Aroylamino- and heteroaroylamino-substituted piperidines as glyt-1 inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula I , where R1 is a hydrogen atom, a lower alkyl, CD3, -(CH2)n-CHO, -(CH2)n-O-lower alkyl, -(CH2)n-OH, -(CH2)n-cycloalkyl or is a heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O); R2 is a hydrogen atom, a halogen atom, hydroxy, lower alkyl, di-lower alkyl, -OCH2-O-lower alkyl or lower alkoxy; or the piperidine ring along with R2 forms a spiro-ring selected from 4-aza-spiro[2,5]oct-6-yl; Ar is an aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), optionally having one, two or three substitutes selected from a halogen atom, lower alkyl, lower alkyl having as substitutes, a halogen atom, a lower alkoxy having as substitutes, a halogen atom, cycloalkyl, lower alkoxy, S-lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with N), or optionally having as substitutes, phenyl, optionally having R' as substitutes, and R' is a halogen atom, CF3, lower alkyl, lower alkoxy or a lower alkoxy having as substitutes, a halogen atom, or is a heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N and S); R is a lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O), aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), Where the aryl and heteroaryl optionally have as substitutes, one or two R'; n equals 0, 1, 2 or 3; or to a pharmaceutically acceptable acid addition salt, a racemic mixture or a corresponding enantiomer and/or optical isomer of said compound. The invention also relates to pharmaceutical compositions based on a glycine reuptake inhibitor of a compound of formula I.

EFFECT: obtaining novel compounds and a pharmaceutical composition based thereon, which can be used in medicine to treat neurological and psychoneurological disorders.

22 cl, 1 tbl, 128 ex

 

The present invention relates to a compound of General Formula I

where

R1represents a hydrogen atom, lower alkyl, CD3, -(CH2)n-CHO, -(CH2)n-O-lower alkyl, -(CH2)n-OH, -(CH2)n-cycloalkyl or is heteroseksualci;

R2represents a hydrogen atom, halogen atom, hydroxy, lower alkyl, di-lower alkyl, -co2-O-lower alkyl or lower alkoxy; or piperidine ring together with R2forms a Spiro ring selected from 4-Aza-Spiro[2,5]Oct-6-yl;

Ar represents aryl or heteroaryl, which may have one, two or three substituent selected from a halogen atom, lower alkyl, lower alkyl having as substituents, halogen atom, lower alkoxy having as substituents halogen atom, cycloalkyl, lower alkoxy, S-lower alkyl, heteroaryl, geterotsiklicheskie, or may have as substituents of the phenyl which may have as substituents R', and

R' represents a halogen atom, lower alkyl, lower alkoxy or lower alkoxy having as substituents halogen atom, or represents heteroaryl;

R represents lower alkyl, cycloalkyl, heteroseksualci, aryl or heteroaryl, where aryl and hetero is the Rila, may have as substituents one or two R';

n is 0, 1, 2 or 3;

or pharmaceutically acceptable salt accession acid, racemic mixtures or the corresponding enantiomer and/or optical isomer of this compound.

In addition, the present invention relates to pharmaceutical compositions containing the compounds of Formula I and to their use in the treatment of neurological and neuropsychiatric disorders.

It has been unexpectedly found that compounds of General Formula I are good inhibitors of the glycine vector 1 (GlyT-1) and that they have good selectivity for inhibitors of glycine vector 2 (GlyT-2).

Schizophrenia is a progressive and debilitating neurological disease characterized by episodic positive symptoms such as delusions, hallucinations, thought disorder and psychosis, and persistent negative symptoms such as blunted affect, impaired attention and social withdrawal, and cognitive impairment (Lewis DA and Lieberman JA, Neuron, 2000, 28:325-33). For several decades, research has been focused on the hypothesis that dopaminergic hyperactivity disorder", which led to therapeutic interventions, including the blockade of the dopaminergic system (Vandenberg RJ and Aubrey KR., Exp.Opin. Ther. Targets, 200, 5(4): 507-518; Nakazato A and Okuyama S, et al., 2000, Exp. Opin. Ther. Patents, 10(1): 75-98). This pharmacological approach is ill-suited to the treatment of negative and cognitive symptoms, which are the best indicators of functional outcome (Sharma So, Br.J.Psychiatry, 1999, 174 (suppl. 28): 44-51).

In the mid 1960's was proposed additional model of schizophrenia based on psychotomimetics action caused by blockade of glutamate system compounds such as phencyclidine (PCP) and related agents (ketamine), which are non-competitive antagonists of the NMDA receptor. Interestingly, in healthy volunteers PCP-induced psychotomimetic action includes positive and negative symptoms and cognitive dysfunction and, thus, strongly resembles schizophrenia patients (Javitt DC, et al., 1999, Biol. Psychiatry, 45: 668-679 and references in this description). In addition, transgenic mice expressing reduced levels of NMDAR1 subunit, show anomalies in behavior similar to those observed in pharmacologically induced models of schizophrenia, which confirms the model in which a decrease in the activity of the NMDA receptor leads to schizophrenic behavior (Mohn AR, et al., 1999, Cell 98: 427-236).

Glutamic neurotransmission, in particular the activity of the NMDA receptor plays a key role in synaptic plasticity, learning and memory namely NMDA receptors, apparently, serve as a differential switch for synchronization threshold synaptic plasticity and memory formation (Hebb DO, 1949 The organization of behavior, Wiley, NY, Bliss TV and Collingridge GL, 1993, Nature, 361: 31-39). Transgenic mouse sverkhekspressiya MK2 B-subunit of NMDA receptors, have shown an increased synaptic plasticity, have better learning and better memory (Tang JP, et al., 1999, Nature: 401: 63-69).

Thus, if the pathophysiology of schizophrenia involves a deficiency of glutamate, it can be expected that the increase in glutamate transmission, in particular through activation of the NMDA receptor, will be called as antipsychotic effects, and the effects of increasing cognitive function.

It is known that in the Central nervous system amino acid glycine has at least two important functions. By binding to the strychnine-sensitive glycine receptors, it acts as a brake amino acid, and acting as the main coagonist glutamate function of the receptor N-methyl-D-aspartate (NMDA), this amino acid also affects the excitatory activity. While glutamate released from synaptic endings depending on activity, glycine is present presumably at a more constant level and, apparently, modulating/controlling receptor to its response to glutamate.

One of the most e the effective ways of controlling synaptic concentrations of the neurotransmitter is to affect its reuptake at synapses. By removing neurotransmitters from the extracellular space vectors of neurotransmitters can control their extracellular lifetime and thereby modulate the parameters of synaptic transmission (Gainetdinov RR et al, 2002, Trends in Pharm. Sci., 23(8): 367-373).

Glycine vectors that belong to the sodium and Harizanova the family of vectors neurotransmitters play an important role in the termination of postsynaptic glycinergic impacts and the maintenance of low extracellular concentration of glycine by reuptake of glycine into the presynaptic nerve endings and in the nearby thin glial processes.

From the brain of mammals have been cloned two different gene glycine vectors (GlyT-1 and GlyT-2), which give rise to two vectors with approximately 50% homology of amino acid sequence. GlyT-1 is represented by four isoforms resulting from alternative splicing and alternative use of promoters (1A, 1b, 1c and 1d). Only two of these isoforms were found in the brain of rodents (GlyT-1a, GlyT-1b). GlyT-2 also shows a certain degree of heterogeneity. In the brain of rodents were identified two isoforms GlyT-2 (2A and 2b). It is known that GlyT-1 is localized in the CNS and in peripheral tissues, whereas GlyT-2 I which is specific to .GlyT-1 has a predominantly glial distribution, and it is found not only in the areas corresponding to the strychnine-sensitive glycine receptor, but also outside these areas, where, as expected, he is involved in the modulation of the function of the NMDA receptor (Lopez-Corcuera In et al., 2001, Mol. Mem. Biol., 18: 13-20). Accordingly, one method of increasing the activity of the NMDA receptor consists in increasing the concentration of glycine in the local microenvironment of synaptic NMDA receptors by inhibition of GlyT-1 vector (Bergereon R. et al. 1998, Proc. Natl. Acad. Sci. USA, 95: 15730-15734; Chen L et al., 2003, J. Neurophysiol., 89 (2): 691-703).

Inhibitors of glycine vectors suitable for treatment of neurological and neuropsychiatric disorders. Most related illnesses are psychosis, schizophrenia (Armer RE and Miller DJ, 2001, Exp. Opin. Ther. Patents, 11 (4): 563-572), psychotic mood disorders such as major depressive disorder severe type, mood disorders associated with psychotic disorders such as acute manic syndrome or depression associated with bipolar disorders, and mood disorders associated with schizophrenia (Pralong ET et al., 2002, Prog. Neurobiol., 67: 173-202), autistic disorder (Carlsson ML, 1998, J. Neural Transm. 105: 525-535), cognitive disorders such as dementia, including age-related dementia and the senile dementia-type disorders pam is ti in mammals, including humans, syndromes attention deficit and pain (Armer RE and Miller DJ, 2001, Exp.Opin. Ther. Patents, 11 (4): 563-572).

Accordingly, the increased activation of NMDA receptors via inhibition of GlyT-1 can lead to agents that treat psychosis, schizophrenia, dementia and other diseases in which impaired cognitive processes, such as syndromes attention deficit or Alzheimer's disease.

Objects of the present invention are the compounds of Formula I per se, the use of compounds of the Formula I and their pharmaceutically acceptable salts in the manufacture of medicaments for the treatment of diseases that can be affected by activation of NMDA receptors via inhibition of GlyT-1, obtaining mentioned compounds, medicaments based on a compound according to the invention and their manufacture, as well as the use of compounds of Formula I in the treatment or prevention of diseases such as psychoses, dysfunction in memory and learning, schizophrenia, dementia and other diseases in which impaired cognitive processes, such as syndromes attention deficit or Alzheimer's disease.

Preferred indications for the use of the compounds of the present invention is schizophrenia, a cognitive disorder, and Alzheimer's disease.

In addition, the invention includes all racemic mixtures, all corresponding enantiomers and/or Opticheskie isomers.

In the context of this description, the term "lower alkyl" means a group with a saturated normal or branched chain, containing from 1 to 7 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl and the like. Preferred alkyl groups are groups containing from 1 to 4 carbon atoms.

In the context of this description, the term "lower alkoxy" means a lower alkyl group such as defined above, which is associated with the atom O.

The term "cycloalkyl" means a saturated or partially unsaturated ring containing from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cycloheptenyl. Preferred cycloalkyl rings are cyclopropyl and cyclopentyl.

The term "heteroseksualci" means a saturated or partially unsaturated ring containing from 3 to 6 carbon atoms, where at least one carbon atom is replaced by a heteroatom selected from N, S or O, for example piperazinil, pyrrolidinyl, oxetanyl, morpholinyl, piperidinyl or tetrahydropyranyl.

The term "halogen" means chlorine atom, iodine atom, fluorine atom and bromine atom.

The term "aryl" means a monovalent cyclic aromatic hydrocarbon radical consisting of one ring or not is how many of condensed rings, which at least one ring is aromatic in nature, for example phenyl or naphthyl.

The term "lower alkyl having as substituents halogen atom"means a lower alkyl group such as defined above, where at least one hydrogen atom replaced by a halogen atom, for example the following groups: CF3, CHF2CH2F, CH2CF3CH2CHF2CH2CH2F, CH2CH2CF3CH2CH2CH2CF3CH2CH2Cl, CH2CF2CF3CH2CF2CHF2, CF2CHFCF3, (CH3)2CF3CH(CH3CF3or CH(CH2F)CH2F.

The term "lower alkoxy having as substituents halogen atom"means alkoxy group such as defined above, where at least one hydrogen atom replaced by a halogen atom.

The term "heteroaryl" means a cyclic aromatic hydrocarbon radical consisting of a single ring or multiple condensed rings containing from 5 to 14 ring atoms, preferably containing from 5 to 10 ring atoms in which at least one ring is aromatic in nature and which contains at least one heteroatom selected from N, O or S, such as honokalani, dihydroisoquinoline, pyrazinyl, pyridazinyl, Piras is poured, pyridinyl, pyridyl, pyrimidinyl, oxadiazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, furyl, imidazolyl, benzofuranyl, dihydrobenzofuranyl and benzo[1,3]dioxol. Preferred heteroaryl group represents pyridinyl.

The term "pharmaceutically acceptable salts join acid" includes salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, para-toluensulfonate acid and the like.

Preferred compounds of Formula I are compounds in which R1represents lower alkyl and Ar and R are phenyl.

Especially preferred are compounds in which the phenyl group Ar is as substituents at least two groups of CF3for example the following compounds:

rat-2-fluoro-N-(1-methyl-3-phenyl-piperidine-3-yl)-4,6-bis-trifluoromethyl-benzamide;

rat-2-methoxy-N-(1-methyl-3-phenyl-piperidine-3-yl)-4,6-bis-trifluoromethyl-benzamide;

rat-2-ethyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4,6-bis-trifluoromethyl-benzamide;

rat-N-[3-(4-fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-4,6-bis-trifluoromethyl-benzamide or

2-is ethoxy-N-((R)-1-methyl-3-phenyl-piperidine-3-yl)-4,6-bis-trifluoromethyl-benzamide.

Other preferred compounds are compounds in which the phenyl group Ar is as substituents at least one group of CF3for example the following compounds:

rat-2-ethyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;

rat-2-bromo-6-methoxy-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;

rat-N-(1,2-dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

rat-2-cyclopropyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;

rat-2-methoxy-N-(1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;

rat-N-(1-methyl-3-phenyl-piperidine-3-yl)-2-methylsulfanyl-4-trifluoromethyl-benzamide;

rat-N-[3-(4-fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

rat-N-[3-(4-chloro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

2-methoxy-N-((S)-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;

2-methoxy-N-((R)-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;

rat-2-deformedarse-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;

rat-N-[3-(3-chloro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

rat-2-methoxy-N-[3-(4-methoxy-phenyl)-1-methyl-piperidine-3-yl]-6-methylsulfanyl-4-triform the Teal-benzamide;

rat-N-(5-fluoro-1-methyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

rat-N-(1-isopropyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

2-cyclopropyl-N-((S)-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;

2-cyclopropyl-N-((R)-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;

rat-2-cyclobutyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;

rat-N-[3-(2,4-debtor-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

rat-N-[3-(2-fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

rat-N-[3-(2,5-debtor-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

rat-2-isopropyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;

rat-2-methoxy-6-methylsulfanyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,4']bipyridinyl-3-yl)-4-trifluoromethyl-benzamide;

rat-2-ethyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,4']bipyridinyl-3-yl)-4-trifluoromethyl-benzamide;

rat-2-methoxy-6-methylsulfanyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,3']bipyridinyl-3-yl)-4-trifluoromethyl-benzamide;

rat-2-ethyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,3']bipyridinyl-3-yl)-4-trifluoromethyl-benzamide hydrochloride;

2-methoxy-N-((3RS,5SR)-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;

2-cyclopropyl-N-((3RS,5SR)-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;

2-ethyl-N-((3RS,5SR)-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;

rat-2,6-dimethoxy-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;

2-cyclopropyl-N-((3RS,5SR)-1,5-dimethyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;

rat-2-cyclopropyl-4-trifluoromethyl-N-(1,5,5-trimethyl-3-phenyl-piperidine-3-yl)-benzamide;

rat-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-N-(1,6,6-trimethyl-3-phenyl-piperidine-3-yl)-benzamide;

N-((3RS,5SR)-1,5-dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

2-methoxy-N-((3RS,5SR)-5-methoxyethoxy-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;

rat-N-[3-(3-bromo-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

rat-N-[3-(2-chloro-4-fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

rat-2-methoxy-6-methylsulfanyl-N-[1-methyl-3-(3-trifluoromethyl-phenyl)-piperidine-3-yl]-4-trifluoromethyl-benzamide;

rat-2-methoxy-N-[3-(3-methoxy-phenyl)-1-methyl-piperidine-3-yl]-6-methylsulfanyl-4-trifluoromethyl-benzamide;

rat-N-[3-(3-fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

rat-N-[3-(3-chloro-4-fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

rat-N-[3-(3,4-debtor-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-triptime the l-benzamid;

rat-2-methoxy-6-methylsulfanyl-N-(1-methyl-3-meta-tolyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;

rat-N-[3-(4-fluoro-3-methyl-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

rat-N-[3-(3,5-debtor-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

rat-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-N-(1,5,5-trimethyl-3-phenyl-piperidine-3-yl)-benzamide;

rat-2-ethyl-3-methyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;

rat-N-(1-tert-butyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

rat-2-methoxy-N-(4-methyl-6-phenyl-4-Aza-Spiro[2,5]Oct-6-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;

N-((3R,5S) or (3S,5R)-5-hydroxy-1-methyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

2-methoxy-N-((3R,5S) or (3S,5R)-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;

2-methoxy-N-((3S,5R) or (3R,5S)-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;

N-[(R or S)-3-(2-fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

N-[(R or S)-3-(2,5-debtor-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

2-ethyl-N-((R or S)-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;

2-methoxy-6-methylsulfanyl-4-trifluoromethyl-N-((S and R)-1,5,5-trimethyl-3-phenyl-piperidine-3-yl)-benzamide;

N-((3S,6S) or (3R,6R)-1,6-dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

N-((3R,6R)or (3S,6S)-1,6-dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

N-((3R,6S) or (3S,6R)-1,6-dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

N-((3S,5R) or (3R,5S)-1,5-dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;

N-((3R,5S) or (3S,5R)-1,5-dimethyl-3-phenyl-piperidine-3-yl)-2-ethyl-4-trifluoromethyl-benzamide;

2-ethyl-N-((3R,5S) or (3S,5R)-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;

2-cyclopropyl-N-((3R,5S) or (3S,5R)-5-methoxy-1-methyl-3-phenyl-piperidine-3-

yl)-4-trifluoromethyl-benzamide or

2,6-dimethoxy-N-(R or S)-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide.

Preferred compounds of Formula I are compounds in which R1is cycloalkyl or heteroseksualci and Ar and R are phenyl, for example

rat-N-(1-cyclopentyl-3-phenyl-piperidine-3-yl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide,

rat-N-(1-cyclopropylmethyl-3-phenyl-piperidine-3-yl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide or

rat-2-methoxy-N-[3-phenyl-1-(tetrahydro-Piran-4-yl)-piperidine-3-yl]-4,6-bis-trifluoromethyl-benzamide.

Preferred compounds of Formula I are compounds in which R1is with the battle of lower alkyl, Ar represents phenyl and R represents heteroaryl, for example

rat-N-(5-fluoro-1'-methyl-1',4',5',6'-tetrahydro-2 N-[2,3']bipyridinyl-3'-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide,

rat-2-methoxy-6-methylsulfanyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,4']bipyridinyl-3-yl)-4-trifluoromethyl-benzamide,

rat-2-ethyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,4']bipyridinyl-3-yl)-4-trifluoromethyl-benzamide hydrochloride

rat-2-methoxy-6-methylsulfanyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,3']bipyridinyl-3-yl)-4-trifluoromethyl-benzamide or

rat-2-ethyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,3']bipyridinyl-3-yl)-4-trifluoromethyl-benzamide.

Preferred compounds of Formula I are compounds in which R1represents a hydrogen atom, and Ar and R are phenyl, for example

rat-2-cyclopropyl-N-(3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide.

Preferred compounds of Formula I are compounds in which R2represents hydroxy, for example

rat-N-(5-hydroxy-1-methyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide or

N-((3R,5S) or (3S,5R)-5-hydroxy-1-methyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide.

Preferred compounds of Formula I are compounds in which R2represents a halogen atom, for example

rat-N-(5-fluoro-1-methyl-3-f the Nile-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide.

Preferred compounds of Formula I are compounds in which R1is a CD3for example the following compounds:

[2N-methyl]-2-methoxy-N-(R) or (S)-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide hydrochloride.

Compounds of the present invention of the Formula I and their pharmaceutically acceptable salts may be obtained using methods known in the art, for example using techniques described below, which include a) the interaction of the compounds of Formula

with the compound of the Formula

in the presence of an activating agent such as HATU (ortho-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate) or thionyl chloride, to obtain the compounds of Formula

,

where the substituents are as defined above, or (b) the interaction of the compounds of Formula

,

with the compound of the Formula

R1X

in the presence of a base, such as N-ethyldiethanolamine, obtaining the compounds of Formula

,

where X represents a halogen atom and the other substituents are as defined above, or

(C) the interaction of the compounds of Formula

carbonelli reagent of Formula R 4-C(O)-R5

in the presence of a reducing agent, such as cyanoborohydride sodium, obtaining the compounds of Formula

,

where the substituents are as defined above, R4and R5represent lower alkyl or together with the carbon atom to which they are attached, form cycloalkyl or geterotsyklicescoe group, and if desired, the conversion of the compounds obtained into pharmaceutically acceptable salts accession acids.

The compounds of Formula I can be obtained using one of the methods a), b) or c) in accordance with the following Schemes 1-12. The original substances either are commercially available or can be obtained in accordance with known methods.

Scheme 1

Compounds of General Formula I can be obtained as a result of interaction piperidinovyh derivatives of the Formula II with an acid of Formula III in the presence of an activating agent such as HATU (ortho-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate) or thionyl chloride. Piperidine derivatives of Formula II can be obtained as a result of interaction piperidinol derivative VI with an ORGANOMETALLIC reagent such as a Grignard reagent, followed by treatment of the resulting alcohol VII sodium azide in prisutstvie the acid, such as TFU, and transformations of the obtained azide derivative VIII to the compound II in the presence of a reducing agent, such as alumalite lithium.

Scheme 2

Alternative piperidine derivatives of the Formula II, where R2represents a hydrogen atom, can be obtained from nitro-piperidone derivatives XII in the recovery of the nitro-group regenerating agent such as Raney Nickel in a hydrogen atmosphere or zinc in the presence of acid, such as hydrochloric acid, and subsequent recovery of the obtained amino-piperidino derivatives XIII to compound II, which can be performed in the presence of a reducing agent, such as alumalite lithium. Nitro-piperidone derivative XII can be obtained from the nitro-derivatives of XI using the intramolecular reaction of manniche performed in the presence of an amine R1NH2and aldehyde, such as formaldehyde.

Compound XI can be obtained by attaching nitro-methyl-aryl derivatives IX to methyl acrylate in the presence of a base, such as Amberlyst A21 or Triton, using Michael's reaction or interaction arylalkenes derivatives of X with methyl 4-nitrobacteria in the presence of a palladium catalyst such as Pd2dba3ligand such as 2-(di-tert-butylphosphino)-2'-methylbiphenyl, and base, such as cesium carbonate, in accordance with the methodology described by Buchwald et al. in J. Org. Chem. 2002, 106.

Scheme 3

Alternative piperidine derivatives of the Formula II, where R represents an alkyl group, can be obtained from an acid XVI by using the rearrangement of kurzius in the presence of reagent such as DPPA (diphenylphosphonate), and subsequent hydrolysis of the resulting isocyanate XVII in the presence of a base such as sodium hydroxide, to the protected piperidine XVIII, which is reduced to compound II in the presence of a reducing agent, such as alumalite lithium. Acid XVI can be obtained from the ester XIV as a result of processing base, such as diisopropylamide lithium, and an alkylating agent R-X and the next

saponification of the obtained intermediate compound, ester XV, before joining XVI in the presence of a base such as lithium hydroxide.

Scheme 4

The substituents are as described above, R4and R5represent lower alkyl or together with the carbon atom to which they are attached, form cycloalkyl or geterotsyklicescoe group.

Alternative compounds of General Formula I can be obtained in resultativity piperidino derived IV or with an alkylating agent R 1X in the presence of a base, such as N-ethyldiethanolamine, or with a carbonyl reagent V in the presence of a reducing agent, such as cyanoborohydride sodium. Piperidine derived IV can be obtained in the recovery azide VIII this reagent, such as sodium borohydride, to obtain the amine derivative XIX, which can then be subjected to the interaction with the acid III in the presence of an activating agent such as HATU or thionyl chloride, and the subsequent transformations of the obtained amide derivative of XX in compound IV by removing the N-protective group.

Scheme 5

Alternative piperidine derivatives of the Formula II, where R2represents a fluorine atom, can be obtained from the fluorinated nitro-piperidone XXI by two successive restorations, first with the use of such an agent as Raney Nickel, and then using such an agent, as alumalite lithium. Compound XXI can be obtained by the interaction of the nitro-piperidine XII with a base, such as Diisopropylamine lithium, and subsequent processing of electrophilic fluorinating agent such as N-forbindelseshastighed.

Scheme 6

Alternative piperidine derivatives of the Formula II, where R2is particularly the alkyl, can be derived from alkylated nitro-piperidone XXIII by two successive restorations, first with the use of such an agent as Raney Nickel, and then using such an agent, as alumalite lithium. Compound XXIII can be obtained by the interaction of the nitro-piperidine XII with a base, such as Diisopropylamine lithium, and subsequent processing electrophilic alkylating agent such as R2X, where X represents a halogen atom.

Scheme 7

Alternative piperidine derivatives of the Formula II which contain two genialnyh alkyl group, R2can be obtained from the bis-alkylated nitro-piperidone XXV by two successive restorations, first with the use of such an agent as Raney Nickel, and then using such an agent, as alumalite lithium. Compound XXV can be obtained by the interaction of mono-alkylated nitro-piperidine XXIII with a base, such as Diisopropylamine lithium, in the presence of TMEDA (tetramethylethylenediamine) and subsequent processing electrophilic alkylating agent such as R2X, where X represents a halogen atom.

Scheme 8

Alternative piperidine derivatives of the Formula II, where R2the present is the focus of a hydroxyl (R 6=N) or alkoxy group (R6=Alkyl)can be obtained from hydroxy nitro-piperidone XXVII or alkoxy nitro-piperidone XXVIII by two successive restorations, first with the use of such an agent as Raney Nickel, and then using such an agent, as alumalite lithium. Compound XXVIII can be obtained from compound XXVII as a result of interaction with a base such as sodium hydride, and an electrophilic alkylating agent such as R6X, where X represents a halogen atom. Compound XXVII can be obtained by the interaction of the nitro-piperidine XII with a base, such as Diisopropylamine lithium, and subsequent processing electrophilic gidrauxiliruetsa agent such as (oxodipine(pyridine) (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone)molybdenum(IV)), or bis(trimethylsilyl)peroxide.

Scheme 9

Alternative piperidine derivatives of the Formula II, where R is a heteroaryl group such as pyridine, can be obtained from nitro-piperidinedione XXX by two successive restorations, first with the use of such agents as sodium borohydride and then with the use of such an agent as Raney Nickel. Connection XXX can be obtained from nitro-piperidine XXII as a result of interaction with the reagent is of awesone.

Scheme 10

Alternative piperidine derivatives of the Formula II which contain two genialny methyl group, can be obtained from Boc-protected amino-piperidine XXXII as a result of interaction with bromide Metalmania and chloride of zirconium (IV) and subsequent removal of the Boc group under acidic conditions. Compound XXXII can be obtained by the interaction of amino-piperidone XIII with di-tert-butyl dicarbonate.

Scheme 11

Alternative piperidine derivatives of the Formula II which contain cyclopropyl, can be obtained from Boc-protected amino-piperidine XXXII as a result of interaction with the bromide of ateline and isopropoxide titanium and subsequent removal of the Boc group under acidic conditions.

Scheme 12

Alternative piperidine derivatives of the Formula II, where R2represents an alkyl group, can be obtained from the nitro-derivative XXXIX using the intramolecular reaction of manniche performed in the presence of an aldehyde, such as formaldehyde, and subsequent processing of the received nitro-piperidine XXXX regenerating agent such as Raney Nickel. Connection XXXIX can be obtained by release of the Boc-protected nitro-derived XXXVIII, which signal is to be obtained by the interaction of the nitro-derivative XXXXI with a halogenated compound XXXVII in the presence of a base, such as n-utillity. Compound XXXVII can be obtained by introducing a protective group into amerosport XXXV and subsequent halogenation.

Racemic mixtures of chiral compounds I can be separated using chiral ghvd.

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

Experimental part

Abbreviations

HATU O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate

DMF Dimethylformamide

DMSO dimethyl Sulfoxide

THF Tetrahydrofuran

TMEDA Tetramethylethylenediamine

The intermediate compounds

Example A.1

Getting rat-1-Methyl-3-phenyl-piperidine-3-ylamine

a) stage 1: rat-3-Hydroxy-3-phenyl-piperidine-1-carboxylic acid benzyl ester

To a solution of 9 ml (9 mmol) of bromide vinylmania (1 M solution in THF) in THF (13 ml) was added over 15 min a solution of 1.5 g (6,00 mmol) 3-oxo-piperidine-1-carboxylic acid benzyl ester (commercially available) in THF (5 ml) at room temperature. This mixture was stirred those which begins 30 minutes and then extinguished 20% solution of ammonium chloride (4 ml), using cooling in an ice bath. The organic layer decantation and the residue once were extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The crude oil was purified on silica gel (eluent: heptane/ethyl acetate 0-50%) with the output specified in the title compound (0.55 g, 30%) as a white solid. Mass spectrum (m/z): 312,0 (M+H+).

b) stage 2: rat-3-Azido-3-Phenyl-piperidine-1-carboxylic acid benzyl ester

1.0 g (3,212 mmol) 3-hydroxy-3-phenyl-piperidine-1-carboxylic acid benzyl ester was dissolved in a cold mixture (10°C) triperoxonane acid (12.3 ml) and water (2.0 ml). This solution was cooled to 0°C. was added in portions sodium azide (1,46 g, 22,48 mmol). The temperature rose to 10°C. the Ice bath was removed and the mixture was stirred for 3 h at room temperature. Then the mixture was cooled in an ice bath and was podslushivaet, adding dropwise a 25% ammonium hydroxide solution (13,0 ml), keeping the temperature below 20°C. the Mixture was diluted with water (45 ml) and 3 times was extracted with dichloromethane. The combined extracts once washed with saline, dried over sodium sulfate, filtered and concentrated under vacuum to obtain specified in the title compounds as a light yellow the oil, which was used in the next stage without additional purification.

(C) stage 3: rat-1-Methyl-3-phenyl-piperidine-3-ylamine

To a suspension of 126 mg (3,15 mmol) LiAIH4in THF (2.7 ml) at a temperature below 10°C was added dropwise a solution of 530 mg (1,576 mmol) rat-3-azido-3-phenyl-piperidine-1-carboxylic acid benzyl ester in THF (5.3 ml). The ice bath was removed. The temperature rose to 35°C. Then the mixture was heated for 1 h at 65°C in an oil bath. Then the mixture was cooled to 0°C. was Added dropwise water (125 μl), 5 N. NaOH (125 ml) and again water (0,375 ml), keeping the temperature below 10°C. the Mixture was diluted with ethyl acetate. Was added sodium sulfate. This mixture was filtered and the filtrate concentrated under vacuum. The crude oil was purified on silica gel (eluent:heptane/ethyl acetate 0-100%) with the output specified in the title compound (0.14 g, 47%) as a yellow oil. Mass spectrum (m/z): 191,5 (M+H+).

Example A.2

Getting rat-3-(4-Fluoro-phenyl)-1-methyl-piperidine-3-ylamine

Specified in the title compound was obtained from 3-oxo-piperidine-1-5 carboxylic acid benzyl ester (commercially available) and bromide 4-fluoro-vinylmania using methods analogous to the methods of synthesis described in Example A.1 (stages 1-3). Mass spectrum (m/z): 209,2 (M+N+).

Example A.3

Getting rat-3-(4-Chloro-phenyl)--methyl-piperidine-3-ylamine

Specified in the title compound was obtained from 3-oxo-piperidine-1-carboxylic acid benzyl ester (commercially available) and bromide 4-chloro-vinylmania using methods analogous to the methods of synthesis described in Example A.1 (stages 1-3). Mass spectrum (m/z): 225,3 (M+N+).

Example A.4

Getting rat-1-Methyl-3-para-tolyl-piperidine-3-ylamine

Specified in the title compound was obtained from 3-oxo-piperidine-1-carboxylic acid benzyl ester (commercially available) and bromide 4-methyl-vinylmania using methods analogous to the methods of synthesis described in Example A.1 (stages 1-3). Mass spectrum (m/z): 205,3 (M+H+).

Example A.5

Getting rat-1,2-Dimethyl-3-phenyl-piperidine-3-ylamine

a) stage 1: 3-Hydroxy-2-methyl-piperidine-1-carboxylic acid benzyl ester

To a solution of 1.4 g (9,232 mmol) of 2-methyl-piperidine-3-ol (CAS: 4766-56-7) 9.8 ml of dichloromethane in an argon atmosphere at room temperature was added to 2.57 ml (18,46 mmol) of triethylamine. This mixture was stirred for 15 min and then was cooled to 0°C. was Added dropwise to 1.37 ml (9,232 mmol) of Harborview acid benzyl ester. This reaction mixture was left to warm to room temperature and stirring food is tight during the night. The mixture is then three times were extracted with water and the combined extracts were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column flash chromatography on silica gel (eluent: heptane/ethyl acetate 0-30) with the output specified in the title compound (800 mg, 34,8%) as a colourless oil. Mass spectrum (m/z): 272,4 (M+Na+).

b) stage 2: rat-2-Methyl-3-oxo-piperidine-1-carboxylic acid benzyl ester

To mix the solution 309,5 ál (3,530 mmol) oxalicacid in 3 ml of dichloromethane at a temperature from -50°C to -60°C was added a solution of 873 μl DMSO in 2 ml of dichloromethane. This reaction mixture was stirred for 10 minutes, then for 10 min was added a solution of 800 mg (to 3.209 mmol) 3-hydroxy-2-methyl-piperidine-1-carboxylic acid benzyl ester in 3 ml of dichloromethane. Stirring was continued for additional 30 min and Then to the mixture was added 2,24 ml (of 16.05 mmol) of triethylamine. This reaction mixture was stirred for 15 min, then left to warm to room temperature, suspended in water, the layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers washed twice with water, dried over sodium sulfate, filtered and concentrated under vacuum. The crude product is CT was purified by column flash chromatography on silica gel (eluent: heptane/ethyl acetate 0-40) with the output specified in the title compound (600 mg, 76%) as a pale yellow oil. Mass spectrum (m/z): 270,2 (M+Na+).

(C) stage 3: rat-1,2-Dimethyl-3-phenyl-piperidine-3-ylamine

Specified in the title compound was obtained from rat-2-methyl-3-oxo-piperidine-1-carboxylic acid benzyl ester and bromide vinylmania using methods analogous to the methods of synthesis described in Example A.1 (stages 1-3). Mass spectrum (m/z): 205,2 (M+H+).

Example A6

Getting rat-3-(3-Chloro-phenyl)-1-methyl-piperidine-3-ylamine

a) stage 1: rat-4-(3-Chloro-phenyl)-4-nitro-butyric acid methyl ester

To a solution of 1 g (5,828 mmol) 1-chloro-3-nitro methyl-benzene (CAS: 38362-91-3) at 0°C in 2 ml of dioxane was added 0,512 g (5,828 mmol) of methyl acrylate and then to 3.3 g of Amberlyst A-21. This reaction mixture was stirred over night at room temperature, was filtered and the filtrate was dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column flash chromatography on silica gel (eluent: heptane/ethyl acetate 0-10%) to obtain the specified title compound (980 mg, 65%) as a colourless oil.

b) stage 2: rat-5-(3-Chloro-phenyl)-1-methyl-5-nitro-piperidine-2-he

To stir at room temperature a solution of 164 μl (1,940 mmol) of methylamine (41% solution in water) in 1 m the dioxane was added dropwise 141 μl (1,940 mmol) of formaldehyde (37% solution in water) (exothermic reaction). This mixture was stirred for 5 min and then was added at once a solution of 0.5 g (1,940 mmol) rat-4-(3-chloro-phenyl)-4-nitro-butyric acid methyl ester in 1.5 ml of dioxane. This mixture was stirred for 6 h at 65°C. Then the mixture was cooled to room temperature, was added ethyl acetate and a saturated solution of NaCl. The aqueous phase was extracted 2 times with ethyl acetate. The combined organic phases were washed with saturated NaCl solution, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column flash chromatography on silica gel (eluent: heptane/ethyl acetate 0-100%) with the output specified in the title compound (395 mg, 76%) as a colourless oil. Mass spectrum (m/z): 269,2 (MH+).

(C) stage 3: rat-5-Amino-5-(3-chloro-phenyl)-1-methyl-piperidine-2-he

To a solution of 115 mg (0,428 mmol) 5-(3-chloro-phenyl)-1-methyl-5-nitro-piperidine-2-it in 0.5 ml of dioxane was added 2 ml of 3 N. HCI and 280 mg (4,28 mmol) of zinc dust. This mixture was stirred for 30 min at room temperature. Then the mixture was filtered and the obtained filtrate was podslushivaet 5 N. NaOH solution. Added ethyl acetate. The mixture was filtered through a pillow dicalite. The organic layer was separated and the aqueous layer was twice extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filter is Ali and concentrated under vacuum to obtain specified in the title compound (88 mg, 86%) as a pale yellow oil. Mass spectrum (m/z): 239,0 (MN+).

d) stage 4: rat-3-(3-Chloro-phenyl)-1-methyl-piperidine-3-ylamine

To a suspension of 20 mg (0,494 mmol) LiAIH4in 0.5 ml of THF was added dropwise a solution of 59 mg (0,247 mmol) rat-5-amino-5-(3-chloro-phenyl)-1-methyl-piperidine-2-it in 0.6 ml THF at room temperature. This mixture was subjected to reflux distilled for 30 minutes and Then the mixture was cooled in an ice bath and carefully extinguished by adding 20 μl water, 20 μl of 5 N. NaOH and then 60 μl of water. Added ethyl acetate. The mixture was filtered and the filtrate was concentrated under vacuum to obtain specified in the title compound (48 mg, 86%) as a colourless oil. Mass spectrum (m/z): 225,2 (MH+).

Example A.7

Getting rat-3-(4-Methoxy-phenyl)-1-methyl-piperidine-3-ylamine

a) stage 1: rat-4-(4-Methoxy-phenyl)-4-nitro-butyric acid methyl ester

In accordance with the methodology described by Buchwald et al. (J. Org. Chem. 2002, 106), the reaction flask was added sequentially 187 mg (0,198 mmol) Pd2dba3, 247 mg (0,791 mmol) of 2-(di-tert-butylphosphino)-2'-methylbiphenyl and 1,555 g (4,747 mmol) of cesium carbonate. This mixture was placed in an argon atmosphere was added sequentially 740 mg (3,956 mmol) of 4-bromoanisole, 15 ml of DME (dimethylamine) and then 600 mg (3,956 mmol) of methyl 4-nitrobutane. This mixture intensively eremetical for 1 min at room temperature, then the flask was placed in a pre-heated up to 50°C oil bath and stirred at the same temperature throughout the night. The reaction mixture was cooled to room temperature and was added a saturated solution of NH4Cl and ethyl acetate. The aqueous phase was extracted 3 times with ethyl acetate and the combined organic phases are washed with salt solution and concentrated under vacuum. The crude product was purified by column flash chromatography on silica gel (eluent: heptane/ethyl acetate 0-20%) with the output specified in the connection header (897 mg, 90%) as an orange oil.

b) stage 2: rat-3-(4-Methoxy-phenyl)-1-methyl-piperidine-3-ylamine

Specified in the title compound was obtained from rat-4-(4-methoxy-phenyl)-4-nitro-butyric acid methyl ester using methods analogous to the methods of synthesis described in Example A.6 (stage: 2-4). Mass spectrum (m/z): 221,2 (MN+).

Example A.8

Getting rat-5-fluoro-1'-methyl-1',4',5',6'-tetrahydro-2H-[2,3']bipyridinyl-3'-ylamine

Specified in the title compound was obtained from methyl 4-nitrobutane and 2-bromo-5-herperidin using methods analogous to the methods of synthesis described in Example 7 A. (stage: 1-2). Mass spectrum (m/z): 210,2 (MH+).

Example A.9

Getting rat-5-fluoro-1-methyl-3-phenyl-piperidine-3-ylamine

a) stage 1: rat-1-Methyl-5-nitro-5-phenyl-piperidine-2-he

Specified in the title compound was obtained from the nitro methyl-benzene (CAS: 622-42-4) using methods analogous to the methods of synthesis described in Example A.6 (stage 1-2). Mass spectrum (m/z): 235,2 (MH+).

b) stage 2: rat-3-Fluoro-1-methyl-5-nitro-5-phenyl-piperidine-2-he

To a solution 78,4 ál (0,555 mmol) Diisopropylamine in 2 ml of THF was added 347 μl (0,555 mmol) of 1.6 M solution of n-BuLi in hexane at a temperature of -5°C. the solution was stirred for 15 min at 0°C and then cooled to -70°C. was Added dropwise a solution of 100 mg (0,427 mmol) rat-1-methyl-5-nitro-5-phenyl-piperidine-2-it 1 ml of THF. The obtained brown solution was stirred at -70°C for 45 minutes was Added dropwise a solution of 180 mg (0,555 mmol) N-forbindelseshastighed in 1 ml THF. This mixture was stirred for 1.5 h at -70°C, was suppressed by adding 2 ml of 20% solution of NH4Cl and left to warm to room temperature. Added water and ethyl acetate. The aqueous layer was twice extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The crude oil was purified on silica gel (eluent: heptane/ethyl acetate 0-100%) with the output specified in the title compound (58 mg, 54%) as velo-yellow solid. Mass spectrum (m/z): 253,2 (M+H).

(C) stage 3: rat-5-Amino-3-fluoro-1-methyl-5-phenyl-piperidine-2-he

To a solution of 55 mg (0,218 mmol) rat-3-fluoro-1-methyl-5-nitro-5-phenyl-piperidine-2-it in 1.5 ml THF at 0°C was added 100 μl of Raney Nickel (50% in water). This mixture was stirred in an atmosphere of hydrogen for 2 h at 0°C. Then the mixture was filtered and the catalyst washed using THF. The filtrate was concentrated under vacuum to obtain specified in the title compound (48 mg, 99%) as a pale yellow solid. Mass spectrum (m/z): 223,3 (M+H).

d) stage 4: rat-5-fluoro-1-methyl-3-phenyl-piperidine-3-ylamine

Specified in the title compound was obtained from the rat-5-amino-3-fluoro-1-methyl-5-phenyl-piperidine-2-she is using a technique similar to the method of synthesis described in Example A.6 (stage 4). Mass spectrum (m/z): 192,3 (M-NH2).

Example A.10

Getting rat-5-Methoxyethoxy-1-methyl-3-phenyl-piperidine-3-ylamine

a) stage 1: rat-3-Hydroxy-1-methyl-5-nitro-5-Phenyl-piperidine-2-he

To a solution of 118 μl (0,833 mmol) Diisopropylamine in 3 ml of THF was added 520 ál (0,833 mmol) of 1.6 M solution of n-BuLi in hexane at a temperature of -5°C. the solution was stirred for 15 min at 0°C and then cooled to -70°C. was Added dropwise a solution of 150 mg (0,641 mmol) rat-1-methyl-5-nitro-5-Hairdryer is l-piperidine-2-it (Example A9, stage 1) in 1.5 ml THF. The obtained brown solution was stirred for 45 min at -70°C. At -70°C was added in portions 517 mg (1,282 mmol) (oxodipine(pyridine)(1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone)molybdenum (IV)). This mixture was stirred for 1 h at -70°C and then left to warm to 0°C. the Mixture was stirred for 1 h at 0°C and then extinguished by adding 2.5 ml of a saturated solution of sodium sulfite. Added water and ethyl acetate. The aqueous layer once were extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The crude oil was purified on silica gel (eluent: heptane/ethyl acetate 0-100%) with the output specified in the title compound (82 mg, 51%) as a light brown oil. Mass spectrum (m/z): 251,1 (MH+).

b) stage 2: rat-3-Methoxyethoxy-1-methyl-5-nitro-5-phenyl-piperidine-2-he

To a solution of 50 mg (0.2 mmol) rat-3-hydroxy-1-methyl-5-nitro-5-phenyl-piperidine-2-she and 52 μl (0.3 mmol) N-ethyl Diisopropylamine in 1,2-dimethoxyethane was added to 23 μl (0.3 mmol) chloromethylmethylether ether at room temperature. After 1 h, the solution was heated in an oil bath at 60°C for 20 hours and Then the mixture was cooled to room temperature. Added 52 μl (0.3 mmol) N-ethyl Diisopropylamine and 23 μl (0.3 mmol) chlorodimethyl the new ether. This mixture was heated in an oil bath at 60°C for 4 h the Solvent was removed under vacuum. The residue was transferred into ethyl acetate. This mixture once washed with water. The aqueous layer once were extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated under vacuum. The crude oil was purified on silica gel (eluent: heptane/ethyl acetate 0-100%) with the output specified in the title compound (30 mg, 51%) as a yellow oil. Mass spectrum (m/z): 295,2 (MH+).

(C) stage 3: rat-5-Amino-3-methoxyethoxy-1-methyl-5-phenyl-piperidine-2-he

Specified in the title compound was obtained from the rat-3-methoxyethoxy-1-methyl-5-nitro-5-phenyl-piperidine-2-she is using a technique similar to the method of synthesis described in Example A.9 (stage 3). Mass spectrum (m/z): 265,1 (MH+).

d) stage 4: rat-5-Methoxyethoxy-1-methyl-3-phenyl-piperidine-3-ylamine

Specified in the title compound was obtained from the rat-5-amino-3-methoxyethoxy-1-methyl-5-phenyl-piperidine-2-she is using a technique similar to the method of synthesis described in Example A.6 (stage 4). Mass spectrum (m/z): 251,2 (MH+).

Example a

Getting rat-3-Cyclohexyl-1-methyl-piperidine-3-ylamine

a) stage 1: rat-4-Cyclohexyl-4-nitro-butyric acid methyl ester/p>

To a solution 3,18 g (22,2 mmol) nitro methyl-cyclohexane (CAS: 2625-30-1) in 1 ml tert-butanol and 0.12 ml of 35% hydroxide designed in methanol, heated to 40°C, was added to 1.99 ml (22,2 mmol) of methyl acrylate. The yellow mixture was stirred for 2 h at 40°C, then diluted with water and extracted with ethyl acetate. The combined extracts were washed with saline, dried over sodium sulfate, filtered and evaporated. Specified in the title compound was obtained as a yellowish oil:

Mass spectrum (E1): 198 (M•+-MeO), 183 (M•+-NO2), 151 (M-(MeO+NO2+H))•+(100%).

b) stage 2: rat-5-Cyclohexyl-1-methyl-5-nitro-piperidine-2-he

To 4,25 g (18.5 mmol) rat-4-cyclohexyl-4-nitro-butyric acid methyl ester was added 4,56 ml (32.5 mmol) of 1,3,5-trimethylhexane-1,3,5-triazine and the mixture was heated to 100°C for 4 h Then the reaction mixture was cooled to ambient temperature and was adsorbing on silica gel, which was applied on a column of silica gel. In the purification by flash chromatography using a gradient 10-75% ethyl acetate in heptane got to 2.55 g specified in the title compounds as colorless oils. Mass spectrum (m/z): 240 (MH+).

(C) stage 3: rat-5-Amino-5-cyclohexyl-1-methyl-piperidine-2-he

To a solution of 500 mg (of 2.08 mmol) rat-5-cyclohexyl-1-methyl-5-nitro-piperidine-2-it in 5 ml of methanol was added 500 mg of wet Raney Nickel and the mixture was stirred in hydrogen atmosphere at normal pressure and ambient temperature for 22 hours and Then the reaction mixture was filtered through a pillow dicalite, the precipitate was washed with methanol and the filtrate was evaporated to obtain 452 mg specified in the title compound as a colourless oil which was used without purification in the next stage.

a) stage 4: rat-3-Cyclohexyl-1-methyl-piperidine-3-yl-amine

To to 2.06 ml of 2.5 M solution of lithium aluminum hydride in tetrahydrofuran, cooled to 0°C, was added dropwise a solution of 452 mg (2,15 mmol) rat-5-amino-5-cyclohexyl-1-methyl-piperidine-2-it in 6 ml of tetrahydrofuran. Then this solution was heated to 65°C for 1 h Obtained turbid reaction mixture was cooled with an ice bath to a temperature below 12°C and added dropwise with 0.13 ml of water, 0,32 ml 2 N. NaOH and then to 0.19 ml of water. This suspension was diluted with tert-butylmethylamine ether, dried over sodium sulfate, filtered and evaporated to obtain 368 mg specified in 5 the title compound as a colourless oil which was used without purification in the next stage.

Example a

Getting rat-1-Methyl-3-(tetrahydro-Piran-4-yl)-piperidine-3-ylamine

a) stage 1: 4-nitro methyl-tetrahydro-Piran

To a cooled to 0°C. stirred suspension of 1.81 g (to 11.8 mmol) of silver nitrate in 6 ml of acetonitrile, placed in the reaction flask wrapped in aluminum foil, dropwise over 5 min was added to 1.60 g (8,93 mmol) 4-methyl bromide-tetrahydro-Piran. Stirring was continued for 93 hours at ambient temperature. Then the reaction mixture was filtered and thoroughly washed with diethyl ether. The resulting filtrate was mixed with silica gel and evaporated. The residue was applied on a column of silica gel and purified by flash chromatography on silica gel (eluent: heptane/ethyl acetate 9:1) to obtain the specified title compound (441 mg) as a colourless oil.

b) stage 2: rat-1-Methyl-3-(tetrahydro-Piran-4-yl)-piperidine-3-ylamine

Specified in the title compound was obtained from 4-nitro methyl-tetrahydro-Piran using methods analogous to the methods of synthesis described in Example a (stages 1-4).

Example a

Getting rat-1,3-Dimethyl-piperidine-3-ylamine dihydrochloride

a) stage 1: rat-3-Isocyanato-3-methyl-piperidine-1-carboxylic acid tert-butyl methyl ether

To a suspension 727 mg (3.0 mmol) rat-3-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ether (CAS:534602-47-6) in 8 ml of toluene was added at ambient temperature of 0.42 ml (3.0 mmol) of triethylamine. To the resulting solution was added with stirring to 0.72 ml (3.3 mmol) diphenylphosphinite and this mixture was heated to 90°C (gas) for 90 minutes Then the reaction mixture was poured into a mixture of ice/water and 3 times was extracted with tert-butylmethylamine ether. The combined extracts were washed with saline, dried over sodium sulfate, filtered and evaporated. Specified in the title compound was obtained as a yellowish oil, which was used in the next stage without purification. Mass spectrum (m/z): 240 (M).

b) stage 2: rat-3-Amino-3-methyl-piperidine-1-carboxylic acid tert-butyl methyl ether

To a solution of 812 mg (3,38 mmol) rat-3-isocyanato-3-methyl-piperidine-1-carboxylic acid tert-butyl ester in 17 ml of THF was added to 16.9 ml of 2 N. NaOH, and the resulting emulsion was intensively stirred for 20 h at ambient temperature. Then the emulsion was diluted with tert-butylmethylamine ether and three times were extracted. The combined extracts were washed with saline to obtain a neutral pH, dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel using a gradient of 10-100% ethyl acetate in heptane, then a mixture of ethyl acetate /Meon exit 232 mg specified in the connection header in the form bestwe the aqueous oil which crystallized at ambient temperature. Mass spectrum (m/z): 215,2(M+H).

(C) stage 3: rat-1,3-Dimethyl-piperidine-3-reminderville

To 3,15 ml of 1 M lithium aluminum hydride in THF was added dropwise at 5-10°C. a solution of 225 mg (1.05 mmol) rat-3-amino-3-methyl-piperidine-1-carboxylic acid tert-butyl ester in 4 ml of dry THF. This reaction mixture was heated to 65°C for 1 h Obtained turbid reaction mixture was cooled with an ice bath to a temperature below 12°C, was added dropwise with 0.13 ml of water, 0,32 ml 2 N. NaOH and then to 0.19 ml of water. This suspension was diluted with tert-butylmethylamine ether, dried over sodium sulfate, filtered and acidified by adding 2 N. HCl in diethyl ether. In the evaporation was obtained 210 mg specified in the title compounds as colorless semi-solid substances. Mass spectrum (m/z): to 129.3 (M+H).

Example a

Getting rat-3-(2,4-Differenl)-1-methyl-piperidine-3-ylamine

Specified in the title compound was obtained from 2,4-debtor-1-nitro methyl-benzene using methods analogous to the methods of synthesis described in Example A.6 (stages 1-4).

Example a

Getting rat-3-(2-Fluoro-phenyl)-1-methyl-piperidine-3-ylamine

Specified in the title compound was obtained from 1-fluoro-2-nitro methyl-benzene with the use of the cation techniques analogous to the methods of synthesis described in Example A.6 (stages 1-4).

Example a

Getting rat-3-(2,5-Debtor-phenyl)-1-methyl-piperidine-3-ylamine

Specified in the title compound was obtained from 1,4-debtor-2-nitro methyl-10 benzene using methods analogous to the methods of synthesis described in Example A.6 (stages 1-4).

Example a Getting rat-1-Methyl-1,4,5,6-tetrahydro-2H-[3,4']bipyridinyl-3-ylamine

a) stage 1: rat-1-Methyl-3-nitro-2,3,4,5-tetrahydro-1H-[3,4']bipyridinyl-6-he

Specified in the title compound was obtained from 4-nitro methyl-pyridine (CAS: 22918-06-5) using methods analogous to the methods of synthesis described in Example A.6 (stage 1-2).

b) stage 2: rat-1-Methyl-3-nitro-2,3,4,5-tetrahydro-1H-[3,4']bipyridinyl-6-tion

To a solution of 125 mg (mean HDI of 0.531 mmol) rat-1-methyl-3-nitro-2,3,4,5-tetrahydro-1H-[3,4']bipyridinyl-6-it in 2.5 ml of toluene was added 240 mg (0,584 mmol) of the reagent Lawesson. The resulting suspension was heated at 80°C in oil bath for 30 minutes the mixture is Then concentrated under vacuum. The crude oil was purified on silica gel (eluent: heptane/ethyl acetate 0-100%) with the output specified in the title compound (105 mg, 79%) as a pale yellow solid. Mass spectrum (m/z): 252,1 (M+H).

(C) tadia 3: rat-1-Methyl-3-nitro-1,2,3,4,5,6-hexahydro-[3,4']bipyridinyl

To a solution of 105 mg (0,418 mmol) rat-1-methyl-3-nitro-2,3,4,5-tetrahydro-1H-[3,4']bipyridinyl-6-thione in 2.1 ml of methanol was added 144 mg (3.8 mmol) NaBH4. This mixture was stirred for 20 min at room temperature. Was added water (1.0 ml). The mixture was stirred for 1 h, the Methanol was removed under vacuum. The residue was diluted with water and 3 times was extracted with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated under vacuum. The crude oil was purified on silica gel (eluent: heptane/ethyl acetate 0-100%) with the output specified in the title compound (53 mg, 57%) as a yellow oil. Mass spectrum (m/z): 222,3 (M+H).

d) stage 4: rat-1-Methyl-1,4,5,6-tetrahydro-2H-[3,4']bipyridinyl-3-ylamine

To a cooled to 0°C. a solution of 52 mg (0,235 mmol) rat-1-methyl-3-nitro-1,2,3,4,5,6-hexahydro-[3,4']bipyridinyl in 2.0 ml THF was added 150 μl of Raney Nickel (50% in water). This mixture was stirred at 0°C in an atmosphere of hydrogen for 7 hours the Catalyst was filtered and the filtrate was concentrated under vacuum to obtain specified in the title compound (45 mg, 88%) as a pale yellow oil. Mass spectrum (m/z): 192,4 (M+H).

Example a Getting rat-1-Methyl-1,4,5,6-tetrahydro-2H-[3,3']bipyridinyl-3-ylamine

a) stage 1: rat-1-Methyl-3-nitro-2,3,4,5-tetrahydro-1H-[3,3']piperid the Nile-6-he

Specified in the title compound was obtained from 3-nitro methyl-pyridine (CAS: 69966-29-6) using methods analogous to the methods of synthesis described in Example A.7 (stage 1-2).

b) stage 2: rat-1-Methyl-1,4,5,6-tetrahydro-2H-[3,3']bipyridinyl-3-ylamine

Specified in the title compound was obtained from rat-1-methyl-3-nitro-2,3,4,5-tetrahydro-1H-[3,3']bipyridinyl-6-it is using a technique similar to the method of synthesis described in Example a (stages 2-4).

Example a Receive (3RS,5SR)-5-Methoxy-1-methyl-3-phenyl-piperidine-3-ylamine

a) stage 1: (3SR,5RS)-3-Methoxy-1-methyl-5-nitro-5-phenyl-piperidine-2-he

A solution of 1.15 g (4,595 mmol) rat-3-hydroxy-1-methyl-5-nitro-5-phenyl-piperidine-2-it (Example A.10, stage 1) in 11.5 ml DMF was cooled to 0°C. was Added 220 mg (5,514 mmol) NaH (60% in oil). The temperature rose to 3°C. the Mixture was stirred for 15 min at 0°C. was Added 430 μl (6,893 mmol) of iodomethane and this mixture was stirred for 30 min at 0°C. was Added to 6.5 ml of water and the solvent was removed under vacuum. The residue was transferred into ethyl acetate. The resulting solution was twice washed with water. The aqueous layers obtained after washing, re-extracted once with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and koncentrirane and under vacuum. The crude oil was purified on silica gel (eluent: heptane/ethyl acetate 0-100%) with the output specified in the header of the compound (500 mg, 42%) as a light brown solid. Mass spectrum (m/z): 265,1 (M+H).

b) stage 2: (3SR,5RS)-5-Amino-3-methoxy-1-methyl-5-phenyl-piperidine-2-he

Specified in the title compound was obtained from (3SR,5RS)-3-methoxy-1-methyl-5-nitro-5-phenyl-piperidine-2-she is using a technique similar to the method of synthesis described in Example a (stage 4).

(C) stage 3: (3RS,5SR)-5-Methoxy-1-methyl-3-phenyl-piperidine-3-ylamine

Specified in the title compound was obtained from (3SR,5RS)-5-amino-3-methoxy-1-methyl-5-phenyl-piperidine-2-she is using a technique similar to the method of synthesis described in Example A.6 (stage 4).

Example a

Receiving (3RS,5SR)-1,5-Dimethyl-3-phenyl-piperidine-3-ylamine

a) stage 1: (3SR,5RS)-1,3-Dimethyl-5-nitro-5-phenyl-piperidine-2-he

To a solution of 1.6 ml (11.1 mmol) of Diisopropylamine in 40 ml of THF was added 7 ml (11.1 mmol) of 1.6 M solution of n-BuLi in hexane at -5°C. the solution was stirred for 15 min at 0°C and then cooled to -70°C. was Added dropwise a solution of 2 g (8,538 mmol) rat-1-methyl-5-nitro-5-phenyl-piperidine-2-it (Example A9, step 1) in 20 ml of THF. The obtained brown solution was stirred for 45 m is h at -70°C. Was added dropwise at -70°C 639 ál (of 10.25 mmol) methyliodide in THF (8 ml). This mixture was stirred for 1 h at -70°C and then left to warm to 0°C. the Mixture was stirred for 30 min at 0°C and then extinguished by adding 30 ml of 20% solution of NH4Cl. Added water and ethyl acetate. The aqueous layer once were extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified on silica gel (eluent: heptane/ethyl acetate 0-100%) with the output specified in the connection header (1,72 g, 81%) as a yellow oil. Mass spectrum (m/z): 249,2 (M+H).

b) stage 2: (3SR,5RS)-5-AMINO-1,3-dimethyl-5-phenyl-piperidine-2-he

Specified in the title compound was obtained from (3SR,5RS)-1,3-dimethyl-5-nitro-5-phenyl-piperidine-2-she is using a technique similar to the method of synthesis described in Example a, (stage 4,). Mass spectrum (m/z): 202,2 (M-NH2).

(C) stage 3: (3RS,5SR)-1,5-Dimethyl-3-phenyl-piperidine-3-ylamine

Specified in the title compound was obtained from (3SR,5RS)-5-amino-1,3-dimethyl-5-phenyl-piperidine-2-she is using a technique similar to the method of synthesis described in Example A.6 (stage 4). Mass spectrum (m/z): 205,3 (M+H).

Example a

Getting rat-1,5,5-Trimethyl-3-phenyl-piperidine-3-ylamine

15

a) the Article is Diya 1: 1,3 .3m-Trimethyl-5-nitro-5-Phenyl-piperidine-2-he

To a solution of 170,7 ál (1,208 mmol) Diisopropylamine in 4 ml of THF was added 755 μl (1,208 mmol) of 1.6 M solution of n-BuLi in hexane at -5°C. the solution was stirred for 15 min at 0°C and then cooled to -70°C. Then added 300 μl of a solution of NMRA (triamide hexamethylphosphoric acid). Was added dropwise 200 mg (0,805 mmol) of (3SR,5RS)-1,3-dimethyl-5-nitro-5-phenyl-piperidine-2-it (Example a, step a) in 2 ml of THF. The obtained brown solution was stirred for 45 min at -70°C. was Added dropwise 151 μl (2,415 mmol) methyliodide in THF (1 ml) at -70°C. the Mixture was stirred for 1 h at -70°C and then left to warm to 0°C. the Mixture was stirred for 1 h at 0°C, then extinguished by adding 7 ml of 20% solution of NH4Cl. Added water and ethyl acetate. The aqueous layer once were extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified on silica gel (eluent: heptane/ethyl acetate 0-100%) with the output specified in the title compound (131 mg, 62%) as a yellow oil. Mass spectrum (m/z): 263,2 (M+H).

b) stage 2: rat-1,5,5-Trimethyl-3-phenyl-piperidine-3-ylamine

Specified in the title compound was obtained from 1,3 .3m-trimethyl-5-nitro-5-phenyl-piperidine-2-she is using a technique similar to the technique of synthesis, description is authorized in Example a, (stage 2 to 3). Mass spectrum (m/z): RUR 219.4 (M+H).

Example a

Getting rat-1,6,6-Trimethyl-3-phenyl-piperidine-3-ylamine

a) stage 1: 5-Amino-1-methyl-5-phenyl-piperidine-2-he

Specified in the title compound was obtained from 1-methyl-5-nitro-5-phenyl-piperidine-2-it (Example A9, step 1) using methods analogous to the methods of synthesis described in Example A.6 (stage 3). Mass spectrum (m/z): 205,2 (M+H).

b) stage 2: (1-Methyl-6-oxo-3-phenyl-piperidine-3-yl)-carbamino acid tert-butyl methyl ether

To a solution of 1.5 g (7,35 mmol) 5-amino-1-methyl-5-phenyl-piperidine-2-she's in 30 ml of THF under nitrogen atmosphere at room temperature was added to 2.1 ml (14.7 mmol) of triethylamine. Was added dropwise a solution of 3,24 g (14.7 mmol) of di-tert-butyl-dicarbonate in 15 ml of THF. This reaction mixture was stirred in an oil bath at 55°C for 7 h and then overnight at room temperature. Added 100 ml of water. This mixture 3 times were extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified on silica gel (eluent: heptane/ethyl acetate 0-100%) with the output specified in the connection header (1,21 g, 54%) as a yellow oil. Mass spectrum (m/z): 305,3 (M+H).

(C) stage 3: (1.6.-Trimethyl-3-phenyl-piperidine-3-yl)-carbamino acid tert-butyl methyl ether

A solution of 61 mg (0.2 mmol) (1-methyl-6-oxo-3-phenyl-piperidine-3-yl)-carbamino acid tert-butyl ester in 2 ml of THF was cooled to -20°C. was Added in one step 48 mg (0.2 mmol) of the chloride of zirconium (IV). The temperature rose to -12°C. the Mixture was stirred for 30 min at -10°C. was Added dropwise 400 μl (1.2 mmol) of 3 M solution of bromide Metalmania in diethyl ether, maintaining the temperature below -10°C. After 10 min the mixture was left to warm to room temperature. After 2 h the mixture was cooled in an ice bath and was suppressed by adding 2 ml of a saturated solution of NH4Cl. Added ethyl acetate and water. The organic layer was separated and the aqueous layer was twice extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under vacuum to obtain specified in the title compound (50 mg, 80%) as a yellow oil. Mass spectrum (m/z): 319,3 (M+H).

d) stage 4: rat-1,6,6-Trimethyl-3-phenyl-piperidine-3-ylamine

To a solution of 50 mg (of) 0.157 mmol) (1,6,6-trimethyl-3-phenyl-piperidine-3-yl)-carbamino acid tert-butyl ester in 0.3 ml of dioxane was added to 0.39 ml (1.57 mmol) of 4 M HCl solution in dioxane at room temperature. After 30 min was added 0.3 ml of methanol to dissolve the product. Then the mixture was stirred for 5 h at room temperature. The solvent UDA is Yali under vacuum. The residue was dissolved in water. The aqueous layer was twice extracted with ethyl acetate and then podslushivaet 2 M solution of sodium carbonate. The aqueous layer was extracted 3 times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated under vacuum to obtain specified in the title compound (22 mg, 64%) as a brown oil. Mass spectrum (m/z): RUR 219.4 (M+H).

Example a

Getting rat-3-(3-Bromo-phenyl)-1-methyl-piperidine-3-ylamine

a) stage 1: rat-3-(3-Bromo-phenyl)-1-methyl-3-nitro-piperidine

Specified in the title compound was obtained from 1-bromo-3-nitro methyl-benzene (CAS: 854634-33-6) using methods analogous to the methods of synthesis described in Example a (stages 1-3). Mass spectrum (m/z): 300,3 (M+H).

b) stage 2: rat-3-(3-Bromo-phenyl)-1-methyl-piperidine-3-ylamine

Specified in the title compound was obtained from the rat-3-(3-bromo-phenyl)-1-methyl-3-nitro-piperidine using methods analogous to the methods of synthesis described in Example A.6 (stage 3). Mass spectrum (m/z): 269,2 (M+H).

Example a

Getting rat-3-(2-Chloro-4-fluoro-phenyl)-1-methyl-piperidine-3-ylamine

Specified in the title compound was obtained from 2-chloro-4-fluoro-1-nitro methyl-benzene using methods analogous to the methods of synthesis, described in Example A.6 (stages 1-4).

Example a Getting rat-3-(5-Chloro-2-fluoro-phenyl)-1-methyl-piperidine-3-ylamine

Specified in the title compound was obtained from 4-chloro-1-fluoro-2-nitro methyl-benzene using methods analogous to the methods of synthesis described in Example A.6 (stages 1-4).

Example a

Getting rat-1-Methyl-3-(3-trifluoromethyl-phenyl)-piperidine-3-ylamine

Specified in the title compound was obtained from 1-nitro methyl-3-trifluoromethyl-benzene using methods analogous to the methods of synthesis described in Example A.6 (stages 1-4).

Example a Getting rat-1-Methyl-3-(3-triptoreline-phenyl)-piperidine-3-ylamine

Specified in the title compound was obtained from 1-nitro methyl-3-triptoreline-benzene using methods analogous to the methods of synthesis described in Example A.6 (stages 1-4).

Example a

Getting rat-3-(3-Methoxy-phenyl)-1-methyl-piperidine-3-ylamine

Specified in the title compound was obtained from 1-methoxy-3-nitro methyl-benzene using methods analogous to the methods of synthesis described in Example A.6 (stages 1-4).

Example a

Getting rat-3-(3-Deformedarse-phenyl)-1-methyl-piperidine-3-ylamine

The decree is Noah in the title compound was obtained from 1-deformedarse-3-nitro methyl-benzene using techniques analogous to the methods of synthesis described in Example A.6 (stages 1-4).

Example a

Getting rat-3-(3-Fluoro-phenyl)-1-methyl-piperidine-3-ylamine

Specified in the title compound was obtained from 1-fluoro-3-nitro methyl-benzene using methods analogous to the methods of synthesis described in Example A.6 (stages 1-4).

Example a

Getting rat-3-(3-Chloro-4-fluoro-phenyl)-1-methyl-piperidine-3-ylamine

Specified in the title compound was obtained from 2-chloro-1-fluoro-4-nitro methyl-benzene using methods analogous to the methods of synthesis described in Example A.6 (stages 1-4).

Example a

Getting rat-3-(3,4-Debtor-phenyl)-1-methyl-piperidine-3-ylamine

Specified in the title compound was obtained from 1,2-debtor-4-nitro methyl-benzene using methods analogous to the methods of synthesis described in Example A.6 (stages 1-4).

Example a

Getting rat-1-Methyl-3-meta-tolyl-piperidine-3-ylamine

Specified in the title compound was obtained from 1-methyl-3-nitro methyl-benzene using methods analogous to the methods of synthesis described in Example A.6 (stages 1-4).

Example a

Getting rat-3-(4-Fluoro-3-methyl-phenyl)-1-methyl-piperidine-3-ylamine

Ukazannoi the title compound was obtained from 1-fluoro-2-methyl-4-nitro methyl-benzene using techniques analogous to the methods of synthesis described in Example A.6 (stages 1-4).

Example a

Getting rat-3-(3,5-Debtor-phenyl)-1-methyl-piperidine-3-ylamine

Specified in the title compound was obtained from 1,3-debtor-5-nitro methyl-benzene using methods analogous to the methods of synthesis described in Example A.6 (stages 1-4).

Example A

Getting rat-1-Methyl-3-(3-thiazol-2-yl-phenyl)-piperidine-3-ylamine

Specified in the title compound was obtained from 2-(3-nitro methyl-phenyl)-thiazol using methods analogous to the methods of synthesis described in Example A.6 (stages 1-4).

Example a

Getting rat-1-tert-Butyl-3-phenyl-piperidine-3-ylamine

a) stage 1: rat-4-Nitro-4-phenyl-butyric acid methyl ester

Specified in the title compound was obtained from the nitro methyl-benzene (CAS: 622-42-4) using methods analogous to the methods of synthesis described in Example A.6 (stage 1).

b) stage 2: rat-5-Nitro-5-phenyl-piperidine-2-he

To mix the solution 2,11 g (26,88 mmol) of ammonium acetate in 15 ml of ethanol in a nitrogen atmosphere at room temperature was added to 980 μl (13,44 mmol) of formaldehyde (37% in water) and then a solution of 3 g (13,44 mmol) rat-4-Nitro-4-phenyl-oil is islote methyl ester in 7.5 ml of ethanol. This mixture was subjected to reflux distilled for 26 h, then cooled to room temperature and the solvent evaporated. Added water. The resulting suspension was stirred for 15 min, filtered, washed with water, then diethyl ether and dried under vacuum to yield specified in the connection header (2,49 g, 84,1%) as a white solid. Mass spectrum (m/z): 221,2 (M+H).

(C) stage 3: rat-5-Amino-5-Phenyl-piperidine-2-he

Specified in the title compound was obtained from the rat-5-nitro-5-phenyl-piperidine-2-she is using a technique similar to the method of synthesis described in Example a (stage 4). Mass spectrum (m/z): 191,4 (M+H).

d) stage 4: rat-3-Phenyl-piperidine-3-ylamine

Specified in the title compound was obtained from the rat-5-amino-5-phenyl-piperidine-2-she is using a technique similar to the method of synthesis described in Example A.6 (stage 4). Mass spectrum (m/z): 177,7 (M+H).

(e) stage 5: rat-2-(3-Amino-3-phenyl-piperidine-1-yl)-2-methyl-propionitrile

To a solution of 300 mg (1,701 mmol) rat-3-phenyl-piperidine-3-ylamine in 1.3 ml of acetic acid was added dropwise 188 μl (2,553 mmol) of acetone. This mixture was stirred for 5 min at room temperature. Was added dropwise 320 μl (2,553 mmol) trimethylsilylacetamide. The temperature was raised the camping to 31°C. The mixture was stirred for 4 h at room temperature. Then the mixture was diluted with dichloromethane and was cooled to 0°C. the Mixture was podslushivaet by adding dropwise 2 N. NaOH. The organic layer was separated and the aqueous layer was twice extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum to obtain specified in the title compound (315 mg, 76,1%) as a yellow oil. Mass spectrum (m/z): 244,4 (M+H).

f) stage 6; rat-1-tert-Butyl-3-phenyl-piperidine-3-ylamine

To a solution of 100 mg (0,411 mmol) rat-2-(3-amino-3-phenyl-piperidine-1-yl)-2-methyl-propionitrile in 2.0 ml of tetrahydrofuran over the molecular sieve at 0°C in an atmosphere of nitrogen was added dropwise to 1.4 ál (4,11 mmol) of 3 M solution of bromide Metalmania in diethyl ether. This mixture was stirred for 10 min at 0°C and then for 30 h at 60°C. Then the mixture was cooled in an ice bath and was suppressed by adding a saturated solution of ammonium chloride. Then the mixture 3 times were extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated under vacuum to obtain specified in the title compound (60 mg, 63%) as a yellow resin. Mass spectrum (m/z): 233,2 (M+H).

Example a

Getting rat-4-Methyl-6-phenyl-4-Aza-Spiro[2,5]Oct-6-ylamine hydrochloride

(a) one Hundred who ia 1: rat-(4-Methyl-6-Phenyl-4-Aza-Spiro[2,5]Oct-6-yl)-carbamino acid tert-butyl methyl ether

A solution of 333 μl (1.0 mmol) of 3 M solution of bromide of etermine in diethyl ether in 4 ml of THF was cooled to -70°C. was Added dropwise a solution of 124 μl (0.42 mmol) of isopropoxide titanium in 0.4 ml of THF. The obtained pale-brown mixture was stirred for 2 minutes was Added dropwise a solution of 122 mg (0.4 mmol) rat-(1-methyl-6-oxo-3-phenyl-piperidine-3-yl)-carbamino acid tert-butyl ester (Example a, stage 2) in 2.4 ml of THF. The mixture was left to warm to room temperature and was stirred for 3 hours

Then the mixture was cooled in an ice bath and was suppressed by adding a 20% solution of ammonium chloride. Added water and ethyl acetate. The obtained white suspension was filtered through a pillow dicalite. The organic layer was separated and the aqueous layer was twice extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified on silica gel (eluent: heptane/ethyl acetate 0-100%) with the output specified in the title compound (14 mg, 11%) as a colourless oil. Mass spectrum (m/z): 317,2 (M+H).

b) stage 2: rat-4-Methyl-6-Phenyl-4-Aza-Spiro[2,5]Oct-6-ylamine hydrochloride

Specified in the title compound was obtained from the rat-(4-methyl-6-phenyl-4-Aza-Spiro[2,5]Oct-6-yl)-carbamino acid tert-butyl ester using the method of the Ki, analogous to the methods of synthesis described in Example a (stage 4). Mass spectrum (m/z): 217,4 (M+H).

Example B.1

Obtain 2-bromo-6-methoxy-4-trifluoromethyl-benzoic acid

To a cooled to -75°C. THF (70 ml) for 5 min was added dropwise 36 ml (50.0 mmol) of a 1.4 M solution of sec-BuLi in cyclohexane, keeping the temperature below -70°C. for 5 min was added dropwise 7.5 ml (50.0 mmol) of TMEDA at a temperature below -70°C. for 20 min was added dropwise a solution of 5.0 g (22,71 mmol) 2-methoxy-4-(trifluoromethyl)benzoic acid (commercially available) in THF (25 ml). The obtained dark green solution was stirred for 2 h at -75°C. was Added dropwise a solution of 29.6 g (90,84 mmol) of 1,2-dibromotetrachloroethane in THF (30 ml). The obtained yellow suspension was stirred for 1 h at -75°C and then left to warm to room temperature. The obtained yellow solution was suppressed, was added dropwise 60 ml of water using cooling in an ice bath. The mixture was diluted with ethyl acetate (70 ml) and water (30 ml). The aqueous layer was extracted with ethyl acetate (50 ml), acidified by addition of 25% HCl and was extracted with ethyl acetate (3×50 ml). The extracts were combined, dried over sodium sulfate, filtered and concentrated under vacuum. The crude product is triturated in heptane, filtered and dried. Hard substance as stylizowane from heptane (7 ml) and ethyl acetate (2 ml) to obtain the specified title compound (815 mg, 12%) as a white solid. Mass spectrum (m/z): to 298.9 (M-N).

Example B.2

Getting 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid

Specified in the title compound was obtained from 2-methoxy-4-(trifluoromethyl)benzoic acid (commercially available) and dimethyl disulfide using methods analogous to the methods of synthesis described in Example B.1.

Example B.3

Getting 2-Cyclopropyl-4-trifluoromethyl-benzoic acid

a) stage 1: 2-Bromo-4-trifluoromethyl-benzoic acid methyl ester

To a solution of 2 g (7,434 mmol) of 2-bromo-4-trifluoromethyl-benzoic acid (CAS: 328-89-2) in 20 ml of DMF under nitrogen atmosphere at room temperature was added 1.13 g (8,177 mmol) of potassium carbonate and 557 μl (8,921 mmol) methyl iodide. This mixture was stirred overnight under nitrogen atmosphere. Then the mixture was poured into water (300 ml). The aqueous layer was extracted with ethyl acetate (2×80 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated under vacuum. The crude oil was purified on silica gel (eluent: heptane/ethyl acetate 0 to 10%) with the output specified in the title compound (1.75 g, 83%) as an orange oil.

b) stage 2: 2-Cyclopropyl-4-trifluoromethyl-benzoic acid methyl ester

To a solution of 400 mg (1,413 mmol) of 2-bromo-4-trifluoromethyl-benzoic acid methyl ester, 146 mg (1,696 mmol) of cyclopropylboronic acid, 1,21 g (4,946 mmol) of potassium orthophosphate monohydrate, of 40.9 mg (0,141 mmol) tricyclohexylphosphine in 6 ml of toluene and 0.3 ml of water under nitrogen atmosphere at room temperature was added to 15.9 mg (0,0707 mmol) of palladium acetate. This mixture was stirred in an oil bath at 100°C for 4 h and overnight at room temperature in a nitrogen atmosphere. Then the mixture was cooled to room temperature. Added water and the mixture was extracted with ethyl acetate. The organic layer was once washed with saline, dried over sodium sulfate, filtered and concentrated under vacuum. The crude compound was purified on silica gel (eluent: heptane/ethyl acetate 0 to 10%) with the output specified in the title compound (0.24 g, 71%) as a yellow oil.

(C) stage 3: 2-Cyclopropyl-4-trifluoromethyl-benzoic acid

To a suspension of 485 mg (1,986 mmol) 2-cyclopropyl-4-trifluoromethyl-benzoic acid methyl ester in 8 ml of ethanol at room temperature was added 1,99 ml (3,972 mmol) 2 N. NaOH. This mixture was heated at 80°C in oil bath for 30 minutes the resulting solution was cooled to room temperature and evaporated ethanol. The residue was diluted with water, acidified added by the I 2 N. HCl to pH 2 and was added dichloromethane. The aqueous phase was twice extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified on silica gel (eluent: heptane/ethyl acetate 0-100%) with the output specified in the connection header (0,197 g, 27%) as a pale yellow solid. Mass spectrum (m/z): 229,0 (M-N).

Example B.4

Getting 5-Trifluoromethyl-biphenyl-2-carboxylic acid

A mixture of 300 mg (0,949 mmol) 2-iodine-4-trifluoromethyl-benzoic acid (CAS: 54507-44-7), 239 mg (1,898 mmol) of phenylboronic acid, 302 mg (2,847 mmol) of sodium carbonate and 10.7 mg (0,0475 mmol) of palladium acetate (4.5 ml of water was stirred for 48 h at room temperature. Then the mixture was filtered and the obtained filtrate was acidified by addition of 37% HCl. Then the mixture was stirred for 30 min at room temperature. The solid was filtered, washed with water and dried to obtain specified in the title compound (225 mg, 89%) as a brown solid. Mass spectrum (m/z): 264,9 (M+H+).

Example B.5

Getting 2-Isopropoxy-4-trifluoromethyl-benzoic acid

To a solution of 500 mg (2,271 mmol) 2-hydroxy-4-trifluoromethyl-benzoic acid methyl ester (CAS: 345-28-8), 209 μl (2,725 mmol) 2-Pro is anola and 706,2 mg (2,612 mmol) of triphenylphosphine in 6.5 ml of tetrahydrofuran in a nitrogen atmosphere at 0°C was added dropwise a solution of 575,2 mg (2,498 mmol) di-tert-utilization.bacteria in 1 ml of tetrahydrofuran. This reaction mixture was left to warm to room temperature and was stirred for 1.5 hours was Added 8 ml (15.9 mmol) of 2 N. NaOH and this reaction mixture was heated for 5 h at 80°C. Then the reaction mixture was extracted twice with 5 ml of diethyl ether. The aqueous layer was acidified using cooling in an ice bath 5 N. HCl solution to pH 1. The precipitate was filtered and dried under vacuum to obtain 444 mg (yield: 78.8 per cent) of the desired compound as a white solid. Mass spectrum (m/z): 247,0 (MH+).

Example B.6

Getting 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride

A mixture of 51 mg (0,191 mmol) 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (Example C.2) and 140 μl (1,91 mmol) of thionyl chloride in toluene (0.5 ml) was heated at 80°C in oil bath for 4 h the Solvent was removed under vacuum to obtain specified in the connection header.

Example V

Getting 2-Ethyl-4,6-bis-trifluoromethyl-benzoyl chloride

a) stage 1: 2-Ethyl-4,6-bis-trifluoromethyl-benzoic acid

Specified in the title compound was obtained from 2,4-bis-trifluoromethyl-benzoic acid (commercially available) and ethyliodide using methods analogous to the methods of synthesis described in the Application is e q.1

Example Q. 8

Getting 2-Deformedarse-4-trifluoromethyl-benzoic acid

a) stage 1: 2-Deformedarse-4-trifluoromethyl-benzoic acid methyl ester

To a solution of 500 mg (2,271 mmol) 2-hydroxy-4-trifluoromethyl-benzoic acid methyl ester (CAS: 345-28-8) in 5 ml of N,N-dimethylformamide at room temperature was added 470,8 mg (3,407 mmol) of potassium carbonate and was then added dropwise 293,4 ál (2,725 mmol) Hortiflorexpo acid methyl ester. This reaction mixture was heated at 65°C in oil bath for 22 h were Added water and ethyl acetate. The organic phase is washed 3 times with water. The organic phase was dried over sodium sulfate, filtered and concentrated under vacuum to obtain specified in the title compound (449 mg) as a pink oil, which was used in the next stage without any further purification.

b) stage 2: 2-Deformedarse-4-trifluoromethyl-benzoic acid

Specified in the title compound was obtained from 2-deformedarse-4-trifluoromethyl-benzoic acid methyl ester using methods analogous to the methods of synthesis described in Example B.3 (stage 3). Mass spectrum (m/z): 254,9 (M-N).

Example B.9

Getting 2-Pyrrolidin-1-yl-4-trifluoromethyl-benzoic acid

<> a) stage 1: 2-Pyrrolidin-1-yl-4-trifluoromethyl-benzoic acid methyl ester

To 30 mg (0,0318 mmol) Pd2dba3, to 37.9 mg (0,106 mmol) of 2-(dicyclohexylphosphino)biphenyl and 315 mg (1,484 mmol) orthophosphate potassium in the atmosphere of argon at room temperature was added a solution of 105.2 ál (1,272 mmol) pyrrolidine in 5.5 ml of dry toluene and then 300 mg (1.06 mmol) of 2-bromo-4-trifluoromethyl-benzoic acid methyl ester (CAS: 328-89-2). This reaction mixture was heated at 80°C during the night. Then the mixture was cooled to room temperature and diluted with dichloromethane. This suspension was filtered. The obtained filtrate was concentrated under vacuum. The residue was purified on silica gel (eluent: heptane/ethyl acetate 0-10%) to obtain the specified title compound (88 mg, 30,4%) as an orange oil. Mass spectrum (m/z): 274,3 (MH+).

b) stage 2: 2-Pyrrolidin-1-yl-4-trifluoromethyl-benzoic acid

Specified in the title compound was obtained from 2-pyrrolidin-1-yl-4-trifluoromethyl-benzoic acid methyl ester using methods analogous to the methods of synthesis described in Example VZ (stage 3). Mass spectrum (m/z): 258,0 (M-N).

Example B.10

Getting 2-Cyclohexyl-4-trifluoromethyl-benzoic acid

a) stage 1: 2-Iodine-4-trifluoromethyl-benzoic acid methyl ester

Specified in the title compound was obtained from 2-iodine-4-trifluoromethyl-benzoic acid using methods analogous to the methods of synthesis described in Example B.3 (stage 1).

b) stage 2: 2-Cyclohexyl-4-trifluoromethyl-benzoic acid methyl ester

To a solution of 300 mg (0,909 mmol) 2-iodine-4-trifluoromethyl-benzoic acid methyl ester, to 14.4 mg (0,0455 mmol) Pd(dppf)Cl2and 10.6 mg (0,0545 mmol) of copper iodide (I) in THF (5 ml) was added at room temperature 2,73 ml (1,364 mmol) of bromide cycloheximide (0.5 M). This mixture was stirred for 3 hours Then the mixture was heated to 50°C. and was stirred for 4 h and at room temperature over night. The mixture is then concentrated under vacuum and dissolved in ethyl acetate. The mixture is then twice washed with 1 N. HCl solution, twice with saturated sodium bicarbonate solution and once with brine. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified on silica gel (eluent: heptane/ethyl acetate 0-20%) to obtain the specified title compound (176 mg, 68%) as a pale yellow oil. Mass spectrum (m/z): 286 (MH+).

(C) stage 3: 2-Cyclohexyl-4-trifluoromethyl-benzoic acid

Specified in the title compound was obtained from 2-cyclohexyl-4-trifluoromethyl-benzoic acid methyl ester is using techniques analogous to the methods of synthesis described in Example B.3 (stage 3). Mass spectrum (m/z): 271,2(M-H).

Example V

Getting 2-cyclopentyl-4-trifluoromethyl-benzoic acid

Specified in the title compound was obtained from 2-iodine-4-trifluoromethyl-benzoic acid methyl ester and bromide cyclopentenone with subsequent saponification of the resulting product with sodium hydroxide in accordance with methods analogous to the methods of synthesis described in Example C. 10. Mass spectrum (m/z): to 257.0 (M-N).

Example century.12

Getting 2-Cyclobutyl-4-trifluoromethyl-benzoic acid

Specified in the title compound was obtained from 2-iodine-4-trifluoromethyl-benzoic acid methyl ester and bromide cyclobutanone with subsequent saponification of the resulting product with sodium hydroxide in accordance with methods analogous to the methods of synthesis described in Example C. 10. Mass spectrum (m/z): 243,0 (M-N).

Example V

Getting 2-Isopropyl-4-trifluoromethyl-benzoic acid

Specified in the title compound was obtained from 2-iodine-4-trifluoromethyl-benzoic acid methyl ester and bromide 2-propylzinc with subsequent saponification of the resulting product with sodium hydroxide in accordance with 5 methods analogous to the methods of synthesis described in Example C. 10. Mass spec is p (m/z): 231,0 (M-N).

Example V

Obtaining 2,6-Dimethoxy-4-trifluoromethyl-benzoic acid

To a solution of sodium hydroxide (to 5.66 g,141,4 mmol) in 33 ml of water and 33 ml of ethanol at room temperature under nitrogen atmosphere was added 2,6-dimethoxy-4-trifluoromethyl-benzonitrile (CAS: 51271-36-4) (3,27 g, 14,14 mmol). This reaction mixture was heated at 90°C in oil bath for 37 hours Then the reaction mixture was cooled to room temperature and was added 130 ml of water. The product was collected by filtration and dried to obtain yellow solids (3,05 g). To a solution of nitrogylcerin acid (15.6 g, 110,2 mmol) in 9.5 ml of water at 0°C under nitrogen atmosphere was added dropwise a suspension obtained above substances in 19 ml of dichloromethane. The reaction mixture was stirred for 4.5 h at 0°C. Then the reaction mixture was poured into ice and extracted with dichloromethane. The combined organic layers were dried over Na2SO4that was filtered and dried to obtain 1.51 g of product. The aqueous phase was filtered and the white solid was dried to obtain 1,36 g of the product. Both portions of the product were mixed with obtaining specified in the connection header (2,87 g, 93,7%) as a white solid. Mass spectrum (m/z): 249,1 (M-N).

Example V

Getting 2-Methoxy-6-(2,2,2-Cryptor-ethoxy)-4-trifluoromethyl-benzoic acid

<> a) stage 1: 2-Methoxy-6-nitro-4-trifluoromethyl-benzonitrile

To a solution of 3 g (11,49 mmol) of 2,6-dinitro-4-trifluoromethyl-benzonitrile (CAS: 35213-02-6) in 30 ml of methanol at 0°C under nitrogen atmosphere was added 2.3 ml (11,49 mmol) of 5 M of sodium methylate in methanol. This reaction mixture was stirred for 1.5 h at 0°C, then poured into ice water, stirred for 60 min and the product was collected by filtration. The crude solid was purified on silica gel (eluent: heptane/ethyl acetate 0-30%) with the output specified in the title compound (2.24 g, 79%) as a pale yellow solid.

b) stage 2: 2-Methoxy-6-(2,2,2-Cryptor-ethoxy)-4-trifluoromethyl-benzonitrile

To a solution of 200 mg (0,804 mmol) 2-methoxy-6-nitro-4-trifluoromethyl-benzonitrile 2.4 ml of 2,2,2-triptoreline in an argon atmosphere at 0°C was added dropwise a solution of a 81.3 mg (1,246 mmol) of potassium hydroxide in 600 μl water. This mixture was subjected to reflux distilled for 2 hours, then cooled to room temperature and was poured into a mixture of ice/water. The resulting suspension was filtered and dried under vacuum to yield specified in the title compound (112 mg, 47%) as a white solid. Mass spectrum (m/z): 317,2 (M+H).

(C) stage 3: 2-Methoxy-6-(2,2,2-Cryptor-ethoxy)-4-trifluoromethyl-benzoic acid

Specified in the header with the unity was obtained from 2-methoxy-6-(2,2,2-Cryptor-ethoxy)-4-trifluoromethyl-benzonitrile using techniques analogous to the methods of synthesis described in Example L. Mass spectrum (m/z): 316,9 (M-N).

Example V

Getting 2-Ethyl-3-methyl-4-trifluoromethyl-benzoyl chloride

a) stage 1: 2-(2-Methoxy-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazol

To a solution of 24,98 g (113 mmol) of 4-(trifluoromethyl)-2-methoxy-benzoic acid in 220 ml of toluene was added 82 ml (1.13 mol) of thionyl chloride and 5 drops of dimethylformamide. This mixture was heated up to 80°C for 3 h Then the reaction mixture was concentrated at 50°C./10 mbar (100 PA). The remaining acid chloride, 27.9 g of a light yellow liquid was dissolved in 160 ml) cooled to 0°C. dichloromethane and the solution was added 20,34 g (228 mmol) of 2-amino-2-methyl-propan-1-ol in 60 ml of dichloromethane. This mixture was left to mix for 16 h at ambient temperature. The obtained yellow suspension was diluted with water, the aqueous phase was evaporated and the organic phase is 3 times were extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product, N-(2-hydroxy-1,1-dimethyl-ethyl)-2-methoxy-4-Cryptor-methyl-benzamide (33,2 g, light yellow oil) was dissolved in 220 ml of dichloromethane and cooled to 0°C. Then was added dropwise to 24.7 ml (340 mmol) of thionyl chloride and the resulting light yellow rastvoritelyami for 16 h at ambient temperature. Then the pH was brought to 10 by adding a saturated aqueous solution of Na2CO3. The aqueous layer was separated and 3 times was extracted with tert-butylmethylamine ether. The combined organic phases are washed twice with saline, dried over Na2SO4, filtered and concentrated to obtain specified in the title compound as a pale yellow oil which was used without further purification. Mass spectrum (m/z): 274,1 (M+H+).

b) stage 2: 2-(2-Methoxy-3-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazol

To a solution of 5,465 g (20 mmol) of 2-(2-methoxy-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole in 60 ml of dry THF at a temperature of < -60°C was added to 11.0 ml (22 mmol) of 2 M solution of diisopropylamide lithium in a mixture of THF/heptane/ethylbenzene, and this mixture was stirred for 1.5 h at a temperature of < -60°C. To the resulting dark brown solution is added dropwise within 10 min was added 2.5 ml (40 mmol) of iodomethane (exothermic reaction, Ti < -48°C). The obtained light brown solution was stirred at a temperature of < -50°C for 2.5 h, then was suppressed by adding a saturated aqueous solution of NH4Cl and three times were extracted /tert-butylmethylamine ether. The combined organic phases are washed 3 times with saline, dried over Na2SO4, filters the if and evaporated obtaining 7,002 g yellow solid, which was purified by flash chromatography on silica gel (5-10% AcOEt in heptane for 25 min and heptane/AcOEt 90:10 for 20 min) to obtain the specified title compound as a pale yellow oil. Mass spectrum (m/z): 288,12 (M+N+).

(C) stage 3: 2-(2-Ethyl-3-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazol

To a chilled solution of 355 mg (1,17 mmol) of 2-(2-methoxy-3-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole in 4 ml of THF dropwise over 20 min at a temperature of < 10°C was added 2.35 ml (4.7 mmol) of 2 M solution of chloride of etermine in THF. The obtained brown solution was stirred for 1 h at ambient temperature, then was suppressed by adding a saturated aqueous solution of NH4Cl (with cooling in an ice bath) and three times was extracted with tert-butylmethylamine ether. The combined organic phases were washed three times with saline, dried over Na2SO4, was filtered and was evaporated to obtain 2-(2-ethyl-3-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole in the form of a yellow oil. Mass spectrum (ISPS (inarabitta in the positive ion mode)): 286,1 ((M+N)+).

a) stage 4: 2-(2-Ethyl-3-methyl-4-trifluoromethyl-phenyl)-3,4,4-trimethyl-4,5-dihydro-oxazol-3-FL iodide

To a solution of 837 mg (2.9 mmol) of 2-(2-ethyl-3-methyl-4-reformer-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole in 8 ml of nitromethane was added to 1.47 ml (23.5 mmol) of methyl iodide and the mixture was heated in a sealed tube to 70°C for 18 hours The obtained brown solution was diluted with tert-butylmethylamine ether, the suspension was filtered and the precipitate washed with tert-butyllithium with ether, and dried to obtain 2-(2-ethyl-3-methyl-4-trifluoromethyl-phenyl)-3,4,4-trimethyl-4,5-dihydro-oxazol-3-FL iodide in the form of a colorless solid. Mass spectrum (ISP): 300,1 (M+).

(e) stage 5: 2-Ethyl-3-methyl-4-trifluoromethyl-benzoic acid

A solution of 960 mg (2.25 mmol) of 2-(2-ethyl-3-methyl-4-trifluoromethyl-phenyl)-3,4,4-trimethyl-4,5-dihydro-oxazol-3-FL iodide in 10 ml of Meon and 5 ml of 20% NaOH was heated to 70°C for 17 hours Obtained yellow solution was cooled to room temperature, kept the Meon and the residue was acidified to pH 1 by adding concentrated HCl and three times was extracted with tert-butylmethylamine ether. The combined organic phases are washed twice with saline, dried over Na2SO4, was filtered and was evaporated to obtain 2-ethyl-3-methyl-4-trifluoromethyl-benzoic acid as a yellow solid. Mass spectrum (ISN (inarabitta in the negative ion mode)): 231,06((M-N)-).

f) stage 6: 2-Ethyl-3-methyl-4-trifluoromethyl-benzoyl chloride

Specified in the title compound was obtained from 2-ethyl-3-methyl-4-trifluoromethyl-benzoic acid using a technique similar to the method of synthesis, the description of the Noi in Example B.6.

Example C.1

Obtaining N-(1,6-Dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide

a) stage 1: (3-Hydroxy-1-methyl-propyl)-methyl-carbamino acid tert-butyl methyl ether

To a solution of 2 g (19,39 mmol) 3-(methylamino)-1-butanol (commercially available, CAS: 89585-18-2) in 15 ml of dichloromethane in a nitrogen atmosphere at room temperature was added 3,24 ml (23,27 mmol) of triethylamine. This reaction mixture was cooled to 0°C was added dropwise a solution to 5.13 g (23,27 mmol) di-tert-butyl-dicarbonate in 5 ml of dichloromethane. This reaction mixture was stirred at room temperature for 2 days, then extinguished by adding a saturated solution of sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified on silica gel (eluent: heptane/ethyl acetate 0-40%) to obtain the specified title compound (3.3 g, 84%) as a colourless oil. Mass spectrum (m/z): 204,3 (M+H).

b) stage 2: (3-Bromo-1-methyl-propyl)-methyl-carbamino acid tert-butyl methyl ether

To a solution of 1 g (4,919 mmol) (3-hydroxy-1-methyl-propyl)-methyl-carbamino acid tert-butyl ester in 12.5 ml of dichloromethane in a nitrogen atmosphere at 0°C was added a 1.46 g (5,411 mmol) of triphenylphosphine and C is the solution to 1.79 g (5,411 mmol) tetrabromide carbon in 3.5 ml of dichloromethane. This reaction mixture was stirred for 3 h at room temperature. The resulting suspension was concentrated under vacuum. The residue was purified on silica gel (eluent: heptane/ethyl acetate 0-15%) to obtain the specified title compound (0.74 g, 57%) as a colourless oil. Mass spectrum (m/z): 210,1 (M-56).

(C) stage 3: Methyl-(1-methyl-4-nitro-4-phenyl-butyl)-carbamino acid tert-butyl methyl ether

To a solution of 304 mg (2,219 mmol) nitro methyl-benzene (CAS: 622-42-4) in 5 ml of tetrahydrofuran over a molecular sieve and 1.29 ml NMRA having a temperature of -78°C, was added only 2.91 ml (4,654 mmol) n-BuLi (1.6 M in hexane).

The solution was kept for 45 min at -78°C, then was added dropwise a solution of 590,7 mg (2,219 mmol) of (3-bromo-1-methyl-propyl)-methyl-carbamino acid tert-butyl ester in 1.5 ml of tetrahydrofuran over a molecular sieve. The reaction mixture was stirred for 1 h at -78°C, then left slowly over 2 h to warm to -15°C. Then the mixture was again cooled to -78°C and was suppressed by adding 0.75 ml of acetic acid, then added 13 ml of saturated ammonium chloride. The mixture was again heated to room temperature and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified on when likehere (eluent: heptane/ethyl acetate 0-10%) to obtain the specified title compound (201 mg, 28%) as a colourless oil. Mass spectrum (m/z): 323,3 (M+H).

d) stage 4: Methyl-(1-methyl-4-nitro-4-phenyl-butyl)-amine

Specified in the title compound was obtained from methyl(1-methyl-4-nitro-4-phenyl-butyl)-carbamino acid tert-butyl ester using methods analogous to the methods of synthesis described in Example a (stage 4). Mass spectrum (m/z): 223,3 (M+H).

(e) stage 5: 1.2-Dimethyl-5-nitro-5-phenyl-piperidine

To a suspension of 138 mg (0,621 mmol) methyl-(1-methyl-4-nitro-4-phenyl-butyl)-amine in 2.2 ml of dioxane in an argon atmosphere at room temperature was added 49,8 ál (0,683 mmol) of formaldehyde (37% in water). This mixture was stirred for 30 min at room temperature and then for 4.5 h at 65°C. Then the mixture was cooled to room temperature and was diluted with ethyl acetate. Was added sodium sulfate. The mixture was filtered and the obtained filtrate was concentrated under vacuum. The residue was purified on silica gel (eluent: heptane/ethyl acetate 0-20%) to obtain the specified title compound (76 mg, 52%) as a colourless oil. Mass spectrum (m/z): 235,3 (M+H).

f) stage 6: 1,6-Dimethyl-3-phenyl-piperidine-3-ylamine

Specified in the title compound was obtained from 1,2-dimethyl-5-nitro-5-phenyl-piperidine using methods analogous to the methods with which NASA, described in Example a (stage 4). Mass spectrum (m/z): 205,3 (M+H).

d) stage 7: N-(1,6-Dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide

Specified in the title compound was obtained from 1,6-dimethyl-3-phenyl-piperidine-3-ylamine and 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6) using methods analogous to the methods of synthesis described in Example 16. Mass spectrum (m/z): 453,2 (M+H).

Example C.2

Obtaining N-((3RS,5SR)-1,5-Dimethyl-3-phenyl-piperidine-3-yl)-2-ethyl-4-trifluoromethyl-benzamide

Specified in the title compound was obtained from (3RS,5SR)-1,5-dimethyl-3-phenyl-piperidine-3-ylamine (Example e) and 2-ethyl-4-trifluoromethyl-benzoic acid (CAS: 854531-63-8) using methods analogous to the methods of synthesis described in Example 1. Mass spectrum (m/z): 405,4 (M+H).

Description of examples of the preparation of compounds

Example 1

rat-2-Chloro-N-(1-methyl-3-phenyl-piperidine-3-yl)-3-trifluoromethyl-benzamide

To a solution of 33 mg (0.144 mmol) of 2-chloro-3-(trifluoromethyl)benzoic acid (commercially available), 75 mg (0,197 mmol) HATU and 90 μl (0,524 mmol) of N-ethyldiethanolamine in DMF (1 ml) solution was added 25 mg (0,131 mmol) rat-1-methyl-3-phenyl-piperidine-3-ylamine (Example A.1) in DMF (0.25 ml). This mixture was stirred for 22 h at room temperature. The solvent was removed is under vacuum. The residue was dissolved in ethyl acetate. The resulting solution was once washed with water and twice with a saturated solution of sodium carbonate. The aqueous layer once were extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified on silica gel (eluent: heptane/ethyl acetate 0-100%) with the output specified in the title compound (27 mg, 52%) as a pale yellow oil. Mass spectrum (m/z): Mass spectrum (m/z): 397,2 (M+H).

By analogy with the compound of Example 1 connections 2-15, shown in the following Table, obtained from the corresponding acid derivatives and piperidinovyh derivatives.

When
measures No.
StructureThe systematic-
ical name
EductFound:
MM (MH+)
2rat-N-(1-Methyl-3-phenyl-piperidine-3-yl)-2,4-bis-trifluoromethyl-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2,4-bis(trifluoromethyl)benzoic acid (imeetsyav sale) that amount to 431,3
3rat-2-Bromo-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-Bromo-4-trifluoromethyl-benzoic acid (CAS: 328-89-2)441,2
4rat-2-Ethyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-Ethyl-4-trifluoromethyl-benzoic acid (CAS: 854531-63-8)391,2
5rat-2-Fluoro-N-(1-methyl-3-phenyl-piperidine-3-yl)-4,6-bis-trifluoromethyl-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-fluoro-4,6-bis(trifluoromethyl)benzoic acid (commercially available)449,2
6rat-2-Chloro-N-(1-methyl-3-phenyl-piperidine-3-yl)-4,6-bis-Tr is formetal-benzamid rat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-chloro-4,6-bis(trifluoromethyl)benzoic acid (commercially available)465,1
7rat-2-Bromo-6-methoxy-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-Bromo-6-methoxy-4-trifluoromethyl-benzoic acid (Example B1)471,1
8rat-2-Methoxy-6-methylsulfanyl-N-(1-methyl-3-para-tolyl-piperidine-3-yl)-4-trifluoromethyl-benzamiderat-1-Methyl-3-para-tolyl-piperidine-3-ylamine (Example A4) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (Example C.2)453,3
9rat-4'-Fluoro-biphenyl-2-carboxylic acid (1-methyl-3-phenyl-piperidine-3-yl)-amiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 4'-forbiden-2-Urbanova acid (commercially available) 389,1
10rat-N-(1-Methyl-3-phenyl-piperidine-3-yl)-2-pyridin-3-yl-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-pyrid-3-yl-benzoic acid (commercially available)372,2
11rat-N-(1,2-Dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamiderat-1,2-Dimethyl-3-phenyl-piperidine-3-ylamine (Example A.5) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (Example C.2)453,2
12rat-2-Ethoxy-N-(1-methyl-3-Hairdryer Il-piperidine-3-yl)-4-trifluoromethyl-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-Ethoxy-4-trifluoromethyl-benzoic acid (CAS: 334018-39-2)407,4
13 rat-2-Cyclopropyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-Cyclopropyl-4-trifluoromethyl-benzoic acid (Example B3)403,3
14rat-5-Trifluoromethyl-biphenyl-2-carboxylic acid (1-methyl-3-phenyl-piperidine-3-yl)-amiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 5-Trifluoromethyl-biphenyl-2-carboxylic acid (Example C.4)439,4
15rat-2-Isopropoxy-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-Isopropoxy-4-trifluoromethyl-benzoic acid (Example B.5)UAH 421,2

Example 16

rat-2-Methoxy-N-(1-methyl-3-phenyl-piperidine-3-yl)-4,6-bis-trifluoromethyl-benzamide

To a solution of 205 mg (of 1.077 mmol) rat-1-methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 369 μl (2,154 mmol) of N-ethyldiethanolamine in dichloromethane(2.5 ml) was added dropwise a solution of 430 mg (1.4 mmol) of 2-methoxy-4,6-bis-trifluoromethyl-benzoyl chloride (CAS: 886503-47-5) in dichloromethane (2.0 ml) at room temperature. This mixture was stirred for 16 h at room temperature. The solvent was removed under vacuum. The crude product was purified on silica gel (eluent: heptane/ethyl acetate 0-100%) with the output specified in the title compound (340 mg, 69%) as a pale yellow foam. Mass spectrum (m/z): 461,4 (M+H).

By analogy with the compound of Example 16 compound 17-28, shown in the following Table, obtained from the corresponding acylchlorides derivatives and related piperidinovyh derivatives.

Example No.StructureThe systematic nameEductFound: MM (MN+)
17rat-2,4-Dichloro-N-(1-methyl-3-phenyl-piperidine-3-yl)-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2,4-dichloro-benzoyl chloride (CAS: 98499-66-2)363,1
18rat-2-Methoxy-N-(1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-triptime-Teal-benzamidrat-1-Methyl-3-phenyl-Pipa is one-3-ylamine (Example A.1) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6) 439,4
19rat-N-(1-Methyl-3-phenyl-piperidine-3-yl)-2-methylsulfanyl-4-trifluoromethyl-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-Methylsulfanyl-4-trifluoromethyl-benzoyl chloride (CAS: 956830-68-5)409,3
20rat-2-Methyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-Methyl-4-trifluoromethyl-benzoyl chloride (CAS: 98499-66-2)377,3
21rat-2-Chloro-N-(1-methyl-3-phenyl-piperidine-3-yl)-5-trifluoromethyl-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-Chloro-5-trifluoromethyl-benzoyl chloride (CAS: 657-05-6)397,2
22rat-Naphthalene-1-carboxylic acid (1-methyl-3-phenyl-piperidine-3-yl)-amiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 1 In tail chloride (commercially available) 345,3
23rat-4-fluoro-2-methoxy-6-methyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 4-fluoro-2-methoxy-6-methyl-benzoyl chloride (CAS: 960531-76-4)357,4
24rat-2-Methyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4,6-bis-trifluoromethyl-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-Methyl-4,6-bis-trifluoromethyl-benzoyl chloride (CAS: 895580-42-4)445,4

25rat-2-Ethyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4,6-bis-trifluoromethyl-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-Ethyl-4,6-bis-trifluoromethyl-benzoyl chloride (Example V)459,4
26rat-N-[3-(4-Fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-4,6-bis-trifluoromethyl-benzamide rat-3-(4-Fluoro-phenyl)-1-methyl-piperidine-3-ylamine (Example A.2) and 2-Methoxy-4,6-bis-Cryptor-methyl-benzoyl chloride (CAS: 886503-47-5)479,1
27rat-N-[3-(4-Fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamiderat-3-(4-Fluoro-phenyl)-1-methyl-piperidine-3-ylamine (Example A.2) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B1)457,2
28rat-N-[3-(4-Chloro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamiderat-3-(4-Chloro-phenyl)-1-methyl-piperidine-3-ylamine (Example A3) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B1)473,3

Example 29

rat-2-Methoxy-N-(3-phenyl-piperidine-3-yl)-4,6-bis-trifluoromethyl-benzamide

a) stage 1: rat-3-Amino-3-phenyl-piperidine-1-carboxylic acid benzyl ester

To the boiling solution of 500 mg (1,486 mmol) rat-3-azido-3-phenyl-piperidine-1-carboxylic acid benzyl ester (Example A.1, step 2) and 281 mg (7,43 mmol) NaBH4wtgf (5 ml) dropwise over 1.5 h was added 2.0 ml of methanol. This mixture was subjected to reflux distilled additionally for 1 h and then stirred overnight at room temperature. Was added 114 mg (3 mmol) NaBH4and the mixture was subjected to reflux distilled for 2 hours Then the mixture was cooled in an ice bath and acidified by adding 1 N. HCl. The mixture was podslushivaet by adding 1 N. NaOH and three times were extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified on silica gel (eluent: heptane/ethyl acetate 0-100%) with the output specified in the title compound (220 mg, 48%) as a colourless oil. Mass spectrum (m/z): 311,4(M+H).

b) stage 2: rat-3-(2-Methoxy-4.6-bis-trifluoromethyl-benzoylamine)-3-Phenyl-piperidine-1-carboxylic acid benzyl ester

Specified in the title compound was obtained from the rat-3-amino-3-phenyl-piperidine-1-carboxylic acid benzyl ester and 2-methoxy-4,6-bis-trifluoromethyl-benzoyl chloride (CAS: 886503-47-5) using methods analogous to the methods of synthesis described in Example 16.

(C) stage 3: rat-2-Methoxy-N-(3-phenyl-piperidine-3-yl)-4,6-bis-trifluoromethyl-benzamide

To a solution of 445 mg (0,767 mmol) rat-3-(2-methoxy-4,6-bis-trifluoromethyl-benzoylamine)-3-phenyl-piperidine-1-carboxylic acid benzyl ester in methanol (4.5 ml) was added 44 mg of 10% Pd/C, This mixture was stirred for 1.5 h at room temperature in a hydrogen atmosphere. The reactor was purged with argon. The catalyst was filtered and the filtrate was concentrated under vacuum to obtain specified in the title compound (330 mg, 96%) as a white foam. Mass spectrum (m/z): 447,3 (M+H).

Example 30

rat-N-(1-Ethyl-3-phenyl-piperidine-3-yl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide

To a solution of 25 mg (0,056 mmol) rat-2-methoxy-N-(3-phenyl-piperidine-3-yl)-4,6-bis-trifluoromethyl-benzamide in 0.25 ml of dichloromethane was added to 19.7 μl (0,112 mmol) of N-ethyldiethanolamine and then to 6.0 μl (0,0728 mmol) of iodata. The solution was stirred for 20 h at room temperature. The solvent was removed under vacuum. The crude product was purified on silica gel (eluent: heptane/ethyl acetate 0-100%) with the output specified in the title compound (15 mg, 58%) as a colourless oil. Mass spectrum (m/z): 475,2 (M+H).

Example 31

rat-N-(1-Isopropyl-3-phenyl-piperidine-3-yl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide

The solution to 35.7 mg (0.08 mmol) of rat-2-methoxy-N-(3-phenyl-piperidine-3-yl)-4,6-bis-trifluoromethyl-benzamide in methanol was added 28 μl (0.48 mmol) of acetic acid, 59 μl (0.8 mmol) of acetone and then 30 mg (0.4 mmol) of cyanoborohydride sodium. This mixture was stirred for 4 h at room temperature. The solvent was removed under vacuum. The residue was transferred into ethyl acetate. This mixture one respomible 1 N. NaOH solution, once with water and once with brine. The aqueous layer once were extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified on silica gel (eluent: heptane/ethyl acetate 0-100%) with the output specified in the title compound (33 mg, 85%) as a white foam. Mass spectrum (m/z): 489,4 (M+H).

By analogy with the compound of Example 31 compound 32-34, shown in the following Table, were obtained from rat-2-methoxy-N-(3-phenyl-piperidine-3-yl)-4,6-bis-trifluoromethyl-benzamide and carbonyl derivatives.

Example No.StructureThe systematic nameEductFound:
MM (MH+)
32rat-N-(1-Cyclopentyl-3-phenyl-piperidine-3-yl)-2-methoxy-4,6-bis-trifluoromethyl-benzamideCyclopentanone515,5
33rat-N-(1-Cyclopropylmethyl-3-Fe is Il-piperidine-3-yl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide cyclopropane boxelder501,3
34rat-2-Methoxy-N-[3-phenyl-1-(tetrahydro-Piran-4-yl)-piperidine-3-yl]-4,6-bis-trifluoromethyl-benzamidetetrahydro-4H-Piran-4-one531,3

Compounds of Examples 35-38 obtained by separation of the racemic mixture using chiral ghvd.

Example No.StructureThe systematic nameThe original racemic mixtureRetention time (min)*Found:
MM (MH+)
352-Methoxy-N-((S)-1-methyl-3-phenyl-piperidine-3-yl)-4,6-bis-trifluoromethyl-benzamiderat-2-Methoxy-N-(1-methyl-3-phenyl-piperidine-3-yl)-4,6-bis-trifluoromethyl-benzamide Example 16)of 5.4461,4

36 2-Methoxy-N-((R)-1-methyl-3-phenyl-piperidine-3-yl)-4,6-bis-trifluoromethyl-benzamiderat-2-Methoxy-N-1-methyl-3-phenyl-piperidine-3-yl)-4,6-bis-trifluoromethyl-benzamide (Example 16)10,3461,4
372-Methoxy-N-(S)-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide hydrochloriderat-2-Methoxy-N-(1-methyl-3-phenyl-piperidine-3-yl)-6-metralha-Neil-4-Cryptor-methyl-benzamide (Example 18)7,3RUR 439,3
382-Methoxy-N-((R)-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-Cryptor-methyl-benzamide hydrochloriderat-2-Methoxy-N-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide (Example 18)14,1RUR 439,3
*Analytical separation:
Column: Chiralpak AD; Eluent: 15% Isopropanol/Heptane; flow: 35 ml, UV registration: 254 nm

By analogy with the compound of Example 1 is soedineniya 39-44, in the following Table, obtained from the corresponding acid derivatives and related piperidinovyh derivatives.

Example No.StructureThe systematic nameEductFound: MM (MH+)
39rat-2-Deformedarse-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-Deformedarse-4-trifluoromethyl-benzoic acid (Example Q. 8)429,2
40rat-2-Chloro-N-(1-methyl-3-phenyl-piperidine-3-yl)-6-trifluoromethyl-nicotinamide hydrochloriderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-chloro-6-(trifluoromethyl)nicotinic acid (commercially available)398,1
41rat-2-Chloro-N-(1-methyl-3-phenyl-piperidine-3-yl)-6-trifluoromethyl-nicotinamide of hydrochl the Reid rat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-pyrrolidin-1-yl-4-trifluoromethyl-benzoic acid (Example B.9)432,4
42rat-4-Cyclopropyl-2-trifluoromethyl-pyrimidine-5-carboxylic acid (1-methyl-3-phenyl-piperidine-3-yl)-amiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 4-cyclopropyl-2-cryptomailer-midin-5-carboxylic acid (commercially available)405,4
43rat-2-Cyclohexyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-Cyclohexyl-4-trifluoromethyl-benzoic acid (Example B.10)445,4
44rat-2-Cyclopentyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-Cyclopentyl-4-trifluoromethyl-benzoic acid (Example V)that amount to 431,3

By analogy with the connection P is the iMER 16 connection 45-48, in the following Table, obtained from the corresponding acylchlorides derivatives and piperidinovyh derivatives.

Example No.StructureThe systematic nameEductFound:
MM (MH+)
45rat-N-[3-(3-Chloro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide hydrochloriderat-3-(3-Chloro-phenyl)-1-methyl-piperidine-3-ylamine (Example A6) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)473,2
46rat-2-Methoxy-N-[3-(4-methoxy-phenyl)-1-methyl-piperidine-3-yl]-6-methylsulfanyl-4-trifluoromethyl-benzamiderat-3-(4-Methoxy-phenyl)-1-methyl-piperidine-3-ylamine (Example A7) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)469,2
47 rat-N-(5-fluoro-G-methyl-1',4',5',6'-tetrahydro-2 N-[2,3']bipyridinyl-3'-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamiderat-5-fluoro-G-methyl-1',4',5',6'-tetrahydro-2H-[2,3']bipyridinyl-3'-ylamine (Example A. 8) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)458,2
48rat-N-(5-fluoro-1-methyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamiderat-5-fluoro-1-methyl-3-phenyl-piperidine-3-ylamine (Example A.9) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)457,2

Example 49 rat-2-Cyclopropyl-N-(3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide

Specified in the title compound was obtained from the rat-3-amino-3-phenyl-piperidine-1-carboxylic acid benzyl ester and 2-cyclopropyl-4-trifluoromethyl-benzoic acid (Example B3) using methods analogous to the methods of synthesis described in Example 29. Mass spectrum (m/z): 389,1 (MH+).

Example 50

rat-2-Methoxy-6-methylsulfanyl-N-(3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide hydrochloride

(a) one Hundred who ia 1: rat-3-(2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoylamine)-3-phenyl-piperidine-1-carboxylic acid benzyl ester

Specified in the title compound was obtained from the rat-3-amino-3-phenyl-piperidine-1-carboxylic acid benzyl ester (Example 29, step 1) and 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6) using methods analogous to the methods of synthesis described in Example 16. Mass spectrum (m/z): 559,1 (MH+).

b) stage 2: rat-2-Methoxy-6-methylsulfanyl-N-(3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide hydrochloride

To a solution of 50 mg (0,0895 mmol) rat-3-(2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoylamine)-3-phenyl-piperidine-1-carboxylic acid benzyl ester in 1 ml of ethanol in an argon atmosphere at room temperature was added 57 mg (0,895 mmol) of ammonium formate and 50 mg of 10% Pd/C. This mixture was subjected to reflux distilled for 20 min, filtered and the resulting filtrate was concentrated under vacuum. The residue is transferred into the water. The aqueous layer was podslushivaet 2 m solution of Na2CO3and 3 times was extracted with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified on silica gel (eluent: heptane/ethyl acetate 0-100%) with access to 13.4 mg of product which was dissolved in methanol. This solution was acidified 1.6 M solution of HCl in methanol. The solvent was removed under vacuum to obtain 13 mg specified the CSOs in the title compound as a pale yellow solid. Mass spectrum (m/z): 425,1 (MH+).

Example 51

rat-N-(5-Hydroxy-1-methyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide

a) stage 1: rat-2-Methoxy-N-(5-methoxyethoxy-1-methyl-3-Phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide

Specified in the title compound was obtained from the rat-5-methoxyethoxy-1-methyl-3-phenyl-piperidine-3-ylamine (Example A.10) and 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6) using methods analogous to the methods of synthesis described in Example 16. Mass spectrum (m/z): 499,3 (MH+).

b) stage 2: rat-N-(5-Hydroxy-1-methyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide

To a solution of 17 mg (0,0341 mmol) rat-2-methoxy-N-(5-methoxyethoxy-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide in 0.5 ml of methanol was added 102 μl (is 0.102 mmol) of 1 n HCI solution in water. This mixture was stirred for 30 min at room temperature and then at 65°C in oil bath for 24 h the Solvent was removed under vacuum. The residue is transferred into the water. The aqueous layer was podslushivaet 2 m solution of Na2CO3and 3 times was extracted with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated under vacuum. Received n the purified product was purified on silica gel (eluent: heptane/ethyl acetate 0-100%) with the output specified in the title compound (8 mg, 52%) as a white solid. Mass spectrum (m/z): to 455.2 (MH+).

Example 52

rat-2-Methoxy-N-[1-(2-methoxy-ethyl)-3-phenyl-piperidine-3-yl]-6-methylsulfanyl-4-trifluoromethyl-benzamide hydrochloride

Specified in the title compound was obtained from rat-2-methoxy-6-methylsulfanyl-N-(3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide hydrochloride (Example 50) and 2-pomatoleios ester using methods analogous to the methods of synthesis described in Example 30. Mass spectrum (m/z): 483,2 (MH+).

Example 53

rat-N-[1-(2-Hydroxy-ethyl)-3-phenyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide hydrochloride

Specified in the title compound was obtained from rat-2-methoxy-6-methylsulfanyl-N-(3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide hydrochloride (Example 50) and 2-gadatanili using methods analogous to the methods of synthesis described in Example 30. Mass spectrum (m/z): 469,2 (MH+).

Example 54

rat-N-(1-Cyclobutyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide hydrochloride

Specified in the title compound was obtained from rat-2-methoxy-6-methylsulfanyl-N-(3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide hydrochloride (Example 50) and cyclobutanone using methods similar to the methods of synthesis, described in Example 31. Mass spectrum (m/z): 479,1 (MH+).

Example 55

rat-N-(1-Isopropyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide hydrochloride

Specified in the title compound was obtained from rat-2-methoxy-6-methylsulfanyl-M-(3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide hydrochloride (Example 50) and acetone using methods analogous to the methods of synthesis described in Example 31. Mass spectrum (m/z): 467,2 (MH+).

Connection Examples 56-57 obtained by separation of the racemic mixture using chiral ghvd and subsequent transformation into cleaners containing hydrochloride salt using HCL/Methanol.

Example No.StructureThe systematic nameThe original racemic mixtureRetention time (min)*Found:
MM (MH+)
562-Cyclopropyl-N-((S)-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide hydrochloriderat-2-Cyclopropyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide (Example 13) 5,6403,3
572-Cyclopropyl-N-((R)-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide hydrochloriderat-2-Cyclopropyl-N-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide Example 13)18,8403,3
*Analytical separation:
Column: Chiralpak AD; Eluent: 15% Isopropanol/Heptane; flow 35 ml, UV-registration: 254 nm

Example 58

rat-N-(3-Cyclohexyl-1-methyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide

Specified in the title compound was obtained from the rat-3-cyclohexyl-1-methyl-piperidine-3-ylamine (Example e) and 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B6) using methods analogous to the methods of synthesis described in Example 16. Mass spectrum (m/z): 445,2 (MH+).

Example 59

rat-2-Methoxy-6-methylsulfanyl-N-[1-methyl-3-(tetrahydro-Piran-4-yl)-piperidine-3-yl]-4-trifluoromethyl-benzamide

Specified in the title compound was obtained from rat-1-methyl-3-(tetrahydro-Piran-4-yl)-piperidine-3-ylamine (Example e) and-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B6) using techniques analogous to the methods of synthesis described in Example 16. Mass spectrum (m/z): 447,2 (MH+).

Example 60

rat-N-(1,3-Dimethyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide

Specified in the title compound was obtained from rat-1,3-dimethyl-piperidine-3-ylamine dihydrochloride (Example a) and 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B6) using methods analogous to the methods of synthesis described in Example 16. Mass spectrum (m/z): 377,3 (MH+).

Connection Examples 61-62 obtained by separation of the racemic mixture using chiral ghvd.

Example No.StructureThe systematic nameThe original racemic mixtureRetention time (min)*Found:
MM (MH+)
612-Methoxy-6-methylsulfanyl-N-((S) or (R)-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamiderat-2-Methoxy-6-methylsulfanyl-N-(3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide (Example 50)11,0425,1
622-Methoxy-6-methylsulfanyl-N-((R) or 5)-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamiderat-2-Methoxy-6-methylsulfanyl-N-(3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide (Example 50)13,5425,1
*Analytical separation:
Column: ChiralpakAD; Eluent: 15% Isopropanol/Heptane

Example 63

[2N-methyl]-2-Methoxy-N-(R) or (S)-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide hydrochloride

Specified in the title compound was obtained from 2-methoxy-6-methylsulfanyl-N-((R) or (S)-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide (Example 62) and three-deteriorated iodide using methods analogous to the methods of synthesis described in Example 30. Mass spectrum (m/z): 442,3 (MH+).

Example 64

rat-2-Methoxy-6-methylsulfanyl-N-(1-oxetan-3-yl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide hydrochloride

Specified in the title compound was obtained from rat-2-methoxy-6-methylsulfanyl-N-(3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide hydrochloride (Example 50) and oxetane is and using methods analogous to the methods of synthesis described in Example 31. Mass spectrum (m/z): 481,1 (MH+).

Example 65

N-((3RS,5RS)-5-Hydroxy-1-methyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide

a) stage 1: rat-2-Methoxy-N-(1-methyl-5-oxo-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide

To a solution of 11 μl (0.21 mmol) of oxalicacid in 0.8 ml dichloromethane, having a temperature of -50°C for 15 min was added to a solution of 17.2 μl DMSO in 0.2 ml of dichloromethane. This reaction mixture was stirred for 10 min, then was added over 15 min a solution of 50 mg (0.11 mmol) rat-N-(5-hydroxy-1-methyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (Example 51) in 0.8 ml dichloromethane. After stirring for 30 min was added 77 μl (0.55 mmol) of triethylamine. The reaction mixture was stirred for 15 min, then left to warm to room temperature and extinguished with water, the aqueous layer was extracted with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified on silica gel (eluent: heptane/ethyl acetate 0-15%) to obtain the specified title compound (44 mg, 89%) as a white foam. Mass spectrum (m/z): 453,1 (MH+).

b) stage 2: N-((3RS,5RS)-5-is hydroxy-1-methyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide

To a solution of 23 mg (0,0508 mmol) rat-2-methoxy-N-(1-methyl-5-oxo-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide in and 0.46 ml of methanol was added 3.9 mg (is 0.102 mmol) sodium borohydride. This mixture was stirred for 30 min at room temperature, was suppressed by adding 1.0 ml of 1 N. HCl and was stirred for 15 minutes was Added water and the resulting mixture was podslushivaet 2 M solution of sodium carbonate. Then the mixture 3 times was extracted with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified on silica gel (eluent: heptane/ethyl acetate 0-100%) with the output specified in the title compound (4.5 mg, 20%) as a white solid. Mass spectrum (m/z): to 455.2 (MH+).

By analogy with the compound of Example 1 connection 66-84, shown in the following Table, obtained from the corresponding acid derivatives and related piperidinovyh derivatives.

Example No.StructureThe systematic nameEductFound:
MM (MH+)
66 rat-2-Cyclobutyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide hydrochloriderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-Cyclobutyl-4-trifluoromethyl-benzoic acid (Example century.12)417,3
67rat-N-[3-(2,4-Debtor-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamiderat-3-(2,4-Differenl)-1-methyl-piperidine-3-ylamine (Example A. 14) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (Example C.2)475,5

68rat-N-[3-(2-Fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamiderat-3-(2-Fluoro-phenyl)-1-methyl-piperidine-3-ylamine (Example e) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (Example C.2)457,6
69rat-N-[3-(2,5-Debtor-phenyl)-1-methyl-piperidine-3-yl]-2-methods the si-6-methylsulfanyl-4-trifluoromethyl-benzamide eats-3-(2,5-Debtor-phenyl)-1-methyl-piperidine-3-ylamine (Example e) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (Example C.2)475,5
70rat-2-Isopropyl-M-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide hydrochloriderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-Isopropyl-4-trifluoromethyl-benzoic acid (Example V)405,4
71rat-2-Methoxy-6-methylsulfanyl-N-(1-Methyl-1,4,5,6-etrahydro-2H-3,4']bipyridinyl-3-yl)-4-trifluoromethyl-benzamiderat-1-Methyl-1,4,5,6-etrahydro-2H-3,4']bipyridinyl-3-ylamine (Example A. 17) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (Example C.2)440,2
72rat-2-Ethyl-N-(1-methyl-1,4,5,6-etrahydro-2H-3,4']bipyridinyl-3-yl)-4-trifluoromethyl-benzamide hydrochloriderat-1-Methyl-1,4,5,6-tetrahydro-2H-3,4']bipyridinyl-3-Ilam is n (Example a) and 2-Ethyl-4-trifluoromethyl-benzoic acid (CAS: 854531-63-8) 392,2
73rat-2-Methoxy-6-methylsulfanyl-N-(1-Methyl-1,4,5,6-etrahydro-2H-3,3']bipyridinyl-3-yl)-4-trifluoromethyl-benzamiderat-1-Methyl-1,4,5,6-tetrahydro-2H-3,3']bipyridinyl-3-ylamine (Example e) and 2-Methoxy-6-methylsulfanyl-4-reformer-benzoic acid (Example C.2)440,2
74rat-2-Ethyl-N-(1-methyl-1,4,5,6-etrahydro-2H-3,3']bipyridinyl-3-yl)-4-trifluoromethyl-benzamide hydrochloriderat-1-Methyl-1,4,5,6-tetrahydro-2H-3,3']bipyridinyl-3-ylamine (Example A. 18) and 2-Ethyl-4-trifluoromethyl-benzoic acid (CAS: 854531-63-8)392,2
752-Methoxy-N-((3RS,5SR}-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-6-metralha-Neil-4-trifluoromethyl-benzamide(3RS,5SR}-5-Methoxy-1-methyl-3-phenyl-piperidine-3-ylamine (Example A. 19) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (Example C.2)469,2
76 2-Cyclopropyl-N-((3RS,5SR)-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide(3RS,5SR}-5-Methoxy-1-methyl-3-phenyl-piperidine-3-ylamine (Example e) and 2-Cyclopropyl-4-trifluoromethyl-benzoic acid (Example B3)433,4
772-Ethyl-N-((3RS,5SR)-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide(3RS,5SR)-5-Methoxy-1-methyl-3-phenyl-piperidine-3-ylamine (Example e) and 2-Ethyl-4-trifluoromethyl-benzoic acid (CAS: 854531-63-8)421,1
78rat-2,4-Dichloro-6-methoxy-N-(1-methyl-3-phenyl-piperidine-3-yl)-benzamide hydrochloriderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2,4-Dichloro-6-methoxy-benzoic acid (CAS: 92294-09-4)393
79rat-4-Methoxy-2,6-dimethyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-benzamiderat-1-Methyl-3-phenyl-piperidine-3-silts is (Example A.1) and 4-Methoxy-2,6-dimethyl-benzoic acid (CAS: 37934-89-7) 353,3
80rat-2,6-Dimethoxy-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2,6-Dimethoxy-4-trifluoromethyl-benzoic acid (Example V)423,2
81rat-2-Methoxy-N-1-methyl-3-phenyl-piperidine-3-yl)-6-(2,2,2-Cryptor-ethoxy)-4-trifluoromethyl-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1) and 2-Methoxy-6-(2,2,2-Cryptor-ethoxy)-4-trifluoromethyl-benzoic acid (Example C. 15)491,2
822-Cyclopropyl-N-((3RS,5SR)-1,5-dimethyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide hydrochloride(3RS,5SR)-1,5-Dimethyl-3-phenyl-piperidine-3-ylamine (Example e) and 2-Cyclopropyl-4-trifluoromethyl-benzoic acid (Example B3)417,3
83R is C-2-Cyclopropyl-4-trifluoromethyl-N-(1,5,5-trimethyl-3-phenyl-piperidine-3-yl)-benzamide rat-1,5,5-Trimethyl-3-phenyl-piperidine-3-ylamine (Example e) and 2-Cyclopropyl-4-trifluoromethyl-benzoic acid Example B.3)that amount to 431,3
84rat-2-Methoxy-6-methylsulfanyl-4-Cryptor-methyl-N-(1,6,6-trimethyl-3-phenyl-piperidine-3-yl)-benzamide hydrochloriderat-1,6,6-Trimethyl-3-phenyl-piperidine-3-ylamine (Example e) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (Example C.2)467,2

By analogy with the compound of Example 16 compound 85-105, shown in the following Table, obtained from the corresponding acylchlorides derivatives and related piperidinovyh derivatives.

Example No.StructureThe systematic nameh eductFound:
MM (MH+)
85N-((3RS,5SR)-1,5-Dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide hydroch Oric (3RS,5SR)-1,5-Dimethyl-3-phenyl-piperidine-3-ylamine (Example e) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)453,5
862-Methoxy-N-({3RS,5SR)-5-methoxyethoxy-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamiderat-5-Methoxyethoxy-1-methyl-3-phenyl-piperidine-3-ylamine (Example A. 10) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)499,3
87rat-N-[3-(3-Bromo-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide hydrochloriderat-3-(3-Bromo-phenyl)-1-methyl-piperidine-3-ylamine (Example e) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)from 517.2
88rat-N-[3-(2-Chloro-4-fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide/td> rat-3-(2-Chloro-4-fluoro-phenyl)-1-methyl-piperidine-3-ylamine (Example e) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)491,1
89rat-2-Methoxy-6-methylsulfanyl-N-[1-methyl-3-(3-trifluoromethyl-phenyl)-piperidine-3-yl]-4-trifluoromethyl-benzamiderat-1-Methyl-3-(3-trifluoromethyl-phenyl)-piperidine-3-ylamine (Example e) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)507,2
90EAC-2-Methoxy-6-methylsulfanyl-N-[1-methyl-3-(3-triptoreline-phenyl)-piperidine-3-yl]-4-trifluoromethyl-benzamiderat-1-Methyl-3-(3-giftomatics-phenyl)-piperidine-3-ylamine (Example e) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)523,1
91rat-2-Methoxy-N-[3-(3-methoxy-phenyl)-1-methyl-piperidine-3-yl]-6-methylsulfanyl-4-reformer-benzamid rat-3-(3-Methoxy-phenyl)-1-methyl-piperidine-3-ylamine (Example e) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)469,2
92rat-N-[3-(3-Deformedarse-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide, salt of formic acidrat-3-(3-Deformedarse-phenyl)-1-methyl-piperidine-3-ylamine (Example e) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)505,2
93rat-N-[3-(3-Fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide, salt of formic acidrat-3-(3-Fluoro-phenyl)-1-methyl-piperidine-3-ylamine (Example AZO) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)457,2
94rat-N-[3-(3-Chloro-4-fluoro-phenyl)-1-methyl-piperidine--yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide rat-3-(3-Chloro-4-fluoro-phenyl)-1-methyl-piperidine-3-ylamine (Example e) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)491,1
95rat-N-[3-(3,4-Ceptor-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamiderat-3-(3,4-Debtor-phenyl)-1-methyl-piperidine-3-ylamine (Example e) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)475,1
96rat-2-Methoxy-6-methylsulfanyl-N-(1-methyl-3-meta-tolyl-piperidine-3-yl)-4-trifluoromethyl-benzamiderat-1-Methyl-3-meta-tolyl-piperidine-3-ylamine (Example e) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)453,2
97rat-N-[3-(4-Fluoro-3-methyl-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide rat-3-(4-Fluoro-3-methyl-phenyl)-1-methyl-piperidine-3-ylamine (Example A. 34) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)471,2
98rat-N-[3-(3,5-Debtor-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamiderat-3-(3,5-Debtor-phenyl)-1-methyl-piperidine-3-ylamine (Example e) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)475,1
99rat-2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-N-(1,5,5-trimethyl-3-phenyl-piperidine-3-yl)-benzamide hydrochloriderat-1,5,5-Trimethyl-3-phenyl-piperidine-3-ylamine (Example e) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)467,2
100rat-N-[3-(3-Chloro-phenyl)-1-methyl-piperidine-3-yl]-2-methylsulfanyl-4-trifluoromethyl-benzamiderat-3-(3-the ers-phenyl)-1-methyl-piperidine-3-ylamine (Example A6) and 2-Methylsulfanyl-4-trifluoromethyl-benzoyl chloride (CAS: 956830-68-5) 443,1
101rat-2-Chloro-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamiderat-1-Methyl-3-phenyl-piperidine-3-ylamine(Example A. 1) and 2-Chloro-4-trifluoromethyl-benzoyl chloride (CAS: 76286-03-8)397,1
102rat-2-Methoxy-6-methylsulfanyl-N-[1-methyl-3-(3-Gasol-2-yl-phenyl)-piperidine-3-yl]-4-trifluoromethyl-benzamide, salt of formic acidrat-1-Methyl-3-(3-Gasol-2-yl-phenyl)-piperidine-3-ylamine (Example E) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)522,1
103rat-2-Ethyl-3-methyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide, salt of formic acidrat-1-Methyl-3-phenyl-piperidine-3-ylamine (Example A.1 and 2-Ethyl-3-methyl-4-trifluoromethyl-benzoyl chloride (Example V)405,2
104rat-N-(1-tert-butyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamiderat-1-tert-Butyl-3-phenyl-piperidine-3-ylamine (Example e) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)481,2
105rat-2-Methoxy-N-(4-methyl-6-phenyl-4-Aza-Spiro[2,5]Oct-6-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamiderat-4-Methyl-6-phenyl-4-Aza-Spiro[2,5]Oct-6-ylamine hydrochloride (Example a) and 2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6)465,2

Connection Examples 106-128 obtained by separation of the racemic mixture using chiral ghvd.

Example No.StructureThe systematic nameThe original racemic mixtureType of columnRetention time (min)* Found: MM (MH+)
106N-((3S,5R) or (3R,5S)-5-Hydroxy-1-methyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide hydrochloriderat-N-(5-Hydroxy-1-methyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (Example 51)And6,9to 455.2
107N-((3R,5S) or (3S,5R)-5-Hydroxy-1-methyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-Cryptor-methyl-benzamide hydrochloriderat-N-(5-Hydroxy-1-methyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (Example 51)And10,2to 455.2
1082-Methoxy-N-((3R,5S) or (3S,5R)-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide-Methoxy-N-{{3RS,5SR)-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide (Example 75) In22,7469,2
1092-Methoxy-N-((3S,5R) or (3R,5S)-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide2-Methoxy-N-((3RS,5SR)-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide Example 75)Inof 31.4469,2

110N-[(S or R)-3-(2-Fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamiderat-N-[3-(2-Fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide Example 68)And8,0457,2
111N-[(R or S)-3-(2-Fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide rat-N-[3-(2-Fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (Example 68)And14,6457,2
112N-[(S or R)-3-(2,5-Debtor-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamiderat-N-[3-(2,5-Debtor-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide Example 69)And14,6475,1
113N-[(R or S)-3-(2,5-Debtor-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamiderat-N-[3-2,5-Debtor-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (Example 69)And15,8475,1
1142-Ethyl-N-((S or R)-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide hydrochloriderat-2-Ethyl-1-(1-methyl-3-phenyl-PIP is ridin-3-yl)-4-trifluoromethyl-benzamide (Example 4) Andof 5.4391,2
1152-Ethyl-N-({R or S)-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide hydrochloriderat-2-Ethyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide (Example 4)And9,9to € 391.1
1162-Methoxy-6-methyl-effect-free remedy 4-Cryptor-methyl-n-((5 or R)-1,5,5-trimethyl-3-phenyl-piperidine-3-yl)-benzamiderat-2-Methoxy-6-methylal-panel-4-griffore-Gil-N-(1,5,5-trimethyl-3-phenyl-piperidine-3-yl)-benzamide hydrochloride Example 99)9,8467,2
117N-((3S,6S) or (3R,6R)-1,6-Dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamideN-(1,6-Dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (Example C.1)And7,5 453,2

118N-((3S,6R) or (3R,6S)-1,6-Dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamideN-(1,6-Dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (Example C.1)And8,9453,2
119N-((3R,6R) or (3S,6S)-1,6-Dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamideN-(1,6-Dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (Example C.1)And10,8453,2
120N-((3R,6S) or (3S,6R)-1,6-Dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamideN-(1,6-Dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (Example C.1)And15,7121N-((3S,5R) or (3R,5S)-1,5-Dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamideN-((3RS,5SR)-1,5-Dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide hydrochloride (Example 85)14.4V453,2
122N-((3R,5S) or (3S,5R)-1,5-Dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamideN-((3RS,5SR)-1,5-Dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide hydrochloride (Example 85)17,7453,2
123N-((3S,5R) or (3R,5S)-1,5-Dimethyl-3-phenyl-piperidine-3-yl)-2-ethyl-4-trifluoromethyl-benzamideN-((3RS.5SR)-1,5-Dimethyl-3-phenyl-piperidine-3-yl)-2-ethyl-4-trifluoromethyl-benzamide (Example C.2)And5,6405,2
124N-((3R,5S) or (3S,5R)-1,5-Dimethyl-3-phenyl-piperidine-3-yl)-2-ethyl-4-trifluoromethyl-benzamideN-((3RS.5SR)-1,5-Dimethyl-3-phenyl-piperidine-3-yl)-2-ethyl-4-trifluoromethyl-benzamide (Example C.2)And17,8405,2
1252-Ethyl-N-((3R,5S) or (3S,5R)-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide2-Ethyl-N-((3RS,5SR)-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide (Example 77)In7,1UAH 421,2

1262-Cyclo-propyl-N-((3R,5S) or (3S,5R)-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide2-Cyclo-propyl-N-((3RS,5SR)-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide (Example 76)18433,4
1272,6-Di is ethoxy-N-((S) or (R)-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide rat-2,6-Dimethoxy-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide (Example 80)Inthe 9.7423,2
1282,6-Dimethoxy-N-(R or S)-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamiderat-2,6-Dimethoxy-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide (Example 80)In20,7423,2
*Analytical separation:
Column: A: Chiralpak AD; In: Lux 2 cellulose; S: Reprosil chiral NR. Eluent: 15% Isopropanol/Heptane

The compounds of Formula I and their pharmaceutically acceptable salts accession possess useful pharmacological properties. Specifically, it was found that the compounds of the present invention are good inhibitors of the glycine vector I (GlyT-1).

These compounds were investigated using tests described in the present description below.

Solutions and substances

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

Buffer to absorb (UB): 150 mm NaCl, 10 mm Hepes (N-2-hydroxyethylpiperazine-N'-2-econsultancy acid)-Tris, pH of 7.4, 1 mm CaCl2, 2.5 mm KCl, 2.5 mm MgSO4, 10 mm ( + )-D-glucose.

Cells Flp-in™-CHO (Invitrogen, Cat no.R758-07), stable transfetsirovannyh mGlyTlb cDNA.

Analysis of the inhibition of the absorption of glycine (mGlyT-lb)

On the first day of mammalian cells (Flp-in™-CHO), transfetsirovannyh mGlyT-lb cDNA, were seeded with a density of 40,000 cells/well in complete medium F-12 without hygromycin in 96-well culture plates. On the second day, the medium was aspirated and cells washed twice with buffer to absorb. Then cells were incubated for 20 min at 22°With or without a potential inhibitor (1), or with 10 mm non-radioactive glycine (2), or with the potential inhibitor in any concentration (3). In order to obtain data to calculate the concentration of inhibitor resulting in 50%-th inhibition (for example, IR50concentration of competing compound providing 50%inhibition of the absorption of glycine)used a range of concentrations of potential inhibitors. Immediately after this was added a solution containing 60 nm of [3H]-glycine (11-16 Ci/mmol) and 25 μm non-radioactive glycine. The plates were incubated at weak shaking, the reaction was stopped by odasi the project for the mixture and washing (three times) cooled to 0°C UB. Cells were literally scintillation fluid was shaking for 3 hours, counting the radioactivity of the cells using a scintillation counter.

Compounds described in the Examples 1-60 have the meanings IR50<1,0 μm. Preferred values IR50(<0.2 μm) for compounds 1-128 are shown in Table 1.

Table 1
ExampleIR50(µm)ExampleIR50(µm)
40,0264770,0881
50,1074800,1759
70,0854820,0253
110,0202830,03
13 0,013840,0173
160,1379850,0313
180,0244860,0715
190,0672870,0396
250,1256880,1457
260,0593890,107
270,0262910,1132
280,0277930,0479
360,0839940,0596
370,1817950,0515
380,0101960,0682
390,1843970,1851
450,0245980,0622
460,1693990,0366
470,18111030,0773
480,19731040,1734
510,05821050,0293
550,07771070,0312
560,16171080,0409
570,02271090,1507
580,15611110,0573
630,01001130,0564
660,2431150,0259
670,12891160,0358
680,17461170,0324
690,11751190,0139
700,19731200,0127
710,05591210,0165
720,03691240,0127
730,05441250,1761
740,12261260,0312
750,05381280,1255
760,0929

The compounds of Formula I and pharmaceutically acceptable salts of compounds of Formula I can be used as medicaments, for example in the form of pharmaceutical preparations. Data 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. However, it can also be done rectal administration, for example in the form of suppositories, or parenteral administration, for example in the form of solutions for injection.

For the manufacture of pharmaceutical preparations of the compounds of Formula I can be used together with pharmaceutically inert, inorganic or organic carriers. For example, as such carriers for tablets, coated tablets, dragées and hard gelatin capsules can be used lactose, corn starch or its derivatives, talc, stearic acid or its salts and the like. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. However, depending on the nature of the active substance in the case of soft Gelati the new capsules carriers usually are not required. Suitable carriers for the manufacture of solutions and syrups are, for example, water, polyols, glycerine, vegetable oil, and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

Moreover, the pharmaceutical preparations can contain preservatives, soljubilizatory, stabilizing agents, moistening agents, emulsifiers, sweeteners, colorants, corrigentov, salts for regulating the osmotic pressure, buffer agents, masking agents or antioxidants. They can also contain other therapeutically useful substances.

Drugs, containing a compound of Formula I or its pharmaceutically acceptable salt and a therapeutically inert carrier are also an object of the present invention, as the method of their production, which comprises bringing one or more compounds of the Formula I and/or their pharmaceutically acceptable salts accession acids and, if required, one or more other therapeutically useful substances to form Galanova drug together with one or more therapeutically inert carriers.

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

Of course, the dosage can vary within wide limits and is generally in each case it should be selected in accordance with individual needs. 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 dose may be entered as a single dose or in the form of fractional doses, and, in addition, can also be exceeded when indicated.

The drug tablets (wet granulation)

ItemIngredientsmg tablet
5 mg25 mg100 mg500 mg
1.The compound of the Formula I525100500
2. Lactose anhydrous DTG12510530150
3.Sta-Rx150066630
4.Microcrystalline cellulose303030150
5.Magnesium stearate1111
6.Only167167167831

The method of production

1. Mix the substances 1, 2, 3 and 4 and the mixture granularit with purified water.

2. Dry the granules at 50°C.

3. Pass the granules through a suitable milling equipment.

4. Add substance 5 and stirred for three minutes; pressed on a suitable press.

Drug capsules

Item Ingredientsmg tablet
5 mg25 mg100 mg500 mg
1.The compound of the Formula I525100500
2.Lactose water159123148-
3.Corn starch25354070
4.Talc10151025
5.Magnesium stearate1225
6.Only200 200300600

The method of production

1. Mix the substances 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add substances 4 and 5 and mix for 3 minutes.

3. Fill a suitable capsule.

1. The compound of General Formula

where
R1represents a hydrogen atom, lower alkyl, CD3, -(CH2)n-CHO, -(CH2)n-O-lower alkyl, -(CH2)n-OH, -(CH2)n-cycloalkyl or is heteroseksualci (where heteroseksualci represents a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is replaced by O);
R2represents a hydrogen atom, halogen atom, hydroxy, lower alkyl, di-lower alkyl, -OCH2-O-lower alkyl or lower alkoxy; or piperidine ring together with R2forms a Spiro ring selected from 4-Aza-Spiro[2,5]Oct-6-yl;
Ar represents aryl or heteroaryl (where heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring containing 6 ring atoms, and which contains at least one heteroatom selected from N), which may have one, two or three substituent selected from a halogen atom, lower alkyl, NISS the th alkyl, having as substituents, halogen atom, lower alkoxy having as substituents halogen atom, cycloalkyl, lower alkoxy, S-lower alkyl, geterotsiklicheskie (where heteroseksualci represents a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is replaced by N), or may have as substituents of the phenyl which may have as substituents R', and
R' represents a halogen atom, CF3, lower alkyl, lower alkoxy or lower alkoxy having as substituents halogen atom, or represents heteroaryl (where heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring containing 5 ring atoms, and which contains at least one heteroatom selected from N and S);
R represents lower alkyl, heteroseksualci (where heteroseksualci represents a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is replaced by O), aryl or heteroaryl (where heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring containing 6 ring atoms, and which contains at least one heteroatom selected from N), where aryl and heteroaryl may have as the substituents one or two R';
n is 0, 1, 2 or 3;
or its pharmaceutically acceptable salt accession acid, racemic mixture, or the corresponding enantiomer and/or optical isomer.

2. The compound of Formula I according to claim 1, where R1represents lower alkyl.

3. The compound of Formula I according to claim 2, where each of Ar and R represents phenyl.

4. The compound of Formula I according to claim 3, where the phenyl group Ar is as substituents at least two groups of CF3.

5. The compound of Formula I according to claim 4, where connections are
rat-2-fluoro-N-(1-methyl-3-phenyl-piperidine-3-yl)-4,6-bis-trifluoromethyl-benzamide,
rat-2-methoxy-N-(1-methyl-3-phenyl-piperidine-3-yl)-4,6-bis-trifluoromethyl-benzamide,
rat-2-ethyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4,6-bis-trifluoromethyl-benzamide,
rat-N-[3-(4-fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-4,6-bis-trifluoromethyl-benzamide or
2-methoxy-N-((R)-1-methyl-3-phenyl-piperidine-3-yl)-4,6-bis-trifluoromethyl-benzamide.

6. The compound of Formula I according to claim 3, where the phenyl group Ar is as substituents at least one group of CF3.

7. The compound of Formula I according to claim 6, where connections are
rat-2-ethyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;
rat-2-bromo-6-methoxy-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;
rat-N-(1,2-dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trift rmeil-benzamide;
rat-2-cyclopropyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;
rat-2-methoxy-N-(1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rat-N-(1-methyl-3-phenyl-piperidine-3-yl)-2-methylsulfanyl-4-trifluoromethyl-benzamide;
rat-N-[3-(4-fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rat-N-[3-(4-chloro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
2-methoxy-N-((S)-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;
2-methoxy-N-((R)-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rat-2-deformedarse-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;
rat-N-[3-(3-chloro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rat-2-methoxy-N-[3-(4-methoxy-phenyl)-1-methyl-piperidine-3-yl]-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rat-N-(5-fluoro-1-methyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rat-N-(1-isopropyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
2-cyclopropyl-N-((S)-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;
2-cyclopropyl-N-((R)-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;
rat-2-cyclobutyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;
rat-N-[3-(2,4-debtor-phenyl)-1-ethyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rat-N-[3-(2-fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rat-N-[3-(2,5-debtor-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rat-2-isopropyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;
rat-2-methoxy-6-methylsulfanyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,4']bipyridinyl-3-yl)-4-trifluoromethyl-benzamide;
rat-2-ethyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,4']bipyridinyl-3-yl)-4-trifluoromethyl-benzamide;
rat-2-methoxy-6-methylsulfanyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,3']bipyridinyl-3-yl)-4-trifluoromethyl-benzamide;
rat-2-Ethyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,3']bipyridinyl-3-yl)-4-trifluoromethyl-benzamide hydrochloride;
2-methoxy-N-((3RS,5SR)-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;
2-cyclopropyl-N-((3RS,5SR)-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;
2-ethyl-N-((3RS,5SR)-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;
rat-2,6-dimethoxy-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;
2-cyclopropyl-N-((3RS,5SR)-1,5-dimethyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;
rat-2-cyclopropyl-4-trifluoromethyl-N-(1,5,5-trimethyl-3-phenyl-piperidine-3-yl)-benzamide;
rat-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-N-(1,6,6-trimethyl-3-phenyl-piperidine-3-yl)-benzamide;
N-((3RS,5SR)-1,5-dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-matilal the Anil-4-trifluoromethyl-benzamide;
2-methoxy-N-((3RS,5SR)-5-methoxyethoxy-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rat-N-[3-(3-bromo-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rat-N-[3-(2-chloro-4-fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rat-2-methoxy-6-methylsulfanyl-N-[1-methyl-3-(3-trifluoromethyl-phenyl)-piperidine-3-yl]-4-trifluoromethyl-benzamide;
rat-2-methoxy-N-[3-(3-methoxy-phenyl)-1-methyl-piperidine-3-yl]-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rat-N-[3-(3-fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rat-N-[3-(3-chloro-4-fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rat-N-[3-(3,4-debtor-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rat-2-methoxy-6-methylsulfanyl-N-(1-methyl-3-meta-tolyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;
rat-N-[3-(4-fluoro-3-methyl-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rat-N-[3-(3,5-debtor-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rat-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-N-(1,5,5-trimethyl-3-phenyl-piperidine-3-yl)-benzamide;
rat-2-ethyl-3-methyl-N-(1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;
rat-N-(1-tert-butyl-3-phenyl-piperidine-3-yl)-2-methox the-6-methylsulfanyl-4-trifluoromethyl-benzamide;
rat-2-methoxy-N-(4-methyl-6-phenyl-4-Aza-Spiro[2,5]Oct-6-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;
N-((3R,5S) or (3S,5R)-5-hydroxy-1-methyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
2-methoxy-N-((3R,5S) or (3S,5R)-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;
2-methoxy-N-((3S,5R) or (3R,5S)-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide;
N-[(R or S)-3-(2-fluoro-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
N-[(R or S)-3-(2,5-debtor-phenyl)-1-methyl-piperidine-3-yl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
2-ethyl-N-((R or S)-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide;
2-methoxy-6-methylsulfanyl-4-trifluoromethyl-N-((S or R)-1,5,5-trimethyl-3-phenyl-piperidine-3-yl)-benzamide;
N-((3S,6S) or (3R,6R)-1,6-dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
N-((3R,6R) or (3S,6S)-1,6-dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
N-((3R,6S) or (3S,6R)-1,6-dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
N-((3S,5R) or (3R,5S)-1,5-dimethyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide;
N-((3R,5S) or (3S,5R)-1,5-dimethyl-3-phenyl-piperidine-3-yl)-2-ethyl-4-trifluoromethyl-benzamide;
2-ethyl-N-((3R,5S) or (3S,5R)-5-methoxy-1-methyl-3-phenyl-PIP is ridin-3-yl)-4-trifluoromethyl-benzamide;
2-cyclopropyl-N-((3R,5S) or (3S,5R)-5-methoxy-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide or
2,6-dimethoxy-N-(R or S)-1-methyl-3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide.

8. The compound of Formula I according to claim 1, where R1is cycloalkyl or heteroseksualci and each of Ar and R represents phenyl.

9. The compound of Formula I of claim 8, where connections are
rat-N-(1-cyclopentyl-3-phenyl-piperidine-3-yl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide,
rat-N-(1-cyclopropylmethyl-3-phenyl-piperidine-3-yl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide or
rat-2-methoxy-N-[3-phenyl-1-(tetrahydro-Piran-4-yl)-piperidine-3-yl]-4,6-bis-trifluoromethyl-benzamide.

10. The compound of Formula I according to claim 1, where R1represents lower alkyl, Ar is a phenyl and R represents heteroaryl.

11. The compound of Formula I of claim 10, where the connection is a
rat-N-(5-fluoro-1'-methyl-1',4',5',6'-tetrahydro-2 N-[2,3']bipyridinyl-3'-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide,
rat-2-methoxy-6-methylsulfanyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,4']bipyridinyl-3-yl)-4-trifluoromethyl-benzamide,
rat-2-ethyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,4']bipyridinyl-3-yl)-4-trifluoromethyl-benzamide hydrochloride
rat-2-methoxy-6-methylsulfanyl-N-(1-methyl-1,4,5,6-tetrahydro-2H-[3,3']bipyridinyl-3-yl)-4-trifluoromethyl-benzamide or
rat-2-ethyl-N-(1-methyl-1,4,5,6-tetr the hydro-2H-[3,3']bipyridinyl-3-yl)-4-trifluoromethyl-benzamide.

12. The compound of Formula I according to claim 1, where R1represents a hydrogen atom, and Ar and R are phenyl.

13. The compound of the Formula I indicated in paragraph 12, where the compound is a rat-2-cyclopropyl-N-(3-phenyl-piperidine-3-yl)-4-trifluoromethyl-benzamide.

14. The compound of Formula I according to claim 1, where R2represents hydroxy.

15. The compound of Formula I through 14, where the compound is a
rat-N-(5-hydroxy-1-methyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide or
N-((3R,5S) or (3S,5R)-5-hydroxy-1-methyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide.

16. The compound of Formula I according to claim 3, where R2represents a halogen atom.

17. The compound of Formula I according to clause 16, where the connection is a
rat-N-(5-fluoro-1-methyl-3-phenyl-piperidine-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide.

18. The compound of Formula I according to claim 1, where R1is a CD3.

19. The compound of Formula I according p, where connection is a
[2H-methyl]-2-methoxy-N-((R) or (S)-1-methyl-3-phenyl-piperidine-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide hydrochloride.

20. Drug for the treatment of diseases based inhibitor of the reuptake of glycine containing one or more than one compound according to any one of claims 1 to 19 and a pharmaceutically acceptable excipients.

21. Drug in claim 20, where diseases are psychoses, pain, dysfunction in memory and learning, attention deficit, schizophrenia, demenziale disorders or Alzheimer's disease.

22. The use of compounds according to any one of claims 1 to 19 in the manufacture of drugs for the treatment of psychoses, pain, dysfunction in memory and learning, attention deficit, schizophrenia, demenziale disorders or Alzheimer's disease.



 

Same patents:

Cetp inhibitors // 2513107

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I, or its pharmaceutically acceptable salt where: X stands for -O-; Z stands for -C(=O)-; Y stands for -(CRR1)-, where R1 is selected from -C1-C2alkyl; R stands for H or -C1-C5alkyl; R5 stands for H; R2 and B each is selected from A1 and A2, where one of R2 and B stands for A1, and the other from R2 and B stands for A2; where A1 has structure (a); A2 is selected from the group, which includes phenyl, pyridyl, pyrazolyl, thienyl, 1,2,4-triazolyl and imodazolyl; A3 is selected from the group including phenyl, thiazolyl and pyrazolyl; A4 is selected from the group, including phenyl, pyridyl, thiazolyl, pyrazolyl, 1,2,4-triazolyl, pyrimidinyl, piperidinyl, pyrrolidinyl and asetidinyl; A2 is optionally substituted with 1-3 substituents, independently selected from halogen atom, -OCH3 and -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A3 is substituted with one A4 group and is optionally substituted with 1-2 substituents, independently selected from halogen atom, -OH, -OCH3, -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A4 is optionally substituted with 1-3 substituents, independently selected from the group, which includes: (a) -C1-C5alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with group -OH, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) halogen atom, (j) -CN, (k) -NO2, (l) -C(=O)NR3R4, (m) -OC1-C2alkyleneOC1-C2alkyl, (n) -OC1-C3alkyl, optionally substituted with 1-3 halogen atoms, (o) -C(=O)OC1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (q) -NR3R4 and (r) -S(O)xNR3R4, on condition that A4 stands for heterocyclic group, attached to A3 by means of ring carbon atom in A4, at least, one substituent in A4 must be selected from Re, where Re is selected from the group including: (a) -C1-C5alkyl, substituted with -OH group and optionally substituted with 1-3 halogen atoms, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) -CN, (j) -NO2, (k) -C(=O)NR3R4, (l) -OC1-C2alkyleneOC1-C2alkyl, (m) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (n) -NR3R4(=O)OC1-C2alkyl, (o) -NR3R4 and (p) -S(O)xNR3R4; p equals 0, 1 or 2; and Ra is selected from halogen atom, -CH3, -CF3, -OCH3 and -OCF3; R3 and R4 each is independently selected from H and CH3; and x equals 0, 1 or 2.

EFFECT: formula (I) compound is applied for medication, which possesses properties of CETP inhibitor, for increase of HDL-C and for reduction of LDL-C Technical result is compounds, inhibiting cholesterol ether transferring protein (CETP).

10 cl, 140 ex

FIELD: chemistry.

SUBSTANCE: invention relates to triazole compounds which are represented by specific chemical formulae and which can be used for preventing or treating diseases in which 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) participates, particularly dementia. It was found that the triazole derivative, in which one of 3rd and 5th positions of the triazole ring accommodates a (di)alkyl methyl or cycloalkyl, each substituted, -O-aryl or heterocyclic group, each of which can be substituted, or (lower alkylene)cycloalkyl, and the other position accommodates an aryl, heterocyclic or cycloalkyl group, each of which can be substituted, or a pharmaceutically acceptable salt thereof, has powerful inhibiting action on 11β-HSD1.

EFFECT: improved properties of the derivatives.

8 cl, 141 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds being aspartyl protease inhibitors applicable for treating cardiovascular, neurodegenerative disorders and fungal infection of formula , wherein W represents -C(=O)-; X represents -NH-; U represents -C(R6)(R7)-; R1 represents methyl, R2, R3 and R6 represent H, R4 and R7 represent optionally substituted phenyl, as well as tautomers and pharmaceutically acceptable salts thereof.

EFFECT: there are presented new effective aspartyl protease inhibitors specified in rennin, cathepsin D, BACE-1, for treating cardiovascular diseases, cognitive and neurodegenerative diseases, as well as fungal infections.

67 cl, 1 tbl, 4393 ex

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula I , where R1 and R2 independently denote hydrogen, C3-C7cycloalkyl, C1-C6alkyl, C2-C6alkynyl, hydrogen or pyridine; or R1 and R2 together with a nitrogen atom which binds them form a pyrroline group; R3 denotes hydrogen, C1-C6halogenalkyl, C1-C6alkyl, halogen, cyano group, nitro group, C1-C4alkoxy group, phenyl, halogen-substituted phenyl, (R51)(R52)(R53)Si-(C2-C6alkynyl)-, where R51, R52, R53 independently denote halogen, cyano group, C1-C6alkyl, C2-C6alkenyl, C3-C8cycloalkyl, C5-C8cycloalkenyl, C2-C6alkynyl, C1-C6alkoxy group, benzyl or phenyl; R4 denotes hydrogen, halogen, phenyl, imidazolyl, amino group, C1-C6alkoxy group or C1-C6alkyl; R5 denotes C1-C12alkyl or a group A, where A denotes a 3-10-member monocyclic or condensed bicyclic ring system which can be aromatic, partially unsaturated or completely saturated, where said 3-10-member ring system can be mono- or polysubstituted with substitutes independently selected from a group comprising halogen, C1-C6alkyl, C1-C6halogenalkyl, C1-C6alkoxy group and C1-C6alkylthio group; R6 denotes hydrogen; and R7 denotes hydrogen or C1-C6alkyl and agronomically acceptable salts/metal complexes/metalloid complexes/isomers/structural isomers/stereoisomers. The invention also relates to methods of controlling infection of useful plants by phytopathogenic microorganisms by applying a compound of formula I onto the plants, a part thereof or place where said plants grow, as well as a composition for controlling infection by phytopathogenic microorganisms.

EFFECT: novel compounds which are suitable for use as microbiocides are obtained and described.

7 cl, 48 ex, 151 tbl

Amide compound // 2479576

FIELD: chemistry.

SUBSTANCE: compounds exhibit antagonistic activity towards the EP4 receptor, which enables use thereof as an active ingredient in a pharmaceutical composition for treating chronic kidney disease or diabetic nephropathy.

EFFECT: high efficiency of the compounds.

27 cl, 228 tbl, 86 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of general formula:

or its pharmaceutically acceptable salt wherein the ring A represents a phenyl group which can contain 1-3 substitutes specified in a group of substitutes, or a thienyl group which can contain 1-3 substitutes specified in a group of substitutes α; L represents a single bond or a group of formula -NRC CO- (wherein Re represents a hydrogen atom), the ring B represents C6-14 aryl group which can contain 1-3 substitutes specified in a group of substitutes α, or a 5-10-member heterocyclic group which can contain 1-3 substitutes specified in a group of substitutes α; the X, Y, Z , R1 and R2 , R3, R4, R5 and R6 radical values are presented in cl.1 of the patent claim which possess an effect of Aβ protein production inhibition or an effect of BACE1 inhibition.

EFFECT: preparing the compound which is applicable as a preventive or therapeutic agent for neurodegenerative disease caused by Aβ.

13 cl, 35 tbl, 285 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, namely to method of obtaining 3,3'-(1,2-phenylene)-bis-1,5,3-dithiazepinane and 3,3'-[methylene-bis-(1,4-phenylene)]-bis-1,5,3-dithiazepinane of general formula (1):

, R=1,2-C6H4; 4-C6H4-CH2C6H4-4, which lies in the following: α,ω-diamines (1,2-phenylenediamine or 4,4'-diaminodiphenylmethane) is subjected to interaction with 1,3,6-oxadithiapinane in presence of catalyst Sm(NO3)3·6H2O in mole ratio α,ω-diamine : 1,3,6-oxadithiapinane : Sm(NO3)3·6H2O = 10 : 20 : (0.3-0.7) in chlorophorm and argon atmosphere for 2.5-3.5 h.

EFFECT: elaborated is method of obtaining novel compounds, which cam be applied as antibacterial, antifungal and antiviral agents, as biologically active complexing agents, selective sorbents and extractants of precious metals, special reagents for suppression of vital activity of bacteria in various technical media.

1 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclopropylamine derivatives of formula: or its pharmaceutically acceptable salt, wherein: one of R1 and R2 means a group of formula -L2-R6a-L3-R6b; the other of R1 and R2 means H, C1-10alkyl, C1-10alkoxy, halogen, CN; each R3, R3a R3b independently means H, C1-6alkyl, trifluoromethyl, C1-10alkoxy, CN; R4 and R5 taken together with a nitrogen atom whereto each attached form a non-aromatic cycle of formula: R7, R8, R9 and R10 each H, C1-10alkyl; R6a means cyanophenyl, phenyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, [1,2,3]triazolyl, [1,2,4]triazolyl, azepanyl, azetidinyl, azetidin-2-onyl, pyridazin-3(2H)-onyl, pyridin-2(1H)-onyl, pyrimidin-2(1H)-onyl, pyrrolidin-2-onyl, benzothiazolyl wherein the pyridinyl and pyrimidinyl groups optionally contain 1-3 substitutes specified in a group consisting of C1-10alkyl and C1-10alkoxy; R6b means H; L means - [C(R16)(R17)]k; L2 means a bond, C2-10alkylene, -O-, -C(=O)-, -NH-, -N(R16)C(=O), -C(=O)N(R16) and -N(C1-6alkyl)-;L3 means a bond; R15 means H, C1-6alkyl, C1-6alkoxycarbonyl, amido and formyl R16 , R17 in each specific case means H, C1-6alkyl; Rx and Ry in each specific case independently mean H, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, fluorine, diC1-6alkylamino; k is equal to 1, 2 or 3; m is equal to 2.

EFFECT: compounds show H3 receptor inhibitory activity that makes them applicable in a pharmaceutical composition.

10 cl, 7 dwg, 44 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof, where R1 denotes C1-C8-alkylaminocarbonyl, which is optionally substituted with a 5- or 6-member heterocyclic ring containing 3-4 ring heteroatoms selected from a group consisting of oxygen, nitrogen and sulphur, where the ring can be optionally substituted with C1-C8-alkyl or C1-C8-alkoxy group ; R2 denotes C1-C3-alkyl or a halogen; one of R3 and R4 denotes R6, and the other denotes R7; R5 denotes hydrogen or halogen; R6 denotes hydrogen, hydroxy group amino group, -SO2R8, -SO2NH2, -SO2NR9R10, -COR8, -CONHR8, -NHSO2R8, nitrile, carboxy, -OR8 or C1-C8-halogenalkyl; R7 denotes hydrogen, OR11, halogen, carboxy, -SO2R8, cyanogroup or C1-C8-halogenalkyl, or when R4 denotes R7, then R7 can also denote -NR12 R13 ; R8 R11 independently denote C1-C8-alkyl or C3-C8-cycloalkyl, which can be optionally substituted with hydroxy group, C1-C8-alkoxy group, nitrile, amino group, C1-C8-alkylamino group or di-C1-C8-alkyl)amino group; any R9 denotes C1-C8-alkyl or C3-C8-cycloalkyl, which can optionally be substituted with hydroxy group, C1-C8-alkoxy group, nitrile, amino group, C1-C8-alkylamino group, di(C1-C8-alkyl)amino group or a 5- or 6-member heterocyclic ring containing one or two ring heteroatoms selected from a group consisting of oxygen and nitrogen, where the ring can optionally be substituted with C1-C8-alkyl, and R10 denotes hydrogen or C1-C8-alkyl; or R9 and R10 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring which can contain one or two additional nitrogen heteroatoms, where the ring can be optionally substituted with C1-C8-alkyl; any R12 denotes C1-C8-alkyl or C3-C8-cycloalkyl which can be optionally substituted with di(C1-C8-alkyl)aminogroup, and R13 denotes hydrogen or C1-C8-alkyl; or R12 and R13 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring which contains one or two additional nitrogen heteroatoms, where the ring can optionally be substituted with C1-C8-alkyl.

EFFECT: possibility of using the compounds to produce a pharmaceutical agent for treating diseases mediated by phosphatidylinositol-3 kinase.

6 cl, 3 tbl, 181 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 5-membered heterocyclic compounds of general formula (I), their prodrugs or pharmaceutically acceptable salts, which possess xanthine oxidase inhibiting activity. In formula (I) T represents nitro, cyano or trifluoromethyl; J represents phenyl or heteroaryl ring, where heteroaryl represents 6-membered aromatic heterocyclic group, which has one heteroatom, selected from nitrogen, or 5-membered aromatic heterocyclic group, which has one heteroatom, selected from oxygen; Q represents carboxy, lower alkoxycarbonyl, carbomoyl or 5-tetrasolyl; X1 and X2 independently represent CR2 or N, on condition that both of X1 and X2 do not simultaneously represent N and, when two R2 are present, these R2 are not obligatorily similar or different from each other; R2 represents hydrogen atom or lower alkyl; Y represents hydrogen atom, hydroxy, amino, halogen atom, perfluoro(lower alkyl), lower alkyl, lower alkoxy, optionally substituted with lower alkoxy; nitro, (lower alkyl)carbonylamino or (lower alkyl) sulfonylamino; R1 represents perfluoro(lower alkyl), -AA, -A-D-L-M or -A-D-E-G-L-M (values AA, A, D, E, G, L, M are given in i.1 of the invention formula).

EFFECT: invention relates to xanthine oxidase inhibitor and pharmaceutical composition, which contain formula (I) compound.

27 cl, 94 tbl, 553 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel radiolabelled compounds of formula I in which R1 represents isopropoxy or 2,2,2-trifluoro-1-methyl-ethoxy; and R2 represents radiolabelled CH3 group, where radionuclide represents 3H or 11C. Invention also relates to pharmaceutical composition for diagnostic visualisation of GlyT1 transporter (glycine transporter type 1).

EFFECT: obtained are novel radiolabelled compounds, which can be applied in medicine as radioactive indicator in PET (positron emission tomography) for labeling and diagnostic molecular visualisation of functionality of glycine transporter type 1.

13 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-[2,4-dioxo-6-(tetrahydrofuran-2-yl)-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]methanesulphonamide and N-[6-(1-isopropoxyethyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H- quinazolin-3-yl] methanesulphonamide, having antagonistic activity on the AMPA receptor. The invention also relates to a pharmaceutical composition.

EFFECT: use of said compounds to produce drugs for treating AMPA mediated conditions and primarily for treating epilepsy or schizophrenia.

6 cl, 81 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a method for obtaining [1S-[1α,2α,3β(1S*,2R*),5β]]-3-[7-[2-(3,4-difluorophenyl)-cyclopropylamino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol of formula (I) .

EFFECT: improving yield of the compound of the formula and its high quality when recrystallisation is not available.

5 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I

or a pharmaceutically acceptable salt thereof, where R1 is H or R1 and R2 together with a nitrogen group can form where A, B, C and D are independently selected from a group consisting of CR1a and N; where at least one of A, B, C and D is CR1a; where R1a is selected from a group consisting of H, -ORi, -SRii, -S(O)Riii, -C(O)NRvRvi and CF3, where Ri is selected from a group consisting of methyl, ethyl, propyl, hydroxyethyl, hydroxypropyl, 2-oxo-2-phenylethyl, butyl, acetonitrile and benzyl; Rii, Riii and Riv denote methyl; Rv and Rvi are independently selected from a group consisting of H, methyl, ethyl, hydroxyethyl, hydroxypropyl, diethyalminoethyl, phenyl, pyridinyl, methoxyethyl, hydroxyethoxyethyl, benzyl, phenylethyl, 2-hydroxy-1-hydroxymethyl-2-phenylethyl and carbomoylethyl, or Rv and RVi together form morpholine or ethyl ester of piperazine; R2 is selected from a group consisting of phenyl, naphthyl, pyrazolyl and C1-C8alkylene phenyl; R3 is C1-C8alkylene; R4 is selected from a group consisting of H, C1-C8alkyl and -C=NH(NH2). The invention also relates to compounds of formulae I-A

I-B I-C

I-D I-E

values of radicals of which are given in the claim; a method of treating said pathological conditions, a pharmaceutical composition based on said compounds, a method of identifying a Trp-p8 agonist and specific compounds.

EFFECT: obtaining compounds which are useful as Trp-p8 modulators.

25 cl, 19 dwg, 8 tbl, 17 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyranyl aryl methylbenzoquinazolinone compounds of formula (I), which are positive allosteric modulators of the M1 receptor and which can be used to treat diseases associated with the M1 receptor, such as Alzheimer's disease, schizophrenia, pain disorders or sleep disturbance. In formula (I) X-Y are selected from a group comprising (1) -O-CRARB-, (2) -CRARB-O-, (3) -CRARB-SRC-, (4) -CRARB-NRC- and (5) -NRC-CRARB-, where each RA and RB is a hydrogen atom, and RC is selected from a group comprising (a) hydrogen, (b) -C(=O)-C1-6alkyl, (c) -C1-6alkyl, (d) -C(=O)-CH2-C6H5, (e) -S(=O)2-C1-6 alkyl, R1 is a hydroxy group, R2 is selected from a group comprising (1) -phenyl, (2) - heteroaryl, where the phenyl or heteroaryl group R2 is optionally substituted; the rest of the values of the radicals are given in the claim.

EFFECT: obtaining novel pyranyl aryl methylbenzoquinazolinone compounds.

28 cl, 12 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 1,3-dihydroimidazole-2-thione derivatives of formula I: , in which R1, R2 and R3, identical or different, denote hydrogen or halogen; R4 denotes alkyl aryl; X denotes an oxygen atom; n equals 2 or 3; individual (R)-enantiomers thereof; or pharmaceutically acceptable salts thereof, where the term "alkyl" denotes straight or branched hydrocarbon chains which contain one to six carbon atoms; the term "aryl" denotes a phenyl or naphthyl group; the term "halogen" denotes fluorine, chlorine, bromine or iodine. The invention also relates to a method of producing said compounds, a pharmaceutical composition based on said compounds, having inhibiting action on dopamine-beta-hydroxylase, methods of treating different cardiovascular diseases such as hypertension and chronic heart failure, and use of compounds of formula 1 to produce drugs for treating said diseases.

EFFECT: improved properties of derivatives.

32 cl, 2 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to triazole compounds which are represented by specific chemical formulae and which can be used for preventing or treating diseases in which 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) participates, particularly dementia. It was found that the triazole derivative, in which one of 3rd and 5th positions of the triazole ring accommodates a (di)alkyl methyl or cycloalkyl, each substituted, -O-aryl or heterocyclic group, each of which can be substituted, or (lower alkylene)cycloalkyl, and the other position accommodates an aryl, heterocyclic or cycloalkyl group, each of which can be substituted, or a pharmaceutically acceptable salt thereof, has powerful inhibiting action on 11β-HSD1.

EFFECT: improved properties of the derivatives.

8 cl, 141 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: infrared-inert substrates include moulded polymer articles, films, fibres, coatings and other organic and inorganic materials. The method of producing said substrates involves adding an effective amount of dispersed bis-oxodihydroindolylene benzodifuranone dye into the substrate or onto the surface of the substrate. The resultant substrates have reflecting power and are transparent for a large part of non-reflected near-infrared radiation. A wide application is disclosed - for casings of electronic devices, garden furniture, motor car, naval or aerospace parts, laminates, artificial leather, textile materials, optical fibres and in multicolour printing processes. The obtained substrates can be laser welded. Novel bis-oxodihydroindolylene benzodifuranone compounds are also disclosed.

EFFECT: low heat build-up and high value of substrates in many fields of application.

16 cl, 5 dwg, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrole derivatives of the formula (1): or pharmaceutically acceptable salts thereof, where: R1 denotes H, halogen; R2 denotes an 8-10-member bicyclic hydrocarbon group, optionally substituted, or a bicyclic heterocyclic group consisting of one or two atoms selected from nitrogen, oxygen and sulphur and 5-9 carbon atoms, optionally substituted, where the optional substitute is halogen, lower alkyl, OH, lower alkoxy, oxo, NO2, CN; R3 denotes H.

EFFECT: compounds have inhibiting action of production of IL-6, which enables use thereof in a pharmaceutical composition and when treating a range of diseases.

12 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 5-membered heterocyclic compounds of general formula (I), their prodrugs or pharmaceutically acceptable salts, which possess xanthine oxidase inhibiting activity. In formula (I) T represents nitro, cyano or trifluoromethyl; J represents phenyl or heteroaryl ring, where heteroaryl represents 6-membered aromatic heterocyclic group, which has one heteroatom, selected from nitrogen, or 5-membered aromatic heterocyclic group, which has one heteroatom, selected from oxygen; Q represents carboxy, lower alkoxycarbonyl, carbomoyl or 5-tetrasolyl; X1 and X2 independently represent CR2 or N, on condition that both of X1 and X2 do not simultaneously represent N and, when two R2 are present, these R2 are not obligatorily similar or different from each other; R2 represents hydrogen atom or lower alkyl; Y represents hydrogen atom, hydroxy, amino, halogen atom, perfluoro(lower alkyl), lower alkyl, lower alkoxy, optionally substituted with lower alkoxy; nitro, (lower alkyl)carbonylamino or (lower alkyl) sulfonylamino; R1 represents perfluoro(lower alkyl), -AA, -A-D-L-M or -A-D-E-G-L-M (values AA, A, D, E, G, L, M are given in i.1 of the invention formula).

EFFECT: invention relates to xanthine oxidase inhibitor and pharmaceutical composition, which contain formula (I) compound.

27 cl, 94 tbl, 553 ex

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