Method for reducing of broken opyoid receptor functions

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of formula I , wherein G is carbon or nitrogen atom; A is i) phenyl substituted with any from -COOH, -CONH2, COOCH3, -CN, -NH2 or -COCH3; ii) naphthyl, benzophuranyl, and quinolinyl; and iii) formulae , , .

Compounds of present invention are useful in particular in pain treatment.

EFFECT: new agents for pain treatment.

58 ex

 

The scope of the invention

The present invention relates to a method of treating diseases mediated by opioid receptors, using piperazinone or pyridazinone compounds, to a method for producing such compounds and including their pharmaceutical compositions. In particular, this invention relates to the use of these compounds for the treatment of pain.

Background of invention and prior art

It was found that δ-receptor plays an important role in many body functions, such as cardiovascular and pain systems. Therefore, the ligands for δ-receptor can be potentially used as analgesics and/or antihypertensive drugs. It was also found that the ligands for δ-receptor also possess immunomodulatory activity.

Identify at least three different populations of opioid receptors (μ, δ and κ) now easily feasible, and all three types of receptors are easy to find in both the Central and peripheral nervous systems of many species, including humans.

Currently known selective opioid δ-ligands, with few exceptions, are peptide nature and are not suitable for the introduction of a system of ways. Some time used ones δ-antagonists (OPI is the W given Takemori, Portoghese, 1992, Ann, Rev. Pharmacol. Tox., 32:239-269). These compounds, such as naltrindole possess a very low (for example, more than 10-fold) selectivity for δ-receptor against linking μ-receptor and do not show analgesic activity, which emphasizes the need to develop highly selective ones δ-agonists.

In the publication mentioned above as a reference, it is emphasized that the drugs applicability antagonists in many cases depends on a reliable correlation of their activity in vitro and in vivo. In particular, in such cases, ones ligands are preferred because they are usually able to penetrate into the CNS, and they are less susceptible to metabolic inactivation. Ones are selective antagonists of opioid receptors also have potential clinical applicability in the treatment of several disorders in which endogenous opioids may play a role modulators. Such disorders include slow, labored or systematically insufficient bowel movements, immune disorders, drug dependency and alcoholism. A more complete list of diseases for which effective antagonists of opioid receptors, are shown in Olson, G. A., R. D. Olson, Kastin, A., 1988, Peptides, 10: 1253-1280.

Next, with reference to the results of numerous in vitro and in vivo, the factors for naltrindole and its derivatives, in particular the N-methyl and benzofuranol derivatives, it is shown that these compounds exert their activity in relation to δ- and κ-opioid receptors. For this reason, compounds with such kind of activity, can be considered as a new type of mixed agonist-antagonist analgesics which act as agonists in relation to δ-opioid receptors and as an antagonist against κ-opioid receptors, respectively.

Recently ones δ-agonist, BW 373U86 was described Ghang et al., 1993, J. Pharmacol. Exp. Ther., 267:852-857, as the first δ-selective ones agonist, analgesic activity, but it has a significant affinity to μ-receptor.

Thus, the aim of the present invention is the discovery of new analgesics with good analgesic effect and less side effects compared to existing μ-agonists and potential oral performance, as well as their use in the treatment of diseases, for example, to relieve pain, which involves the impact of these compounds on these receptors.

Identified known analgesics have many disadvantages: they have poor pharmacokinetic properties and do not have analgesia what his actions with the introduction of a system of ways. It was also documented that the preferred compounds described previously, the systematic introduction cause significant convulsive effect.

In WO 93/15062 and WO 95/045051 describes some diarylpyrimidine and diarylpyrimidine compounds, including BW 373U86, however, these known compounds differ in structure from the compounds in accordance with the present invention.

The above objective has been achieved through the development of new piperazinone and been the analogs of piperidine compounds, as described below.

Description of the invention

For the treatment of diseases mediated by opioid receptors, for example, for the treatment of pain, in accordance with the present invention offers new compounds having the formula (I)

where

G represents a carbon atom or nitrogen;

And choose from

(i) phenyl substituted by any of-COOH, -CONH2SOON3, -CN, NH2or-PINES3;

(ii) naphthyl, benzofuranyl and hineline; and

(iii)

,

,

and

,

where the phenyl ring of each substituent may be optionally and independently substituted with one or two substituents selected from hydrogen, CH3;

R1selected from hydrogen is; branched or straight C1-C6of alkyl, C1-C6alkenyl, -CO(C1-C6alkyl); C4-C8(alkyl-cycloalkyl), where alkyl represents a C1-C2-alkyl, and cycloalkyl represents a C3-C6cycloalkyl; phenyl;

R2selected from hydrogen;

each of R9, R10, R13, R14, R17and R18independently has the meanings indicated above for R1;

Represents a substituted or unsubstituted aromatic, optionally substituted C5-C10hydroaromatics residue being optionally and independently substituted with one or two substituents, independently selected from hydrogen, CH3, halogen, OR7; R7selected from C1-C6the alkyl.

In the scope of the present invention includes pharmaceutically acceptable salts of compounds of formula (I), their isomers, hydrates, isoforms, and prodrugs.

Preferred compounds in accordance with this invention are the compounds of formula (I),

where

G represents a carbon atom or nitrogen;

And choose from

(i) phenyl substituted by any of-COOH, -CONH2SOON3, -CN, NH2or-PINES3;

(ii) naphthyl, benzofuranyl and hineline; and

(iii)

,

,

and

,

where the phenyl ring of each substituent may be optionally and independently substituted with one or two substituents selected from hydrogen, CH3;

each of R1independently selected from hydrogen; branched or straight C1-C4of alkyl, allyl, -CO-(C1-C6alkyl), where alkyl represents a C1-C2alkyl, and cycloalkyl - C3-C6cycloalkyl; and phenyl;

R2represents hydrogen;

each of R9, R10, R13, R14, R17and R18independently has the meanings indicated above for R1;

Choose from phenyl, naphthyl, indolyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl;

with each In-group is optionally substituted with 1-2 substituents independently selected from hydrogen, CH3, halogen and OR7where R7have the above values.

Particularly preferred compounds in accordance with this invention are the compounds of formula (I),

where

G represents a nitrogen atom;

And choose from

,

,

and

,

where

each of R9, R10, R13, R14, R17and R18represents an ethyl group;

R1selected from hydrogen, methyl, ethyl, allyl or CH2-cyclopropyl;

R2represents H, methyl or or1where R1have the above meanings;

Choose from phenyl, naphthyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl;

with each In-group is optionally substituted with 1-2 substituents independently selected from hydrogen, CH3, halogen and OR7where R7have the above meanings;

each of R3, R4, R5and R6independently selected from N, CH3CH(Me)2CH2CH(Me)2CH (Me)CH2CH3.

The substituents a and b, respectively, can be optionally substituted in any position of the ring.

By "halogen" means chlorine, fluorine, bromine and iodine.

By "aryl" refers to aromatic ring having 6 to 10 carbon atoms, such as phenyl and naphthyl.

Under the "heteroaryl" we mean an aromatic ring in which one or more of the 5 to 10 atoms in the ring are carbon, and other elements such as N, S and O.

Under "hydroaromatics connection" means a partially or fully saturated structures of the aromatic ring, having 5-10 ring carbon atoms.

Under "isomers" refers to the compounds of formula (I), differing in the position of its functional groups and/or orientation. Under "orientation" refers to stereoisomers, diastereoisomers, regioisomers and enantiomers.

Under the "isoform" refers to the compounds of formula (I), distinguished by its crystal lattice, such as crystalline compound and amorphous compounds.

By "prodrug" means the pharmacologically acceptable derivatives such as esters and amides, in which the biotransformation product of the derivative is the active drug. The reference to Goodman and Gilmans, The Pharmacological Basis of Therapeutics, 8 th ed., McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p.13-15, describes prodrugs in General.

New connections in accordance with the present invention can be used in therapy, especially for the treatment of pain.

These compounds can also be used to modulate the analgesic effect, acting on the level of receptor subtype μ-opioid, and the modulation side effects occur when using agents, acting at the level of receptor subtype μ-opioid, such as morphine, particularly respiratory depression, intestinal peristalsis and the tendency to abuse drugs.

Join this invention can also be used as immunomodulators, especially for the treatment of autoimmune diseases such as arthritis, skin grafting, agencies and similar surgical procedures for the treatment of collagen diseases, various allergies, as antitumor and antiviral agents.

Compounds according to this invention can be used to treat degeneration or dysfunction of opioid receptors, and also to prevent them. In diagnostic equipment, visualisierung devices, such as positron emission tomography, can be used labeled with isotopic variants of the compounds according to this invention.

Compounds according to this invention can be used to treat diarrhea, depression, urinary incontinence, various mental illnesses, cough, lung edema, various gastro-intestinal disorders, spinal cord injuries and drug abuse, including abuse of alcohol, nicotine, opioid, and other drugs, as well as to treat disorders of the sympathetic nervous system, such as hypertension.

The best way of implementing the present invention known at present is the use of compounds in accordance with Example 21 (compound 33), Example 22 (compound 34), Example 23 (compound 37), Example 24 (compound 38), Example 25 (compound 41), When the leader 26 (compound 42), Example 27 (compound 45), Example 29 (compound 51), Example 30 (compound 54), Example 35 (compound 64), Example 36 (compound 65), Example 50 and Example 51. The numbering of the compounds corresponds to the following Examples, as well as following Schema.

WAYS to GET

Generic way And

The aldehyde or ketone is heated with a nucleophile such as a Grignard reagent or organolithium, to obtain the corresponding alcohol. Then the alcohol may be converted into a suitable tsepliaeva group (X), such as ether, sulfonate or halide, which, in turn, can be substituted by nucleophilic compound, such as substituted or unsubstituted piperazine. Derivatives of N-(4)-unsubstituted piperazine can then be appropriately substituted by various groups through their organohalide or equivalent connection or etilirovany different allerease connections. This procedure leads to the formation of compounds according to General formula I.

Generic method

N-protected amino acid, as its activated ester may be subjected to reaction with a second amino acid ester. After treatment with acid, these compounds can be subjected to cyclization to obtain piperazinone. This Dion can be restored with the help of many standard methods to the appropriate piperazine (e.g., regenerating agent such as lithium aluminum hydride, conversion in thioamide and subsequent desulfurization, hydrogenation in the presence of POCl3and so on). Then, the piperazine may be alkylated or allerban on one or more attach and/or may be used later in the synthesis method A.

In this case, you may need to deprotect functional groups or further modification; each of these individual cases are described. Specific examples illustrating the above transformations described in experimental form.

All reagents, designed for transformations (including salt), solvents, known in chemistry and Bioperine carried out in an appropriate biological environment for carrying out these transformations include all agents that enhance the reaction (for example, NMR), and chiral resolution using chiral salt formation and chiral biological permissions.

Detailed description of the invention

Hereinafter the invention is described in more detail by using examples that do not imply a limitation.

In the examples the following abbreviations are used:

s - singlet; d - doublet; dd, double doublet;

t - triplet, m = multiplet; brs - Shire. the singlet.

SCHEME 1

(±)-3-(((αR*/S*)-α-((2S*,5R*)-4-Allyl-2,5-dimethyl-1-piperazinil)-1-naphthyl)anisole (4 and 5)

EXAMPLES

Compounds according to Examples 1-3 are synthesized, as shown in the Diagram above, 1.

And

I. Obtain 3-methoxy-α-(1-navtree) benzyl alcohol (compound 1)

To a solution of 3-bromoanisole (5,61 g, 30.0 mmol) in dry tetrahydrofuran (80 ml) was added dropwise a solution of n-butyl lithium-hexane (1.6 m, 37.5 ml, 60 mmol) in a nitrogen atmosphere at -78°C. the Reaction mixture allow to warm to room temperature over 2 hours and before adding 1-naphthaldehyde (4,69 g, 30.0 mmol in 10 ml of tetrahydrofuran (THF), and again cooled to -78°C. the Mixture is heated to room temperature for 3 hours, then abruptly cool a solution of aqueous NH4Cl and extracted with ethyl acetate (3×50 ml). The combined organic phases are washed with saturated saline and dried over MgSO4. Removing the solvents in vacuo, the obtained 3-methoxy-α-(1-naphthyl)benzyl alcohol (4,25 g, 54%). Gas chromatography - mass spectroscopy (GC-MS) (Rt=10,41 min) 264 (M+), 245, 231, 215, 202, 155, 135, 128, 109.

II. Obtain 3-methoxy-α-(1-naphthyl)benzyl chloride (compound 2)

To a solution of 3-methoxy-α-(1-naphthyl)benzyl alcohol (2.5 g, 9.5 mmol) in diethyl ether (5 ml) at 0°add 35% hydrochloric acid (10 ml). The reaction mixture is heated to room temperature within 1 cha is a, and then extracted with ethyl acetate (3×50 ml). The combined organic layers washed with aqueous solution of NH4Cl and saturated saline and then dried over MgSO4. Viparita solvents, get 3-methoxy-α-(1-naphthyl)benzyl chloride (1,94 g, 72%). GC-MS (Rt=10,30 min) 282 (M+), 247, 232, 215, 202, 189, 163, 151, 139, 123, 101.

EXAMPLE 1.

Receive (±) TRANS-1-(3-methoxy-α-(1-naphthyl)benzyl)-2,5-dimethylpiperazine (compound 3)

A mixture of TRANS-2,5-dimethylpiperazine (456 mg, 4.0 mmol), 3-methoxy-α-(1-naphthyl)benzyl chloride (430 mg, 1.5 mmol) and triethylamine (2 ml) in dry dimethylformamide (10 ml) were boiled under reflux for 2 hours in nitrogen atmosphere. After cooling to room temperature the reaction mixture is cooled rapidly 1N aqueous solution of NH4OH and extracted with ethyl acetate (3×50 ml). The combined organic layers washed with 0,5N aqueous solution of NaOH, saturated aqueous NH4Cl and saturated saline and then dried over MgSO4. Removing the solvents, get (±) -TRANS-1-(3-methoxy-α-(1'-naphthyl)benzyl)-2,5-DIMETHYLPROPANE-zine used without processing at the next stage: GC-MS (two isomers: Rt=12,98 and 13,10 min) 360 (M+), 301, 276, 247, 232, 215, 189, 165, 131, 113.

EXAMPLES 2 and 3.

Receive (±)-3-((αR*/S*)-α-((2S*,5R*)-4-Allie-2,5-dimethyl-1-piperazinil)-1-naphthyl)anisole(compound 4 and 5)

The mixture obtained above (±)-TRANS-1-(3-methoxy-α-(1-

naphthyl)benzyl)-2,5-dimethylpiperazine, K2CO3(276 mg, 2.0 mmol) and allylbromide (242 mg, 2.0 mmol) in dimethylformamide (5 ml)/tetrahydrofuran (10 ml) is stirred for 3 hours at room temperature. The reaction mixture is cooled rapidly 1N NH4OH and extracted with ethyl acetate (3×50 ml). The combined organic layers washed with saturated aqueous NH4Cl and saturated saline and then dried over MgSO4. Viparita solvents, get soggy (±)-3-((αR*/S*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinil)-1-naphthyl) anisole, which is cleaned at silikagelevye column and elute AcOEt-hexane (2:98→100:1) to obtain two isomers (a total of 267 mg, 45% of 2):

The first isomer, compound 4: GC-MS (Rt=14.84 min) 401.15 (M++1, 0.3%), 400.15 (M+, 0.9), 359.15 (0.6), 330.15 (0.4), 302.15 (3.2), 274.15 (8.0), 247.05 (23.0), 215.10 (12.7), 202.05 (7.8), 153.15 (100), 126.15 (10.1); δn(400 MHz, CDCl3) 1.02 (d, J=6.4 Hz, 6H), 2.15 (dd, J=11.2, 6.4 Hz, 1H), 2.31 (dd, J=11.2, 6.4 Hz, 1H), 2.60 (m, 1H), 2.74 (dd, J=11.2, 3.2 Hz, 1H), 2.80 (dd, J=11.2, 3.2 Hz, 1H), 2.94 (dd, J=13.6, 7.2 Hz, 1H), 3.03 (dt, J=6.4, 3.2 Hz, 1H), 3.20 (dd, J=13.6, 5.6 Hz, 1H), 3.73 (s, 3H), 5.12 (m, 2H), 5.73 (brs, 1H), 5.83 (m, 1H), 6.68 (dd, J=8.0, 2.4 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 7.12 (m, 2H), 7.42 (m, 3H). 7.62 (d, J=7.2 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 8.28 (brs, 1H); δc-13(100 MHz, CDCl3) 13.2, 14.2, 35.6, 52.1, 53.0, 55.1, 55.2, 57.2, 63.8, 111.6, 114.4, 117.2, 121.1, 123.8, 125.2, 125.7, 125.8, 127.2, 127.5, 127.8, 128.9, 132.1, 134.0, 135.5, 137.4, 145.5, 1595.

Its HCl salt: TPL 124-135°C (ether);

νmax(KBr) cm-13483, 1601, 1264;

Anal. for C27H32N2O•2HCl•N2About:

Calculated C, 65.98; H, 7.38; N, 5.70.

Found: C, 66.12; H, 7.25; N, 5.42.

The second isomer, compound 5; GC-MS (Rt=14.65 min) 401.25 (M++1, 0.2%), 400.25 (M+0.8), 359.15 (0.4), 330.15 (0.4), 302.15 (3.1), 274.15 (8.0), 247.05 (21.7), 215.10 (13.0), 202.05 (7.0), 153.15 (100), 126.15 (9.7); δn(400 MHz, CDCl3) 0.93 (d, J=6.4 Hz, 3H), 1.15 (d, J=6.4 Hz, 3H), 2.14 (m,2H), 2.37 (m, 1H), 2.60 (dd, J=11.6, 2.8 Hz, 1H), 2.84 (m, 2H), 2.96 (m,1H), 3.35 (dd, J=13.2, 5.2 Hz, 1H), 5.13 (m, 2H), 5.81 (s, 1H), 5.86 (m, 1H), 6.73 (dd, J=8.0, 2.8 Hz, 1H), 6.81 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 7.16 (m, 1H), 7.40 (m, 3H), 7.70 (m, 2H), 7.80 (d, J=8.0 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H); δc-13(100 MHz, CDCl3) 15.7, 16.3, 38.8, 53.6, 55.0, 55.6, 56.8, 59.3, 63.6, 111.5, 115.6, 117.4, 121.9, 124.6, 125.0, 125.1, 125.4, 126.2, 127.4, 128.5, 128.9, 131.6, 133.9, 135.0, 138.3, 142.2, 159.4.

Its HCl salt: TPL 150,5-153°C (ether);

νmax(KBr) cm-13483, 1600, 1262;

Anal. to:27H32N2O•2HCl•N2About:

Calculated: C, 66.59; H, 7.35; N, 5.75.

Found: C, at 66.41; H, 7.03; N, 5.48.

SCHEME 2.

(±)-3-((αR*/S*)-α-((2S*,5R*)-4-updid-2,5-dimethyl-1-piperazinil)-2-naphthyl) anisole (9 and 10)

Compounds according to Examples 4-6 synthesize,

as shown in the Diagram above, 2.

Century

I. Obtain 3-methoxy-α-(2-naphthyl)gasoline ethanol (compound 6)

Connection 6 receive, using pried the ru synthesis, described for compound 1, but replacing 1-naphthaldehyde 2-naphthaldehyde.

GC-MS (Rt=10.68 min) 264 (M+), 247, 231, 215, 202, 155, 135, 128, 109; δn(400 MHz, CDCl3) 3.15 (brs, 1H), 3.59 (s, 3H), 5.71 (s, 1H), 6.69 (dd, J=8.4, 2.8 Hz, 1H), 6.87 (m, 2H), 7.11 (t, J=8.0 Hz, 1H), 7.29 (dd, J=8.4, 1.2 Hz, 1H), 7.35 (m, 2H), 7.63 (d, J=8.4 Hz, 1H), 7.70 (m, 3H); δc-13(100 MHz, CDCl3) 55.0, 75.9, 112.1, 112.8, 118.9, 124.6, 124.9, 125.7, 125.9, 127.5, 127.9, 128.1, 129.3, 132.7, 133.1, 141.0, 145.2, 159.5.

II. Obtain 3-methoxy-α-(2-naphthyl)benzyl chloride (compound 7)

Connection 7 receive, using the synthesis procedure described for compound 2 but replacing compound 1 with compound 6.

GC-MS (Rt=10.58 min), 282 (M+), 247, 231, 215, 202, 189, 151, 123, 101.

EXAMPLE 4.

Receive (±)-TRANS-1-(3-methoxy-α-(2-naphthyl)benzyl)-2,5-dimethyl-piperazine (compound 8)

Compound 8 receive, using the synthesis procedure described for compound 3, but substituting compound 2 compound 7.

Use without processing at the next stage: GC-MS (Rt-14.03 min) 360 (M+), 331, 301, 276, 247, 219, 169, 131, 113.

EXAMPLES 5 and 6.

Receive (±)-3-((αR*/S*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinil)-2-naphthyl)anisole (compound (9) and (10)

The compounds of these Examples receive, using the synthesis procedure described for Examples 2 and 3, but substituting compound 3 for compound 8.

Compound 9 (one pure isomer): GC-MS (Rt=16.05 min) 401.25 (0.2%), 400.25 (0.8), 359.15 (0.4), 330.15 (0.4), 302.15 (31), 274.15 (8.0), 247.05 (21.7), 215.10 (13.0), 202.05 (7.0), 153.15 (100), 126.15 (9.7); δn(400 MHz, CDCl3) 1.36 (d, J=6.4 Hz, 3H), 1.41 (d, J=6.4 Hz, 3H), 3.16 (dd, J=13.2, 2.4 Hz, 1H), 3.26 (d. J=13.2 Hz, 1H), 3.46 (m, 1H), 3.86 (s, 3H), 3.94 (dd, J=11.2, 2.8 Hz, 1H), 4.10 (m, 2H), 4.46 (m, 2H), 5.58 (m, 2H), 5.78 (s, 1H), 6.05 (m, 1H), 6.96 (dd, J=8.0, 2.0 Hz, 1H), 7.18 (s, 1H), 7.33 (m, 1H), 7.44 (m, 1H), 7.50(m, 2H), 7.83 (m, 3H), 8.04 (d, J=8.0 Hz, 1H), 8.13 (s, 1H), 13.6 (brs, 2H).

Its HCl salt: TPL 129-138°C (ether);

νmax(KBr) cm-13426, 1600, 1262;

Anal. for C27H32H2About•2HCl•N2O:

Calculated: C, 66.59; H, 7.35; N, 5.75;

Found: C, 66.80; H, 7.11; N, 5.42.

Compound 10 (mixture of two isomers). Its HCl salt: TPL 160-162,5°C (ether);

νmax(KBr) cm-13380, 1600, 1261;

Anal. for C27H32N2About•2HCl•N2About:

Calculated: C, 67.21; H, 7.31; N, 5.81;

Found: C, 67.13; H, 6.97; N, 5.47.

The SCHEMA. 3.

(±)-3-((αR*/S*)-α-((2S*,5R*)-4-alkyl-2,5-dimethyl-1-piperazinil)-2-benatural)anisole (14, 15, 16 and 17)

Compounds according to Examples 7-11 are synthesized, as shown in the Diagram above, 3.

C.

I. Obtain 3-methoxy-α-(2-benzofuranyl) gasoline ethanol (compound 11)

The connection in this example, the gain, using the synthesis procedure described in Example 1.

GC-MS (Pt=9.54 min) 254.15 (M+, 100%), 237.10 (73.8), 221.05 (19.6), 194.10 (17.8), 165.10 (30.3), 147.05 (76.7), 135.10 (69.2), 118.10 (35.4), 108.10 (26.5), 91.10 (47.1); δn(400 MHz, CDCl 3), 3.21 (brs, 1H), 3.72 (s, 3H), 5.82 (s, 1H), 6.47 (s, 1H), 6.80-7.50 (m, 8H).

II. Obtain 3-methoxy-α-(2-benzofuranyl)benzyl chloride (compound 12)

Connection 12 receive, using the synthesis procedure described for compound 2 but replacing compound 1 with compound 11.

GC-MS (Rt=9.08 min) 272.05 (M+, 4.1%), 237.10 (100), 221.05 (4.5), 194.10 (14.7), 165.10 (23.1); δn(400 MHz, CDCl3) 3.78 (s, 3H), 6.11 (s, 1H), 6.56 (s, 1H), 6.85-7.50 (m, 8H).

EXAMPLE 7.

Receive (±)-TRANS-1-(3-metoxy-α-(2'-benzofuranyl)-benzyl)-2,5-dimethylpiperazine (compound 13)

Connection 13 receive, using the synthesis procedure described for compound 3, but substituting compound 2 compound 12.

GC-MS (Rt=11.87 min and Rt=12.09 min) 351.15 (M++1, 2.2%), 350.15 (M+, 8.6), 321.20 (0.4), 308.15 (0.2), 294.20 (18.3), 266.10 (58.6), 237.10 (100), 221.05 (3.0), 194.10 (10.0), 178.05 (4.1), 165.10 (13.0), 131.05 (2.9), 113.10 (43.8); δn(400 MHz, CDCl3) (isomer at Rt=11.87 min) 0.92 (d, J=6.4 Hz, 3H), 1.20 (d, J=6.4 Hz, 3H), 1.92 (dd, J=11.2, 10.8 Hz, 1H), 2.44 (m, 1H), 2.69 (dd, J=11.2, 10.8 Hz, 1H), 2.83 (m, 2H), 2.90 (m, 1H), 3.78 (s, 3H) 5.56 (s, 1H), 6.61 (s, 1H), 6.80 (d,, J=8.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 7.10 (s, 1H), 7.24 (m, 3H), 7.46 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H); (isomer at Rt=12.09 min) 0.96 (d, J=6.4 Hz, 3H), 1.22 (d, J=6.4 Hz, 3H), 1.83 (dd, J=11.2, 10.8 Hz, 1H), 2.40 (m, 1H), 2.65 (m, 1H), 2.90 (m, 3H), 3.80 (s, 3H), 5.47 (s, 1H), 6.63 (s, 1H), 6.84 (m, 2H), 7.21 (m, 2H), 7.24 (m, 2H), 7.46 (d, J=8.0 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H).

Its HCl salt: TPL 115-125°C (ether);

νmax(KBr) 3373, 1595, 1257;

Anal. for C22H26H2O2/sub> •1.70HCl•N2O:

Calculated: C, 63.51; H, 6.81; N, 6.73;

Found; C, 63.60; H, 6.80; N, 6.70.

EXAMPLES 8 and 9.

Receive (±)-3-((αR*/S*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinil)-2-benzofuranyl) anisole (compound 14 and 15)

The compounds of these Examples receive, using the synthesis procedure described for Examples 2 and 3, but substituting compound 3 for compound 13.

The first isomer, compound 14; GC-MS (Rt=13.03 min) 390.20 (M+, 1.5%), 349.15 (0.4), 320.10 (0.3), 292.10 (1.7), 264.10 (4.2), 237.10 (25.1), 221.05 (1.4), 194.10 (5.2), 165.10 (5.5), 153.15 (100), 126.15 (4.8), 98.05 (8.7), 84.10 (17.8); δn(400 MHz, CDCl3) 0.97 (d, J=6.4 Hz, 3H), 1.21 (d, J=6.4 Hz, 3H), 2.12 (m, 2H), 2.35 (m, 1H), 2.65 (m, 1H), 2.75 (dd, J=11.6, 2.4 Hz, 1H), 2.81 (m, 3H), 3.42 (dd, J=13.6, 5.2 Hz, 1H), 3.78 (s, 3H), 5.14 (m, 2H), 5.51 (s, 1H), 5.85 (m, 1H), 6.61 (s, 1H), 6.81 (dd,.3=8.0, 2.4 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 7.11 (s, 1H), 7.24 (m, 3H), 7.44 (d, J-8.0 Hz, 1H), 7.54(d, J=8.0 Hz, 1H); δc-13(100 MHz, CDCl3) 17.2, 17.5, 53.1, 54.4, 55.2, 56.0, 56.6, 59.2, 60.4, 106.8, 111.3, 112.1, 114.2, 117.8, 120.6, 120.7, 122.6, 123.8, 128.1, 129.0, 134.8, 141.4, 154.9. 155.2, 159.6.

Its HCl salt: TPL 122-128°C (ether);

νmax(KBr) cm-13490, 1602, 1253;

Anal. for C25H30N2O2•2HCl•0.25H2About:

Calculated: C, 64.17; H, 7.00; N, 5.99;

Found: C, 64.27; H, 6.92: N, 5.92.

The second isomer, compound 15: GC-MS (Rt=13.23 min) 390.20 (M+, 3.1%), 349.15 (0.5), 292.10 (2.2), 264.10 (5.5), 237.10 (33.2), 221.05 (1.8), 194.10 (7.1), 165.10 (7.7), 153.15 (100), 126.15 (7.1), 98.15 (18.4), 84.10 (25.0); δn(400 MHz, CDCl3) 1.00 (d, J=6.4 Hz, 3H), 1.21 (d, J=6.4 Hz, 3H), 2.12 (m, 2H), 248 (m, 1H), 2.61 (m, 1H), 2.78 (dd, J=11.6, 2.4 Hz, 1H), 2.83 (m, 3H), 3.42 (dd, J=13.6, 5.6 Hz, 1H), 3.79 (s, 3H), 5.15 (m, 2H), 5.40 (s, 1H), 5.85 (m, 1H), 6.64 (s, 1H), 6.86 (m, 3H), 7.20 (m, 3H), 7.44 (d, J=8.0 Hz, 1H), 7.50(d, J=8.0 Hz, 1H).

Its HCl salt: TPL 97-104°C (ether);

νmax(KBr) cm-13438, 1601 (s), 1260;

Anal. for C25H30H2O2•2HCl•N2About:

Calculated: C, at 63.56; H, 7.04; N, 5.93;

Found: C, 63.70; H, 6.68; N, 5.83.

EXAMPLES 10 and 11.

Receive (±)-3-((αR*/S*)-α-((2S*,5R*)-4-cyclopropylmethyl-2,5-dimethyl-1-piperazinil) -2-benzofuranyl) anisole (compound 16 and 17)

The compounds of these Examples receive, using the synthesis procedure described for examples 2 and 3, except for cyclopropylmethyl iodide and replacement connection 3 connection 13.

The first isomer, compound 16: GC-MS (Rt=14.87 min) 405.25 (M++1, 2.3%), 404.25 (M+, 8.2), 362.20 (0.5), 349.15 (0.4), 320.20 (0.8), 292.20 (4.1), 291.10 (3.4), 265.10 (16.5), 237.10 (65.9), 194.10 (11.5), 167.20 (100), 140.20 (3.9), 124.15 (4.6), 98.15 (44.0); 5h (400 MHz, CDCl3) 0.05 (m, 2H), 0.46 (m, 2H), 0.80 (m, 1H), 0,92(d, J=6.0 Hz, 3H), 1.21 (d, J=6.0 Hz, 3H), 2.01 (dd, J=12.8, 7.2 Hz, 1H), 2.17 (m, 2H), 2.35 (m,1H), 2.64 (dd, J=13.2, 6.4 Hz, 1H), 2.66 (m, 1H), 2.72 (dd, J=12.0, 2.4 Hz, 1H), 3.04 (dd, J=11.2, 3.2 Hz, 1H), 3.75 (s, 3H), 5.50 (s, 1H), 6.58 (s, 1H), 6.79 (dd, J=8.0, 2.4 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 7.09 (s, 1H), 7.20 (m, 3H), 7.41 (d, J=8.0 Hz, 1H), 7.51 (m, 1H); δc-13(100 MHz, CDCl3) 3.2, 4.7, 7.4, 17.4, 17.7, 53.1, 54.5, 55.2, 56.0, 58.3, 59.2, 60.8, 106.8, 111.3, 112.0, 114.2, 120.6, 120.7, 122.6, 123.7, 128.0, 129.0, 141.4, 154.8, 155.2, 159.6.

Its HCl salt: TPL 162-164°C (ether);

νmax(KBr) cm-13414, 1599, 1255;

Anal. for C26H32N2O2•2HCl•N2About:

Calculated: C, 64.19; H, 7.25; N, 5.76;

Found: C, 64,43; H, 7.30; N, 5.78.

The second isomer, compound 17: GC-MS (Rt=15.17 min) 405.25 (M++1, 2.2%), 404.25 (M+, 8.9), 362.10 (0.6), 349.15 (0.4), 320.10 (0.8), 292.10 (5.0), 291.10 (3.9), 265.10 (19.4), 237.10 (72.2), 194.10 (12.8), 167.20 (100), 140.10 is expected (3.9), 124.15 (4.8), 98.15 (45.5); δn(400 MHz, CDCl3) 0.08 (m, 2H), 0.48 (m, 2H), 0.82 (m, 1H), 0.97 (d, J=6.4 Hz, 3H), 1.25 (d, J=6.4 Hz, 3H), 2.10 (m, 2H), 2.28 (dd, J=11.2, 10.0 Hz, 1H), 2.49 (m,1H), 2.62 (dd, J=13.2, 6.0 Hz, 1H), 2.63 (m, 1H), 2.83 (dd, J=11.2, 2.8 Hz, 1H), 3.02 (dd, J=11.2, 3.2 Hz, 1H), 3.78 (s, 3H), 5.43 (s, 1H), 6.64 (s, 1H), 6.87 (m, 3H), 7.21 (m, 3H), 7.45(dd, J=7.6, 1.2 Hz, 1H), 7.50 (m, 1H); δc-13(100 MHz, CDCl3) 3.3, 4.6, 7.4, 17.0, 17.6, 52.6, 55.2, 55.4, 55.6, 58.3, 60.3, 61.6, 105.7, 111.3, 112.5, 115.9, 120.5, 122.1, 112.5, 123.5, 128.4, 128.9, 137.3, 155.0, 158.3, 159.3.

Its HCl salt: TPL 92-105°C (ether);

νmax(KBr) cm-13398, 1599, 1257;

Anal. for C26H32N2O2•2HCl•0.5H2O;

Calculated: C, 64.19; H, 7.25; N, 5.76;

Found: C, 64.38; H, 7.14; N, 5.73.

The SCHEMA. 4.

(±)-3-((αR*/S*)-α-((2S*,5R*)-4-alkyl-2,5-dimethyl-1-piperazinil)-6-chinoline) anisole (22, 23, 24 and 25)

D

I. Receiving 6-chinainternational

A mixture of 6-methylinosine (5,72 g, 40.0 mmol) and selenium oxide (4.44 g, 40.0 mmol) was heated to 220°C for 1 hour. After cooling, the residue is dissolved in ethyl acetate (100 ml). The organic solution was washed with brine and dried over MgSO4After evaporation of the solvents get a solid substance, recrystallization from a mixture of ether-hexane (1:1) to obtain 6-chinainternational (3,45 g, 55%).

GC-MS (Rt=5.29 min) 157.15 (M+, 100%), 156.15 (92.2), 128.15 (62.9), 101.15 (16.0); δn(400 MHz, CDCl3) 7.53 (m, 1H), 8.21 (m, 2H), 8.33 (m, 2H), 9.06 (m, 1H), 10.21 (s, 1H): δc-13(100 MHz, CDCl3) 122.1, 126.6, 127.6, 130.7, 133.5, 134.2, 137.3, 150.8, 153.0, 191.3.

Compounds according to Examples 12-17 are synthesized, as shown in the Diagram above, 4.

II. Obtain 3-methoxy-α-(6-chinoline)benzyl alcohol (compound 18)

The connection 18 receive, using the synthesis procedure described for compound 1, but replacing 1-naphthaldehyde 6-chinainternational.

GC-MS (Rt=11.13 min) 265.10(M+, 49.0%), 248.05(2.3), 204.05 (9.7), 156.05 (37.6), 135.00 (100), 109.00 (43.5); δn(400 MHz, CDCl3) 3.73 (s, 3H), 5.94 (s, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.95 (m, 2H), 7.22 (m, 1H), 7.31 (m, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.83 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 8.73 (m, 1H); δc-13(100 MHz, CDCl3) 55.2, 75.7, 112.3, 113.1, 119.1, 121.2, 124.6, 128.5, 129.4, 129.6, 136.3, 142.1, 145.2, 147.6, 150.1, 159.8.

III. Obtain 3-methoxy-α-(6-chicolini)benzyl chloride (compound 19)

Connection 19 receive, using the synthesis procedure described for compound 2 but replacing compound 1 to compound 18.

Use without processing at the next stage: δn(400 MHz, CDCl3) 3.73 (s, 3H), 5.98 (s, 1H), 6.8-8.2 (m, 9H), 8.80(s, 1H).

EXAMPLES 12 AND 13.

Receive (±)-TRANS-1-(3-methoxy-α-(6'-chinoline)-b is nil)-2,5-dimethylpiperazine (compounds 20 and 21)

The compounds of these Examples receive, using the synthesis procedure described for compound 3, but substituting compound 2 for compound 19.

GC-MS (Rt=14.91 min) 361.20(M+, 0.8%), 332.15 (0.3), 306.15 (0.6), 302.15 (14.4), 277.15 (52.5), 248.05 (100), 233.00 (10.6), 204.05 (17.1). 176.05 (2.7), 151.05 (1.4), 142.10 (1.8), 113.10 (19.9).

The first isomer, compound 20; δn(400 MHz, CDCl3) 1.06 (d, J=6.4 Hz, 3H), 1.24 (d, J=6.4 Hz, 3H), 1.84 (dd, J=11.6, 9.2 Hz, 1H), 2.60 (m, 2H), 2.77 (m, 2H), 3.06 (m, 2H), 3.80 (s, 3H), 5.44 (s, 1H), 6.77 (s, 1H), 6.83(d, J=8.0 Hz, 1H), 6.88(dd, J=8.0, 2.4 Hz,1H), 7.31 (m, 1H), 7.37 (m, 1H), 7.82 (s, 1H), 7.84 (m, 1H), 8.03 (d, J=8.8 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 8.87 (m, 1H).

Compound 21 (mixture of two isomers-25% of compound (20):

δn(400 MHz, CDCl3) 1.20 (m, 6H), 2.05 (m, 1H), 2.73 (m, 2H), 2.87 (m, 1H), 3.13 (m, 2H), 3.73 and 3.76 (s, 3H), 5.38 (s, 1H), 6.38 (brs, NH), 6.70-8.15 (m, 9H), 8.84 (m, 1H).

EXAMPLE 14.

Receive (±)-3-((αR*/S*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinil)-6-chinoline) anisole (compound 22)

The compound of this Example will be received, using the synthesis procedure described for Examples 2 and 3, but replacing compound 3 compound 20.

GC-MS (Rt=17.22 min) 401.25 (M+, 0.3%), 360.20 (0.3), 331.10 (0.2), 303.20 (1.7), 276.10 (4.5), 248.10 (17.2), 233.10 (4.5), 204.10 (8.0), 176.10 (1.3), 153.20 (100), 126.20 (5.4); δn(400 MHz, CDCl3) 1.0 (d, J=6.4 Hz, 3H), 1.21 (d, J=6.4 Hz, 3H), 1.99 (m, 1H), 2.20 (m, 1H), 2.56 (m, 1H), 2.66 (m,1H), 2.71 (m, 1H), 2.85 (m, 1H), 2.90 (m, 1H), 3.37 (dd, J=13.2, 4.0 Hz, 1H), 3.78 (s, H), 5.17 (m, 2H,), 5.35 (s, 1H), 5.87 (m, 1H), 6.82 (m, 3H), 7.26 (t, J=7.6 Hz, 1H), 7.36 (m, 1H), 7.81 (s, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 8.09 (d, J=7.6 Hz, 1H), 8.87 (m, 1H); δ c-13(100 MHz, CDCl3) 15.7, 16.4, 52.0, 53.7, 55.2, 55.5, 56.8, 58.9, 65.9, 112.1, 116.3, 117.8, 120.9, 122.5, 126.5, 127.9, 128.9, 129.0, 130.2, 134.8, 136.0, 139.2, 141.1, 147.6, 150.0, 159.5.

Its HCl salt: TPL 128-140°C (ether);

νmax(KBr) cm-13376, 1596, 1263;

Anal. for C26H31N3About•2.30HCl•N2O:

Calculated: C, 64.10; H, 6.93; N, at 8.62;

Found: C, 64.08; H, 6.92; N, 8.35.

EXAMPLE 15.

Receive (±)-3-((αR*/S*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinil)-6-chinoline) anisole (compound 23)

The compound of this Example will be received, using the synthesis procedure described for Examples 2 and 3, but replacing compound 3 compound 21.

GC-MS (Rt=17.21 min) 401.35 (M+, 0.4%), 360.30 (0.2), 331.20 (0.2), 303.20 (1.6), 276.10 (4.8), 248.10 (17.3), 233.10 (4.4), 204.10 (8.1), 176.10 (1.3), 153.20 (100), 126.20 (5.6); δn(400 MHz, CDCl3) 1.01 (d, J=6.0 Hz, 3H), 1.21 (d, J=6.0 Hz, 3H), 1.95 (m, 1H), 2.16 (m, 1H), 2.56 (m, 1H), 2.66 (m, 1H), 2.74 (m, 1H), 2.80 (m, 1H), 2.87 (m, 1H), 3. 30 (dd, J=13. 6, 5.6 Hz, 1H), 3.77(s, 3H), 5.13 (m, 2H), 5.34 (s, 1H), 5.82 (m, 1H), 6.77 (dd, J=8.0, 2.4 Hz, 1H), 6.99 (d, J=7.6 Hz, 1H), 7.11 (s, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.38 (dd, J=8.4, 4.0 Hz, 1H), 7.59 (d, J-8.4 Hz, 1H), 7.66 (s, 1H), 8.03 (d, J=8.8 Hz, 1H). 8.11 (d, J=8.4 Hz, 1H), 8.88 (m, 1H); δc-13(100 MHz, CDCl3) 15.3, 16.2, 51.9, 53.4, 55.2, 55.3, 56.8, 58.5, 66.1, 111.8, 114.0, 117.6, 120.6, 121.1, 127.9, 128.3, 128.9, 129.1, 131.4, 134.9, 136.0, 137.1, 144.1, 147.7, 150.2, 159.6.

Its HCl salt: TPL 177-182°C (ether);

νmax(KBr) cm-13405, 1597, 1260;

Anal. for C26H31N3O•2.80HCl:

Calculated: C, 62.01; H, 6.76; N, 8.34.

Found: C, 61.98; H, 6.77; N, 8.03.

EXAMPLES 16 and 17.

Receive (±)-3-((αR*/S*)-α-((2S*,5R*)-4-cyclopropylmethyl-2,5-dimethyl-1-piperazinil)-6-chinoline) anisole (compound 24 and 25)

The compound of this Example will be received, using the synthesis procedure as described for Examples 2 and 3, but replacing allylbromide cyclopropanemethylamine.

The first isomer, compound 24: GC-MS (Rt=20.77 min) 415.25 (M+, 3.8%), 344.15 (2.4), 302.10 (9.5), 276.10 (58.8), 248.15 (79.1), 233.10 (17.2), 204.10 (29.4), 176.10 (4.2), 167.15 (100), 138.15 (14.2), 112.15 (47.0); δn(400 MHz, CDCl3) 0.10 (m, 2H), 0.51 (m, 2H), 0.86 (m, 1H), 0.97(d, J=6.4 Hz, 3H), 1.25 (d, J=6.4 Hz, 3H), 1.98 (dd, J=11.2, 8.8 Hz, 1H), 2.14 (dd, J=l3.2, 6.4 Hz, 1H), 2.32 (dd, J=10.8, 5.6 Hz, 1H), 2.58 (m, 2H), 2.66 (dd, J=11.6, 2.8 Hz, 1H), 2.73 (m, 1H), 3.07 (dd, J=11.2, 3.2 Hz, 1H), 3.78 (s, 3H), 5.39 (s, 1H), 6.79 (s, 1H), 6.84 (m, 2H), 7.26 (t, J=8.0 Hz, 1H), 7.35 (dd, J=8.4, 4.0 Hz, 1H), 7.83 (s, 1H), 7.89 (d, J=8.8 Hz, 1H), 8.03 (d, J=9.2 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 8.86 (dd, J=4.0, 2.0 Hz, 1H); δc-13(100 MHz, CDCl3) 3.4, 4.4, 7.6, 16.2, 16.9, 52.1, 53.8, 55.2, 55.6, 58.5, 59.7, 65.6, 112.0, 116.3, 120.9, 122.6, 126.5, 127.9, 128.8, 129.0, 130.2, 136.0, 139.1, 141.1, 147.6, 149.9, 159.4.

Its HCl salt: TPL 127-157°C (ether);

νmax(KBr) cm-13402, 1596, 1262;

Anal. for C27H33N3About•3HCl•N2O:

Calculated: C, 60.23; H, 7.02; N, 7.80;

Found: C, 60.49; H, 7.00; N, 7.73.

The second isomer, compound 25: GC-MS (Rt=20.73 min) 415.25 (M+, 3.2%), 344.05 (2.3), 302.10 (7.7), 276.10 (48.5), 248.15 (69.6), 233.10 (15.7), 204.10 (25.8), 176.10 (3.7), 167.15 (100), 138.15 (12.2), 112.15 (46.8); δn(400 MHz, CDCl3) 0.17 (m, 2H), 0.56 (m, 2H), 0.97(m, 1H), 1.11 (brs, 3H), 1.27 (brs, 3H), 2.24 (m, 1H), .38 (m, 1H), 2.51 (m, 1H), 2.61 (m, 1H), 2.87 (m, 3H), 3.13 (m, 1H), 3.77 (s, 3H), 5.34 (s, 1H), 6.78 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 7.08 (s, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.39 (dd, J=8.4, 4.4 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 8.04 (d, J=8.8 Hz, 1H), 8.16 (d, J=8.4 Hz, 1H), 8.89 (d, J=4.0 Hz, 1H); δc-13(100 MHz, CDCl3) 4.07, 4.37, 6.9, 14.8, 15.1, 51.4, 55.2, 56.2, 58.2, 60.3, 66.4, 111.8, 114.2, 120.6, 121.2, 128.0, 128.1, 129.2, 131.0, 136.0, 137.0, 143.8, 147.7, 150.3, 159.6.

Its HCl salt: TPL 92-105°C (ether);

νmax(KBr) cm-13345, 1596, 1259.

SCHEME 5.

(±)-3-((αR*/S*)-α-((2S*,5R*)-4-alkyl-2,5-dimethyl-1-piperazinil)-4-chinoline)anisole (29 and 30)

Compounds according to Examples 18-20 are synthesized, as shown in the Diagram above, 5.

E.

I. Obtain 3-methoxy-α-(4-chinoline)benzyl alcohol (compound 26)

The connection 26 receive, using the synthesis procedure described for compound 1, but replacing 1-naphthaldehyde 4-hyalinobatrachium.

GC-MS (Rt=10.81 min) 266.10 (M++1, 11.8%), 265.10 (M+, 61.0), 248.05 (6.1), 232.00 (6.2), 216.05 (4.7), 204.00 (10.5), 191.05 (2.0), 176.00 (3.8), 156.00 (13.9), 135.10 (100), 129.10 (86.6), 109.10 (68.2), 102.10 (25.5); δn(400 MHz, CDCl3) 3.67 (s, 3H), 5.30 (brs, 1H), 6.41 (s, 1H), 6.76 (d, J=7.2 Hz, 1H), 6.90 (m, 2H), 7.18(t, J=7.6 Hz, 1H), 7.38 (m, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.62 (m, 1H), 7.92 (d, J=8.4 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 8.64 (dd, J=4.4, 1.2 Hz, 1H); δc-13(100 MHz, CDCl3) 55.1, 72.1, 113.0, 113.2, 118.5, 119.5, 123.9, 125.7, 126.5, 129.0, 129.5, 129.7, 143.8, 147.8, 149.1, 149.9, 159.7.

II. Obtain 3-methoxy-α-(4-chinoline)benzyl chloride (compound 27)

<> Connection 27 receive, using the synthesis procedure described for compound 2 but replacing compound 1 compound 26.

Use without processing at the next stage: GC-MS (Rt=10.54 min) 285.10 (M++2, 11.5%), 283.10 (M+, 33.10), 268.05 (0.2), 248.15 (100), 233.10 (37.0), 217.05 (27.2), 204.10 (45.5), 178.10 (5.9), 176.10 (11.5), 151.10 (5.7), 139.05 (2.1), 108.60 (11.0), 102.10 (17.4).

EXAMPLE 18.

Receive (±)-TRANS-1-(3-methoxy-α-(4-chinoline) benzyl-2,5-dimethylpiperazine (compound 28)

The compound of this Example will be received, using the synthesis procedure described for compound 3, but substituting compound 2 compound 27.

GC-MS (Rt=13.96 min) 362.20 (M++1, 1.4%), 361.20 (M+, 6.6), 306.10 (2.0), 302.15 (18.3), 277.15 (59.6), 248.15 (100), 233.10 (15.8) 204.10 (20.9), 176.10 (3.8), 151.00 (1.8), 143.15 (1.4), 113.15 (15.8); δn(400 MHz, CDCl3) 0.92 (d, J=6.4 Hz, 3H), 1.12 (d, J=6.4 Hz, 3H), 1.82 (dd, J=11.6, 10.0 Hz, 1H), 2.52 (brs, 1H), 2.62 (dd, J=11.6, 2.8 Hz, 1H), 2.72 (m, 1H), 2.77 (m, 1H), 2.88 (m, 1H), 2.98 (dd, J=11.6, 2.0 Hz, 1H), 3.72 (s, 3H), 5.86 (s, 1H), 6.69 (s, 1H), 6.72 (d, J=8.0, 1H), 6.78 (dd, J=8.0, 2.4 Hz, 1H), 7.20 (t, J=8.0 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.65 (d, J=4.4 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 8.89 (d, J=4.4 Hz, 1H).

EXAMPLES 19 and 20.

Receive (±)-3-((αR*/S*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinil)-4-chinoline) anisole (compound 29 and 30)

The compounds of these Examples receive, using the synthesis procedure described for Examples 2 and 3, but replacing compound 3 compound 28.

The first isomer, compound 29: GC-MS (Rt=At 15.97 min) 401.15 (the +, 0.8%), 360.20 (0.8), 303.15 (3.3), 276.15 (5.7), 248.05 (15.3), 217.05 (6.3), 204.10 (10.4), 176.00 (2.2), 153.20 (100), 126.10 (5.3), 98.10 (13.8); δn(400 MHz, CDCl3) 0.96 (d, J=6.0 Hz, 3H), 1.14(d,J=6.0 Hz, 3H), 2.01(m, 1H), 2.16 (t, J=10.0 Hz, 1H), 2.47 (m, 1H), 2.59 (d, J=11.2 Hz, 1H), 2.86 (m, 2H), 2.95 (t, J=6.0 Hz, 1H), 3.36 (dd, J=13.6, 4.4 Hz, 1H), 3.72 (s, 3H), 5.15 (m, 2H), 5.77 (s, 1H), 5.85 (m, 1H), 6.74 (m, 3H), 7.17(t, J=7.6 Hz, 1H), 7.38 (t, J-8.0 Hz, 1H), 7.60 (dd, J=7.2, 0.8 Hz, 1H), 7.73 (d, J=4.4 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 8.08 (d, J=8.8 Hz,1H), 8.90 (d, J=3.6 Hz, 1H); δc-13(100 MHz, CDCl3) 15.9, 16.6, 53.8, 55.1, 55.5, 56.7, 59.4, 63.2, 112.0, 115.7, 117.7, 120.6, 121.9, 124.4, 126.0, 126.8, 128.6, 129.3, 130.1, 134.8, 140.3, 148.5, 148.6, 150.2, 159.5.

Its HCl salt: TPL 158-166°C (AcOEt-ether);

νmax(KBr) cm-13400, 1596, 1263;

Anal. for C26H31N3About•3.0HCl•N2O:

Calculated: C, 59.24; H, 6.85; N, 7.97;

Found: C, 59.31; H, 6.94; N, 7.80.

The second isomer, compound 30: GC-MS (Rt=16.19 min) 401.25 (M+, 0.5%), 386.20 (6.2), 360.20 (0.7), 331.10 (0.3), 303.15 (3.3), 276.15 (4.7), 248.15 (13.7), 233.10 (5.8), 217.05 (4.9), 204.10 (9.8), 176.10 (1.8), 153.20 (100), 126.20 (5.2), 98.10 (13.9); δn(400 MHz, CDCl3); δc-13(100 MHz, CDCl3).

Its HCl salt: TPL 155-165°C (AcOEt-ether).

Scheme 6.

Compounds according to Examples 21 and 22 are synthesized, as shown in the Diagram above, 6.

F.

I. Receiving (±)-4-((α-hydroxy)-4-Chlorobenzyl)-N,N-diethylbenzamide (compound 31)

4-Formyl-N,N-diethylbenzamide (putting on 2,088 g, 10.1 mmol) is dissolved in 45 ml of anhydrous tetrahydrofuran. The solution of the OHL is to promote -78° With, and then added dropwise 10.1 ml (10.1 mmol) of 1.0 M solution of 4-Chloroaniline bromide in ether. The mixture is heated to room temperature within 3 hours. Then add 50 ml of a saturated solution of NH4Cl and the mixture is extracted with ethyl acetate (3×30 ml). The combined organic layers washed with water (2×30 ml) and saturated salt solution (1×30 ml), dried (Na2SO4), filtered and removed solvent in vacuo. The residue is subjected to chromatography on silica gel, elwira methanol: dichloromethane (1:125-3:125) to obtain the target compound as a colourless oil.

νmax(KBr) cm-13329, 2977, 1595, 1461, 1289, 1094, 1051, 830;

δn(400 MHz, CDCl3) 1.09 (3H, br 5), 1.21 (3H, br s), 3.22 (2H, br s), 3.33 (1H, d, J 3), 3.50 (2H, br s), 5.74 (1H, d, J 3), 7.22-7.34 (m, 8H);

II. Receive (±)-4-((α-chloro)-4-Chlorobenzyl)-N,N-diethylbenzamide (compound 32)

The connection 32 receive, using the synthesis procedure described for compound 2 but replacing compound 1 with compound 31

Use without processing at the next stage.

EXAMPLE 21.

Receive (±)-4-((α-(1-piperazinil))-4-Chlorobenzyl)-N,N-diethylbenzamide (compound 33)

The compound of this Example will be received, using the synthesis procedure described for compound 3, but substituting compound 2 compound 32.

TPL 112-113°With (from acetonitrile), νmax(KBr) cm-13347, 2947, 2809, 1615, 1451, 1318, 1284, 1094, 836; δn(400 MHz, CDCl3) 1.10 (3H, br s), 1.21 (3H, br s), 1.69 (1H, br s), 2.33 (4H, br s), 2.86-2.89 (4H, m), 3.24 (2H, br s), 3.51 (2H, brs), 4.22 (1H, s), 7.23-7.41 (8H, m);

C22H28N3OCl•0.3H2O requires: C, 67.52; H, 7.37; N, 10.74;

Found: C, 67.68; H, 7.37; N, 10.73.

EXAMPLE 22.

Receive (±)-4-((α-((4-allyl)-1-piperazinil)-4-Chlorobenzyl)-N,N-diethylbenzamide •2HCl (compound 34)

The compound of this Example will be received, using the synthesis procedure described in Examples 2 and 3, but replacing compound 3 compound 33.

TPL 147-163°C (from ether), νmax(KBr)/cm-13418, 2974, 2355, 1626, 1435, 1286, 1092, 945, 812: δn(400 MHz, CDCl3) 1.06 (3H, br s), 1.19 (3H, br s), 3.0-3.7 (14H, m), 5.4-5.6 (2H, m), 6.0-6.2 (1H, br m), 7.2-7.8 (9H, m);

With25H34N3OCl3requires: C, 60.18; H, 6.87; N, 8.42;

Found: C, 60.48; H, 6.89; N, 8.31.

SCHEME 7.

Compounds according to Examples 23-24 synthesized, as shown in the Diagram above, 7.

G.

I. Receiving (±)-4-((α-hydroxy) -2-naphthyl-methyl)-N,N-diethylbenzamide (compound 35)

The connection 35 receive, using the synthesis procedure described for compound 1, but replacing 3-bromoanisole 2-bromoanisole and 1-naphthaldehyde N,N-diethyl-4-carboxybenzene.

νmax(KBr) cm-13302, 2976, 1607, 1430, 1290, 1098, 813; δn(400 MHz, CDCl3) 1.09 (H, br s), 1.22 (3H, br s), 2.60 (1H, d, J 3), 3.24 (2H, br s), 3.52 (2H, br s), 6.00 (1H, d, J 3), 7.30-7.50 (7H, m), 7.76-7.88 (4H, m);

II. Receive (±)-4-((α-chloro)-2-naphthyl-methyl)-N,N-diethylbenzamide (compound 36)

The connection 36 receive, using the synthesis procedure described for compound 2 but replacing compound 1 with compound 35.

Use without processing at the next stage.

EXAMPLE 23.

Receive (±)-4-((α-(1-piperazinil))-2-naphthylmethyl)-N,N-diethylbenzamide (compound 37)

The compound of this Example will be received, using the synthesis procedure described for Example 1, but substituting compound 2 compound 36.

TPL 106-108°With (from acetonitrile), νmax(KBr)/cm-13324, 3052, 2964, 2810, 2774, 1613, 1465, 1287, 1130, 1098; δn(400 MHz, CDCl3) 1.07 (3H, br s), 1.19 (3H, br s), 1.89 (1H, brs), 2.40 (4H, br s), 2.89-2.92 (4H, m), 3.21 (2H, br s), 3.50 (2H, br s), 4.41 (1H, s), 7.24-7.84 (11H, 3m);

With26H31N3About•N2O requires: C, 74.75; H, 7.91; N, 10.06;

Found: C, 74.68; H, 7.56; N, 10.38.

EXAMPLE 24.

Receive (±)-4-((α-((4-allyl)-1-piperazinil))-2-naphthylmethyl)-N,N-diethylbenzamide (compound 38)

The compound of this Example will be received, using the synthesis procedure described for Examples 2 and 3, but replacing compound 3 compound 37,

νmax(KBr) /cm-13053, 2968, 2805, 1629, 1426, 1288, 1141, 1095, 921, 817; δn(400 MHz, CDCl3) 1.06 (3H, br s), 1.19 (3H, br s), 2.49 (6H, br s), 3.00 (2H, m), 3.20 (2H, br s), 3.49 (2H, br s), 4.41 (1H, s), 5.08-5.22 (2H, m, 5.78-5.92 (1H, m), 7.26-7.84 (11H, m).

With25H34N3OCl3•N2O requires: C, 76.99; H, 8.07; N, 9.29;

Found: C, 77.06; H, 8.09; N, 9.32%

SCHEME 8.

Compounds according to Examples 25-26 synthesized, as shown in the Diagram above, 8.

N.

I. Receiving (±)-4-((α-hydroxy)-4-xylyl)-N,N-diethylbenzamide (compound 39)

The connection 39 to receive, using the synthesis procedure described for compound 31, but substituting 4-chloraniline bromide for 4-toluylene bromide.

νmax(KBr)/cm-13364, 2970, 1602, 1455, 1381, 1291, 1101, 1054, 802; δn(400 MHz, CDCl3) 1.09 (3H, br s), 1.22 (3H, br s), 2.33 (3H, s), 2.55 (1H, br s), 3.24 (2H, br s), 3.52 (2H, br s), 5.78 (1H, d, J 3), 7.11-7.41 (8H, m);

II. Receive (±)-4-((α-chloro)-4-xylyl)-N,N-diethylbenzamide (compound 40)

The connection 40 receive, using the synthesis procedure described for compound 2.

Use in the next stage without further purification.

EXAMPLE 25.

Receive (±)-4-((α-(1-piperazinil))-4-xylyl)-N,N-diethylbenzamide (compound 41)

The compound of this Example will be received, using the synthesis procedure described for compound 3.

TPL 129-132°With (from acetonitrile), νmax(KBr)/cm-13320, 2957, 2811, 1610, 1437, 1285, 1128, 1010, 838; δn(400 MHz, CDCl3) 1.10 (3H, br s), 1.20 (3H, br s), 1.83 (1H, br s), 2.30 (3H, s), 2.34 (4H, br s), 2.86-2.89 (4H, m), 3.24 (2H, br s), 3.51 (2H, br s), 4.20 (H, s), 7.06-7.46 (8H, 3m);

With23H31N3O requires; C, 75.58; H, 8.55; N, 11.50;

Found: C, 75.30; H, 8.54; N, 11.56.

EXAMPLE 26.

Receive (±)-4-((α-((4-allyl)-1-piperazinil))-4-xylyl)-N,N-diethylbenzamide •2HCl (compound 42)

The compound of this Example will be received, using the synthesis procedure described for Examples 2 and 3.

TPL > 160°decomp. (from ether); νmax(KBr)/cm-13437, 2973, 2402, 1625, 1433, 1289, 1097, 944, 809: δn(400 MHz, CDCl3, free base) 1.10 (3H, br s), 1.20 (3H, br s), 2.29 (3H, s), 2.35-2.60 (6H, m), 3.03 (2H, m), 3.24 (2H, br s), 3.52 (2H, br s), 4.22 (1H, s), 5.12-5.23 (2H, m), 5.81-5.93 (1H, m), 7.05-7.45(8H, 3m);

The SCHEMA. 9.

Compounds according to Example 27 synthesize, as shown in the Diagram above, 9.

I.

I. Receiving (±)-4-((α-hydroxy)-3-xylyl)-N,N-diethylbenzamide (compound 43)

The connection 43 to receive, using the synthesis procedure described for compound 31, but substituting 4-chloraniline bromide m-toluylene bromide.

νmax(KBr)/cm-13406, 2972, 1613, 1429, 1360, 1287, 1097, 1053, 789; δn(400 MHz, CDCl3) 1.10 (3H, br s), 1.22 (3H, br s), 2.34 (3H, s), 2.55 (1H, d, J 3.5), 3.25 (2H, br s), 3.52 (2H, br s), 5.80 (1H, d, J3), 7.12-7.42 (8H, m);

II. Receive (±)-4-((α-chloro)-3-xylyl)-N,N-diethylbenzamide (compound 44)

The connection 44 to receive, using the synthesis procedure described for compound 2.

Use next hundred the AI without further purification.

EXAMPLE 27.

Receive (±)-4-((α-(1-piperazinyl))-4-xylyl)-N,N-1-diethylbenzamide •2HCl (compound 45)

The compound of this Example will be received, using the synthesis procedure described for compound 3.

TPL > 130°decomp. (from ether), νmax(KBr)/cm-12971, 2805, 2715, 1624, 1434, 1289, 1096, 783; δn(400 MHz, CDCl3, free base) 1.10 (3H, br s), 1.20 (3H, br s), 2.31 (3H, s), 2.35-2.45 (5H, m), 2.89-2.92 (4H, m), 3.25 (2H, br s), 3.51 (2H, br s), 4.19 (1H,s), 6.98-7.46 (8H, 4m);

SCHEME 10.

Compounds in accordance with Example 28 are synthesized, as shown in the Diagram above, 10.

J.

I. Receiving (±)-4-((δ-hydroxy)-cyclohexylmethyl)-N,N-diethylbenzamide (compound 46)

The connection 46 receive, using the synthesis procedure as described for compound 31.

δn(400 MHz, CDCl3) 0.85-2.0 (18H, m), 3.26 (2H, br s), 3.53 (2H, br s), 4.35-4.43 (1H, m), 7.28-7.36 (4H, m);

II. Receive (±)-4-((α-chloro)cyclohexylmethyl)-N,N-diethylbenzamide (compound 47)

Connection 47 receive, using the synthesis procedure as described for compound 2.

Use in the next stage without further purification.

EXAMPLE 28.

Receive (±)-4-((α-(1-piperazinil))-cyclohexylmethyl)-N,N-diethylbenzamide (compound 48)

The compound of this Example will be received, using the synthesis procedure, opican the Yu for compound 3.

TPL 113-116°With (from acetonitrile), νmax(KBr)/cm-13330, 2936, 2845, 1623, 1431, 1286, 1096, 823;

δn(400 MHz, CDCl3) 0.64-2.02 (18H, m), 2.18-2.40 (4H, m), 2.75-2.87 (4H, m), 3.06 (1H, d, J 8.8), 3.27 (2H, br s), 3.52 (2H, br s), 7.11 (2H, d, J8.4), 7.29 (2H, d, J8.4);

SCHEME 11.

Compounds according to Example 29 are synthesized, as shown in the Diagram above, 11.

K.

I. Receiving (±)-4-((α-hydroxy)-3,4-dimethylbenzyl)-N,N-diethylbenzamide (compound 49)

The connection 49 receive, using the synthesis procedure described for compound 1.

δn(400 MHz, CDCl3) 1.09 (3H, br s), 2.23 (6H, s), 2.85 (1H, d, J 3), 3.24 (2H, br s), 3.51 (2H, br s), 5.73 (1H, d, J 2), 7.03-7.12 (m, 3H), 7.26-7.39 (m, 4H).

II. Receive (±)-4-((α-chloro)-3,4-dimethylbenzyl)-N,N-diethylbenzamide (compound 50)

The connection 50 receive, using the synthesis procedure described for compound 2.

Use in the next stage without further purification.

EXAMPLE 29.

Receive (±)-4-((α-piperazinil)-3,4-dimethylbenzyl)-N,N-diethylbenzamide (compound 51)

The compound of this Example will be received, using the synthesis procedure described for compound 3.

νmax(KBr)/cm-13304, 2939, 2810, 1626, 1429, 1286, 1096, 846; δn(400 MHz, CDCl3) 1.11 (3H, br s), 1.20 (3H, br s), 1.87 (1H, br s), 2.20 (3H, s), 2.22 (3H, s), 2.34 (4H, br s), 2.86-2.89 (4H, m), 3.25 (2H, br s), 3.51 (2H, br s), 4.15(1H, s), 7.02-7.15 (3H, m), 7.26-7.30 (2H, m), 7.42-7.46 (2H, m).

SCHEME 1.

Compounds in accordance with Example 30 receive, using the synthesis procedure, as shown in the Diagram above, 12.

L.

I. Receiving (±)-4-((α-hydroxy)-1-naphthylmethyl)-N,N-diethylbenzamide (compound 52)

The connection 52 receive, using the synthesis procedure as described for compound 1.

δn(400 MHz, CDCl3) 1.06 (3H, br s), 1.20 (3H, br s), 3.01 (1H, d, J 4), 3.21 (2H, br s), 3.49 (2H, br s), 6.47 (1H, d, J 4), 7.24-7.48 (7H, m), 7.55-7.58 (1H, m), 7.78-7.87 (2H, m), 7.98-8.01 (1H, m).

II. Receive (±)-4-((α-chloro)-1-naphthylmethyl)-N,N-diethylbenzamide (compound 53)

The connection 53 get using the synthesis procedure as described for compound 2.

Use in the next stage without further purification.

EXAMPLE 30.

Receive (±)-4-((α-(1-piperazinil))-1-naphthylmethyl)-N,N-diethylbenzamide (compound 54)

The compound of this Example will be received, using the synthesis procedure described for compound 3.

νmax(KBr)/cm-13307, 3050, 2966, 2814, 1625, 1431, 1287, 1098, 843, 797; δn(400 MHz, CDCl3) 1.04 (3H, br s), 1.17 (3H, br s), 2.14 (1H, br s), 2.40 (2H, br s), 2.46 (2H, br s), 2.83-2.95 (4H, m), 3.17 (2H, br s), 3.48 (2H, br s), 5.05 (1H, s), 7.22-7.28 (2H, m), 7.40-7.54 (5H, m), 7.70-7.94(3H, m), 8.40-8.43(1H, m);

Modification piperazino rings:

General experiments and examples

Compounds according to Examples 31-42 synthesized, as shown in the Diagram below, 13.

M/p>

I. Getting 2-dimethyl-5-methylpiperazin-3,5-dione (Compound 55)

N-tert-Butoxycarbonyl-2-aminoethanol acid (5.0 g, 25 mmol) and D,L-alanine methylether hydrochloride (3.5 g, 25 mmol) dissolved in dry dichloromethane (50 ml) and cooled to 0°C. Add triethylamine (3.5 ml, 25 mmol), then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.8 g, 25 mmol) and the mixture was stirred at 0°to dissolve the lumps. The reaction mixture was then left in the freezer 4d at -20°C. the Organic solution washed with water, 1M citric acid (aq.), with water, dried (Na2SO4) and is evaporated in vacuum, obtaining 6.0 g (83%) binder product. A large part of the binder product (5 g) is dissolved in formic acid (50 ml) and stirred for 12 hours at 25°C. the Acid is removed in vacuo, the residue is dissolved in 2-butanol and heated under reflux for 4 hours. The solution is cooled to 0°With, the crystals are filtered and dried in vacuum at 100°C. the Yield is 2.6 g of pure compound 55 (82%), which can be recrystallized from methanol, TPL > 300°C;

IR (KBr) (cm-1): 3000 (br), 1680(s) (C=O).

1H NMR (D2O):δ=4.75(s, 2H, NH), 4.21 (q, 1H, CHMe), 1.50-1.42 (m, 9H, me).

C7H12N2O2requires: C, at 53.83; H, 7.74; N, 17.94;

Found: C, 53.89; H, 7.90; N, 17.79.

II. Obtaining 3-dimethyl-5-methyl-piperazin the dihydrochloride (compound 56)

Compound 55 (2.2 g, 14 mmol) dissolved in dry tetrahydrofuran (120 ml). Small portions add socialwise hydride (42 ml, 1M in tetrahydrofuran). After the addition, the solution is heated under reflux during the night. Solution allow to cool, then the excess hydride is destroyed by adding dropwise water (1.6 ml), NaOH (1.6 ml, 15% solution) and water. Granular precipitate is filtered off and the solvent is evaporated in vacuum. The residue is dissolved in dichlormethane, dried (K2CO3)to give, after evaporation of the solvent in vacuum, 1.5 g (84%). Treating excess HCl in ether, receive dihydrochloride, compound 56, which may be recrystallized from methanol/ether, TPL > 300°IR KBr (cm-1): 2760, 1570 (R2NH2+) MS (Amin): 128, 113, 84, 71, 58.

1H NMR (D2O+DSS): δ=2.70-2.50(m, 5H, CH2-N, CH-N), 1.14 (s, 3H, 1 Me), 1.00-0.94 (s+d, 6H, 2 Me).

C7H16N2•2HCl requires: C, 41.80; H, 9.02; N, 13.93;

Found: C, 42.03; H, 9.24; N, 14.00.

EXAMPLE 31.

Getting 4-(4-(2-dimethyl-5-methylpiperazine)-3-methoxy-benzyl) -N,N-diethylbenzamide dihydrochloride (compound 57)

4-(Chloro-(3-methoxyphenyl)methyl)-N,N-diethylbenzamide (and 0.61 g, 2.0 mmol) and compound 56 (0.50 g, 3.9 mmol) dissolved in dry acetonitrile (5 ml). Add potassium carbonate (0.26 g, 2.0 mmol) and the mixture heated under reflux for 2d. The solvent UDA is Aut in vacuo and the residue purified flash chromatography on silica (CH 2Cl2/-MeOH/NH3(aq.), 98:1:1-95:5:1, receiving 0.65 g (79%). Treatment with excess HCl in ether, filtering and drying the crystals in vacuum over KOH results dihydrochloride, compound 57, TPL: 134-136°C. IR (HCl salt, KBr) (cm-1): 3400 (br, OH), 2900 (br, R2NH2+), 1600 (s, C=O, or R2NH2+), 1283, 1038 (C-O). MS (Amin) 3 peak: 423, 353, 325, 296, 127.1H NMR: (Amin, CDCl3): δ=7.40-6.60 (m, 8H, Ar-H), 5.26, 5.25, 4.61 (3s, 1H CHAr2), 3.70 (s, 3H, MeO), 3.4, 3.2 (2 br s, 4H, Mesn2), 3.1-2.0 (m, 5H, piperazine-H), 1.3-0.9 (m, 15H, me).

With26H37H3O2•2HCl requires: C, 62.89; H, 7.92; N, 8.46;

Found: C, 63.41; H, 8.38; N, 8.56.

EXAMPLE 32.

Getting 4-(4-(1-allyl-2-dimethyl-5-methyl-piperazinil)-3-methoxybenzyl)-N,N-diethylbenzamide dihydrochloride (compound 58)

Compound 57 (0.39 g, to 0.92 mmol) dissolved in dry acetonitrile (5 ml). Add potassium carbonate (0,13 g to 0.92 mmol) and allylbromide (90 μl, of 1.02 mmol). After 3 hours the solvent is evaporated at 25°and the residue purified flash chromatography on silica (CH2Cl2/MeOH), 98:2-95:5, receiving generally 0.39 g (92%). Treatment with excess HCl in ether, filtering and drying the crystals in vacuum over KOH results dihydrochloride, compound 58, TPL 105-121°C. IR (HCl salt, KBr) (cm-1): 3400 (br, OH), 2500 (br, R2NH2+), 1620 (s) (C=O, or R2NH2+), 1285, 1043 (C-O).

1H NMR: (Amin, CDCl3): 4 =7.50-6.60 (m, 8H, Ar-H), 5.70 (m, 1H, allyl-H), 5.00 (m, 2H, allyl-H), 4.70 (s,1H, CHAr2), 3.70 (s, 3H, MeO), 3.5+3.3(2br s, 4H, MeCH2), 3.0-1. 9 (m, 7H, piperazine-H), 1.2-0.8 (m, 15H, 5Me).

With29H41N3About2•2HCl requires: C, 64.91; H, 8.08; N, 7.83;

Found: C, 65.70; H, 8.60; N, 8.29.

N.

I. Receiving 4-allyl-2-dimethyl-5-methylpiperazine (compound 59)

Compound 56 (0.14 g, of 0.91 mmol) was dissolved in acetonitrile and 0°With add allylbromide (80 μl, of 0.91 mmol). After an hour, add another portion of allylbromide. After two hours the solvent is evaporated and the residue purified flash chromatography on silica (CH2Cl2/MeOH), 95:5-80:20, getting monoallyl, the connection 59, 116 mg (69%).

EXAMPLE 33.

Getting 4-(1-(4-allyl-2-dimethyl-5-methylpiperazine)-3-methoxybenzyl)-N,N-diethylbenzamide dihydrochloride (compound 60).

The compound of this Example will be received, using the synthesis procedure described for Example 3.

TPL 125-130°C. IR (2HCl, KBr) (cm-1): 3430 (br), 2978, 2480(br), 1607, 1436, 1285. MS (free amine): 366, 296, 167.1H NMR: (D2O+DSS): δ=7.60-6.90 (m, 9H, Ar-H), 6.0-5.5 (m, 4H allyl-H+Ar2CH), 3.80 (2s, 3H, MeO), 4.0-3.7 (m, 11H, allyl-N, piperazine-N, amide-CH2), 1.3-1.0(m, 15H, piperazine-IU, amide-IU).

Anal. for C29H41N3About2•2HCl•N2O:

Calculated: C, 59.15; H, 8.35; N, 7.14;

Found: C, 59.05; H, 8.00; N, 7.22.

EXAMPLE 34.

Getting 4-(1-(2-dimethyl-5-methylpiperazine is)-3-methoxybenzyl)-N,N-diethylbenzamide dihydrochloride (compound 61)

Compound 56 (42 mg, 0.33 mmol) and potassium carbonate (46 mg, 0.33 mmol) dissolved in water (2 ml) and add dicret-BUTYLCARBAMATE (79 mg, 0.36 mmol). After stirring for 1 hour the solvent is evaporated in vacuo and the residue purified by chromatography on silica (CH2Cl2/MeOH, 90:10, receiving 43 mg of mono-N-Boc-protected 55, which is dissolved in dry acetonitrile with potassium carbonate (26 mg, 0,19 mmol) and 4-(chloro-(3-methoxyphenyl)methyl)-N,N-diethylbenzamide (63 mg, 0,19 mmol). After heating for 4 days under reflux, the solvent is removed in vacuo and the residue purified by chromatography on silica (CH2Cl2/MeOH), 100:0, 95:5. Treatment with formic acid (5 ml) for 3 hours, evaporation of the solvent in vacuo and extraction of the residue with the help of CH2Cl2/1M NaOH, drying of the organic phase (K2CO3) and evaporation of the solvent in vacuo yields a 27 mg (33%) of free amine. Treatment with excess HCl in ether results dihydrochloride, which is dissolved in water and lyophilizers, TPL 145-150°C. IR (2HCl, KBr) (cm-1): 3500-3400 (br), 1601, 1442, 1285. MS (free amine):423, 296, 325, 127.

1H NMR (CDCl3): δ=7.4-6.6 (m, 8H, Ar-H), 5.39, 5.36 (2s, 1H, Ar2CH), 3.75 (s, 3H, MeO), 3.5, 3.25 (2 br.s, 4H, amide-IU), 2.80, 2.50, 2.05 (3m, 5H, piperazine-H), 1.5 (br.s,1H, N-H), 1.25-1.0 (br m, 6H, amide-Me), 1.15 (s, 3H, Me), 0.90 (d, 3H, Me), 0.85 (s, 2H, Me).

26H37N3O2•2HCl•N2O:

Calculated: C, 49.58; H, 8.61; N, 6.67;

Found: C, 49.61; H, 7.73; N, 6.56.

O.

I. Obtaining 4-(phenyl-hydroxymethyl)-N,N-diethylbenzamide (compound 62)

The connection 62 receive, using the synthesis procedure described for compound 1.

MS: 282, 211, 165, 105.1H NMR: (CDCl3): δ=7.38-7.20 (m, 9H), 5.80 (d, J=3.5 Hz, 1H), 3.5, 3.2 (2 br s, 4H), 1.2, 1.05(2 br s, 6H).

II. Getting 4-(chloroformyl)-N,N-diethylbenzamide (compound 63)

Connection 63 receive, using the synthesis procedure described for compound 2.

GC-MS (2 maximum): 296, 225, 165, 121, 300, 266, 229, 195, 165.1H NMR: (CDCl3): 6-7.45-7 .20 (m, 9H), 6.09 (s, 1H), 3.4 (br m, 4H), 1.1 (br m, 6H).

EXAMPLE 35.

Getting 4-((1-piperazinil)-benzyl)-N,N-diethylbenzamide dihydrochloride (compound 64)

The compound of this Example will be received, using the synthesis procedure described for compound 3.

TPL 157-169°C. IR (Amin, CDCl3in cells KBr) (cm-1): 3690, 3630, 1613, 1435, 1265. MS (free amine): 351, 306, 295, 266, 194, 165.1H NMR: (free amine, CDCl3): 8 7.46-7.16 (m, 9H, Ar-H), 4.24 (s, 1H, CHAr2), 3.5+3.2 (2 br s, 4H, MeCH2), 2.89 (m, 4H, piperazine-H), 2.36 (br s, 4H, piperazine-H), 1.94 (br s, 1H, NH), 1.2+1.1 (2 br s, 6H, 2Me).

Anal. for C22H29N3O•2HCl•N2O

Calculated: C, 57.61; H, 7.65; N: 9.16;

Found: C, 57.59; H, 7.66; N, 8.92.

EXAMPLE 36.

Getting 4-((4-allyl-1-piperazinil)benzyl)-N,N-dieselben the amide dihydrochloride (compound 65)

The compound of this Example will be received, using the synthesis procedure described for Examples 2 and 3.

TPL 175-205°C. IR (Amin, CDCl3in cells KBr) (cm-1): 3689, 1613, 1455, 1434, 1290, 1143. MS (free amine): 391, 165, 125.1H NMR: (free amine CDCl3): δ=7.42-7.12 (m, 9H, Ar-H), 5.81 (m, 1H, allyl-H), 5.10 (m,2H, allyl-H), 4.23 (s, 1H, CHAr2), 3.5+3.2 (2 br s, 4H, MeCH2), 3.00 (m, 2H, allyl-H), 2.6-2.4 (br s, 8H, piperazine-H), 1.1 (2 br s, 6H, 2Me).

Anal. for C25H35N3O•2HCl•N2O:

Calculated: C, 62.23; H, 7.73; N, 8.71;

Found: C, 62.22; H, 7.49; N, 8.42.

R.

I. Getting 2-gidroksimetil-5-methyl-piperazine-3,5-dione (compound 66)

(D,L)-N-tert-Butoxycarbonylamino (5.0 g, 26 mmol) dissolved in methylene chloride (50 ml) with triethylamine (8.1 ml), dried with molecular sieves 4A and transferred to a dry flask in a stream of nitrogen. At -10°With add isobutylparaben (3.8 ml, 29 mmol). The solution is stirred for 15 minutes, then add D,L-serenityluver hydrochloride (4.1 g, 26 mmol), then the solution is allowed the opportunity to warm up to 25°and mix it within 12 hours. Washing solution, brine, dried (MgSO4) and evaporation of the solvent in vacuo yields a solid which is treated with formic acid for 1 hour. Acid is removed in vacuo and the residue is dissolved in anhydrous 2-butanol (5 ml) and heated at the reflux for 2 days. The solvent is removed and the residue crystallized, after receiving treatment with acetone, 1 g of compound 66 (24%).

II. Getting 2-hydroxymethyl-5-methyl-piperazine (compound 67)

Connection 67 receive, using the synthesis procedure described for compound 55.

II. Getting 2-(tert-butyldiphenylsilyl)methyl-5-methyl-piperazine (compound 68)

Compound 67 (0,41 g, 3.1 mmol) dissolved in dimethylformamide (5 ml). Add chloro-tert-butyldiphenylsilyl (0.95 g, 3.4 mmol) and imidazole (0,47 g, 6,9 mmol) and stirring is continued for 12 hours. The product is extracted, adding shaking ethyl acetate, brine and 1M NaOH. The organic phase is dried and evaporated in vacuum. After chromatography of the residue on silica (CH2Cl2/MeOH, 100:0, 95:5, 90:10 and 80:20) to obtain 0.39 g (34%) of pure compound 68.

EXAMPLE 37.

Getting 4-(4-(2-hydroxymethyl-5-methyl)piperazinylmethyl)-N,N-diethylbenzamide dihydrochloride (compound 69)

The compound of this Example will be received, using the synthesis procedure described for compound 3.

TPL-150°C. IR (2HCl, KBr) (cm-1): 3300 (br), 2700 (br), 1612, 1446, 1382, 1296, 1080. MS (free amine): 381, 218, 181, 91.1H NMR: (free amine, CDCl3): δ=7.44-7.18 (m, 9H, Ar-H), 5.17, 5.14 (2s, 1H, ArCH2), 3.75-2.60 (m, 12H, piperazine-N, amide-CH2), 2.02 (m, 1H, piperazine-H), 1.30-1.05 (m, N, piperazine-IU+amide-IU).

Anal. for C24H33N 3O2•2HCl•1.8H2O:

Calculated: C, 57.55; H, 7.77; N, 8.39;

Found: C, 57.05; H, 7.67; N, 8.19.

EXAMPLE 38.

Getting 4-((4-(2-hydroxymethyl-5-methyl)piperazinil)-3-methoxy-benzyl)-N,N-diethylbenzamide dihydrochloride (compound 70)

The compound of this Example will be received, using the synthesis procedure described for compound 3.

TPL 185-190°C. IR (2HCl, KBr) (cm-1): 3500-2500 (br), 1596, 1440, 1045.1H NMR: (free amine, CDCl3): δ=7.40-6.60 (m, 8H, Ar-H), 5.05, 5.10 (2s, 1H, Ar2CH), 3.70 (s, 3H, MeO), 3.8-2.5 (m, 12H, piperazine, amide CH2), 1.2-1.0 (br s, 9H, amide-IU, piperazine-IU).

EXAMPLE 39.

Getting 4-((4-(1-allyl-2-hydroxymethyl-5-methyl)-piperazinil) -3-methoxybenzyl)-N,N-diethylbenzamide dihydrochloride (compound 71)

The compound of this Example will be received, using the synthesis procedure described for Examples 2 and 3.

TPL 125-130°C. IR (2HCl, KBr) (cm-1): 3400 (br), 1603, 1445, 1285. MS (free amine): two peaks: 310, 239, 135 and 312, 241, 135.1H NMR: (free amine, CDCl3): δ=7.50-6.70 (m, 8H, Ar-H). 5.80, 5,20, 5.00 (3m, 3H, allyl-H), 4.0-2.3 (m, 14H, piperazine-N, allyl-H, amide-CH2), 3.80 (s, 3H, MeO), 1.2 (br s, 6N, amide-IU).

Anal. for C25H35N3O3•2HCl•3.7H2O:

Calculated: C, 55.57; H, 8.06; N, 6.94;

Found: C, 55.53; H, 7.82; N, 7.16.

Q

I. Obtain methyl 3-(hydroxy-(2-naphthyl)methyl)-phenyl ester (compound 72)

The connection 72 receive, use the Zuya the synthesis procedure, described for compound 1.

MS: 264, 155, 135, 128, 109, 101.1H NMR: (CDCl3): δ=7.90-6.78 (m, 11H, Ar-H), 5.98 (d, J=3.5 Hz, 1H, Ar2H), 3.78 (s, 3H, MeO), 2.32 (d, J=3.5 Hz, 1H, HE).

II. Obtain methyl 3-(chloro-(2-naphthyl)methyl)-phenyl ester (compound 73)

Connection 73 receive, using the synthesis procedure described for compound 2.

GC-MS (2 peak): 278, 247, 215, 171, 155, 135 and 282, 248, 247, 231, 215.1H NMR:(CDCl3): 5=7.86-6.81 (m, 11H, Ar-H), 6.25 (s, 1H, Ar2H), 3.76 (s, 3H, MeO).

III. Getting 4-allyl-2-methylpiperazine (compound 74)

2-Methylpiperazin (0.4 g, 4 mmol) dissolved in acetonitrile (5 ml) and at 0°add allyl bromide (86 μl, 1 mmol). Stirring is continued at 0°C for 1 hour and then at 25°C for 6 hours. Evaporation of the solvent in vacuo and chromatography on silica (CH2Cl2/MeOH, 80:20) to yield 80 mg (57%) of pure compound 74.

EXAMPLE 40.

Getting dihydrochloride methyl 3-((2-naphthyl)-(3-methyl-piperazinil)methyl) phenyl ester (compound 75)

The compound of this Example will be received, using the synthesis procedure described for compound 3.

TPL 170-174°C: IR (KBr) (cm-1): 3461, 2458, 1600, 1439, 1263, 1043. MS (Amin): 386, 247, 215, 139, 112.1H NMR: (Amin, CDCl3): δ=7.84-6.66 (m, 11H, Ar-H), 4.33 (s, 1H, CHAr2), 3.74, 3.73 (2H, 3H, MeO), 3.00-2.70 (m, 6H, piperazine-H), 1.95, 1.65 (2m, 2H, piperazine-H), 0.98-0.92 (2d, J=6.4 Hz, 3H), piperazine-IU).

Anal. for C 23H26N2O•2HCl•N2O.

Calculated: C, 61.14; H, 7.05; N, 6.20;

Found: C, 61.05; H, 6.48; n 6.07.

EXAMPLE 41.

Getting dihydrochloride methyl 3-((2-naphthyl)-(4-allyl-2-methylpiperazine) methyl) phenyl ester (compound 76)

The compound of this Example will be received, using the synthesis procedure described for Example 3.

TPL 173-182°C. IR (KBR) (cm-1): 3430, 2500, 2355, 1601, 1436, 1265, 1047. MS (Amin): 386, 274, 247, 215, 139, 125.1H NMR: (Amin, CDCl3): δ=7.86-6.66 (m, 11H, Ar-H), 5.82 (m, 1H, allyl-H), 5.12 (m, 2H, allyl-H), 4.95 (br.s, 1H, CHAr2), 3.76, 3.75 (2s, 3H, MeO), 3.04-2.32 (m, 9H, piperazine-H), 1.15-1.11 (2d, 3H, Me).

Anal. for C26H32N2O•2HCl•0.4H2O;

Calculated: C, 66.92; H, 7.08; N, 6.00;

Found: C, 67.03; H, 7.09; N, 5.88.

EXAMPLE 42.

Obtain hydrochloride of 4-((4-acetyl-1-piperazinil)-benzyl)-N,N-diethylbenzamide (compound 77)

The free amine of compound 64 (100 mg, 0.28 mmol) is dissolved in methylene chloride (5 ml), cooled to 0°C. Add triethylamine (43 μl, 0.31 mmol)and then dropwise add acetylchloride (23 μl, 0.31 mmol). After 10 minutes the solution is washed with potassium carbonate (10%), dried (K2CO3) and evaporated in vacuo. The residue is purified by chromatography on silica (CH2Cl2/Meon/NH3, 95:5:0.5), and getting 116 mg of compound 77 (˜100%).

TPL 140-150°C. IR (KBr.) (cm-1): 3480 (br), 2987, 2500 (br), 1623, 1429, 1285, 145. MS (free amine): 393, 267, 165, 127.1H NMR: (free amine, CDCl3): δ=7.46-7.18 (m, 9H, Ar-H), 4.25 (s, 1H, CHAr2), 3.70-3.15 (m, 8H, amide-CH2, piperazine-H), 2.36 (m, 4H, piperazine-H), 2.05 (s, 3H, MeCO), 1.15(br.m, 6N, amide-IU).

Anal. for C24H31N3About2•1HCl•N2O:

Calculated: C, 64.87; H, 7.62; N, 9.46;

Found: C, 65.01; H, 7.76; N, 9.42.

SCHEME 13.

Replacement diethylbenzamide to etc.

Compounds according to Examples 43-48 receive, as shown in the Diagram below 14.

R.

I. Obtaining 4-((4-tert-butoxycarbonyl-1-piperazinil)-benzyl)-benzoic acid (compound 78)

Compound 64 (6.0 g, 17 mmol) was dissolved in 6N hydrochloric acid and heated at 120°C for 3 days. Then the solution is neutralized aqueous NaOH (˜12 g). The solution is concentrated to 100 ml, mixed with tetrahydrofuran (100 ml) and added dropwise dissolved in tetrahydrofuran (50 ml) di-tert-butyl dicarbonate (3.7 g, 17 mmol). After stirring for 1 hour at 25°the aqueous phase is acidified with 1M citric acid and extracted twice with ethyl acetate. The organic phase is dried (K2CO3) and evaporated, and the residue is purified by chromatography on silica (EtOAc/heptane/Asón, 10:90:0-66:33:1), produces the overall of 3.85 g (57%) of compound 78.

EXAMPLE 43.

Getting dihydrochloride 4-((1-piperazinil)-benzyl)-benzoic acid (compound 79)

Compound 78 (150 mg, 0.38 mmol) is treated with excess HCl in acetic acid. Acid is removed in vacuo, and the residue is dissolved in methanol and precipitated by adding ether. The precipitate is dried in vacuum at 100°C.

TPL 172-180°C. IR (KBr) (cm-1): 3000(br), 1700, 1606, 1454.

1H NMR: (DMSO-d6): δ=12.85 (s, 1H, CO2H), 8.95 (s, 2H, NH), 7.92-7.20 (m, 9H, Ar-H), 4.56 (s, 1H, Ar2CH), 3.33 (s, 8H, piperazine-H).

Anal. for C18H20N2O2•2HCl:

Calculated: C, 58.54; H, 6.00; N, 7.59;

Found: C, 59.90; H, 6.47; N, 7.88.

EXAMPLES 44 and 45.

Obtain methyl 4-((4-tert-butoxycarbonyl-1-piperazinil)-benzyl) benzoate (compound 80) and methyl 4-((1-piperazinil)-benzyl)benzoate dihydrochloride (compound 81)

Compound 78 (0.15 g, 0.38 mmol) and cesium carbonate (0.25 g, from 0.76 mmol) are mixed in dimethylformamide (2 ml) and add methyliodide (72 μl, 1.1 mmol). After 2 hours at 25°add potassium carbonate (10%, water.) and the solution extracted with ethyl acetate. After evaporation of the solvent in vacuo the residue is purified by chromatography on silica (EtOAc/heptane, 30:70), receiving of 0.13 g (87%) of methyl ester, compound 80. Vos-deprotection carry out the processing of excess HCl in methanol at 50°C. the Solvent is removed and the residue is again purified on silica. Dihydrochloride is, compound 81 (35 mg), receive, using the method described above.

TPL 185-195°C. IR (KBr) (cm-1): 3400 (br), 2700 (br), 1720, 1612, 1430, 1285, 1190, 1112. MS (EI, free amine): 310, 265, 225, 206, 165.1H NMR: (D2O/CD3OD+DSS): δ=8.20-7.34 (m, 9H, Ar-H), 5.03 (s, 1H, CHAr2), 3.89(s, 3H, MeO), 3.42 (m, 4H, piperazine-H), 3.08(m, 4H, piperazine-H).

Anal. for C19H22N2O2•HCl•1H2O.

Calculated: C, 56.86; H, 6.53; N, 6.98;

Found: C, 56.82; H, 6.54; N, 7.00.

S.

I. Obtaining 4-((1-piperazinil)-benzyl)-benzamide dihydrochloride (compound 82)

Compound 78 (0.11 g, 0.28 mmol) dissolved in dry methylene chloride/tetrahydrofuran, 1:1 (5 ml), and cooled to -20°C. Add the first triethylamine (78 μl, of 0.56 mmol), and then isobutylparaben (37 μl, 0.28 mmol). After 10 minutes, add ammonia in methylene chloride (0.51 ml, 1,1M, 0,56 mmol) and allow the temperature to rise slowly to 25°C. After 3 hours the solvent is removed in vacuo and the residue purified by chromatography on silica (CH2Cl2/Meon/NH3, 95:5:1 and 90:10:1)to give 70 mg (62%). Treatment with HCl in methanol for 3 hours at 50°With removal of the solvent in vacuo and chromatography on silica (CH2Cl2/Meon/NH3, 90:10:1 and 80:20:1) to yield the free amine, which was converted into the dihydrochloride salt 82.

TPL 192-200°C. IR (KBr) (cm-1): 3939 (br), 3184 (br), 2700 (br), 1665, 1610, 1565,1426. MS (Amin): 295, 250, 210, 165, 152.1H NMR: (Amin, CD3OD): δ=7.96-7.22 (m, 9H, Ar-H), 4.93 (s, 2H, NH), 4.40 (s, 1H, Ar2CH), 2.94+2.46 (2m, 8H, piperazin-N).

Anal. for C18H21N3O•2HCl•1.1H2O:

Calculated: C, 55.70; H, 6.54; N, 10.83;

Found: C, 55.83; H, 6.76; N, 10.75.

EXAMPLE 46.

Getting 4-((1-piperazinil)-benzyl)-N-ethylbenzamide hydrochloride (compound 83).

The compound of this Example will be received, using the synthesis procedure as described for compound 82, but replacing the ammonia ethylamine.

TPL 180-185°C. IR (KBr) (cm-1): 3331 (br), 2700 (br), 1640, 1545, 1440, 1308. MS: (EI, Amin) 323, 278, 267, 238, 195, 165.1H NMR (Amin, CD3OD): δ=7.84-7.14 (m, N, Ar-H), 4.9 (br. s, NH), 4.45 (s, 1H, Ar2CH), 3.40 (m, 2H, ethyl-CH2), 3.25, 2.65 (2m, 8H, piperazine-H), 1.20 (m, 3H, ethyl-IU).

EXAMPLE 47.

Getting 4-(1-piperazinil-benzyl) benzonitrile dihydrochloride (compound 84)

Compound 82 (45 mg, of 0.11 mol) dissolved in dry tetrahydrofuran (2 ml) and cooled to 0°C. Add pyridine (36 μl, 0.44 mmol) and triperoxonane anhydride (31 μl, 0.22 mmol) and stirring is continued for 1 hour at 25°C. water is Added and the solution extracted with ethyl acetate. The organic phase is washed with dilute NaHCO3(aq.), dried (K2CO3) and evaporated in vacuo. The residue is treated with HCl in methanol for 3 hours at 50°C. removing the solvent in vacuum, chromatography the residue on silica (CH 2Cl2/MeOH/NH3, 90:10:1) results in 15 mg (49%). Treating excess HCl in ether/methanol, get dihydrochloride, compound 84, which precipitated, dissolved in water and lyophilizers.

TPL 141-145°C. IR (KBr) (cm-1): 3400 (br), 2700 (br), 2230, 1434. MS (free amine): 277, 232, 192, 165.1H NMR: (free amine, CDCl3): δ=7.58-7.18 (m, 9H, Ar-H), 4.27 (s, 1H, CHAr2) 2.89, 2.35 (2m, 8H, piperazine-H), 1.70 (s, NH).

Anal. for C18H19N3•2HCl•1H2O:

Calculated: C, 58.70; H, 6.29; N, 11.41;

Found: C, 58.88; H, 6.46; N, 11.24.

EXAMPLE 48.

Getting 4-(1-piperazinil-benzyl)-acetophenone dihydrochloride (compound 85)

Compound 78 (0.20 g, 0.50 mmol) dissolved in dry tetrahydrofuran (5 ml) and cooled to 0°C in nitrogen atmosphere. In for 1 minute add motility (3.1 ml, 0.8m in ether, 2.5 mmol) and continue stirring for 2 hours. Add chlorotrimethylsilane (0.63 ml, 5.0 mmol) and allow the temperature to rise to 25°With, then add ammonium chloride (aq.). The organic phase is poured, is evaporated and the residue purified by chromatography on silica (CH2Cl2/Meon/NH3, 95:5:1)to give 0.11 g (75%) of the ketone without Re-group. Salt dihydrochloride, compound 85, receive treatment with excess HCl in ether.

TPL 175-185°C. IR (KBR) (cm-1); 3400 (br), 2700 (br), 1680, 1607, 1424, 1269. MS (EI, free amine): 294, 249, 209, 165.1NAMR: (free amine, CDCl3): δ=7.77-7.04 (m, 9H, Ar-H), 4.22 (s, 1H, CHAr2), 2.92 (m, 4H, piperazine-H), 2.43 (s, 3H, MeCO), 2.40 (m, 4H, piperazine-H).

Anal. for C19H22H2About•2HCl•N2O:

Calculated: C, 57.61; H, 6.92; N, 7.07;

Found: C, 57.54; H, 6.75; N, 6.91.

SCHEME 14.

SCHEME 15.

Compounds according to Example 49 synthesize, as shown in the Diagram above, 15.

So

I. Receiving 4-benzoyl-N-threat-butoxycarbonyl-piperidine (compound 86)

A mixture of 4-benzoylpiperidine hydrochloride (6,77 g, 30,0 mmol), decret-BUTYLCARBAMATE (7.2 g, 33.0 mmol) and knso3(6.0 g, 60 mmol) in N2On-tetrahydrofuran (50/20 ml) is refluxed for 1 hour. The reaction mixture was extracted with ethyl acetate (2×100 ml). The combined organic layers washed with brine and dried over MgSO4. Removing the solvents, receive a 4-benzoyl-N-tert-butoxycarbonylamino: (8,54 g, 98%).

δn(400 MHz, CDCl3) 1.47 (s, 9H), 1.70 (m, 2H), 1.83 (m, 2H), 2.91 (m, 2H), 3.42 (m, 2H), 4.18 (brs, 2H), 7.46 (m, 2H), 7.56 (m, 1H), 7.93 (m, 2H).

II. Getting 4-(α-hydroxy-α-(4-N-tert-butoxy-carbonyldiimidazole)benzyl)-N,N-diethylbenzamide (compound 87)

To a solution of 4-iodo-N,N-diethylbenzamide (3.03 g, 10.0 mmol) and TMEDA (1.28 g, 11.0 mmol) in dry tetrahydrofuran (30 ml) at 78°add tert-utility (10.0 ml, 1,7M, 17 mmol). After 10 minutes, added dropwise 4-benzoyl-N-tert-butoxycarbonylmethyl (2,89 g, 10.0 mmol) in tetrahydrofuran (5 ml). The reaction mixture is heated to room temperature, then quenched with aqueous solution of NH4Cl and extracted with ethyl acetate (2×100 ml). The combined organic layers washed with brine and dried over MgSO4. Removing the solvents, get the crude product, which was purified on silikagelevye column, elwira with Meon-CH2Cl2(0:100→2:98) to obtain 4-(α-hydroxy-α-(4-N-tert-butoxy-carbonyldiimidazole)benzyl)-N,N-diethylbenzamide (MTL 0327, 2,60 g, 56%):

TPL 100-103°C (CH2Cl2): νmax(KBr) cm-1: 3426, 2973, 1687, 1618, 1428, 1289, 1168; δn(400 MHz, CDCl3): 1.08 (brs, 3H), 1.20 (brs, 3H), 1.30 (m, 4H), 1.41 (s, 9H), 2.50 (t, J=11.2 Hz, 1H), 2.66 (m, 2H), 2.86 (s, OH), 3.22 (brs, 2H), 3.50 (brs, 2H), 4.09 (brs, 2H), 7.18 (m, 1H), 7.26 (m, 4H), 7.45(m, 4H); δc-13(100 MHz, CDCl3): 12.8, 14.1, 26.2, 28.3, 39.1, 43.2, 44.3, 53.3, 79.2, 79.4, 125.75, 125.79, 126.2, 126.6, 128.1, 135.1, 145.3, 146.8, 154.6, 171.0.

EXAMPLE 49.

Getting 4-((α-4-piperidinyl) benzyl)-N-N-diethyl-benzamide (compound 88)

To a solution of 4-(α-hydroxy-α-(4-N-tert-butoxycarbonylamino)benzyl)-N-N-diethylbenzamide (466 mg, 1.0 mmol) and triethylsilane (232 mg, 2.0 mmol) in dry dichloromethane (10 ml) at room temperature add triperoxonane acid (10.0 ml). After 30 minutes at room temperature again EXT is make triethylsilane (232 mg, 2,0 mol). The reaction mixture is stirred for 14 hours at room temperature, and then condense. The residue is dissolved in AcOEt (100 ml). The resulting solution was washed with 1N NaOH solution, aqueous solution of NH4Cl and brine, dried over MgSO4. Removing the solvents, get the crude product, which was purified on silikagelevye column, elwira with NH4OH (1N)-MeOH-CH2Cl2(2,5:15:82,5) to obtain 4-((α-4-piperidinyl) benzyl)-N,N-diethyl-benzamide (245 mg, 70%). TPL 160-162°C: (CH2Cl2); νmax(KBr) cm-13325, 2937, 1613, 1461, 1283, 1095; δn(400 MHz, CDCl3) 1.05 (brs, 3H), 1.07 (m, 2H), 1.19 (brs, 3H), 1.53 (m, 2H), 2.04 (brs, NH), 2.20 (m, 1H), 2.55 (t, J-11.6Hz, 2H), 3.01 (m, 2H), 3.23 (brs, 2H), 3.51 (d, J=10.4 Hz, 1H), 3.52 (brs, 2H), 7.15 (m, 1H), 7.27 (m, 8H);

δc-13(100 MHz, CDCl3) 12.8, 14.1, 32.2, 39.0, 39.9, 43.1, 46,5, 59.0, 126.1, 126.5, 127.9, 128.0, 128.3, 134.8, 143.0, 144.7, 171.0.

EXAMPLE 50.

Obtaining N,N-diethyl-4-(3-methoxybenzyl-1-piperazinil)-benzamide

Use the same procedure as for N,N-diethyl-4-[(2,5,5-trimethyl-1-piperazinil)-3-methoxybenzyl]benzamide. N,N-Diethyl-4-(chloro-3-methoxybenzyl)-benzamide (1.6 g, 4.8 mmol) is subjected to reaction with piperazine (1.6 g, 19 mmol) in acetonitrile (20 ml) for 4 hours at 80°to obtain General 1.1 g of product (63%), which is converted into the dihydrochloride salt.

TPL 165-182°C. IR (Amin, CDCl3in the cell KBr) (cm-1): 3688, 1611, 1458, 1436, 1285. MS (free and is in"): 381, 336, 296, 224, 196, 165, 152, 112.1H NMR: (Amin, CDCl3): δ=1.05, 1.15 (2br s,6H, 2Me), 2.51, 3.02(2br.s, 8H, piperazine-H), 3.2, 3.45 (2br.s, 4H MeCH2), 3.72, 3.73 (2s, 3H, MeO), 4.21(s, 1H, CHAr2), 4.5 (br.s, 1H, NH), 6.60-7.40 (m, 8H, Ar-H).

With23H31N3O2•2HCl•N2O requires: C, 58.92; H, 7.44; N, 8.96;

Found: C, 58.98; H, 7.76; N, 8.86.

EXAMPLE 51.

Obtaining N,N-diethyl-4-[(4-allyl-1-piperazinil)-3-methoxybenzyl]benzamide

Use the same procedure as for N,N-diethyl-4-[(4-allyl-2,5,5-trimethyl-1-piperazinil)-3-methoxybenzyl]benzamide.

Of N,N-diethyl-4-(3-methoxybenzyl-1-piperazinil)benzamide (0.16 g, 0.42 mmol) to obtain 30 mg of the product (20%), which is converted into the dihydrochloride salt.

TPL 151-176°C. IR (Amin, CDCl3in the cell, KBr (cm-1): 3688, 1611, 1457, 1435, 1288. MS (free amine): 421, 125.1H NMR: (Amin, CDCl3): δ=1.1 (2br.s, 6H, me), 2.3-2.6 (br.s, 8H, piperazine-H), 3.00 (m, 2H, allyl-H), 3.2-3.5 (2br.s, 4H, MeCH2), 3.78 (s, 3H, MeO), 4.20 (s, 1H, CHAr2), 5.14 (m, 2H, allyl-H)-, 5.85 (m, 1H, allyl-H), 6.70-7.46 (m, 8H, Ar-H).

With26H35N3O2•2HCl•N2O requires: C, 60.09; H, 7.72; N, 8.08;

Found: C, 60.12; H, 7.59; N, 7.88.

SCHEME 16.

Connection Examples 52-55 synthesized, as shown in the Diagram above, 16.

U.

Compound I: 4-(α-hydroxybenzyl) -nitrobenzene

4-Nigromante (4,55 g of 20.1 mmol) of rest the accelerate in 70 ml of anhydrous methanol, cooled to 0°C in an ice bath, then under the current N2added NaBH4(0,915 g, and 24.2 mmol), the mixture is stirred at room temperature overnight, quenched with saturated aqueous solution of NH4Cl, evaporated Meon and add EtOAc. The mixture is washed with water, the organic layer is dried over MgSO4and concentrate, getting a solid substance in the form of the target product (˜4,58 g, output ˜100%).

1H NMR (CDCl3TMS): δ (ppm): 2.40(br s, 1H,); 5.92 (d, J=3.2 Hz, 1H,), 7.30-7.40 (m, 5H, Ar); 7.58 (d, J=8.6, 2H, Ar-NO2); 8.18 (d, J=8.6 Hz, 2H, Ar-NO2).

Compound II: 4-(α-chlorbenzyl)-nitrobenzene

Compound I (4/58 g/ 20 mmol) dissolved in anhydrous CH2Cl2then to the mixture under current N2add thionyl chloride (4.68 g, to 39.4 mmol), the reaction mixture is subjected to boiling under reflux for 5 hours and cooled to room temperature, the solvent and excess thionyl chloride is evaporated in a vacuum, getting yellowish solid substance in the form of the target product (yield ˜100%).

1H NMR (CDCl3TMS): δ (ppm): 6.16 (s, 1H,); 7.30-7.40 (m, 5H, Ar); 7.59 (d, J=8.6 Hz, 2H, Ar-NO2); 8.20 (d, J=8.6 Hz, 2H, Ar-NO2).

Compound III: 4-[(N-benzyl-1-piperazinil)-benzyl]-nitrobenzene

To compound II (1.0 g, 4.1 mmol) and N-benzylpiperazine (1.45 g, 8,2 what they say), dissolved in anhydrous acetonitrile, add a catalytic amount of potassium carbonate, and the reaction mixture refluxed overnight.

After cooling to room temperature, the mixture was washed with brine, the organic layer was concentrated in vacuo, receiving oil which is then purified using MPLC using CH2Cl2/MeOH/NH4OH=95/5/1 as a solvent for elution to obtain pure desired product (1.2 g, yield 76%).

1H NMR (CDCl3TMS): δ: 2.41-2.48 (8H, br, pieperazinove ring), 3.51 (2H, s,), 4.34 (1H, s,), 7.20-8.12 (14N, Ar) ppm.

13With NMR (CDCl3TMS): δ: 51.7, 53.1, 62.9, 75.5, 123.8, 127.0, 128.1, 128.5, 128.7, 129.2, 137.9, 140.9, 146.8, 150.6 ppm.

EXAMPLE 52.

Getting 4-[(N-benzyl-1-piperazinil)benzyl]aniline (compound 91)

To compound III (900 mg, of 2.33 mmol), dissolved in 10 ml of Meon, added Ra-Ni (150 mg) and the temperature was raised to 35°C. Then slowly with a syringe, with stirring, add hydrazine (380 mg, 11,63 mmol), the temperature of the mixture was raised to 70°until there is no further gas evolution. The reaction mixture is cooled to room temperature, filtered over telicom and concentrate, receiving the oil, which is purified using MPLC using CH2Cl2/MeOH=99/1-99/5 as a solvent for elution to the floor is solid yellowish substance in the form of the target product (660 mg, output ˜80%).

Elemental analysis for: C24H27H3•N2About:

Calculated: C, 79.64; H, 7.43; N, 11.55;

Found: C, 79.83; H, 7.65; N, at 11.64.

IR (NaCl, film): ν=2807, 1620, 1513, 1451, 1282, 1137 cm-1.1H NMR (CDCl3TMS): δ: 2.3-2.48 (8H, br pieperazinove ring), 3.45 (2H, br s,), 3.48 (2H, s,), 4.10 (1H, s,), 6.51 (2H, m, Ar), 7.11-7.37 (12H, m, Ar) ppm.

EXAMPLE 53.

Getting 4-[(N-benzyl-1-piperazinil)benzyl]-acetanilide (compound 92)

4-[(N-Benzyl-1-piperazine)benzyl]aniline (compound 91) (50 mg, 0.14 mmol) and anhydrous pyridine (excess) dissolved in anhydrous dichloromethane, and then add acetic anhydride (4 EQ.). The reaction mixture was stirred at room temperature for 30 minutes and quenched with H2Oh, then washed with saturated aqueous NaHCO3and brine. The organic layer is dried over anhydrous MgSO4filter and concentrate getting the product in the form of oil (44 mg, yield 80%).

1H NMR: (CDCl3TMS) δ: 2.1 (3H, s,), 2.3-2.48 (8H, br, pieperazinove ring), 3.48 (2H, s,), 4.16 (1H, s,), 7.20-8.12 (14N, Ar) ppm.

Elemental analysis for: C26H29N3About•2,1HCl•0,3H2About:

Calculated: C, 64,83; N, Only 6.64; N, 8,40;

Found: C, 64,86; N, Only 6.64; N, 8,3.

EXAMPLE 54.

Getting 4-[N-benzyl-1-piperazinil)benzyl]methanesulfonamide

4-[(N-benzyl-1-piperazinil)benzyl]aniline (compound 91) (100 mg, 0.28 mmol) and pyridine (excess) dissolved in anhydrous dichloromethane (5 ml), and then add methanesulfonyl anhydride (97,55 mg of 0.56 mmol). The reaction mixture was stirred at room temperature for 20 minutes, subjected to thin-layer chromatography, and then quenched by adding a drop of water. To this mixture 10 ml of EtOAc, washed with saturated aqueous NH4Cl and brine, the organic layer is dried over MgSO4, concentrated and purified via MPLC, using CH2Cl2/MeOH=99/1˜95/5 as a solvent to obtain pure product as white solid (˜90 mg, yield ˜70%).

Melting point: 195˜200°C (decomp.)

1H NMR: (CDCl3TMS) δ: 2,3-2,48(8H, br, pieperazinove ring), 2.96 (3H, s,), 3.51 (2H, s,), 4.21 (1H, s,), 6.25 (1H, br,), 7.10-7.41 (14H, m, Ar) ppm.

13With NMR: (CDCl3) δ: 142.4, 140.2, 137.9, 135.3, 129.2, 129.1, 128.5, 128.1, 127.9, 127.0, 121.0, 75.5, 63.0, 53.2, 51.8, 39.3 ppm.

Elemental analysis for: C25H29N3About2S•0,N2About:

Calculated: C, 66,46; H, 6.87; N, of 9.30;

Found: C, 66,53; N, Is 6.61; N, 9,23.

EXAMPLE 55.

Obtaining methyl--4-[(N-benzyl-1-piperazinil)benzyl]-2-methyl acetate

4-[(N-benzyl-1-piperazinil)benzyl]aniline (compound 91) (100 mg, 0.28 mmol), lithium hydride (2.5 mg, 0.3 mmol) and 1-Bromeliaceae (44,16 mg, 0.28 mmol) are mixed in anhydrous tetrahydrofuran, the reaction mixture is subjected to boiling under reflux for 2 hours and cooled to room temperature, then quenched with drops of water, washed twice with brine, dried over anhydrous MgSO4and concentrated to an oil, purified by using MPLC using CH2Cl2/MeOH=98/2 as solvent, getting the product in the form of oil (˜23 mg, 20%).

IR (film, NaCl); HCl salt

ν=3404 (br), 2922 (br), 1745, 1610, 1517, 1439, 1207 cm-1

1H NMR: (CDCl3) δ: 2.40(8H, br, pieperazinove ring), 3.50 (2H, s,), 3.75 (3H, s,), 3.85 (2H,d, J=5.2 Hz,), 4.12 (1H, s,), 4.18 (1H, t, J=5.2 Hz,), 6.49 (2H, d, J=8.4 Hz, -N-Ar), 7.14-7.38 (12H, m, Ar) ppm.

Anal. to:27H31N3O2•3HCl:

Calculated: C, 60.17; H, 6.36; N, 7.80;

Found: C, 59.97; H, 6.61; N, 7.46.

Compound IV: 4-(3-Futuro-α-hydroxybenzyl)acetonitrile

1-Fluorescent-3-iodobenzoyl (7,53 g, to 33.9 mmol) dissolved in anhydrous tetrahydrofuran and cooled to -78°C. To the reaction mixture via syringe slowly add n-utility (2,5M in tetrahydrofuran, to 33.9 mmol). The mixture is stirred is for 10 minutes, and then there was added a solution of 4-acetamidobenzaldehyde (1.84 g, 11.3 mmol) in 5 ml of dry DME. Before quenching with an aqueous solution of NH4Cl, the reaction mixture was stirred at -78°C for 30 minutes. The organic layer was washed with brine and dried over anhydrous MgSO4, filtered and concentrated to an oil, purified by using MPLC using a 10% heptane in CH2Cl2and 100% of CH2Cl2to obtain the pure product (1.65 g, yield 56%).

1H NMR: (CDCl3) δ: 2.14 (3H,s,), 2.55 (1H, s.br,), 5.76 (1H, d, J=3.2 Hz,), 7.35 (1H, s,), 6.90-7.50 (8H, m, Ar) ppm.

Compound V: 4-(3-fluorescent-α-chlorbenzyl)acetonitrile

This connection will be received, using the method described to obtain the compound (II), but using the compound (IV). It is used in the next stage of the reaction without purification.1H NMR: (CDCl3) δ: 2.15 (3H, s,), 6.10 (1H, s,), 7.84 (1H, s,), 6.90-7.6 (8H, m, Ar), 7.84 (1H, s,) ppm.

EXAMPLE 56.

Getting 4-[(N-benzyl-1-piperazinil)-3-terbisil]-acetanilide (compound 95)

This connection will be received, using the method described to obtain compound (III), but using the compound (V).

1H NMR: (CDCl3) δ: 214 (3H, s,), 2.40 (8H, br, piperazine),

3.51 (2H, s,), 4.19 (1H, s,), 6.80-7.40 (13H, m, Ar) ppm.

Anal. to:26H28FN3About•2HCl•SN2Cl2·2H2About

Calculated: C, 56.24; H, 6.02; N, 7.13.

Found: C, 56.29; H, 6.10; N, 6.88.

The pharmaceutical composition

New compounds for the treatment of disorders associated with the functions of opiate receptors in accordance with this invention, can be administered orally, intramuscularly, subcutaneously, intraperitoneally, vnutritorakalnah, intravenous, podvoloshino and intracerebroventricular.

The dosage depends on the method of administration, the severity of the disease, age and weight of the patient, and other factors normally considered by the attending physician when determining the individual regimen and dosage of the medicinal product, the most suitable for a particular patient.

Inert, pharmaceutically acceptable carriers used to obtain pharmaceutical compositions of the compounds of this invention may be solid or liquid. Drugs that have a solid dosage form include powders, tablets, dispersible granules, capsules, starch pills and suppositories.

A solid carrier can include one or more substances which may also deystvovate thinners, the corrigentov, solvents, oil, suspendresume agents, binders or agents, disintegrating tablets; it may also include encapsulating material.

In powders, the carrier is a finely ground solid substance in a mixture with finely ground active ingredient. In tablets, the active ingredient is mixed with carrier having the necessary binding properties in suitable proportion, and pressed tablets of the desired shape and size.

Upon receipt of the compositions for the suppository wax with a low melting point, such as a mixture of glycerides of fatty acids or cocoa butter, is first melted and dispersed active ingredient, for example by stirring. The molten homogeneous mixture is poured into molds of the desired size and enable it to cool and harden.

Suitable carrier materials include carbonate and magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragakant, methylcellulose, sodium carboxymethylcellulose, a wax with a low melting temperature, cocoa butter, etc.

Pharmaceutically acceptable salts include the acetate, bansilalpet, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, camsylate, carbonate, chloride, citrat, dihydrochloride, edetate, edisylate, estolate, Eilat, fumarate, gluceptate, gluconate, glutamate, Picolines is nilat, hexylresorcinol, geranamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isetionate, lactate, lactobionate, malate, maleate, mandelate, mesilate, bromide, methylnitrate, methyl sulfate, mukat, napsylate, nitrate, pamoate (embonate), Pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannat, tartrate, teoclate, triethiodide, benzathine, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.

Preferred pharmaceutically acceptable salts are hydrochloride and citrates.

The term "composition" means a mixture of the active ingredient with encapsulating material as carrier providing a capsule in which the active ingredient (along with other media or without them) is surrounded by carrier, which is thus in Association with it. This term also implies starch wafers.

Tablets, powders, starch wafers and capsules can be used as solid dosage forms suitable for oral administration.

Compositions having liquid form include solutions, suspensions and emulsions. As an example, liquid preparations suitable for parenteral administration may be referred to sterile water or water-propylene glycol solutions active is soedinenii. Liquid compositions may also be in the form of a solution in an aqueous solution of polyethylene glycol.

Aqueous solutions for oral administration can be obtained by dissolving the active component in water and, if desired, adding a suitable dye, corrigentov, stabilizers and thickeners. Aqueous suspensions for oral use can be obtained by dispersing finely ground active component in water with viscous material, such as natural and synthetic resins, polymers, methylcellulose, sodium carboxymethylcellulose and other suspendresume agents known in the pharmaceutical formulations of medicines.

The pharmaceutical compositions preferably have the form of unit dosage forms. In this form, the composition is divided into unit (single) dose containing appropriate quantities of the active component. A single dose is a product package containing discrete quantities, such as the packaging of tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be in the form of capsules, starch wafer or simply tablet, it can also include the appropriate number of any pre-packaged forms.

Biological research

A) MODEL IN VITRO

Cellular cool the tour

Human 293S cells expressing the cloned human receptors μ, δ and κand resistance to neomycin, grown in suspension at 37°C and 5% CO2in shake tubes containing free calcium modified by way of Dulbecco Wednesday Needle (DMEM), 10% fetal bovine serum (FBS), 5% BCS, with 0.1% Pluronic F-68 and 600 g/ml geneticin.

Obtaining membrane

Cells precipitated by centrifugation and re-suspended in Lisina buffer (50 mm Tris, pH 7.0, 2.5 mm, ethylendiamine-tetraoxane acid, while PMSF added just before use to 0.1 mm from 0,1M mixture in ethanol), incubated on ice for 15 minutes, and then homogenized by Poltrona within 30 seconds. The suspension is centrifuged at 1000 g (max) for 10 minutes at 4°C. the Upper layer remain on ice, and the pellet again suspended and centrifuged as described previously. The upper layers of both spins are combined and centrifuged at 46000 g (max) for 30 minutes. Granules are again suspended in cold Tris buffer (50 mm Tris/Cl, pH 7.0) and centrifuged. The obtained granules were again suspended in membrane buffer (50 mm Tris, 0.32 M sucrose, pH 7.0). Aliquot fraction (1 ml) in polypropylene tubes, frozen in a dry ice/ethanol and stored at -70°s to use. The protein concentration is determined by modificirowan the analysis of Lowry using sodium dodecyl sulfate.

Analysis of the binding.

Membranes are thawed at 37°C, cooled on ice, passed 3 times through a needle No. 25 and diluted with binding buffer (50 mm Tris, 3 mm MgCl21 mg/ml bovine serum albumin (BSA) (Sigma A-7888), pH 7.4, and stored at 4°after filtration through a 0.22 m filter, to which immediately before use add 5 µg/ml Aprotinin, 10 μm Astanina, 10 μm diprolene And not containing dithiothreitol (DTT). Aliquot share of volume of 100 ál add frozen in polypropylene tubes size 12×75 mm containing 100 μl of each radioligand and 100 µl sample of proteins with different concentrations. Total (TV) and nonspecific (NS) binding determined in the absence and presence of 10 μm naloxone, respectively. The tubes rotate and incubated at 25°for 60-75 minutes, after which their contents are quickly subjected to vacuum filtration and washed with approximately 12 ml/tube of ice-cold wash buffer (50 mm Tris, pH 7.0, 3 mm MgCl2through filters GF/B (Whatman), pre-soaked for at least 2 hours in 0.1% polyethylenimine. Radioactivity (disintegrations per minute)acquired by the filters was measured by a beta counter after soaking the filters, at least within 12 hours miniplane containing 6-7 ml of scintillation fluid. If the analysis Prov is car Ried out in 96-well tablet, the filtering carried out at 96 monofilter soaked polyethylenimine, washed 3×1 ml of washing buffer and dried in an oven at 55°C for 2 hours. Plate of the filter are counted by a counter TopCount (Packard) after adding to each well 50 μl of scintillation fluid MS-20.

Data analysis

Specific binding (SB) count as TB-NS, while the specific binding of various investigated peptides expressed as percentage of control specific binding. The value of the IC50and the hill coefficient (nnfor ligand substitution is specifically linked radioligand calculated on the basis of logit-charts or selection programs around curves, such as Ligand, GraphPad Prism, SigmaPlot or ReceptorFit. The value of Kicalculate using the equation of Cheng-Prusova. The average IC50, Kiand nnidentify ligands studied for at least three curves offset.

Experiments on saturation of the receptor

The magnitude of radioligand Toδdetermined by analyses on binding to cell membranes with the appropriate radio at a concentration of 0.2 to 5 times the estimated value of Kδ(up to 10 times if the number of required radioligand is real). Specic binding of radioligand is expressed in terms of molar parts/mg membrane protein. The value of Kδand Inmaxin separate experiments are a result of nonlinear selection specifically associated (In) vs nM free (F) radioligand of the object in accordance with a single-site model.

In the BIOLOGICAL MODEL (MODEL IN VIVO)

Mechano-allodynia in rats caused complete adjuvant's adjuvant and the cuff on the sciatic nerve.

Animals

Use of male rats Sprague-Dawley (Charles River, St-Constant, Canada) weighing 175-200 g at the time of surgery. Groups of three individuals they are placed in cells where thermostat temperature is maintained at 20°with the cycle of light/dark time, constituting 12:12, and free access to food and water. After placing the animals provide an opportunity to acclimate before surgery, at least for 2 days. Experiments approved by the Committee on medical ethics for the study of animals.

Experimental procedure

Full beta-blockers

First, rats in the anaesthetize ftorotanovogo the camera, then subcutaneously injected with 10 μl of complete adjuvant-blockers in the dorsal portion of the left foot between the second and third outer fingers. Then the animals give the opportunity to recover from anesthesia under supervision in their own cells.

The cuff on the sciatic nerve

Animals are prepared in accordance with the method described Moscoini and Kruger (1996). the Rys anaesthetize administered intraperitoneally with a mixture of ketamine/celeine (2 ml/kg), put on the right side and make a cut along the axis side of the left thigh. Pushing muscles of the upper quadriceps and expose the sciatic nerve, which put a plastic sleeve (tube D 60, length 2 mm). Then the incision is closed with two layers of vicryl 3-0 and put silk sutures.

Determination of the mechanical and allodynia, using a sample of von Frey

The test is carried out between 8.00 and 16.00 hours, using the method described by Chaplan et al. (1994). Rats are placed in a Plexiglas cage with a wire bottom that allows you to touch the feet and give them the opportunity to get used within 10-15 minutes. The test is carried out in the middle of the sole of the left hind legs, avoiding less sensitive pads on the soles. To the foot trays set of 8 hairs von Frey with logarithmically increasing rigidity(0,41, 0,69, 1,20, 2,04, 3,63, 5,50, 8,51 and 15,14 g; Stoelting, Il, USA). Hair von Frey bring the bottom side of the wire bottom of the cell, perpendicular to the surface of the foot with enough force so that it is slightly bent, touching the soles, and hold approximately 6-8 seconds. The reaction is considered positive if the rat sharply draws back paw. Wince immediately after removal of the hair is also considered a positive reaction. The movement is unclear reaction, and in such cases, the test is repeated.

The testing Protocol

The group kr is s, which introduced the full beta-blockers, is subjected to testing on the first postoperative day, and a group of rats with the cuff on the sciatic nerve is the seventh postoperative day. 50%threshold of otdergivanija determine, using the method of Dixon (1980) "up-down". The sample starts with a balance weight 2,04 g, located in the middle of a set. Irritation is always performed sequentially, in ascending or descending order. In the absence of reaction otdergivanija paws on the originally selected hair use a stronger stimulus when OTDELENIE feet use the following, weaker stimulus. The optimal calculation of the threshold by using this method requires 6 reactions in the immediate vicinity of the 50%threshold, and counting these 6 reactions begins by first modifying the response, i.e. when the first threshold crossing. In cases where the thresholds are outside stimuli, takes the value 15,14 (normal sensitivity) or 0,41 (maximum allogenically). The results of positive and negative reactions bring to the table, using the following legend: X = no otdergivanija, 0 = OTDELENIE, and 50%threshold of otdergivanija interpolate using the following formula:

50% g threshold=10(xf+Kδ)/10000,

where Xf= value of the last used hair von Frey (log units); K = ublica value (Chaplan et al. (1994)) for a scheme of positive/negative reactions; and δ=the average difference between the stimuli (log units). In this case δ=0,224.

Thresholds von Frey translated in percentage of the maximum possible effect (% MPE) according to Chaplan et al. (1994). For calculation of % MPE using the following equation:

The introduction of the analyte of interest

Before the breakout of the von Frey rats injected (subcutaneously, intraperitoneally or orally) the test substance, the time between the introduction of the analyte and the breakdown Von Frey varies depending on the nature of the analyte.

The way to restore disturbed functions of opioid receptors, including the introduction of the needy in this procedure, the effective number pieperazinove or pyridazinone the compounds of formula (I)

where G represents a carbon atom or nitrogen;

And choose from

(i) phenyl substituted by any of-COOH, -CONH2SOON3, -CN, NH2or-PINES3;

(ii) naphthyl, benzofuranyl and hineline; and

(iii)

and

where the phenyl ring of each substituent And can the t can be optionally and independently substituted with one or two substituents, selected from hydrogen, CH3;

R1selected from hydrogen; branched or straight1-C6of alkyl, C1-C6alkenyl, -CO(C1-C6alkyl);4-C8(alkyl-cycloalkyl), where alkyl represents a C1-C2-alkyl, and cycloalkyl represents a C3-C6cycloalkyl; phenyl;

R2, R3, R4, R5and R6selected from hydrogen;

each of R9, R10, R13, R14, R17and R18independently has the meanings indicated for R1;

Represents a substituted or unsubstituted aromatic, optionally substituted C5-C10hydroaromatics residue being optionally and independently substituted with one or two substituents, independently selected from hydrogen, CH3, halogen, OR7; R7selected from C1-C6of alkyl,

or its pharmaceutically acceptable salt, isomer, hydrate, or isoforms.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of adamantane of the general formula:

wherein m = 1 or 2; each R1 represents independently hydrogen atom; A represents C(O)NH or NHC(O); Ar represents the group:

or

wherein X represents a bond, oxygen atom or group CO, (CH2)1-6, CH=, O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, CR'(OH), NR5, (CH2)1-6NR5, CONR5, S(O)n, S(O)nCH2, CH2S(O)n wherein n = 0, 1 or 2; R' represents hydrogen atom; one of R2 and R3 represents halogen atom, nitro-group, (C1-C6)-alkyl; and another is taken among R2 and R3 and represents hydrogen or halogen atom; either R4 represents 3-9-membered saturated or unsaturated aliphatic heterocyclic ring system comprising one or two nitrogen atoms and oxygen atom optionally being heterocyclic ring system is substituted optionally with one or more substitutes taken independently among hydroxyl atoms, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, -NR6R7, -(CH2)rNR6R7; or R4 represents 3-8-membered saturated carbocyclic ring system substituted with one or more substitutes taken independently among -NR6R7, -(CH2)NR6R7 wherein r = 1; R5 represents hydrogen atom; R6 and R7 each represents independently hydrogen atom or (C1-C6)-alkyl, or (C2-C6)-hydroxyalkyl group eliciting antagonistic effect with respect to R2X7-receptors. Also, invention describes a method for their preparing, pharmaceutical composition comprising thereof, a method for preparing the pharmaceutical composition and their applying in therapy for treatment of rheumatic arthritis and obstructive diseases of respiratory ways.

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

13 cl, 88 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to N-(indolcarbonyl)piperazine derivatives of general formula I

, wherein R1 is optionally substituted phenyl or naphthyl; R2 and R3 are independently Hal or Het1, A, OA, CN; R4 is H, CN, acyl, Hal, CONH2, CONHA or CONA; R1 is H; or R4 and R5 together form C3-C5-group; Het1 is aromatic heterocyclic ring, optionally substituted with one or two halogen atoms and containing 1-3 similar or different heteroatoms such as nitrogen, sulfur and oxygen, A-(C1-C6)-alkyl; Hal is F, Cl,Br, and J; and indole ring may be substituted with isatin, except for (1H-indole-5-yl)-(4-phenethylpiperazine-1-yl)-methanone and 1-((5-methoxy-1H-indole-7-yl)-carbonyl)-4-(2-phenethyl)-piperazine. Claimed compounds are potent 5-HT2A antagonists and are useful in treatment of psychosis, schizophrenia, depression, neurological diseases, dismepodia, Parlinson's disease, Alzheimer's disease, Hungtington's disease, amyotrophic lateral sclerosis, bulimia or anorexia, premenstrual syndrome, and/or in alleviation of hypomania.

EFFECT: new pharmaceutical agents.

9 cl, 10 ex, 1 tbl

FIELD: organic synthesis.

SUBSTANCE: invention provides substituted methyl-N-amidooxamoyl-N-phenyl-D,L-alaninates having general formula I:

where R1 and R2 represent C1-C4-alkyl, R3 and R4 either represent H, C1-C6-alkyl or form together group -(CH3)2-X-(CH2)2- wherein X is O or CH2. Compounds exhibit fungicide activity and can be used to prevent and treat plant diseases.

EFFECT: increased choice of fungicides.

5 cl, 1 tbl, 11 ex

The invention relates to derivatives of piperazine or piperidine derivatives of General formula I, in which G represents a carbon atom or nitrogen; And selected from (i) phenyl substituted by a group-COOH, CONH2-SOON3, -CN, NH2or-PINES3; (ii) naphthyl, benzofuranyl and hineline; or a group of the formula (iii), R1selected from hydrogen; branched or straight C1-C6of alkyl, C1-C6alkenyl - (C1-C6alkyl); each of R9, R10, R13, R14, R17and R18independently has the meanings indicated above for R1; Represents a substituted or unsubstituted aromatic, optionally substituted C5-C10hydroaromatics balance

The invention relates to new derivatives of piperidine-ketocarboxylic acids of the formula (I), where R1- COR4or SO2R4, R4means of alkenyl, substituted phenyl or pyridine, naphthyl, honokalani, chinoline, benzothiophene, dihydroxyphenyl or pyridyl, substituted with allmineral, R2- C1-C6-alkyl which can be substituted by phenyl or pyridium, R3group-OR6or other6where R6means hydrogen, C1-C6-alkyl, which may be a phenyl, pyridine or morpholinium, their tautomeric and isomeric forms, and salts

The invention relates to new thiazole derivative of the formula I, where R1denotes a group of formula (a), (b), (C), R2denotes a group of formula (d), where Het represents a five - or six-membered heterocyclic group which is substituted by9and in the loop which, in addition to the nitrogen atom, can optionally contain an oxygen atom, R3denotes hydrogen, alkyl, cycloalkyl, phenyl, R4denotes hydrogen, phenyl, R5- R8independently of one another denotes hydrogen, R9denotes a group of formula (e) and (f), R10denotes phenyl, a-i denotes 0 or a positive integer, i.e
The invention relates to a method for anticancer drug prospidina, which is used in oncological practice, as well as in the treatment of rheumatoid arthritis

The invention relates to the derivatives of diphenyl, in particular, it relates to derivatives of diphenyl who are antagonistic towards 2-defeminization and/or 2-serotoninreuptake and which is clinically used as a therapeutic-help tools for mental disorders, such as vascular dysfunction brain, aggressive behavior due to senile dementia, mental arousal, pornomania, delirium, hallucination, hyperkinesia, schizophrenia, emotional disorder, depression, neurosis, psycho-physiological disorder and neurosis of fear

The invention relates to new compounds, levogyrate and programada, optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl] -4-[(were)sulfonyl]-piperazine of the formula I:

< / BR>
the method of production of these compounds, their use as levogyrate and programalso, optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl] -piperazine

FIELD: organic chemistry.

SUBSTANCE: claimed method includes reaction of C60-fullerene with 1,2-diaminepropane in presence of Cp2TiCl2 as catalyst in toluene medium at room temperature (approximately 20°C) for 44-52 hours. Yield of target product is 73-90 %. Compound of present invention is useful as chelating agent, sorbent, biologically active compound and for production of new materials with desired electronic, magnetic and optical properties. .

EFFECT: new compound; method of increased yield and selectivity.

1 tbl, 1 ex

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the general formula (I): wherein X1, X2, X3, X4 and X5 mean -CH2 or one of them represents -NH and another X1-X5 represent -CH2; k = 0, 1 or 2; when t = 2, then radicals R1 are similar or different; R1 represents direct or branched (C1-C8)-alkyl or (C1-C8)-alkoxy-group; A means phenyl or pyridinyl; R2 means hydrogen atom (H), hydroxyl, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; n = 0, 1-4; radicals R2 are similar or different, when n > 1; p = 0 or 1-5; Y means -OC(O); Z means -CH, or to their pharmaceutically acceptable salts. Compounds of the formula (I) possess agonistic activity with respect to muscarinic receptors and can be used in medicine as medicinal preparations for treatment of neurodegenerative diseases or diseases associated with increased intraocular pressure.

EFFECT: valuable medicinal properties of derivatives.

6 cl, 1 tbl, 2 dwg, 16 ex

The invention relates to peptide compositions with delayed release, representing a compound (I) containing the compound (A) formula

and the polymer containing lactide links, glycolide links and links tartaric acids - which are found in the polymer at the next sootnoshenii: lactide units constitute from about 71% to about 73%, glycolide links from about 26% to about 28%; and the parts of tartaric acid from about 1% to 3%, and the amino group of the compound (a) relate ionic bond with the carboxyl groups of the acid units of the polymer; the particles of compound I, an average size of from about 10 microns to about 100 microns; pharmaceutical composition with delayed release and two methods of treatment of various diseases, including the introduction to the patient an effective amount of compound A, or microparticles

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of General formula

where X1-X5denote SN2or one of them denotes NH, and the other X1-X5are CH2; k is 0 or 1, R1is1-8the alkyl, C1-8hydroxyalkoxy; t is 0, 1 or 2; And represents phenyl or pyridinyl; R2is H, hydroxyl, halogen or1-6the alkyl, C1-6alkoxygroup; n is 0, 1-4; p is 0 or an integer from 1 to 5, Y is-C(O)-; Z is CH2or their pharmaceutically acceptable salts

The invention relates to derivatives of piperazine or piperidine derivatives of General formula I, in which G represents a carbon atom or nitrogen; And selected from (i) phenyl substituted by a group-COOH, CONH2-SOON3, -CN, NH2or-PINES3; (ii) naphthyl, benzofuranyl and hineline; or a group of the formula (iii), R1selected from hydrogen; branched or straight C1-C6of alkyl, C1-C6alkenyl - (C1-C6alkyl); each of R9, R10, R13, R14, R17and R18independently has the meanings indicated above for R1; Represents a substituted or unsubstituted aromatic, optionally substituted C5-C10hydroaromatics balance
The invention relates to a method for producing 2-trifluoromethyl-10-[3-(1-methyl-piperazinil-4)-propyl)] -fenotiazina used to treat diseases of the Central nervous system

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: Described are derivatives of general formula I (all symbols are as described in specification), pharmaceutically acceptable salts thereof or cyclodextrin clathrates. Such compounds hardly bind of EP2 subtype of PGE receptor and are useful in prophylaxis of immune diseases, allergy, death of neuronal cells, liver or kidney insufficiency, etc.

EFFECT: new agent for prophylaxis of various diseases.

18 cl, 388 ex, 68 tbl, 3 dwg

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