Derivatives of piperazine or piperidine derivatives and pharmaceutical composition

 

(57) Abstract:

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. Also described pharmaceutical composition on the basis of the claimed compounds. Compounds have analgesic activity and can be used in therapy, in particular for the treatment of pain. 2 C. and 10 C.p. f-crystals, 1 PL.

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The scope of the invention

The invention relates to new compounds, to a method of production thereof, their use and pharmaceutical compositions comprising these compounds. New the Oia and the prior art

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

Identify at least three different populations of opioid receptors (and ) 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-ligands, with few exceptions, are peptide nature and are not suitable for the introduction of a system of ways. Some time used ones-antagonists (description given Takemori and 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 the receptor against the binding-receptor and do not show analgesic activity, which emphasizes the need to develop highly selective ones-agonists.

Ateny agonist, analgesic activity, but it has a significant affinity to the 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 agonists and potential oral performance.

Identified known analgesics have many disadvantages: they have poor pharmacokinetic properties and do not have analgesic 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

New connections in BR> And choose from

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

(ii) naphthyl, benzofuranyl and hineline; and

(iii)

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and

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where the phenyl ring of each substituent may be optionally and independently substituted with one or two substituents selected from hydrogen, CH3, (CH2)oCF3, halogen, CONR7R8, CO2R7, COR7, (CH2)oNR7R8, (CH2)oCH3(CH2)oSOR7, (CH2)oSO2R7and (CH2)oSO2NR7R8where o=0,1 or 2, a R7and R8have the meanings stated below;

R1selected from hydrogen; branched or straight C1-C6of alkyl, C1-C6alkenyl, -CO(C1-C6alkyl); (C1-C6alkyl) -, where b has the meanings stated below; C3-C8cycloalkyl; C4-C8(alkyl-cycloalkyl), where alkyl represents a C1-C2alkyl, and cycloalkyl represents a C3-C6cycloalkyl; C6-C10aryl; and heteroaryl having from 5 to 10 atoms selected from any of C, S, N and O; C6-odored, CH3, (CH2)oCF3, halogen, CONR7R8, CO2R7, COR7, (CH2)oNR7R8, (CH2)oCH3(CH2)oSOR7,

(CH2)oSO2R7and (CH2)oSO2NR7R8where = 0,1 or 2, and R7and R6have the meanings stated below;

each of R7and R8independently has the meanings indicated above for R1;

R2selected from hydrogen, CH3, OR1, CO2R1and CH2CO2R1where R1have the above meanings;

each of R9, R10, R11, R12, R13, R14, R15, R16, R17and R18independently has the meanings indicated above for R1;

Represents a substituted or unsubstituted aromatic, optionally substituted C5-C10hydroaromatics, heteroaromatic or heterokedasticity residue, each of which has from 5 to 10 atoms selected from any of C, S, N and O being optionally and independently substituted with one or two substituents, independently selected from hydrogen, CH3, CF3, halogen, (CH2)pCONR7R8, (CH)pSOR7, (CH2)pSO2R7and (CH2)pSO2-NR7R8; where p = 0,1, 2, or 3, and where R7and R8have the above meanings;

each of R3, R4, R5and R6independently selected from R7, (CH2)pCONR7R8, (CH2)pNR7R8, (CH2)pCONR7R8, (CH2)pCO2R7, (CH2)pPh, (CH2)p(p-OHPh), (CH2)p-3-indolyl, (CH2)pSR7(CH2)pOR7; where p = 0, 1, 2, 3 or 4, a R7and R8have the above meanings;

provided that when a represents a phenyl ring substituted by the group-CN, or a group-NH2In may not be

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where Z1represents hydroxyl and its esters;

hydroxymethyl and its esters; or amino, and carboxamides and sulfonamides.

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 the choice is
(ii) naphthyl, benzofuranyl and hineline; and

(iii)

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and

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where the phenyl ring of each substituent may be optionally and independently substituted with one or two substituents selected from hydrogen, CH3, (CH2)oCF3, halogen, CONR7R8, CO2R7, COR7, (CH2)oNR7R8, (CH2)oCH3(CH2)oSOR7, (CH2)oSO2R7and (CH2)oSO2NR7R8where = 0,1 or 2, a R7and R8have the meanings stated below;

each of R1, R7and R8independently selected from hydrogen; branched or straight C1-C4of alkyl, allyl, -CO-(C1-C6alkyl); (C1-C6alkyl) -, where b has the meanings stated below;

WITH3-C5cycloalkyl,4-C8(alkyl-cycloalkyl), where alkyl represents a C1-C2alkyl, and cycloalkyl3-C6cycloalkyl; and phenyl;

R2represents hydrogen, methyl or or1where R1have the above meanings;

each of R9, R10, R11, R12, R13, R14, R15, R16, R17and R
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with each In-group is optionally substituted with 1-2 substituents independently selected from hydrogen, CH3, CF3, halogen, (CH2)pCONR7R8, (CH2)pNR7R8, (CH2)pCOR7, (CH2)pCO2R7and OR7; where p= 0 or 1, and where R7and R8have the above meanings; and

each of R3, R4, R5and R6independently selected from hydrogen, CH3CH(Me)2CH2CH(Me)2CH(Me)CH2CH3(CH2)pCONR7R8, (CH2)pNR7R8, (CH2)pCONR7R8,

(CH2)pCO2R7, (CH2)pPh, (CH2)p(p-OHPh), (CH2)p-3-indolyl, (CH2)pSR7and (CH2)pOR7where p = 0, 1, 2 or 3, and where R7and R8have the above meanings;

provided that when A represents sostavljaet a hydroxyl and its esters;

hydroxymethyl and its esters; or amino, and carboxamides and sulfonamides.

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

G represents a nitrogen atom;

And choose from

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and

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where each of R9, R10, R11, R12, R13, R14, R15, R16, 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, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophene, furanyl, chinoline, izochinolina, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrofuryl, tetrahydroisoquinoline, tetrahydrofuranyl, indazolinone and

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with each In-group is optionally substituted with 1-2 substituents independently selected from hydrogen, methyl, CF3, halogen, (CH2)pCONR7R8, (CH2)pNR7R8, (CH2)pCOR7nye above for R1;

each of R3, R4, R5and R6independently selected from N, CH3CH(Me)2CH2CH(Me)2CH(Me)CH2CH3(CH2)pCONR7R8, (CH2)pNR7R8, (CH2)pCONR7R8,

(CH2)pCO2R7, (CH2)pRH, (CH2)p(p-OHPh), (CH2)p-3-indolyl, (CH2)pSR7and (CH2)pOR7where p = 0, 1, or 2, and where R7and R8have the above values

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 structure, an aromatic ring having 5-10 ring carbon atoms.

Under "heteroeroticism connection" Podrezov in the ring are carbon, but other elements, such as N, S and O.

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, 8th ed., McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p.13-15, describing 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-opioid, and the modulation side effects occur when using agents, acting at the level of receptor subtype-opioid, is the only means.

Compounds according to 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 and imaging 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 to implement this is 21 (compound 33), Example 22 (compound 34), Example 23 (compound 37), Example 24 (compound 38), Example 25 (compound 41), Example 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 Schemes.

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.

A generalized method IN

N-protected amino acid, in the form of its aktivirovannyye 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 l3and 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 permission.

Detailed description of the invention

Hereinafter the invention is described in more detail by using examples that do not require it, the nd doublet;

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

EXAMPLES

Compounds according to Examples 1-3 are synthesized as shown in Scheme 1, see the end of the description).

AND

I. Obtaining 3-methoxy--(1-naphthyl)binalewala 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 nitrogen atmosphere at -78oC. the Reaction mixture was 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 -78oC. the Mixture is heated to room temperature for 3 hours, then cooled rapidly with a solution of aqueous NH4Cl and extracted with ethyl acetate (3 x 50 ml). The combined organic phases are washed with saturated saline and dried over MgSO4. Removing the solvents in vacuo, the obtained 3-methoxy--(1-naphthyl)benzyl alcohol (4,25 g, 54%). Gas chromatography mass spectroscopy (GC-MS) (Rt= 10,41 minutes) 264 (M+), 245, 231, 215, 202, 155, 135, 128, 109.

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

To a solution of 3-methoxy--(1-naphthyl)benzyl alcohol (2.5 g, 9.5 mmol) is based temperature for 1 hour, and then extracted with ethyl acetate (3 x 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--(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 ()of TRANS-1(3-methoxy--(1-naphthyl)benzyl)-2,5-dimethylpiperazine (compound 3)

A mixture of TRANS-2,5-dimethylpiperazine (456 mg, 4.0 mmol), 3-methoxy--(1-naphthyl)benzyl chloride (430 mg, 1.5 mmol) 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 NH4HE and extracted with ethyl acetate (3 x 50 ml). The combined organic layers washed with 0.5 N aqueous NaOH solution, saturated aqueous NH4Cl and saturated saline and then dried over gSO4. Removing the solvents, get ()-TRANS-1(3-methoxy--(1'-naphthyl)benzyl)-2,5-dimethylpiperazine 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.

Five 4 and 5)

The mixture obtained above ()-TRANS-1-(3-methoxy--(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 x 50 ml). The combined organic layers washed with saturated aqueous NH4Cl and saturated saline and then dried over MgSO4. Viparita solvents, get soggy ()-3-(((R*/S*)--((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);n(400 MHz, CDC13) 1.02(d,J=6.4 Hz, 6N), 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);C-13(100 MHz, D13) 13.2, 14.2, 35.6, 52.1, 53.0, 55.1, 55.2, 57.2, 63.8, 111.6,�FYR);

max(KBR) cm-13483, 1601, 1264;

Anal. for C27H32N22l1.0H2ABOUT:

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);n(400 MHz, Dl3) 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);C-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: so pl. 150,5-153oC (ether);

max(KBR) cm-13483, 1600, 1262;

Anal. to:27H32N22l0.N2ABOUT:

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

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

Compounds according to Examples 4-6 are synthesized as shown in Scheme 2 (see the end of the description).

Century

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

Connection 6 receive, using the synthesis procedure described for compound 1, but replacing 1-naphthaldehyde 2 is H), 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); C-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. Obtaining 3-methoxy--(2-naphthyl) beneil 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--(2-naphthyl)benzyl)-2,6-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((R*/S*)--((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(3.1), 274.15(8.0), 247.05(21.7), 215.10(13.0), 202.05 (7.0), 153.15(100), 126..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: so pl. 129-138oC (ether);

max(KBR) cm-13426, 1600, 1262;

Anal. for C27H32H2O2l0.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). His model HC1 salt: so pl. 160-162,5oC (ether);

max(KBr) cm-13380, 1600, 1261;

Anal. for C27H32H2O2l0.50N2O:

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

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

Compounds according to Examples 7-11 are synthesized as shown in Scheme 3 (see end of description).

C.

I. Obtaining 3-methoxy--(2-benzofuranyl) benzyl alcohol (compound 11)

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

GC-MS(Rt= 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);n(400 MHz, Dl3) 3.21(brs, 1H), 3.72(s,3H), 5.82(s, 1H), 6.47(s, 1H), 6.80-7.50(m, 8H).

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

Connection 12 receive, using the procedure from(M+, 4.1%), 237.10(100), 221.05 (4.5), 194.10(14.7), 165.10(23.1); n(400 MHz, D13) 3.78 (s,3H), 6.11(s,1H), 6.56(s,1H), 6.85-7.50(m,8H).

EXAMPLE 7.

Receive ()-TRANS-1-(3-methoxy--(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++l, 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),n(400 MHz, Dl3) (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). His model HC1 salt: so pl. 115-125oC (ether);

max(KBr) 3373, 1595, 1257;

Anal. for C22H26N2O21.70l0.20N2O:

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-((R*/S*)--((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinil)-2-benzofuranyl)anisole (srow 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);n(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, J=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);

C-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: so pl. 122-128oC (ether);

max(KBr) cm-13490, 1602, 1253;

Anal. for C25H30N2O22l0.25N2O:

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);n(400 MHz, CDCl3) 1.00(d, J=6.4 Hz, 3H), 1.21(d, J=6.4 Hz, 3H), 2.12(m, 2H), 2.48(m, lH), 2.61(m,lH), 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, lH), 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: so pl. 97-104oC (ether);

max(KBr) cm-13438, 1601 (s), 1260;

With, 63.70; H, 6.68; N, 5.83.

EXAMPLES 10 and 11.

Receive ()-3-((R*/S*)--((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); n(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,lH), 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);C-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.

His model HC1 salt: so pl. 162-164oC (ether);

max(KBR) cm-13414, 1599, 1255;

Anal. for C26H32N2O22l0.5H2O:

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+, 8.3
) 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);C-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.

His model HC1 salt: so pl. 92-105oC (ether);

max(KBR) cm-13398, 1599, 1257;

Anal. for C26H32N2O22HCl0.5H2O;

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

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

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. ) heated to 220oC for 1 hour. After cooling, the residue is dissolved in ethyl acetate (100 ml). The organic solution was washed with brine and dried over MgSO4. After 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);n(400 MHz, CDCl3) 7.53(m, 1H), 8.21 (m,2H), 8.33(m,2H), 9.06(m, 1H), 10.21(s,1H):C-13(100 MHz, CDCl3) 122.1, 126.6, 127.6, 130.7, 133.5, 134.2, 137.3, 150.8, 153.0, 191.3.

Connection is Getting 3-methoxy--(6-chinoline)gasoline ethanol (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);n(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);C-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. Obtaining 3-methoxy--(6-chinoline)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:n(400 MHz, CDCl3) 3.73(s,3H), 5.98(s,1H), 6.8-8.2 (m, N), 8.80(s, 1H).

EXAMPLES 12 AND 13.

Receive ()-TRANS-1(3-methoxy--(6'-chinoline)-benzyl)-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;n(400.88(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, 0=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):

n(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-((R*/S*)--((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);

n(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, 0= 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);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: so pl. 128-140oC (ether);

max(KBR) cm-13376, 1596, 1263;

Anal. for C26H31N3O2.30l0.1H2O:

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

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

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);n(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);C-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: so pl. 177-182oC (ether);

max(KBR) cm-13405, 1597, 1260;

Anal. for C26H31N3O2.80l:

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((R*/S*)--((2S*,5B*)-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 cyclopropylmethyl-iodide.

The first isomer, compound 24: GC-MS (Rt= 20.77 min) 415.25 (M+, 3.8%), 34 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=13.2, 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);C-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: so pl. 127-157oC (ether);

max(KBr) cm-13402, 1596, 1262;

Anal. for C27H33N3O3HCl0.75H2O:

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);n(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), 2.38(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);C-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: so pl. 92-105oC (ether);

max(KBR) cm-13345, 1596, 1259.

Connection with the I. Obtaining 3-methoxy--(4-chinoline)gasoline ethanol (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);n(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);C-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. Obtaining 3-methoxy--(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--(4-chinoline) benzyl - 2,5-dimethylpiperazine (compound 28)

The compound of this Example will be received, using the synthesis procedure described for compound 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);n(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((R*/S*)--((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(M+, 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);n(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);C-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: so pl. 158-166oC (AcOEt-ether);

max(KBR) cm7;

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(0.2), 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); n(400 MHz, CDCl3);C-13(100 MHz, CDCl3).

Its Hcl salt: so pl. 155-165oC (AcOEt-ether)

Compounds according to Examples 21 and 22 are synthesized as shown in Scheme 6 (see the end of the description).

F.

I. Receive ()-4((-hydroxy)-4-Chlorobenzyl)-N, N-diethylbenzamide (compound 31)

4-Formyl-N, N-diethylbenzamide (putting on 2,088 g, 10.1 mmol) dissolved in 45 ml of anhydrous tetrahydrofuran. The solution is cooled to -78oWith, and then added dropwise 10.1 ml (10.1 mmol) 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 x 30 ml). The combined organic layers washed with water (2 x 30 ml) and saturated brine (1 x 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 colorless is 1(3H,brs), 3.22 (2H,brs), 3.33(1H, d, J 3), 3.50(2H,brs), 5.74 (1H, d, J 3), 7.22-7.34(m,8H);

II. Receive ()-4((-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(((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.

So pl. 112-113o(From acetonitrile),max(KBR) cm-13347, 2947, 2809, 1615, 1451, 1318, 1284, 1094, 836;n(400 MHz, CDCl3) 1.10(3H,brs), 1.21(3H, brs), 1.69(1H, brs), 2.33(4H,brs), 2.86-2.89(4H,m), 3.24(2H,brs), 3.51 (2H,brs), 4.22(1H,s), 7.23-7.41(8H,m);

C22H28N3OCl0.3H2O requires: C, 67.52; H, 7.37; N, 10.74;

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

EXAMPLE 22.

Getting()-4-((-((4-allyl)-1-piperazinil)-4 - Chlorobenzyl)-N, N-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.

So pl. 147-163oC (from ether),max(KBR)/cm-13418, 2974, 2355, 1626, 1435, 1286, 1092, 945, 812:3requires: C, 60.18; H, 6.87; N, 8.42;

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

Compounds according to Examples 23-24 synthesized as shown in Scheme 7 (see the end of the description).

G.

I. Receive ()-4-((-hydroxy-2-naphthylmethyl)-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.

max(KBR) cm-13302, 2976, 1607, 1430, 1290, 1098, 813;n(400 MHz, CDCl3) 1.09(3H,brs), 1.22(3H,brs), 2.60(1H, d, J 3), 3.24(2H,brs), 3.52(2H, brs), 6.00(1H, d, J 3), 7.30-7.50(7H,m), 7.76-7.88(4H,m);

II. Receive ()-4((-chloro)-2-naphthylmethyl)-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((-(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.

So pl. 106-108o(From acetonitrile),max(KBR)/cm-13324, 3052, 2964, 2810, 277H,s), 7.24-7.84 (11,3 m);

WITH26H31N3O0.9H2O requires: C, 74.75; H, 7.91; N, 10.06;

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

EXAMPLE 24. Getting()-4-((-((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,

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

C25H34N3OCl30.6 H2O requires: C, 76.99; H, 8.07; N, 9.29;

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

Compounds according to Examples 25-26 synthesized as shown in Scheme 8 (see end of description).

N.

I. Receive ()-4-((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.

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

II. Receive ()-4-((-chloro)-4-xylyl)-N,N-ditives the x2">

Use in the next stage without further purification.

EXAMPLE 25.

Getting()-4-((-(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.

So pl. 129-132o(From acetonitrile),max(KBR)/cm-13320, 2957, 2811, 1610, 1437, 1285, 1128, 1010, 838;

n(400 MHz, CDCl3) 1.10(3H,brs), 1.20(3H,brs), 1.83(1H,brs), 2.30(3H, s), 2.34(4H,brs), 2.86-2.89 (4H,m), 3.24(2H,brs), 3.51(2H,brs), 4.20(1H,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.

Getting()-4((-((4-allyl)-1-piperazinil))-4-xylyl)-N, N-2l (compound 42)

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

So pl. >160oWith decomp. (from ether);max(KBR)/cm-13437, 2973, 2402, 1625, 1433, 1289, 1097, 944, 809:n(400 MHz, CDCl3, free base) 1.10(3H, brs), 1.20 (3H, brs), 2.29(3H, s), 2.35-2.60 (6H,m), 3.03(2H,m), 3.24(2H, brs), 3.52(2H,brs), 4.22(1H,s), 5.12-5.23 (2H,m), 5.81-5.93 (1H,m), 7.05-7.45 (8H, 3m);

Compounds according to Example 27 are synthesized as shown in Scheme 9 (see at the end of the description).

I.

I. Receive ()-4((-hydroxy)-3-xylyl)-N,N-dieti 31, but replacing 4-chloraniline bromide m-toluylene bromide.

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

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

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

Use in the next stage without further purification.

EXAMPLE 27.

Receive ()-4((-(1-piperazinil))-4-xylyl)-N, N - 1-2l (compound 45)

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

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

Compounds in accordance with Example 28 are synthesized as shown in Scheme 10 (see the end of the description).

J.

I. Receive ()-4((-hydroxy)-cyclohexylmethyl)-N, N-diethylbenzamide (compound 46)

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

n(400 MHz, CDC is benzamide(compound 47)

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

Use in the next stage without further purification.

EXAMPLE 28.

Getting()-4-((-(1-piperazinil))-cyclohexylmethyl)-N,N-diethylbenzamide (compound 48)

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

So pl. 113-116o(From acetonitrile),max(KBR)/cm-13330, 2936, 2845, 1623, 1431, 1286, 1096, 823;

n(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,brs), 3.52(2H,brs), 7.11(2H, d, J 8.4), 7.29(2H, d, J 8.4);

Compounds according to Example 29 are synthesized as shown in Scheme 11 (see the end of the description).

K.

I. Receive ()-4-((hydroxy)-3,4-dimethylbenzyl)-N,N-diethylbenzamide (compound 49)

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

n(400 MHz, CDCl3) 1.09(3H,brs), 2.23(6H,s), 2.85(1H, d, J 3), 3.24(2H, brs), 3.5l(2H,brs), 5.73(1H, d, J 2), 7.03-7.12(m,3H), 7.26-7.39(m,4H).

II. Receive ()-4((-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 dalnas(compound 51)

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

max(KBR)/cm-13304, 2939, 2810, 1626, 1429, 1286, 1096, 846;n(400 MHz, CDCl3) 1.11(3H,brs), 1.20(3H,brs), 1.87(1H,brs), 2.20(3H,s), 2.22(3H, s), 2.34(4H, brs), 2.86-2.89(4H,m), 3.25(2H,brs), 3.51(2H,brs), 4.15(1H,s), 7.02-7.15(3H,m), 7.26-7.30(2H,m), 7.42-7.46(2H,m);< / BR>
Compounds in accordance with Example 30 receive, using the procedure of synthesis as shown in Scheme 12 (see the end of the description).

L.

I. Receive ()-4-((hydroxy)-1-naphthylmethyl)-N, N-diethylbenzamide (compound 52)

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

n(400 MHz, CDCl3) 1.06(3H, brs), 1.20(3H, brs), 3.01(1H, d, J 4), 3.21(2H, brs), 3.49(2H, brs), 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-((-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.

Getting()-4-((-(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.

max
Modification piperazinovogo rings:

General experiments and examples

Compounds according to Examples 31-42 synthesized as shown in Scheme 13 (see the end of the description).

M

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 0oC. 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 0oC to dissolve lumps. The reaction mixture was then left in the freezer 4d at -20oC. 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 25oC. 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 0oWith Chris is which can be recrystallized from methanol, so pl. >300oC;

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

1H NMR (D2O): =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. Getting 2-dimethyl-5-methyl-piperazine 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 vacuo 1.5 g (84%). Treating excess Hcl in ether, receive dihydrochloride, compound 56, which may be recrystallized from methanol/ether, so pl. >300oWith IR KBR (cm-1): 2760, 1570 (R2NH2+) MS (Amin): 128, 113, 84, 71, 58.

1H NMR (D2O+DSS): = 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).

C7H16N is e 4-(4-(2-dimethyl-5-methylpiperazine)-3-methoxybenzyl)-N, N-diethylbenzamide dihydrochloride (compound 57)

4-(Chloro-(3-methoxyphenyl)methyl)-N,N-diethylbenzamide (and 0.61 g, 2.0 mmol) and the connection 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 is heated under reflux for 2d. The solvent is removed in vacuo and the residue purified flash chromatography on silica (CH2Cl2/-Meon/NH3, (aq.), 98:1:1-95: 5:1, getting 0.65 g (79%). Treatment with excess Hcl in ether, filtering and drying the crystals in vacuum over KOH results dihydrochloride, compound 57, so pl.: 134-136oC. IR (model HC1 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): = 7.40-6.60 (m, 8H, Ar-H), 5.26, 5.25, 4.61(3s,lH CHAr2), 3.70(s,3H, MeO), 3.4, 3.2(2 br s, 4H, MeCH2), 3.1-2.0 (m, 5H, piperazine-H), 1.3-0.9 (m, 15H, me).

WITH26H37N2O22hcl 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-methylpiperazine)-3-methoxybenzyl)-N,N-diethylbenzamide dihydrochloride (compound 58)

Compound 57 (0.39 g, to 0.92 mmol) dissolved in dry acetonitrile (5 ml). Add the carbonate kalimat 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, so pl. 105-121oC. IR (model HC1 salt, KBR) (cm-1): 3400 (br, OH), 2500 (br, R2NH2+), 1620 (s) (C=O, or R2NH2+), 1285, 1043 (C-O).

1H NMR: (Amin, CDCl3): = 7.50-6.60(m,8H, Ar-H), 5.70(m, 1H, allyl-H), 5.00(m,2H, allyl-H), 4.70(s,lH, Snug2), 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).

WITH29H41N3ABOUT22hcl 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) dissolved in acetonitrile and at 0oWith 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 poluchaut, 2480(br), 1607, 1436, 1285. MS (free amine): 366, 296, 167.1H NMR: (D2O + DSS): = 7.60-6.90(m, 9H, Ar-H), 6.0-5.5 (m,4H allyl-H+AG2CH), 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 C29H41N3ABOUT22l2.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)-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 added dropwise di-tert-buildconf (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/Meon, 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/Meon), 100:0, 95: 5. Treatment with formic acid (5 ml) for 3 hours, evaporation )2CO3) 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, so pl. 145-150oC. IR (2hcl, KBR) (cm-1): 3500-3400 (br), 1601, 1442, 1285. MS(free amine):423, 296, 325, 127.

1H NMR (CDCl3): = 7.4-6.6(m, 8H, Ar-H), 5.39, 5.36(2s,1H, AG2CH), 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,3H, Me).

For C26H37N3O22l7.4H2O:

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

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

O.

I. Obtaining 4-(phenylhydroxylamine)-N,N-diethyl-benzamide (compound 62)

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

MS: 282, 211, 165, 105.1H NMR: (CDCl3): = 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 brs, 6H).

II. Getting 4-(chloroformyl)-N,N-diethylenediamine

(compound 63)

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

GC-MS (2 maximum): 296, 225, 165, 121 and 300, 266, 229, 195, 165.1H NMR: (CDCl3): = 7.45-7.20(m,9H), 6.09(s,1H), 3.4 (br m,4H), 1.1(br m, 6H).

EXAMPLE 35.

So pl. 157-169oC. 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): 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 C22H29N3O2l1.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-diethylbenzamide dihydrochloride (compound 65)

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

So pl. 175-205oC. IR (Amin, CDCl3in cells KBR) (cm-1): 3689, 1613, 1455, 1434, 1290, 1143. MS (free amine): 391, 165, 125.1H NMR: (free amine DCl3): = 7.42-7.12 (m, 9H, Ar-H), 5.81(m,1H, allyl-H), 5.10(m, 2H, allyl-H), 4.23(s,1H, Snug2), 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 C25H35N32l1.0H2ABOUT:

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

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

R.

I. Getting 2-hydroxymethyl-5-methylpiperazin-3,5-d is tiramina (8.1 ml), dried molecular sieves 4A and transferred to a dry flask in a stream of nitrogen. If -10oWith 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 the 25oWith and mix it within 12 hours. Washing solution, brine, drying (gSO4) 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 under 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-methylpiperazine (compound 67)

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

II. Getting 2-(tert-butyldiphenylsilyl)methyl-5-methylpiperazine (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. Producut 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.

So pl. 145-150oC. 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): = 7.44-7.18 (m, N, 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, 9H, piperazine-IU+amide-IU).

Anal. for C24H33N3O22l1.8H2O:

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-methoxybenzyl)-N, N-diethylbenzamide dihydrochloride (compound 70)

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

So pl. 185-190oC. IR (2hcl, KBR) (cm-1): 3500-2500 (br), 1596, 1440, 1045.1H NMR: (free amine, CDCl3): = 7.40-6.60 (m, 8H, Ar-H), 5.05, 5.10(2s, 1H, AG2CH), 3.70(s,3H, MeO), 3.8-2.5(m,12H, the Lil-2-hydroxamate-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.

So pl. 125-130oC. 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): = 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(brs, 6N, amide-IU).

Anal. for C25H35N3ABOUT32l3.7H2O:

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, using the synthesis procedure described for compound 1.

MS: 264, 155, 135, 128, 109, 101.1H NMR: (CDCl3): = 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, OH).

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): = 7.86-6.81 (m, 11H, Ar-H), 6.25(s,1H, AG2H), 3.76(s,3H, MeO).

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

2-Methylpiperazin (0.4 g, 4 mmol.) R is at 0oC for 1 hour and then at 25oC 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-methylpiperazine)methyl) phenyl ester (compound 75)

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

So pl. 170-174oC. IR (KBR) (cm-1): 3461, 2458, 1600, 1439, 1263, 1043. MS(Amin): 386, 247, 215, 139, 112.1H NMR: (Amin, CDCl3): = 7.84-6.66(m, 11N, Ar-H), 4.33(s,1H, CHAr2), 3.74, 3.73(2s,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 C23H26N2O2HCl1.8H2O:

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.

So pl. 173-182oC. IR (KBR) (cm-1): 3430, 2500, 2355, 1601, 1436, 1265, 1047. MS (Amin): 386, 274, 247, 215, 139, 125.1H NMR: (Amin, CDCl3): = 7.86-6.66 (m, 11HASS="ptx2">

Anal. for C26H32N2O2HCl0.4H2O,

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

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

EXAMPLE 42.

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

The free amine of compound 64 (100 mg, 0.28 mmol) dissolved in methylene chloride (5 ml), cooled to 0oC. Add triethylamine (43 μl, 0.31 mmol, ), and then added dropwise to 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%).

So pl. 140-150oC. IR (KBR) (cm-1): 3480 (br), 2987, 2500(br), 1623, 1429, 1285, 1245. MS (free amine): 393, 267, 165, 127.1H NMR: (free amine, CDCl3): 7.46-7.18 (m, 9H, Ar-H), 4.25(s,1H, Snug2), 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 C24H31N3ABOUT21l0.N2O:

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

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

Replacement diethylbenzamide etc.

Compounds according to Examples 43-48 get as retinyl)-benzyl)-benzoic acid (compound 78)

Compound 64 (6.0 g, 17 mmol) dissolved in 6N hydrochloric acid and heated at 120oWith in 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 25oWith 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), receiving in the whole 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) treated with excess model HC1 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 100oC.

So pl. 172-180oC. IR (KBR) (cm-1): 3000 (br), 1700, 1606, 1454.1H NMR: (DMSO-d6): = 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 C18H20N2O2HCl:

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

Compound 78 (0.15 g, 0.38 mmol) and cesium carbonate (0.25 g, 0.76 to mmol.) mixed in dimethylformamide (2 ml) and add methyliodide (72 μl, 1.1 mmol. ). After 2 hours at 25oWith added potassium carbonate (10%, aq.) 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 surplus model HC1 in methanol at 50oC. the Solvent is removed and the residue is again purified on silica. The dihydrochloride, compound 81 (35 mg), receive, using the method described above.

So pl. 185-195oC. 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/CD3D+DSS): 8.20-7.34(m, N, Ar-H), 5.03(s,1H, Snug2), 3.89(s, 3H, MeO), 3.42(m,4H, piperazine-H), 3.08(m,4H, piperazine-H).

Anal. for C19H22N2O22HCl1H2O:

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

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

S.

I. Getting 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 -20OTM add ammonia in methylene chloride (0.51 ml, 1.1 M, 0,56 mmol.) and allow the temperature to rise slowly to 25oC. 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%). Processing model HC1 in methanol for 3 hours at 50oWith the 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.

So pl. 192-200oC. 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): = 7.96-7.22(m,9H, Ar-H), 4.93(s,2H, NH), 4.40(s,1H, Ar2CH), 2.94+2.46(2m, 8H, piperazine-H).

Anal.for C18H21N3O2HCl1.1H2O:

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.

So pl. 180-185oC. IR (KBR) (cm-1): 3331 (br), 2700 (br), 1640, 1545, 1440, 1308. MS: (EI, Amin) 323, 278, 267, 238, 195, 165.1H NMR (Amin, CD3D): = 7.84-7.14 (mmer 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 0oC. Add pyridine (36 μl, 0.44 mmol) and triperoxonane anhydride (31 μl, 0.22 mmol) and stirring is continued for 1 hour at 25oC. 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 50oC. Removal of the solvent in vacuo and chromatography of the residue on silica (CH2CL2/Meon/NH3, 90:10:1) results in 15 mg (49%). Treating excess model HC1 in ether/methanol, get dihydrochloride, compound 84, which precipitated, dissolved in water and lyophilizers.

So pl. 141-145oC. IR (KBR) (cm-1): 3400 (br), 2700 (br), 2230, 1434. MS (free amine): 277, 232, 192, 165.1H NMR: (free amine, CDCl3): = 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 C18H19N32HCl1H2O:

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

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

EXAMPLE 48.

Getting 4-(dry tetrahydrofuran (5 ml) and cooled to 0oC in nitrogen atmosphere. In for 1 minute add motility (3.1 ml, 0.8 M 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 25oWith, 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.

So pl. 175-185oC. IR (KBR) (cm-1); 3400 (br), 2700 (br), 1680, 1607, 1424, 1269. MS (E1, free amine): 294, 249, 209, 165.1H NMR: (free amine, CDCl3): = 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 C19H22H2O2l1.6N2ABOUT:

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

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

Compounds according to Example 49 are synthesized as shown in Scheme 15 (see the end of the description).

So

I. Receiving 4-benzoyl-N-tert-butoxycarbonylamino (compound 86)

A mixture of 4-benzoylpiperidine hydrochloride (6,77 g, 30.0 mmol), di-tert-BUTYLCARBAMATE (7.2 g, 33.0 mmol) and knso3(6.0 g, 60 the camping extracted with ethyl acetate (2 x 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%).

n(400 MHz, D13) 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-(-hydroxy--(4-N-tert-butoxycarbonylamino)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 78oWith added tert-utility (10.0 ml, 1.7 M, of 17.0 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 x 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-CH2CL; (0:100 --> 2:98) to obtain 4-(-hydroxy--(4-N-tert-butoxycarbonylamino)benzyl)-N, N-diethylbenzamide (MTL 0327, 2,60 g, 56%):

So pl. 100-103oC (CH2C12): max(KBR) cm-1: 3426, 2973, 1687, 1618, 1428, 1289, 1, .18(m,1H), 7.26(m,4H), 7.45(m, 4H);C-13(100 MHz, Dl3): 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-((-4-piperidinyl)benzyl)-N-N-diethylbenzamide (compound 88)

Crestore-(-hydroxy--(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 add triethylsilane (232 mg, and 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((-4-piperidinyl)benzyl)-N,N-diethylbenzamide (245 mg, 70%).

So pl. 160-162oC (CH2CL2);max(KBR) cm-13325, 2937, 1613, 1461, 1283, 1095;n(400 MHz, D13) 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=11.6 Hz, 2H), 3.01(m,2H), 3.23 (brs,2H), 3.51(d, J=10.4 Hz, 1H), , 71.0.

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) subjected to reaction with piperazine (1.6 g, 19 mmol) in acetonitrile (20 ml) for 4 hours at 80oWith to obtain in General 1.1 g of product (63%), which is converted into the dihydrochloride salt.

So pl. 165-182oC. IR (Amin, Dl3in the cell KBR) (cm-1): 3688, 1611, 1458, 1436, 1285. MS (free amine): 381, 336, 296, 224, 196, 165, 152, 112.1H NMR: (Amin, Dl3): = 1.05, 1.15(2br s,6H, 2Me), 2.51, 3.02(2br.s,8H, piperazine-H), 3.2, 3.45(2br. s,4H of Mesn2), 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).

WITH23H31N3O22l0.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. ) get 30 mg of product (20%), which in turn salt is (free amine): 421, 125.1H NMR: (Amin, D13): = 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, Snug2,), 5.14(m,2H, allyl-H), 5.85(m,1H, allyl-H), 6.70-7.46(m,8H, Ar-H).

WITH26H35N3O22l1.4H2ABOUT

requires: C, 60.09; H, 7.72; N, 8.08;

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

Connection Examples 52-55 synthesized as shown in Scheme 16 (see the end of the description).

U.

Compound I: 4-(-hydroxybenzyl)-nitrobenzene

4-Nitrobenzoic (4,55 g, 20,1 mmol.) dissolved in 70 ml of anhydrous methanol, cooled to 0oC 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, yield ~100%).

1H NMR (Dl3TMS): (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-NR2); 8.18(d, J=8.6 Hz, 2H, Ar-NR2).

Compound II: 4-(Chlorobenzyl)-nitrobenzene

Compound I (4,58 g, 20 mmol.) dissolved in anhydrous CH2Cl2, the Yu 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 (D13TMS): (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 mmol. ) 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 (D13TMS): : 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): : 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), the Prica, with stirring, add hydrazine (380 mg, 11,63 mmol), the temperature of the mixture was raised to 70oWith 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/Meon = 99/1-99/5 as a solvent for elution to obtain a yellowish solid substance in the form of the target product (660 mg, yield ~ 80%).

Elemental analysis for: C24H27N30.2 H2O:

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

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

IR (NaCl film): = 2807, 1620, 1513, 1451, 1282, 1137 cm-1.

1H NMR (D13TMS): : 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 Panso3and dis is de oil (44 mg, yield 80%).

1H NMR: (D13TMS) : 2.1(3H,s ), 2.3-2.48 (8H, br, pieperazinove ring), 3.48(2H, s ), 4.16(1H,s ), 7.20-8.12(14H, Ar) ppm.

Elemental analysis for: C26H29N3O2,1l0,3H2ABOUT:

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

Found: C, 64,86; N, Only 6.64; N, 8,73.

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: 195~200oC (decomp.)

1H NMR: (Dl3TMS) : 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.

elementary analysis: C25H29N3ABOUT2SO,9H2ABOUT:

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-N-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) 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/Meon = 98/2 as solvent, getting the product in the form of oil (~23 mg, 20%).

IR (film, NaCl); Hcl salt

= 3404(br), 2922(br), 1745, 1610, 1517, 1439, 1207 cm-1< / BR>
1H NMR: (Dl3) : 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:27H31N3ABOUT23l:

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

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

Compound IV: 4-(3-fluorescent-hydroxybenzyl)acetonitrile

1-Fluorescent-3-iodobenzoyl (7,53 g, to 33.9 mmol) Rast add n-utility (2.5 M in tetrahydrofuran, to 33.9 mmol). The mixture is stirred 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 -78oC for 30 minutes. The organic layer was washed with brine and dried over anhydrous gSO4, 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: (D13) : 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-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: (D13) : 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: (Dl3) : 2.14(3H,s ), 2.40(8H, br, piperazine), 3.51(2H, s ), 4.19(1H,s,, ), 6.80-7.40 (1�: With, 56.24; H, 6.02; N, 7.13.

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

Pharmaceutical compositions

New connections 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 act as diluents, corrigentov, solvents, oil, suspendresume agents, binders or agents, disintegrating tablets; it may also include encapsulating the paper is echenim active component. 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, glcalllist, hexylresorcinol, geranamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isetionate, lactate, lactobionate, malate, maleate, mandelate, mesilate, methylpentanoate, 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 citrate.

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 wafer.

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 of the active compounds. Liquid compositions may also be in the form of a solution in an aqueous solution of polyethylene glycol.

Aqueous solutions of DL is Alenia 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) IN VITRO MODEL

Cell culture

Human 293S cells expressing the cloned human receptors , and , as well as resistance to neomycin LCIA 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 ethylendiaminetetraacetic acid, while PMSF added just before use to 0.1 mm of 0.1 M 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 4oC. the Top 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, of 0.32 M sucrose, pH 7.0). Aliquot fraction (1 ml) in polypropylene tubes, frozen in a dry ice/ethanol and stored at -70oWith to use. The protein concentration determined by a modified Lowry analysis using sodium dodecyl sulfate.

Analysis of the binding.

Membranes are thawed at 37oC, cooled on ice, miss 3 times across the mA A-7888), pH 7.4, and stored at 4oAfter filtration through a 0.22 m filter, which directly before ispolzovaniem add 5 µg/ml Aprotinin, 10 μm Astanina, 10 μm diprolene And not containing dithiothreitol (DTT). Aliquot share of volume of 100 µl (µg protein is indicated in the table) add frozen in polypropylene tubes size h mm containing 100 μl of each radioligand (see table) 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 25oFor 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 is performed in 96-well tablet, then filtering is performed via 96 monofil Uchenie 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 Kdetermined by analyses on binding to cell membranes with the appropriate radio at a concentration of 0.2 to 5 times the estimated value of K(up to 10 times if the number of required radioligand is real). Specific binding of radioligand expressed in terms of molar parts/mg membrane specificeski associated (In) against PM 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 20oWith 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 in animal research.

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). Rats anaesthetize administered intraperitoneally with a mixture of ketamine/xylazine (2 ml/kg), placed on PR who have sciatic nerve, to put plastic sleeve (tube D 60 length 2 ml). 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

A group of rats, which was what ngatai on sciatic nerve on 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+K)/10000

where Xf= value of the last used hair von Frey (log units); K = tabular value (Chaplan et al. (1994)m if = 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:

< / BR>
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.

1. Derivatives of piperazine or piperidine derivatives of General formula (I)

< / BR>
where G represents a carbon atom or nitrogen;

And are selected from (i) phenyl substituted by a group-COOH, -N2SOON3, -CN, NH2or-PINES3;

(ii) naphthyl, benzofuranyl and hineline; and (iii)

< / BR>
< / BR>
and

< / BR>
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; branched or straight C1-C6of alkyl, C1-C6alkenyl, -CO(C1-C6alkyl);4-C8(alkylsilane), where alkyl represents a C1-C2alkyl, and cycloalkyl is C0
, R13, R14, R17and R18independently has the meanings indicated above for R1;

Represents a substituted or nezamechennye aromatic, optionally substituted C5-C10hydroaromatics residue being optionally substituted by one or two substituents, independently selected from hydrogen, CH3, halogen, OR7where R7means C1-C6alkyl;

each of R3, R4, R5and R6independently selected from R7where R7have the above meanings;

as well as pharmaceutically acceptable salts of compounds of formula (I), their isomers, hydrates, isoforms, and prodrugs.

2. The compound of formula I under item 1, where G represents a carbon atom or nitrogen; And selected from (i) phenyl substituted by any of-COOH, -N2SOON3, -CN, NH2or-SOON3; (ii) naphthyl, benzofuranyl and hineline; and (iii)

< / BR>
< / BR>
and

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

R1each independently selected from hydrogen; branched or straight C1-C4alkyl>
-C2alkyl, and cycloalkyl represents a C3-C6cycloalkyl; and phenyl;

R2represents hydrogen;

R9, R10, R13, R14, R17and R18each independently has the meanings indicated above for R1;

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, OR7where R7have the above meanings; R3, R4, R5and R6each independently selected from hydrogen, CH3CH(Me)2CH2CH(Me)2CH(Me)CH2CH3.

3. The compound of formula I under item 1, where G represents a nitrogen atom; And choose from (iii)

< / BR>
< / BR>
and

< / BR>
where R9, R10, R13, R14, R17and R18each represents an ethyl group;

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

R2represents H;

Choose from phenyl, naphthyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, the C hydrogen, methyl, halogen and OR7where R7has the values listed above;

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

4. The compound of formula (1) under item 1, representing any of the following connections:

()-TRANS-1-(3-methoxy--(1-naphthyl)benzyl)-2,5-dimethylpiperazine (compound 3);

()-3-((R*/S*)--((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinil)-1-naphthyl)anisole (compound 4 and 5);

()-TRANS-1-(3-methoxy--(2-naphthyl) benzyl)-2,5-dimethylpiperazine (compound 8);

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

()-trucks-1-(3-methoxy--(2'-benzofuranyl)benzyl)-2,5-dimethylpiperazine (compound 13);

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

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

()-TRANS-1-(3-methoxy--(6'-chinoline)benzyl)-2,5-dimethylpiperazine (compounds 20 and 21);

()-3-((R*/S*)--((2S*, 5R*)-4-allyl-2,5-dimethyl-l-piperazinil)-6-chinoline)anisole (compound 22);

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

()-3-((R*/S*)--((2S*, 5R*)-4-cycle is l)benzyl)-2,5-dimethylpiperazine (compound 28);

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

()-4-((-(1-piperazinil))-4-Chlorobenzyl)-N, N-diethylbenzamide (compound 33);

()-4((-(4-allyl))-1-piperazinil)-4-Chlorobenzyl)-N, N-2l (compound 34);

()-4-((-(1-piperazinil))-2-naphthylmethyl)-N, N-diethylbenzamide (compound 37);

()-4-((-(4-allyl)-1-piperazinil))-2-naphthylmethyl)-N, N-diethylbenzamide (compound 38);

()-4-((-(1-piperazinil))-4-xylyl)-N, N-diethylbenzamide (compound 41);

-()4-((-(4-allyl)-1-piperazinil))-4-xylyl)-N, N-2l (compound 42);

()4-((-(1-piperazinil))-3-xylyl)-N, N-diethylbenzamide (compound 45);

()4-((-(1-piperazinil))-cyclohexylmethyl)-N, N-diethylbenzamide (compound 48);

()4-((-(1-piperazinil))-3,4-dimethylbenzyl)-N, N-diethylbenzamide (compound 51);

()4-((-(1-piperazinil))-1-naphthylmethyl)-N, N-diethylbenzamide (compound 54);

4-(4(2-dimethyl-5-methylpiperazine)-3-methoxybenzyl)-N, N-diethylbenzamide the dihydrochloride (compound 57);

4-(4-(1-allyl-2-dimethyl-5-methylpiperazine)-3-methoxybenzyl)-N, N-diethylbenzamide the dihydrochloride (compound 58);

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

4-(1-(2-dimethyl-5-methylpiperazine)-3-metodologia (compound 64);

4-((4-allyl-1-piperazinil)benzyl)-N, N-diethylbenzamide the dihydrochloride (compound 65);

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

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

4-((4-(2-hydroxymethyl-5-methyl)piperazinil)-3-methoxybenzyl)-N, N-diethylbenzamide the dihydrochloride (compound 70);

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

methyl 3-((2-naphthyl)-(3-methylpiperazine)methyl)vinylether the dihydrochloride (compound 75);

methyl 3((2-naphthyl) (4-allyl-2-methyl-piperazinyl) methyl)-phenyl ester dihydrochloride (compound 76);

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

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

methyl 4-((4-tert-butoxycarbonyl-1-piperazinil)benzyl)-benzoate (compound 80);

methyl 4-((1-piperazinil)benzyl)benzoate the dihydrochloride (compound 81);

4-(1-piperazinylmethyl)-benzonitrile the dihydrochloride (compound 84);

4-(1-piperazinylmethyl)-the acetophenone dihydrochloride (compound 85);

4((-4-piperidinyl) benzyl)-N, N-diethylbenzamide (compound 88);

N, N-titlename (Example 51);

4-[(N-benzyl-1-piperazinil)benzyl} -aniline(compound 91);

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

4-[ (N-benzyl-1-piperazinil)benzyl} -methanesulfonamide (Example 54);

methyl-N-4-[(N-benzyl-1-piperazinil)benzyl] -2-acetate (Example 55); and

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

5. Saedinenie according to any one of paragraphs. 1-4 in the form of cleaners containing hydrochloride salt.

6. Saedinenie according to any one of paragraphs. 1-5, intended for use in therapy.

7. Connection on p. 6, designed to relieve the pain.

8. Connection on p. 6, designed for the treatment of gastrointestinal diseases.

9. Connection on p. 6, designed for the treatment of spinal cord injuries.

10. Connection on p. 6, designed for the treatment of disorders of the sympathetic nervous system.

11. The compound according to any one of paragraphs. 1-5, analgesic activity.

12. The pharmaceutical composition exhibiting analgesic activity and comprising an effective amount of a compound according to any one of paragraphs. 1-5 as an active ingredient together with a pharmaceutically acceptable carrier.

 

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< / BR>
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