RU2366654C2 - New disubstituted phenyl piperidines/piperazines as modulators of dopamine neurotransmission - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula 1:

whereat : X is N or CH; R₁ is selected from the group consisting of OSO₂CH₃, SOR₄, SO₂R₄, SO₂NH₂, SO₂NHCH₃, SO₂N(CH₃)₂, COR₄, CN, OCF₃, CF₃, F, Cl, Br, I, CH(OH)CF₃, CH₂SO₂CF₃, CH₂SO₂CH₃, CH₂CF₃, CH₂COCH₃, CH₂COCF₃; R₂ is selected from the group consisting of CN, CF₃, OH, OR4, F, CI, Br, I, CH₃; R₃ is selected from the group consisting of C₁-C₄ alkyls, allyl, CH₂CH₂OCH₃, CH₂CH₂CH₂F, CH₂CH₂CHF₂, CH₂CH₂F, CH₂CHF₂, CH₂CF₃, 3,3,3-trifluoropropyl, 4,4,4-trifluorobuthyl; CH₂CH₂OH, CH₂CH₂CH₂OH, CH₂CH(OH)CH₃, CH₂CH₂COCH₃,

,

;

R₄ is selected from the group consisting of C₁-C₃ alkyls, CF₃, CHF₂, CH₂F; provided that when R₁ is CN, OCF₃, CF₃, F or Cl X is not CH, R₂ is not F, CI, Br, CH₃, and R₃ is not C₁-C₃ alkyl or allyl; provided that when R₁ is CF₃ or CN, X is not CH, R₂ is not F, CI, Br, CH₃, and R₃ is not C₁-C₂ alkyl; provided that when X is N: R₁ is not Cl, when R₂ is CH₃, and R₃ is CH₂CH₂OH; R₁ is not Cl, when R₂ is Cl, and R₃ is CH₃; R₁ is not F, when R₂ is CN, and R₃ is CH₃; R₁ is not Cl, when R₂ is Cl, and R₃ is CH₂CH₂CH₂OH; R₁ is not Cl, when R₂ is Cl, and R₃ is CH₂CH₂OH; and provided that when R₁ is SO₂R₄, SO₂NH₂, SO₂NHCH₃ or SO₂N(CH₃)₂ R₂ is not OH. The present invention refers also to the pharmaceutically acceptable salts of the said compounds, to the intermediate compounds, to their pharmaceutical composition as well as to the method of central nervous system abnormalities treatment.

EFFECT: obtaining of the new bioactive compounds active as modulators of dopamine neurotransmission.

43 cl, 79 ex, 7 tbl

Description

The invention relates to new modulators of dopamine neurotransmission and, more specifically, to new 4- (ortho, meta-disubstituted phenyl) -1-alkylpiperidines and piperazines and their use.

Dopamine is a brain neurotransmitter. Since its discovery in 1950, the function of dopamine in the brain has been extensively studied. To date, it is well established that dopamine is necessary for several aspects of brain function, including motor, cognitive, sensory, emotional and self-management functions (for example, regulation of appetite, body temperature, sleep). Thus, modulation of dopaminergic function may be beneficial in treating a wide range of disorders affecting brain function. Indeed, drugs that act directly or indirectly on central dopamine receptors are usually used in the treatment of neurological and psychiatric disorders, such as Parkinson's disease and schizophrenia. However, currently available dopaminergic pharmaceuticals can have serious side effects. For example, dopamine antagonists are known to induce both motor (extrapyramidal side effects; EPS) and psychic side effects (e.g. anhedonia, dysphoria and impaired consciousness), and dopaminergic agonists are known to induce dyskinesias and psychoses (Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed. / McGraw-Hill, USA. Chapter 18, p 407-416, Chapter 22, p 509-512, p 515-516). The approach taken by many researchers to improve the efficacy and reduce side effects of dopaminergic pharmaceuticals is to develop new dopamine receptor ligands with selectivity for specific dopamine receptor subtypes or with regional selectivity. Another class of compounds acting through the dopamine systems of the brain are dopaminergic stabilizers, which have been shown to be useful in treating both neurological and psychiatric disorders (A. Ekesbo, PhD Thesis, Uppsala University, Sweden: Functional consequences of dopaminergic degeneration; clinical and experimental studies using a novel stabilizer of dopaminergic systems: Ekesbo et al., (-) -OSU6162 inhibits levodopa-induced dyskinesias in a monkey model of Parkinson's disease, Neuroreport, 8.2567, 1997; Tedroff et al. Long-lasting improvement in motor function following (-) -OSU6162 in a patient with Huntington's disease. Neurology, 22; 53: 1605-6, 1999; Gefvert O, et al., (-) - OSU6162 induces a rapid onset of antipsychotic effect after a single dose. A double-blind pla cebo-controlled pilot study. Scandinavian Society for Psychopharmacology, 41st Annual Meeting, Copenhagen Denmark Nordic Journal of Psychiatry 54/2 93-94, April 2000: Carlsson et al., Annu. Rev. Pharmacol Toxicol., 41, 237, 2001; Carlsson et al. Current Medicinal Chemistry, 11,267,2004).

Another dopaminergic compound, referred to as a systemic stabilizer of dopamine-serotonin, as well as a partial DA D2 receptor agonist, is the recently released antipsychotic compound aripiprazole (Burris et al., Pharm. Exp. Ther, vol. 302, 381, 2002 ) In addition, compounds referred to as dopaminergic stabilizers have been described in W001 / 46145, W001 / 46146, Pettersson et al. The development of ACR16, A new class of dopaminergic stabilizers. Society for Neuroscience 32nd Annual Meeting, Abstract 2002, Vol. 28 part 1 1028, Orlando USA 2002, and Nyberg et al., Efficacy and tolerability of the new dopamine stabilization ACR16 a randomized placebo-controlled add-on study in patients with schizophrenia 12th BIENNIAL WINTER WORKSHOP ON SCHIZOPHRENIA, February 7-13, 2004, Davos, Switzerland.

The typical pharmacological action that is characteristic of dopaminergic stabilizers, as described in W001 / 46145, W001 / 46146 and Pettersson et al., 2002, can be briefly summarized as follows: 1) increased turnover of dopamine in the terminal regions of the ascending dopaminergic projection in the mammalian brain; 2) the absence or presence of only weak behavioral effects on otherwise treated rats; and 3) the inhibition of behavioral effects induced by psychostimulants or psychomimetic compounds in rats. In the present invention, these facts are referred to as a dopaminergic stabilizer profile.

This invention relates to the field of treatment of mammals suffering from central nervous system disorders, the symptoms of which can be influenced by dopaminergic functions, where the treatment comprises administering to said mammal an amount of a new type of compound having a dopaminergic stabilizer profile.

Compounds belonging to the class of substituted 4-phenyl-N-alkylpiperidines have been described previously. Among these compounds, some are inactive in the central nervous system, some exhibit serotonergic or mixed serotonergic / dopaminergic pharmacological profiles, while some are full or partial dopamine receptor agonists or antagonists with high affinity for dopamine receptors.

In Costall et al. European J. Pharm. 31, 94, (1975) and Mewshaw et al. Bioorg. Med. Chem. Lett., 8.295, (1998) reports compounds that are substituted 4-phenylpiperazines, most of which are 2-, 3-, or 4-OH phenyl-substituted and exhibit DA auto-receptor agonist properties. Fuller R. W. et al., J. Pharmacol. Exp. Therapeut. 218, 636, (1981) describe substituted piperazines (e.g., 1- (meta-trifluoro-methylphenyl) piperazine) that are reported to act as serotonin agonists and inhibit reuptake of serotonin. A comparative effect on the concentration of 5-hydroxy-indoleacetic acid in the rat brain under the action of 1- (p-chlorophenol) piperazine is described by Fuller R. W. et al., Res. Commun. Chem. Pathol. Pharmacol 29, 201, (1980). Fuller R. W. et al., Res. Commun. Chem. Pathol. Pharmacol 17,551, (1977) describe the comparative effect of 1- (p-chlorophenol) piperazine on the concentration of 3,4-dihydroxyphenylacetic acid in the rat brain.

Boissier J. et al., Chem Abstr. 61: 10691c, disubstituted piperazines are described. The compounds are reported to be adrenolytics, antihypertensives, barbiturate enhancers, and central nervous system depressants.

Data have been published on a number of differently substituted piperazines as 5-HT1A receptor ligands, for example, Glennon R. A. et al., J. Med. Chem., 31.1968, (1988), Mokrosz, J. et al., Arch. Pharm. (Weinheim) 328,143-148 (1995), and van Steen B. J., J. Med. Chem., 36, 2751, (1993), Dukat M.-L., J. Med. Chem., 39,4017, (1996).

GB 2027703 describes substituted phenylpiperazines as analgesics and psychotropic agents. GB1560271 describes para-substituted meta-trifluoromethylphenylpiperazines and their therapeutic use for central nervous system disorders and cardiovascular disorders. US Pat. No. 4,202,898 describes substituted phenylpiperazines for the treatment of anxiety and depression. US Pat. No. 3,331,616 describes various N-alkyl substituted 4- (3-trifluoromethyl-phenyl) piperazines for treating anxiety conditions and related psychiatric conditions. Patent W09811068 describes substituted piperazines as a selective dopamine D4 ligand for use in the treatment of anxiety, depression, schizophrenia, obsessions, Parkinson's disease, tardive dyskinesia, nausea and gastrointestinal disorders.

A number of derivatives of 4-phenylpiperidine are known. EP0369887 describes substituted 4- (meta-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridines for the treatment of anxiety conditions. WO00 / 03713 describes a method for treating schizophrenia and other dysfunctions of the dopamine system using substituted 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridines.

Glennon et al. (US Pat. No. 6,057,371) claimed a method for treating a central nervous system disorder associated with a sigma receptor, comprising administering arylamines, including aryl piperidines, which are either unsubstituted or monosubstituted in the aryl ring. The compounds exhibit a high binding affinity for the sigma receptor. WO 91/095954 states that the term “high affinity” is intended to mean a compound that exhibits an IC50 of less than 100 nM in the anti-3H-DTG assay described in Weber et al. Proc. Natl. Acad. Sci. (USA) 83: 8784-8788). In particular, WO 91/095954 describes compositions related to “the discovery of the fact that some phenylalkyl amines, aminotetralin, piperazine, piperidine and related derivatives exhibit high binding to the sigma receptor and unexpectedly low binding for PCP and DA receptors” ( see page 11, lines 33-36).

Both WO 91/095954 and WO 93/00313 require compounds to have high binding affinity for the sigma receptor, and it is not disclosed that the compounds are pharmacologically active in the absence of affinity for the sigma receptor. In addition, clinical studies examining the properties of sigma receptor ligands in patients with schizophrenia have not confirmed either antipsychotic activity or activity for any other central nervous system disorders. Two of the most extensively studied selective sigma receptor antagonists BW234U (Rimcazole) and BMY14802 have been unsuccessful in clinical trials in patients with schizophrenia (Borison et al., 1991, Psychopharmacol Bull 27 (2): 103-106; Gewirtz et al., 1994, Neuropsychopharmacology 10: 37-40).

US Pat. No. 4,415,736 describes 4- (2,3-dimethoxy-phenyl) -1-methyl-4-piperidinol (column 9, lines 18-19) as a synthetic intermediate.

In addition, it is known that the compounds of formula II (W001 / 46145) and III (W001 / 46146) have the properties of a dopaminergic stabilizer.

Formula II Formula III

In the formula II;

X is, inter alia, CH, R ₁ selected from the group consisting of OSO ₂ CF ₃ , OSO ₂ CH ₃ , SOR ₃ , SO ₂ R ₃ , COR ₃ , CN, NO ₂ , CONHR ₃ , CF ₃ (at provided that X represents CH or C), F, Cl, Br, I (where R ₃ is as defined below);

R _{2 is} selected from the group consisting of C ₁ -C ₄ alkyl, allyl, CH ₂ SCH ₃ , CH ₂ CH ₂ OCH ₃ , CH ₂ CH ₂ CH ₂ F, CH ₂ CF ₃ , 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl or - (CH ₂ ) -R ₄ (where R ₄ is as defined below);

R _{3 is} selected from the group consisting of C ₁ -C ₃ alkyl, CF ₃ or N (R ₂ ) ₂ ;

R _{4 is} selected from the group consisting of C ₃ -C ₆ cycloalkyl, 2-tetrahydrofuran, 3-tetrahydrofuran.

In formula III, X is, inter alia, CH, R ₁ selected from the group consisting of OSO ₂ CF ₃ , OSO ₂ CH ₃ , SOR ₇ , SO ₂ R ₇ , COR ₇ , CN, NO ₂ , CONHR ₃ , CF ₃ , F, Cl, Br, I (where R ₃ is as defined below), 3-thiophene, 2-thiophene, 3-furan, 2-furan;

R _{2 is} selected from the group consisting of F, Cl, Br, I, CN, CF ₃ , CH ₃ , OCH ₃ , OH, NH ₂ ;

R ₃ and R ₄ independently represent H or C ₁ -C ₄ alkyl;

R _{5 is} selected from the group consisting of C ₁ -C ₄ alkyl, allyl, CH ₂ SCH ₃ , CH ₂ CH ₂ OCH ₃ , CH ₂ CH ₂ CH ₂ F, CH ₂ CF ₃ , 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl or - (CH ₂ ) -R ₆ ;

R _{6 is} selected from the group consisting of C ₃ -C ₆ cycloalkyl, 2-tetrahydrofuran, 3-tetrahydrofuran;

R ₇ selected from the group consisting of C ₁ -C ₃ alkyl, CF ₃ or N (R ₄ ) ₂ .

However, in patent W001 / 46145 (formula II) only monosubstitution of the aryl ring is described and ortho-substitution is not illustrated. Patent W001 / 46146 does not describe 2,3-disubstitution of the aryl ring, and it can be seen that an alternative substitution model (e.g., 3,4-disubstitution where the halogen atom is in the 4-position) is not as effective as 2,3- Disubstitution disclosed in the present invention.

Summary of the invention

The objective of the present invention is to develop new pharmaceutically active compounds, especially useful for the treatment of disorders of the central nervous system, with increased efficiency as dopaminergic stabilizers.

It was found that the substances according to the present invention in tests on rats preferably act on the dopaminergic systems of the brain. They have an effect on biochemical brain indices with characteristic features of dopamine antagonists. However, the substances according to the invention did not show or showed only limited inhibitory effects on spontaneous movement over a wide dosage range. In addition, the substances according to the invention can induce mild behavioral activation, in particular when the locomotor activity baseline is low. However, the substances of the present invention inhibit behavioral activation induced by psychostimulants and psychomimetics.

The present invention relates to new 4- (ortho, meta-disubstituted phenyl) -1-alkylpiperidines and piperazines in the form of free bases or pharmaceutically acceptable salts, pharmaceutical compositions containing these compounds, and the use of these compounds in therapy.

Specifically, the invention relates to a compound of formula 1:

Where

X represents N or CH;

R _{1 is} selected from the group consisting of OSO ₂ CF ₃ , OSO ₂ CH ₃ , NHSO ₂ CH ₃ , NHSO ₂ CF ₃ , SOR ₄ , SO ₂ R ₄ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N ( CH ₃ ) ₂ , COR ₄ , CN, OCF ₃ , SCF ₃ , OCHF ₂ , SCHF ₂ , CF ₃ , F, Cl, Br, I, NO ₂ , SF ₅ , SCN, OCN, OCOCF ₃ , SCOCF ₃ , OCOCH ₃ , SCOCH ₃ , CH (OH) CF ₃ , CH (OH) CH ₃ , CH ₂ NO ₂ , CH ₂ CN, CH ₂ SO ₂ CF ₃ , CH ₂ SO ₂ CH ₃ , CH ₂ CF ₃ , CH ₂ COCH ₃ , CH ₂ COCF ₃ ;

R _{2 is} selected from the group consisting of CN, CF ₃ , OH, NH ₂ , OR ₄ , F, Cl, Br, I, CH ₃ ;

R _{3 is} selected from the group consisting of C ₁ -C ₄ alkyl, allyl, CH ₂ CH ₂ ОCH ₃ , CH ₂ CH ₂ CH ₂ F, CH ₂ CH ₂ CHF ₂ , CH ₂ CH ₂ F, CH ₂ CHF ₂ , CH ₂ CF ₃ , 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl; CH ₂ CH ₂ OH, CH ₂ CH ₂ CH ₂ OH, CH ₂ CH (OH) CH ₃ , CH ₂ CH ₂ COCH ₃ ,

R ₄ selected from the group consisting of C ₁ -C ₃ alkyl, CF ₃ , CHF ₂ , CH ₂ F, CN;

with the proviso that when R ₁ is CN, OCF ₃ , OCHF ₂ , SCF ₃ , SCHF ₂ , CF ₃ , F or Cl; X is not CH, R _{2 is} not F, Cl, Br, CH ₃ , and R _{3 is} not C ₁ -C ₃ alkyl or allyl;

with the proviso that when R ₁ is CF ₃ or CN, X is not CH, R _{2 is} not F, Cl, Br, CH ₃ , and R _{3 is} not C ₁ -C ₂ alkyl;

and provided that when R ₁ is SO ₂ R ₄ , SO ₂ NH ₂ , SO ₂ NHCH _3, or SO ₂ N (CH ₃ ) ₂ ; R _{2 is} not OH

and its pharmaceutically acceptable salts.

In this group of compounds, R _{1 is} preferably selected from the group consisting of OSO ₂ CF ₃ , OSO ₂ CH ₃ , SO ₂ CH ₃ , SO ₂ CF ₃ , COCH ₃ , COCF ₃ , CN, and CF ₃ .

As used herein, the term C ₁ -C ₄ alkyl refers to an alkyl group containing 1-4 carbon atoms in any isomeric form. Various carbon fragments are defined as follows: alkyl refers to an aliphatic hydrocarbon radical and includes branched and unbranched forms such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Alkyl is preferably ethyl or propyl. The term “allyl” refers to the group —CH ₂ —CH═CH ₂ .

The addition of two substituents to the aryl ring of such compounds — one at the 2-position and the other at the 3-position — increases their ability to modulate dopamine neurotransmission. An unprecedented increase in the efficacy of these 2,3-disubstituted compounds compared to mono-substituted or 3,4-disubstituted compounds is illustrated in Tables 1 and 4.

Table 1
Estimated ED ₅₀ values for increasing DOPAC (3,4-dihydroxyphenylacetic acid) in the rat striatum after systemic administration of the test compound. For methods and statistical calculations, see the attached tests. Examples ED ₅₀ DOPAC * μmol / kg Comparative examples ED ₅₀ DOPAC *
μmol / kg

Пример 1

Example 1 28
(25-32)

Example 6 in WO01 / 46145 82
(71-102)

Example 3 9.9
(8.6-14)

Example 15 28
(25-35)

Example 4 58
(41-72)

Example 2 68
(48-86)

Example 12 in WO01 / 46145 154
(121-198)

Example 17 84
(54-124)

Stated in WO01 / 46145 208
(135-359)

Example 7 9.7
(7.5-12)

Stated in WO01 / 46145 84
(47-110)

Example 9 1.9
(1.5-2.3)

Example 9 in WO01 / 46146 40 **
(36-47)

Example 10 6.2
(5.2-7.8)

Example 43 in WO01 / 46146 35 **
(27-44)

Example 11 3,5
(2.2-5.5)

Examples 1 and 2 in US patent 4415736 n.d. ***

Example 14 2,4
(1.9-2.8)

12
(9.5-14) * in ED ₅₀ estimates, the maximum effect was limited to 350 - 400% of the control. ** in ED ₅₀ estimates, the maximum effect was set at 200% of control. *** nd Not determined; The ED ₅₀ value could not be calculated, since sufficiently high DOPAC levels were not achieved for the compound after administration of 100 μmol / kg.

One of the objectives of the present invention is to develop new compounds for therapeutic use and more specifically compounds for modulating the dopaminergic system in the brain of mammals, including the human brain.

Another objective of the present invention is to provide compounds having a therapeutic effect when administered orally.

In a first embodiment, the present invention relates to 4- (ortho, meta-disubstituted phenyl) -1-alkylperidines (i.e., compounds of formula 1 in which X = CH):

and their pharmaceutically acceptable salts, where R ₁ , R ₂ , R ₃ and R ₄ are as defined above.

In this group of compounds, R ^{1 is} preferably selected from the group consisting of OSO ₂ CF ₃ , OSO ₂ CH ₃ , SO ₂ CH ₃ , SO ₂ CF ₃ , COCH ₃ , COCF ₃ , CN, and CF ₃ . More preferably, R ^{1 is} selected from the group consisting of OSO ₂ CH ₃ , SO ₂ CH ₃ and SO ₂ CF ₃ .

In one embodiment, R ^{2 is} selected from the group consisting of F (provided that R ^{1 is} not CN or CF ₃ ), Cl (provided that R ^{1 is} not CN or CF ₃ ) and OH (provided that R ^{1 is} not SO ₂ CH ₃ or SO ₂ CF ₃ ). In another embodiment, R ^{3 is} selected from the group consisting of n-propyl and ethyl. Particularly preferred compounds of the invention are those in which R ² is F and R ^{3 is} selected from the group consisting of n-propyl and ethyl. Other preferred compounds are those in which R ¹ is SO ₂ CH ₃ , R ² is F, and R ^{3 is} selected from the group consisting of n-propyl and ethyl.

Preferred structures are:

4- [3-fluoro-2- (trifluoromethyl) phenyl] -1-propylpiperidine

1-ethyl-4- (3-fluoro-2- (trifluoromethyl) phenyl] piperidine

4- [3-fluoro-2- (trifluoromethyl) phenyl] -1- (2-methoxyethyl) piperidine

1-allyl-4- [3-fluoro-2- (trifluoromethyl) phenyl] piperidine

2-fluoro-6- (1-propylpiperidin-4-yl) phenol

2- (1-ethylpiperidin-4-yl) -6-fluorophenol

2-fluoro-6- [1- (2-methoxyethyl) piperidin-4-yl] phenol

2- (1-allylpiperidin-4-yl) -6-fluorophenol

2-fluoro-6- (1-propylpiperidin-4-yl) aniline

2- (1-ethylpiperidin-4-yl) -6-fluoroaniline

2-fluoro-6- [1- (2-methoxyethyl) piperidin-4-yl] aniline

2- (1-allylpiperidin-4-yl) -6-fluoroaniline

2-fluoro-6- (1-propylpiperidin-4-yl) benzonitrile

2- (1-ethylpiperidin-4-yl) -6-fluorobenzonitrile

2- (1-allylpiperidin-4-yl) -6-fluorobenzonitrile

4- [2-methyl-3- (trifluoromethyl) phenyl] -1-propylpiperidine

1-allyl-4- [2-methyl-3- (trifluoromethyl) phenyl] piperidine

4- [2-fluoro-3- (trifluoromethyl) phenyl] -1-propylpiperidine

1-allyl-4- [2-fluoro-3- (trifluoromethyl) phenyl] piperidine

2- (1-propylpiperidin-4-yl) -6- (trifluoromethyl) phenol

2- (1-ethylpiperidin-4-yl) -6- (trifluoromethyl) phenol

2- [1- (2-methoxyethyl) piperidin-4-yl] -6- (trifluoromethyl) phenol

2- (1-allylpiperidin-4-yl) -6- (trifluoromethyl) phenol

2- (1-propylpiperidin-4-yl) -6- (trifluoromethyl) aniline

2- (1-ethylpiperidin-4-yl) -6- (trifluoromethyl) aniline

2- [1- (2-methoxyethyl) piperidin-4-yl] -6- (trifluoromethyl) aniline

2- (1-allylpiperidin-4-yl) -6- (trifluoromethyl) aniline

2- (1-propylpiperidin-4-yl) -6- (trifluoromethyl) benzonitrile

2- (1-ethylpiperidin-4-yl) -6- (trifluoromethyl) benzonitrile

2- (1-allylpiperidin-4-yl) -6- (trifluoromethyl) benzonitrile

4- [2-chloro-3- (trifluoromethyl) phenyl] -1-propylpiperidine

1-allyl-4- [2-chloro-3- (trifluoromethyl) phenyl] piperidine

1- [2-methyl-3- (1-propylpiperidin-4-yl) phenyl] ethanone

1- [3- (1-ethylpiperidin-4-yl) -2-methylphenyl] ethanone

1- {3- [1- (2-methoxyethyl) piperidin-4-yl] -2-methylphenyl} ethanone

1- [3- (1-allylpiperidin-4-yl) -2-methylphenyl] ethanone

1- [2-fluoro-3- (1-propylpiperidin-4-yl) phenyl] ethanone

1- [3- (1-ethylpiperidin-4-yl) -2-fluorophenyl] ethanone

1- {2-fluoro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenyl} ethanone

1- [3- (1-allylpiperidin-4-yl) -2-fluorophenyl] ethanone

2-acetyl-6- (1-propylpiperidin-4-yl) benzonitrile

2-acetyl-6- (1-ethylpiperidin-4-yl) benzonitrile

2-acetyl-6- [1- (2-methoxyethyl) piperidin-4-yl] benzonitrile

2-acetyl-6- (1-allylpiperidin-4-yl) benzonitrile

1- [2-chloro-3- (1-propylpiperidin-4-yl) phenyl] ethanone

1- [2-chloro-3- (1-ethylpiperidin-4-yl) phenyl] ethanone

1- {2-chloro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenyl} ethanone

1- [3- (1-allylpiperidin-4-yl) -2-chlorophenyl] ethanone

2-methyl-3- (1-propylpiperidin-4-yl) phenylmethanesulfonate

3- (1-ethylpiperidin-4-yl) -2-methylphenylmethanesulfonate

3- [1- (2-methoxyethyl) piperidin-4-yl] -2-methylphenylmethanesulfonate

3- (1-allylpiperidin-4-yl) -2-methylphenylmethanesulfonate

2-fluoro-3- (1-propylpiperidin-4-yl) phenylmethanesulfonate

3- (1-ethylpiperidin-4-yl) -2-fluorophenylmethanesulfonate

2-fluoro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenylmethanesulfonate

3- (1-allylpiperidin-4-yl) -2-fluorophenylmethanesulfonate

2-cyano-3- (1-propylpiperidin-4-yl) phenylmethanesulfonate

2-cyano-3- (1-ethylpiperidin-4-yl) phenylmethanesulfonate

2-cyano-3- [1- (2-methoxyethyl) piperidin-4-yl] phenylmethanesulfonate

3- (1-allylpiperidin-4-yl) -2-cyanophenylmethanesulfonate

2-chloro-3- (1-propylpiperidin-4-yl) phenylmethanesulfonate

2-chloro-3- (1-ethylpiperidin-4-yl) phenylmethanesulfonate

2-chloro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenylmethanesulfonate

3- (1-allylpiperidin-4-yl) -2-chlorophenylmethanesulfonate

4- [2-methyl-3- (methylsulfonyl) phenyl] -1-propylpiperidine

1-ethyl-4- [2-methyl-3- (methylsulfonyl) phenyl] piperidine

1- (2-methoxyethyl) -4- [2-methyl-3- (methylsulfonyl) phenyl] piperidine

1-allyl-4- [2-methyl-3- (methylsulfonyl) phenyl] piperidine

4- [2-fluoro-3- (methylsulfonyl) phenyl] -1-propylpiperidine

1-ethyl-4- [2-fluoro-3- (methylsulfonyl) phenyl] piperidine

4- [2-fluoro-3- (methylsulfonyl) phenyl] -1- (2-methoxyethyl) piperidine

1-allyl-4- [2-fluoro-3- (methylsulfonyl) phenyl] piperidine

2- (methylsulfonyl) -6- (1-propylpiperidin-4-yl) benzonitrile

2- (1-ethylpiperidin-4-yl) -6- (methylsulfonyl) benzonitrile

2- [1- (2-methoxyethyl) piperidin-4-yl] -6- (methylsulfonyl) benzonitrile

2- (1-allylpiperidin-4-yl) -6- (methylsulfonyl) benzonitrile

4- [2-chloro-3- (methylsulfonyl) phenyl] -1-propylpiperidine

4- [2-chloro-3- (methylsulfonyl) phenyl] -1-ethylpiperidine

4- [2-chloro-3- (methylsulfonyl) phenyl] -1- (2-methoxyethyl) piperidine

1-allyl-4- [2-chloro-3- (methylsulfonyl) phenyl] piperidine

4- (2-methyl) -3 - [(trifluoromethyl) sulfonyl] phenyl} -1-propylpiperidine

1-ethyl-4- {2-methyl-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine

1- (2-methoxyethyl) -4- (2-methyl-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine

1-allyl-4- {2-methyl-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine

4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} -1-propylpiperidine

1-ethyl-4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine

4 - {(2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} -1- (2-methoxyethyl) piperidine

1-allyl-4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine

2- (1-propylpiperidin-4-yl) -6 - [(trifluoromethyl) sulfonyl] benzonitrile

2- (1-ethylpiperidin-4-yl) -6 - [(trifluoromethyl) sulfonyl] benzonitrile

2- [1- (2-methoxyethyl) piperidin-4-yl] -6 - [(trifluoromethyl) sulfonyl] benzonitrile

2- (1-allylpiperidin-4-yl) -6 - [(trifluoromethyl) sulfonyl] benzonitrile

4- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -1-propylpiperidine

4- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -1-ethylpiperidine

4- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -1- (2-methoxyethyl) piperidine

1-allyl-4- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine

2-methyl-3- (1-propylpiperidin-4-yl) phenyl trifluoromethanesulfonate

3- (1-ethylpiperidin-4-yl) -2-methylphenyl trifluoromethanesulfonate

3- [1- (2-methoxyethyl) piperidin-4-yl] -2-methylphenyl trifluoromethanesulfonate

3- (1-allylpiperidin-4-yl) -2-methylphenyl trifluoromethanesulfonate

2-fluoro-3- (1-propylpiperidin-4-yl) phenyl trifluoromethanesulfonate

3- (1-ethylpiperidin-4-yl) -2-fluorophenyl trifluoromethanesulfonate

2-fluoro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenyl trifluoromethanesulfonate

3- (1-allylpiperidin-4-yl) -2-fluorophenyl trifluoromethanesulfonate

2-cyano-3- (1-propylpiperidin-4-yl) phenyl trifluoromethanesulfonate

2-cyano-3- (1-ethylpiperidin-4-yl) phenyl trifluoromethanesulfonate

2-cyano-3- [1- (2-methoxyethyl) piperidin-4-yl] phenyl trifluoromethanesulfonate

3- (1-allylpiperidin-4-yl) -2-cyanophenyl trifluoromethanesulfonate

2-chloro-3- (1-propylpiperidin-4-yl) phenyl trifluoromethanesulfonate

2-chloro-3- (1-ethylpiperidin-4-yl) phenyl trifluoromethanesulfonate

2-chloro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenyl trifluoromethanesulfonate

3- (1-allylpiperidin-4-yl) -2-chlorophenyl trifluoromethanesulfonate

4- [3-chloro-2- (trifluoromethyl) phenyl] -1-propylpiperidine

4- [3-chloro-2- (trifluoromethyl) phenyl] -1-ethylpiperidine

4- [3-chloro-2- (trifluoromethyl) phenyl] -1- (2-methoxyethyl) piperidine

1-allyl-4- [3-chloro-2- (trifluoromethyl) phenyl] piperidine

2-chloro-6- (1-propylpiperidin-4-yl) phenol

2-chloro-6- (1-ethylpiperidin-4-yl) phenol

2-chloro-6- [1- (2-methoxyethyl) piperidin-4-yl] phenol

2- (1-allylpiperidin-4-yl) -6-chlorophenol

2-chloro-6- (1-propylpiperidin-4-yl) aniline

2-chloro-6- (1-ethylpiperidin-4-yl) aniline

2-chloro-6- [1- (2-methoxyethyl) piperidin-4-yl] aniline

2- (1-allylpiperidin-4-yl) -6-chloroaniline

2-chloro-6- (1-propylpiperidin-4-yl) benzonitrile

2-chloro-6- (1-ethylpiperidin-4-yl) benzonitrile

2- (1-allylpiperidin-4-yl) -6-chlorobenzonitrile

2- (difluoromethoxy) -6- (1-propylpiperidin-4-yl) phenol

2- (difluoromethoxy) -6- (1-ethylpiperidin-4-yl) phenol

2- (difluoromethoxy) -6- [1- (2-methoxyethyl) piperidin-4-yl] phenol

2- (1-allylpiperidin-4-yl) -6- (difluoromethoxy) phenol

2- (difluoromethoxy) -6- (1-propylpiperidin-4-yl) aniline

2- (difluoromethoxy) -6- (1-ethylpiperidin-4-yl) aniline

2- (difluoromethoxy) -6- [1- (2-methoxyethyl) piperidin-4-yl] aniline

2- (1-allylpiperidin-4-yl) -6- (difluoromethoxy) aniline

2- (difluoromethoxy) -6- (1-propylpiperidin-4-yl) benzonitrile

2- (difluoromethoxy) -6- (1-ethylpiperidin-4-yl) benzonitrile

2- (1-allylpiperidin-4-yl) -6- (difluoromethoxy) benzonitrile

2- (1-propylpiperidin-4-yl) -6- (trifluoromethoxy) phenol

2- (1-ethylpiperidin-4-yl) -6- (trifluoromethoxy) phenol

2- [1- (2-methoxyethyl) piperidin-4-yl] -6- (trifluoromethoxy) phenol

2- (1-allylpiperidin-4-yl) -6- (trifluoromethoxy) phenol

2- (1-propylpiperidin-4-yl) -6- (trifluoromethoxy) aniline

2- (1-ethylpiperidin-4-yl) -6- (trifluoromethoxy) aniline

2- [1- (2-methoxyethyl) piperidin-4-yl] -6- (trifluoromethoxy) aniline

2- (1-allylpiperidin-4-yl) -6- (trifluoromethoxy) aniline

2- (1-propylpiperidin-4-yl) -6- (trifluoromethoxy) benzonitrile

2- (1-ethylpiperidin-4-yl) -6- (trifluoromethoxy) benzonitrile

2- (1-allylpiperidin-4-yl) -6- (trifluoromethoxy) benzonitrile

2,2,2-trifluoro-1- [2-methyl-3- (1-propylpiperidin-4-yl) phenyl] ethanone

1- [3- (1-ethylpiperidin-4-yl) -2-methylphenyl] -2,2,2-trifluoroethanone

2,2,2-trifluoro-1- {3- [1- (2-methoxyethyl) piperidin-4-yl] -2-methylphenyl} ethanone

1- [3- (1-allylpiperidin-4-yl) -2-methylphenyl] -2,2,2-trifluoroethanone

2,2,2-trifluoro-1- [2-fluoro-3- (1-propylpiperidin-4-yl) phenyl] ethanone

1- [3- (1-ethylpiperidin-4-yl) -2-fluorophenyl] -2,2,2-trifluoroethanone

2,2,2-trifluoro-1- {2-fluoro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenyl} ethanone

1- [3- (1-allylpiperidin-4-yl) -2-fluorophenyl] -2,2,2-trifluoroethanone

2- (1-propylpiperidin-4-yl) -6- (trifluoroacetyl) benzonitrile

2- (1-ethylpiperidin-4-yl) -6- (trifluoroacetyl) benzonitrile

2- [1- (2-methoxyethyl) piperidin-4-yl] -6- (trifluoroacetyl) benzonitrile

2- (1-allylpiperidin-4-yl) -6- (trifluoroacetyl) benzonitrile

1- [2-chloro-3- (1-propylpiperidin-4-yl) phenyl] -2,2,2-trifluoroethanone

1- [2-chloro-3- (1-ethylpiperidin-4-yl) phenyl] -2,2,2-trifluoroethanone

1- (2-chloro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenyl) -2,2,2-trifluoroethanone

1- [3- (1-allylpiperidin-4-yl) -2-chlorophenyl] -2,2,2-trifluoroethanone

2,2,2-trifluoro-1- [2-methyl-3- (1-propylpiperidin-4-yl) phenyl] ethanol

1- [3- (1-ethylpiperidin-4-yl) -2-methylphenyl] -2,2,2-trifluoroethanol

2,2,2-trifluoro-1- {3- [1- (2-methoxyethyl) piperidin-4-yl] -2-methylphenyl} ethanol

1- [3- (1-allylpiperidin-4-yl) -2-methylphenyl] -2,2,2-trifluoroethanol

2,2,2-trifluoro-1- [2-fluoro-3- (1-propylpiperidin-4-yl) phenyl] ethanol

1- [3- (1-ethylpiperidin-4-yl) -2-fluorophenyl] -2,2,2-trifluoroethanol

2,2,2-trifluoro-1- {2-fluoro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenyl} ethanol

1- [3- (1-allylpiperidin-4-yl) -2-fluorophenyl] -2,2,2-trifluoroethanol

2- (1-propylpiperidin-4-yl) -6- (2,2,2-trifluoro-1-hydroxyethyl) benzonitrile

2- (1-ethylpiperidin-4-yl) -6- (2,2,2-trifluoro-1-hydroxyethyl) benzonitrile

2- [1- (2-methoxyethyl) piperidin-4-yl] -6- (2,2,2-trifluoro-1-hydroxyethyl) benzonitrile

2- (1-allylpiperidin-4-yl) -6- (2,2,2-trifluoro-1-hydroxyethyl) benzonitrile

1- [2-chloro-3- (1-propylpiperidin-4-yl) phenyl] -2,2,2-trifluoroethanol

1- [2-chloro-3- (1-ethylpiperidin-4-yl) phenyl] -2,2,2-trifluoroethanol

1- {2-chloro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenyl} -2,2,2-trifluoroethanol

1- [3- (1-allylpiperidin-4-yl) -2-chlorophenyl] -2,2,2-trifluoroethanol

2-methyl-3- (1-propylpiperidin-4-yl) benzonitrile

3- (1-allylpiperidin-4-yl) -2-methylbenzonitrile

2-fluoro-3- (1-propylpiperidin-4-yl) benzonitrile

3- (1-allylpiperidin-4-yl) -2-fluorobenzonitrile

2-hydroxy-3- (1-propylpiperidin-4-yl) benzonitrile

3- (1-ethylpiperidin-4-yl) -2-hydroxybenzonitrile

2-hydroxy-3- [1- (2-methoxyethyl) piperidin-4-yl] benzonitrile

3- (1-allylpiperidin-4-yl) -2-hydroxybenzonitrile

2-amino-3- (1-propylpiperidin-4-yl) benzonitrile

2-amino-3- (1-ethylpiperidin-4-yl) benzonitrile

2-amino-3- [1- (2-methoxyethyl) piperidin-4-yl] benzonitrile

3- (1-allylpiperidin-4-yl) -2-aminobenzonitrile

3- (1-propylpiperidin-4-yl) phthalonitrile

3- (1-ethylpiperidin-4-yl) phthalonitrile

3- (1-allylpiperidin-4-yl) phthalonitrile

2-chloro-3- (1-propylpiperidin-4-yl) benzonitrile

3- (1-allylpiperidin-4-yl) -2-chlorobenzonitrile.

The most preferred structures in this class are:

2- (1-ethylpiperidin-4-yl) -6- (trifluoromethyl) phenol

1- [3- (1-ethylpiperidin-4-yl) -2-fluorophenyl] ethanone

1- [2-chloro-3- (1-ethylpiperidin-4-yl) phenyl] ethanone

3- (1-ethylpiperidin-4-yl) -2-fluorophenylmethanesulfonate

2-chloro-3- (1-ethylpiperidin-4-yl) phenylmethanesulfonate

1-ethyl-4- [2-fluoro-3- (methylsulfonyl) phenyl] piperidine

4- [2-chloro-3- (methylsulfonyl) phenyl] -1-ethylpiperidine

1-ethyl-4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine

4- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -1-ethylpiperidine

3- (1-ethylpiperidin-4-yl) -2-fluorophenyl trifluoromethanesulfonate

2-chloro-3- (1-ethylpiperidin-4-yl) phenyl trifluoromethanesulfonate

1- [3- (1-ethylpiperidin-4-yl) -2-fluorophenyl] -2,2,2-trifluoroethanone

1- [2-chloro-3- (1-ethylpiperidin-4-yl) phenyl] -2,2,2-trifluoroethanone

1- [3- (1-ethylpiperidin-4-yl) -2-fluorophenyl] -2,2,2-trifluoroethanol

1- [2-chloro-3- (1-ethylpiperidin-4-yl) phenyl] -2,2,2-trifluoroethanol

3- (1-ethylpiperidin-4-yl) -2-hydroxybenzonitrile

2- (1-propylpiperidin-4-yl) -6- (trifluoromethyl) phenol

1- [2-fluoro-3- (1-propylpiperidin-4-yl) phenyl] ethanone

1- [2-chloro-3- (1-propylpiperidin-4-yl) phenyl] ethanone

2-fluoro-3- (1-propylpiperidin-4-yl) phenylmethanesulfonate

2-chloro-3- (1-propylpiperidin-4-yl) phenylmethanesulfonate

4- [2-fluoro-3- (methylsulfonyl) phenyl] -1-propylpiperidine

4- [2-chloro-3- (methylsulfonyl) phenyl] -1-propylpiperidine

4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} -1-propylpiperidine

4- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -1-propylpiperidine

2-fluoro-3- (1-propylpiperidin-4-yl) phenyl trifluoromethanesulfonate

2-chloro-3- (1-propylpiperidin-4-yl) phenyl trifluoromethanesulfonate

2,2,2-trifluoro-1- [2-fluoro-3- (1-propylpiperidin-4-yl) phenyl] ethanone

1- [2-chloro-3- (1-propylpiperidin-4-yl) phenyl] -2,2,2-trifluoroethanone

2,2,2-trifluoro-1- [2-fluoro-3- (1-propylpiperidin-4-yl) phenyl] ethanol

1- [2-chloro-3- (1-propylpiperidin-4-yl) phenyl] -2,2,2-trifluoroethanol

2-hydroxy-3- (1-propylpiperidin-4-yl) benzonitrile

In a second embodiment, the invention relates to 4- (ortho, meta-disubstituted phenyl) -1-alkylpiperazines, i.e. compounds of formula 1 in which X = N):

and their pharmaceutically acceptable salts, where R ¹ , R ² , R ³ and R ⁴ are as defined above.

In this group of compounds, R ^{1 is} preferably selected from the group consisting of OSO ₂ CF ₃ , OSO ₂ CH ₃ , SO ₂ CH ₃ , SO ₂ CF ₃ , COCH ₃ , COCF ₃ , CN, and CF ₃ . More preferably, R ^{1 is} selected from the group consisting of OSO ₂ CH ₃ , SO ₂ CH ₃ and SO ₂ CF ₃ .

In one embodiment, R ^{2 is} selected from the group consisting of F, Cl, and OH (provided that R ^{1 is} not SO ₂ CH ₃ , SO ₂ CF ₃ ). In another embodiment, R ^{3 is} selected from the group consisting of n-propyl and ethyl. Particularly preferred compounds of the invention are those in which R ² is F and R ^{3 is} selected from the group consisting of n-propyl and ethyl. Further preferred compounds are those in which R ¹ is CF ₃ , R ² is F, and R ^{3 is} selected from the group consisting of n-propyl and ethyl.

Preferred structures are:

1- (3-fluoro-2-methylphenyl) -4-propylpiperazine

1-ethyl-4- (3-fluoro-2-methylphenyl) piperazine

1- (3-fluoro-2-methylphenyl) -4- (2-methoxyethyl) piperazine

1-allyl-4- (3-fluoro-2-methylphenyl) piperazine

1- (2,3-difluorophenyl) -4-propylpiperazine

1- (2,3-difluorophenyl) -4-ethylpiperazine

1- (2,3-difluorophenyl) -4- (2-methoxyethyl) piperazine

1-allyl-4- (2,3-difluorophenyl) piperazine

1- [3-fluoro-2- (trifluoromethyl) phenyl] -4-propylpiperazine

1-ethyl-4- [3-fluoro-2- (trifluoromethyl) phenyl] piperazine

1- [3-fluoro-2- (trifluoromethyl) phenyl] -4- (2-methoxyethyl) piperazine

1-allyl-4- [3-fluoro-2- (trifluoromethyl) phenyl] piperazine

2-fluoro-6- (4-propylpiperazin-1-yl) phenol

2- (4-ethylpiperazin-1-yl) -6-fluorophenol

2-fluoro-6- [4- (2-methoxyethyl) piperazin-1-yl] phenol

2- (4-allylpiperazin-1-yl) -6-fluorophenol

2-fluoro-6- (4-propylpiperazin-1-yl) aniline

2- (4-ethylpiperazin-1-yl) -6-fluoroaniline

2-fluoro-6- [4- (2-methoxyethyl) piperazin-1-yl] aniline

2- (4-allylpiperazin-1-yl) -6-fluoroaniline

2-fluoro-6- (4-propylpiperazin-1-yl) benzonitrile

2- (4-ethylpiperazin-1-yl) -6-fluorobenzonitrile

2-fluoro-6- [4- (2-methoxyethyl) piperazin-1-yl] benzonitrile

2- (4-allylpiperazin-1-yl) -6-fluorobenzonitrile

1- (2-chloro-3-fluorophenyl) -4-propylpiperazine

1- (2-chloro-3-fluorophenyl) -4-ethylpiperazine

1- (2-chloro-3-fluorophenyl) -4- (2-methoxyethyl) piperazine

1-allyl-4- (2-chloro-3-fluorophenyl) piperazine

1- [2-methyl-3- (trifluoromethyl) phenyl] -4-propylpiperazine

1-ethyl-4- [2-methyl-3- (trifluoromethyl) phenyl] piperazine

1- (2-methoxyethyl) -4- [2-methyl-3- (trifluoromethyl) phenyl] piperazine

1-allyl-4- [2-methyl-3- (trifluoromethyl) phenyl] piperazine

1- [2-fluoro-3- (trifluoromethyl) phenyl] -4-propylpiperazine

1-ethyl-4- [2-fluoro-3- (trifluoromethyl) phenyl] piperazine

1- [2-fluoro-3- (trifluoromethyl) phenyl] -4- (2-methoxyethyl) piperazine

1-allyl-4- [2-fluoro-3- (trifluoromethyl) phenyl] piperazine

2- (4-propylpiperazin-1-yl) -6- (trifluoromethyl) phenol

2- (4-ethylpiperazin-1-yl) -6- (trifluoromethyl) phenol

2- [4- (2-methoxyethyl) piperazin-1-yl] -6- (trifluoromethyl) phenol

2- (4-allylpiperazin-1-yl) -6- (trifluoromethyl) phenol

2- (4-propylpiperazin-1-yl) -6- (trifluoromethyl) aniline

2- (4-ethylpiperazin-1-yl) -6- (trifluoromethyl) aniline

2- [4- (2-methoxyethyl) piperazin-1-yl] -6- (trifluoromethyl) aniline

2- (4-allylpiperazin-1-yl) -6- (trifluoromethyl) aniline

2- (4-propylpiperazin-1-yl) -6- (trifluoromethyl) benzonitrile

2- (4-ethylpiperazin-1-yl) -6- (trifluoromethyl) benzonitrile

2- [4- (2-methoxyethyl) piperazin-1-yl] -6- (trifluoromethyl) benzonitrile

2- (4-allylpiperazin-1-yl) -6- (trifluoromethyl) benzonitrile

1- [2-chloro-3- (trifluoromethyl) phenyl] -4-propylpiperazine

1- [2-chloro-3- (trifluoromethyl) phenyl] -4-ethylpiperazine

1- [2-chloro-3- (trifluoromethyl) phenyl] -4- (2-methoxyethyl) piperazine

1-allyl-4- [2-chloro-3- (trifluoromethyl) phenyl] piperazine

1- [2-methyl-3- (4-propylpiperazin-1-yl) phenyl] ethanone

1- [3- (4-ethylpiperazin-1-yl) -2-methylphenyl] ethanone

1- {3- [4- (2-methoxyethyl) piperazin-1-yl] -2-methylphenyl} ethanone

1- [3- (4-allylpiperazin-1-yl) -2-methylphenyl] ethanone

1- [2-fluoro-3- (4-propylpiperazin-1-yl) phenyl] ethanone

1- [3- (4-ethylpiperazin-1-yl) -2-fluorophenyl] ethanone

1- {2-fluoro-3- [4- (2-methoxyethyl) piperazin-1-yl] phenyl} ethanone

1- [3- (4-allylpiperazin-1-yl) -2-fluorophenyl] ethanone

2-acetyl-6- (4-propylpiperazin-1-yl) benzonitrile

2-acetyl-6- (4-ethylpiperazin-1-yl) benzonitrile

2-acetyl-6- [4- (2-methoxyethyl) piperazin-1-yl] benzonitrile

2-acetyl-6- (4-allylpiperazin-1-yl) benzonitrile

1- [2-chloro-3- (4-propylpiperazin-1-yl) phenyl] ethanone

1- [2-chloro-3- (4-ethylpiperazin-1-yl) phenyl] ethanone

1- {2-chloro-3- [4- (2-methoxyethyl) piperazin-1-yl] phenyl} ethanone

1- [3- (4-allylpiperazin-1-yl) -2-chlorophenyl] ethanone

2-methyl-3- (4-propylpiperazin-1-yl) phenylmethanesulfonate

3- (4-ethylpiperazin-1-yl) -2-methylphenylmethanesulfonate

3- [4- (2-methoxyethyl) piperazin-1-yl] -2-methylphenylmethanesulfonate

3- (4-allylpiperazin-1-yl) -2-methylphenylmethanesulfonate

2-fluoro-3- (4-propylpiperazin-1-yl) phenylmethanesulfonate

3- (4-ethylpiperazin-1-yl) -2-fluorophenylmethanesulfonate

2-fluoro-3- [4- (2-methoxyethyl) piperazin-1-yl] phenylmethanesulfonate

3- (4-allylpiperazin-1-yl) -2-fluorophenylmethanesulfonate

2-cyano-3- (4-propylpiperazin-1-yl) phenylmethanesulfonate

2-cyano-3- (4-ethylpiperazin-1-yl) phenylmethanesulfonate

2-cyano-3- [4- (2-methoxyethyl) piperazin-1-yl] phenylmethanesulfonate

3- (4-allylpiperazin-1-yl) -2-cyanophenylmethanesulfonate

2-chloro-3- (4-propylpiperazin-1-yl) phenylmethanesulfonate

2-chloro-3- (4-ethylpiperazin-1-yl) phenylmethanesulfonate

2-chloro-3- [4- (2-methoxyethyl) piperazin-1-yl] phenylmethanesulfonate

3- (4-allylpiperazin-1-yl) -2-chlorophenylmethanesulfonate

1- [2-methyl-3- (methylsulfonyl) phenyl] -4-propylpiperazine

1-ethyl-4- [2-methyl-3- (methylsulfonyl) phenyl] piperazine

1- (2-methoxyethyl) -4- [2-methyl-3- (methylsulfonyl) phenyl] piperazine

1-allyl-4- [2-methyl-3- (methylsulfonyl) phenyl] piperazine

1- [2-fluoro-3- (methylsulfonyl) phenyl] -4-propylpiperazine

1-ethyl-4- [2-fluoro-3- (methylsulfonyl) phenyl] piperazine

1- [2-fluoro-3- (methylsulfonyl) phenyl] -4- (2-methoxyethyl) piperazine

1-allyl-4- [2-fluoro-3- (methylsulfonyl) phenyl] piperazine

2- (methylsulfonyl) -6- (4-propylpiperazin-1-yl) benzonitrile

2- (4-ethylpiperazin-1-yl) -6- (methylsulfonyl) benzonitrile

2- [4- (2-methoxyethyl) piperazin-1-yl] -6- (methylsulfonyl) benzonitrile

2- (4-allylpiperazin-1-yl) -6- (methylsulfonyl) benzonitrile

1- [2-chloro-3- (methylsulfonyl) phenyl] -4-propylpiperazine

1- [2-chloro-3- (methylsulfonyl) phenyl] -4-ethylpiperazine

1- [2-chloro-3- (methylsulfonyl) phenyl] -4- (2-methoxyethyl) piperazine

1-allyl-4- [2-chloro-3- (methylsulfonyl) phenyl] piperazine

1- {2-methyl-3 - [(trifluoromethyl) sulfonyl] phenyl} -4-propylpiperazine

1-ethyl-4- {2-methyl-3 - [(trifluoromethyl) sulfonyl] phenyl} piperazine

1- (2-methoxyethyl) -4- {2-methyl-3 - [(trifluoromethyl) sulfonyl] phenyl} piperazine

1-allyl-4- {2-methyl-3 - [(trifluoromethyl) sulfonyl] phenyl} piperazine

1- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} -4-propylpiperazine

1-ethyl-4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperazine

1- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} -4- (2-methoxyethyl) piperazine

1-allyl-4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperazine

2- (4-propylpiperazin-1-yl) -6 - [(trifluoromethyl) sulfonyl] benzonitrile

2- (4-ethylpiperazin-1-yl) -6 - [(trifluoromethyl) sulfonyl] benzonitrile

2- [4- (2-methoxyethyl) piperazin-1-yl] -6 - [(trifluoromethyl) sulfonyl] benzonitrile

2- (4-allylpiperazin-1-yl) -6 - [(trifluoromethyl) sulfonyl] benzonitrile

1- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -4-propylpiperazine

1- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -4-ethylpiperazine

1- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -4- (2-methoxyethyl) piperazine

1-allyl-4- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperazine

2-methyl-3- (4-propylpiperazin-1-yl) phenyl trifluoromethanesulfonate

3- (4-ethylpiperazin-1-yl) -2-methylphenyl trifluoromethanesulfonate

3- [4- (2-methoxyethyl) piperazin-1-yl] -2-methylphenyl trifluoromethanesulfonate

3- (4-allylpiperazin-1-yl) -2-methylphenyl trifluoromethanesulfonate

2-fluoro-3- (4-propylpiperazin-1-yl) phenyl trifluoromethanesulfonate

3- (4-ethylpiperazin-1-yl) -2-fluorophenyl trifluoromethanesulfonate

2-fluoro-3- [4- (2-methoxyethyl) piperazin-1-yl] phenyl trifluoromethanesulfonate

3- (4-allylpiperazin-1-yl) -2-fluorophenyl trifluoromethanesulfonate

2-cyano-3- (4-propylpiperazin-1-yl) phenyl trifluoromethanesulfonate

2-cyano-3- (4-ethylpiperazin-1-yl) phenyl trifluoromethanesulfonate

2-cyano-3- [4- (2-methoxyethyl) piperazin-1-yl] phenyl trifluoromethanesulfonate

3- (4-allylpiperazin-1-yl) -2-cyanophenyl trifluoromethanesulfonate

2-chloro-3- (4-propylpiperazin-1-yl) phenyl trifluoromethanesulfonate

2-chloro-3- (4-ethylpiperazin-1-yl) phenyl trifluoromethanesulfonate

2-chloro-3- [4- (2-methoxyethyl) piperazin-1-yl] phenyl trifluoromethanesulfonate

3- (4-allylpiperazin-1-yl) -2-chlorophenyl trifluoromethanesulfonate

1- (3-chloro-2-methylphenyl) -4-propylpiperazine

1- (3-chloro-2-methylphenyl) -4-ethylpiperazine

1- (3-chloro-2-methylphenyl) -4- (2-methoxyethyl) piperazine

1-allyl-4- (3-chloro-2-methylphenyl) piperazine

1- (3-chloro-2-fluorophenyl) -4-propylpiperazine

1- (3-chloro-2-fluorophenyl) -4-ethylpiperazine

1- (3-chloro-2-fluorophenyl) -4- (2-methoxyethyl) piperazine

1-allyl-4- (3-chloro-2-fluorophenyl) piperazine

1- [3-chloro-2- (trifluoromethyl) phenyl] -4-propylpiperazine

1- [3-chloro-2- (trifluoromethyl) phenyl] -4-ethylpiperazine

1- [3-chloro-2- (trifluoromethyl) phenyl] -4- (2-methoxyethyl) piperazine

1-allyl-4- [3-chloro-2- (trifluoromethyl) phenyl] piperazine

2-chloro-6- (4-propylpiperazin-1-yl) phenol

2-chloro-6- (4-ethylpiperazin-1-yl) phenol

2-chloro-6- [4- (2-methoxyethyl) piperazin-1-yl] phenol

2- (4-allylpiperazin-1-yl) -6-chlorophenol

2-chloro-6- (4-propylpiperazin-1-yl) aniline

2-chloro-6- (4-ethylpiperazin-1-yl) aniline

2-chloro-6- [4- (2-methoxyethyl) piperazin-1-yl] aniline

2- (4-allylpiperazin-1-yl) -6-chloroaniline

2-chloro-6- (4-propylpiperazin-1-yl) benzonitrile

2-chloro-6- (4-ethylpiperazin-1-yl) benzonitrile

2-chloro-6- [4- (2-methoxyethyl) piperazin-1-yl] benzonitrile

2- (4-allylpiperazin-1-yl) -6-chlorobenzonitrile

1- (2,3-dichlorophenyl) -4-propylpiperazine

1- (2,3-dichlorophenyl) -4-ethylpiperazine

1- (2,3-dichlorophenyl) -4- (2-methoxyethyl) piperazine

1-allyl-4- (2,3-dichlorophenyl) piperazine

1- [3- (difluoromethoxy) -2-methylphenyl] -4-propylpiperazine

1- [3- (difluoromethoxy) -2-methylphenyl] -4-ethylpiperazine

1- [3- (difluoromethoxy) -2-methylphenyl] -4- (2-methoxyethyl) piperazine

1-allyl-4- [3- (difluoromethoxy) -2-methylphenyl] piperazine

1- [3- (difluoromethoxy) -2-fluorophenyl] -4-propylpiperazine

1- [3- (difluoromethoxy) -2-fluorophenyl] -4-ethylpiperazine

1- [3- (difluoromethoxy) -2-fluorophenyl] -4- (2-methoxyethyl) piperazine

1-allyl-4- [3- (difluoromethoxy) -2-fluorophenyl] piperazine

2- (difluoromethoxy) -6- (4-propylpiperazin-1-yl) phenol

2- (difluoromethoxy) -6- (4-ethylpiperazin-1-yl) phenol

2- (difluoromethoxy) -6- [4- (2-methoxyethyl) piperazin-1-yl] phenol

2- (4-allylpiperazin-1-yl) -6- (difluoromethoxy) phenol

2- (difluoromethoxy) -6- (4-propylpiperazin-1-yl) aniline

2- (difluoromethoxy) -6- (4-ethylpiperazin-1-yl) aniline

2- (difluoromethoxy) -6- [4- (2-methoxyethyl) piperazin-1-yl] aniline

2- (4-allylpiperazin-1-yl) -6- (difluoromethoxy) aniline

2- (difluoromethoxy) -6- (4-propylpiperazin-1-yl) benzonitrile

2- (difluoromethoxy) -6- (4-ethylpiperazin-1-yl) benzonitrile

2- (difluoromethoxy) -6- [4- (2-methoxyethyl) piperazin-1-yl] benzonitrile

2- (4-allylpiperazin-1-yl) -6- (difluoromethoxy) benzonitrile

1- [2-chloro-3- (difluoromethoxy) phenyl] -4-propylpiperazine

1- [2-chloro-3- (difluoromethoxy) phenyl] -4-ethylpiperazine

1- [2-chloro-3- (difluoromethoxy) phenyl] -4- (2-methoxyethyl) piperazine

1-allyl-4- [2-chloro-3- (difluoromethoxy) phenyl] piperazine

1- [2-methyl-3- (trifluoromethoxy) phenyl] -4-propylpiperazine

1-ethyl-4- [2-methyl-3- (trifluoromethoxy) phenyl] piperazine

1- (2-methoxyethyl) -4- [2-methyl-3- (trifluoromethoxy) phenyl] piperazine

1-allyl-4- [2-methyl-3- (trifluoromethoxy) phenyl] piperazine

1- [2-fluoro-3- (trifluoromethoxy) phenyl] -4-propylpiperazine

1-ethyl-4- [2-fluoro-3- (trifluoromethoxy) phenyl] piperazine

1- [2-fluoro-3- (trifluoromethoxy) phenyl] -4- (2-methoxyethyl) piperazine

1-allyl-4- [2-fluoro-3- (trifluoromethoxy) phenyl] piperazine

2- (4-propylpiperazin-1-yl) -6- (trifluoromethoxy) phenol

2- (4-ethylpiperazin-1-yl) -6- (trifluoromethoxy) phenol

2- [4- (2-methoxyethyl) piperazin-1-yl] -6- (trifluoromethoxy) phenol

2- (4-allylpiperazin-1-yl) -6- (trifluoromethoxy) phenol

2- (4-propylpiperazin-1-yl) -6- (trifluoromethoxy) aniline

2- (4-ethylpiperazin-1-yl) -6- (trifluoromethoxy) aniline

2- [4- (2-methoxyethyl) piperazin-1-yl] -6- (trifluoromethoxy) aniline

2- (4-allylpiperazin-1-yl) -6- (trifluoromethoxy) aniline

2- (4-propylpiperazin-1-yl) -6- (trifluoromethoxy) benzonitrile

2- (4-ethylpiperazin-1-yl) -6- (trifluoromethoxy) benzonitrile

2- [4- (2-methoxyethyl) piperazin-1-yl] -6- (trifluoromethoxy) benzonitrile

2- (4-allylpiperazin-1-yl) -6- (trifluoromethoxy) benzonitrile

1- [2-chloro-3- (trifluoromethoxy) phenyl] -4-propylpiperazine

1- [2-chloro-3- (trifluoromethoxy) phenyl] -4-ethylpiperazine

1- [2-chloro-3- (trifluoromethoxy) phenyl] -4- (2-methoxyethyl) piperazine

1-allyl-4- [2-chloro-3- (trifluoromethoxy) phenyl] piperazine

2,2,2-trifluoro-1- [2-methyl-3- (4-propylpiperazin-1-yl) phenyl] ethanone

1- [3- (4-ethylpiperazin-1-yl) -2-methylphenyl] -2,2,2-trifluoroethanone

2,2,2-trifluoro-1- {3- [4- (2-methoxyethyl) piperazin-1-yl] -2-methylphenyl} ethanone

1- [3- (4-allylpiperazin-1-yl) -2-methoxyphenyl] -2,2,2-trifluoroethanone

2,2,2-trifluoro-1- [2-fluoro-3- (4-propylpiperazin-1-yl) phenyl] ethanone

1- [3- (4-ethylpiperazin-1-yl) -2-fluorophenyl] -2,2,2-trifluoroethanone

2,2,2-trifluoro-1- {2-fluoro-3- [4- (2-methoxyethyl) piperazin-1-yl] phenyl} ethanone

1- [3- (4-allylpiperazin-1-yl) -2-fluorophenyl] -2,2,2-trifluoroethanone

2- (4-propylpiperazin-1-yl) -6- (trifluoroacetyl) benzonitrile

2- (4-ethylpiperazin-1-yl) -6- (trifluoroacetyl) benzonitrile

2- [4- (2-methoxyethyl) piperazin-1-yl] -6- (trifluoroacetyl) benzonitrile

2- (4-allylpiperazin-1-yl) -6- (trifluoroacetyl) benzonitrile

1- [2-chloro-3- (4-propylpiperazin-1-yl) phenyl] -2,2,2-trifluoroethanone

1- [2-chloro-3- (4-ethylpiperazin-1-yl) phenyl] -2,2,2-trifluoroethanone

1- {2-chloro-3- [4- (2-methoxyethyl) piperazin-1-yl] phenyl} -2,2,2-trifluoroethanone

1- [3- (4-allylpiperazin-1-yl) -2-chlorophenyl] -2,2,2-trifluoroethanone

2,2,2-trifluoro-1- [2-methyl-3- (4-propylpiperazin-1-yl) phenyl] ethanol

1- [3- (4-ethylpiperazin-1-yl) -2-methylphenyl] -2,2,2-trifluoroethanol

2,2,2-trifluoro-1- {3- [4- (2-methoxyethyl) piperazin-1-yl] -2-methylphenyl} ethanol

1- [3- (4-allylpiperazin-1-yl) -2-methylphenyl] -2,2,2-trifluoroethanol

2,2,2-trifluoro-1- [2-fluoro-3- (4-propylpiperazin-1-yl) phenyl] ethanol

1- [3- (4-ethylpiperazin-1-yl) -2-fluorophenyl] -2,2,2-trifluoroethanol

2,2,2-trifluoro-1- {2-fluoro-3- [4- (2-methoxyethyl) piperazin-1-yl] phenyl} ethanol

1- [3- (4-allylpiperazin-1-yl) -2-fluorophenyl] -2,2,2-trifluoroethanol

2- (4-propylpiperazin-1-yl) -6- (2,2,2-trifluoro-1-hydroxyethyl) benzonitrile

2- (4-ethylpiperazin-1-yl) -6- (2,2,2-trifluoro-1-hydroxyethyl) benzonitrile

2- [4- (2-methoxyethyl) piperazin-1-yl] -6- (2,2,2-trifluoro-1-hydroxyethyl) benzonitrile

2- (4-allylpiperazin-1-yl) -6- (2,2,2-trifluoro-1-hydroxyethyl) benzonitrile

1- [2-chloro-3- (4-propylpiperazin-1-yl) phenyl] -2,2,2-trifluoroethanol

1- [2-chloro-3- (4-ethylpiperazin-1-yl) phenyl] -2,2,2-trifluoroethanol

1- {2-chloro-3- [4- (2-methoxyethyl) piperazin-1-yl] phenyl} -2,2,2-trifluoroethanol

1- [3- (4-allylpiperazin-1-yl) -2-chlorophenyl] -2,2,2-trifluoroethanol

2-methyl-3- (4-propylpiperazin-1-yl) benzonitrile

3- (4-ethylpiperazin-1-yl) -2-methylbenzonitrile

3- [4- (2-methoxyethyl) piperazin-1-yl] -2-methylbenzonitrile

3- (4-allylpiperazin-1-yl) -2-methylbenzonitrile

2-fluoro-3- (4-propylpiperazin-1-yl) benzonitrile

3- (4-ethylpiperazin-1-yl) -2-fluorobenzonitrile

2-fluoro-3- [4- (2-methoxyethyl) piperazin-1-yl] benzonitrile

3- (4-allylpiperazin-1-yl) -2-fluorobenzonitrile

2-hydroxy-3- (4-propylpiperazin-1-yl) benzonitrile

3- (4-ethylpiperazin-1-yl) -2-hydroxybenzonitrile

2-hydroxy-3- [4- (2-methoxyethyl) piperazin-1-yl] benzonitrile

3- (4-allylpiperazin-1-yl) -2-hydroxybenzonitrile

2-amino-3- (4-propylpiperazin-1-yl) benzonitrile

2-amino-3- (4-ethylpiperazin-1-yl) benzonitrile

2-amino-3- [4- (2-methoxyethyl) piperazin-1-yl] benzonitrile

3- (4-allylpiperazin-1-yl) -2-aminobenzonitrile

3- (4-propylpiperazin-1-yl) phthalonitrile

3- (4-ethylpiperazin-1-yl) phthalonitrile

3- [4- (2-methoxyethyl) piperazin-1-yl] phthalonitrile

3- (4-allylpiperazin-1-yl) phthalonitrile

2-chloro-3- (4-propylpiperazin-1-yl) benzonitrile

2-chloro-3- (4-ethylpiperazin-1-yl) benzonitrile

2-chloro-3- [4- (2-methoxyethyl) piperazin-1-yl] benzonitrile

3- (4-allylpiperazin-1-yl) -2-chlorobenzonitrile

The most preferred structures in this class are:

1- [2-fluoro-3- (trifluoromethyl) phenyl] -4-propylpiperazine

1-ethyl-4- [2-fluoro-3- (trifluoromethyl) phenyl] piperazine

1- [2-fluoro-3- (trifluoromethyl) phenyl] -4- (2-methoxyethyl) piperazine

1-allyl-4- [2-fluoro-3- (trifluoromethyl) phenyl] piperazine

1- [2-chloro-3- (trifluoromethyl) phenyl] -4-propylpiperazine

1- [2-chloro-3- (trifluoromethyl) phenyl] -4-ethylpiperazine

1- [2-chloro-3- (trifluoromethyl) phenyl] -4- (2-methoxyethyl) piperazine

1-allyl-4- [2-chloro-3- (trifluoromethyl) phenyl] piperazine

1- [2-fluoro-3- (methylsulfonyl) phenyl] -4-propylpiperazine

1-ethyl-4- [2-fluoro-3- (methylsulfonyl) phenyl] piperazine

1- [2-fluoro-3- (methylsulfonyl) phenyl] -4- (2-methoxyethyl) piperazine

1-allyl-4- [2-fluoro-3- (methylsulfonyl) phenyl] piperazine

1- [2-chloro-3- (methylsulfonyl) phenyl] -4-propylpiperazine

1- [2-chloro-3- (methylsulfonyl) phenyl] -4-ethylpiperazine

1- [2-chloro-3- (methylsulfonyl) phenyl] -4- (2-methoxyethyl) piperazine

1-allyl-4- [2-chloro-3- (methylsulfonyl) phenyl] piperazine

1- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} -4-propylpiperazine

1-ethyl-4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperazine

1- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} -4- (2-methoxyethyl) piperazine

1-allyl-4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperazine

1- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -4-propylpiperazine

1- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -4-ethylpiperazine

1- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -4- (2-methoxyethyl) piperazine

1-allyl-4- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperazine

The volume of substituents in the compounds of formula 1 is significant. In particular, it was found that in the case when the calculated van der Waals volume of R ₂ exceeds 27Å ³ , then the total van der Waals volume of R ₁ and R ₂ (R ₁ + R ₂ ) should not be more than 70Å ³ . One example where the compound has not been found to be active is 4- [3- (methylsulfonyl) -2- (trifluoromethyl) phenyl] -1-propylpiperidine, in which the total volume is 71Å ³ and the volume of R ₂ exceeds 27Å ³ .

It was also shown that the polarity of the compounds of formula 1 is significant so that the resulting compounds have high activity. In particular, it was found that the calculated octanol / water distribution constant should be greater than 0.6, preferably greater than 0.9.

The present invention also relates to intermediates that are used in the synthesis of compounds of formula 1. One such intermediate has the structure:

where R ₁ , R ₂ , R ₃ and R ₄ are as defined above.

In this group of compounds, R _{1 is} preferably selected from the group consisting of OSO ₂ CF ₃ , OSO ₂ CH ₃ , SO ₂ CH ₃ , SO ₂ CF ₃ , COCH ₃ , COCF ₃ , CN and CF ₃ . More preferably, R _{1 is} selected from the group consisting of OSO ₂ CH ₃ , SO ₂ CH ₃ and SO ₂ CF ₃ .

In one embodiment, R _{2 is} selected from the group consisting of F, Cl and OH (provided that R _{1 is} not SO ₂ CH ₃ , SO ₂ CF ₃ ). In another embodiment, R _{3 is} selected from the group consisting of n-propyl and ethyl. Particularly preferred compounds of the invention are those in which R ₂ is F and R _{3 is} selected from the group consisting of n-propyl and ethyl. In addition, preferred compounds are those in which R ₁ is SO ₂ CH ₃ , R ₂ is F, and R _{3 is} selected from the group consisting of n-propyl and ethyl.

Another intermediate compound in the synthesis of compounds of formula 1 has the formula:

where X, R ₁ , R ₂ and R ₄ are as defined above.

Among these intermediates, those of interest are those in which R _{1 is} selected from the group consisting of OSO ₂ CF ₃ , OSO ₂ CH ₃ , SO ₂ CH ₃ , SO ₂ CF ₃ , COCH ₃ , COCF ₃ , CN and CF ₃ . Then, among such intermediates, of interest are those in which R _{1 is} selected from the group consisting of OSO ₂ CH ₃ , SO ₂ CH ₃ and SO ₂ CF ₃ . Additionally, R ₂ may be selected from the group consisting of F, Cl and OH (provided that R _{1 is} not SO ₂ CH ₃ , SO ₂ CF ₃ ).

The invention also relates to the use of a compound of formula 1 for the preparation of a pharmaceutical composition for treating disorders of the central nervous system and to the pharmaceutical compositions themselves. The present invention relates to a method for treating central nervous system disorders by administering a therapeutically effective amount of the compound of FIG. 1 to a mammal, including a human suffering from such a disorder. The present invention also relates to a method for treating any disorder referred to herein by administering a therapeutically effective amount of the compound of FIG. 1 to a mammal, including a human suffering from such a disorder.

The compounds of the present invention have dopamine modulating properties, and both themselves and their pharmaceutical compositions can be used to treat numerous disorders of the central nervous system, including both psychiatric and neurological disorders. In particular, the compounds and their pharmaceutical compositions can be used to treat CNS disorders in which the dopaminergic system is dysfunctional due to direct or indirect causes.

The compounds and compositions according to the invention can be used to improve the condition in all forms of psychosis, including schizophrenia, schizomorphic [schizophrenic] psychosis and bipolar disorders, as well as drug-induced psychotic disorders. It is also possible to treat iatrogenic and non-neutrogenic psychoses and hallucinogenic conditions.

Mood disorders and anxiety, depression, and obsessive-compulsive diseases can also be treated using the compounds and compositions of the invention.

Compounds with a modulating effect on dopaminergic systems can also be used to improve motor and cognitive functions and to treat emotional disorders related to age, neurodegenerative (e.g. dementia and age-related impairment of consciousness) and developmental disorders (such as disorders autism spectrum, ADHD, cerebral palsy, Gilles de la Tourette syndrome), as well as brain damage. Such brain injuries can be induced by traumatic, inflammatory, infectious, neoplastic, vascular, hypoxic and metabolic causes or toxic reactions to exogenous chemical compounds, where the exogenous chemical compounds are selected from the group consisting of substance abuse, pharmaceutical compounds and environmental toxins.

Compounds and pharmaceutical compositions according to the invention can also be used for behavioral disorders, usually first diagnosed in infancy, childhood or adolescence, as well as impaired impulse control.

They can also be used to treat drug abuse disorders as well as malnutrition disorders. In addition, they are useful for treating a condition selected from the group consisting of sleep disorders, sexual disorders, eating disorders, obesity and headaches and other types of pain in conditions characterized by increased muscle tone.

Neurological indications include the use of compounds and their pharmaceutical compositions to improve mental and motor function in Parkinson's disease and related parkinson-like syndromes, dyskinesias (including L-DOPA-induced dyskinesias), and dystonia. They can also be used to relieve tics and tremors of various organs. Moreover, they can be used to reduce pain in conditions characterized by increased muscle tone.

They can also be used to treat Huntington's disease and other movement disorders, as well as movement disorders caused by drugs. Fatigued Leg Syndrome and related disorders, as well as narcolepsy, can also be treated using the compounds included in the present invention.

The compounds and their pharmaceutical compositions of the present invention can be used to treat Alzheimer's disease or related disorders associated with dementia.

The compounds of the present invention have been shown to exhibit a dopaminergic stabilizer profile with improved efficacy. They exert an effect on biochemical brain indices with characteristic features of dopamine antagonists, for example, causing an increase in the concentration of dopamine metabolites.

The compounds of this invention do not show or show little effect on spontaneous locomotor activity in a wide dosage range (table 2).

table 2
The effect of the compounds of the present invention on locomotor activity in non-drug rats. Animals were placed in motion meters immediately after drug administration and locomotor activity was recorded for 60 minutes (total / 60 minutes ± standard deviation). Control group 11 μmol / kg 33 μmol / kg 100 μmol / kg

Пример 1

Example 1 7049 ± 1230 9500 ± 617 7371 ± 992 8103 ± 1047

Example 2 8545 ± 1596 13113 ± 1795 12744 ± 1291 12530 ± 2577

Example 3 7725 ± 1354 6078 ± 605 3023 ± 246 1327 ± 299

Example 4 9485 ± 2066 8972 ± 1124 9023 ± 1415 4473 ± 924

Example 7 9224 ± 1175 7008 ± 700 4694 ± 986 2829 ± 358

Example 9 8246 ± 698 3721 ± 242 3518 ± 435 4265 ± 758

Example 11 11346 ± 2133 5149 ± 374 4032 ± 828 3299 ± 637

In some cases, when the background activity is low, they can induce mild behavioral activation (table 3). Behavioral activation is limited, not achieving strong increases in activity induced by direct or indirect dopaminergic agonists.

Table 3
The effect of the compounds of the present invention on locomotor activity in non-drug rats. Animals were placed in motion meters immediately after drug administration and locomotor activity was recorded for 30 to 60 minutes (total / 30 minutes ± standard deviation). During this time, the animals accustomed to the environment, and therefore motor activity is low in the control group. Control group 11 μmol / kg 33 μmol / kg 100 μmol / kg

Пример 1

Example 1 241 ± 131 1708 ± 922 1337 ± 141
(P = 0.001) 1365 ± 460
(P = 0.057)

Example 2 705 ± 581 2254 ± 804 2499 ± 766
(P = 0.1) 2418 ± 703
(P = 0.1)

Example 13 400 ± 175 960 ± 710 2870 ± 613
(P = 0.008) 4366 ± 1389
(P = 0.030)

Example 17 559 ± 252 1836 ± 504
(P = 0.064) 1258 ± 623 1085 ± 211

On the other hand, preferred substances reduce the increase in activity induced by direct or indirect dopaminergic agonists, i.e. d-amphetamine and similar compounds (table 4). It has also been found that the compounds of the invention are more effective than the comparative examples of W001 / 145, W001 / 146 and US Pat. No. 4,415,736 (which were found to be inactive).

Table 4
The effect of the compounds of the present invention on the reduction of amphetamine-induced hypermotor activity. Comparative examples of the prior art are also included. Methods and statistical calculations see in the attached tests. Examples ED ₅₀ μmol / kg Comparative examples ED ₅₀ μmol / kg

Пример 1

Example 1 16
(8.8-31)

Example 6 in WO01 / 46145 52
(35-76)

Example 3 eleven
(8.2-17)

Example 2 28
(19-56)

Example 12 in WO01 / 46145 86
(34-137)

Example 33 19
(8.7-38)

Example 29 16
(8.7-26)

Example 43 in WO01 / 46146 thirty
(21-44)

Example 32 12,4
(8.3-17)

Example 9 1.4
(0.4-2.6)

Example 9 in WO01 / 46146 34
(12-54)

Example 31 6.2
(2.9-10)

Examples 1 and 2 in US patent 4415736 Inactive

Thus, the compounds of this invention exhibit a dopaminergic stabilizer profile (see Tables 1-4) with increased efficiency (see Tables 1 and 4). Considering the involvement of dopamine in a large number of central nervous system functions and the clinical deficiency of currently available pharmaceutical drugs acting on dopamine systems, the new class of dopaminergic modulators presented in this invention can confirm the superiority compared to currently known dopaminergic compounds for the treatment of several disorders, related to central nervous system dysfunctions in terms of effectiveness, as well as side effects.

It was also shown that the compounds of the present invention exhibit high metabolic stability in rat liver microsomes, measured as turnover in 15 minutes (example 1: 3%, example 2: 1%, example 4: 4%, example 7: 22%, example 8: 49%) and the high oral bioavailability in rats, illustrated by Example 1 (approximately 100%), Example 2 (87%), Example 7 (29%).

Thus, these compounds are suitable for the preparation of orally administered pharmaceutical preparations. In the previous level of development of this area, there are no instructions on how to obtain compounds with the profile of the dopamine stabilizer (table 1 - table 4) with increased efficiency on the dopamine systems of the brain.

Pharmacology

There is evidence that dopaminergic neurotransmission in the central nervous system is excited in psychiatric and neurological diseases. In many cases, for example, with schizophrenia, Parkinson’s disease, Huntington’s disease, bipolar disorder and dementia, pharmaceutical preparations based on antagonism or agonism for dopamine receptors can be used, but they are not optimal. In recent years, in order to increase efficiency and reduce side effects, numerous attempts have been made to search for new and selective compounds for subtypes (Dl, D2, D3, D4, D5) of dopamine receptors.

The present invention proposes another principle of new therapeutic agents based on interactions with the dopamine system. The present invention has developed compounds having, as a main characteristic feature, a stabilizing effect on the dopaminergic system of the brain.

Description of animal models used in the invention

The compounds of the invention have an effect on brain neurochemistry similarly to dopamine D2 receptor antagonists (i.e., in a dose-dependent manner, the content of the dopamine metabolite DOPAC is increased in the cortical, groove, and limbic regions of the brain). The compounds of this invention do not show or show a slight inhibitory effect on spontaneous locomotor activity. Under certain conditions, they can induce behavioral activation. Behavioral activation is limited, not achieving strong increases in activity induced by direct or indirect dopamine receptor agonists. However, preferred substances lower the increase in activity induced by the indirect dopaminergic d-amphetamine agonist. The increase in activity after treatment with d-amphetamine is a standard model of hyperdopaminergia (table 4). In this model, dopaminergic neurotransmission is increased by systemically administering d-amphetamine at a dose that is high enough to cause a large increase in locomotor activity. The ability of a compound to antagonize this hyperactivity reflects anti-dopaminergic properties that are part of the dopaminergic stabilizer profile. In addition, the antagonism of d-amphetamine-induced hyperactivity is widely used as a standard assay for antipsychotic activity (see Psychopharmacology 4th Generation of progress Chapter 68, p 793-795).

Another animal model of antipsychotic activity is based on the introduction of the glutamate antagonist MK-801. Glutamate antagonists (i.e., NMDA antagonists) can induce psychoses in humans (see Psychopharmacology, 4th Generation of progress Chapter 101, p. 1205 and 1207) and induce behavioral aberrations in animals. Thus, the ability of a drug to affect schizophrenia and psychotic conditions can be measured using behavioral models based on experimentally induced hypoglutamatergic conditions. In this study, an NMDA antagonist, MK-801 (0.7 mg / kg, ip) was used to create a hypoglutamatergic state in which rats exhibit abnormal hyperactive behavior. The compounds of the present invention in a dose-dependent manner reverse the behavioral abnormality induced by MK-901 (Table 5).

It is known that dopaminergic brain systems interact strongly with other transmitter systems (see Psychopharmacology, 4th Generation of progress, Chapter 101, pages 1208-1209). Such interactions can explain the powerful effect of dopaminergic stabilizers on behavioral abnormalities induced by the glutamate antagonist MK-801, although these abnormalities are not primarily based or are not caused by changes in dopaminergic transmissions.

Table 5
The effect of the compounds of the present invention on the locomotor activity of rats pretreated with MK-801 (0.7 mg / kg, intraperitoneally 90 minutes before administration of the test compound). Animals were placed in motion meters immediately after drug administration and locomotor activity was recorded from 30 to 60 minutes after administration (total amount / 30 minutes ± standard deviation). Control group MK-801
0.7 mg / kg ip MK + example
33 μmol / kg

578 ± 510 51333 ± 2148 29636 ± 10019
(P = 0.08)

369 ± 330 25899 ± 9703 4911 ± 2953 ¹ (P = 0.08)

47 ± 21 45714 ± 7127 5916 ± 1918 ² (P = 0.002) 1) 100 μmol / kg
2) 11 μmol / kg

Therapeutic use of dopaminergic stabilizers

In the claimed invention, compounds are developed having, as their main distinguishing feature, a stabilizing effect on the dopaminergic system of the brain. These compounds can be used to treat disorders of the central nervous system in which symptoms may be caused by impaired dopaminergic functions. In support of this statement, see the following links.

* In support of schizophrenia and psychosis, the authors of the present invention refer to Psychopharmacology 4th Generation of progress Chapter 26, p. 295-301;

* Parkinson's disease (Psychopharmacology 4th Generation of progress Chapter 26, p 295, Chapter 1479-1482);

* anxiety states (Psychopharmacology 4th Generation of progress Chapter 21, p. 227 and 237, Chapter 111, p. 1317-1318 and 1320);

* mood disorders (Psychopharmacology 4th Generation of progress Chapter 80, p. 921-928) and

* drug abuse (Psychopharmacology 4th Generation of progress Chapter 25, p. 283 and 292, Chapter 66, p. 759-760, Chapter 147, p. 1725 (see also Nisell et al., "Systemic Nicotine-Induced Dopamine Release in the Rat Nucleus Accumbens is Regulated by Nicotinic receptors in the Ventral Tegmental Area; Synapse (1994) 16: 36-44). Chapter 149, p. 1745-1747 and 1751-1752). Drugs abused by humans preferentially increase synaptic dopamine concentration in The mesolimbic system of freely moving rats Di Chiara et al., Proc Natl Acad Sci USA 85,5274, 1988; Drug addiction as a disorder of associative learning. Role of nucleus accumbens shell / extended amygdala dopamine Ann NY Acad Sci 877,461, 1999.

As shown by these links, the claimed disease states are recognized in the art as conditions related to dopaminergic neutrotransmission.

In addition, it is widely believed that pharmacological interaction with dopaminergic neurotransmission is useful for treating several disorders of the central nervous system, which are not supposed to be directly caused by breaks in dopaminergic neurotransmission. For example, symptoms of Huntington's disease and other motor disorders can be treated with dopaminergic agents by involving dopamine in motor function (see Psychopharmacology 4th Generation of progress, Chapter 26, p. 295-301). Moreover, cognitive impairment is known (see Psychopharmacology 4th Generation of progress Chapters 25, p. 292, Chapter 120, p. 1417 and 1420, Chapter 123, p. 1447 and 1452 and 1455-1457), autism (see Psychopharmacology 4th Generation of progress Chapter 142, p. 1653 and 1661), disorders related to hyperactivity and attention deficit (see Psychopharmacology 4th Generation of progress Chapter 141, p. 1643 and 1649-1650), sexual disorders (see Psychopharmacology 4th Generation of progress Chapters 65, p. 743-746 and Chapter 22, p. 245 and 254) and eating disorders (see Psychopharmacology 4th Generation of progress Chapters 137, p. 1600, Chapter 138, p. 1609-1610 and 1612 ) can be treated with agents that interact with dopaminergic transmission by. Thus, the above references support the argument that the compounds of the invention can be used to treat such diseases.

Depression

Dopamine and norepinephrine are catecholamines. The catecholamine hypothesis of depression was formulated in the 1960s (Schildkraut 1967). There is evidence regarding the role of norepinephrine in depression (Principles of Neuropsychopharmacology, 1997; Sinauer Asociates Inc, USA. Chapter 19, p. 838-9). There is also evidence regarding the role of dopamine in depression (Principles of Neuropsychopharmacology, 1997; Sinauer Asociates Inc, USA. Chapter 19, p. 848). Cortical abnormalities have been reported in patients suffering from major depression Neuropsychopharmacology: The fifth generation of progress, 2002, American college of Neuropsychopharmacology, USA, Chapter 73, p. 1054 and chapter 74, p. 1067).

Some antidepressants predominantly affect intercellular levels of norepinephrine and dopamine relative to 5-HT in the cerebral cortex, as measured by microdialysis. A common feature for all clinically effective classes of antidepressants is an increase in the levels of dopamine and norepinephrine in the cerebral cortex (Tanda, Carboni et al. 1994; Millan, Lejeune et al. 2000). It has been shown that a clinically effective antidepressant (remeron) primarily increases intercellular norepinephrine and dopamine in the cerebral cortex (see Fig. 1, Devoto, Flore et al. 2004). Since the compounds of the present invention increase the levels of dopamine and norepinephrine in the cerebral cortex, the authors of the present invention claim that they function as antidepressants (see figure 2, example 2 of the present invention).

Figure 1. Remeron 10 mg / kg subcutaneously, cerebral cortex

Remeron is administered as an injection (subcutaneously) at time 0. The values indicated on the graph represent the percentage of control relative to the baseline. Microdialysis was performed on awake and freely moving rats. Error limits = standard error.

Figure 2. 50 μmol / kg subcutaneously, total amine cortex coefficient n: 2.4.

The compound of Example 2 was administered as an injection (subcutaneously) at time 0. The values indicated on the graph represent the percentage of control relative to the baseline. Microdialysis was performed on awake and freely moving rats. Error limits = standard error.

References:

Devoto, P., G. Flore, L. Pira, G. Longu, and G. L. Gessa (2004). "Mirtazapine-induced corelease of dopamine and noradrenaline from noradrenergic neurons in the medial prefrontal and occipital cortex." Eur J Pharmacol 487 (1-3): 105-11.

Millan, M. J., F. Lejeune and A. Gobert (2000). "Reciprocal autoreceptor and heteroreceptor control of serotonergic, dopaminergic and noradrenergic transmission in the frontal cortex: relevance to the actions of antidepressant agents." J Psychopharmacol 14 (2): 114-38.

Tanda, G., E. Carboni, R. Frau and G. Di Chiara (1994). "Increase of extracellular dopamine in the prefrontal cortex: a trait of drugs with antidepressant potential?" Psychopharmacology (Berl) 115 (1-2): 285-8.

Schildkraut, J. J. (1967). "The catecholamine hypothesis of affective disorders. A review of supporting evidence." Int J Psychiatry 4 (3): 203-17.

METHODS FOR PRODUCING

Compounds of the invention may be prepared as shown below in Schemes 1-4. However, the invention is not limited to these methods. Compounds can also be obtained as described for their structurally related analogues in the section on the previous level of development of this field. The reactions can be carried out in accordance with standard methods ^1,2 or as described in the working examples. The starting materials for the methods described in this application are known or can be easily obtained by conventional methods from commercially available chemicals.

Specialists in this field will understand that to obtain the compounds according to the invention in an alternative, and in some cases more convenient way, the individual stages of the previously mentioned methods can be carried out in a different order, and / or individual reactions can be carried out at other stages of the general reaction path ( i.e. chemical transformations can be carried out for other intermediates than those which bind to a particular reaction).

Scheme 1

Scheme 2

Scheme 3

Scheme 4

The substituents in schemes 1-4 are as follows: Z represents a leaving group, G ₁ represents R ₁ or a group that can be transformed to R ₁ , G ₂ represents R ₂ or a group that can be transformed to R ₂ , A represents alkyl, hydrogen or a protecting group. X, R ₁ , R ₂ and R ₃ are as defined above.

References

1. Comprehensive Organic Transformations: A Guide to Functional Group Preparations. Richard C. Larock, October 22, 1999, Wiley-VCH, ISBN: 0471190314.

2. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition. Michael B. Smith, Jerry March, January 15, 2001, Wiley-Interscience, ISBN: 0471585890.

The term “patient,” as used herein, refers to an individual in need of treatment according to the invention.

The term “treatment,” as used herein, refers to both treatment to cure or alleviate a disease or condition and to treatment to prevent the development of a disease or condition. Treatment can be carried out in an acute case or in a chronic manner.

It is implied that any chemical formula or name given in this description includes all stereo and optical isomers and racemates, and mixtures thereof in any ratio. Various isomers can be obtained by standard methods well known to specialists in this field, for example, by chromatography or fractional crystallization. For example, mixtures of cis / trans isomers can be resolved into individual stereoisomers using stereoselective synthesis. Enantiomers or diastereomers can be isolated by separation from mixtures, for example, by fractional crystallization, optical resolution or HPLC. Alternatively, separation can be accomplished by derivatization with a chiral reagent. Stereoisomers can be obtained by stereoselective synthesis from stereochemically pure starting materials under conditions that do not cause a loss of stereochemical integrity. All stereoisomers are included in the scope of the invention.

The compounds of the present invention can be isolated at any level of purity using standard methods and purification can be carried out by conventional methods known to those skilled in the art, such as distillation, recrystallization and chromatography.

The present invention relates to pharmaceutical compositions comprising the compounds of the present invention, and their use for the treatment of CNS disorders. Both organic and inorganic acids can be used to produce non-toxic pharmaceutically acceptable acid addition salts of the compounds of the invention. Suitable acid addition salts of the compounds of the present invention include those formed as pharmaceutically acceptable salts, such as toluenesulfonate, methanesulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, nitrate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, aliphatic , alicyclic, aromatic or heterocyclic carboxylate, succinate, maleate, fumarate, gluconate, glycolate, sugar, ascorbate, acetate, propionate, benzoate, pyruvate, pamoate [(i.e. 1,1'-methylene bis (2-hydroxy- 3-naphthoate)], phosphate, ki ly phosphate, sulphate or bisulfate salts. These salts are readily prepared by methods known in the art. It should also be appreciated that the compounds of the invention may exist in solvated as well as unsolvated forms such as hydrated forms.

Pharmaceutical compositions comprising a compound of the invention may also include substances used to facilitate the preparation of pharmaceutical preparations or for the administration of preparations. Such substances are well known to those skilled in the art and, for example, may be pharmaceutically acceptable adjuvants, carriers and preservatives.

In clinical practice, the compounds of the present invention will usually be administered orally, rectally, nasally or by injection in the form of pharmaceutical preparations comprising the active ingredient or as a free base, or as a pharmaceutically acceptable non-toxic acid addition salt such as hydrochloride, lactate, acetate or sulfamate salt in combination with a pharmaceutically acceptable carrier. The carrier may be a solid, semi-solid or liquid preparation. Typically, the active substance will be from 0.1 to 99% by weight of the drug, more specifically, from 0.5 and 20% by weight of the drug intended for injection and from 0.2 to 50% by weight of the drug suitable for oral administration.

To obtain pharmaceutical preparations containing the compounds of the invention in the form of oral dosage forms, the selected compound may be mixed with a solid excipient, for example, lactose, sucrose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives with a binder, such as gelatin or polyvinylpyrrolidone, and a lubricant, such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin and the like, and then compressed into tablets. If coated tablets are needed, the tablet core (prepared as described above) may be coated with a concentrated sugar solution, which may contain gum arabic, gelatin, talc, titanium dioxide and the like. Alternatively, the tablet may be coated with a polymer coating known to one skilled in the art, dissolved in a volatile organic solvent or a mixture of organic solvents. Dyes may be added to these coatings for easy recognition between tablets containing various active substances or different amounts of active compound.

To obtain soft gelatin capsules, the active substance can be mixed, for example, with vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the active substance using either of these tablet excipients, for example, lactose, sucrose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose or gelatin derivatives. Hard gelatin capsules may also be filled with liquid or semi-solid forms of the drug.

Examples of tablet and capsule formulations suitable for oral administration are given below:

Tablet I mg / tablet Compound one hundred Lactose (European pharmaceutical quality) 182.75 Croscarmellose sodium 12.0 Corn Starch, Paste (5% w / v) 2.25 Magnesium stearate 3.0 Tablet II mg / tablet Compound fifty Lactose (European pharmaceutical quality) 223.75 Croscarmellose sodium 6.0 Corn starch 15.0 Polyvinylpyrrolidone (5% w / v, paste) 2.25 Magnesium stearate 3.0

Tablet III mg / tablet Compound 1,0 Lactose (European pharmaceutical quality) 93.25 Croscarmellose sodium 4.0 Corn Starch, Paste (5% w / v) 0.75 Magnesium stearate 3.0 Capsule mg / capsule Compound 10 Lactose (European pharmaceutical quality) 488.5 Magnesium 1,5

Formulations for rectal administration may be solutions or suspensions, or may be prepared in the form of suppositories comprising the active substance in admixture with a neutral fat base or in the form of gelatin rectal capsules comprising the active substance in admixture with vegetable oil or paraffin base oil. Liquid preparations for oral administration can be in the form of syrups or suspensions, for example, in the form of solutions containing from about 0.2% to about 20% by weight of the active substance described herein, the rest will be sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations may contain colorants, flavors, saccharin and carboxymethyl cellulose as a thickener and other excipients known to those skilled in the art.

Solutions for parenteral administration by injection can be prepared as an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance, preferably in a concentration of from 0.5% to about 10% by weight. These solutions may also contain stabilizing agents and / or buffering agents and can easily be provided in ampoules with different dosages. The use and administration to the patient being treated will be apparent to the ordinary person skilled in the art.

For intranasal administration or administration by inhalation, the compounds of the present invention may be delivered to the body in the form of a solution, dry powder or suspension. The administration may be via a container with a spray pump that is pressurized or pumped to the patient, or by aerosol spray from a container under pressure or a nebulizer using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide and other suitable gas .

The compounds of the invention can also be administered using a dry powder inhaler or as a fine powder in combination with a suitable carrier material (e.g., saccharide), or as microspheres. The inhaler, pump nebulizer or aerosol spray can be in the form of a single or multiple doses. Dosage can be controlled using a valve that delivers a measured amount of active substance.

The compounds of the invention can also be administered as controlled release formulations. Compounds are released at the required rate to maintain a constant pharmacological activity for a desired period of time. Such dosage forms provide delivery of the drug to the body over a predetermined period of time and thus maintain drug levels in the therapeutic range for longer periods of time than uncontrolled release formulations. The compounds may also be formulated in controlled release formulations in which the release of the drug is targeted. For example, the release of the compound may be limited to a specific area of the digestive system due to the pH sensitivity of the drug. Such formulations are well known to those skilled in the art.

Depending on the disorder being treated by the patient and the route of administration, the compositions may be administered in various doses. Dosage will also depend on absorption capacity and frequency and route of administration. Such dosages can be administered one, two or three, or more than once a day. The compounds of this invention can be administered to subjects in dosages ranging from 0.01 mg to 500 mg per kg of body weight per day, although changes will inevitably occur depending on the weight, gender and condition of the subject being treated, the disease being treated, and specific chosen route of administration. However, the dosage level, which is in the range from 0.1 mg to 10 mg, in the form of a single dose or divided doses is most preferably used to treat diseases in humans. Alternatively, the dosage level is such that a concentration of the compound in the blood serum of 0.1 nM to 10 μM is achieved.

The invention is further illustrated by examples, which are in no way intended to limit the scope of the invention.

Example 1:

4- [2-fluoro-3- (methylsulfonyl) phenyl] -1-propylpiperidine

To a solution of 4- [2-fluoro-3- (methylsulfonyl) phenyl] piperidine (0.4 g, 1.55 mmol) in acetonitrile (40 ml) was added potassium carbonate (0.3 g, 2.17 mmol) and 1 iodopropane (0.151 ml, 1.55 mmol) and the mixture was heated at the boil under reflux for 15 hours. The mixture was cooled to ambient temperature and water (50 ml) was added. The aqueous residue was extracted with ethyl acetate (3 × 50 ml) and the combined organic phases were dried, concentrated and purified by flash column chromatography (ethyl acetate / methanol, 1: 1) to obtain the title compound (0.37 g, 79%). The amine was converted to a hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 255-257 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 299 (M +, 2), 271 (16), 270 (main peak), 147 (9) 133 (10).

Example 2:

1-Ethyl-4- [2-fluoro-3- (methylsulfonyl) phenyl] piperidine

Preparation according to Example 1: 4- [2-fluoro-3- (methylsulfonyl) phenyl] piperidine (0.185 g, 0.72 mmol), acetonitrile (10 ml), potassium carbonate (0.2 g, 1.44 mmol ), 1-iodoethane (0.06 ml, 0.75 mmol). Yield: 0.15 g (73%). The amine was converted to several different salts and recrystallized from ethanol / diethyl ether. Salt of hydrochloric acid - so pl. 273-275 ° C, hydrobromic acid salt - mp. 267-268 ° C, fumaric acid salt - mp. 204-206 ° C, oxalic acid salt - mp. 163-165 ° C, sulfate salt - mp. 263-265 ° C, maleic acid salt - 112-113 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 285 (M +, 12), 271 (15), 270 (main peak), 147 (7) 133 (8).

Example 2: (synthesized in another way)

1-Ethyl-4- [2-fluoro-3- (methylsulfonyl) phenyl] piperidine

A mixture of 1-ethyl-4- [2-fluoro-3- (methylsulfonyl) phenyl] -1,2,3,6-tetrahydropyridine (5 g, 17.7 mmol), formic acid (3.4 ml, 90 mmol) and palladium-on-charcoal (1.1 g) in isopropanol (50 ml) was shaken in a Parr apparatus for 20 hours. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated and evaporated to dryness. Aqueous sodium carbonate (10%, 200 ml) was added and the mixture was extracted with ethyl acetate (3 × 100 ml). The combined organic phases were dried (MgSO ₄ ) and evaporated to dryness. Flash column chromatography (ethyl acetate / methanol, 1: 1) gave the title compound (3.5 g, 70%). The amine was converted to a hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 280.2 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 285 (M +, 12), 270 (main peak), 57 (19), 84 (15) 133 (9).

Example 3:

4- [2-Chlorine-3- (Methylsulfonyl) phenyl] -1-propylpiperidine

A mixture of 4- [2-chloro-3- (methylsulfonyl) phenyl] -1-propyl-1,2,3,6-tetrahydropyridine (0.46 g, 1.47 mmol), platinum oxide (0.11 g) and hydrochloric acid (0.1 ml, conc.) in methanol (30 ml) was hydrogenated at a pressure of 50 psi for 1 hour in an atmosphere of gaseous hydrogen. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated and evaporated to dryness to give 0.48 g of the crude product as a hydrochloric acid salt. Purification by flash column chromatography (ethyl acetate / methanol, 1: 1) gave the title compound (0.35 g, 75%). The amine was converted to a hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 250-252 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 315 (M +, 3), 288 (37), 287 (15), 286 (main peak) 129 (7).

Example 4:

4- [2-methyl-3- (methylsulfonyl) phenyl] -1-propylpiperidine

Preparation according to Example 1: 4- [2-methyl-3- (methylsulfonyl) phenyl] piperidine (0.41 g, 1.62 mmol), acetonitrile (40 ml), potassium carbonate (0.53 g, 4, 8 mmol) and 1-iodopropane (0.127 ml, 1.62 mmol). Yield: 0.238 g (50%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 233-235 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 295 (M +, 4), 267 (17), 266 (main peak), 129 (13), 115 (14).

Example 5:

3- (1-Ethylpiperidin-4-yl) -2-hydroxybenzonitrile

To a solution of 3- (1-ethylpiperidin-4-yl) -2-fluorobenzonitrile (10 mg, 0.031 mmol) in dimethyl sulfoxide (1 ml) was added 2-butyn-1-ol (4.3 mg, 0.062 mmol) and tert- potassium butoxide (7 mg, 0.063 mmol). The mixture was heated to 125 ° C in a sealed tube under microwave irradiation for 120 seconds. Aqueous hydrochloric acid (10%, 10 ml) was added and the aqueous phase was washed with diethyl ether (2 × 20 ml). The aqueous phase was made basic by adding sodium hydroxide (5 M, 5 ml) and extracted with ethyl acetate (3 × 20 ml). The combined organic phase was dried (MgSO ₄ ) and evaporated under reduced pressure to obtain the title compound. Mass spectrum: m / z (relative intensity, 70 eV) 230 (M +, 60), 229 (24), 216 (23), 215 (main peak) 110 (30).

Example 6:

2- (Methylsulfonyl) -6- (1-propylpiperidine-4-yl) aniline

4- [2-fluoro-3- (methylsulfonyl) phenyl] -1-propylpiperidine (0.45 g, 1.52 mmol) was dissolved in a solution of ammonia in methanol (7M, 15 ml). The mixture was heated at 160 ° C. in a sealed tube under microwave irradiation for 20 hours. The solvent was evaporated and the crude product was purified by preparative HPLC system. Yield: 0.125 g (30%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 232-233 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 296 (M +, 22), 267 (main peak), 224 (31), 130 (23), 117 (20).

Example 7

2- (1-PROPYLPIPERIDIN-4-IL) -6- (trifluoromethyl) benzonitrile.

To a solution of 4- [2-fluoro-3- (trifluoromethyl) phenyl] -1-propylpiperidine (1.57 g, 5.4 mmol) in N, N-dimethylformamide (35 ml) was added sodium cyanide (1.0 g, 20 mmol) and 18-crown-6-ether (50 mg). The mixture was heated at the boil under reflux for 15 hours and then brought to ambient temperature. Aqueous sodium carbonate (10%, 50 ml) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2 × 50 ml) and the combined organic phases were dried (MgSO ₄ ) and evaporated under reduced pressure to give an oil. Purification by flash column chromatography (ethyl acetate / methanol, 1: 1) gave the title compound: 0.72 g (45%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 272-274 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 296 (M +, 4), 268 (16), 267 (main peak), 204 (3), 184 (3).

Example 8:

4- [2-METHOXY-3- (TRIFLUOROMETHYL) Phenyl] -1-PROPYLPIPERIDINE

Preparation in accordance with Example 1: 4- [2-methoxy-3- (trifluoromethyl) phenyl] piperidine (0.38 g, 1.47 mmol), acetonitrile (40 ml), potassium carbonate (0.4 g, 3, 7 mmol) and 1-iodopropane (0.115 ml, 1.47 mmol). Yield: 0.33 g (74%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 235.5 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 301 (M +, 7), 273 (22), 272 (main peak), 229 (6), 159 (13).

Example 9:

1- [2-Fluoro-3- (trifluoromethyl) phenyl] -4-propylpiperazine

Obtaining in accordance with example 1: 1- [2-fluoro-3- (trifluoromethyl) phenyl] piperazine (0.97 g, 3.9 mmol), acetonitrile (50 ml), potassium carbonate (0.81 g, 5, 86 mmol) and 1-iodopropane (0.457 ml, 4.6 mmol). Yield: 0.57 g (50%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 180-181 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 290 (M +, 22), 262 (13), 261 (main peak), 218 (18), 190 (22).

Example 10:

1- [2-Fluoro-3- (trifluoromethyl) phenyl] -4- (2-methoxyethyl) piperazine

Obtaining in accordance with example 1: 1- [2-fluoro-3- (trifluoromethyl) phenyl] piperazine (0.5 g, 2.0 mmol), acetonitrile (25 ml), potassium carbonate (0.42 g, 3, 0 mmol) and 1-bromo-2-methoxyethane (0.189 ml, 2.0 mmol). Yield: 0.26 g (42%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 170-171 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 306 (M +, 9), 262 (13), 261 (main peak), 218 (23), 190 (23).

Example 11:

1- (2,3-Dichlorophenyl) -4-propylpiperazine

Preparation according to Example 1: 1- (2,3-dichlorophenyl) piperazine (1.0 g, 3.74 mmol), acetonitrile (40 ml), potassium carbonate (1.55 g, 11.2 mmol) and 1 iodopropane (0.293 ml, 3.74 mmol). Yield: 0.23 g (20%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 220-221 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 274 (M +, 15), 272 (M +, 22), 245 (63), 243 (main peak), 174 (22), 172 (27).

Example 12:

1-allyl-4- [2-methyl-3- (methylsulfonyl) phenyl] piperidine

Preparation according to Example 1: 4- [2-methyl-3- (methylsulfonyl) phenyl] piperidine (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01) and allyl bromide (0.01 g) . Mass spectrum: m / z (relative intensity, 70 eV) 293 (M +, 16), 292 (16), 278 (26), 266 (main peak), 129 (19).

Example 13:

3- (1-propylpiperidine-4-yl) -2- (trifluoromethyl) benzonitrile

Preparation according to Example 7: 4- [3-fluoro-2- (trifluoromethyl) phenyl] -1-propylpiperidine (0.81 g, 2.8 mmol), N, N-dimethylformamide (30 ml), sodium cyanide ( 0.5 g, 10 mmol) and 18-crown-6-ether (30 mg). Yield: 0.53 g (64%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 266-269 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 296 (M +, 3), 268 (16), 267 (main peak), 204 (3), 184 (3).

Example 14:

3- (4-PROPYLPIPERAZIN-1-IL) -2- (TRIFFORMETHYL) Benzonitrile

Preparation according to Example 1: 3-piperazin-1-yl-2- (trifluoromethyl) benzonitrile (0.83 g, 3.25 mmol), acetonitrile (40 ml), potassium carbonate (0.88 g, 8.1 mmol) and 1-iodopropane (0.255 ml, 3.25 mmol). Yield: 0.74 g (77%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 234-236 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 297 (M +, 15), 269 (14), 268 (main peak), 225 (26), 177 (8).

Example 15:

2- (Methylsulfonyl) -6- (1-propylpiperidine-4-yl) benzonitrile

Preparation according to Example 7: 4- [2-fluoro-3- (methylsulfonyl) phenyl] -1-propylpiperidine (0.2 g, 0.67 mmol), N, N-dimethylformamide (30 ml), sodium cyanide ( 0.82 g, 1.67 mmol) and 18-crown-6-ether (5 mg). Yield: 0.06 g (29%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: Mass spectrum: m / z (relative intensity, 70 eV) 306 (M +, 3), 279 (6), 278 (16), 277 (main peak ), 198 (5).

Example 16:

4- [3-Fluoro-2- (trifluoromethyl) phenyl] -1-propylpiperidine

Raney nickel was added to a solution of 4- [3-fluoro-2- (trifluoromethyl) phenyl] -1-propyl-1,2,3,6-tetrahydropyridine (1.73 g, 6.0 mmol) in ethanol (30 ml) (suspension in water, 10 ml) and the reaction mixture was hydrogenated with hydrogen (50 ft / sq. inch) for 2 days. Filtration through a pad of celite and evaporation of the filtrate afforded 1.35 g of a crude product. Mass spectrum: m / z (relative intensity, 70 eV) 289 (M +, 4), 261 (16), 260 (main peak), 176 (6) 70 (20).

Example 17:

4- [2-fluoro-3- (methylsulfonyl) phenyl] -1- (2-methoxyethyl) piperidine

Obtaining in accordance with example 1: 4- [2-fluoro-3- (methylsulfonyl) phenyl] piperidine (0.53 g, 1.64 mmol), acetonitrile (20 ml), potassium carbonate (0.45 g, 3, 2 mmol), 1-bromo-2-methoxyethane (0.167 ml, 1.72 mmol). Mass spectrum: m / z (relative intensity, 70 eV) 315 (M +, 1), 271 (14), 270 (main peak), 147 (10) 133 (9).

Example 18:

4- [2-fluoro-3- (methylsulfonyl) phenyl] -1-methylpiperidine

To a solution of 4- [2-fluoro-3- (methylsulfonyl) phenyl] piperidine (0.02 g, 0.078 mmol) in acetonitrile (2 ml) was added potassium carbonate (0.02 g, 0.14 mmol) and iodomethane (0 , 0047 ml, 0.078 mmol). The mixture was stirred at ambient temperature for 1 hour. Mass spectrum: m / z (relative intensity, 70 eV) 271 (M +, 66), 270 (main peak), 192 (9), 133 (13) 97 (32).

Example 19:

1-butyl-4- [2-fluorine-3- (methylsulfonyl) phenyl] piperidine

Preparation according to Example 1: 4- [2-fluoro-3- (methylsulfonyl) phenyl] piperidine (0.02 g, 0.078 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol ), 1-bromobutane (0.009 ml, 0.082 mmol). Mass spectrum: m / z (relative intensity, 70 eV) 313 (M +, 2), 271 (14), 270 (main peak), 147 (7) 133 (7).

Example 20:

4- [2-fluoro-3- (methylsulfonyl) phenyl] -1-isopropylpiperidine

Preparation according to Example 1: 4- [2-fluoro-3- (methylsulfonyl) phenyl] piperidine (0.02 g, 0.078 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol ), 2-bromopropane (0.008 ml, 0.082 mmol). Mass spectrum: m / z (relative intensity, 70 eV) 299 (M +, 3), 285 (15), 284 (main peak), 205 (6) 133 (4).

Example 21:

4- [2-fluoro-3- (methylsulfonyl) phenyl] -1-isobutyl-piperidine

Preparation according to Example 1: 4- [2-fluoro-3- (methylsulfonyl) phenyl] piperidine (0.02 g, 0.078 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol ), 1-bromo-2-methylpropane (0.009 ml, 0.082 mmol). Mass spectrum: m / z (relative intensity, 70 eV) 313 (M +, 1), 271 (15), 270 (main peak), 147 (8) 133 (8).

Example 22:

4- [2-fluoro-3- (methylsulfonyl) phenyl] -1- (3,3,3-trifluoropropyl) piperidine

Preparation according to Example 1: 4- [2-fluoro-3- (methylsulfonyl) phenyl] piperidine (0.02 g, 0.078 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol ), 1,1,1-trifluoro-3-iodopropane (0.010 ml, 0.082 mmol). Mass spectrum: m / z (relative intensity, 70 eV) 353 (M +, 11), 271 (15), 270 (main peak), 152 (14) 133 (9).

Example 23:

2-fluorine-3- (1-propylpiperidin-4-yl) phenylmethanesulfonate

Obtaining in accordance with example 1: 2-fluoro-3-piperidin-4-ylphenylmethanesulfonate (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and iodopropane (0.01 g). Mass spectrum: m / z (relative intensity, 70 eV) 315 (M +, 4), 287 (16), 286 (main peak), 236 (2), 207 (41).

Example 24:

3- (1-Allylpiperidine-4-yl) -2-fluorophenylmethanesulfonate

Obtaining in accordance with example 1: 2-fluoro-3-piperidin-4-ylphenylmethanesulfonate (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and allyl bromide (0.01 g). Mass spectrum: m / z (relative intensity, 70 eV) 313 (M +, 28), 312 (25), 286 (42), 234 (main peak), 207 (19).

Example 25:

2-fluoro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenylmethanesulfonate

Preparation according to Example 1: 2-fluoro-3-piperidin-4-ylphenylmethanesulfonate (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1-bromo-2-methoxyethane (0, 01 g). Mass spectrum: m / z (relative intensity, 70 eV) 331 (M +, 1), 288 (6), 287 (15), 286 (main peak), 207 (47).

Example 26:

1- [2- (1,3-DIOXOLAN-2-IL) Ethyl] -4- [2-Fluoro-3- (Methylsulfonyl) phenyl] piperidine

Obtaining in accordance with example 1: 4- [2-fluoro-3- (methylsulfonyl) phenyl] piperidine (0.42 g, 1.63 mmol), acetonitrile (20 ml), potassium carbonate (0.45 g, 3, 2 mmol) and 2- (2-bromoethyl) -1,3-dioxolane (0.205 ml, 1.65 mmol). Yield: 0.18 g (31%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 224-225 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 357 (M +, 3), 270 (main peak), 257 (59), 256 (27), 178 (90).

Example 27:

2- {4- [2-Fluoro-3- (trifluoromethyl) phenyl] piperidine-1-yl} ethanol

Preparation in accordance with Example 1: 4- [2-fluoro-3- (trifluoromethyl) phenyl] piperidine (0.45 g, 1.82 mmol), acetonitrile (20 ml), potassium carbonate (0.6 g, 1, 1 mmol) and 2-iodoethanol (0.16 ml, 2.0 mmol). Yield: 0.35 g (66%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 224-226 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 291 (M +, 1), 260 (main peak), 217 (5), 189 (3), 177 (7).

Example 28:

4- [2-Chloro-3- (Methylsulfonyl) phenyl] -1-Ethylpiperidine

Preparation according to Example 3: 4- [2-chloro-3- (methylsulfonyl) phenyl] -1-ethyl-1,2,3,6-tetrahydropyridine (0.6 g, 2.0 mmol), methanol (25 ml), platinum oxide (0.15 g). Yield: 0.35 g (58%). The amine was converted to the hydrochloride salt and recrystallized from ethanol / diisopropyl ether: mp. 264-265 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 301 (M +, 6), 301 (13), 300 (11), 288 (35) 286 (main peak).

Example 29:

2- (1-PROPYLPIPERIDIN-4-IL) -6- (TRIFFORMETHYL) Phenol

4- [2-methoxy-3- (trifluoromethyl) phenyl] -1-propylpiperidine (0.18 g, 0.6 mmol) and pyridine hydrochloride (2 g) were heated to 190 ° C and stirred for 2 hours. Aqueous sodium carbonate (10%, 50 ml) and ethyl acetate (50 ml) were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2 × 50 ml) and the combined organic phase was dried (MgSO ₄ ) and evaporated under reduced pressure to give an oil. Purification by flash column chromatography (ethyl acetate / methanol, 1: 1) gave the title compound: 0.17 g (98%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 218-220 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 287 (M +, 10), 259 (14), 258 (main peak), 238 (15), 195 (19).

Example 30:

2- (1-PROPYLPIPERIDIN-4-IL) -6- (TRIFTORMETOXY) Phenol

Preparation according to Example 29: 4- [2-methoxy-3- (trifluoromethoxy) phenyl] -1-propylpiperidine (1.32 g, 4.16 mmol), pyridine hydrochloride (3 g). Yield: 0.7 g (55%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 203-205 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 303 (M +, 11), 275 (15), 274 (main peak), 145 (4), 117 (6).

Example 31:

3- (1-PROPYLPIPERIDIN-4-IL) Phthalonitrile

To a solution of 4- [2-fluoro-3- (methylsulfonyl) phenyl] -1-propylpiperidine (0.2 g, 0.67 mmol) in N, N-dimethylformamide (30 ml) was added sodium cyanide (0.82 g, 1.67 mmol) and 18-crown-6-ether (5 mg). The mixture was heated at the boil under reflux for 15 hours and then cooled to ambient temperature. Aqueous sodium carbonate (10%, 50 ml) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2 × 50 ml) and the combined organic phases were dried (MgSO ₄ ) and evaporated under reduced pressure to give an oil. Purification by flash column chromatography (ethyl acetate / methanol, 1: 1) gave the title compound: 0.07 g (41%). Mass spectrum: m / z (relative intensity, 70 eV) 253 (M +, 3), 225 (17), 224 (main peak), 154 (6), 70 (12).

Example 32:

3- {4- [2-Fluoro-3- (trifluoromethyl) phenyl] piperidine-1-yl} propan-1-ol

Preparation in accordance with Example 1: 4- [2-fluoro-3- (trifluoromethyl) phenyl] piperidine (0.45 g, 1.82 mmol), acetonitrile (20 ml), potassium carbonate (0.6 g, 1, 1 mmol) and 3-bromo-1-propanol (0.185 ml, 2.0 mmol). Yield: 0.16 g (29%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 259-261 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 305 (M +, 4), 261 (16), 260 (main peak), 217 (5), 177 (9).

Example 33:

3- (1-Ethylpiperidine-4-yl) -2-fluorophenylmethanesulfonate

To a solution of 3- (1-ethylpiperidin-4-yl) -2-fluorophenol (0.44 g, 1.97 mmol) in methylene chloride (20 ml) was added triethylamine (4 ml) and methanesulfonyl chloride (0.56 ml, 3 , 67 mmol). The mixture was stirred for 20 hours and water (50 ml) and methylene chloride (50 ml) were added and the phases were separated. The aqueous phase was extracted with methylene chloride (2 × 50 ml) and the combined organic phases were dried (MgSO ₄ ) and evaporated under reduced pressure to give an oil. Purification by flash column chromatography (ethyl acetate / methanol, 1: 1) gave the title compound: 0.39 g (66%). The amine was converted to an oxalic acid salt and recrystallized from ethanol / diethyl ether: mp. 161.5-163.2 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 301 (M +, 15), 287 (15), 286 (main peak), 222 (23), 207 (38).

Example 34:

3- (1-Ethylpiperidin-4-yl) -2-fluorophenyl trifluoromethanesulfonate

To a solution of 3- (1-ethylpiperidin-4-yl) -2-fluorophenol (0.5 g, 2.24 mmol) in methylene chloride (20 ml) was added triethylamine (4 ml) and trifluoromethanesulfonic anhydride (0.75 ml) 4.5 mmol). The mixture was stirred for 20 hours, water (50 ml) and methylene chloride (50 ml) were added, and the phases were separated. The aqueous phase was extracted with methylene chloride (2 × 50 ml) and the combined organic phases were dried (MgSO ₄ ) and evaporated under reduced pressure to give an oil. Purification by flash column chromatography (ethyl acetate / methanol, 1: 1) gave the title compound: 0.47 g (59%). The amine was converted to a fumaric acid salt and recrystallized from ethanol / diethyl ether: mp. 158-159 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 355 (M +, 20), 341 (18), 340 (main peak), 222 (18), 207 (77).

Example 35:

3- (1-Ethylpiperidin-4-yl) -2-fluoro-n, n-dimethylbenzenesulfonamide

Preparation according to Example 3: 3- (1-ethyl-1,2,3,6-tetrahydropyridin-4-yl) -2-fluoro-N, N-dimethylbenzenesulfonamide (0.27 g, 0.86 mmol), methanol (10 ml), platinum oxide (0.05 g). Yield: 0.16 g (59%). The amine was converted to a fumaric acid salt and recrystallized from ethanol / diisopropyl ether: mp. 151-152 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 314 (M +, 18), 313 (11), 300 (17), 299 (main peak) 191 (11).

Example 36:

1- [3- (1-Ethylpiperidin-4-yl) -2-fluorophenyl] ethanone

To a solution of 1-ethyl-4- [2-fluoro-3- (2-methyl-1,3-dioxolan-2-yl) phenyl] piperidine (0.28 g, 0.95 mmol) in methanol (20 ml) a solution of hydrogen chloride in ethanol (5 ml, saturated) was added and the mixture was stirred for 20 hours. The solvent was evaporated and the crude product was recrystallized from ethanol / diethyl ether to give the title compound as a hydrochloric acid salt. Yield: 0.13 g (47%). Mp 199-202 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 249 (M +, 19), 235 (15), 234 (main peak), 149 (11) 133 (18).

Example 37:

1- [3- (1-Ethylpiperidin-4-yl) -2-hydroxyphenyl] ethanone

Preparation according to Example 5: 1- [3- (1-ethylpiperidin-4-yl) -2-fluorophenyl] ethanone (12 mg, 0.048 mmol), dimethyl sulfoxide (1 ml), 2-butyn-1-ol (6 7 mg, 0.096 mmol), potassium tert-butoxide (11 mg, 0.096 mmol). Mass spectrum: m / z (relative intensity, 70 eV) 247 (M +, 57), 232 (main peak), 218 (28), 147 (24) 84 (67).

Example 38:

1- [2-fluoro-3- (methylsulfonyl) phenyl] -4-propylpiperazine

Obtaining in accordance with example 1: 1- [2-fluoro-3- (methylsulfonyl) phenyl] piperazine (0.13 g, 0.52 mmol), acetonitrile (4 ml), potassium carbonate (0.14 g, 1, 1 mmol) and 1-iodopropane (0.05 ml, 0.55 mmol). Yield: 0.1 g (64%). The amine was converted to a hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 241-243 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 300 (M +, 18), 272 (14), 271 (main peak), 228 (11), 70 (49).

Example 39:

1-Ethyl-4- {2-fluorine-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine

Preparation according to Example 1: 4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine (0.11 g, 0.35 mmol), acetonitrile (4 ml), potassium carbonate (0.063 g, 0 7 mmol) and 1-iodoethane (0.055 g, 0.35 mmol). Yield: 0.068 g (57%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 189-191 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 339 (M +, 8), 325 (15), 324 (main peak), 205 (6), 191 (15).

Example 40:

1-ALLYL-4- [2-fluoro-3- (methylsulfonyl) phenyl] piperidine

Preparation according to Example 1: 4- [2-fluoro-3- (methylsulphonyl) phenyl] piperidine (0.34 g, 1.32 mmol), acetonitrile (4 ml), potassium carbonate (0.34 g, 2, 6 mmol) and allyl bromide (0.12 ml, 1.38 mmol). Yield: 0.2 g (51%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 259-261 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 297 (M +, 87), 296 (82), 270 (main peak, 268 (41), 133 (57).

Example 41:

1-Ethyl-4- [2-fluorine-3- (methylsulfonyl) phenyl] piperazine

Obtaining in accordance with example 1: 1- [2-fluoro-3- (methylsulfonyl) phenyl] piperazine (0.13 g, 0.52 mmol), acetonitrile (4 ml), potassium carbonate (0.14 g, 1, 1 mmol) and iodoethane (0.48 ml, 0.52 mmol). Yield: 0.09 g (60%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 214-216 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 286 (M +, 59), 272 (14), 271 (87), 201 (11), 57 (main peak).

Example 42:

2- (1-Ethylpiperidine-4-yl) -6- (trifluoromethyl) phenol

Obtaining in accordance with example 1: 2-piperidin-4-yl-6- (trifluoromethyl) phenol (0.01 g, 0.04 mmol), acetonitrile (2 ml), potassium carbonate (0.01 g) and iodoethane ( 0.01 ml). Mass spectrum: m / z (relative intensity, 70 eV) 273 (M +, 37), 259 (15), 258 (main peak), 238 (18), 195 (19).

Example 43:

2- [1- (2-Fluoroethyl) piperidine-4-yl] -6- (trifluoromethyl) phenol

Obtaining in accordance with example 1: 2-piperidin-4-yl-6- (trifluoromethyl) phenol (0.01 g, 0.04 mmol), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1- bromo-2-fluoroethane (0.01 ml). Mass spectrum: m / z (relative intensity, 70 eV) 291 (M +, 29), 259 (15), 258 (main peak), 194 (22), 167 (11).

Example 44:

2- (1-Iso-propylpiperidin-4-yl) -6- (trifluoromethyl) phenol

Preparation according to Example 1: 2-piperidin-4-yl-6- (trifluoromethyl) phenol (0.01 g, 0.04 mmol), acetonitrile (2 ml), potassium carbonate (0.01 g) and isopropyl bromide ( 0.01 ml). Mass spectrum: m / z (relative intensity, 70 eV) 287 (M +, 13), 272 (main peak), 253 (13), 252 (44), 166 (12).

Example 45:

2- (1-Isobutylpiperidine-4-yl) -6- (trifluoromethyl) phenol

Obtaining in accordance with example 1: 2-piperidin-4-yl-6- (trifluoromethyl) phenol (0.01 g, 0.04 mmol), acetonitrile (2 ml), potassium carbonate (0.01 g) and isobutyl bromide ( 0.01 ml). Mass spectrum: m / z (relative intensity, 70 eV) 301 (M +, 4), 259 (13), 258 (main peak), 238 (9), 194 (11).

Example 46:

2- [1- (2,2,2-TRIFTORORETHYL) PIPERIDIN-4-IL] -6- (TRIFTORORMETHYL) Phenol

Obtaining in accordance with example 1: 2-piperidin-4-yl-6- (trifluoromethyl) phenol (0.01 g, 0.04 mmol), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1, 1,1-trifluoro-3-iodopropane (0.01 ml). Mass spectrum: m / z (relative intensity, 70 eV) 341 (M +, 40), 258 (main peak), 195 (25), 167 (28), 152 (56).

Example 47:

4- [2-Fluoro-3- (trifluoromethyl) phenyl] -1- (2-methoxyethyl) piperidine

Preparation in accordance with Example 1: 4- [2-fluoro-3- (trifluoromethyl) phenyl] piperidine (0.45 g, 1.82 mmol), acetonitrile (20 ml), potassium carbonate (0.6 g, 1, 1 mmol) and 1-bromo-2-methoxyethane (0.16 ml, 2.0 mmol). Yield: 0.34 g (61%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 180-181 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 305 (M +, 2), 261 (14), 260 (main peak), 217 (5), 177 (9).

Example 48:

4- [2-Methyl-3- (methylsulfonyl) phenyl] -1-ethylpiperidine

Preparation according to Example 1: 4- [2-methyl-3- (methyl-sulfonyl) phenyl] piperidine (0.17 g, 0.67 mmol), acetonitrile (20 ml), potassium carbonate (0.23 g, 1.67 mmol) and 1-iodoethane (0.065 ml, 0.74 mmol). Yield: 0.12 g (64%). Mass spectrum: m / z (relative intensity, 70 eV) 281 (M +, 22), 267 (17), 266 (main peak), 129 (12), 115 (24).

Example 49:

1-Ethyl-4- [2-fluoro-3- (methylsulfinyl) phenyl] piperidine

Preparation according to Example 2: 1-ethyl-4- [2-fluoro-3- (methylsulfinyl) phenyl] -1,2,3,6-tetrahydropyridine (150 mg, 0.56 mmol), formic acid (0, 1 ml, 2.8 mmol), palladium-on-charcoal (0.1 g), isopropanol (20 ml). Mass spectrum: m / z (relative intensity, 70 eV) 269 (M +, 11), 254 (main peak), 239 (84), 84 (13), 57 (11).

Example 50:

4- {2-Fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} -1-propylpiperidine

Preparation according to Example 1: 4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1-iodopropane (0.01 g). Mass spectrum: m / z (relative intensity, 70 eV) 353 (M +, 1), 325 (15), 324 (main peak), 191 (37), 133 (14).

Example 51:

1-ALLYL-4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine

Preparation according to Example 1: 4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and allyl bromide (0 , 01 g). Mass spectrum: m / z (relative intensity, 70 eV) 351 (M +, 47), 350 (61), 324 (main peak), 322 (29), 133 (36).

Example 52:

4- {2-Fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} -1- (2-methoxyethyl) piperidine

Preparation according to Example 1: 4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1-bromine -2-methoxyethane (0.01 g). Mass spectrum: m / z (relative intensity, 70 eV) 369 (M +, 1), 325 (15), 324 (main peak), 191 (37), 133 (14).

Example 53:

2- (4- {2-Fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidin-1-yl) ethanol

Preparation according to Example 1: 4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 2-iodoethanol (0.01 g). Mass spectrum: m / z (relative intensity, 70 eV) 355 (M +, 1), 325 (15), 324 (main peak), 191 (36), 133 (12).

Example 54:

4- {2-Fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} -1-methylpiperidine

Preparation according to Example 18: 4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and iodomethane (0 , 01 g). Mass spectrum: m / z (relative intensity, 70 eV) 325 (M +, 63), 324 (main peak), 305 (13), 191 (32), 133 (24).

Example 55:

1- (2-Methoxyethyl) -4- [2-methyl-3- (methylsulfonyl) phenyl] piperidine

Preparation according to Example 1: 4- [2-methyl-3- (methylsulfonyl) phenyl] piperidine (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01) and allyl bromide (0.01 g) . Mass spectrum: m / z (relative intensity, 70 eV) 311 (M +, 2), 267 (17), 266 (main peak), 129 (8), 70 (10).

Example 56:

2- (1-Ethylpiperidine-4-yl) -6- (trifluoromethoxy) phenol

Obtaining in accordance with example 1: 2-piperidin-4-yl-6- (trifluoromethoxy) phenol (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 2-iodoethane (0.01 d). Mass spectrum: m / z (relative intensity, 70 eV) 289 (M +, 45), 288 (20), 275 (15), 274 (main peak), 84 (26).

Example 57:

2- [1- (2-HYDROXYETHYL) PIPERIDIN-4-IL] -6- (TRIFFORMETOXY) Phenol

Obtaining in accordance with example 1: 2-piperidin-4-yl-6- (trifluoromethoxy) phenol (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 2-iodoethanol (0.01 d). Mass spectrum: m / z (relative intensity, 70 eV) 305 (M +, 1), 275 (15), 274 (main peak), 117 (5), 70 (20).

Example 58:

1- [2-Fluoro-3- (1-propylpiperidin-4-yl) phenyl] ethanone

Obtaining in accordance with example 1: 1- (2-fluoro-3-piperidin-4-ylphenyl) ethanone (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 2-iodopropane (0 , 01 g). Mass spectrum: m / z (relative intensity, 70 eV) 263 (M +, 4), 235 (15), 234 (main peak), 163 (3), 133 (4).

Example 59:

1- {2-fluoro-3- [1- (2-hydroxyethyl) piperidin-4-yl] phenyl} ethanone

Preparation according to Example 1: 1- (2-fluoro-3-piperidin-4-ylphenyl) ethanone (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 2-iodoethanol (0 , 01 g). Mass spectrum: m / z (relative intensity, 70 eV) 265 (M +, 1), 235 (16), 234 (main peak), 133 (5), 109 (5).

Example 60:

1- [3- (1-Allylpiperidin-4-yl) -2-fluorophenyl] ethanone

Obtaining in accordance with example 1: 1- (2-fluoro-3-piperidin-4-ylphenyl) ethanone (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and allyl bromide (0.01 d). Mass spectrum: m / z (relative intensity, 70 eV) 261 (M +, 89), 260 (82), 234 (main peak), 218 (25), 82 (32).

Example 61:

1- {2-fluoro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenyl} ethanone

Obtaining in accordance with example 1: 1- (2-fluoro-3-piperidin-4-ylphenyl) ethanone (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1-bromo-2 methoxyethane (0.01 g). Mass spectrum: m / z (relative intensity, 70 eV) 279 (M +, 1), 235 (16), 234 (main peak), 163 (3), 133 (4).

Example 62:

1- [3- (1-Allylpiperidin-4-yl) -2-fluorophenyl] -2,2,2-trifluoroethanone

Preparation according to Example 1: 2,2,2-trifluoro-1- (2-fluoro-3-piperidin-4-ylphenyl) ethanone (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and allyl bromide (0.01 g). Mass spectrum: m / z (relative intensity, 70 eV) 315 (M +, 60), 314 (82), 288 (main peak), 286 (31), 96 (36).

Example 63:

2,2,2-TRIFTOR-1- {2-fluoro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenyl} ethanone

Preparation according to Example 1: 2,2,2-trifluoro-1- (2-fluoro-3-piperidin-4-ylphenyl) ethanone (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1-bromo-2-methoxyethane (0.01 g). Mass spectrum: m / z (relative intensity, 70 eV) 333 (M +, 1), 289 (15), 288 (main peak), 264 (4), 148 (6).

Example 64:

1- [3- (1-Ethylpiperidin-4-yl) -2-fluorophenyl] -2,2,2-trifluoroethanone

Preparation according to Example 1: 2,2,2-trifluoro-1- (2-fluoro-3-piperidin-4-ylphenyl) ethanone (0.70 g, 2.54 mmol), acetonitrile (30 ml), carbonate potassium (0.35 g) and 2-iodoethane (0.40 g. 2.54 mmol). Yield: 0.21 g (27%). The amine was converted to a fumaric acid salt and recrystallized from ethanol / diethyl ether: mp. 109-110 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 303 (M +, 13), 302 (10), 289 (16), 288 (main peak), 234 (7).

Example 65:

2,2,2-TRIFTOR-1- [2-fluoro-3- (1-propylpiperidin-4-yl) phenyl] ethanone

Preparation according to Example 1: 2,2,2-trifluoro-1- (2-fluoro-3-piperidin-4-ylphenyl) ethanone (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1-iodopropane (0.01 g). Mass spectrum: m / z (relative intensity, 70 eV) 317 (M +, 3), 289 (15), 288 (main peak), 248 (4), 109 (6).

Example 66:

2,2,2-TRIFTOR-1- {2-fluoro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenyl} ethanol

Obtaining in accordance with example 1: 2,2,2-trifluoro-1- (2-fluoro-3-piperidin-4-ylphenyl) ethanol (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1-bromo-2-methoxyethane (0.01 g). Mass spectrum: m / z (relative intensity, 70 eV) 335 (M +, 1), 291 (15), 290 (main peak), 207 (4), 149 (7).

Example 67:

1- [3- (1-Ethylpiperidin-4-yl) -2-fluorophenyl] -2,2,2-trifluoroethanol

Obtaining in accordance with example 1: 2,2,2-trifluoro-1- (2-fluoro-3-piperidin-4-ylphenyl) ethanol (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and iodoethane (0.01 g). Mass spectrum: m / z (relative intensity, 70 eV) 305 (M +, 17), 304 (13), 291 (15), 290 (main peak), 149 (5).

Example 68:

2,2,2-TRIFTOR-1- [2-fluoro-3- (1-propylpiperidin-4-yl) phenyl] ethanol

Obtaining in accordance with example 1: 2,2,2-trifluoro-1- (2-fluoro-3-piperidin-4-ylphenyl) ethanol (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and iodopropane (0.01 g). Mass spectrum: m / z (relative intensity, 70 eV) 319 (M +, 4), 291 (14), 290 (main peak), 220 (3), 149 (3).

Example 69:

3- (1-Ethylpiperidine-4-yl) phthalonitrile

Preparation according to Example 31: 1-ethyl-4- [2-fluoro-3- (methylsulfonyl) phenyl] piperidine (1.06 g, 3.72 mmol), N, N-dimethylformamide (30 ml), sodium cyanide (0.7 g, 14.0 mmol) and 18-crown-6-ether (5 mg). Yield: 0.35 g. Mass spectrum: m / z (relative intensity, 70 eV) 239 (M +, 3), 225 (17), 224 (main peak), 154 (6), 71 (5).

Example 70:

1-ALLYL-4- [2-fluoro-3- (trifluoromethyl) phenyl] piperidine

Preparation in accordance with Example 1: 4- [2-fluoro-3- (trifluoromethyl) phenyl] piperidine (0.45 g, 1.82 mmol), acetonitrile (20 ml), potassium carbonate (0.6 g, 1, 1 mmol) and allyl bromide (0.16 ml, 2.0 mmol). Yield: 0.42 g (80%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 224-226 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 287 (M +, 70), 286 (90), 260 (main peak), 258 (53), 82 (95).

Example 71:

4- [2-Fluoro-3- (trifluoromethyl) phenyl] -1-propylpiperidine

A mixture of 4- [2-fluoro-3- (trifluoromethyl) phenyl] -1-propyl-1,2,3,6-tetrahydropyridine (5.0 g, 17.4 mmol), palladium-on-carbon (0.4 d) and hydrochloric acid (0.5 ml, conc.) in methanol (30 ml) were hydrogenated in a hydrogen atmosphere at a pressure of 50 ft / in for 15 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated and evaporated to dryness to give 4.7 g of a crude product. Purification by flash column chromatography (isooctane / ethyl acetate, 1: 1) gave the title compound (2.57 g, 51%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 258-260 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 289 (M +, 4), 261 (16), 260 (main peak), 177 (6) 70 (15).

The synthesis of intermediates used in the above examples is described further in the preparations.

Getting 1:

4- [2-Fluoro-3- (trifluoromethyl) phenyl] -1-propylpiperidine-4-ol

To a solution of 3-bromo-2-fluorobenzotrifluoride (9.0 g, 37 mmol) in anhydrous tetrahydrofuran (100 ml) in a nitrogen atmosphere was added dropwise at -78 ° C n-butyllithium (2.5 M in hexane, 16.2 ml, 40.5 mmol). The mixture was stirred for 1 hour, after which a solution of freshly distilled 4-propyl-1-piperidone (5.2 g, 37 mmol) in anhydrous tetrahydrofuran (50 ml) was added dropwise. The resulting mixture was stirred at -78 ° C for 30 minutes and then brought to ambient temperature. Water (100 ml) was added and the mixture was extracted with ethyl acetate (3 × 100 ml). The combined organic phases were dried (MgSO ₄ ), filtered and evaporated to dryness. The oily residue was purified by flash column chromatography (ethyl acetate / methanol, 1: 1) to obtain the title compound (8.0 g). Mass spectrum: m / z (relative intensity, 70 eV) 305 (M +, 5), 276 (main peak), 258 (35), 191 (21), 185 (17).

Getting 2:

4- [2-Fluoro-3- (trifluoromethyl) phenyl] -1-propyl-1,2,3,6-tetrahydropyridine

A solution of 4- [2-fluoro-3- (trifluoromethyl) phenyl] -1-propylpiperidin-4-ol (8.0 g, 26 mmol) in trifluoroacetic acid (80 ml) was heated at the boil under reflux for 20 hours. The mixture was poured onto ice and made basic with 10M sodium hydroxide solution. The mixture was extracted with ethyl acetate (3 × 100 ml) and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated to dryness. The residue was purified by flash column chromatography (ethyl acetate / methanol, 1: 1) to obtain the title compound (5.6 g). Mass spectrum: m / z (relative intensity, 70 eV) 287 (M +, 22), 259 (16), 258 (main peak), 177 (10), 147 (10).

Getting 3:

1-BROM-2-CHLOR-3- (METHYLTHIO) BENZENE

To a solution of 1,3-dibromo-2-chlorobenzene (3.4 g, 12.6 mmol) in anhydrous diethyl ether (60 ml) in a nitrogen atmosphere at -78 ° C was added dropwise n-butyllithium (2.5 M in hexane, 5.0 ml, 12.6 mmol). The mixture was stirred for 1 hour, after which dimethyldisulfide (1.0 ml, 13.9 mmol) was added dropwise. The resulting mixture was stirred at -78 ° C for 30 minutes and then brought to ambient temperature. Water (100 ml) was added and the mixture was extracted with ethyl acetate (3 × 100 ml). The combined organic phases were dried (MgSO ₄ ), filtered and evaporated to dryness. The residue was purified by flash column chromatography (isooctane) to give the title compound (1.23 g). Mass spectrum: m / z (relative intensity, 70 eV) 240 (M +, 28), 238 (M +, main peak), 236 (71), 205 (29), 142 (27).

Getting 4:

1-BROM-2-CHLOR-3- (METHYL SULFONIL) BENZENE

To a mixture of 1-bromo-2-chloro-3- (methylthio) benzene (1.23 g, 5.2 mmol) and sodium periodate (3.3 g, 15.6 mmol) in a mixture of carbon tetrachloride / acetonitrile / water ( 1: 1: 2, 30 ml) ruthenium trichloride (1 mg, 0.05 mol%) was added. The resulting mixture was stirred at ambient temperature for 20 minutes, after which an aqueous solution of sodium carbonate (10%, 50 ml) was added and the mixture was extracted with ethyl acetate (3 × 100 ml). The combined organic phases were dried (MgSO ₄ ), filtered and evaporated to dryness to afford the title compound (1.4 g). Mass spectrum: m / z (relative intensity, 70 eV) 270 (M +, 66), 268 (M +, 48), 208 (65), 190 (77), 75 (main peak).

Getting 5:

4- [2-Chlorine-3- (Methylsulfonyl) phenyl] pyridine

To a mixture of 1-bromo-2-chloro-3- (methylsulfonyl) benzene (1.3 g, 4.8 mmol), 1-pyridyl-4-boronic acid (0.78 g, 6.3 mmol) and sodium carbonates (0.98 g, 12 mmol) in toluene / ethanol (1: 1, 60 ml) in a nitrogen atmosphere was added tetrakispalladium (0.7 g, 0.48 mmol). The mixture was heated at the boil under reflux for 48 hours, cooled to ambient temperature, after which water (50 ml) and ethyl acetate (100 ml) were added. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (2 × 50 ml). The combined organic phases were evaporated to dryness and dissolved in aqueous hydrochloric acid (10%, 50 ml). The solution was washed with diethyl ether (2 × 40 ml), made basic with 2M sodium hydroxide and extracted with ethyl acetate (2 × 50 ml). The combined organic phases were dried (MgSO ₄ ) and evaporated to dryness to afford the title compound (1.0 g). Mass spectrum: m / z (relative intensity, 70 eV) 269 (M +, 39), 267 (M +, main peak), 188 (67), 153 (47), 126 (82).

Getting 6:

4- [2-CHLORO-3- (METHYLSULFONIL) PHENYL] -1-PROPYL-1,2,3,6-TETRAGYDROPYRIDINE

To undiluted 4- [2-chloro-3- (methylsulfonyl) phenyl] pyridine (1.0 g, 3.8 mmol) was added 1-iodopropane (5 ml), and the resulting mixture was heated at 100 ° C. for 2 hours. Excess 1-iodopropane was evaporated under reduced pressure, and ethanol (60 ml) was added. The mixture was cooled to −20 ° C. and sodium borohydride (1.3 g, 38 mmol) was added portionwise. The resulting mixture was stirred for 1 hour, after which an aqueous solution of sodium carbonate (10%, 50 ml) was added. The aqueous phase was extracted with ethyl acetate (3 × 100 ml) and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated to dryness. The residue was purified by flash column chromatography (ethyl acetate / methanol, 1: 1) to obtain the title compound (0.5 g). Mass spectrum: m / z (relative intensity, 70 eV) 313 (M +, 18), 286 (39), 285 (17), 284 (main peak), 128 (12).

Getting 7:

1-BROM-2-METHOXY-3- (TRIFFORMETHYL) BENZENE

To a solution of 3-bromo-2-fluorobenzotrifluoride (1.0 g, 4.1 mmol) in methanol (5 ml) was added a solution of sodium methoxide in methanol (30%, 0.73 ml, 4.1 mmol). The mixture was heated under microwave irradiation at 150 ° C for 10 minutes. The reaction mixture was poured into water and extracted with ethyl acetate (3 × 50 ml). The combined organic phases were dried (MgSO ₄ ), filtered and evaporated to dryness to afford the title compound (0.89 g). Mass spectrum: m / z (relative intensity, 70 eV) 256 (M +, 87), 254 (M +, 89), 239 (26), 211 (24), 132 (main peak).

Getting 8:

4- [2-METHOXY-3- (trifluoromethyl) phenyl] pyridine

Preparation according to Preparation 5: 1-bromo-2-methoxy-3- (trifluoromethyl) benzene (0.89 g, 3.5 mmol), toluene (30 ml), ethanol (30 ml), 1-pyridyl-4 -boronic acid (0.56 g) and sodium carbonate (0.71 g), tetrakispalladium (0.51 g). Yield: 0.42 g. Mass spectrum: m / z (relative intensity, 70 eV) 253 (M +, main peak), 238 (29), 233 (18), 183 (31), 133 (19).

Getting 9:

4- [2-METHOXY-3- (trifluoromethyl) phenyl] piperidine

To a solution of 4- [2-methoxy-3- (trifluoromethyl) phenyl] pyridine (0.42 g, 1.66 mmol) in methanol (10 ml) was added platinum oxide (0.10 g) and hydrochloric acid (0.1 ml, conc.) and the reaction mixture was hydrogenated in a hydrogen atmosphere at a pressure of 50 psi for 1 hour. Filtration through a celite pad and evaporation of the filtrate afforded 0.48 g of the crude product as a hydrochloric acid salt. The salt was dissolved in an aqueous solution of sodium carbonate (10%, 50 ml) and was extracted with ethyl acetate (3 × 50 ml). The combined organic phases were dried (MgSO ₄ ), filtered and evaporated to dryness to afford the title compound (0.38 g). Mass spectrum: m / z (relative intensity, 70 eV) 260 (M +, 2), 258 (M +, 7), 229 (14), 228 (main peak) 59 (15).

Getting 10:

1-BROM-2-METHYL-3- (METHYLTHIO) BENZENE

To a solution of 1-bromo-3-fluoro-2-methylbenzene (2.0 g, 10.6 mmol) in N, N-dimethylformamide (10 ml) was added sodium methanethiolate (0.85 g, 11.7 mmol) and the mixture stirred for 15 minutes at 150 ° C. After cooling, an aqueous sodium carbonate solution (10%, 50 ml) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2 × 50 ml) and the combined organic phases were dried (MgSO ₄ ) and evaporated under reduced pressure to give an oil. The residue was purified by flash column chromatography (isooctane) to give the title compound (1.33 g). Mass spectrum: m / z (relative intensity, 70 eV) 218 (M +, 98), 216 (M +, 92), 202 (26), 200 (26), 122 (main peak), 121 (56).

Getting 11:

1-BROM-2-METHYL-3- (METHYLSULFONIL) BENZENE

The compound was prepared in accordance with the preparation of 4: 1-bromo-2-methyl-3- (methylthio) benzene (1.33 g), carbon tetrachloride (8 ml), acetonitrile (8 ml), water (16 ml), sodium periodate (3.9 g), ruthenium trichloride (1 mg). Yield: 1.6 g. Mass spectrum: m / z (relative intensity, 70 eV) 250 (M +, 69), 248 (M +, 67), 169 (49), 90 (63), 89 (main peak) .

Getting 12:

4- [2-Methyl-3- (methylsulfonyl) phenyl] pyridine

The compound was prepared in accordance with the preparation of 5: 1-bromo-2-methyl-3- (methylsulfonyl) benzene (1.1 g, 4.5 mmol), toluene (30 ml), ethanol (30 ml), 1-pyridyl- 4-boronic acid (0.73 g) and sodium carbonate (0.91 g), tetrakispalladium (0.65 g). Yield: 0.40 g. Mass spectrum: m / z (relative intensity, 70 eV) 247 (M +, 96), 246 (51), 168 (53), 167 (main peak), 139 (51).

Getting 13:

4- [2-methyl-3- (methylsulfonyl) phenyl] piperidine

The compound was obtained in accordance with the preparation of 9: 4- [2-methyl-3- (methylsulfonyl) phenyl] pyridine (0.4 g, 1.6 mmol), methanol (10 ml), platinum oxide (0.10 g), hydrochloric acid (0.1 ml, conc.). Yield: 0.41 g. Mass spectrum: m / z (relative intensity, 70 eV) 247 (M +, 96), 246 (51), 168 (53), 167 (main peak), 139 (51).

Getting 14:

4- [3-Fluoro-2- (trifluoromethyl) phenyl] -1-propylpiperidine-4-ol

The compound was prepared in accordance with the preparation of 1: 1-bromo-3-fluoro-2- (trifluoromethyl) benzene (2.5 g, 10.3 mmol), anhydrous diethyl ether (100 ml), n-butyllithium (2.5 M in hexane, 4.0 ml, 10.3 mmol), 4-propyl-1-piperidone (1.45 g, 10.3 mmol). Yield: 2.98 g. Mass spectrum: m / z (relative intensity, 70 eV) 305 (M +, 7), 277 (14), 276 (main peak), 258 (57), 163 (7).

Getting 15:

4- [3-Fluoro-2- (trifluoromethyl) phenyl] -1-propyl-1,2,3,6-tetrahydropyridine

The compound was prepared in accordance with the preparation of 2: 4- [3-fluoro-2- (trifluoromethyl) phenyl] -1-propylpiperidin-4-ol (2.98 g, 9.8 mmol), hydrochloric acid (40 ml, conc. ) Yield: 2.37 g. Mass spectrum: m / z (relative intensity, 70 eV) 305 (M +, 7), 277 (14), 276 (main peak), 258 (57), 163 (7).

Getting 16:

4- [3-Fluoro-2- (trifluoromethyl) phenyl] -1-propylpiperidine

To a solution of 4- (3-fluoro-2- (trifluoromethyl) phenyl] -1-propyl-1,2,3,6-tetrahydropyridine (1.73 g, 6.0 mmol) in ethanol (30 ml) was added Raney nickel (suspension in water, 10 ml) and the reaction mixture was hydrogenated in a hydrogen atmosphere (50 psi) for 2 days. Filtration through a pad of celite and evaporation of the filtrate gave 1.35 g of the crude product. Mass spectrum: m / z (relative intensity, 70 eV) 289 (M +, 4), 261 (16), 260 (main peak), 176 (6) 70 (20).

Getting 17:

3- (1-Ethylpiperidin-4-yl) -2-fluorobenzonitrile

To a solution of 3- (1-ethylpiperidin-4-yl) -2-fluorobenzamide (0.46 g, 1.83 mmol) in anhydrous N, N-dimethylformamide (4 ml) was added freshly distilled phosphorus trichloride (0.42 ml, 4 , 57 mmol) and the reaction mixture was stirred for 1 hour. The solution was poured onto ice and made basic by the addition of an aqueous solution of sodium carbonate (10%, 50 ml). Ethyl acetate (50 ml) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2 × 50 ml) and the combined organic phases were dried (MgSO ₄ ) and evaporated under reduced pressure to give an oil. Purification by flash column chromatography (ethyl acetate / methanol, 1: 1) gave the title compound: 0.32 g (75%). The amine was converted to an oxalic acid salt and recrystallized from ethanol / diethyl ether: mp. 156-158 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 232 (M +, 12), 218 (14), 217 (main peak), 147 (10), 134 (13).

Getting 18:

4- [2-Fluoro-3- (trifluoromethyl) phenyl] -1-propylpiperidine

A mixture of 4- [2-fluoro-3- (trifluoromethyl) phenyl] -1-propyl-1,2,3,6-tetrahydropyridine (5.0 g, 17.4 mmol), palladium-on-carbon (0.4 d) and hydrochloric acid (0.5 ml, conc.) in methanol (30 ml) were hydrogenated in a hydrogen atmosphere at a pressure of 50 ft / in for 15 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated and evaporated to dryness to give 4.7 g of a crude product. Purification by flash column chromatography (isooctane / ethyl acetate, 1: 1) gave the title compound (2.57 g, 51%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 258-260 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 289 (M +, 4), 261 (16), 260 (main peak), 177 (6) 70 (15).

Getting 19:

T-BUTYL-4- [2-FLUOR-3- (TRIFFORMETOXY) Phenyl] -4-HYDROXYPIPERIDINE-1-CARBOXYLATE

The production method in accordance with obtaining 30: 1-fluoro-2- (trifluoromethoxy) benzene (10 g, 55.5 mmol), dry tetrahydrofuran (30 ml), lithium diisopropylamide (2 M in hexane, 31 ml, 62 mmol) and 4-Boc-1-piperidone (13.3 g, 66.6 mmol). Yield: 11.5 g. Mass spectrum: m / z (relative intensity, 70 eV) 379 (M +, 1), 306 (7), 305 (14), 261 (10), 57 (main peak).

Getting 20:

4- [2-Fluoro-3- (trifluoromethoxy) phenyl] -1,2,3,6-tetrahydropyridine

The compound was prepared in accordance with Preparation 31: tert-butyl-4- [2-fluoro-3- (trifluoromethoxy) phenyl] -4-hydroxypiperidin-1-carboxylate (11.5 g, 30.3 mmol), polyphosphoric acid ( 15 ml). Yield: 3.33 g. Mass spectrum: m / z (relative intensity, 70 eV) 261 (M +, main peak), 232 (17), 193 (24), 147 (64), 82 (86).

Getting 21:

3-PIPERAZIN-1-IL-2- (trifluoromethyl) benzonitrile

A solution of 3-fluoro-2- (trifluoromethyl) benzonitrile (1.2 g, 6.3 mmol) and piperazine (0.72 g, 8.4 mmol) in acetonitrile (6 ml) was heated under microwave irradiation at 150 ° C in for 15 minutes. The reaction mixture was poured into water (50 ml) and the aqueous phase was extracted with ethyl acetate (3 × 50 ml). The combined organic phases were dried (MgSO ₄ ), filtered and evaporated to dryness. Purification by flash column chromatography (ethyl acetate / methanol, 1: 1) gave the title compound: 1.1 g. Mass spectrum: m / z (relative intensity, 70 eV) 255 (M +, 16), 214 (11) , 213 (main peak), 171 (8), 151 (7).

Getting 22:

1- [2-Fluoro-3- (trifluoromethyl) phenyl] piperazine

To a solution of 3-bromo-2-fluorobenzotrifluoride (1.72 g, 7.1 mmol) in toluene (50 ml) in a nitrogen atmosphere was added piperazine (0.89 g, 10.6 mmol), potassium tert-butoxide (0, 95 g, 9.9 mmol), bis (dibenzylideneacetone) palladium (0) (0.19 g, 0.21 mmol) and (+/-) - 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate ( 0.13 g, 0.21 mmol). The resulting mixture was heated at 80 ° C for 20 hours. Filtration through a pad of celite and evaporation of the filtrate gave 2.1 g of a crude product. The residue was purified by flash column chromatography (ethyl acetate / methanol, 1: 1) to obtain the title compound (0.96 g). Mass spectrum: m / z (relative intensity, 70 eV) 248 (M +, 23), 207 (10), 206 (main peak), 190 (17), 163 (8).

Getting 23:

1-BROM-2-fluoro-3- (methylthio) benzene

To a solution of 1-bromo-2-fluorobenzene (2.0 g, 11.4 mmol) in anhydrous tetrahydrofuran (50 ml) in a nitrogen atmosphere at -78 ° C was added lithium diisopropylamide (2.5 M in hexane, 6.28 ml 15.4 mmol). The mixture was stirred for 5 minutes, after which dimethyl disulfide (0.92 ml, 15.4 mmol) was added and stirring was continued at -78 ° C for an additional hour. The temperature of the reaction mixture was brought to ambient temperature and an aqueous solution of sulfuric acid (10%, 50 ml) was added. The phases were separated and the aqueous phase was extracted with ethyl acetate (3 × 100 ml). The combined organic phases were dried (MgSO ₄ ) and evaporated to dryness to give an oil. The residue was purified by flash column chromatography (isooctane) to give the title compound (1.26 g). Mass spectrum: m / z (relative intensity, 70 eV) 222 (M +, main peak), 220 (M +; 91), 189 (24), 187 (25), 126 (97).

Getting 24:

TRET-BUTYL-4- [2-fluoro-3- (methylthio) phenyl] -4-hydroxypiperidine-1-carboxylate

To a solution of 1-bromo-2-fluoro-3- (methylthio) benzene (1.1 g, 4.95 mmol) in anhydrous tetrahydrofuran (50 ml) in a nitrogen atmosphere at -78 ° C was added dropwise n-butyllithium (2 5 M in hexane, 2.1 ml, 5.2 mmol). The mixture was stirred for 30 minutes at −78 ° C. and then brought the temperature to −20 ° C. over 2 minutes and cooled again to −78 ° C. To the resulting mixture at -78 ° C was added dropwise a solution of 4-Boc-1-piperidone (1.04 g, 5.2 mmol) in anhydrous tetrahydrofuran (50 ml). The mixture was stirred at -78 ° C for 10 minutes and then brought to ambient temperature. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (100 ml) and was extracted with ethyl acetate (3 × 100 ml). The combined organic phases were dried, concentrated and purified by flash column chromatography (isooctane / ethyl acetate 2: 1) to give the title compound (1.25 g). Mass spectrum: m / z (relative intensity, 70 eV) 341 (M +, 11), 285 (24), 267 (14), (11), 57 (main peak).

Getting 25:

4- [2-fluoro-3- (methylthio) phenyl] -1,2,3,6-tetrahydropyridine

The compound was prepared in accordance with the preparation of 2: tert-butyl-4- [2-fluoro-3- (methylthio) phenyl] -4-hydroxypiperidin-1-carboxylate (2.0 g, 5.86 mmol), trifluoroacetic acid (20 ml). Yield: 1.42 g. Mass spectrum: m / z (relative intensity, 70 eV) 223 (M +, main peak), 222 (32), 147 (61), 146 (47), 133 (27).

Getting 26:

METHYL-4- [2-fluoro-3- (methylthio) phenyl] -3,6-dihydropyridine-1 (2H) -carboxylate

To a solution of 4- [2-fluoro-3- (methylthio) phenyl] -1,2,3,6-tetrahydropyridine (1.35 g, 6.05 mmol) and triethylamine (1.2 ml, 7.2 mmol) in methylene chloride (20 ml) at 0 ° C, a solution of methyl chloroformate (0.49 g, 6.6 mmol) in methylene chloride (5 ml) was added dropwise. The mixture was stirred for 15 minutes at 0 ° C and for 1 hour at ambient temperature. The reaction was quenched with an aqueous solution of sodium carbonate (10%, 50 ml), the phases were separated and the aqueous phase was extracted with methylene chloride (3 × 50 ml). The combined organic phases were dried (MgSO ₄ ), filtered and evaporated to dryness to afford the title compound (0.95 g). Mass spectrum: m / z (relative intensity, 70 eV) 281 (M +, 65), 267 (16), 266 (main peak), (27), 146 (25).

Getting 27:

METHYL-4- [2-fluorine-3- (methylsulfonyl) phenyl] -3,6-dihydropyridine-1 (2H) -carboxylate

To a solution of methyl 4- [2-fluoro-3- (methylthio) phenyl] -3,6-dihydropyridin-1 (2H) -carboxylate (0.9 g, 3.2 mmol) in methylene chloride (50 ml) at 0 ° C, m-chloroperbenzoic acid (1.21 g, 7.0 mmol) was added portionwise over 30 minutes. The mixture was stirred at 0 ° C for 1.5 hours and then further for one hour at ambient temperature. An aqueous solution of sodium carbonate (10%, 100 ml) was added and the phases were separated. The aqueous phase was extracted with methylene chloride (3 × 50 ml) and the combined organic phases were washed with brine (50 ml), dried (MgSO ₄ ) and evaporated to dryness to give the title compound (1.24 g). Mass spectrum: m / z (relative intensity, 70 eV) 313 (M +, 47), 298 (main peak), 254 (25), (22), 146 (26).

Getting 28:

METHYL-4- [2-fluorine-3- (methylsulfonyl) phenyl] piperidine-1-carboxylate

The compound was prepared according to Preparation 18: methyl 4- [2-fluoro-3- (methylsulfonyl) phenyl] -3,6-dihydropyridin-1 (2H) -carboxylate (1.45 g, 4.6 mmol), palladium -coal (0.2 g) and hydrochloric acid (0.5 ml, conc.). Yield: 0.76 g. Mass spectrum: m / z (relative intensity, 70 eV) 315 (M +, 41), 256 (main peak), 236 (54), 141 (43) 114 (50).

Getting 29:

4- [2-fluoro-3- (methylsulfonyl) phenyl] piperidine

To a solution of methyl 4- [2-fluoro-3- (methylsulfonyl) phenyl] piperidine-1-carboxylate (0.7 g, 2.2 mmol) in ethanol (4 ml) was added hydrochloric acid (3 M, 10 ml) and the mixture was heated at the boil under reflux for 24 hours. Ethanol was evaporated and the aqueous residue was basified with sodium hydroxide (5 M) and extracted with ethyl acetate (3 × 50 ml). The combined organic phases were washed with brine (50 ml), dried (MgSO ₄ ) and evaporated to dryness to afford the title compound (0.5 g, 91%). Mass spectrum: m / z (relative intensity, 70 eV) 257 (M +, 6), 237 (95), 208 (83), 173 (main peak) 130 (69).

Getting 30:

4- [2-Fluoro-3- (trifluoromethoxy) phenyl] -1-propylpiperidine-4-ol

To a solution of 1-fluoro-2- (trifluoromethoxy) benzene (1.22 g, 6.77 mmol) in anhydrous tetrahydrofuran (30 ml) at -78 ° C, lithium diisopropylamide (2.5 M in hexane, 3.0 ml, 7.45 mmol). The mixture was stirred for 1 hour, after which a solution of freshly distilled 4-propyl-1-piperidone (0.96 g, 6.77 mmol) in anhydrous tetrahydrofuran (20 ml) was added dropwise. The resulting mixture was stirred at -78 ° C for 30 minutes and then brought to ambient temperature. Water (100 ml) was added and the mixture was extracted with ethyl acetate (3 × 100 ml). The combined organic phases were dried (MgSO ₄ ), filtered and evaporated to dryness. The oily residue was purified by flash column chromatography (ethyl acetate / methanol, 1: 1) to obtain the title compound (0.83 g). Mass spectrum: m / z (relative intensity, 70 eV) 321 (M +, 5), 293 (14), 292 (main peak), 274 (25), 207 (10).

Getting 31:

4- [2-fluoro-3- (trifluoromethoxy) phenyl] -1-propyl-1,2,3,6-tetrahydropyridine

A mixture of 4- [2-fluoro-3- (trifluoromethoxy) phenyl] -1-propyl-piperidin-4-ol (0.83 g, 2.6 mmol) and polyphosphoric acid (10 ml) was heated at 100 ° C for 2 hours. The mixture was poured onto ice and made basic with 5M sodium hydroxide solution. The mixture was extracted with ethyl acetate (3 × 100 ml) and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated to dryness to give the title compound (0.62 g). Mass spectrum: m / z (relative intensity, 70 eV) 303 (M +, 24), 275 (14), 274 (main peak), 147 (7), 133 (6).

Getting 32:

4- [2-fluoro-3- (trifluoromethoxy) phenyl] -1-propylpiperidine

The compound was prepared according to Preparation 18: 4- [2-fluoro-3- (trifluoromethoxy) phenyl] -1-propyl-1,2,3,6-tetrahydropyridine (0.55 g, 1.8 mmol), palladium- on charcoal (0.09 g) and hydrochloric acid (0.5 ml, conc.). Yield: 0.22 g (40%). The amine was converted to hydrochloric acid salt and recrystallized from ethanol / diethyl ether: mp. 221-222 ° C. Mass spectrum: m / z (relative intensity, 70 eV) 305 (M +, 3), 277 (14), 276 (main peak), 233 (6) 193 (8).

Getting 33:

4- [2-Fluoro-3- (trifluoromethoxy) phenyl] piperidine

The compound was prepared in accordance with the preparation of 18: 4- [2-fluoro-3- (trifluoromethoxy) phenyl] -1,2,3,6-tetrahydropyridine (3.33 g, 12.7 mmol), palladium on carbon ( 0.35 g), hydrochloric acid (0.5 ml), methanol (30 ml). Yield: 2.68 g. Mass spectrum: m / z (relative intensity, 70 eV) 263 (M +, 39), 262 (27), 206 (8), 178 (7) 56 (main peak).

Getting 34:

4- [2-METHOXY-3- (TRIFTORMETOXY) Phenyl] -1-PROPYLPIPERIDINE

To a solution of 4- [2-fluoro-3- (trifluoromethoxy) phenyl] -1-propylpiperidine (1.92 g, 6.3 mmol) in N, N-dimethylformamide (20 ml) was added a solution of sodium methoxide in methanol (30% , 3 ml) and the mixture was heated at 150 ° C for 1 hour. Water (50 ml) and ethyl acetate (50 ml) were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2 × 50 ml) and the combined organic phases were dried (MgSO ₄ ) and evaporated under reduced pressure to give an oil. The residue was purified by flash column chromatography (ethyl acetate / methanol, 1: 1) to obtain the title compound (1.32 g). Mass spectrum: m / z (relative intensity, 70 eV) 317 (M +, 6), 289 (17), 288 (main peak), 204 (6), 175 (8).

Getting 35:

3-Bromine-2-fluoro-N, N-dimethylbenzenesulfonamide

3-bromo-2-fluorobenzenethiol (1.9 g, 9.2 mmol), sodium periodate (4.8 g, 22.9 mmol) and ruthenium trichloride (5 mg) in acetonitrile (60 ml) were stirred at 0 ° C within 5 minutes, after which sulfonyl chloride (1.9 ml, 22.9 mmol) was added dropwise. The mixture was stirred for an additional hour and ethyl acetate (50 ml) and an aqueous solution of sodium carbonate (10%, 50 ml) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 × 50 ml). Dimethylamine (40% in water, 10 ml) was added to the combined organic phase, and the mixture was stirred for 1 hour. Evaporation of the solvents and purification by flash chromatography afforded the title compound (1.1 g). Mass spectrum: m / z (relative intensity, 70 eV) 283 (M +, 47), 281 (M +, 44), 239 (32), 73 (59), 94 (main peak).

Getting 36:

2-Fluoro-N, N-dimethyl-3-pyridine-4-ylbenzenesulfonamide

The compound was prepared in accordance with the preparation of 5: 3-bromo-2-fluoro-N, N-dimethylbenzenesulfonamide (1.2 g, 3.54 mmol), toluene (30 ml), ethanol (30 ml), 1-pyridyl-4 -boronic acid (0.57 g, 4.25 mmol), sodium carbonate (0.8 g), tetrakispalladium (0.55 g). Yield: 0.51 g. Mass spectrum: m / z (relative intensity, 70 eV) 280 (M +, main peak), 173 (95), 172 (90), 145 (32), 125 (40).

Getting 37:

3- (1-Ethyl-1,2,3,6-tetrahydropyridin-4-yl) -2-fluoro-n, n-dimethylbenzenesulfonamide

The compound was prepared in accordance with the preparation of 6: 2-fluoro-N, N-dimethyl-3-pyridin-4-ylbenzenesulfonamide (0.59 g, 2.11 mmol), 1-iodoethane (3 ml), ethanol (40 ml) Sodium borohydride (0.4 g, 10.5 mmol). Yield: 0.27 g. Mass spectrum: m / z (relative intensity, 70 eV) 312 (M +, main peak), 311 (33), 297 (93), 146 (36), 110 (32).

Getting 38:

1-BROM-2-fluoro-3 - [(trifluoromethyl) thio] benzene

1-Bromo-3 - [(3-bromo-2-fluorophenyl) dithio] -2-fluorobenzene (1.23 g, 2.98 mmol) was dissolved in anhydrous tetrahydrofuran (40 ml) and trifluoromethyltrimethylsilane (2M in THF). The solution was cooled to −10 ° C. and tris (dimethylamino) sulfur (trimethylsilyl) difluoride (3 ml, 6.0 mmol) was added portionwise. The mixture was warmed to room temperature and stirred for 12 hours. Water (50 ml) and ethyl acetate (50 ml) were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2 × 50 ml) and the combined organic phases were dried (MgSO ₄ ) and evaporated under reduced pressure to give an oil. The residue was purified by flash column chromatography (isooctane / ethyl acetate, 1: 1) to obtain the title compound (0.45 g). Mass spectrum: m / z (relative intensity, 70 eV) 276 (M +, 62), 274 (M +, 58), 207 (35), 205 (31), 126 (main peak).

Getting 39:

1-BROM-2-fluorine-3 - [(trifluoromethyl) sulfonyl] benzene

The compound was obtained in accordance with the preparation of 4: 1-bromo-2-fluoro-3 - [(trifluoromethyl) thio] benzene (0.37 g), carbon tetrachloride (4 ml), acetonitrile (4 ml), water (8 ml) , sodium periodate (0.86 g), ruthenium trichloride (1 mg). Yield: 0.3 g. Mass spectrum: m / z (relative intensity, 70 eV) 308 (M +, 18), 306 (M +, 19), 239 (57), 173 (60), 94 (main peak) .

Getting 40:

4- {2-Fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} pyridine

The compound was prepared in accordance with the preparation of 5: 1-bromo-2-fluoro-3 - [(trifluoromethyl) sulfonyl] benzene (0.3 g, 0.98 mmol), toluene (20 ml), ethanol (20 ml), 1 -pyridyl-4-boronic acid (0.16 g, 1.17 mmol), sodium carbonate (0.22 g), tetrakispalladium (0.15 g). Yield: 0.16 g. Mass spectrum: m / z (relative intensity, 70 eV) 305 (M +, main peak), 236 (64), 172 (79), 145 (35), 125 (36).

Getting 41:

4- {2-Fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine

The compound was obtained in accordance with the preparation of 9: 4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} pyridine (0.16 g, 0.53 mmol), methanol (10 ml), platinum oxide (0.02 d). Yield: 0.11 g. Mass spectrum: m / z (relative intensity, 70 eV) 311 (M +, 2), 291 (47), 164 (92), 130 (62) 69 (main peak).

Getting 42:

TRET-BUTYL-4- [2-fluoro-3- (trifluoromethyl) phenyl] -4-hydroxypiperidine-1-carboxylate

The compound was prepared in accordance with the preparation of 24: 1-bromo-2-fluoro-3- (trifluoromethyl) benzene (8.0 g, 32.9 mmol), anhydrous diethyl ether (100 ml), n-butyl lithium (2.5 M in hexane, 13 ml, 32.9 mmol), 4-boc-1-piperidone (7.8 g, 39.5 mmol). Yield: 8.5 g. Mass spectrum: m / z (relative intensity, 70 eV) 363 (M +, 2), 289 (44), 245 (28), 191 (23), 57 (main peak).

Getting 43:

4- [2-Fluoro-3- (trifluoromethyl) phenyl] -1,2,3,6-tetrahydropyridine

The compound was prepared in accordance with Preparation 31: tert-butyl-4- [2-fluoro-3- (trifluoromethyl) phenyl] -4-hydroxypiperidin-1-carboxylate (8.5 g, 23.4 mmol), polyphosphoric acid (30 ml). Yield: 4.2 g. Mass spectrum: m / z (relative intensity, 70 eV) 245 (M +, main peak), 244 (52), 177 (45), 147 (99), 82 (96).

Getting 44:

4- [2-Fluoro-3- (trifluoromethyl) phenyl] piperidine

The compound was prepared in accordance with the preparation of 18: 4- [2-fluoro-3- (trifluoromethyl) phenyl] -1,2,3,6-tetrahydropyridine (4.2 g, 17.1 mmol), methanol (20 ml), palladium-on-charcoal (0.42 g) and hydrochloric acid (0.2 ml, conc.). Yield: 1.8 g. Mass spectrum: m / z (relative intensity, 70 eV) 247 (M +, 22), 190 (8), 177 (5), 169 (7) 56 (main peak).

Getting 45:

4- [2-CHLORO-3- (METHYLSULFONIL) PHENYL] -1-Ethyl-1,2,3,6-TETRAGYDROPYRIDINE

The compound was prepared in accordance with the preparation of 6: 4- [2-chloro-3- (methylsulfonyl) phenyl] pyridine (1.77 g, 6.6 mmol), 1-iodoethane (5 ml), ethanol (40 ml), borohydride sodium (2.2 g, 58 mmol). Yield: 0.6 g. Mass spectrum: m / z (relative intensity, 70 eV) 300 (M +, 24), 299 (M +, 71), 298 (33), 284 (main peak), 110 (74) .

Getting 46:

1- (BENZYLOXY) -3-BROM-2-fluorobenzene

To a solution of 3-bromo-2-fluorophenol (1.8 g, 9.42 mmol) in acetone (25 ml) was added sodium carbonate (2.55 g, 20 mmol) and the mixture was stirred for 5 minutes. Benzyl bromide (1.2 ml, 10.3 mmol) was added and the reaction mixture was heated at the boil under reflux for 20 hours. Water (50 ml) and ethyl acetate (50 ml) were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2 × 50 ml) and the combined organic phases were dried (MgSO ₄ ) and evaporated under reduced pressure to give an oil. The residue was purified by flash column chromatography (isooctane / ethyl acetate, 5: 1) to obtain the title compound (2.8 g). Mass spectrum: m / z (relative intensity, 70 eV) 282 (M +, 2), 280 (M +, 2), 163 (2), 161 (2), 91 (main peak).

Getting 47:

4- [3- (Benzyloxy) -2-fluorophenyl] -1-ethylpiperidine-4-ol

The compound was prepared in accordance with the preparation of 1: 1- (benzyloxy) -3-bromo-2-fluorobenzene (2.8 g, 9.96 mmol), anhydrous diethyl ether (100 ml), n-butyllithium (2.5 M in hexane, 5.2 ml, 9.9 mmol), 4-ethyl-1-piperidone (1.5 ml, 10.9 mmol). Yield: 2.1 g. Mass spectrum: m / z (relative intensity, 70 eV) 329 (M +, 30), 314 (56), 296 (20), 238 (59), 91 (main peak).

Getting 48:

3- (1-Ethyl-1,2,3,6-tetrahydropyridin-4-yl) -2-fluorophenol

The compound was prepared in accordance with the preparation of 2: 4- [3- (benzyloxy) -2-fluorophenyl] -1-ethylpiperidin-4-ol (1.9 g, 5.77 mmol), trifluoroacetic acid (5 ml). Yield: 1.1 g. Mass spectrum: m / z (relative intensity, 70 eV) 221 (M +, main peak), 220 (43), 206 (95), 163 (10), 110 (14).

Getting 49:

3- (1-Ethylpiperidine-4-yl) -2-fluorophenol

The compound was obtained in accordance with the preparation of 18: 3- (1-ethyl-1,2,3,6-tetrahydropyridin-4-yl) -2-fluorophenol (1.1 g, 4.97 mmol), methanol (20 ml) , palladium-on-charcoal (0.26 g) and hydrochloric acid (0.2 ml, conc.). Yield: 1.1 g. Mass spectrum: m / z (relative intensity, 70 eV) 223 (M +, 32), 222 (17), 209 (13), 208 (main peak) 84 (20).

Getting 50:

3-Trimethylsilyl-2-fluorobromobenzene

To a solution of 1-bromo-2-fluorobenzene (2.0 g, 11.42 mmol) and trimethylsilyl chloride (5.79 ml, 45.69 mmol) in anhydrous tetrahydrofuran (30 ml) at -78 ° C under nitrogen was added drops of lithium diisopropylamide (2 M in hexane, 28 ml, 12.56 mmol). The mixture was stirred for 1 hour and then the temperature was brought to ambient temperature. 10% hydrochloric acid (100 ml) was added and the mixture was extracted with ethyl acetate (3 × 100 ml). The combined organic phases were dried (MgSO ₄ ), filtered and evaporated to dryness. The oily residue was purified by flash column chromatography (ethyl acetate / isooctane, 1: 1) to obtain the title compound (2.3 g). Mass spectrum: m / z (relative intensity, 70 eV) 248 (M +, 22), 246 (20), 151 (96), 105 (main peak), 75 (64).

Getting 51:

1- (3-BROMO-2-fluorophenyl) ethanone

Aluminum trichloride (1.51 g, 11.3 mmol) in anhydrous methylene chloride (10 ml) was cooled to 0 ° C and acetyl chloride (0.80 ml, 11.3 mmol) was added in one portion. The mixture was stirred for 15 minutes, after which a solution of 3-trimethylsilyl-2-fluorobromobenzene (2.33 g, 9.4 mmol) in anhydrous methylene chloride (10 ml) was added dropwise. The mixture was warmed to ambient temperature and stirred for 2 hours. The temperature of the mixture was maintained at ambient temperature in a water bath, and aqueous sodium carbonate (10%, 50 ml) was slowly added. The aqueous phase was extracted with ethyl acetate (2 × 50 ml) and the combined organic phase was dried (MgSO ₄ ), filtered and evaporated. Purification by flash chromatography (ethyl acetate / isooctane, 1: 1) gave the title compound (1.7 g). Mass spectrum: m / z (relative intensity, 70 eV) 218 (M +, 32), 216 (M +, 34), 203 (main peak), 201 (97), 94 (61).

Getting 52:

1- (2-fluoro-3-pyridin-4-ylphenyl) ethanone

The compound was prepared in accordance with the preparation of 5: 1- (3-bromo-2-fluorophenyl) ethanone (2.18 g, 10.0 mmol), toluene (20 ml), ethanol (20 ml), 1-pyridyl-4- boronic acid (1.35 g, 11.0 mmol), sodium carbonate (2.65 g), tetrakispalladium (0.9 g). Yield: 1.14 g. Mass spectrum: m / z (relative intensity, 70 eV) 215 (M +, 35), 201 (12), 200 (main peak), 171 (18), 125 (14).

Getting 53:

4- [2-Fluoro-3- (2-methyl-1,3-dioxolan-2-yl) phenyl] pyridine

A mixture of 1- (2-fluoro-3-pyridin-4-ylphenyl) ethanone (1.28 g, 5.95 mmol), ethylene glycol (1.66 ml, 29.75 mmol), molecular sieves (5 g, 3Å) and p-toluenesulfonic acid monohydrate (0.11 g, 0.59 mmol) in toluene (20 ml) was heated at the boil under reflux for 2 hours. The molecular sieves were filtered off and the residue was evaporated to dryness. Purification by flash column chromatography (ethyl acetate) gave the title compound (1.0 g). Mass spectrum: m / z (relative intensity, 70 eV) 259 (M +, 1), 245 (15), 244 (main peak), 200 (56), 87 (17).

Getting 54:

1-Ethyl-4- [2-fluoro-3- (2-methyl-1,3-dioxolan-2-yl) phenyl] -1,2,3,6-tetrahydropyridine

The compound was prepared in accordance with the preparation of 6: 4- [2-fluoro-3- (2-methyl-1,3-dioxolan-2-yl) phenyl] pyridine (0.95 g, 3.66 mmol), 1-iodoethane (4 ml), ethanol (40 ml), sodium borohydride (1.0 g, 29.3 mmol). Yield: 0.88 g. Mass spectrum: m / z (relative intensity, 70 eV) 291 (M +, main peak), 276 (94), 219 (29), 110 (46), 87 (29).

Getting 55:

1-Ethyl-4- [2-fluoro-3- (2-methyl-1,3-dioxolan-2-yl) phenyl] piperidine

The compound was prepared in accordance with the preparation of 18: 1-ethyl-4- (2-fluoro-3- (2-methyl-1,3-dioxolan-2-yl) phenyl] -1,2,3,6-tetrahydropyridine (0 , 73 g, 2.5 mmol), methanol (20 ml), palladium-on-charcoal (0.32 g) and hydrochloric acid (0.2 ml, conc.). Yield: 0.7 g. Mass spectrum : m / z (relative intensity, 70 eV) 293 (M +, 23), 292 (12), 279 (15), 278 (main peak), 84 (16).

Getting 56:

3-BROMO-2-FLUORBENZOIC ACID

To a solution of 1-bromo-2-fluorobenzene (6.0 g, 34.3 mmol) in anhydrous tetrahydrofuran (50 ml) in a nitrogen atmosphere at -78 ° C was added lithium diisopropylamide (2.5 M in hexane, 18.8 ml 37.7 mmol). The mixture was stirred for 50 minutes and then poured onto crushed hard dry ice (solid carbon dioxide). The temperature of the reaction mixture was brought to ambient temperature and aqueous sodium carbonate (10%, 50 ml) was added. The aqueous phase was washed with diethyl ether (2 × 100 ml) and then acidified by the addition of aqueous hydrochloric acid. The acidified aqueous phase was extracted with ethyl acetate (2 × 50 ml), the combined organic phases were dried (MgSO ₄ ) and evaporated to dryness to give the title compound (4.24 g).

Getting 57:

3-BROMO-2-fluorobenzamide

To a solution of 3-bromo-2-fluorobenzoic acid (3.77 g, 17.2 mmol) in anhydrous tetrahydrofuran (200 ml) was added triethylamine (4.77 ml, 34.4 mmol) and thionyl chloride (1.69 ml, 21.5 mmol). The reaction mixture was stirred for 1 hour and then quenched with ammonia in methanol (10 ml, saturated solution). After further stirring for one hour, the mixture was evaporated, and the crude product was purified by flash column chromatography (ethyl acetate / isooctane 1: 1) to obtain the title compound (1.76 g). Mass spectrum: m / z (relative intensity, 70 eV) 219 (M +, 26), 217 (M +, 26), 203 (62), 201 (70), 94 (main peak).

Getting 58:

2-FLUOR-3-PYRIDIN-4-ILBENZAMIDE

Preparation in accordance with the preparation of 5: 3-bromo-2-fluorobenzamide (1.2 g, 5.5 mmol), toluene (20 ml), ethanol (20 ml), 1-pyridyl-4-boronic acid (0.74 g, 6.05 mmol), sodium carbonate (2.65 g), tetrakispalladium (0.57 g). Yield: 0.47 g. Mass spectrum: m / z (relative intensity, 70 eV) 216 (M +, 76), 200 (main peak), 172 (20), 145 (18), 125 (19).

Getting 59:

3- (1-Ethyl-1,2,3,6-tetrahydropyridin-4-yl) -2-fluorobenzamide

The compound was prepared in accordance with the preparation of 6: 2-fluoro-3-pyridin-4-ylbenzamide (0.94 g, 4.34 mmol), 1-iodoethane (3 ml), ethanol (40 ml), sodium borohydride (1, 25 g, 34.8 mmol). Yield: 0.75 g. Mass spectrum: m / z (relative intensity, 70 eV) 248 (M +, main peak), 247 (37), 233 (99), 146 (22), 110 (41).

Getting 60:

3- (1-Ethylpiperidine-4-yl) -2-fluorobenzamide

The compound was obtained in accordance with the preparation of 18: 3- (1-ethyl-1,2,3,6-tetrahydropyridin-4-yl) -2-fluorobenzamide (0.75 g, 3.0 mmol), methanol (20 ml) , palladium-on-charcoal (0.2 g) and hydrochloric acid (0.2 ml, conc.). Yield: 0.57 g. Mass spectrum: m / z (relative intensity, 70 eV) 250 (M +, 48), 249 (26), 236 (34), 235 (main peak), 109 (30).

Getting 61:

2-PIPERIDIN-4-IL-6- (trifluoromethyl) phenol

The compound was prepared according to Example 29: 4- [2-methoxy-3- (trifluoromethyl) phenyl] piperidine (0.07 g, 0.27 mmol), pyridine hydrochloride (0.4 g). Yield: 0.05 g. Mass spectrum: m / z (relative intensity, 70 eV) 245 (M +, main peak), 226 (21), 167 (25), 140 (15), 56 (42).

Getting 62:

1- [2-Fluoro-3- (methylthio) phenyl] piperazine

The compound was obtained in accordance with the preparation of 22: 1-bromo-2-fluoro-3- (methylthio) benzene (2.15 g, 9.7 mmol), toluene (50 ml), piperazine (4.19 g, 48.5 mmol), potassium tert-butoxide (1.31 g, 13.6 mmol), bis (dibenzylideneacetone) palladium (0) (0.27 g, 0.064 mmol) and (+/-) - 1,1'-binaphthyl- 2,2'-diyl hydrophosphate (0.18 g, 0.064 mmol). Yield: 1.25 g. Mass spectrum: m / z (relative intensity, 70 eV) 226 (M +, 20), 191 (12), 185 (10), 184 (main peak), 168 (15).

Getting 63:

METHYL-4- [2-fluoro-3- (methylthio) phenyl] piperazine-1-carboxylate

The compound was obtained in accordance with the preparation of 26: 1- [2-fluoro-3- (methylthio) phenyl] piperazine (1.25 g, 5.53 mmol), triethylamine (1.2 ml, 7.2 mmol), methylene chloride (50 ml), methyl chloroformate (0.49 g, 6.6 mmol). Yield: 1.56 g. Mass spectrum: m / z (relative intensity, 70 eV) 284 (M +, 99), 196 (main peak), 184 (44), 169 (54), 56 (60).

Getting 64:

METHYL-4- [2-fluorine-3- (methylsulfonyl) phenyl] piperazine-1-carboxylate

To a ice-cooled solution of methyl 4- [2-fluoro-3- (methylthio) phenyl] piperazine-1-carboxylate (1.4 g, 4.9 mmol) in sulfuric acid (1 M, 10 ml) was added sodium tungstate ( 0.016 g, 0.05 mmol) in one portion, followed by dropwise addition of hydrogen peroxide (30%, 1.25 ml, 12.2 mmol). The reaction mixture was heated to 55 ° C and stirred for 20 hours. The temperature of the reaction mixture was brought to ambient temperature and an aqueous solution of sodium hydroxide (5 M, 50 ml) was added. The aqueous phase was extracted with ethyl acetate (2 × 50 ml). The combined organic phase was dried (MgSO ₄ ) and evaporated to dryness to afford the title compound. Yield (1.1 g). Mass spectrum: m / z (relative intensity, 70 eV) 316 (M +, 58), 296 (30), 228 (main peak), 216 (38), 56 (71).

Getting 65:

1- [2-fluoro-3- (methylsulfonyl) phenyl] piperazine

The compound was prepared according to Preparation 29: methyl 4- [2-fluoro-3- (methylsulfonyl) phenyl] piperazine-1-carboxylate (1.0 g, 3.16 mmol) in ethanol (8 ml), hydrochloric acid ( 6 M, 20 ml). Yield: 0.34 g. Mass spectrum: m / z (relative intensity, 70 eV) 258 (M +, 17), 215 (13), 216 (main peak), 209 (6), 137 (9).

Getting 66:

4- [2-METHOXY-3- (TRIFTORMETOXY) Phenyl] Piperidine

The compound was obtained in accordance with the preparation of 34: 4- [2-fluoro-3- (trifluoromethoxy) phenyl] piperidine (1.23 g, 4.7 mmol), N, N-dimethylformamide (20 ml), sodium methoxide in methanol ( 30%, 2.35 ml, 13.2 mmol). Yield: 1.32 g.

Getting 67:

2-PIPERIDIN-4-IL-6- (TRIFTORMETOXY) Phenol

The compound was prepared according to Example 29: 4- [2-methoxy-3- (trifluoromethoxy) phenyl] piperidine (1.31 g, 4.7 mmol), pyridine hydrochloride (4 g). Yield: 0.5 g. Mass spectrum: m / z (relative intensity, 70 eV) 261 (M +, main peak), 260 (31), 244 (11), 215 (6), 56 (93).

Getting 68:

1- (2-Fluoro-3-piperidine-4-ylphenyl) ethanone

The compound was prepared in accordance with the preparation of 9: 1- (2-fluoro-3-pyridin-4-ylphenyl) ethanone (0.2 g, 0.93 mmol), hydrochloric acid (0.05 ml, conc.), Methanol ( 5 ml), platinum oxide (0.02 g). Yield: 0.2 g. Mass spectrum: m / z (relative intensity, 70 eV) 221 (M +, 25), 220 (37), 178 (96), 149 (41) 101 (20).

Getting 69:

1- (3-BROMO-2-fluorophenyl) -2,2,2-trifluoroethanone

To a solution of 1-bromo-2-fluorobenzene (5.0 g, 28.6 mmol) in anhydrous tetrahydrofuran (50 ml) in a nitrogen atmosphere at -78 ° C was added lithium diisopropylamide (2.0 M in hexane, 15.7 ml 31.4 mmol). The mixture was stirred for 5 minutes, after which ethyl trifluoroacetate (3.76 ml, 31.4 mmol) was added and stirring was continued at -78 ° C for another hour. The temperature of the reaction mixture was brought to ambient temperature and water (50 ml) was added. The phases were separated and the aqueous phase was extracted with ethyl acetate (3 × 100 ml). The combined organic phases were dried (MgSO ₄ ) and evaporated to dryness to give an oil. The residue was purified by flash column chromatography (isooctane) to give the title compound (2.38 g). Mass spectrum: m / z (relative intensity, 70 eV) 272 (M +, 11), 270 (M +, 11), 203 (97), 201 (main peak), 173 (46).

Getting 70:

2,2,2-TRIFTOR-1- (2-fluoro-3-pyridin-4-ylphenyl) ethanone

The compound was prepared in accordance with the preparation of 5: 1- (3-bromo-2-fluorophenyl) -2,2,2-trifluoroethanone (2.38 g, 8.78 mmol), toluene (40 ml), ethanol (40 ml) , 1-pyridyl-4-boronic acid (1.43 g, 10.5 mmol), sodium carbonate (2.0 g), tetrakispalladium (1.38 g, 0.88 mmol). Yield: 1.36 g. Mass spectrum: m / z (relative intensity, 70 eV) 269 (M +, 43), 200 (main peak), 172 (22), 145 (18), 125 (22).

Getting 71:

2,2,2-TRIFTOR-1- (2-fluoro-3-piperidine-4-ylphenyl) ethanone

The compound was obtained in accordance with the preparation of 9: 2,2,2-trifluoro-1- (2-fluoro-3-pyridin-4-ylphenyl) ethanone (1.26 g, 4.68 mmol), hydrochloric acid (0.2 ml, conc.), methanol (20 ml), platinum oxide (0.12 g). Yield: 0.98 g. Mass spectrum: m / z (relative intensity, 70 eV) 275 (M +, 94), 274 (66), 149 (23), 101 (25) 56 (main peak).

Getting 72:

2,2,2-TRIFTOR-1- (2-fluoro-3-piperidine-4-ylphenyl) ethanol

2,2,2-trifluoro-1- (2-fluoro-3-piperidin-4-ylphenyl) ethanone (0.045 g, 0.16 mmol) was dissolved in ethanol (10 ml) and sodium borohydride (0.026 g, 0.064 mmol) was added. ) The resulting mixture was stirred for 24 hours, after which an aqueous solution of sodium carbonate (10%, 20 ml) was added. The aqueous phase was extracted with ethyl acetate (3 × 20 ml) and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated to dryness. Yield: 0.03 g. Mass spectrum: m / z (relative intensity, 70 eV) 277 (M +, 87), 276 (69), 178 (14), 103 (19), 56 (main peak).

Getting 73:

2-Fluoro-3-piperidine-4-ylphenylmethanesulfonate

3- (1-ethylpiperidin-4-yl) -2-fluorophenylmethanesulfonate (0.020 g, 0.033 mmol) was dissolved in anhydrous 1,2-dichloroethane (5 ml) and α-chloroethyl chloroformate (0.014 ml, 0.033 mmol) was added. The resulting mixture was heated at the boil under reflux for 1 hour, and the solvent was evaporated. Mass spectrum: m / z (relative intensity, 70 eV) 273 (M +, 2), 195 (11), 194 (main peak), 178 (5), 56 (60).

Getting 74:

1-Ethyl-4- [2-fluoro-3- (methylthio) phenyl] piperidine-4-ol

The compound was prepared according to Preparation 1 except that n-hexillithium was used instead of n-butyllithium: 1-bromo-2-fluoro-3- (methylthio) benzene (15 g, 67.8 mmol), anhydrous tetrahydrofuran (70 ml ), n-hexyllithium (2.3 M in hexane, 31 ml, 71 mmol), 1-ethylpiperidin-4-one (9.06 g, 71 mmol). Yield: 20.7 g. Mass spectrum: m / z (relative intensity, 70 eV) 269 (M +, 49), 254 (main peak), 236 (36), 56 (31), 84 (23).

Getting 75:

1-Ethyl-4- [2-fluorine-3- (methylthio) phenyl] -1,2,3,6-tetrahydropyridine

A mixture of 1-ethyl-4- [2-fluoro-3- (methylthio) phenyl] piperidin-4-ol (42 g, 156 mmol), sulfuric acid (conc., 8.5 ml) and toluene (200 ml) was heated with a Dean Stark trap for 20 hours. The mixture was cooled to 70 ° C, water (200 ml) was added and the phases were separated. The aqueous phase was made basic with an aqueous solution of sodium hydroxide (5 M) and extracted with ethyl acetate (2 × 50 ml). The combined organic phases were dried (MgSO ₄ ) and evaporated to dryness to afford the title compound (22.6 g). Mass spectrum: m / z (relative intensity, 70 eV) 251 (M +, main peak), 236 (85), 147 (65), 146 (45), 110 (44).

Getting 76:

1-Ethyl-4- [2-fluorine-3- (methylsulfonyl) phenyl] -1,2,3,6-tetrahydropyridine

The compound was prepared in accordance with the preparation of 64: 1-ethyl-4- [2-fluoro-3- (methylthio) phenyl] -1,2,3,6-tetrahydropyridine (22.5 g, 89.6 mmol), sulfuric acid (1 M, 180 ml), sodium tungstate (0.296 g, 0.89 mmol), hydrogen peroxide (30%, 22.9 ml, 224 mmol). Flash column chromatography (ethyl acetate / methanol, 1: 1) gave the title compound (17.2 g). Mass spectrum: m / z (relative intensity, 70 eV) 283 (M +, 63), 268 (main peak), 146 (51), 110 (87), 56 (59).

Getting 77:

1-Ethyl-4- [2-fluoro-3- (methylsulfinyl) phenyl] -1,2,3,6-tetrahydropyridine

Flash column chromatography (ethyl acetate / methanol, 1: 1) of the reaction mixture of Preparation 76 afforded the title compound (150 mg). Mass spectrum: m / z (relative intensity, 70 eV) 267 (M +, main peak), 252 (87), 237 (74), 146 (43), 110 (43).

Getting 78:

4- [2-Fluoro-3- (trifluoromethyl) phenyl] -1-propyl-1,2,3,6-tetrahydropyridine

A solution of 4- [2-fluoro-3- (trifluoromethyl) phenyl] -1-propylpiperidin-4-ol (8.0 g, 26 mmol) in trifluoroacetic acid (80 ml) was heated at the boil under reflux for 20 hours. The mixture was poured onto ice and made basic with 10M sodium hydroxide solution. The mixture was extracted with ethyl acetate (3 × 100 ml) and the combined organic phases were dried (MgSO ₄ ), filtered and evaporated to dryness. The residue was purified by flash column chromatography (ethyl acetate / methanol, 1: 1) to obtain the title compound (5.6 g). Mass spectrum: m / z (relative intensity, 70 eV) 287 (M +, 22), 259 (16), 258 (main peak), 177 (10), 147 (10).

Getting 79:

4- [2-Fluoro-3- (trifluoromethyl) phenyl] -1-propylpiperidine-4-ol

To a solution of 3-bromo-2-fluorobenzotrifluoride (9.0 g, 37 mmol) in anhydrous tetrahydrofuran (100 ml) in a nitrogen atmosphere was added dropwise at -78 ° C n-butyllithium (2.5 M in hexane, 16.2 ml, 40.5 mmol). The mixture was stirred for 1 hour, after which a solution of freshly distilled 4-propyl-1-piperidone (5.2 g, 37 mmol) in anhydrous tetrahydrofuran (50 ml) was added dropwise. The resulting mixture was stirred at -78 ° C for 30 minutes, and then the temperature was brought to ambient temperature. Water (100 ml) was added and the mixture was extracted with ethyl acetate (3 × 100 ml). The combined organic phases were dried (MgSO ₄ ), filtered and evaporated to dryness. The oily residue was purified by flash column chromatography (ethyl acetate / methanol, 1: 1) to obtain the title compound (8.0 g). Mass spectrum: m / z (relative intensity, 70 eV) 305 (M +, 5), 276 (main peak), 258 (35), 191 (21), 185 (17).

The following tests were used to evaluate the compounds of the invention.

In vivo test: behavior

Behavioral activity was measured using eight Digiscan activity monitors (RXYZM (16) TAO, Omnitech Electronics, Columbus, OH, USA) connected to an Omnitech Digiscan analyzer and an Apple Macintosh computer equipped with a digital interface (NB DIO-24, National Instruments, USA). Each monitor for determining activity consisted of a square metal frame (W × D = 40cm × 40cm), equipped with sensor sensors for photo emission. During measurements of behavioral activity, the rat was placed in a transparent acrylic cage (W × D × H = 40 × 40 × 30 cm), which in turn was placed in a monitor to determine activity. For monitoring activity, each monitor was equipped with three rows of infrared sensor sensors; each row consisted of 16 sensor sensors. Two rows were placed along the front and side of the cell floor with an angle of 90 °, and the third row was placed at a height of 10 cm above the floor to measure vertical activity. Sensors of photoelectric radiation were placed at a distance of 2.5 cm. Each of the monitors for measuring activity was installed in the same boxes, softening sounds and light with weak daylight and a fan.

Computer software was written using task-oriented programming (LabVIEW®, National instruments, Austin, TX, USA).

Behavioral data for each monitor to determine activity, representing the position (horizontal for the center of gravity and vertical activity) of the animal at each time point, was recorded at a sampling frequency of 25 Hz and collected using a specially written LabVIEW® application. Data for each registration session was stored and analyzed relative to the distance traveled. Each behavior assessment session lasted 60 minutes, starting approximately 4 minutes after the injection of the test compound. The same behavioral registration procedures were performed for untreated rats and for rats pretreated with the drug. Rats that were pretreated with d-amphetamine were given a dose of 1.5 mg / kg, ip, 10 minutes before registration in the monitor to determine activity. Rats that were previously treated with MK-801 were given a dose of 0.7 mg / kg, intraperitoneally, 90 minutes before registration in the monitor to determine activity. The results are presented as totals / 60 minutes or totals / 30 minutes in arbitrary units of length. Statistical comparisons were made using Student's t-test relative to the control group. In animals pretreated with MK-801 or amphetamine, statistical comparisons were made with respect to the control treated with MK-801 or amphetamine, respectively.

The ED ₅₀ values for decreasing amphetamine-induced hypermotor activity were calculated by plotting experimental curves on the points. For most compounds, the estimate is based on 16 pretreated amphetamine-treated animals in a dosage range of 0, 11, 33, and 100 μmol / kg, subcutaneously, in the same experiment with additional doses in separate experiments. Calculations are based on distance during the last 45 minutes from measurements in one hour. The distances were normalized to the amphetamine control and selected by the least square method to the function “End- (End-Control) / (1+ (dose / ED ₅₀ ) ^slope )”. Four parameters were selected with restrictions: ED ₅₀ > 0, 0.5 <slope <3, end> 0% control. To assess the level of confidence for the parameters, the graph was repeated 100 times with statistically uniformly distributed weight squares for each measured value. The ED ₅₀ ranges presented cover 95% of these values.

In vivo test: neurochemistry

After determining the behavioral activity of the rats, they were decapitated, their brain was quickly removed and placed on ice-cooled Petri dishes. The limbic forebrain, striatum, anterior cortex and the remaining hemispherical parts of the brain of each rat were excised and frozen. Each part of the brain was subsequently analyzed for the content of monoamines and their metabolites in it.

The content of substances - monoamine transmitters (NA (norepinephrine), DA (dopamine), 5-HT (serotonin)), and also their metabolites - amines (NM (normetanfrin), 3-MT (3-methoxy tyramine) were quantified in the homogenates of brain tissue ) and acids (DOPAC (3,4-dihydroxyphenylacetic acid), 5-HIAA (5-hydroxyindoleacetic acid), HVA (homovanilic acid)) by HPLC separation and electrochemical detection.

The analytical method is based on two chromatographic separations intended for amines or acids. For two chromatographic systems, there is one joint auto-injector with a 10-port valve and two sample loops for simultaneous insertion into two systems. Both systems are equipped with a reverse phase column (Luna C18 (2), diameter 3 μm, 50 * 2mm i.d., Phenomenex), and electrochemical detection is carried out at two potentials on polished carbon electrodes (MF-1000, Bioanalytical Systems, Inc.). The effluent from the column is passed through the T-shape connection to the detection cell or to the discharge outlet. This is accomplished using two solenoid valves that block either the discharge outlet or the detector output. By preventing the detector from reaching the chromatographic front, better detection conditions are achieved. The aqueous mobile phase (0.4 ml / min) for the acidic system contains citric acid 14 mM, sodium citrate 10 mM, MeOH 15% (v / v) and EDTA 0.1 mM. The detection potentials relative to the Ag / AgCl reference electrode are 0.45 and 0.65V.

The ED ₅₀ values for increasing DOPAC in the striatum were calculated by plotting experimental curves on the points. For most compounds, the estimate is based on 20 animals in a dosage range of 0, 3.7, 11, 33 and 100 μmol / kg, subcutaneously, in one experiment. DOPAC levels were normalized to control and selected using the least squares method to the function "End- (End-Control) / (1+ (dose / ED ₅₀ ) ^slope )". Four parameters were selected with restrictions: ED ₅₀ > 0, 0.5 <slope <3, 350 <end <400 or End = 200% of the control (see table 1). To assess the level of confidence for the parameters, the graph was repeated 100 times with statistically uniformly distributed weight squares for each measured value. The ED ₅₀ ranges presented cover 95% of these values.

In vivo test: oral bioavailability

The experiments were performed 24 hours after implantation of arterial and venous catheters. Test compounds were administered orally at a dose of 12.5 μmol / kg or intravenously at a dose of 5 μmol / kg using venous catheters, n = 3 per group. Arterial blood samples were then taken for six hours at time points 0, 3, 9, 27, 60, 120, 180, 240, 300 and 360 minutes after administration of the test compound. Oral bioavailability was calculated as the ratio of AUC (area under the curve) obtained after oral administration to AUC obtained after intravenous administration for each rat. The AUC parameter was calculated in accordance with the following: AUC: area under the plasma concentration curve relative to the time curve from time zero to the time of the last concentration measurement (Clast) calculated using the log / trapezoidal line method.

Test compound levels were measured by liquid chromatography mass spectrometry (Hewlett-Packard 1100MSD Series). The LC-MS module includes a four-part pump system, a vacuum degasser, a thermostatically controlled autosampler for feeding samples, a thermostatically controlled column compartment, a diode array detector, and an API-ES electrospray. Data processing was performed using the HP ChemStation rev. A.06.03. Instrument Settings: MDS Method: Selected Ion Polarity Monitoring (SIM): Positive. Gas temperature: 350 ° C. Drying gas: 13.0 l / min. Atomizing gas: 50 ft. / Sq. Inch, capillary voltage: 5000 V. Fragmentation voltage: 70V. Analytical column: Zorbax eclipse XDB-C8 (4.6 · 150 mm, 5 μm) at 20 ° C. The mobile phase was acetic acid (0.03%) (solvent A) and acetonitrile (solvent B). The flow rate of the mobile phase was 0.8 ml / min. Elution was started at 12% solvent B with a constant composition of the eluent for 4.5 minutes, then the concentration was linearly increased to 60% over 4.5 minutes.

Method of extraction: Blood plasma samples (0.25-0.5 ml) were diluted with water to 1 ml and 60 pmol (100 μmol) of internal standard (-) - OSU6241 was added. The pH was adjusted to 11 by adding 25 μl of a saturated solution of Na ₂ CO ₃ . After stirring, the samples were extracted with 4 ml of dichloromethane, shaking for 20 minutes. The organic layer after centrifugation was transferred to a test tube of a smaller volume and evaporated to dryness in a stream of nitrogen. The residue was then dissolved in 120 μl of the mobile phase (acetic acid (0.03%): acetonitrile, 95: 5) for LC-MS analysis (10 μl injection). The selected ion (MH ⁺ ) was monitored for each sample and MH ⁺ was 296 for (-) - OSU6241 ((3- [3- (ethylsulfonyl) phenyl] -1-propylpiperidine). A standard curve was obtained in the range of 1-500 pmol by adding suitable amounts of the test compound in "empty" blood plasma samples.

In vitro test: metabolic stability in rat liver microsomes

Rat liver microsomes were isolated as described by Förlin (1980) Tox Appl Pharm. 54 (3) 420-430, with minor modifications, for example, 3 ml / g of liver were added before homogenization with 0.1 M Na / K * PO ₄ buffers with 0.15 M KCl, pH 7.4 (buffer 1), the homogenate was centrifuged for 20 minutes instead of 15, the supernatant was ultracentrifuged at 100,000 g instead of 105,000 g, and the pellet after ultracentrifugation was resuspended at the rate of 1 ml / g of liver in 20% v / v. 87% glycerol in buffer 1.

1 μl of 0.2 or 1 mM of the test substance diluted in water and 10 μl of 20 mg / ml rat liver microsomes were mixed with 149 μl of buffer 1 at 37 ° C and the reaction was started by adding 40 μl of 4.1 mg / ml NADPH. After incubation for 0 or 15 minutes at 37 ° C in a thermal block (LAB-LINE, MULTI-BLOK heater or lab4you, TS-100 thermal shaker at 700 rpm), the reaction was stopped by adding 100 μl of pure acetonitrile. The protein precipitate was then removed by discarding the precipitate after centrifugation at 10,000 g for 10 minutes (Heraeus, Biofuge fresco) at 4 ° C. The test compound was analyzed using HPLC-Mass spectrometry (Hewlett-Packard 1100MSD Series) on a Zorbax SB-C18 column (2.1 × 150 mm, 5 μm) using 0.03% formic acid and acetonitrile as the mobile phase (gradient ) or on a Zorbax Eclipse XDB-C18 column (3 × 75 mm, 3.5 μm) using 0.03% acetic acid and acetonitrile as the mobile phase (gradient). A 15-minute revolution was calculated as the fraction of the test compound withdrawn after 15 minutes, expressed as a percentage of 0 minutes, i.e. 100 · [concentration of test compound at 0 minutes — concentration at 15 minutes / concentration at 0 minutes.

The preparation of rat liver microsomes was performed as described by Forlin (1980). Protocols for incubation with rat liver microsomes are mentioned in publications by Crespi et Stresser (2000), and Renwick et al (2001).

References

Crespi C. L., and D. M Stressser (2000). Fluorometric screening for metabolism based drug-drug interactions. J. Pharm. Tox. Meth. 44, 325-331

Forlin L. (1980) Effects of Clophen A50, 3-methylcholantrene, pregnenolone-16aq-carbonitrile and Phenobarbital on the hepatic microsomal cytochrome P-450-dependent monooxygenaser system in rainbow trout, salmo gairdneri, of different age and sex. Tox Appl Pharm. 54 (3), 420-430.

Renwick, A.B et al. (2001). Metabolism of 2,5-bis (trifluoromethyl) -7-benzyloxy-4-trifluoromethylcoumarin by human hepatic CYP isoforms: evidence for selectivity towards CYP3A4. Xenobiotica 31 (4): 187-204.

Calculation of CloqP Values

The calculated values of the octanol / water distribution constants (ClogP values) were calculated for the compounds of the invention using the Bio-Loom program for Windows software, version 1.0 from BioByte Corporation (www.biobvte.com) using the SMILES representations of structures as input. ClogP values for selected compounds of the invention are given below (Table 6).

Table 6
ClogP Values for Selected Compounds of the Invention Example Clogp one 2.47 2 1.95 3 3.04 four 2.66 7 4.3 9 4.6 10 3.73 eleven 4.75 17 1,6

Calculations of van der Waals volumes (V (vdW)) for substituents R1 and R2

The volume of each substituent was calculated as the difference between the volume of its monosubstituted phenyl and the volume of benzene [V (vdW) subst. = V (vdW) substitution-Ph - V (vdW) Ph]. Volume calculations were performed using geometry obtained by minimizing energy using the Merck molecular force field (mmff94) in the Molecular Operating Environment (MOE) software 2004.03 Chemical Computing Group's (www.chemcomp.com). Selected van der Waals volumes are shown in table 7.

Table 7
Selected calculated van der Waals volumes of functional groups according to isoberetium. title structure Deputy Volume title structure Deputy Volume SCN

39,656255 COME

35,437505 OSOM

43.031255 COCF ₃

43,875005 Scome

51,890625 OSO ₂ CF ₃

62,437505 SCOCF ₃

64,125005 OSO ₂ Me

55,265625 OCOCF ₃

52,312505 CF ₃

27,000005 CH ₂ CN

32,062505 OCF ₃

32,906255 CH ₂ CF ₃

41,343755 OCHF ₂

30,375005 CH ₂ SO ₂ Me

59,062505 CN

18.984375 CH ₂ SO ₂ CF3

72,562505 F

2,953125 CH ₂ COMe

48,515625 Cl

15,187505 CH ₂ NO ₂

35,437505 SO ₂ NMe ₂

76,359375 CH (0H) CF3

47.250005 IT

3.796875 CH (OH) Me

38,812505 OMe

22,359375 NSO ₂ CF ₃

64,968755 Me

17,718755 NS0 ₂ Me

51,468755 NH ₂

9.281255 S0 ₂ Me

44.296875 SO ₂ NH ₂

37.546875 SO ₂ CF ₃

53,156255 SO ₂ CN

42.609375 N

0

References

Crespi C. L., and DM Stressser (2000). Fluorometric screening for metabolism based drug-drug interactions. J. Pharm. Tox. Meth. 44, 325-331

Forlin L. (1980) Effects of Clophen A50, 3-methylcholantrene, pregnenolone-16aq-carbonitrile and Phenobarbital on the hepatic microsomal cytochrome P-450-dependent monooxygenaser system in rainbow trout, salmo gairdneri, of different age and sex. Tox Appl Pharm. 54 (3), 420-420.

Renwick, AB et al. (2001). Metabolism of 2,5-bis (trifluoromethyl) -7-benzyloxy-4-trifluoromethylcoumarin by human hepatic CYP isoforms: evidence for selectivity towards CYP3A4, Xenobiotica 31 (4): 187-204.

Microdialysis

In all experiments, male Sprague-Dawley rats weighing 220-320 g were used. Before the experiment, animals were placed in groups of five animals per cage with free access to water and food. Before surgery, animals were placed at least one week after arrival and used in experiments. Each rat was used for microdialysis only once.

The authors of the present invention used a modified version (Waters, Lofberg et al. 1994) of the I-shape probe (Santiago and Westerink 1990). The dialysis membrane used was an AN69 polyacrylonitrile / sodium methyl sulfonate copolymer (HOSPAL; outer diameter / inner diameter 310/220 μm: Gambro, Lund, Sweden). For the dorsal striatum, probes with a naked length of 3 mm were used for dialysis membranes, and for the prefrontal cortex, the corresponding length was 2.5 mm. Rats were operated on with isfuran under inhalation anesthesia, which was maintained using a Kopf stereotactic device. Coordinates were calculated relative to bregma; dorsal striatum AP + 1, ML ± 2.6, DV - 6.3; prefrontal cortex, AP +3.2, 8 ° ML ± 1.2, DV - 4.0 according to (Paxinos and Watson 1986). A dialysis probe was placed in the opening of the bit under stereotactic control and fixed with phosphatin dental cement.

Animals were individually housed in cells 48 hours before the dialysis experiment, giving them the opportunity to recover from surgery and minimizing the risk of drug interaction with anesthetic drugs during the following experiments. During this period, rats had free access to food and water. On the day of the experiment, the rats were connected to the microperfusion pump through a swivel joint and placed in a cage, where they could move freely within it. The perfusion medium was a Ringer's solution containing in mmol / L: NaCl; 140, CaCl ₂ ; 1,2, KCl; 3.0, MgCl ₂ ; 1.0 and ascorbic acid; 0.04, in accordance with (Moghaddam and Bunney 1989). The pump was set at a perfusion rate of 2 μl / min and 40 μl samples were collected every 20 minutes.

30 μl of each sample was introduced into the chromatograph. On a 10-port injector (Valco C10W) with two sample loops arranged in order (2 μl and 20 μl), each brain dialysate sample was loaded into both loops simultaneously. When the valve was turned on for injection, the bulk of 20 μl of the sample was injected into a reversed-phase ion-pair system to determine dopamine (DA), norepinephrine (NA), normetanfrin (NM), 3-methoxytyramine (3-MT) and serotonin (5- hydroxytryptamine, 5-HT) (large loop), while a small fraction (2 μl, from the small loop) was injected into the reverse phase column for chromatography of acid metabolites of monoamine: 3,4-di-hydroxyphenylacetic acid (DOPAC), homovanilic acid ( HVA) and 5-hydroxyindoleacetic acid (5-HIAA). The currents generated by two EC detectors were converted to digital data and evaluated using Chromelion software (Dionex, Sunnyvale, California) on a personal computer. In this method, the rotation of the sample in time was 4.5 minutes, and two parallel experiments were analyzed together on this system. After the experiment, the rats were disconnected from the perfusion pump and decapitated. Their brains were quickly removed and fixed in Neo-fix solution (Kebo-lab, Sweden) for subsequent examination of the probe localization. The Animal Ethics Committee in Gothenburg, Sweden, approved the procedures used in these experiments.

Moghaddam, B. and B. S. Bunney (1989). "Ionic Composition of Microdialysis Perfusing Solution Alters the Pharmacological Responsiveness and Basal Outflow of Striatal Dopamine." J. Neurochem. 53: 652-654.

Paxinos, G. and C. Watson (1986). The Rat Brain in Stereotaxic Coordinates. New York, Academic Press.

Santiago, M. and B. H. C. Westerink (1990). "Characterization of the in vivo release of dopamine as recorded by different types of intracerebral microdialysis probes." Naunyn-Schmiedeberg's Arch. Pharmacol 342: 407-414.

Waters, N., L. Lofberg, S. Haadsma-Svensson, K. Svensson, C. Sonesson and A. Carlsson (1994). "Differential effects of dopamine D2 and D3 receptor antagonists in regard to dopamine release, in vivo receptor displacement and behavior." J Neural Transm Gen Sect 98 (1): 39-55.

Claims (43)

1. The compound of formula 1

where X represents N or CH;
R _{1 is} selected from the group consisting of OSO ₂ CH ₃ , SOR ₄ , SO ₂ R ₄ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , COR ₄ , CN, OCF ₃ , CF ₃ , F, Cl, Br, I, CH (OH) CF ₃ , CH ₂ SO ₂ CF ₃ , CH ₂ SO ₂ CH ₃ ,
CH ₂ CF ₃ , CH ₂ COCH ₃ , CH ₂ COFF ₃ ;
R _{2 is} selected from the group consisting of CN, CF ₃ , OH, OR ₄ , F, Cl, Br, I, CH ₃ ;
R ₃ selected from the group consisting of C ₁ -C ₄ alkyl, allyl, CH ₂ CH ₂ OCH ₃ ,
CH ₂ CH ₂ CH ₂ F, CH ₂ CH ₂ CHF ₂ , CH ₂ CH ₂ F, CH ₂ CHF ₂ , CH ₂ CF ₃ , 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl; CH ₂ CH ₂ OH, CH ₂ CH ₂ CH ₂ OH, CH ₂ CH (OH) CH ₃ , CH ₂ CH ₂ COCH ₃ ,

,

;
R ₄ selected from the group consisting of C ₁ -C ₃ alkyl, CF ₃ , CHF ₂ , CH ₂ F; with the proviso that when R ₁ is CN, OCF ₃ , CF ₃ , F or Cl, X is not CH, R _{2 is} not F, Cl, Br, CH ₃ , and R _{3 is} not C ₁ -C ₃ alkyl or allyl;
with the proviso that when R ₁ is CF ₃ or CN, X is not CH, R _{2 is} not F, Cl, Br, CH ₃ , and R _{3 is} not C ₁ -C ₂ alkyl;
provided that when X is N:
R _{1 is} not Cl when R ₂ is CH ₃ and R ₃ is
CH ₂ CH ₂ OH;
R _{1 is} not Cl when R ₂ is Cl and R ₃ is CH ₃ ;
R _{1 is} not F when R ₂ is CN and R ₃ is CH ₃ ;
R _{1 is} not Cl when R ₂ is Cl and R ₃ is CH ₂ CH ₂ CH ₂ OH;
R _{1 is} not Cl when R ₂ is Cl and R ₃ is CH ₂ CH ₂ OH;
and provided that when R ₁ is SO ₂ R ₄ , SO ₂ NH ₂ , SO ₂ NHCH ₃ or SO ₂ N (CH ₃ ) ₂ , R _{2 is} not OH,
and its pharmaceutically acceptable salts. 2. The compound according to claim 1, where R _{1 is} selected from the group consisting of OSO ₂ CH ₃ , SO ₂ CH ₃ , SO ₂ CF ₃ , COCH ₃ , COF ₃ , CH (OH) CF ₃ , CN and CF ₃ . 3. The compound according to any one of claims 1 to 2, where X represents CH. 4. The compound according to claim 3, where R ₂ selected from the group consisting of F, Cl and OH. 5. The compound according to claim 3, where R _{1 is} selected from the group consisting of OSO ₂ CH ₃ , SO ₂ CH ₃ and SO ₂ CF ₃ . 6. The compound according to claim 3, where R ₃ selected from the group consisting of n-propyl and ethyl. 7. The compound according to claim 3, where R ₂ represents F, and R ₃ selected from the group consisting of n-propyl and ethyl. 8. The compound according to claim 3, where R ₁ represents SO ₂ CH ₃ , R ₂ represents F, and R ₃ selected from the group consisting of n-propyl and ethyl. 9. The compound according to claim 3, selected from the group consisting of:
4- [3-fluoro-2- (trifluoromethyl) phenyl] -1-propylpiperidine
1-ethyl-4- (3-fluoro-2- (trifluoromethyl) phenyl] piperidine
4- [3-fluoro-2- (trifluoromethyl) phenyl] -1- (2-methoxyethyl) piperidine
1-allyl-4- [3-fluoro-2- (trifluoromethyl) phenyl] piperidine
2-fluoro-6- (1-propylpiperidin-4-yl) phenol
2- (1-ethylpiperidin-4-yl) -6-fluorophenol
2-fluoro-6- [1- (2-methoxyethyl) piperidin-4-yl] phenol
2- (1-allylpiperidin-4-yl) -6-fluorophenol
2-fluoro-6- (1-propylpiperidin-4-yl) benzonitrile
2- (1-ethylpiperidin-4-yl) -6-fluorobenzonitrile
2- (1-allylpiperidin-4-yl) -6-fluorobenzonitrile
4- [2-methyl-3- (trifluoromethyl) phenyl] -1-propylpiperidine
1-allyl-4- [2-methyl-3- (trifluoromethyl) phenyl] piperidine
4- [2-fluoro-3- (trifluoromethyl) phenyl] -1-propylpiperidine
1-allyl-4- [2-fluoro-3- (trifluoromethyl) phenyl] piperidine
2- (1-propylpiperidin-4-yl) -6- (trifluoromethyl) phenol
2- (1-ethylpiperidin-4-yl) -6- (trifluoromethyl) phenol
2- [1- (2-methoxyethyl) piperidin-4-yl] -6- (trifluoromethyl) phenol
2- (1-allylpiperidin-4-yl) -6- (trifluoromethyl) phenol
2- (1-propylpiperidin-4-yl) -6- (trifluoromethyl) benzonitrile
2- (1-ethylpiperidin-4-yl) -6- (trifluoromethyl) benzonitrile
2- (1-allylpiperidin-4-yl) -6- (trifluoromethyl) benzonitrile
4- [2-chloro-3- (trifluoromethyl) phenyl] -1-propylpiperidine
1-allyl-4- [2-chloro-3- (trifluoromethyl) phenyl] piperidine
1- [2-methyl-3- (1-propylpiperidin-4-yl) phenyl] ethanone
1- [3- (1-ethylpiperidin-4-yl) -2-methylphenyl] ethanone
1- {3- [1- (2-methoxyethyl) piperidin-4-yl] -2-methylphenyl} ethanone
1- [3- (1-allylpiperidin-4-yl) -2-methylphenyl] ethanone
1- [2-fluoro-3- (1-propylpiperidin-4-yl) phenyl] ethanone
1- [3- (1-ethylpiperidin-4-yl) -2-fluorophenyl] ethanone
1- {2-fluoro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenyl} ethanone
1- [3- (1-allylpiperidin-4-yl) -2-fluorophenyl] ethanone
2-acetyl-6- (1-propylpiperidin-4-yl) benzonitrile
2-acetyl-6- (1-ethylpiperidin-4-yl) benzonitrile
2-acetyl-6- [1- (2-methoxyethyl) piperidin-4-yl] benzonitrile
2-acetyl-6- (1-allylpiperidin-4-yl) benzonitrile
1- [2-chloro-3- (1-propylpiperidin-4-yl) phenyl] ethanone
1- [2-chloro-3- (1-ethylpiperidin-4-yl) phenyl] ethanone
1- {2-chloro-3- [4- (2-methoxyethyl) piperidin-4-yl] phenyl} ethanone
1- [3- (1-allylpiperidin-4-yl) -2-chlorophenyl] ethanone
2-methyl-3- (1-propylpiperidin-4-yl) phenylmethanesulfonate
3- (1-ethylpiperidin-4-yl) -2-methylphenylmethanesulfonate
3- [1- (2-methoxyethyl) piperidin-4-yl] -2-methylphenylmethanesulfonate
3- (1-allylpiperidin-4-yl) -2-methylphenylmethanesulfonate
2-fluoro-3- (1-propylpiperidin-4-yl) phenylmethanesulfonate
3- (1-ethylpiperidin-4-yl) -2-fluorophenylmethanesulfonate
2-fluoro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenylmethanesulfonate
3- (1-allylpiperidin-4-yl) -2-fluorophenylmethanesulfonate
2-cyano-3- (1-propylpiperidin-4-yl) phenylmethanesulfonate
2-cyano-3- (1-ethylpiperidin-4-yl) phenylmethanesulfonate
2-cyano-3- [1- (2-methoxyethyl) piperidin-4-yl] phenylmethanesulfonate
3- (1-allylpiperidin-4-yl) -2-cyanophenylmethanesulfonate
2-chloro-3- (1-propylpiperidin-4-yl) phenylmethanesulfonate
2-chloro-3- (1-ethylpiperidin-4-yl) phenylmethanesulfonate
2-chloro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenylmethanesulfonate
3- (1-allylpiperidin-4-yl) -2-chlorophenylmethanesulfonate
4- [2-methyl-3- (methylsulfonyl) phenyl] -1-propylpiperidine
1-ethyl-4- [2-methyl-3- (methylsulfonyl) phenyl] piperidine
1- (2-methoxyethyl) -4- [2-methyl-3- (methylsulfonyl) phenyl] piperidine
1-allyl-4- [2-methyl-3- (methylsulfonyl) phenyl] piperidine
4- [2-fluoro-3- (methylsulfonyl) phenyl] -1-propylpiperidine
1-ethyl-4- [2-fluoro-3- (methylsulfonyl) phenyl] piperidine
4- [2-fluoro-3- (methylsulfonyl) phenyl] -1- (2-methoxyethyl) piperidine
1-allyl-4- [2-fluoro-3- (methylsulfonyl) phenyl] piperidine
2- (methylsulfonyl) -6- (1-propylpiperidin-4-yl) benzonitrile
2- (1-ethylpiperidin-4-yl) -6- (methylsulfonyl) benzonitrile
2- [1- (2-methoxyethyl) piperidin-4-yl] -6- (methylsulfonyl) benzonitrile
2- (1-allylpiperidin-4-yl) -6- (methylsulfonyl) benzonitrile
4- [2-chloro-3- (methylsulfonyl) phenyl] -1-propylpiperidine
4- [2-chloro-3- (methylsulfonyl) phenyl] -1-ethylpiperidine
4- [2-chloro-3- (methylsulfonyl) phenyl] -1- (2-methoxyethyl) piperidine
1-allyl-4- [2-chloro-3- (methylsulfonyl) phenyl] piperidine
4- {2-methyl-3 - [(trifluoromethyl) sulfonyl] phenyl} -1-propylpiperidine
1-ethyl-4- {2-methyl-3 - [(trifluoromethyl) sulfonyl)] phenyl} piperidine
1- (2-methoxyethyl) -4- {2-methyl-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine
1-allyl-4- {2-methyl-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine
4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} -1-propylpiperidine
1-ethyl-4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine
4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} -1- (2-methoxyethyl) piperidine
1-allyl-4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine
2- (1-propylpiperidin-4-yl) -6 - [(trifluoromethyl) sulfonyl] benzonitrile
2- (1-ethylpiperidin-4-yl) -6 - [(trifluoromethyl) sulfonyl] benzonitrile
2- [1- (2-methoxyethyl) piperidin-4-yl] -6 - [(trifluoromethyl) sulfonyl] benzonitrile
2- (1-allylpiperidin-4-yl) -6 - [(trifluoromethyl) sulfonyl] benzonitrile
4- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -1-propylpiperidine
4- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -1-ethylpiperidine
4- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -1- (2-methoxyethyl) piperidine
1-allyl-4- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine
2-methyl-3- (1-propylpiperidin-4-yl) phenyl trifluoromethanesulfonate
3- (1-ethylpiperidin-4-yl) -2-methylphenyl trifluoromethanesulfonate
3- [1- (2-methoxyethyl) piperidin-4-yl] -2-methylphenyl trifluoromethanesulfonate
3- (1-allylpiperidin-4-yl) -2-methylphenyl trifluoromethanesulfonate
2-fluoro-3- (1-propylpiperidin-4-yl) phenyl trifluoromethanesulfonate
3- (1-ethylpiperidin-4-yl) -2-fluorophenyl trifluoromethanesulfonate
2-fluoro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenyl trifluoromethanesulfonate
3- (1-allylpiperidin-4-yl) -2-fluorophenyl trifluoromethanesulfonate
2-cyano-3- (1-propylpiperidin-4-yl) phenyl trifluoromethanesulfonate
2-cyano-3- (1-ethylpiperidin-4-yl) phenyl trifluoromethanesulfonate
2-cyano-3- [1- (2-methoxyethyl) piperidin-4-yl] phenyl trifluoromethanesulfonate
3- (1-allylpiperidin-4-yl) -2-cyanophenyl trifluoromethanesulfonate
2-chloro-3- (1-propylpiperidin-4-yl) phenyl trifluoromethanesulfonate
2-chloro-3- (1-ethylpiperidin-4-yl) phenyl trifluoromethanesulfonate
2-chloro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenyl trifluoromethanesulfonate
3- (1-allylpiperidin-4-yl) -2-chlorophenyl trifluoromethanesulfonate
4- [3-chloro-2- (trifluoromethyl) phenyl] -1-propylpiperidine
4- [3-chloro-2- (trifluoromethyl) phenyl] -1-ethylpiperidine
4- [3-chloro-2- (trifluoromethyl) phenyl] -1- (2-methoxyethyl) piperidine
1-allyl-4- [3-chloro-2- (trifluoromethyl) phenyl] piperidine
2-chloro-6- (1-propylpiperidin-4-yl) phenol
2-chloro-6- (1-ethylpiperidin-4-yl) phenol
2-chloro-6- [1- (2-methoxyethyl) piperidin-4-yl] phenol
2- (1-allylpiperidin-4-yl) -6-chlorophenol
2-chloro-6- (1-propylpiperidin-4-yl) benzonitrile
2-chloro-6- (1-ethylpiperidin-4-yl) benzonitrile
2- (1-allylpiperidin-4-yl) -6-chlorobenzonitrile
2- (1-propylpiperidin-4-yl) -6- (trifluoromethoxy) phenol
2- (1-ethylpiperidin-4-yl) -6- (trifluoromethoxy) phenol
2- [1- (2-methoxyethyl) piperidin-4-yl] -6- (trifluoromethoxy) phenol
2- (1-allylpiperidin-4-yl) -6- (trifluoromethoxy) phenol
2- (1-propylpiperidin-4-yl) -6- (trifluoromethoxy) benzonitrile
2- (1-ethylpiperidin-4-yl) -6- (trifluoromethoxy) benzonitrile
2- (1-allylpiperidin-4-yl) -6- (trifluoromethoxy) benzonitrile
2,2,2-trifluoro-1- [2-methyl-3- (1-propylpiperidin-4-yl) phenyl] ethanone
1- [3- (1-ethylpiperidin-4-yl) -2-methylphenyl] -2,2,2-trifluoroethanone
2,2,2-trifluoro-1- {3- [1- (2-methoxyethyl) piperidin-4-yl] -2-methylphenyl} ethanone
1- [3- (1-allylpiperidin-4-yl) -2-methylphenyl] -2,2,2-trifluoroethanone
2,2,2-trifluoro-1- [2-fluoro-3- (1-propylpiperidin-4-yl) phenyl] ethanone
1- [3- (1-ethylpiperidin-4-yl) -2-fluorophenyl] -2,2,2-trifluoroethanone
2,2,2-trifluoro-1- {2-fluoro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenyl} ethanone
1- [3- (1-allylpiperidin-4-yl) -2-fluorophenyl] -2,2,2-trifluoroethanone
2- (1-propylpiperidin-4-yl) -6- (trifluoroacetyl) benzonitrile
2- (1-ethylpiperidin-4-yl) -6- (trifluoroacetyl) benzonitrile
2- [1- (2-methoxyethyl) piperidin-4-yl] -6- (trifluoroacetyl) benzonitrile
2- (1-allylpiperidin-4-yl) -6- (trifluoroacetyl) benzonitrile
1- [2-chloro-3- (1-propylpiperidin-4-yl) phenyl] -2,2,2-trifluoroethanone
1- [2-chloro-3- (1-ethylpiperidin-4-yl) phenyl] -2,2,2-trifluoroethanone
1- {2-chloro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenyl} -2,2,2-trifluoroethanone
1- [3- (1-allylpiperidin-4-yl) -2-chlorophenyl] -2,2,2-trifluoroethanone
2,2,2-trifluoro-1- [2-methyl-3- (1-propylpiperidin-4-yl) phenyl] ethanol
1- [3- (1-ethylpiperidin-4-yl) -2-methylphenyl] -2,2,2-trifluoroethanol
2,2,2-trifluoro-1- {3- [1- (2-methoxyethyl) piperidin-4-yl] -2-methylphenyl} ethanol
1- [3- (1-allylpiperidin-4-yl) -2-methylphenyl] -2,2,2-trifluoroethanol
2,2,2-trifluoro-1- [2-fluoro-3- (1-propylpiperidin-4-yl) phenyl] ethanol
1- [3- (1-ethylpiperidin-4-yl) -2-fluorophenyl] -2,2,2-trifluoroethanol
2,2,2-trifluoro-1- {2-fluoro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenyl} ethanol
1- [3- (1-allylpiperidin-4-yl) -2-fluorophenyl] -2,2,2-trifluoroethanol
2- (1-propylpiperidin-4-yl) -6- (2,2,2-trifluoro-1-hydroxyethyl) benzonitrile
2- (1-ethylpiperidin-4-yl) -6- (2,2,2-trifluoro-1-hydroxyethyl) benzonitrile
2- [1- (2-methoxyethyl) piperidin-4-yl] -6- (2,2,2-trifluoro-1-hydroxyethyl) benzonitrile
2- (1-allylpiperidin-4-yl) -6- (2,2,2-trifluoro-1-hydroxyethyl) benzonitrile
1- [2-chloro-3- (1-propylpiperidin-4-yl) phenyl] -2,2,2-trifluoroethanol
1- [2-chloro-3- (1-ethylpiperidin-4-yl) phenyl] -2,2,2-trifluoroethanol
1- {2-chloro-3- [1- (2-methoxyethyl) piperidin-4-yl] phenyl} -2,2,2-trifluoroethanol
1- [3- (1-allylpiperidin-4-yl) -2-chlorophenyl] -2,2,2-trifluoroethanol
2-methyl-3- (1-propylpiperidin-4-yl) benzonitrile
3- (1-allylpiperidin-4-yl) -2-methylbenzonitrile
2-fluoro-3- (1-propylpiperidin-4-yl) benzonitrile
3- (1-allylpiperidin-4-yl) -2-fluorobenzonitrile
2-hydroxy-3- (1-propylpiperidin-4-yl) benzonitrile
3- (1-ethylpiperidin-4-yl) -2-hydroxybenzonitrile
2-hydroxy-3- [1- (2-methoxyethyl) piperidin-4-yl] benzonitrile
3- (1-allylpiperidin-4-yl) -2-hydroxybenzonitrile
3- (1-propylpiperidin-4-yl) phthalonitrile
3- (1-ethylpiperidin-4-yl) phthalonitrile
3- (1-allylpiperidin-4-yl) phthalonitrile
2-chloro-3- (1-propylpiperidin-4-yl) benzonitrile, or
3- (1-allylpiperidin-4-yl) -2-chlorobenzonitrile, or
its pharmaceutically acceptable salts. 10. The compound according to claim 3, selected from the group consisting of:
2- (1-ethylpiperidin-4-yl) -6- (trifluoromethyl) phenol
1- [3- (1-ethylpiperidin-4-yl) -2-fluorophenyl] ethanone
1- [2-chloro-3- (1-ethylpiperidin-4-yl) phenyl] ethanone
3- (1-ethylpiperidin-4-yl) -2-fluorophenylmethanesulfonate
2-chloro-3- (1-ethylpiperidin-4-yl) phenylmethanesulfonate
1-ethyl-4- [2-fluoro-3- (methylsulfonyl) phenyl] piperidine
4- [2-chloro-3- (methylsulfonyl) phenyl] -1-ethylpiperidine
1-ethyl-4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperidine
4- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -1-ethylpiperidine
3- (1-ethylpiperidin-4-yl) -2-fluorophenyl trifluoromethanesulfonate
2-chloro-3- (1-ethylpiperidin-4-yl) phenyl trifluoromethanesulfonate
1- [3- (1-ethylpiperidin-4-yl) -2-fluorophenyl] -2,2,2-trifluoroethanone
1- [2-chloro-3- (1-ethylpiperidin-4-yl) phenyl] -2,2,2-trifluoroethanone
1- [3- (1-ethylpiperidin-4-yl) -2-fluorophenyl] -2,2,2-trifluoroethanol
1- [2-chloro-3- (1-ethylpiperidin-4-yl) phenyl] -2,2,2-trifluoroethanol
3- (1-ethylpiperidin-4-yl) -2-hydroxybenzonitrile
2- (1-propylpiperidin-4-yl) -6- (trifluoromethyl) phenol
1- [2-fluoro-3- (1-propylpiperidin-4-yl) phenyl] ethanone
1- [2-chloro-3- (1-propylpiperidin-4-yl) phenyl] ethanone
2-fluoro-3- (1-propylpiperidin-4-yl) phenylmethanesulfonate
2-chloro-3- (1-propylpiperidin-4-yl) phenylmethanesulfonate
4- [2-fluoro-3- (methylsulfonyl) phenyl] -1-propylpiperidine
4- [2-chloro-3- (methylsulfonyl) phenyl] -1-propylpiperidine
4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} -1-propylpiperidine
4- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -1-propylpiperidine
2-fluoro-3- (1-propylpiperidin-4-yl) phenyl trifluoromethanesulfonate
2-chloro-3- (1-propylpiperidin-4-yl) phenyl trifluoromethanesulfonate
2,2,2-trifluoro-1- [2-fluoro-3- (1-propylpiperidin-4-yl) phenyl] ethanone
1- [2-chloro-3- (1-propylpiperidin-4-yl) phenyl] -2,2,2-trifluoroethanone
2,2,2-trifluoro-1- [2-fluoro-3- (1-propylpiperidin-4-yl) phenyl] ethanol
1- [2-chloro-3- (1-propylpiperidin-4-yl) phenyl] -2,2,2-trifluoroethanol
2-hydroxy-3- (1-propylpiperidin-4-yl) benzonitrile,
or its pharmaceutically acceptable salts. 11. The compound according to any one of claims 1 to 2, where X represents N. 12. The compound according to claim 11, where R _{1 is} selected from the group consisting of CF ₃ , SO ₂ CH ₃ and SO ₂ CF ₃ . 13. The compound of claim 11, wherein R _{2 is} selected from the group consisting of F, Cl and OH. 14. The compound of claim 11, wherein R _{3 is} selected from the group consisting of n-propyl and ethyl. 15. The compound according to claim 11, where R ₂ represents F, and R ₃ selected from the group consisting of n-propyl and ethyl. 16. The compound according to claim 11, where R ₁ represents CF ₃ , R ₂ represents F, and R ₃ represents n-propyl. 17. The compound according to claim 11, selected from the group consisting of:
1- (3-fluoro-2-methylphenyl) -4-propylpiperazine
1-ethyl-4- (3-fluoro-2-methylphenyl) piperazine
1- (3-fluoro-2-methylphenyl) -4- (2-methoxyethyl) piperazine
1-allyl-4- (3-fluoro-2-methylphenyl) piperazine
1- (2,3-difluorophenyl) -4-propylpiperazine
1- (2,3-difluorophenyl) -4-ethylpiperazine
1- (2,3-difluorophenyl) -4- (2-methoxyethyl) piperazine
1-allyl-4- (2,3-difluorophenyl) piperazine
1- [3-fluoro-2- (trifluoromethyl) phenyl] -4-propylpiperazine
1-ethyl-4- [3-fluoro-2- (trifluoromethyl) phenyl] piperazine
1- [3-fluoro-2- (trifluoromethyl) phenyl] -4- (2-methoxyethyl) piperazine
1-allyl-4- [3-fluoro-2- (trifluoromethyl) phenyl] piperazine
2-fluoro-6- (4-propylpiperazin-1-yl) phenol
2- (4-ethylpiperazin-1-yl) -6-fluorophenol
2-fluoro-6- [4- (2-methoxyethyl) piperazin-1-yl] phenol
2- (4-allylpiperazin-1-yl) -6-fluorophenol
2-fluoro-6- (4-propylpiperazin-1-yl) benzonitrile
2- (4-ethylpiperazin-1-yl) -6-fluorobenzonitrile
2-fluoro-6- [4- (2-methoxyethyl) piperazin-1-yl] benzonitrile
2- (4-allylpiperazin-1-yl) -6-fluorobenzonitrile
1- (2-chloro-3-fluorophenyl) -4-propylpiperazine
1- (2-chloro-3-fluorophenyl) -4-ethylpiperazine
1- (2-chloro-3-fluorophenyl) -4- (2-methoxyethyl) piperazine
1-allyl-4- (2-chloro-3-fluorophenyl) piperazine
1- [2-methyl-3- (trifluoromethyl) phenyl] -4-propylpiperazine
1-ethyl-4- [2-methyl-3- (trifluoromethyl) phenyl] piperazine
1- (2-methoxyethyl) -4- [2-methyl-3- (trifluoromethyl) phenyl] piperazine
1-allyl-4- [2-methyl-3- (trifluoromethyl) phenyl] piperazine
1- [2-fluoro-3- (trifluoromethyl) phenyl] -4-propylpiperazine
1-ethyl-4- [2-fluoro-3- (trifluoromethyl) phenyl] piperazine
1- [2-fluoro-3- (trifluoromethyl) phenyl] -4- (2-methoxyethyl) piperazine
1-allyl-4- [2-fluoro-3- (trifluoromethyl) phenyl] piperazine
2- (4-propylpiperazin-1-yl) -6- (trifluoromethyl) phenol
2- (4-ethylpiperazin-1-yl) -6- (trifluoromethyl) phenol
2- [4- (2-methoxyethyl) piperazin-1-yl] -6- (trifluoromethyl) phenol
2- (4-allylpiperazin-1-yl) -6- (trifluoromethyl) phenol
2- (4-propylpiperazin-1-yl) -6- (trifluoromethyl) benzonitrile
2- (4-ethylpiperazin-1-yl) -6- (trifluoromethyl) benzonitrile
2- [4- (2-methoxyethyl) piperazin-1-yl] -6- (trifluoromethyl) benzonitrile
2- (4-allylpiperazin-1-yl) -6- (trifluoromethyl) benzonitrile
1- [2-chloro-3- (trifluoromethyl) phenyl] -4-propylpiperazine
1- [2-chloro-3- (trifluoromethyl) phenyl] -4-ethylpiperazine
1- [2-chloro-3- (trifluoromethyl) phenyl] -4- (2-methoxyethyl) piperazine
1-allyl-4- [2-chloro-3- (trifluoromethyl) phenyl] piperazine
1- [2-methyl-3- (4-propylpiperazin-1-yl) phenyl] ethanone
1- [3- (4-ethylpiperazin-1-yl) -2-methylphenyl] ethanone
1- {3- [4- (2-methoxyethyl) piperazin-1-yl] -2-methylphenyl} ethanone
1- [3- (4-allylpiperazin-1-yl) -2-methylphenyl] ethanone
1- [2-fluoro-3- (4-propylpiperazin-1-yl) phenyl] ethanone
1- [3- (4-ethylpiperazin-1-yl) -2-fluorophenyl] ethanone
1- {2-fluoro-3- [4- (2-methoxyethyl) piperazin-1-yl] phenyl} ethanone
1- [3- (4-allylpiperazin-1-yl) -2-fluorophenyl] ethanone
2-acetyl-6- (4-propylpiperazin-1-yl) benzonitrile
2-acetyl-6- (4-ethylpiperazin-1-yl) benzonitrile
2-acetyl-6- [4- (2-methoxyethyl) piperazin-1-yl] benzonitrile
2-acetyl-6- (4-allylpiperazin-1-yl) benzonitrile
1- [2-chloro-3- (4-propylpiperazin-1-yl) phenyl] ethanone
1- [2-chloro-3- (4-ethylpiperazin-1-yl) phenyl] ethanone
1- {2-chloro-3- [4- (2-methoxyethyl) piperazin-1-yl] phenyl} ethanone
1- [3- (4-allylpiperazin-1-yl) -2-chlorophenyl] ethanone
2-methyl-3- (4-propylpiperazin-1-yl) phenylmethanesulfonate
3- (4-ethylpiperazin-1-yl) -2-methylphenylmethanesulfonate
3- [4- (2-methoxyethyl) piperazin-1-yl] -2-methylphenylmethanesulfonate
3- (4-allylpiperazin-1-yl) -2-methylphenylmethanesulfonate
2-fluoro-3- (4-propylpiperazin-1-yl) phenylmethanesulfonate
3- (4-ethylpiperazin-1-yl) -2-fluorophenylmethanesulfonate
2-fluoro-3- [4- (2-methoxyethyl) piperazin-1-yl] phenylmethanesulfonate
3- (4-allylpiperazin-1-yl) -2-fluorophenylmethanesulfonate
2-cyano-3- (4-propylpiperazin-1-yl) phenylmethanesulfonate
2-cyano-3- (4-ethylpiperazin-1-yl) phenylmethanesulfonate
2-cyano-3- [4- (2-methoxyethyl) piperazin-1-yl] phenylmethanesulfonate
3- (4-allylpiperazin-1-yl) -2-cyanophenylmethanesulfonate
2-chloro-3- (4-propylpiperazin-1-yl) phenylmethanesulfonate
2-chloro-3- (4-ethylpiperazin-1-yl) phenylmethanesulfonate
2-chloro-3- [4- (2-methoxyethyl) piperazin-1-yl] phenylmethanesulfonate
3- (4-allylpiperazin-1-yl) -2-chlorophenylmethanesulfonate
1- [2-methyl-3- (methylsulfonyl) phenyl] -4-propylpiperazine
1-ethyl-4- [2-methyl-3- (methylsulfonyl) phenyl] piperazine
1- (2-methoxyethyl) -4- [2-methyl-3- (methylsulfonyl) phenyl] piperazine
1-allyl-4- [2-methyl-3- (methylsulfonyl) phenyl] piperazine
1- [2-fluoro-3- (methylsulfonyl) phenyl] -4-propylpiperazine
1-ethyl-4- [2-fluoro-3- (methylsulfonyl) phenyl] piperazine
1- [2-fluoro-3- (methylsulfonyl) phenyl] -4- (2-methoxyethyl) piperazine
1-allyl-4- [2-fluoro-3- (methylsulfonyl) phenyl] piperazine
2- (methylsulfonyl) -6- (4-propylpiperazin-1-yl) benzonitrile
2- (4-ethylpiperazin-1-yl) -6- (methylsulfonyl) benzonitrile
2- [4- (2-methoxyethyl) piperazin-1-yl] -6- (methylsulfonyl) benzonitrile
2- (4-allylpiperazin-1-yl) -6- (methylsulfonyl) benzonitrile
1- [2-chloro-3- (methylsulfonyl) phenyl] -4-propylpiperazine
1- [2-chloro-3- (methylsulfonyl) phenyl] -4-ethylpiperazine
1- [2-chloro-3- (methylsulfonyl) phenyl] -4- (2-methoxyethyl) piperazine
1-allyl-4- [2-chloro-3- (methylsulfonyl) phenyl] piperazine
1- {2-methyl-3 - [(trifluoromethyl) sulfonyl] phenyl} -4-propylpiperazine
1-ethyl-4- {2-methyl-3 - [(trifluoromethyl) sulfonyl] phenyl} piperazine
1- (2-methoxyethyl) -4- {2-methyl-3 - [(trifluoromethyl) sulfonyl] phenyl} piperazine
1-allyl-4- {2-methyl-3 - [(trifluoromethyl) sulfonyl] phenyl} piperazine
1- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} -4-propylpiperazine
1-ethyl-4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperazine
1- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} -4- (2-methoxyethyl) piperazine
1-allyl-4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperazine
2- (4-propylpiperazin-1-yl) -6 - [(trifluoromethyl) sulfonyl] benzonitrile
2- (4-ethylpiperazin-1-yl) -6 - [(trifluoromethyl) sulfonyl] benzonitrile
2- [4- (2-methoxyethyl) piperazin-1-yl] -6 - [(trifluoromethyl) sulfonyl] benzonitrile
2- (4-allylpiperazin-1-yl) -6 - [(trifluoromethyl) sulfonyl] benzonitrile
1- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -4-propylpiperazine
1- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -4-ethylpiperazine
1- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -4- (2-methoxyethyl) piperazine
1-allyl-4- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperazine
2-methyl-3- (4-propylpiperazin-1-yl) phenyl trifluoromethanesulfonate
3- (4-ethylpiperazin-1-yl) -2-methylphenyl trifluoromethanesulfonate
3- [4- (2- (methoxyethyl) piperazin-1-yl] -2-methylphenyl trifluoromethanesulfonate
3- (4-allylpiperazin-1-yl) -2-methylphenyl trifluoromethanesulfonate
2-fluoro-3- (4-propylpiperazin-1-yl) phenyl trifluoromethanesulfonate
3- (4-ethylpiperazin-1-yl) -2-fluorophenyl trifluoromethanesulfonate
2-fluoro-3- [4- (2- (methoxyethyl) piperazin-1-yl] phenyl trifluoromethanesulfonate
3- (4-allylpiperazin-1-yl) -2-fluorophenyl trifluoromethanesulfonate
2-cyano-3- (4-propylpiperazin-1-yl) phenyl trifluoromethanesulfonate
2-cyano-3- (4-ethylpiperazin-1-yl) phenyl trifluoromethanesulfonate
2-cyano-3- [4- (2- (methoxyethyl) piperazin-1-yl] phenyl trifluoromethanesulfonate
3- (4-allylpiperazin-1-yl) -2-cyanophenyl trifluoromethanesulfonate
2-chloro-3- (4-propylpiperazin-1-yl) phenyl trifluoromethanesulfonate
2-chloro-3- (4-ethylpiperazin-1-yl) phenyl trifluoromethanesulfonate
2-chloro-3- [4- (2- (methoxyethyl) piperazin-1-yl] phenyl trifluoromethanesulfonate
3- (4-allylpiperazin-1-yl) -2-chlorophenyl trifluoromethanesulfonate
1- (3-chloro-2-methylphenyl) -4-propylpiperazine
1- (3-chloro-2-methylphenyl) -4-ethylpiperazine
1- (3-chloro-2-methylphenyl) -4- (2-methoxyethyl) piperazine
1-allyl-4- (3-chloro-2-methylphenyl) piperazine
1- (3-chloro-2-fluorophenyl) -4-propylpiperazine
1- (3-chloro-2-fluorophenyl) -4-ethylpiperazine
1- (3-chloro-2-fluorophenyl) -4- (2-methoxyethyl) piperazine
1-allyl-4- (3-chloro-2-fluorophenyl) piperazine
1- [3-chloro-2- (trifluoromethyl) phenyl] -4-propylpiperazine
1- [3-chloro-2- (trifluoromethyl) phenyl] -4-ethylpiperazine
1- [3-chloro-2- (trifluoromethyl) phenyl] -4- (2-methoxyethyl) piperazine
1-allyl-4- [3-chloro-2- (trifluoromethyl) phenyl] piperazine
2-chloro-6- (4-propylpiperazin-1-yl) phenol
2-chloro-6- (4-ethylpiperazin-1-yl) phenol
2-chloro-6- [4- (2-methoxyethyl) piperazin-1-yl] phenol
2- (4-allylpiperazin-1-yl) -6-chlorophenol
2-chloro-6- (4-propylpiperazin-1-yl) benzonitrile
2-chloro-6- (4-ethylpiperazin-1-yl) benzonitrile
2-chloro-6- [4- (2-methoxyethyl) piperazin-1-yl] benzonitrile
2- (4-allylpiperazin-1-yl) -6-chlorobenzonitrile
1- (2,3-dichlorophenyl) -4-propylpiperazine
1- (2,3-dichlorophenyl) -4-ethylpiperazine
1- (2,3-dichlorophenyl) -4- (2-methoxyethyl) piperazine
1-allyl-4- (2,3-dichlorophenyl) piperazine
1- [2-methyl-3- (trifluoromethoxy) phenyl] -4-propylpiperazine
1-ethyl-4- [2-methyl-3- (trifluoromethoxy) phenyl] piperazine
1- (2-methoxyethyl) -4- [2-methyl-3- (trifluoromethoxy) phenyl] piperazine
1-allyl-4- [2-methyl-3- (trifluoromethoxy) phenyl] piperazine
1- [2-fluoro-3- (trifluoromethoxy) phenyl] -4-propylpiperazine
1-ethyl-4- [2-fluoro-3- (trifluoromethoxy) phenyl] piperazine
1- [2-fluoro-3- (trifluoromethoxy) phenyl] -4- (2-methoxyethyl) piperazine
1-allyl-4- [2-fluoro-3- (trifluoromethoxy) phenyl] piperazine
2- (4-propylpiperazin-1-yl) -6- (trifluoromethoxy) phenol
2- (4-ethylpiperazin-1-yl) -6- (trifluoromethoxy) phenol
2- [4- (2-methoxyethyl) piperazin-1-yl] -6- (trifluoromethoxy) phenol
2- (4-allylpiperazin-1-yl) -6- (trifluoromethoxy) phenol
2- (4-propylpiperazin-1-yl) -6- (trifluoromethoxy) benzonitrile
2- (4-ethylpiperazin-1-yl) -6- (trifluoromethoxy) benzonitrile
2- [4- (2-methoxyethyl) piperazin-1-yl] -6- (trifluoromethoxy) benzonitrile
2- (4-allylpiperazin-1-yl) -6- (trifluoromethoxy) benzonitrile
1- [2-chloro-3- (trifluoromethoxy) phenyl] -4-propylpiperazine
1- [2-chloro-3- (trifluoromethoxy) phenyl] -4-ethylpiperazine
1- [2-chloro-3- (trifluoromethoxy) phenyl] -4- (2-methoxyethyl) piperazine
1-allyl-4- [2-chloro-3- (trifluoromethoxy) phenyl] piperazine
2,2,2-trifluoro-1- [2-methyl-3- (4-propylpiperazin-1-yl) phenyl] ethanone
1- [3- (4-ethylpiperazin-1-yl) -2-methylphenyl] -2,2,2-trifluoroethanone
2,2,2-trifluoro-1- {3- [4- (2-methoxyethyl) piperazin-1-yl] -2-methylphenyl} ethanone
1- [3- (4-allylpiperazin-1-yl) -2-methylphenyl] -2,2,2-trifluoroethanone
2,2,2-trifluoro-1- [2-fluoro-3- (4-propylpiperazin-1-yl) phenyl] ethanone
1- [3- (4-ethylpiperazin-1-yl) -2-fluorophenyl] -2,2,2-trifluoroethanone
2,2,2-trifluoro-1- {2-fluoro-3- [4- (2-methoxyethyl) piperazin-1-yl] phenyl} ethanone
1- [3- (4-allylpiperazin-1-yl) -2-fluorophenyl] -2,2,2-trifluoroethanone
2- (4-propylpiperazin-1-yl) -6- (trifluoroacetyl) benzonitrile
2- (4-ethylpiperazin-1-yl) -6- (trifluoroacetyl) benzonitrile
2- [4- (2-methoxyethyl) piperazin-1-yl] -6- (trifluoroacetyl) benzonitrile
2- (4-allylpiperazin-1-yl) -6- (trifluoroacetyl) benzonitrile
1- [2-chloro-3- (4-propylpiperazin-1-yl) phenyl] -2,2,2-trifluoroethanone
1- [2-chloro-3- (4-ethylpiperazin-1-yl) phenyl] -2,2,2-trifluoroethanone
1- {2-chloro-3- [4- (2-methoxyethyl) piperazin-1-yl] phenyl} -2,2,2-trifluoroethanone
1- [3- (4-allylpiperazin-1-yl) -2-chlorophenyl] -2,2,2-trifluoroethanone
2,2,2-trifluoro-1- [2-methyl-3- (4-propylpiperazin-1-yl) phenyl] ethanol
1- [3- (4-ethylpiperazin-1-yl) -2-methylphenyl] -2,2,2-trifluoroethanol
2,2,2-trifluoro-1- {3- [4- (2-methoxyethyl) piperazin-1-yl] -2-methylphenyl} ethanol
1- [3- (4-allylpiperazin-1-yl) -2-methylphenyl] -2,2,2-trifluoroethanol
2,2,2-trifluoro-1- [2-fluoro-3- (4-propylpiperazin-1-yl) phenyl] ethanol
1- [3- (4-ethylpiperazin-1-yl) -2-fluorophenyl] -2,2,2-trifluoroethanol
2,2,2-trifluoro-1- {2-fluoro-3- [4- (2-methoxyethyl) piperazin-1-yl] phenyl} ethanol
1- [3- (4-allylpiperazin-1-yl) -2-fluorophenyl] -2,2,2-trifluoroethanol
2- (4-propylpiperazin-1-yl) -6- (2,2,2-trifluoro-1-hydroxyethyl) benzonitrile
2- (4-ethylpiperazin-1-yl) -6- (2,2,2-trifluoro-1-hydroxyethyl) benzonitrile
2- [4- (2-methoxyethyl) piperazin-1-yl] -6- (2,2,2-trifluoro-1-hydroxyethyl) benzonitrile
2- (4-allylpiperazin-1-yl) -6- (2,2,2-trifluoro-1-hydroxyethyl) benzonitrile
1- [2-chloro-3- (4-propylpiperazin-1-yl) phenyl] -2,2,2-trifluoroethanol
1- [2-chloro-3- (4-ethylpiperazin-1-yl) phenyl] -2,2,2-trifluoroethanol
1- {2-chloro-3- [4- (2-methoxyethyl) piperazin-1-yl] phenyl} -2,2,2-trifluoroethanol
1- [3- (4-allylpiperazin-1-yl) -2-chlorophenyl] -2,2,2-trifluoroethanol
2-methyl-3- (4-propylpiperazin-1-yl) benzonitrile
3- (4-ethylpiperazin-1-yl) -2-methylbenzonitrile
3- [4- (2-methoxyethyl) piperazin-1-yl] -2-methylbenzonitrile
3- (4-allylpiperazin-1-yl) -2-methylbenzonitrile
2-fluoro-3- (4-propylpiperazin-1-yl) benzonitrile
3- (4-ethylpiperazin-1-yl) -2-fluorobenzonitrile
2-fluoro-3- [4- (2-methoxyethyl) piperazin-1-yl] benzonitrile
3- (4-allylpiperazin-1-yl) -2-fluorobenzonitrile
2-hydroxy-3- (4-propylpiperazin-1-yl) benzonitrile
3- (4-ethylpiperazin-1-yl) -2-hydroxybenzonitrile
2-hydroxy-3- [4- (2-methoxyethyl) piperazin-1-yl] benzonitrile
3- (4-allylpiperazin-1-yl) -2-hydroxybenzonitrile
3- (4-propylpiperazin-1-yl) phthalonitrile
3- (4-ethylpiperazin-1-yl) phthalonitrile
3- [4- (2-methoxyethyl) piperazin-1-yl] phthalonitrile
3- (4-allylpiperazin-1-yl) phthalonitrile
2-chloro-3- (4-propylpiperazin-1-yl) benzonitrile
2-chloro-3- (4-ethylpiperazin-1-yl) benzonitrile
2-chloro-3- [4- (2-methoxyethyl) piperazin-1-yl] benzonitrile or
3- (4-allylpiperazin-1-yl) -2-chlorobenzonitrile, or
its pharmaceutically acceptable salt. 18. The compound according to claim 11, selected from the group consisting of:
1- [2-fluoro-3- (trifluoromethyl) phenyl] -4-propylpiperazine
1-ethyl-4- [2-fluoro-3- (trifluoromethyl) phenyl] piperazine
1- [2-fluoro-3- (trifluoromethyl) phenyl] -4- (2-methoxyethyl) piperazine
1-allyl-4- [2-fluoro-3- (trifluoromethyl) phenyl] piperazine
1- [2-chloro-3- (trifluoromethyl) phenyl] -4-propylpiperazine
1- [2-chloro-3- (trifluoromethyl) phenyl] -4-ethylpiperazine
1- [2-chloro-3- (trifluoromethyl) phenyl] -4- (2-methoxyethyl) piperazine
1-allyl-4- [2-chloro-3- (trifluoromethyl) phenyl] piperazine
1- [2-fluoro-3- (methylsulfonyl) phenyl] -4-propylpiperazine
1-ethyl-4- [2-fluoro-3- (methylsulfonyl) phenyl] piperazine
1- [2-fluoro-3- (methylsulfonyl) phenyl] -4- (2-methoxyethyl) piperazine
1-allyl-4- [2-fluoro-3- (methylsulfonyl) phenyl] piperazine
1- [2-chloro-3- (methylsulfonyl) phenyl] -4-propylpiperazine
1- [2-chloro-3- (methylsulfonyl) phenyl] -4-ethylpiperazine
1- [2-chloro-3- (methylsulfonyl) phenyl] -4- (2-methoxyethyl) piperazine
1-allyl-4- [2-chloro-3- (methylsulfonyl) phenyl] piperazine
1- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} -4-propylpiperazine
1-ethyl-4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperazine
1- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} -4- (2-methoxyethyl) piperazine
1-allyl-4- {2-fluoro-3 - [(trifluoromethyl) sulfonyl] phenyl} piperazine
1- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -4-propylpiperazine
1- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -4-ethylpiperazine
1- {2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl} -4- (2-methoxyethyl) piperazine
1-allyl-4- (2-chloro-3 - [(trifluoromethyl) sulfonyl] phenyl) piperazine, or
its pharmaceutically acceptable salt. 19. The compound according to claim 1, where if the calculated van der Waals volume of R ₂ exceeds 27Å ³ , then the total van der Waals volume of R ₁ and R ₂ (R ₁ + R ₂ ) does not exceed 70Å ³ . 20. The compound according to claim 1, where the value of the calculated distribution constant of octanol / water is more than 0.6, preferably more than 0.9. 21. The intermediate compound of the formula:

where R ₁ , R ₂ and R ₃ are as defined in claim 1. 22. The intermediate compound of claim 21, wherein R _{1 is} selected from the group consisting of OSO ₂ CH ₃ , SO ₂ CH ₃ , SO ₂ CF ₃ , COCH ₃ , COCF ₃ , CN, and CF ₃ . 23. The intermediate compound according to any one of paragraphs.21-22, where R ₂ selected from the group consisting of F, Cl and OH. 24. The intermediate compound according to item 21, where R ₁ selected from the group consisting of OSO ₂ CH ₃ , SO ₂ CH ₃ and SO ₂ CF ₃ . 25. The intermediate compound according to item 21, where R ₃ selected from the group consisting of n-propyl and ethyl. 26. The intermediate compound according to item 21, where R ₂ represents F, and R ₃ selected from the group consisting of n-propyl and ethyl. 27. An intermediate compound of the formula:

where X, R ₁ and R ₂ are as defined in claim 1. 28. The intermediate compound of claim 27, wherein R _{1 is} selected from the group consisting of OSO ₂ CH ₃ , SO ₂ CH ₃ , SO ₂ CF ₃ , COCH ₃ , COFF ₃ , CN, and CF ₃ . 29. The intermediate compound according to any one of paragraphs.27-28, where R ₂ selected from the group consisting of F, Cl and OH. 30. The intermediate compound according to item 27, where R ₁ selected from the group consisting of OSO ₂ CH ₃ , SO ₂ CH ₃ and SO ₂ CF ₃ . 31. A pharmaceutical composition that has activity as modulators of dopamine neurotransmission, comprising a compound according to any one of claims 1 to 20 and one or more pharmaceutically acceptable carriers or diluents. 32. The pharmaceutical composition according to p. 31 for the treatment of disorders of the central nervous system. 33. The pharmaceutical composition according to p. 31 for the treatment of motor disorders selected from the group consisting of Parkinson's disease, Parkinsonism, dyskinesias (including L-DOPA-induced dyskinesia), dystonia, tics, tremors and Huntington's disease. 34. The pharmaceutical composition according to p. 31 for treating a condition selected from the group consisting of iatrogenic and non-neutrogenic psychoses and hallucinations. 35. The pharmaceutical composition according to p. 31 for treating a condition selected from the group consisting of schizophrenia, schizomorphic psychosis and bipolar disorder. 36. The pharmaceutical composition according to p. 31 for treating a condition selected from the group consisting of mood disorders and anxiety, depression and obsessive-compulsive disease. 37. The pharmaceutical composition according to p. 31 for the treatment of disorders of the nervous system selected from the group consisting of autism spectrum disorders, ADHD, cerebral palsy, Gilles de la Tourette syndrome and neurodegenerative disorders selected from the group consisting of dementia and age-related impairment of consciousness. 38. The pharmaceutical composition according to p. 31 for treating a condition selected from the group consisting of sleep disorders, sexual disorders, eating disorders, obesity and headaches and pains of a different type in conditions characterized by increased muscle tone. 39. The pharmaceutical composition according to p. 31 for improving motor functions, cognitive functions and related emotional disorders after brain damage induced by traumatic injury, inflammation, infection, neoplastic, vascular, hypoxic and metabolic cases or brain damage induced by toxic reactions to exogenous chemical compounds where the exogenous chemical compounds are selected from the group consisting of abusive substances, pharmaceutical compounds niy and environmental toxins. 40. The pharmaceutical composition of claim 31 for treating a drug abuse disorder. 41. The pharmaceutical composition according to p. 31 for the treatment of Alzheimer's disease or related disorders causing dementia. 42. A method of treating disorders of the central nervous system, wherein said method comprises administering a therapeutically active amount of a compound according to any one of claims 1 to 20 to a mammal, including a person suffering from such a violation. 43. The method of claim 42 for treating a disorder defined in one or more of claims 32-39.

Images