subjected to interaction with 2-ethyl-5-methyl-2H-pyrazole-3-carbonylchloride.

Example 185

(4-Chlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amide (+/-)-benzo[1,3]dioxol-5-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=from 517.2 (M+H+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-Chloroaniline, and receive (+/-)-(4-chlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with benzo[1.3]dioxol-5-carbonylchloride.

Example 186

[CIS-1-(2-Phenylcyclohexyl)piperidine-4-yl]-n-toolame (+/-)-benzo[1,3]dioxol-5-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=497,3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using n-tolylamino, while receiving (+/-)-{CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-n-tolylamino that at the stage (C) is subjected to interaction with benzo[1.3]dioxol-5-carbonylchloride.

Example 187

(+/-)-4-Cyano-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-n-toolbarname

Specified in the title compound, mass spectrum (ISP): m/e=478,4 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using n-tolylamino, while receiving (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-n, whether the amine, which stage (B) is subjected to interaction with 4-cyanobenzaldehyde.

Example 188

[CIS-1-(2-Phenylcyclohexyl)piperidine-4-yl]-n-toolame (+/-)-benzo[b]thiophene-3-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=509,3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using n-tolylamino, while receiving (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-n-tolylamino that at the stage (C) is subjected to interaction with benzo[b]thiophene-3-carbonylchloride.

Example 189

(+/-)-N-[CIS-1-(2-Phenylcyclohexyl)piperidine-4-yl]-N-n-tolylenediamine

Specified in the title compound, mass spectrum (ISP): m/e=454,2 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using n-tolylamino, while receiving (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-n-tolylamino that at the stage (C) is subjected to interaction with isonicotinohydrazide.

Example 190

(+/-)-4-Cyano-N-(3-methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=494,3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using a 3-methoxyaniline, and receive (+/-)-(3-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected collaboration is July 4-cyanobenzylidene.

Example 191

(+/-)-N-(3-Methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-4-pyrazole-1-ylbenzene

Specified in the title compound, mass spectrum (ISP): m/e=535,3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using a 3-methoxyaniline, and receive (+/-)-(3-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 4-pyrazole-1-eventorganizer.

Example 192

(3-Methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amide (+/-)-1-methyl-1H-benzotriazol-5-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=524,3 (M+N), get the procedure described in example 2, steps (A)-(C). Stage (B) is conducted using a 3-methoxyaniline, and receive (+/-)-(3-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 1-methyl-1H-benzotriazol-5-carbonylchloride.

Example 193

(3-Methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amide (+/-)-5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=507,3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using a 3-methoxyaniline, and receive (+/-)-(3-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage B) is subjected to interaction with 5-chloro-1-methyl-1H-pyrazole-4-carbonylchloride.

Example 194

(+/-)-3,4-Dimethoxy-N-(3-methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=529,3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using a 3-methoxyaniline, and receive (+/-)-(3-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 3,4-dimethoxybenzaldehyde.

Example 195

(3-Methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amide (+/-)-2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=501,3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using a 3-methoxyaniline, and receive (+/-)-(3-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 2-ethyl-5-methyl-2H-pyrazole-3-carbonylchloride.

Example 196

(+/-)-2-Methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-(4-trifloromethyl)benzamid

Specified in the title compound, mass spectrum (ISP): m/e=537,3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-cryptomaterial, and receive (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-(4-trifloromethyl)amine, which is at the stage B) is subjected to interaction with 2-methylbenzothiazol.

Example 197

(+/-)-N-[CIS-1-(2-Phenylcyclohexyl)piperidine-4-yl]-N-(4-trifloromethyl)nicotinamide

Specified in the title compound, mass spectrum (ISP): m/e=524,2 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-cryptomaterial, and receive (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-(4-trifloromethyl)amine, which is at the stage (C) is subjected to interaction with nicotinevalium.

Example 198

[CIS-1-(2-Phenylcyclohexyl)piperidine-4-yl]-(4-trifloromethyl)amide (+/-)-2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=555,3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-cryptomaterial, and receive (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-(4-trifloromethyl)amine, which is at the stage (C) is subjected to interaction with 2-ethyl-5-methyl-2H-pyrazole-3-carbonylchloride.

Example 199

(2-Chlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amide (+/-)-naphthalene-2-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=523,3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 2-Chloroaniline, and receive (+/-)-(2-chlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with naphthalene-2-carbonylchloride.

Example 200

(+/-)-N-(2-Chlorophenyl)-2-methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=487,3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 2-Chloroaniline, and receive (+/-)-(2-chlorophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 2-methylbenzothiazol.

Example 201

(3-Dimethylaminophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amide (+/-)-benzo[1,3]dioxol-5-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=526,3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using a 3-dimethylaminophenyl, and receive (+/-)-(3-dimethylaminophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with benzo[1.3]dioxol-5-carbonylchloride.

Example 202

(+/-)-N-(3-Dimethylaminophenyl)-3,4-dimethoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=USD 542.3 (M+H+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using a 3-dimethylaminophenyl, and receive (+/-)-(3-dimethylaminophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to mutual the action with 3,4-dimethoxybenzaldehyde.

Example 203

(+/-)-5-Chloro-N-(3-dimethylaminophenyl)-2-fluoro-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide

Specified in the title compound, mass spectrum (ISP): m/e=534,7 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using a 3-dimethylaminophenyl, and receive (+/-)-(3-dimethylaminophenyl)-[CIS-[1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 5-chloro-2-tormentilla.

Example 204

(3-Dimethylaminophenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amide (+/-)-5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=520,3 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using a 3-dimethylaminophenyl, and receive (+/-)-(3-dimethylaminophenyl)-[CIS - (1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with 5-chloro-1-methyl-1H-pyrazole-4-carbonylchloride.

Example 205

(+/-)-N-(3-Acetamidophenyl)-2-methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-3-cryptomelane

Specified in the title compound, mass spectrum (ISP): m/e=578,9 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using a 3-acetylaminophenol, and receive (+/-)-N-{3-[CIS-1-(2-phenylcyclohexyl)piperidine-4-ylamine is]phenyl}acetamide", she which stage (B) is subjected to interaction with 2-methyl-3-triftoratsetilatsetonom.

Example 206

(4-Methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amide (+/-)-pyrazin-2-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=and 471.8 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 4-methoxyaniline, and receive (+/-)-(4-methoxyphenyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which is at the stage (C) is subjected to interaction with pyrazin-2-carbonylchloride.

Example 207

(2-Acetylaminophenol)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amide (+/-)-naphthalene-2-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=546,8 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 2-acetylaminophenol, and receive (+/-)-N-{2-[CIS-1-(2-phenylcyclohexyl)piperidine-4-ylamino]phenyl}ndimethylacetamide, which at the stage (C) is subjected to interaction with naphthalene-2-carbonylchloride.

Example 208

(2-Fluoro-4-triptoreline)-[1-((1S,2S)-2-phenylcyclohexyl)piperidine-4-yl]amide (+/-)-isoxazol-5-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=516,1 (M+N+receive according to the method described in example 2, steps (A)-(C). Stage (B) is conducted using 2-fluoro-4-triptorelin, and which are square (+/-)-(2-fluoro-4-tryptophanyl)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine, which stage (B) is subjected to interaction with the isoxazol-5-carbonylchloride.

Example 209

(+/-)-N-[CIS-1-(2-Phenylcyclohexyl)piperidine-4-yl]-N-pyridin-2-ylbenzene

(A) Reductive amination with obtaining (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine. A solution of (+/-)-CIS-1-(2-phenylcyclohexyl)piperidine-4-it (4,67 g, 18,14 mmol) and ammonium formate (or 10.60 g, 168,1 mmol) in technical methanol (48 ml) and water (5.1 ml) is treated using Pd/C (10%, 2,11 g). The resulting suspension is stirred in an argon atmosphere for 18 hours. The catalyst is filtered off, washing with methanol, and the obtained filtrate is evaporated, thus obtaining the crude (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine (4,07 g, yield 87%) as a colourless liquid, mass spectrum (ISP): m/e=259,3 (M+N+).

(B) Condensation (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine with 2-bromopyridine obtaining at the same time (+/-)-[CIS-1 -(2-phenylcyclohexyl)piperidine-4-yl]pyridine-2-ylamine. A suspension of (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine (1,00 g, a 3.83 mmol) in toluene (30 ml) Tegaserod, flowing argon for 10 minutes. Add in an argon atmosphere, the palladium (II) acetate (27.0 mg, 0.12 mmol), RAC-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP, 71,6 mg, 0.11 mmol), tert - piperonyl sodium (0.45 g, the 4.65 mmol) and 2-bromopyridine (0,49 g of 3.13 mmol). The flask is sealed and heated to 70°C for 3 cha is impressive. The resulting mixture was diluted with ethyl acetate (30 ml) and diethyl ether (30 ml) and then washed three times with a saturated solution of sodium chloride. The organic phase is dried with sodium sulfate and evaporated, thus obtaining an orange oily substance. Cleaning is performed rapid chromatography (mixture of dichloromethane/methanol/25% NH3in the ratio 90:10:1). Specified in the title amine (0,326 g, yield 25%) was obtained as a yellow oily substance, mass spectrum (ISP): m/e=336,3 (M+N+).

(B) Acylation with getting at the same time (+/-)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-pyridin-2-ilasamaja. To the aliquot associated with polystyrene 2-tert-Butylimino-2-diethylamino-1,3-dimethylpyridine-1,3,2-diazaphospholidine (PS-BEMP, 2,2 MSL/g, 0,120 g, 0,264 mmol) is added a solution of (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]pyridine-2-ylamine in THF (0.15 M, 0.6 ml, 0,088 mmol) and a solution of benzoyl chloride in THF (1,17 M, 0.3 ml, 0.35 mmol). The resulting mixture was shaken at room temperature for 18 hours, then filtered and washed using THF. The obtained filtrate is injected into the preparative column for GHUR (column: "YMC Combiprep C18", CCASS05-052OWT, 50×20 mm I.D., S-5 μm, 120; flow rate 30 ml/min; program: 0-0,5' 20% acetonitrile in water + 0.05% of HCO2N; 95% @ 2,5'; 95% @ 4,75'; 20% @ 4,80'; end program @ 5 min). Specified in the title compound, mass-Spa is Tr (ISP): m/e=440,4 (M+N +receive in the form of a white solid (5.8 mg, yield 15%).

Example 210

[CIS-1-(2-Phenylcyclohexyl)piperidine-4-yl]pyridine-2-alamid (+/-)-5-methylisoxazol-3-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=445,4 (M+N+)get the procedure described in example 209, stage (A)-(C). Stage (B) is conducted using 2-bromopyridin and receiving at the same time (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]pyridine-2-ylamine, which at the stage (C) is subjected to interaction with 5-methylisoxazol-3-carbonylchloride.

Example 211

(+/-)-N-[CIS-1-(2-Phenylcyclohexyl)piperidine-4-yl]-N-pyridin-3-ylbenzene

Specified in the title compound, mass spectrum (ISP): m/e=440,4 (M+N+)get the procedure described in example 209, stage (A)-(C). Stage (B) is conducted as follows, using 3-bromopyridin: a suspension of (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine (1,00 g, 3.88 mmol) in toluene (30 ml) Tegaserod, flowing argon for 10 minutes. In an argon atmosphere add complex Tris(dibenzylideneacetone)-dipalladium - chloroform (124 mg, 0.12 mmol), RAC-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP, 76,0 mg, 0.12 mmol), tert-piperonyl sodium (0,470 g, 4,89 mmol) and 3-bromopyridin (0,483 g, a 3.06 mmol). The flask is sealed and heated to 70°C for 3 hours. The resulting mixture was diluted with ethyl acetate (30 ml) and diethyl ether (30 ml) and washed with the three times with a saturated solution of sodium chloride. The organic phase is dried with sodium sulfate and evaporated, thus obtaining a red oily substance. Cleaning is performed rapid-chromatography (dichloromethane/methanol/ 25% NH3in the ratio 90:10:1). (+/-)-[CIS-1-(2-Phenylcyclohexyl)piperidine-4-yl]pyridine-3-ylamine (is 0.260 g, yield 20%) was obtained as an orange foam substance, mass spectrum (ISP): m/e=336,3 (M+N+). Then the connection at the stage (C) is subjected to interaction with benzoyl chloride.

Example 212

[CIS-1-(2-Phenylcyclohexyl)piperidine-4-yl]pyridine-3-alamid (+/-)-5-methylisoxazol-3-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=445,4 (M+N+)get the procedure described in example 209, stage (A)-(C). Stage (B) is conducted using a 3-bromopyridin and receiving at the same time (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]pyridine-3-ylamine, which at the stage (C) is subjected to interaction with 5-methylisoxazol-3-carbonylchloride.

Example 213

(+/-)-N-[CIS-1-(2-Phenylcyclohexyl)piperidine-4-yl]-N-pyridin-4-ylbenzene

Specified in the title compound, mass spectrum (ISP): m/e=440,4 (M+N+)get the procedure described in example 209, stage (A)-(C). Stage (B) is conducted as follows, using 4-bromopyridin: a suspension of (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine (0,303 g at 1.17 mmol) in toluene (10 ml) Tegaserod, flowing argon for 10 minutes. In the atmosphere of argon is added palladium (II) acetate (8.0 mg, being 0.036 mmol), RAC-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP, 23,0 mg, 0,037 mmol), tert-piperonyl sodium (0,280 g, only 2.91 mmol) and 4-bromopyridine hydrochloride (0,194 g, 1.00 mmol). The flask is sealed and heated to 70°C for 3 hours. The resulting mixture was diluted with ethyl acetate (10 ml) and diethyl ether (10 ml) and washed three times with a saturated solution of sodium chloride. The organic phase is dried with sodium sulfate and evaporated, thus obtaining an orange oily substance. Cleaning is performed rapid-chromatography (dichloromethane/methanol/25% NH3in the ratio 65:10:1). (+/-)-[CIS-1-(2-Phenylcyclohexyl)piperidine-4-yl]pyridine-4-ylamine (0.187 g, yield 47%) was obtained as light yellow foam substance, mass spectrum (ISP): m/e=336,3 (M+N+). Then the connection at the stage (C) is subjected to interaction with benzoyl chloride.

Example 214

[CIS-1-(2-Phenylcyclohexyl)piperidine-4-yl]pyrimidine-5-alamid (+/-)-5-methylisoxazol-3-carboxylic acid

Specified in the title compound, mass spectrum (ISP): m/e=KZT 446.4 (M+N+)get the procedure described in example 209, stage (A)-(C). Stage (B) is conducted as follows, using a 5-bromopyrimidine. A suspension of (+/-)-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]amine (1,46 g, the 5.65 mmol) in toluene (35 ml) Tegaserod, flowing argon for 10 minutes. In an argon atmosphere add complex Tris(dibenzylideneacetone)on the palladium - chloroform (179 mg, 0,17 mmol), RAC-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP, 108,0 mg, 0,17 mmol), tert-piperonyl sodium (0,660 g, 6,87 mmol) and 5-bromopyrimidine (determined as 0.720 g, a 4.53 mmol). The flask is sealed and heated to 70°C for 3 hours. The resulting mixture was diluted with ethyl acetate (30 ml) and diethyl ether (30 ml) and then washed three times with a saturated solution of sodium chloride. The organic phase is dried with sodium sulfate and evaporated, thus obtaining a red oily substance. Cleaning is performed rapid-chromatography (dichloromethane/methanol/25% NH3in the ratio 90:10:1). (+/-)-[CIS-1-(2-Phenylcyclohexyl)piperidine-4-yl]pyrimidine-5-ylamine (0,392 g, the output of 20.6%) are obtained as an orange foam substance, mass spectrum (ISP): m/e=337,3 (M+N+). Then the connection at the stage (C) is subjected to interaction with 5-methylisoxazol-3-carbonylchloride.

1. The compounds of formula

in which R1represents a lower alkyl, -(CH2)naryl, unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen or trifloromethyl, or a pyridine;

R2represents a lower alkyl, -(CH2)naryl, unsubstituted or substituted by one or two substituents, select nimi from the group consisting of lower alkyl, lower alkoxy, halogen, trifloromethyl, nitro, cyano, -NR'r R', hydroxy, or heteroaryl group, which represents a monovalent heterocyclic 5 - or 6-membered aromatic radical containing N atoms, or R2denotes heteroaryl, which represents a monovalent heterocyclic 5 - or 6-membered aromatic radicals, where the heteroatoms are selected from N, O or S, unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl or halogen;

R3represents a pyridine or represents aryl, unsubstituted or substituted with halogen or lower alkyl;

R4represents hydrogen or hydroxy;

And represents-S(O)2- or-C(O)-;

X, Y independently of one another represent-CH2- or-O-, provided that X and Y are not simultaneously represent-O-;

R R" independently of one another represent hydrogen or lower alkyl;

n means 0, 1 or 2;

and their pharmaceutically acceptable additive salts with acids.

2. Compounds according to claim 1 of the formula

where R1represents lower alkyl, benzyl or represents phenyl, unsubstituted or substituted one or the two substituents, selected from the group consisting of lower alkyl, lower alkoxy, halogen or trifloromethyl;

R2represents lower alkyl, benzyl, thiophenyl, or represents phenyl, unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen or trifloromethyl, nitro, amino, hydroxy;

R3represents pyridin-3-yl, pyridine-4-yl, or represents phenyl, unsubstituted or substituted with halogen or lower alkyl;

R4represents hydrogen or hydroxy;

And represents-S(O)2- or-C(O)-;

X, Y independently of one another represent-CH2- or-O-, provided that X and Y are not simultaneously represent-O-;

and their pharmaceutically acceptable additive salts with acids.

3. Compounds according to claim 1 or 2, in which X and Y both represent-CH2-And means-S(O)2-, R3means unsubstituted phenyl, and R4means hydrogen.

4. Compounds according to claim 3, representing the following connections:

(+/-)-3,4-dichloro-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide,

(+/-)-4-methoxy-N-(3-methoxyphenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide,

(+/-)-4-methoxy-N-phenyl-N-[CIS-1-(2-Hairdryer shall cyclohexyl)piperidine-4-yl]benzosulfimide,

(+/-)-N-(4-forfinal)-4-methyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide,

(+/-)-N-(4-forfinal)-4-methoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzosulfimide,

(+/-)-4-methoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-(3-triptoreline)benzosulfimide, or

(+)-4-methoxy-N-phenyl-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl] benzosulfimide.

5. Compounds according to claim 1 or 2, in which X and Y both represent-CH2-And means-C(O)-, R3means unsubstituted phenyl, and R4means hydrogen.

6. Compounds according to claim 5, representing the following connections:

(+/-)-3-methoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-n-toolbarname,

(+/-)-4-fluoro-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-N-n-toolbarname,

(+/-)-N-(4-chlorophenyl)-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]-3-cryptomelane, or

(+/-)-N-(4-chlorophenyl)-3-methoxy-N-[CIS-1-(2-phenylcyclohexyl)piperidine-4-yl]benzamide.

7. Compounds according to claim 1 or 2, in which X and Y both signify-CH2-A means-C(O)-, R3means unsubstituted phenyl, and R4means hydroxy.

8. Compounds according to claim 7, which represent the following connections:

(+/-)-N-(4-forfinal)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-3-methoxybenzamide,

(+/-)-N-(4-chlorophenyl)-N-[CIS-1-(2-what hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-3-methoxybenzamide,

(+/-)-4-fluoro-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-N-n-toolbarname,

(+/-)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-N-(3-methoxyphenyl)benzamide, or

(+/-)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-3-methoxy-N-n-toolbarname.

9. Compounds according to claim 1 or 2, in which X and Y both signify-CH2-And means-S(O)2-, R3means unsubstituted phenyl or phenyl substituted by chlorine, fluorine or stands, and R4means hydroxy.

10. Compounds according to claim 9, which represent the following connections:

(+/-)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic,

(+)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic,

(+/-)-N-(4-chlorophenyl)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxybenzenesulfonamide,

(+/-)-N-{CIS-1-[2-(4-chlorophenyl)-2-hydroxycyclohexyl]piperidine-4-yl}-4-methoxy-N-vinylbenzenesulfonic,

(+/-)-N-{CIS-1-[2-(4-forfinal)-2-hydroxycyclohexyl]piperidine-4-yl}-4-methoxy-N-vinylbenzenesulfonic,

(+/-)-N-[CIS-1-(2-hydroxy-2-o-tollcollect)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic,

(+/-)-N-(4-forfinal)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxybenzenesulfonamide,

(+/-)-N-(4-forfinal)-N-{qi is-1-[2-(4-forfinal)-2-hydroxycyclohexyl]piperidine-4-yl}-4-methoxybenzenesulfonamide,

(+/-)-N-[CIS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxy-N-(3-methoxyphenyl)benzosulfimide,

(+/-)-N-{CIS-1-[2-(4-forfinal)-2-hydroxycyclohexyl]piperidine-4-yl}-4-methoxy-N-(3-methoxyphenyl)benzosulfimide, or

(+/-)-N-[TRANS-1-(2-hydroxy-2-phenylcyclohexyl)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic.

11. Compounds according to claim 1 or 2, in which X and Y both signify-CH2-And means-S(O)2-, R3means pyridin-3-yl or pyridin-4-yl, and R4means hydroxy.

12. Compounds according to claim 11, which represent the following connections:

(+/-)-N-(4-chlorophenyl)-N-[CIS-1-(2-hydroxy-2-pyridine-3-illlogical)piperidine-4-yl]-4-methoxybenzenesulfonamide,

(+/-)-N-[CIS-1-(2-hydroxy-2-pyridine-4-illlogical)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic,

(+/-)-N-[CIS-1-(2-hydroxy-2-pyridine-3-illlogical)piperidine-4-yl]-4-methoxy-N-vinylbenzenesulfonic,

(+/-)-N-(4-forfinal)-N-[CIS-1-(2-hydroxy-2-pyridine-4-illlogical)piperidine-4-yl]-4-methoxybenzenesulfonamide,

(+/-)-N-[CIS-1-(2-hydroxy-2-pyridine-4-illlogical)piperidine-4-yl]-4-methoxy-N-(3-triptoreline)benzosulfimide, or

(+/-)-N-[CIS-1-(2-hydroxy-2-pyridine-3-illlogical)piperidine-4-yl]-4-methoxy-N-(3-triptoreline)benzosulfimide.

13. Compounds according to claim 1 or 2, in which X is-CH -, Y represents-O-, And means-S(O)2-, R3means unsubstituted phenyl, and R4means hydroxy.

14. The connection 13, which is a (+/-)-N-(4-forfinal)-N-[CIS-1 -(4-hydroxy-4-vinyltetrahydrofuran-3-yl)piperidine-4-yl]-4-methoxybenzenesulfonamide.

Any according to claim 1 or 2, in which X is-CH2-, Y represents-O-, a represents-C(O)-, R3means unsubstituted phenyl, and R4means hydroxy.

16. The connection 15, which is a (+/-)-N-(4-forfinal)-N-[CIS-1-(4-hydroxy-4-vinyltetrahydrofuran-3-yl)piperidine-4-yl]-3-methoxybenzamide.

17. Compounds according to claim 1, in which X and Y both represent-CH2-And means-C(O)-, and R3means pyridine, unsubstituted or substituted with halogen or lower alkyl.

18. Compounds according to claim 1, in which X and Y both represent - CH2-And means-C(O)-, R3is heteroaryl, unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl or halogen, and R4means hydrogen.

19. Drug, possess inhibitory activity against absorption of glycine containing one or more compound according to any one of claims 1 to 18 and a pharmaceutically acceptable fillers.

20. Drug in claim 19 for the treatment of diseases associated with Engibarov the receiving absorption of glycine.

21. Drug for p-20, where diseases are mental illness, pain, disorders of memory and learning ability, schizophrenia, dementia (dementia) and other diseases associated with cognitive processes, such as disturbance or disorder associated with attention deficit or Alzheimer's disease.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to the new derivatives of imide indolylmaleic acid with the formula I , where Ra denotes H; C1-4alkyl or C1-4alkyl, with substituted OH, NH2, NH(C1-4 alkyl) or H(C1-4alkyl)2; Rb denotes H or C1-4alkyl; R denotes a radical of the formula (d) or (e) , where each one from R8 and R11 independently denotes OH; heterocyclic residue; NR16R17, where each from R16 and R17 independently denotes H or C1-4alkyl, or R16 and R17 together with a nitrogen atom; to which they are joined, form a heterocyclic residue; or a radical of the formula -X-RC-Y (α) where X denotes a covalent bond, O, S or NR18, where R18 denotes H or C1-4alkyl; Rc denotes C1-4alkylen or C1-4alkylen, in which one CH2 has been changed with the group CRxRy, whereby one of Rx and Ry denotes H, and the other denotes CH3, each of the Rx and Ry denote CH3 or Rx and Ry together form the group -CH2-CH2-, and Y is joined with the terminal carbon atom and is selected from OH, -NR19R20, where each one of R19 and R20 independently denotes C1-4alkyl; each one of R9, R10, R12, R13 independently denotes H, halogen, C1-4alkyl, OH, NH2, C1-4alkoxy, NH(C1-4alkyl) or N(C1-4alkyl)2 or each E denotes -N= and G denotes -CH= or E denotes -CH= and G denotes -N=, and cycle A is unsubstituted, monosubstituted, where the substitute is selected from a group containing halogen, OH, C1-4alkoxy, C1-4alkyl, NO2, NH2, NH(C1-4alkyl) or N(C1-4alkyl)2 or CN; where the heterocyclic residue is 3-8 member saturated, heterocyclic rings, containing 1-2-heteroatoms, of which one is N, and the other N or O, possibly substituted with one or more carbon atoms in the cycle and/or with a nitrogen atom in the cycle, if it is in the ring; where the substitutes of the carbon atom ring, if they exist, are selected from the group which contains C1-4alkyl, C3-C6cycloalkyl, it is optional to further substitute C1-4alkyl; , where p denotes 1, 2 or 3; and where the substitutes on the nitrogen atom ring if they exist, are selected from a group which contains C1-4alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl C1-4alkyl, phenyl, phenylC1-4alkyl, heterocyclic residue and the residue from the formula β: -R21-Y' (β) R21 - denotes C1-C4alkylen, a Y' denotes OH, NH2, NH(C1-4alkyl) or N(C1-4alkyl)2, where the heterocyclic residue is of importance, as stated above, or its pharmaceutically acceptable salts.

EFFECT: bonds possess an action, which has an inhibitory activity on proteinkinase C and can be used in a pharmaceutical composition for treatment or prophylaxis of acute or chronic rejection of allo or xenotransilants of organs or tissues.

10 cl, 7 tbl, 182 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to derivatives of phtalazine with general formula (I) , in which R represents a methyl or difluromethyl group; R1 represents phenyl or oxazolyl or thiophenyl, chemically bonded to a phtalazine ring through a carbon-carbon bond. Both phenyl and the above mentioned heterocycle are substituted with a carboxylic group, and optionally with a second functional group, chosen from methoxy-, nitro-, N-acetylamino-, N-metanesulphonylamino- group. The invention also relates to pharmaceutical salts of such derivatives. The given compounds with general formula (I) are inhibitors of phosphodiesterase.

EFFECT: objective of the invention is also the method of obtaining compounds with general formula (I) and pharmaceutical compositions for treating allergies and antiphlogistic diseases based on the given compounds.

9 cl, 9 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new bonds in the formula (I-0): or its pharmaceutically acceptable salts, where X represents a carbon atom or nitrogen atom; X1, X2, X3 and X4, each independently, represents a carbon atom or a nitrogen atom; ring A of the formula (II): represents tiazolil, imidazolil, izotiazolil, tiadiazolil, triazolil, oxazolil, oxadiazolil, izoxazolil, pirazinil, piridil, piridazinil, pirazolil or pirimidinil; R¹ represents aryl or represents a 4-10- membered monocyclic or bicyclic heteroring, which has in the ring from 1 to 4 heteroatoms, selected from the group, consisting of a nitrogen atom, sulphur atom and an oxygen atom, and R¹ can be independently substituted with 1-3 R4, and, when the specified heteroring is an aliphatic heteroring, then it can have 1 or 2 double bonds; R² independently represents hydroxy, formyl, -CH3-aFa, -OCH3-aFa, amino, CN, halogen, C1-6 alkyl or -(CH2)1-4OH; R3 represents -C1-6 alkyl, -(CH2)1-6-OH, -C(O)-OC1-6 alkyl, -C(O)-OC1-6 alkyl, -(CH2)1-6-NH2, cyano, -C(O)-C1-6 alkyl, halogen, -C2-6 alkenyl, -OC1-6 alkyl, -COOH, -OH or oxo; R4 independently represents -C1-6 alkyl, and the alkyl can be substituted with identical or different 1-3 hydroxyls, halogens, -OC(O)-C1-6 alkyls, and the alkyl can be substituted with 1-3 halogens or -OC1-6 alkyls, -C3-7 cycloalkyl, -C2-6 alkenyl, -C(O)-N(R51)R52, -S(O)2-N(R51)R52,-O-C1-6 alkyl, and C1-6 alkylcan be substituted with a halogen or N(R51)R52, -S(O)0-2-C1-6 alkyl, -C(O)-C1-6 alkyl, and C1-6 alkyl can be substituted with a halogen, amino, CN, hydroxy, -O-C1-6 alkyl, -CH3-aFa, -OC(O)-C1-6 alkyl, -N(C1-6 alkyl)C(O)O-C1-6 alkyl, -NH-C(O)O-C1-6 alkyl, phenyl, -N(R51)R52, -NH-C(O)-C1-6 alkyl, -N(C1-6 alkyl)-C(O)-C1-6 alkyl or -NH-S(O)0-2-C1-6 alkyl, -C(S)-C3-7 cycloalkyl, -C(S)- C1-6 alkyl, -C(O)-O- C1-6 alkyl, -(CH2)0-4-N(R53)-C(O)-R54, -N(R53)-C(O)-O-R54,-C(O)-aryl, it is optional to substitute the halogen, -C(O)-aromatic heteroring, -C(O)-aliphatic heteroring, heteroring, and the heteroring can be substituted with C1-6 alkyl, optionally substituting the halogen or -O-C1-6 alkyl, phenyl, optionally substituting the halogen, -C1-6 alkyl, -O-C1-6 alkyl, halogen, CN, formyl, COOH, amino, oxo, hydroxy, hydroxyamidine or nitro; R51 and R52, each independently, represents a hydrogen atom, C1-6 alkyl or a nitrogen atom, R51 and R52 together form 4-7-member heteroring; R53 represents a hydrogen atom or C1-6 alkyl, R54 represents -C1-6 alkyl or alkyls for R53 and R54 and -N-C(O)- together form 4-7-member hydrogen containing heteroring, or alkyls for R53 and R54 and -N-C(O)-O- together form 4-7-member hydrogen containing aliphatic heteroring and an aliphatic heteroring can be substituted with oxo, or an aliphatic heteroring can have 1 or 2 double bonds in the ring; X5 represents -O-, -S-, -S(O)-, -S(O)2-, a single bond or -O-C1-6 alkyl; a independently denotes a whole number 1, 2 or 3; q denotes a whole number from 0 till 2; m denotes a whole number from 0 till 2, except in the case when one of the X5 represents -O-, -S-, -S(O)- or -S(O)2-, and the other from X5 represents a single bond, and R1 represents aryl, optionally substituted with 1-3 R4, or a hydrogen containing aromatic heteroring, consisting of from 1 to 4 heteroatoms, selected from the group, comprising of a hydrogen atom, sulphur atom and an oxygen atom, in the case, when X5, both represent single bonds or in cases, when R1, both represent aliphatic heteroring. The invention also relates to the bonding in the formula (I-12), and also to the bonding in the formula (I-0), to the pharmaceutical composition, to the glucokinase activator and to the medication.

EFFECT: getting new bioactive compounds which can be used for treatment and/or prophylaxis of diabetes or obesity.

23 cl, 603 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to non-peptide antagonists GnRH, with general formula 1 , where each of A1, A2 and A3 are independently chosen from A5 and A6; and A4 represents either a covalent bond, or A5; under the condition that, if A4 is a covalent bond, then one of A1-A3 represent A6, and the other two represent A5, and that, if A4 represents A5, then all of A1-A3 represent A5; A5 is chosen from C-R13 and N; A6 is chosen from N-R14, S and O; R1 is chosen from H, NHY1 and COY2, and R2 represents H; or and R1, and R2 represents methyl or together represent =O; each of R3, R4 and R5 independently represents H or low alkyl; each of R6, R7, R8, R9, R10, R11 and R12 are independently chosen from H, NH2, F, CI, Br, O-alkyl and CH2NMe2; R13 is chosen from H, F, CI, Br, NO2, NH2, OH, Me, Et, OMe and NMe2; R14 is chosen from H, methyl and ethyl; W is chosen from CH and N; X is chosen from CH2, O and NH; Y1 is chosen from CO-low alkyl, CO(CH2)bY3, CO(CH2)bCOY3 and CO(CH2)bNHCOY3; Y2 is chosen from OR15, NRI6R17 and NH(CH2)cCOY3; Y3 is chosen from alkyl, OR15 and NR16R17; R15 represents H; each of R16 and R17 is independently chosen from H, low alkyl and (CH2)aR18, or together represent -(CH2)2-Z-(CH2)2-; R18 is chosen from OH, pyridyl, pyrizinyl and oxadiazolyl; Z represents NH; a represents 0-4; and b and c represent 1-3. The invention also relates to use of formula 1 a compound as a therapeutic agent and pharmaceutical composition, with antagonistic effect to GnRH receptor. Description is also given of the method of obtaining compounds with the given formula.

EFFECT: obtaining new compounds, with useful biological properties.

27 cl, 70 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of benzimidazol of the general formula I R1 designates phenyl group which unessentially contains up to three substitutors independently chosen of the group including F, Cl, Br, J, R4; R2 designates monocyclic or bicyclic 5-10-terms heteroaryl group which contains 1-2 heteroatoms, chosen of N, S and O; R3 designates H; R4 designatesC1-6alkyl; A designates C2-6 alkylene group; B designates group COOH, CONH2, CONHR5 or CONR5R5, in each case attached to atom of carbon of group A; R5 and R5 ' independently designate the residue chosen from group includingC1-6 alkyl where one C-atom can be replaced by O, and(C0-3 alkandiil-C3-7 cycloalkyl); and to their pharmaceutically acceptable salts, except for following compounds: 6 [[1-phenyl-2 (pyridine-4-il)-1H-benzimidazol-6-il] oxi] hexanic acid and 6 [[1-phenyl-2 (benzothien-2-il)-1H-benzimidazol-6-il] oxi] hexanic acid. The invention relates also to pharmaceuticals and to application of compounds of general formula I.

EFFECT: new biologically active compounds possess inhibiting effect on activation of microglia.

10 cl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 2- pyrrolidine-2-yl-[1, 3, 4]oxadiazole with common formula I where R1 is aryl or heteroaryl, aryl here being phenyl unsubstituted or substituted with F, Cl, O-alkyl or phenyl, whereas heteroaryl is pyridinyl or thyenyl, R2 designates H, SO2R3 or COR4 where R3 and R4 independently designate C1-C10alkyl, C3-C10cycloalkyl, (C1-C6alkyl)-C3-C10cycloalkyl, aryl, (C1- C6alkyl)aryl, heterocyclyl, carboxylate residues with 3-10 C-atoms, dimethylamide or NR5R6, C1-C10alkyl at that being methyl, propyl, butyl, butenyl, isobutyl, amyl, pent-3-yl, hept-3-yl, hept-4-yl, 2,2-dimethylpropyl, CH2OCH3, CH2O(CH2)2OCH3 or CH(benzyl)MSO2C6H4CH3, C3-C10cycloalkyl is cyclopropyl, cyclobutyl, cycloamyl, adamantane-1-yl, 2-phenylcyclopropyl or 4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-on-1-yl, (C1-C6alkyl)-C3-C10cycloalkyl is CH2-cycloamyl, (CH2)2-cycloamyl or 7,7-dimethyl-1-methylbicyclo[2.2.1]heptane-2-on, aryl is phenyl, benzyl or naphthyl unsubstituted, monosubstituted or polysubstituted with identical or different substitutes, namely: phenyl, NO2, C1-C6alkyl, O-alkyl, CO2-alkyl, C(=O)C1-C6alkyl, CH2OC(=O)C6H5, F, Cl, Br, N(CH3)2, OCF3, CF3 or (C=O)CH3, (C1-C6alkyl)aryl is 3,4-dimethoxyphenyl-CH2, 4-chlorophenoxy-CH2, phenyl-CH=CH, benzyl-OCH2, phenyl-(CH2)2, 2-bromphenyl-CH2, 1-phenylpropyl, 2-chlorophenyl-CH=CH, 3-trifluorinemethylhenyl-CH=CH, phenoxy-CH2, phenoxy-(CH2)3 or phenoxy-CH(CH3), heterocyclyl is pyridinyl, isoxazole, thienyl, furanyl, triazole, benzoxadiazole, thiadiazole, pyrazole or isoquinoline unsubstituted, monosubstituted or polysubstituted with identical or different substitutes, namely: Cl, C1-C6alkyl, phenyl, in their turn unsubstituted or mono- or polysubstituted with identical or different substitutes, namely: Cl or C1-C6alkyl, CF3, carboxylate residues with 3-10 C-atoms are CH3OC(=O)CH2, CH3OC(=O)(CH2)3, CH3CH2OC(=O)CH2, CH3CH2OC(=O)(CH2)2, CH3C(=O)OCH2, CH3C(=O)OC(CH3)2 or CH3C(=O)OCH(C6H5), and R5 and R6 independently designate H or aryl, aryl at that being benzyl or phenyl respectively mono- or polysubstituted with identical or different substitutes, namely: F, C1, O-alkyl, CN, CF3. Invention also relates to method of obtaining, to medicament and to use of compounds with common formula I.

EFFECT: obtaining of new biologically active compounds and medicinal agents based on the above formulas.

9 cl, 248 ex, 2 tbl

Indanol derivatives // 2323937

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I): (where R1 and R2 may be identical or different, and each is a 1,3-substituted aryl with substituents from group α; R3 stands for any of the following groups: -CO-R4, -CO-O-R4, -CO-NH-R4, -CO-CH2-N(Ra)Rb, -(CH2)m-CO-R5, -(CH2)m-R5, -CO-NH-CO-N(Ra)Rb, -CO-NH-SO2-N(Ra)Rb, -CO-NH-CO-(CH2)m-N(Ra)Rb, or -CO-NH2; R4 stands for a lower alkyl, cycloalkyl, cycloalkyl substituted with 1-3 substituent from group α, lower alkenyl, lower alkynyl, halogen-substituted lower alkyl, hydroxyl-substituted lower alkyl, lower alkoxyalkyl, lower aliphatic acyloxyalkyl or lower alkoxycarbonylalkyl; R5 stands for hydroxyl, -OR4 or -N(Ra)Rb; Rа and Rb may be identical or different, each of them stands for hydrogen, hydroxyl, lower alkoxy group, hydroxyl-substituted lower alkoxyl, hydroxyl-substituted lower alkoxyalkyl, lower alkoxy lower alkoxyalkyl, cyano lower alkyl, cyano lower alkoxyalkyl, carboxy lower alkyl, carboxy lower alkoxyalkyl, aliphatic lower alkoxycarbonyl lower alkoxyalkyl, carbamoyl lower alkyl group, carbamoyl lower alkoxyalkyl, lower aliphatic acylamino lower alkyl, lower aliphatic acylamino lower alkoxyalkyl, lower alkylsulphonylamino lower alkyl, lower alkylsulphanylamino lower alkoxyalkyl, (N-hydroxy-N-methylcarbamoyl) lower alkyl, (N-hydroxy-N-methylcarbamoyl) lower alkoxyalkyl, (N-lower alkoxy-N-methylcarbamoyl) lower alkyl, (N-lower alkoxy-14-methylcarbamoyl) lower alkoxyalkyl or R4, or both, including associated nitrogen, stand for nitrogen-containing heterocyclic group or nitrogen-containing 1-3 substituted heterocyclic group with substituents from group α; m is an integer from 1 to 6; А stands for carbonyl; В stands for straight bond; D stands for oxygen atom; Е stands for С14 alkylene; n is an integer from 1 to 3; and α group is a group of substituents, which consist of halogen atoms, lower alkyls, hydroxy lower alkyls, halogen lower alkyls, carboxy lower alkyls, lower alkoxyls, hydroxy lower alkoxyls, hydroxy lower alkoxyalkyls, lower alkoxycarbonyls, carboxyls, hydroxyls, lower aliphatic acyls, lower aliphatic acylamines, (N-hydroxy-N-methylcarbamoyl) lower alkyls, (N-lower alkoxy-N-methylcarbamoyl) lower alkyls, hydroxy lower aliphatic acylamines, amines, carbamoyls and cyano groups), or pharmacologically suitable salt thereof. Invention also relates to pharmaceutical composition and method for disease prevention and treatment.

EFFECT: preparation of novel biologically active compounds.

18 cl, 117 ex

FIELD: medicine, pharmacology.

SUBSTANCE: compound formula I is described, including the pharmaceutically acceptable salts, , where: Z presents ; Q is taken from the group that consists of: -W - presents , and the pharmaceutical composition, application of compound formula (I) for preparation of antiviral medicine.

EFFECT: proposed compounds can be helpful in treatment of HIV and AIDS.

70 cl, 2 tbl, 129 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to therapeutic agents showing effectiveness in treatment of pain, cancer, cerebrospinal sclerosis, Parkinson's disease, Huntington's chorea and/or Alzheimer's disease. Invention describes compound of the formula (I): or its pharmaceutically acceptable salts wherein RF1 and RF2 represent independently electron-acceptor groups; Z is chosen from O=; R1 is chosen from (C1-C10)-alkyl, heterocyclyl-(C1-C6)-alkyl, substituted heterocyclyl-(C1-C6)-alkyl; R2 is chosen from (C1-C6)-alkyl; X represents bivalent (C1-C10)-group that separates groups added to it by one or two atoms; Ar represents bivalent (C4-C12)-aromatic group, and Y is chosen from =CH=. Also, invention describes fields wherein compounds of the formula (I) are used, a pharmaceutical composition based on thereof, and methods for their synthesis. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 35 ex

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

SUBSTANCE: invention relates to novel substituted esters of 1H-indol-3-carboxylic acids of the general formula (1): or their racemates, or their optical isomers, or their pharmaceutical acceptable salts and/or hydrates. Compounds can be used in treatment of such diseases as infectious hepatitis, human immunodeficiency, atypical pneumonia and avian influenza. In compound of the general formula (1) R1, R41 and R42 each represents independently of one another a substitute of amino group chosen from hydrogen atom, optionally linear or branched alkyl comprising 3-12 carbon atoms, optionally substituted cycloalkyl comprising 3-10 carbon atoms, optionally substituted aryl or optionally substituted and possibly an annelated heterocyclyl that can be aromatic or nonaromatic and comprising from 3 to 10 carbon atom in ring with one or some heteroatoms chosen from nitrogen oxygen or sulfur atoms; or R41 and R42 in common with nitrogen atom to which they are bound form 5-10-membered azaheterocycle or guanidyl through R41 and R42; R2 represents an alkyl substitute chosen from hydrogen atom, optionally substituted mercapto group, optionally substituted amino group, optionally substituted hydroxyl; R3 represents lower alkyl; R5 represents a substitute of cyclic system chosen from hydrogen atom, halogen atom, cyano group, optionally substituted aryl or optionally substituted and possibly an annelated heterocycle that can be aromatic or nonaromatic and comprising from 3 to 10 atoms in ring with one or some heteroatoms chosen from nitrogen, oxygen or sulfur atoms. Also, invention relates to methods for treatment, drugs and pharmaceutical compositions using compounds of this invention.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

22 cl, 3 tbl, 8 dwg, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the new pyridine and new pyrimidine derivative, their pharmaceutically accepted salt or hydrate of the general formula (I): . The invention also relates to the pharmaceutical composition, which possesses the inhibiting activity with respect to the receptor of the growth factor of hepatocytes; to the inhibitor of the receptor of the growth factor of hepatocytes, the inhibitor of angiogenesis, the antitumor drug, the inhibitor of cancerous metastatic spreading, that contains the pharmacologically effective dose of the said compounds, its pharmaceutically acceptable salt or hydrate.

EFFECT: inhibitory activity.

27 cl, 45 tbl, 540 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the compounds of the formula (I) where: X is O; Y represents a bond, CH2, NR35, CH2NH, CH2NHC(O), CH(OH), CH(NHC(O)R33), CH(NHS(O)2R34), CH2O or CH2S; Z is C(O), or if Y is a bond, then Z can also be S(O)2; R1 could be substituted with phenyl; R4 is hydrogen, C1-6-alkyl (substituted possibly by C3-6-pilkoalkyl) or C3-6-cycloalkyl; R2, R3, R5, R6, R7 and R8 are independently hydrogen, C1-6-alkyl or C3-6-cycloalkyl; type independently indicate 0 or 1; R9 could possibly be substituted with an aryl or heterocycle; R10, R32 and R35 are independently hydrogen, C1-6-alkyl or C3-6-cycloalkyl; R33 and R34 are C1-6-alkyl or C3-6-cycloalkyl; where the aforesaid aryl and heterocyclic groups, when possible, can be substitute with: halogen cyanogens, nitro, hydroxyl, oxo, S(O)Kr12, OC(O)NR13R14, NR15R16, NR17C(O)R18, NR19C(O)NR20R21, S(O)2NR22R23, NR24S(O)2R25, C(O)NR26R27, C(O)R28, CO2R29, NR30CO2R31, by C1-6-alkyl (which itself can be monosubstituted with NHC(O)phenyl), C1-6-halogenalkyl, C1-6-alkoxy(C1-6)alkyl, C1-6-alkoxy, C1-6-halogenaloxy, C1-6-alkoxy(C1-6)-alkoxy, C1-6-alkylthio, C2-6-alkenyl, C2-6-alkinil, C3-10-cycloalkyl, methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(C1-4)alkyl, phenoxy, phenylthio, phenyl(C1-4)alkyl, morpholinyl, heteroaryl, heteroaryl(C1-4)alkyl, heteroarylhydroxy of heteroaryl(C1-4)alkoxy, where any of the said phenyl and heteroaryl groups can be substituted by halogen, hydroxyl, nitro, S(O)r(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-.4-alkyl)2, cyanogens, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), CO2H, CO2(C1-4-alkyl), NHC(O)( C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)( C1-4-alkyl), CF3 or OCF3; k and r independently mean 0, 1 or 2; R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R26, R27, R29 and R30 independently represent hydrogen, C1-6-alkyl (probably replaced by halogen, hydroxyl or C3-10-cycloalkyl), CH2(C2-6-alkenyl), C3-6-cycloalkyl, phenyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), NH(C1-4-alkyl)2, S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2, cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), C(O)N(C1-4-alkyl)2, CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), CF3 or OCF3) or heterocyclyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), N(C1-4-alkyl)2, S(O)2)(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2, cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), C(O)N(C1-4-alkyl)2, CO2H5 CO2(C1-4-alkyl), NHC(O)( C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)( C1-4-alkyl), CF3 or OCF3); alternatively, NR13R14, NR15R16, NR20R21, NR22R23, NR26R27 can independently form 4-7-member heterocyclic ring, selected from the group, which includes: azetidine (which can be substituted by hydroxyl or C1-4-alkyl), pyrrolidine, piperidine, azepine, 1,4-morpholine or 1,4-piperazine, the latter is probably substituted by C1-4-alkyl on the peripheral nitrogen; R12, R25, R28 and R31 are independently C1-6-alkyl (possibly substituted by halogen, hydroxyl or C3-10-cycloalkyl), CH2(C2-6-alkenyl), phenyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4- alkyl), N(C1-4-alkyl)2, (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2 (and these alkyl groups can connec to form a ring as described hereabove for R13 and R14), cyanogen, C1-4- alkyl, C1-4- alkoxy, C(O)NH2, C(O)NH(C1-4- alkyl), C(O)N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), NHC(O)(C1-4-alkyl), CF3 or OCF3) or heterocyclyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), N(C1-4-alkyl)2, (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4- alkyl), C(O)N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), CF3 or OCF3); or its N-oxide; or its pharmaceutically acceptable salt, solvate or solvate of its salt, which are modulators of activity of chemokines (especially CCR3); also described is the pharmaceutical composition on their basis and the method of treating the chemokines mediated painful condition.

EFFECT: obtaining new compounds possessing useful biological properties.

13 cl, 238 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the tetrahydroquinolin derivatives with the common formula (I) or their pharmaceutically acceptable salts, where R1 and R2 are H or Me; R3 is H, hydroxy or (1-4C)alkoxi; R4 is H, OH, (1-4C)alkoxi; R5 is OH, (1-4C)alkoxi or R7; provided the R4 is H, then R5 differs from OH or (1-4C)alkoxi; R6 is (2-5C)heteroaryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, bromine or chlorine; (6C)aryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, (1-4)C-alkoxi, bromine, chlorine, phenyl or (1-4C) (di)alkylamino; (3-8C)cycloalkyl, (2-6C)heterocycloalkyl or (1-6C)-alkyl; R7 is amino, (di)(1-4C)alkylamino, (6C)arylcarbonylamino, (2-5C)heteroarylcarbonylamino, (2-5C)heteroaryl-carbonylokxi, R8-(2-4C)alkoxi, R9-methylamino or R9-methoxi; R8 is amino, (1-4C)alkoxi, (di)(1-4C)-alkylamino, (2-6C)-heterocycloalkyl, (2-6C)heterocycloalkylcarbonylamino or (1-4C)-alkoxicarbonylamino; and R9 is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl, (2-5C)heteroaryl or (6C)aryl. The invention also relates to the pharmaceutical composition which contains the said derivatives, and to the application of the derivatives in fertility modulating.

EFFECT: novel tetrahydroquinolin derivatives with follicle-stimulating hormone receptors modulating activity are obtained.

15 cl, 51 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to the tetrahydroquinolin derivatives with the common formula (I) , or their pharmaceutically acceptable salts, where R1 and R2 are H, Me; R3 is (2-6C)-hetercycloalkyl(1-4C)alkyl, (2-5C)heteroaryl(1-4C)alkyl, (6C)aryl(1-4C)-alkyl, (2-6C)hetercycloalkylcarbonylamino(2-4C)alkyl, R5-(2-4C)alkyl or R5-carbonyl(1-4C)alkyl; R4 is (2-5C)heteroaryl (6C)aryl, not necessarily substituted with one or more substitutes selected from bromine, chlorine, nitro, phenyl, (1-4C)alkyl, trufluoromethyl, (1-4C)alkoxi or (1-4C)alkylamino; or (2-6C)hetercycloalkyl; R5 is (di (1-4C)alkylamino, (1-4C)alkoxi, amio, hydroxy, (6C)arylamino, (di)(3-4C)alkenylamino, (2-5C)heteroaryl(1-4C)alkylamino, (6C)aryl(1-4C)alkylamino, (di)[(1-4C)alkoxi(2-4C)alkyl]amino, (di)[(1-4C)alkylamino2-4C)alkyl]amino, (di)[amino(2-4C)alkyl]amino or (di)[hydroxy(2-4C)alkyl]amino. The invention also relates to the pharmaceutical composition based on the compound with formula (I) and to the application of the compound with the formula (I).

EFFECT: novel tetrahydroquinolin derivatives with follicle-stimulating hormone receptors modulating activity are obtained.

10 cl, 44 ex

FIELD: chemistry; oxa-and thiazole derivatives.

SUBSTANCE: oxa- and thiazole derivatives have general formula . Their stereoisomers and pharmaceutical salts have PPARα and PPARγ activity. The compounds can be used for treating diseases, eg. diabetes and anomaly of lipoproteins through PPARα and PPARγ activity. In the general formula, x has value of 1, 2, 3 or 4; m has value of 1 or 2; n has value of 1 or 2; Q represents C or N; A represents O or S; Z represents O or a bond; R1 represents H or C1-8alkyl; X represents CH; R2 represents H; R2a, R2b and R2c can be the same or different and they are chosen from H, alkoxy, halogen; R3 represents aryloxycarbonyl, alkyloxycarbonyl, alkyl(halogen)aryloxycarbonyl, cycloalkylaryloxycarbonyl, cycloalkyloxyaryloxycarbonyl, arylcarbonylamino, alkylsulphonyl, cycloheteroalkyloxycarbonyl, heteroarylalkenyl, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl, halogenalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl, aryloxyarylalkyloxycarbonyl, arylalkenylsulphonyl, heteroarylsulphonyl, arylsulphonyl, arylalkenylarylalkyl, arylalkoxycarbonyl-heteroarylalkyl, heteroaryloxyarylalkyl, where alkyl is in form of C1-8alkyl; Y represents CO2R4, where R4 represents H or C1-8alkyl; including all their stereoisomers and pharmaceutical salts, under the condition that, if A is O, then R3 is not aryloxycarbonyl or alkoxyaryloxycarbonyl.

EFFECT: the compounds can be used in curing such diseases as diabetes and lipoprotein anomalies.

10 cl, 30 dwg, 12 tbl, 584 ex

FIELD: chemistry.

SUBSTANCE: derivatives of 1-sulphonyl-4-aminoalcoxyindole of formula (I) are described, or pharmaceutically acceptable salts thereof, where n is 2 or 3; each of R1 and R2 independently of each other stands for hydrogen, or lower alkyl, or R1 and R2 together with corresponding nitrogen atom may be a part of heterocyclic group, which is selected from morpholino, pyrrolidinyl; R3 stands for hydrogen, or R3 and R1 together with R3 nitrogen atom may be a part of four- or five-membered ring, where R1 and R3 together form an alkylene group; R4 stands for hydrogen; R5 stands for hydrogen; R6 stands for naphthyl, phenyl, not necessarily substituted with one or two substituents, each of which may be a lower alkyl, haloid, lower alcoxy, cyano group, lower alkylsulphonyl, acyl, trifluoromethyl, acetamide, or quinolinyle, thienyl, not necessarily halogen-substituted. The said compounds are selective 5-НТ6 antagonists.

EFFECT: pharmaceutical composition is a receptor modulator.

17 cl, 1 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes cyclic-substituted diphenylazethidinones of the formula (I): wherein each radical among R1, R2, R3, R4, R5 and R6 means independently of one another (C1-C30)-alkylene-(LAG)n wherein n = 1-2; one or two carbon atoms in alkylene residue are replaced with phenyl or piperazinyl residues or (C3-C10)-cycloalkyl residue; one or some carbon atoms in alkylene residue can be replaced with -S(O)n wherein n = 2; -O-, -(C=O)- or -NH-; hydrogen atom (H), fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J), O-(C1-C6)-alkyl; (LAG)n means mono- or tricyclic trialkyl ammoniumalkyl residue, -(CH2)0-SO3H, -(CH2)0-COOH, -(CH2)0-C(=NH)(NH2), and pharmaceutically acceptable salts also. Proposed compounds decrease the serum cholesterol content. Also, invention describes using these compounds for preparing a medicinal agent used in treatment of lipid metabolism disorders.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

7 cl, 1 tbl, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts and esters. In the general formula (I) X means oxygen (O) or sulfur (S) atom; R means hydrogen atom (H) or (C1-C6)-alkyl; R1 means H, -COOR, (C3-C8)-cycloalkyl or (C1-C6)-alkyl, (C2-C6)-alkenyl or (C1-C6)-alkoxyl and each of them can be unsubstituted or comprises substitutes; values of radicals R2, R3, R4, R5 and R6 are given in the invention claim. Also, invention relates to a pharmaceutical composition based on compounds of the general formula (I) and to intermediate compounds of the general formula (II) and the general formula (III) that are used for synthesis of derivatives of indane acetic acid. Proposed compounds effect on the blood glucose level and serum triglycerides level and can be used in treatment of such diseases as diabetes mellitus, obesity, hyperlipidemia and atherosclerosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 6 tbl, 6 sch, 251 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of azethedine of the formula (I): in free form or as a salt wherein Ar means phenyl optionally substituted with one or some substitutes chosen from halogen atom, (C1-C8)-alkyl, cyano-group; R1 means hydrogen atom (H), (C1-C8)-alkyl optionally substituted with hydroxy-, (C1-C8)-alkoxy-, (C1-C8)-alkylcarbonyloxy-group, halogen atom, carboxy-group, (C1-C8)-alkoxycarbonyl; R2 means H, (C1-C8)-alkyl, (C3-C10)-cycloalkyl; R3 means (C1-C8)-alkyl substituted with phenyl, phenoxy-, (C1-C8)-alkylcarbonyloxy-group, naphthyl; or R2 represents (C3-C10)-cyclalkyl optionally comprising benzo-group, condensed benzo-group, 5-6-membered heterocyclic group comprising 1-3 different heteroatoms chosen from nitrogen (N), oxygen (O) and sulfur (S), or up to 4 N atoms, or it means 5-6-membered heterocyclic group comprising 1 or 2 ring O or N atoms and optionally substituted with substitutes enumerated in the formula; or R3 means phenyl or naphthyl wherein indicated phenyl, phenoxy- or naphthyl group is substituted optionally with one or some substitutes chosen from halogen atom, cyano-, hydroxy-group, (C1-C8)-alkylcarbonyl, -SO2NH2, (C1-C8)-alkyl, optionally substituted (C1-C8)-alkoxy-, (C1-C8)-alkylthio-group, -SO2-(C1-C8)-alkyl, (C1-C8)-alkoxycarbonyl, (C1-C8)-acylamino-group substituted optionally with (C1-C8)-alkyl by nitrogen atom, (C1-C8)-alkylamino-group, aminocarbonyl, (C1-C8)-alkylaminocarbonyl, di-(C1-C8-alkyl)amino-group, di-(C1-C8-alkyl)aminocarbonyl, di-(C1-C8-alkyl)aminocarbonylmethoxy-group; X means -C(=O)-, -O-, -CH2- or -CH(OH); Y means O, S; m means 1, 2, 3 or 4; each n, p and q means 0 or 1, n + p + q = 1, n + q = 1 and p+ q = 1 and when n means 0 then p means 0. Compounds of the formula (I) inhibit binding eotaxine with CCR-3 receptor that allows their using as component of pharmaceutical composition and for preparing a medicinal agent used in inflammatory or allergic state.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 5 tbl, 201 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine of the general formula (I), which possess properties of the inhibitor of CDK-kinase. In the general formula (I) R1 designates hydrogen, halogen, C1-C6alkyl, R2 designates C1-C10alkyl, C1-C10alkenyl, or C3-C10cycloalkyl which can be mono-, bi- or tricyclic or denotes one- or polysubstituted by identical or different substitutes from the number of hydroxy-group, halogen, C1-C6alkoxygroup, C1-C6kalkylthiogroup, -NH-(CH2)n-C3-C10cycloalkyl, C3-C10 cycloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy-C1-C6alkyl, C1-C6alkoxy-C1-C6alkoxy-C1-C6alkyl, -NHC1-C6alkyl, -N(C1-C6alkyl)2, C1-C6alkanoil, -CONR3R4, -COR5, C1-C6alkylOAc, where Ac indicates C1-C4alkylCO-group, carboxygroups, phenyl, 5-6-member heteroaryl, containing 1-2-heteroatom in the ring, selected from nitrogen, -(CH2)n- phenyl, -(CH2)n-5-6-member heteroaryl containing 1-2-heteroatom in a ring, selected from nitrogen, phenyl-(CH2)n-R5, -(CH2)nPO3(R5)2 and -R6 and -NR3R4C1-C10alkyl, or C3-C10cycloalkyl, in this case phenyl, C3-C10 cycloalkyl, heteroaryl, -(CH2)n-phenyl and -(CH2)n heteroaryl can be one or polysubstituted by identical or different substitutes from halogens, hydroxygroup, C1-C6alkyl, C1-C6alkoxygroup, benzoxy-group and -CF3 groups, and ring of C3-C10 cycloalkyl and C1-C10alkyl can be separated by one or several nitrogen atoms, oxygen and/or sulfur and/or the said ring can be interrupted by one or two groups of =C=O or R2 designates the group X designates oxygen or group-NH-, and one of A and B independently indicates hydrogen, and the other indicates hydrogen, hydroxygroup, C1-C3alkyl, C1-C6alkyoxy,group SR7, SO2R7, CO(OH)R7, CR7(OH)R7, C1-C6alkyl-P(O)OR3OR4, COR7 or A and B together form C3-6-cycloalkyl ring which does not necessarily have to be interrupted by 1-3 atoms of nitrogen, oxygen and/or sulfur and/or can be interrupted by =C=O or =SO2 groups, and/or does not necessarily have to contain one or several double bonds, X designates oxygen or group-NH-, either one from A and B independently indicates hydrogen, and the other indicates hydrogen, hydroxygroup, C1-C3alkyl, C1-C6alkyoxy,group SR7, SO2R7, CO(OH)R7, CR7(OH)R7, C1-C6alkyl-P(O)OR3OR4, COR7 or A and B together form C3-6-cycloalkyl ring which does not necessarily have to be interrupted by 1-3 atoms of nitrogen, oxygen and/or sulfur and/or can be interrupted by =C=O or =SO2 groups, and/or does not necessarily have to contain one or several double bonds, values of R3 -R10 are specified in the formula of the invention.

EFFECT: connections can be used for the treatment of cancer, autoimmune diseases caused by chemotherapeutic means of alopecia and inflammations of mucous membrane, cardiovascular diseases, infectious diseases, chronic neurodegenerative and viral infections.

13 cl, 1 tbl, 540 ex

Up!