Derivatives of piperidine, the method of production thereof, pharmaceutical compositions on their basis and intermediate compounds

 

(57) Abstract:

The invention relates to a piperidine derivative of General formula I

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and their pharmaceutically acceptable salts, where R1is hydrogen, C1-C6-alkyl, C2-C6alkenyl, C3-C8-cycloalkyl, C6-C10aryl that may be substituted for CH3, halogen, OR5where R5- C1-C6-alkyl, C1-C2-alkyl-heteroaryl containing as heteroatoms of S, N or O; And a is phenyl, substituted carbonyl or amino group; - C6-C10-aryl or C5-C10-heteroaryl containing as heteroatoms of S, N or O. the Invention relates also to a method for producing compounds of formula I, and pharmaceutical compositions. The compounds of formula I possess analgesic activity and can find application in medicine. 4 C. and 7 C.p. f-crystals, 2 tab.

The invention relates to new compounds, method of their production, their use and pharmaceutical compositions containing the new compounds. New connections can be used in therapy, especially for the treatment of pain.

Background of invention and prior art

The receptor was ID the s. Ligands for receptors may, therefore, find potential use as analgesic and/or antihypertensive agents. It was also discovered that ligands for receptors possess immunomodulatory activity.

Currently identified at least three different populations of opioid receptors (and ), and all three are found in both Central and peripheral nervous systems of many species of animals, including humans. Analgesia was observed in various animal models, when you have activated one or more of these receptors.

With rare exception, currently available selective opioid-ligands are in the nature of peptide compounds, and are not suitable for the introduction of a system of ways. Some ones antagonists have become available for some last time (see Takemori and Portoghese, 1992, Ann. Rev. Pharmacol. Tox. , 32:239-269.). These compounds, such as naltrindole, characterized by very weak (i.e., weaker in 10-fold) selectivity of binding-receptor compared with the receptor and do not show analgesic activity, a fact that implies the need to develop highly selective ones of ligation, with increased analgesic effect, and improved the profile of side effects compared to modern-agonists and significant oral effectiveness.

Analgesics that have been identified and described in the prior art have many disadvantages, which is manifested in the fact that they have poor pharmacokinetics and do not show analgesic effect with the introduction of a system of ways. In addition, it is well documented that the preferred compounds described in the prior art, are also significant convulsive action when the system introduction.

The problem indicated above is solved by developing new compounds that have the piperidine ring with ekzoticheskoy a double bond, as described below.

Description of the invention

The new compounds of the present invention have the General formula (I)

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where R1selected from hydrogen, branched or unbranched C1-C6-alkyl, C1-C6-alkenyl, C3-C8-cycloalkyl, C4-C8-(alkylcyclohexane), where alkyl is C1-C2-alkyl and cycloalkyl represents C3-C6-cyclea is whether heteroaryl can be optionally and independently substituted by 1 or 2 substituents, independently selected from hydrogen, CH3, -(CH2)pCF3, halogen, -CONR5R4, -COOR5, -COR5, -(CH2)pNR5R4,

-(CH2)pCH3(CH2)pSOR5R4, -(CH2)pSO2R5and -(CH2)pSO2NR5where R4and R5, each independently, such as defined above for R1and p is 0, 1 or 2;

(C1-C2-alkyl)-(C6-C10-aryl) or (C1-C2-alkyl)heteroaryl, and heteroaryl parts have from 5 to 10 atoms selected from C, S, N and O, and where the aryl or heteroaryl can be optionally and independently substituted by 1 or 2 substituents, independently selected from hydrogen, CH3, -(CH2)qCF3, halogen, -CONR5R4, -COOR5, -COR5, -(CH2)qNR5R4, -CH2)qCH3(CH2)qSOR5R4,

-(CH2)qSO2R5, -(CH2)qSOgNR5and -(CH2)pOR5where R4and R5each independently the same as defined above for R1and q is 0, 1 or 2, and

< / BR>
where R18, R19, R20, R21, R22, R23, R24and R25UP> and R3, each independently, represent hydrogen or C1-c6-alkyl;

And choose from

< / BR>
< / BR>
< / BR>
where R8, R9, R10, R11, R12, R13, R14, R15, R16and R17, each independently, such as defined above for R1and where the phenyl ring of each substituent may be optionally and independently substituted on any position of the phenyl ring 1 or 2 substituents Z1and Z2that is, each independently, selected from hydrogen, CH3, -(CH2)qCF3, halogen, -CONR6R7, -COOR6, -COR6, -(CH2)rNR6R7, -(CH2)rCH3(CH2)rSOR6, -(CH2)rSO2R6and -(CH2)rSO2NR6R7where R6and R7, each independently, such as defined above for R1and r is 0, 1 or 2;

Q represents C5-C6-hydroenergy or heterokedasticity radical having 5 or 6 atoms selected from C, S, N and O; C5-C6-cycloalkyl or heteroseksualci having 5 or 6 atoms selected from C, S, N and O; and where each Q is optionally can be substituted for Z1and Z2as defined above;

In ahydro - aromatic portion, having from 5 to 10 atoms selected from C, S, N and O, and optionally and independently substituted by 1 or 2 substituents, independently selected from hydrogen, CH3, -(CH2)tCF3, halogen, -(CH2)tCONR5R4, -(CH2)tNR5R4, -(CH2)tCOR5,

-(CH2)tCOOR5, -OR5, -(CH2)tSOR5, -(CH2)tSO2R5and -(CH2)tSO2NR5R4where R4and R5, each independently, such as defined above for R1and t is 0, 1, 2 or 3; and R4and R5, each independently, such as defined above for R1.

In the scope of this invention also includes pharmaceutically acceptable salts of compounds of formula (I), their isomers, hydrates, isomeric forms and prodrugs.

Preferred compounds of the invention are compounds of formula (I), where

And choose from

< / BR>
< / BR>
< / BR>
where R8, R9, R10R11, R12, R13, R14, R15, R16and R17, each independently, such as defined above for R1and where the phenyl ring of each substituent may be optionally and independently substituted pirut from hydrogen, CH3, -(CH2)qCF3, halogen, -CONR6R7, -COOR6, -COR6, -(CH2)rNR6R7, -(CH2)rCH3(CH2)rSOR6, -(CH2)rSO2R6and -(CH2)rSO2NR6R7where R6and R7, each independently, such as defined above for R1and r is 0, 1 or 2;

Q is chosen from the research, piperidine and pyrrolidine; R1, R4and R5each independently selected from hydrogen, branched or unbranched C1-C4-alkyl, C3-C5-cycloalkyl, C4-C8-alkylcyclohexane), where alkyl is C1-C2-alkyl, and cycloalkyl represents C3-C6-cycloalkyl; C6-C10-aryl or heteroaryl having from 5 to 6 atoms selected from C, S, N and O, and where the aryl or heteroaryl can be optionally and independently substituted by 1 or 2 substituents, independently selected from hydrogen, CH3, -(CH2)pCF3, halogen, -CONR5R4, -COOR5, -COR5, -(CH2)pNR5R4, -(CH2)pCH3(CH2)pSOR5R4, -(CH2)pSO2R5and - (CH2)pSO2
Choose from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophene, parrila, furanyl, chinoline, izochinolina, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrofuryl, tetrahydroisoquinoline, tetrahydrofuranyl, pyrrolidinyl and indazolinone, each of which is optionally and independently substituted by 1 or 2 substituents, independently selected from hydrogen, CH3, CF3, halogen, -(CH2)qCONR5R4, -(CH2)qNR5R4, -(CH2)qCOR5,

-C(CH2)qCO2R5and-OR5where q is 0 or 1 and where R4and R5such as defined above;

R2and R3, each independently, represent hydrogen or methyl.

Particularly preferred compounds of the invention are compounds of formula (I), where

And is

< / BR>
where R8and R9both represent ethyl and where the phenyl ring is optionally and independently may be substituted on any position of the phenyl ring with two substituents Z1and Z2that is, each independently, selected from hydrogen, CH3, -(CH2)qCB>r
CH3(CH2)rSOR6, -(CH2)rSO2R6and -(CH2)rSO2NR6R7where R6and R7, each independently, such as defined above for R1and r is 0, 1 or 2;

R1selected from hydrogen, methyl, ethyl, -CH2CH=CH2, -CH2-cyclopropyl, -CH2-aryl or CH2-heteroaryl, and heteroaryl parts have from 5 to 6 atoms selected from C, S, N and O;

Choose from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophene, furanyl, chinoline, izochinolina, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrofuryl, tetrahydroisoquinoline, tetrahydrofuranyl and indazolinone, each of which is optionally and independently substituted by 1 or 2 substituents, independently selected from hydrogen, CH3, CF3, halogen, -(CH2)qCONR5R4, -(CH2)qNR5R4, -(CH2)qCOR5, -(CH2)qCO2R5and-OR5where q is 0 or 1, and where R4and R5such as defined above;

R2and R3each independently represents hydrogen or methyl.

Zine "halogen" denotes chlorine, fluorine, bromine and iodine.

The term "aryl" denotes an aromatic ring having from 6 to 10 carbon atoms, such as phenyl and naphthyl.

The term "heteroaryl" denotes an aromatic ring in which one or more of the 5 to 10 atoms in the ring are atoms other than carbon, such as N, S and O.

The term "hydroaromatics" denotes a partially or fully saturated aromatic ring having 5 to 10 atoms in the ring.

The term "heterokedasticity" denotes a partially or fully saturated aromatic ring in which one or more of the 5 to 10 atoms in the ring atoms are other than carbon, such as N, S and O.

The term "isomer" refers to compounds of the formula (I), which differ in the position of their functional groups and/or orientation. The term "orientation" refers to stereoisomers, diastereoisomers, regioisomers and enantiomers.

The term "isoform" refers to the compounds of formula (I), which differ in the crystal lattice, such as crystalline compound and amorphous compounds.

The term "prodrug" means the pharmacologically acceptable derivatives such as esters and amides, takingplace Goodman and Gilmans, The Pharmacological basis of Therapeutics, 8thed., McGraw-Hill, Jnt. Ed. 1992, "Biotransformation of Drugs, p. 13-15, describing prodrugs in General, included here as a reference.

The new compounds of this invention are useful in therapy, especially for the treatment of various painful conditions such as chronic pain, acute pain, pain and cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain, etc. This list, however, should not be construed as exhaustive.

Compounds of the invention are useful as immunomodulators, especially in autoimmune diseases such as arthritis, transplantation of skin, organ transplants and similar surgical needs for collagen diseases, various allergies, for use as anticancer agents and antiviral agents.

Compounds of the invention are useful in disease States where there is degeneration or dysfunction of opioid receptors, or opioid receptors involved in this paradigm. This use may include the use of labeled isotopes are variants of the compounds of the invention in diagnostic techniques and applications for imaging, such as positron Emiss is urinary incontinence, various mental illnesses, cough, lung edema, various gastro-intestinal disorders, spinal injury and addiction to the excessive use of drugs, including treatment of alcohol, nicotine, opioid, and other addictions, and disorders of the sympathetic nervous system, such as hypertension.

Compounds of the invention are useful as an analgesic agent for use during General anesthesia and to assist controlled anesthesia. Combinations of agents with different properties are often used to balance the actions required to maintain the shot condition (e.g., amnesia, analgesia, muscle relaxation and sedatives effect). In this combination are entered by inhalation anesthetics, sleeping pills, anxiolytics, neuromuscular blockers and opioids.

The compounds of this invention in the isotope-labeled form can be used as a diagnostic agent.

In the scope of the present invention also includes the use of any of the compounds of the above formula (I) for the manufacture of a medicinal product for the treatment of any of the conditions listed above.

The trail is including the introduction of an effective amount of the compound of the above formula (I) to a patient, in need of such treatment.

Ways to get

The compounds of this invention can be obtained as described in schemes I-IV.

As shown above in schemes I and II, the compounds of the above formula (I) can be obtained by dehydration of hydroxiapatite (g) or (h), where R1, R2, R3And In such, as defined above in formula (I). Subsequent dehydration of the hydroxyl compounds (g) or (h), where R1, R2, R3And In such, as defined above in formula (I) can be carried out without solvents or in a solvent such as water, alcohols, esters, NMRA, dichloromethane, toluene, ethers, ketones, carboxylic acids, or a mixture of solvents in the presence of acids of Bronstedt or Lewis, such as sulfuric acid, hydrochloric acid, triperoxonane acid, trichloride aluminum, ZnCl2or similar, or in the presence of oxides of metals such as Al2O3, Cr2O3, TiO2WO3P2O5or similar, or in the presence of other dehydrating agents, such as I2, dimethylsulfoxide, KHSO4, CuSO4, phthalic anhydride or the like.

The substituents R1, R2and R3and the substituents on a and b is Rovaniemi in literature, see, for example, Protecting groups by Green, or Modern Synthesis Reactions by House, which are well known to the person skilled in the art, after or in the process of obtaining (I) from (g) and (h).

As shown in the method according to scheme I, the compounds of formula (g), as described above, can be obtained by reaction between a ketone of the formula (C), where R1, R2and R3such as defined in formula (I) and a compound of formula (e), where a and b are such as defined in formula (I), and X represents a suitable group such as H, Cl, Br, I, OSO2R or similar.

The reaction can be carried out without solvent or in an organic solvent, such as THF, toluene, simple, ether, sulfoxide, or mixtures of the solvents by treatment with a suitable metal, such as magnesium, lithium, copper, cerium or the like, or by treatment with a metal halide, such as SmI2, CrCl2or similar, or processing of ORGANOMETALLIC agents, such as alkylpolyglucoside, alkylate or similar.

R1, R2and R3and the substituents on a and b In the compounds of formula (g), as defined above, can be modified by methods known in this field, after, or during the reaction of ORGANOMETALLIC compounds (March, 3., Advanced Organic Chemistry, 4thEd, John Willey the means known in the art (March, J. Advanced Organic Chemistry, 4thEd, John Willey and Sons, 1992).

As shown in method b in scheme (II), the compounds of formula (h), as described above, can be obtained by reaction between a ketone of the formula (i), where R1, R2and R3and In such, as defined in the formula (I), and ORGANOMETALLIC reagent of formula (j), where As the same as defined in formula (I), and M represents a group of a suitable metal, such as magnesium, lithium, zinc, copper, cerium or the like. The reaction can be carried out without solvent or in an organic solvent, such as THF, toluene, ethers, dimethyl sulfoxide, or mixtures of solvents.

As shown in method C in scheme II, compounds of formula (h) can also be obtained by reaction between a carbonyl compound of the formula (I), where R1, R2and R3such as defined in formula (I), and X represents a suitable leaving group such as CL, Br, IT, OR, SR, NR2, N(OR')R or the like, and ORGANOMETALLIC reagents of formula (j) and (k), where a and b are such as defined in formula (I), and M represents a group of a suitable metal, such as magnesium, lithium, zinc, copper, cerium or the like. The reaction can be carried out without solvents or in solvents such as

R1, R2and R3and the substituents on a and b compounds (h), as defined above, can be modified by methods known in the field and illustrated in the literature, see, for example. Protecting groups by Green, or Modern Synthesis Reactions by House, which are well known to the person skilled in the art, after or during reactions of ORGANOMETALLIC compounds.

Compounds of formula (i), (j), (k) and (1) may be commercially available or can be obtained by methods known in the art (March, 3., Advanced Organic Chemistry, 4thEd, John Willey and Sons, 1992).

As shown above in scheme III, the compounds of the above formula (I) can be obtained by a combination of Suzuki of vinylchloride (o) (X=Br, I) with Bronevoy acid, boronate ether (b) in the presence of a base, such as PA2CO3TO2CO3TO3RHO4, triethylamine, CsF, NaOH, or alkoxides and palladium catalyst such as (h3)4PD, bis(dibenzylideneacetone)PD(0), Pd-fired with h3; as a catalyst can also be used compounds of Pd(II), including (h3)2PdCl2, 1,4-bis(diphenylphosphinomethyl)palladium(II)chloride, palladium acetate, bis(acetonitrile)palladium(II)chloride, dichloro[1,1'-bis(diphenylphosphino)Fe is found above in the formula (I). The combination of the Suzuki can be carried out in toluene, xylene, anisole, DMF, THF, alcohols, ethers, water or a mixture of solvents.

The compounds of formula (p), where In the same as defined in formula (I), and Z represents B(OH)2may be commercially available or can be obtained by hydrolysis brunatnego ether. The compounds of formula (p), where In the same as defined in formula (I), and Z is B(OR)2(R = Me, Et), can be obtained by reaction of the compound of formula B-M and b(or SIG)3where R = Me or Et, and M represents a group of a suitable metal, such as lithium or magnesium or the like. The compounds of formula (p), where In the same as defined in formula (I), and Z is 9-borabicyclo[3.3.1]nonan (9-BBN), can be obtained by the reaction of ALK-1-ins with borabicyclo[3.3.1]nananom.

The substituents R1, R2and R3and the substituents on a and b In the compounds of formula (I) as defined above, can be modified by methods known in the field and illustrated in the literature, see, for example. Protecting groups by Green, or Modern Synthesis Reactions by House, which are well known to the person skilled in the art, after or in the process of obtaining (I) out (o) and (p).

As shown in scheme III, the compounds of formula (o), where X represents Br or I, can is prohibited in the formula (I). Halogenoalkane can be carried out in a solvent such as dichloromethane, chloroform, carbon tetrachloride, dichloromethane or acetic acid, with the use of molecular bromine or iodine as the halogenation agent. The next stage of cleavage is carried out in a solvent such as water, alcohols, DMF, or ethers, using a base such as sodium hydroxide, potassium hydroxide, alkoxides of metals or triethylamine.

As shown in scheme III, the compounds of formula (n), as described above, can be obtained by Wittig reaction of the ketone of formula (C), where R1, R2and R3such as defined in formula (I), and the reagent of formula (m), where As the same as defined in formula (I), and Y represents a suitable phosphonate or fosfonovoi salt. The Wittig reaction can be carried out in various conditions, known in the field and illustrated in the literature (March, J., Advanced Organic Chemistry, 4thEd, John Willey and Sons, 1992).

Reagents of formula (C) and (m) may be commercially available or can be obtained by methods known in the art (March, J. Advanced Organic Chemistry, 4thEd, John Willey and Sons, 1992).

As shown in the diagram above, IV, compounds of formula (u) can be obtained by dehydration is ratziu can be carried out without solvent or in a solvent, such as water, alcohols, esters, NMRA, dichloromethane, toluene, ethers, ketones, carboxylic acids, or a mixture of solvents in the presence of acids of Bronstedt or Lewis, such as sulfuric acid, hydrochloric acid, triperoxonane acid, trichloride aluminum, ZnCl2or similar, or in the presence of oxides of metals such as Al2Oz, CR2ABOUT3, TiO2WO3, R2O5or similar, or in the presence of other dehydrating agents, such as I2, dimethylsulfoxide, KHSO4, CuSO4, phthalic anhydride or the like.

The substituents R1, R2and R3and the substituent In the compound (u), as defined above, can be modified by methods known in the field and illustrated in the literature, see for example. Protecting groups by Green, or Modern Synthesis Reactions by House, which are well known to the person skilled in the art, after or in the process of obtaining (u) (t).

As shown in the diagram above, IV, compounds of formula (t) can be obtained from compound (s), where R1, R2, R3, R13and such as defined above, using the alkylation reaction by alkylhalogenide, such as Me, in the presence of a base, Taco is given by the reaction between a ketone of the formula (r), where R1, R2, R3, R13such as defined above, and ORGANOMETALLIC reagent of formula (k), where the same as defined in formula (I), and M represents a group of a suitable metal, such as magnesium, lithium, zinc, copper, cerium or the like. The reaction can be carried out without solvent or in solvents such as THF, ethers, dimethylformamide, dioxane, dimethyl-sulfoxide, or a mixture of solvents.

The substituents R1, R2, R3, R13connection (s), as defined above, can be modified by methods known in the field and illustrated in the literature, see, for example, Protecting groups by Green, or Modern Synthesis Reactions by House, which are well known to the person skilled in the art, after or during the receipt (s) from (r) and (k).

As shown in scheme IV, a compound of the formula (r) can be obtained by reaction between a carbonyl compound of the formula (I), where R1, R2and R3such as defined in formula (I), and X represents a suitable leaving group, such as C1, Br, IT, OR, SR, NR2N(OR1R or the like, and ORGANOMETALLIC reagent, obtained first by treatment with a base, such as NaH, compound (q), where R13so, as you defined is in solvents, such as THF, toluene, ethers, dimethylformamide, dioxane, or a mixture of solvents. The substituents R1, R2, R3, R13compounds (r), as defined above, can be modified by methods known in the field and illustrated in the literature, see, for example. Protecting groups by Green, or Modern Synthesis Reactions by House, which are well known to the person skilled in the art, after or in the process of obtaining (r) (q) and (1).

As shown in scheme IV, compounds of formula (q) can be obtained by acylation of 4-iodoaniline using either allamerica or acylchlorides in an organic solvent such as dichloromethane. Deputy R13compound (q) such as defined previously.

The invention is hereinafter described in more detail using the following examples, which should not in any way be considered as limiting the invention.

(A) Scheme of the synthesis of compounds of examples 1-7

The compounds of examples 1-7 was obtained by following the methods shown in scheme 1.

Obtain N-tert-butoxycarbonyl-N'-methyl-N'-methoxymethamphetamine (compound 2)

A mixture of utilisedictated (compound I) (4.71 g 30.0 mmol), di-tert-BUTYLCARBAMATE (6,55 g, 30,0 IMO is impressive. The reaction mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with saline, dried over MgSO4. Removal of the solvent gave N-tert-butoxycarbonylmethylene (to 7.67 g).

H(400 MHz, Dl3): a 1.25 (t, J=7.2 Hz, 3H), 1,45 (s, N), of 1.62 (m, 2H), to 1.87 (m, 2H), 2,43 (m, 1H), 2,84 (m, 2H), was 4.02 (m, 2H), 4,13 (kV, J=7.2 Hz, 2H);C-13(100 MHz, CDCl3) : 14,0, 27,8, 28,2, 40,9, 42,9, 60,2, 79,2, 154,4, 174,2.

The above N-tert-butoxycarbonylamino was dissolved in THF (60 ml) and mixed with NHMe(OMe)HCl (4,39 g of 45.0 mmol). The mixture was treated with ISO-PrMgCl (2.0 M in THF, 45 ml, 90 mmol) at -20oC and the resulting solution was stirred for 1 hour at -5oAnd then extinguished in an aqueous solution of NH4C1 and extracted with ethyl acetate (2100 ml). The combined organic layers were washed with saline, dried over MgSO4. Removal of the solvent gave N-tert-butoxycarbonyl - N'-methyl-N'-methoxynicotinic (compound 2) (8.0 g, 98%).

H(400 MHz, CDCl3): of 1.30 (s, N), and 1.54 (m, 4H), to 2.65 (m, 3H), to 3.02 (s, 3H), of 3.56 (s , 3H), 3,99 (Shir. s, 2H);C-13(100 MHz, Dl3) : 27,7, 28,1, 32,0, 37,8, 43,1, 61,3, 79,1, 154,4, 176,0.

(ii) Obtaining 4-(4'-N', N'-diethylaminocarbonylmethyl)-N-tert-butoxycarbonylamino (compound 3)

To a solution of 4 is, 1.7 M, 60,0 mmol) at -78oC. After 30 min was added dropwise N-tert-butoxycarbonyl-N'-methyl-N'-methoxynicotinic (compound 2) (8.0 g, 29.4 mmol) in THF (10 ml). The reaction mixture was heated to room temperature and then extinguished in an aqueous solution of NH4C1, neutralized with hydrochloric acid (concentrated, 20 ml) at 0oWith and were extracted with ethyl acetate (2100 ml). The combined organic layers were washed with saline, dried over MgSO4. Removal of solvents gave the crude product, which was purified on a column of silica gel with elution MeOH-CH2Cl2(2:98) to give 4-(4' -N', N' -diethylaminocarbonylmethyl)-N-tert-butoxycarbonylmethyl (compound 3) (3,15 g, 28%).

H(400 MHz, Dl3): 1,08 (Shir.s, 3H), 1,23 (Shir.s, 3H), USD 1.43 (s, N), to 1.61 (m, 2H), 1,80 (m, 2H), 2,89 (m, 2H), 3,20 (Shir.s, 2H), 3,40 (m, 1H), 3,53 (Shir. s, 2H), 4,11 (Shir.s, 2H), 7,44 (d, J=8.0 Hz, 2H), 7,94 (d, J=8.0 Hz, 2H).

(iii) Obtaining 4-(-hydroxyl--(4-N-tert-butoxycarbonylmethyl)--(1-naphthyl)methyl)-N,N-diethylbenzamide (compound 4)

To a solution of 1-bromonaphthalene (0.52 g, 2.5 mmol) in dry THF (10 ml) was added n-utility (1.1 ml, 2.5 M, a 2.75 mmol) at -78oC. After 30 min was added dropwise 4-(4'-N', N'-diethylaminocarbonylmethyl)-N-tert-butoxide and then extinguished in an aqueous solution of NH2Cl and extracted with ethyl acetate (250 ml). The combined organic layers were washed with saline, dried over MgSO4. Removal of solvents gave the crude product, which was purified on a column of silica gel with elution MeOH-CH2Cl2(0,5: 99,5-->5: 95) to give 4- (-hydroxyl--(4-N-tert-butoxycarbonylmethyl)--(1-naphthyl)methyl)-N,N-diethylbenzamide (compound 4) (760 mg, 74%).

So pl. 121-124oC (CH2Cl2).

max(KBr), cm-1: 3402, 2960, 1685, 1626, 1425, 1283, 1160.

Elemental analysis. Calculated for C32H40N2O40,50 H2O: 73,11%; N 7,86%; N 5,33%. Found 72,86%; N To 7.64%; N 5,26%.

H(400 MHz, CDCl3): 1,03 (Shir.s, 3H), 1,16 (Shir.s, 3H), 1.18 to about 1.35 (m, 3H), of 1.95 (m, 1H), 2,60 (m, 2H), 2,75 (Shir.s, 2H), 3.15 in (Shir.s, 2H), 3,42 (Shir.s, 2H), 4,10 (Shir.s, 2H), 7,10-to 7.50 (m, 7H), to 7.75 (m, 3H), 8,27 (Shir.s, 1H);C-13(100 MHz, Dl3) : 12,8, 14,1, 27,1, 27,2, 28,4, 39,2, 43,3, 45,4, 79,3, 80,4, 124,1, 124,9, 125,2, 125,3, 126,0, 127,3, 128,8, 129,2, 131,4, 135,0, 135,2, 139,4, 146,5, 154,6, 171,0.

(iv) Obtaining 4-(-hydroxyl--(4-N-tert-butoxycarbonylmethyl)-2,6-dimethylbenzyl)-N,N-diethylbenzamide (compound 5)

Received according to the method described for compound 4, except for using 2-bromo-m-xylene (749 mg, 76%).

So pl. 92-96oC (CH2Cl2B>H42N2O40,50 H2O: 71,54%, N 8,61%; N TO 5.56%. Found: 71,70%; N, 8.34 Per Cent; N 5,62%.

H(400 MHz, Dl3): 1,10 (Shir.s, 3H), 1,21 (Shir.s, 3H), 1,32 (m, 2H), USD 1.43 (s, N), was 1.69 (m, 1H), 1.77 in (m, 1H), 2,32 (C, 6N), 2,47 (s, 1H), 2,75 (m, 3H), 3,25 (Shir.s, 2H), 3,51 (Shir.s, 2H), 4,13 (Shir.s, 2H), 6,91 (m, 2H), 7,00 (m, 1H), 7,26 (d, J=8,4 Hz, 2H), 7,39 (d, J=8,4 Hz, 2H);C-13(100 MHz, Dl3) : 12,6, 14,0, 25,0, 27,7, 28,2, 39,1, 42,9, 43,1, 44,4, 53,3, 79,1, 83,0, 125,8, 126,3, 127,2, 131,2, 135,3, 136,7, 142,9, 147,8, 154,5, 170,7.

Example 1

Obtaining N,N-diethyl-4-(phenylpiperidine-4-ylidenemethyl)benzamide (compound 6)

To a solution of 4-(-hydroxyl--(4-N-tert-butoxycarbonylamino)benzyl)-N, N-diethylbenzamide (932 mg, 2.0 mmol) in dry dichloromethane (10 ml) at room temperature was added triperoxonane acid (10.0 ml). The reaction mixture was stirred for 16 h at room temperature and then concentrated. The residue was dissolved in AcOEt (100 ml). The resulting solution was washed with 1 N. NaOH solution, aqueous solution of NH4Cl and brine, dried over MgSO4. Removal of solvents gave the crude product, which was purified on a column of silica gel with elution MeOH-CH2Cl2(20:80) to give (-phenyl--(4-N',N' -diethylaminocarbonylmethyl))-4-methyleneimine (compound 6) (632 mg, 91%).

H(400 MHz, CD is 24 (m, 4H);C-13(100 MHz, Dl3) : 12,6, 14,1, 32,7, 32,8, 39,1, 43,2, 47,9, 126,0, 126,4, 127,9, 129,6, 134,9, 135,4, 135,9, 141,7, 143,2, 171,1.

The Hcl salt: so pl. 110-120oC (AcOEt-simple ether-CH2Cl2).

max(KBr), cm-1: 3440, 2970, 1617, 1438, 1289.

Elemental analysis. Calculated for C23H28N2O1,0 l0,50 CH2Cl20,25 H2O: 65,35%; N 7,12%; N OF 6.49%. Found: 65,14%; N 7,08%; N 6,55%.

Example 2

Obtaining N, N-diethyl-4-(1-aftereverything-4-ylidenemethyl)benzamide (compound 7)

Received by the method described in example 1, using compound 4 (226 mg, 71%).

So pl. 80-85o(MeOH-CH2Cl2).

max(KBr),cm-1: 3052, 2970, 1628, 1431, 1286.

Elemental analysis. Calculated for C27H30N2O0,20 CH2Cl2:78,62%; N 7,37%; N 6,74%. Found: 78,63%; N 7,07%; N 6,54%.

H(400 MHz, Dl3): 1,06 (Shir.s, 3H), 1,16 (Shir.s, 3H), 2,00 (m, 2H), 2,53 (m, 2H), 2,64 (Shir.s, NH), 2,77 (m, 2H), 2,97 (m, 2H), 3,20 (Shir.s, 2H), 3,47 (Shir. s, 2H), 7,26 (m, 5H), the 7.43 (m, 3H), 7,74 (m, 2H), 8,0 (m, 1H);C-13(100 MHz, Dl3) : 12,8, 14,1, 32,6, 33,5, 39,1, 43,2, 47,9, 48,2, 125,5, 125,7, 125,8, 126,1, 127,1, 127,2, 129,1, 131,9, 132,5, 133,8, 135,1, 138,3, 139,8, 142,6, 171,1.

Example 3

Obtaining N,N-diethyl-4-(2,6-dimethylpiperidin-4-ylidenemethyl)benzamide (compound 8)
oC (AcOEt-simple ether-CH2Cl2).

max(KBr), cm-1: 2970, 2725, 1590, 1464, 1290, 1101.

Elemental analysis. Calculated for C25H32N2O1,0 l0,50 CH2Cl20,25 H2O: 65,94%; N 7,60%; N 6,03%. Found: 65,98%; N 7,37%; N Of 5.81%.

Example 4

Obtaining N,N-diethyl-4-(1-naphthyl-N-arylpiperazine-4-ylidenemethyl)benzamide (compound 9)

A mixture of (-(1-naphthyl)--(4-N',N'-diethylaminocarbonylmethyl))-4-methyleneimine (compound 7) (125 mg), allylbromide (90 mg) and K2CO3(138 mg) in MeCN (10 ml) was stirred for 14 hours at room temperature and then extinguished 1 N. a solution of NH4OH, was extracted with AcOEt (100 ml). The organic phase was washed with an aqueous solution of NH4Cl and brine, dried over MgSO4. Removal of solvents gave the crude product, which was purified on a column of silica gel with elution MeOH-CH2Cl2(2:98) to give (-(1-naphthyl)--(4-N', N'-diethylaminocarbonylmethyl))-4-methylene-N-arylpiperazine (50 mg, 36%).

H(400 MHz, Dl3): 1,08 (Shir.s, 3H), 1,19 (Shir.s, 3H), of 2.08 (m, 2H), 2,39 (m, 2H), 2,61 (m, 4H), 3,01 (m, 2H), 3,24 (Shir.s, 2H), 3,52 (Shir. s, 2H), 5,13 (m, 2H), 5,90 (m, 1H), 7,27 (m, 5H), was 7.45 (m, 3H), 7,80 (m, 2H), 8,04 (m, 1H);C-13(100 MHz Dl3) : 12,8, 14,1, 30,9, 32,0, 39,1, 43,2, 54,7, 54,9, 61,5, 117,8, 125,4, 125,6, 125,8, 1UB>Cl2).

max(KBr), cm-1: 3416, 2961, 1620, 1430, 1288.

Elemental analysis. Calculated for C30H34N2O1,0 l0,50 CH2Cl20,25 H2ABOUT: WITH 70,17%; N 7,05%; N 5.37 PERCENT. Found: 70,15%; N 6,92%; N Of 5.24%.

Example 5

Obtaining N,N-diethyl-4-(phenyl-N-benzylpiperidine-4-ylidenemethyl)benzamide (compound 10)

Received by the method described in example 4, using compound 6 and benzylbromide (215 mg, 98%):

H(400 MHz, Dl3): 1,09 (Shir.s, 3H), 1,19 (Shir.s, 3H), is 2.37 (m, 4H), 2,47 (m, 4H), 3,25 (Shir. s, 2H), 3,50 (Shir.s, 4H), 7,0-7,30 (m, 14N);C-13(100 MHz, CDCl3) : 12,7,

14,0, 31,6, 39,1, 43,1, 54,9, 55,0, 62,8, 125,9, 126,2, 126,8, 127,8, 128,0, 128,9, 129,6, 129,7, 134,9, 135,0, 136,3, 138,2, 141,9, 143,3, 171,0.

The Hcl salt: so pl. 230-245oC (AcOEt-simple ether-CH2Cl2).

max(KBr), cm-1: 3423, 2976, 1624, 1434, 1288.

Elemental analysis. Calculated for C30H34N2O1,0 l0,25 CH2Cl20,25 H2O: 72,55%; N 7,25%; N 5,59%. Found: 72,38%; N, 7.16 Per Cent; N 5,50%.

Example 6

Obtaining N, N-diethyl-4-(N-2,3-epoxypropoxyphenyl-4-ylidenemethyl)benzamide (compound 11)

Received by the method described in example 4, using compound 6 and epibromohydrin (102 mg, 84%).

H(400 MHz, Dl3C-13(100 MHz, Dl3) : 12,8, 14,1, 31,4, 39,1, 43,2, 44,9, 50,1, 55,5, 60,8, 126,0, 126,4, 127,9, 129,6, 129,7, 135,0, 135,3, 135,7, 141,8, 143,2, 171,1.

Example 7

Obtaining N, N-diethyl-4-(1-cyclopropylacetylene-4-ylidenemethyl)benzamide (compound 12)

Received by the method described in example 4, using compound 6 and cyclopropylmethanol (104 mg, 86%).

H(400 MHz, Dl3): 0,20 (m, 2H), 0,59 (m, 2H), 1.04 million (m, 1H), 1.14 in (Shir. s, 3H), 1,24 (Shir.s, 3H), 2,48 (d, J=6,4 Hz, 2H), 2,56 (Shir.s, 4H), 2,80 (Shir.s, 4H), 3,29 (Shir.s, 2H), 3,53 (Shir.s, 2H), 7,14 (m, 4H), 7,22 (m, 1H), 7,27 (m, 4H);C-13(100 MHz, Dl3) : 4,18, 7,3, 12,8, 14,1, 30,3, 39,2, 43,2, 54,3, 62,7, 126,2, 126,6, 128,0, 129,5, 129,6, 134,1, 135,3, 136,3, 141,5, 142,9, 171,0.

The Hcl salt: Razlog.100oC (AcOEt-simple ether-CH2Cl2).

max(KBr), cm-1: 3027, 2359, 1620, 1439, 958.

Elemental analysis. Calculated for C27H34N2O1,0 l0,50 CH2Cl20,75 H2O: 66,73%; N TO 7.64%; N 5,66%. Found: 66,60%; N 7,45%; N 5.78 Percent.

C) Scheme of the synthesis of the compound of example 8

The compound of example 8 was obtained using the following method, shown in scheme 2.

(i) Obtaining 4-(2-benzofuranyl)-N-tert-butoxycarbonylamino (compound 13)

To a solution of 2,3-benzofuran (295 mg, 2.5 mmol) N-tert-butoxycarbonyl-N-methyl-N-methoxynicotinic (544 mg, 2.0 mmol) in THF (2 ml), the reaction mixture was heated to room temperature and then extinguished in an aqueous solution of NH4Cl and extracted with ethyl acetate (250 ml). The combined organic layers were washed with saline, dried over MgSO4. Removal of solvents gave the crude product, which was purified on a column of silica gel with elution MeOH-CH2Cl2(5:95) to give 4-(2-benzofuranyl)-N-tert-butoxycarbonylmethyl (13) (456 mg, 69%).

H(400 MHz, Dl3): of 1.46 (s, N), a 1.75 (m, 2H), 1.91 a (m, 2H), 2.91 in (m, 2H), 3,37 (m, 1H), 4,20 (Shir.s, 2H), 7,29 (m, 1H), 7,46 (m, 1H), 7,53 (s, 1H), 7,56 (m, 1H), 7,69 (m, 1H);C-13(100 MHz, CDCl3) : 27,8, 28,3, 43,1, 44,4, 79,5, 112,3, 112,9, 123,1, 123,8, 126,9, 128,2, 151,8, 154,5, 155,5, 192,8.

(ii) Receiving 4--hydroxy--(4-N-tert-butoxycarbonylmethyl)-2-benzofuran)-N,N-diethylbenzamide (compound 14)

Received by the method described in example 4 using 4-iodine-N, N-diethylbenzamide (425 mg, 61%).

So pl. 102 to 106oC (CH2Cl2).

max(KBr), cm-1: 3362, 2970, 1690, 1617, 1425, 1288, 1160.

H(400 MHz, DlC): 1,06 (Shir.s, 3H), 1,20 (Shir.s, 3H), 1,24 (m, 2H), 1,46 (m, 11N), 2,42 (m, 1H), 2,58 (Shir.s, 2H), 3,20 (Shir.s, 2H), 3,50 (Shir. s, 2H), 4,05 (Shir.s, 2H), 4,37 (s, 1H), 6,70 (s, 1H), 7,16 (m, 2H), 7.23 percent (d, J= 8.0 Hz, 2H), 7,41 (d, J=7,6 Hz, 1H), 7,47 (d, J=7,6 Hz, 1 is 9, 135,3, 144,0, 154,4, 154,5, 160,5, 170,9.

Example 8

Obtaining N, N-diethyl-4-(2-benzofurazan-4-ylidenemethyl)benzamide (compound 15)

Received by the method described in example 1, using compound 14 (135 mg, 88%).

H(400 MHz, CDCl3): 1,20 (Shir.s, 3H), 1,24 (Shir.s, 3H), 2,36 (Shir.s, 2H), 3.00 and (Shir.s, 4H), 3.15 in (Shir.s, 2H), 3.33 and (Shir.s, 2H), 3,56 (Shir.s, 2H), 4,45 (Shir. s, 1H), and 6.25 (s,1H), 7,24 (m, 4H), 7,41 (m, 4H);C-13(100 MHz, Dl3) : 12,9, 14,2, 29,6, 32,0, 32,4, 39,3, 43,4, 47,2, 107,4, 111,0, 120,7, 122,7, 124,2, 126,0, 126,5, 128,2, 129,9, 136,1, 139,5, 140,5, 154,4, 156,2, 171,0.

The Hcl salt: Razlog.120oC (AcOEt-simple ether-CH2Cl2).

max(KBr),cm-1: 2977, 2801, 1586, 1449, 1257.

(C) Scheme of the synthesis of compounds of examples 9-10

The compounds of examples 9 and 10 were obtained using the following method, shown in scheme 3.

(i) Obtaining 4-(4-perbenzoic)-N-tert-butoxycarbonylamino (compound 18)

A mixture of the hydrochloride of 4-(4-perbenzoic)piperidine (compound 16) (2,44 g, 10.0 mmol), di-tert-BUTYLCARBAMATE (2,18 g, 10.0 mmol) and Na2CO3(of 1.59 g, 15 mmol) in N2O-THF (50/5 ml) was boiled under reflux for 1 hour. The reaction mixture was extracted with ethyl acetate (2100 ml). The combined organic layers were washed salt of rstw 701-31, 2.28 g, 74%).

So pl. 80-83oC (CH2Cl2).

max(KBr), cm-1: 2980, 2842, 1680, 1587, 1416, 1160.

H(400 MHz, Dl3) of 1.44 (s, N), was 1.69 (m, 2H), 1,79 (m, 2H), 2,87 (m, 2H), 3,34 (m, 1H), 4,13 (Shir.s, 2H), 7,12 (m, 2H), 7,95 (m, 2H);C-13(100 MHz, Dl3) : 27,4, 28,4, 43,2, 43,4, 79,6, 115,8, 115,9, 130,8, 130,9, 132,2, 154,6, 164,4, 166,9, 200,4.

(ii) Obtaining 4-(4-chlorobenzoyl)-N-tert-butoxycarbonylamino (compound 19)

Received according to the method described for compound 18 using compound 17 (1.23 g, 85%).

So pl. 122-125oC (CH2Cl2).

max(KBr), cm-1: 2970, 2842, 1680, 1582, 1420, 1200.

H(400 MHz, Dl3): of 1.47 (s, N), was 1.69 (m, 2H), is 1.81 (m, 2H), 2,90 (m, 2H), 3,36 (m, 1H), 4,18 (Shir.s, 2H), 7,44 (m, 2H), 7,88 (m, 2H);C-13(100 MHz, CDCl3) : 28,3; 28,4; 43,2; 43,4; 79,6; 129,0; 129,6; 134,1; 139,4; 154.6; 200,7.

(iii)Poluchenie-(-hydroxy--(4-N-tert-butoxycarbonylmethyl)-4-terbisil)-N,N-diethylbenzamide (compound 20)

Received according to the method described for compound 4, using compound 18 and 4-iodine-N,N-diethylbenzamide (454 mg, 47%).

So pl. 84-86oC (CH2Cl2).

max(KBr), cm-1: 3421, 2970, 1685, 1612, 1430, 1288, 1165.

H(400 MHz, Dl3): 1,13 (Shir.s, 3H), 1,23 (Shir.s, 3H), 1,32 (m, 4H), 1,44 ((l, J=8.0 Hz, 2H);C-13(100 MHz, CDCl3) : 12,9; 14,0; 26,2; 28,2; 39,1; 43,2; 43,6; 44,3; 78,9; 79,1; 114,5; 114,7; 125,7; 126,1; 127,5; 127,6; 135,0; 141,2; 146,9; 154,5; 160,0; 162,5; 170,9.

(iv) Obtaining 4-(-hydroxy--(4-N-tert-butoxycarbonylmethyl) - 4-Chlorobenzyl) -N,N-diethylbenzamide (compound 21)

Received according to the method described for compound 4, using compound 19 and 4-iodine-N,N-diethylbenzamide (626 mg, 63%).

So pl. 100-105oC (CH2Cl2).

max(KBr),cm-1: 3411, 2970, 1685, 1617, 1425, 1288, 1165, 1092.

H(400 MHz, Dl3): 1,08 (Shir.s, 3H), 1,20 (Shir.s, 3H), of 1.33 (m, 4H), of 1.41 (s, N), 2,44 (m, 1H), 2.63 in (lat.s, 2H), 3,22 (Shir.s, 2H), 3,49 (Shir.s, 2H), 3,99 (s, 1H), of 4.05 (m, 2H), 7,20 (m, 4H), 7,39 (d, J=8.0 Hz, 2H), 7,44 (d, J= 8.0 Hz, 2H); C-13(100 MHz, CDCl3) : 12,5; 13,9; 25,9; 28,1; 39,0; 43,0; 44,1; 78,7; 79,0; 125,6; 126,0; 127,2; 127,8; 131,9; 134,8; 144,1; 146,6; 154,3; 170,7.

Example 9

Obtaining N, N-diethyl-4-(4-tortenelmietlen-4-ylidenemethyl)benzamide (compound 22)

Received by the method described in example 1 (compound 6), using the connection 20.

1H NMR (400 MHz, CDCl3) : of 1.12 (3H, Shir.m, CH3CH2-), 1,24 (3H, Shir.m, CH3CH2-), 2,32 (4H, m, piperidine-CH-), of 2.54 (1H, Shir. m, NH), only 2.91 (4H, m, piperidine-CH-), of 3.27 (2H, Shir.m, CH2N-), 3,52 (2H, Shir.m, CH2N-), 7,00 (2H, m, AGN), to 7.09 (2H, m, AGN)4-ylidenemethyl)benzamide (compound 23)

Received by the method described in example 1 (compound 6), using the connection 21.

1H NMR (400 MHz, Dl3) : of 1.13 (3H, Shir.m, CH3CH2-), 1,22 (3H, Shir.m, CH3CH2-), 2,02 (1H, Shir. m, NH), 2,30 (4H, m, piperidine-CH-), 2,90 (4H, m, piperidine-CH-), or 3.28 (2H, Shir.m, CH2N-), 3,53 (2H, Shir.m, CH2N -),? 7.04 baby mortality (2H, d, J=8.0 Hz, AGN), 7,11 (2H, d, J=8.0 Hz, AGN), of 7.25 (2H, d, J=8.0 Hz, AGN), 7,30 (2H, d, J=8.0 Hz, AGN).

The Hcl salt: so pl. 115-120oWITH (H2O-CH2Cl2).

IR (KBr): 3337, 2973, 1618, 1431, 1290, 1092 cm-1.

Elemental analysis. Calculated for C23H27ClN2O1,0 l1,20 H2O: 62,64%; N 6,95%; N 6,35%. Found: 62,53%; N 6,91%; N, 6.30%, And.

D) Scheme of the synthesis of the compound of example 11 (see scheme 4).

Example 11

Obtaining N,N-diethyl-4- (phenyl-N-arylpiperazine-4-ylidenemethyl)benzamide (compound 25)

4-(a-Hydroxy--(4-N-arylpiperazines)benzyl) -N, N-diethylbenzamide (compound 24) (81 mg) was dissolved in CH2Cl2(10 ml) and treated with thionyl chloride (2 ml) at room temperature. The reaction mixture is boiled under reflux for 2 h and then concentrated. The residue was dissolved in ethyl acetate (50 ml) and the resulting solution was washed NH4OH (1 ad), aqueous solution of NH4Cl the column with silica gel with elution MeOH-CH2Cl2(1:99-->5:95), receiving-phenyl-- (4-N',N' -diethylaminocarbonylmethyl))-4-methylene-N-arylpiperazine (compound 25, example 11) (32 mg, 40%).

H(400 MHz, Dl3): 1,12 (Shir.s, 3H), 1,21 (Shir.s, 3H), 2,43 (m, 4H), to 2.55 (m, 4H), is 3.08 (d, J=6,8 Hz, 2H), 3,25 (Shir.s, 2H), 3,53 (Shir.s, 2H), 5,18 (m, 2H), 5,86 (m, 1H), 7,12 (m, 4H), 7,20 (m, 1H), 7,27 (m, 4H).

The Hcl salt: so pl. 85-95oC (AcOEt-CH2Cl2).

max(KBr), cm-1: 3491, 2971, 1624, 1428, 1289, 1096.

Elemental analysis. Calculated for C26H32N2OHC10,25 N2O0,25 CH2Cl2:69,95%; N 7,60%; N 6,21%. Found: From 70,00%; N 7,73%; N 6,07%.

Example 12

Obtaining N, N-diethyl-4-(4-chlorophenyl-N-benzylpiperidine-4-ylidenemethyl)benzamide (compound 26)

< / BR>
N, N-Diethyl-4-(4-chlorophenyl-N-benzylpiperidine-4-ylidenemethyl)benzamide (110 mg, 93%) was obtained according to the method described in example 4, using compound 23 (96 mg) and benzylbromide (43 mg).

1H NMR (400 MHz, Dl3): of 1.13 (3H, Shir.m, CH3CH2-), of 1.23 (3H, Shir.m, CH3CH2-), is 2.37 (4H, m, piperidine-CH-), 2,49 (4H, m, piperidine-CH-), or 3.28 (2H, Shir.m, CH3CH2N-), 3,53 (4H, Shir.m, PhCH2N and CH3CH2N -),? 7.04 baby mortality (2H, d, J= 8.0 Hz, AGN), 7,11 (2H, d, J=8.0 Hz, AGN), of 7.25 (2H, d, J=8.0 Hz, AGN), 7,29 (7H, m, AGN).

Salt (CHOHCO2a detailed analysis. Calculated for C34H39ClN2O71,50 H2O: 62,81%; N 6,51%; N OR 4.31%. Found: 62,85%; N 6,17%; N Is 4.21%.

Example 13

Obtaining N, N-diethyl-4-[ (N-3-methyl-2-butenyl)phenylpiperidine-4-ylidenemethyl]benzamide (compound 27)

< / BR>
Received by the method described in example 4, using 1-bromo-3-methyl-2-butene as the alkylating reagent.

IR (NaCl, film): salt Hcl, : 3432, 2976, 1623, 1434 cm-1.

1H NMR (base) (Dl3, TMS) : 1,10-1,30 (6N, Shir. THE N2CH3), of 1.64 (3H, s, = CLO3), is 1.73 (3H, s, =CLO3), is 2.40 (4H, m, NCH2CH2), 2,52 (4H, m = CLO2), and 3.0 (2H, d, J=7,6 Hz, NCH2CH=C), 3,20-of 3.60 (4H, Shir. OCNCH2CH3), 5,28 (1H, m, N2CH=C), 7,16-7,45 (N, m, AG) M. D.

Elemental analysis. Calculated for C28H36N2O1,8 HCl: 69,74%; N Of 7.90%; N Of 5.81%. Found: 69,71%; N Of 7.48%; N 5,58%.

Example 14

Obtaining N,N-diethyl-4-[(1-cyclohexylpiperidine-4-ilidene)phenylmethyl]benzamide (compound 28)

< / BR>
A mixture of compound 6 (100 mg, 0.29 mmol), cyclohexanone (36 μl, 0.35 mmol) and Ti(OPr-i)4(0.17 ml of 0.58 mmol) was treated with ultrasound for 1 hour and then stirred at room temperature overnight under nitrogen atmosphere. The mixture was diluted with ethanol (5 m is the temperature value. For quenching the reaction mixture was added 2 N. NH3H2Oh and the mixture was filtered through celite. The filtrate was extracted several times with ethyl acetate and the combined organic phases are washed with water and brine and dried over Na2SO4. Concentration in vacuo and purification of MPLC (silica gel 60, elution with mixture of EtOAc:heptane, from 0:100 to 100:0) gave specified in the title compound (24 mg, 20%).

So square (model HC1 salt): 105 - 109oC.

IR (model HC1 salt, film): 3394 (NH), 1620 (CONEt2) cm-1.

1H NMR (free amine, 400 MHz, l3) : 1,00-1,25 (17H, m, NCHCH2CH2CH2CH2CH2, 2 x CH3and CH(CH)C=C), 1,60 (1H, m, CH(CH)C=C), OF 1.75 (1H, m, CH(CH)C=C), OF 1.80 (1H, m, CH(CH)C=C), OF 2.30 (3H, m, NCH2and NCH), 2,60 (2H, m, NCH2), 3,20 (2H, Shir.with, N2CH3), a 3.50 (2H, Shir.s, NCH2CH3), 7,00-7,30 (N, m, AG).

13With NMR (free amine, 100 MHz, l3) : 12,7; 14,1; 25,9; 28,7; 32,0; 39,1; 43,2; 50,7; 50,8; 63,6; 126,0; 126,3; 127,9; 129,7; 129,8; 134,7; 134,9; 136,9; 142,0; 143,4; 171,2.

Elemental analysis. Calculated for C29H40N2OCl2: 69,17%; N 8,01%; N TO 5.56%. Found: 69,17%; N Of 7.82%; N 5,18%.

Example 15

Obtaining N,N-diethyl-4-[(N-butyl)phenylpiperidine-4-ylidenemethyl]benzamide (compound 29)

IR (NaCI, film) (model HC1 salt), : 3430, 2967, 2499, 1622, 1433 cm-1.

1H NMR (Dl3, TMS) : to 0.92 (3H, t, J=7.2 Hz, CH2CH3), 1,10-1,26 (6N, Shir. OCNCH2CH3), 1,32 (2H, m , CH2CH3), of 1.53 (2H, m, CH2CH2CH2), 2,42 (6N, m, NCH2), to 2.55 (4H, m =CLO2), 3,20-of 3.60 (4H, Shir. THE N3CH3), 7,10-7,31 (N, m, AG) M. D.

Elemental analysis. Calculated for C27H36N2OHCl0,4 CH2Cl20,4 H2O: 68,24%; N 8,07%; N OF 5.81%. Found: 68,24%; N 8,12%; N Of 5.89%.

Example 16

Obtaining N,N-diethyl-4-[(N-4-methoxybenzyl)phenylpiperidine-4-ylidenemethyl] benzamide (compound 30)

< / BR>
The connection header (160 mg, 68%) was obtained according to the method described in example 4, using compound 6 (174 mg) and 4-methoxybenzylamine (78 mg).

1H NMR (400 MHz, CDCl3) : a 1.11 (3H, Shir. CH3CH2N), of 1.20 (3H, Shir. CH3CH2N), of 2.38 (4H, m, CCH2C) to 2.46 (4H, m, NCH2-), 3,26 (2H, m, NCH2-), 3,47 (2H, s, CH2N-), 3,49 (2H, Shir. CH3CH2N), of 3.77 (3H, s, och3), 6,83 (2H, d, J=8.0 Hz, AGN), 7,05-7,30 (11N, m, AGN).

The Hcl salt: so pl. 100-110oC (CH2Cl2).

IR (KBR): 3425, 2974, 1618, 1515, 1434, 1255 cm-1.

Elemental analysis. Calculated for C31H36N2
< / BR>
The connection header (206 mg, 81%) was obtained according to the method described in example 4, using compound 6 (174 mg) and 2,4-trichlorotoluene (98 mg).

1H NMR (400 MHz, CDCl3) : of 1.12 (3H, Shir. CH3CH2N), to 1.21 (3H, Shir. CH3CH2N-), 2,39 (4H, m, CCH2C) 2,52 (4H, m, NCH2-), or 3.28 (2H, m, NCH2-), 3,53 (2H, Shir., CH3CH2N), of 3.57 (2H, m, NCH2-), 7,05-of 7.48 (M, m, AGN).

The Hcl salt: so pl. 95-110oC (CH2Cl2).

IR (KBR): 3408, 2976, 1620, 1472, 1436, 1288, 1101 cm-1.

Elemental analysis. Calculated for C30H32N2OCl21,0 l0,30 CH2Cl2: 63,91%; N 5,95%; N TO 4.92%. Found: With 63.81%; N 6,03%; N 4,84%.

Example 18

Obtaining N,N-detik-4-[(1-methylpiperidin-4-ilidene)phenylmethyl]benzamide (compound 32)

< / BR>
N, N-Diethyl-4-[(piperidine-4-ilidene)phenylmethyl] benzamide (0.34 g, 1.0 mmol) was dissolved in acetonitrile (5 ml). At 25oWith stirring was added potassium carbonate (0.14 g, 1.0 mmol) and methyliodide (63 μl, 1.0 mmol). After 30 min the reaction mixture is evaporated and introduced into a column with silica gel for purification by chromatography using 0 to 10% Meon (10% NH4OH) CH2ridnyi salt processing model HC1 in a simple ether.

So pl. 110oWith (Razlog.).

IR (KBR), cm-1: 2361, 1695, 1487, 1289.

MS (free amine): 362, 318, 219, 189, 165, 144.

lH NMR (Amin, Dl3): 1,1 (m, 6N, amide-IU), is 2.40 (s, 3H, N), 2,49, 2,60 (2 m, 8H, piperazine-H), 3,40 (m, 4H, amide-CH2), 7,08-7,34 (m, M, ArH).

Elemental analysis. Calculated for C24H30N2O0,1 H2O3,HCl 1: 60,39%; N 7,03%; N, 5.87 Per Cent. Found: 60,43%; N 6,84%; N 5.45 Per Cent.

Example 19

Obtaining N, N-diethyl-4-[(N-tert-butoxycarbonylamino-4-yl)-8-chinainternational]benzamide (compound 33)

< / BR>
To a solution of 4-iodine-N,N-diethylbenzamide (1.52 g, 5.0 mmol) and 8-brainline (1.0 g) in dry THF (30 ml) was added at -78oWith n-utility (7,0 ml, 2.5 M, 17.5 mmol). After 10 min was added dropwise N-tert-butoxycarbonylmethylene (2) (0,77 g, 3.0 mmol) in THF (5 ml). The reaction mixture was heated to 0oAnd then extinguished in an aqueous solution of NH4C1 and extracted with acetate (2100 ml). The combined organic layers were washed with saline, dried over MgSO4. Removal of solvents gave the crude product, which was purified on a column of silica gel with elution MeOH-CH2Cl2(2:98), receiving MTL 0599 (145 mg, 9%).

So pl. 100 - 105oC.

IR (NaCl): 2971, 1686, 1625, 1426, 1167 ; the 7,62%. Found: 71,50%; N Of 7.75%.

1H NMR (400 MHz, Dl3) with 1.07 (3H, Shir. CH3CH2N-), 1,19 (3H, Shir. CH3CH2M-), 1,24 (1H, m, piperidine-CH-), 1,43 (N, s, CH3C) of 1.65 (1H, m, piperidine-CH-), 1,89 (2H, m, piperidine-CH-), 2,52 (1H, m, piperidine-CH-), of 2.64 (1H, Shir. piperidine-CH-), 2,78 (1H, Shir. piperidine-CH-), up 3.22 (2H, Shir. CH3CH2N-), 3,49 (2H, Shir. CH3CH2N), of 4.16 (2H, Shir. piperidine-CH-), from 7.24 (2H, d, J=8.0 Hz, AGN), 7,35 (1H, DD, J=8.0 a, 4,4 Hz, AGN), of 7.55 (2H, d, J= 8.0 Hz, AGN), 7,58 (1H, d, J=8.0 Hz, AGN), 7,71 (1H, d, J=8.0 Hz, AGN), 7,80 (1H, d, J=8.0 Hz, AGN), to 8.14 (1H, d, J=8.0 Hz, AGN), 8,69 (1H, m, AGN), of 9.80 (1H, s, OH).

Example 20

Obtaining N, N-diethyl-4-(8-hyalinized-4-ylidenemethyl)benzamide (compound 34)

< / BR>
A mixture of compound of example 19 (45 mg), triperoxonane acid (1.0 ml) and triftormetilfullerenov acid (1 ml) was boiled under reflux for 8 h and then concentrated. The residue was dissolved in AcOEt (50 ml). The resulting solution was washed with 1 N. NaOH solution, aqueous solution of NH4Cl and brine, dried over MgS04. Removal of solvents gave the crude product, which was purified on a column of silica gel with elution NH4OH (1H.) - MeOH - CH2Cl2(2,5:17,5:80) to give N,N-diethyl-4-(8-hyalinized-4-ylidenemethyl)SUB>3
CH2-), from 2.00 (2H, m, piperidine-CH-), 2,46 (1H, s, NH), 2,52 (2H, m, piperidine-CH-), a 2.75 (1H, m, piperidine-CH-), of 2.92 (2H, m, piperidine-CH-), was 3.05 (1H, m, piperidine-CH-), up 3.22 (2H, m, CH2N-), 3,49 (2H, m, CH2N), of 7.23 (2H, m, AGN), 7,32 (2H, m, AGN), of 7.36 (1H, m, AGN), 7,49 (2H, m, AGN), 7,72 (1H, DD, J=6,4, and 3.2 Hz, AGN), 8,11 (1H, DD, J=8,4, 1,6 Hz, AGN), 8,91 (1H, DD, J= 4.0 a, and 1.6 Hz, ArH).

The Hcl salt: so pl. >170oWith (Razlog.)

IR (KBR): 3410, 2973, 1614, 1551, 1436, 1284 cm-1.

Elemental analysis. Calculated for C26H29N3O 2,0 HCl 0,50 CH2Cl20,75 H2O: 60,23%; N TO 6.39%. Found: 60,27%; N, 6.42 Per Cent.

Example 21

Obtaining N, N-diethyl-4-[(N-tert-butoxycarbonylamino-4-yl)-3-methoxyphenylacetyl]benzamide (compound 35)

< / BR>
Received by way of example 19 using 3-bromoanisole that gave specified in the title compound (226 mg, 23%).

So pl. 95 - 103oC.

IR (NaCl): 3422, 2973, 1684, 1614, 1429, 1289 cm-1.

Elemental analysis. Calculated for C29H40N2O50,60 H2About: With 68,64%; N 8,18%; N5,52%. Found: 68,66%; N 7,98%; N 5,64%.

1H NMR (400 MHz, Dl3) with 1.07 (3H, Shir. CH3CH2N-), 1,19 (3H, Shir. CH3CH2N), is 1.31 (4H, m, piperidine-CH-), 1,41 (N, s, CH3C) to 2.46 (1H, m, piperidine-CH-), of 2.64 (2H, Shir. B>), 4,06 (2H, Shir. piperidine-CH-), 6,69 (1H, m, AGN), 7,01 (1H, d, J=7,6 Hz, AGN), was 7.08 (1H, s, AGN), 7,17 (1H, D, J=8.0 Hz, AGN), 7,21 (2H, d, J=8.0 HZ, AGN), of 7.48 (2H, D, J=8.0 Hz, AGN)

Example 22

Obtaining N,N-diethyl-4-(3-methoxyphenylpiperazine-4-ylidenemethyl)benzamide (compound 36)

< / BR>
Received by the method described in example 1, using compound 21 (100 mg) gave N,N-diethyl-4-(3-methoxyphenylpiperazine-4-ylidenemethyl)benzamide (75 mg, 98%).

1H NMR (400 MHz, CDCl3) : of 1.12 (3H, Shir. CH3CH2N), of 1.23 (3H, Shir. CH3CH2N-), was 2.34 (4H, m, piperidine-CH-), only 2.91 (4H, Shir. piperidine-CH-), 3,17 (1H, s, NH), of 3.27 (2H, Shir. CH3CH2N-), 3,52 (2H, Shir. CH3CH2N-), 3,76 (3H, s, och3), only 6.64 (1H, s, ArH), 6,70 (1H, d, J=8.0 Hz, AGN), 6,76 (1H, d, J=7,6 Hz, ArH), to 7.15 (2H, d, J=8.0 Hz, ArH), 7,22 (1H, m, ArH), 7,29 (2H, d, J=8.0 Hz, ArH).

The Hcl salt: so pl. >90oWith (Razlog.).

IR (NaCl): 2970, 1621, 1430, 1287 cm-1.

Elemental analysis. Calculated for C24H30N2O2HCl 1,70 H2O: 64,69%; N 7,78%; N, 6.29 PER CENT. Found: 64,82%; N 7,60%; N, 6.08% In General.

Example 23

Obtaining N, N-diethyl-4-[(N-benzyl)-3-methoxyphenylpiperazine-4-ylidenemethyl)benzamide (compound 37)

< / BR>
Used the method described in example 4, using the compound of example 22 (38 mg is (400 MHz, D13) : of 1.12 (3H, Shir. CH3CH2N-), 1,25 (3H, Shir. CH3CH2N), of 2.38 (4H, m, piperidine-CH-), 2,48 (4H, Shir. piperidine-CH-), of 3.27 (2H, Shir. CH3CH2N-), 3,52 (2H, s, PhCH2N-), 3,53 (2H, Shir. CH3CH2N-in), 3.75 (3H, s, och3), of 6.65 (1H, s, AGN), 6,69 (1H, d, J = 8.0 Hz, AGN), 6,74 (1H, d, J = 7,6 Hz, AGN), 7,13 (2H, d, J = 8.0 Hz, AGN), 7,13-to 7.32 (8H, m, AGN).

Sol model HC1: so pl. 100 - 110oC (CH2Cl2).

IR (NaCl): 3421, 2972, 1619, 1430, 1287 cm-1.

Elemental analysis. Calculated for C31H36N2O2NS,40 CH2Cl2: 69,96%; N 7,07%; N 5,20%. Found: 69,94%; N 7,06%; N 5,15%.

Example 24

Obtaining N, N-diethyl-4-[(N-tert-butoxycarbonylamino-4-yl)-3-fluorenylacetamide]benzamide (compound 38)

< / BR>
By way of example 19 using 3-bromptonville got mentioned in the title compound (257 mg, 27%).

1H NMR (400 MHz, D13) : of 1.03 (3H, Shir. CH3CH2N -) and 1.15 (3H, Shir. CH3CH2N'), 1,19-of 1.29 (4H, m, piperidine-CH-), 1,35 (N, s, CH3C) 2,39 (1H, m, piperidine-CH-), 2,59 (2H, Shir. piperidine-CH-), 3,17 (2H, Shir. CH3CH2N-), or 3.28 (1H, c), OF 3.45 (2H, Shir, CH3CH2N-), was 4.02 (2H, Shir. piperidine-CH-), to 6.80 (1H, m, AGN), to 7.15 (3H, m, AGN), 7,18 (2H, d, J = 8.0 Hz, AGN), 7,39 (2H, d, J = 8.0 Hz, AGN).

BR> According to the method of example 20, using the compound of example 24 (165 mg) was obtained N,N-diethyl-4-(3-tortenelmietlen-4-ylidenemethyl)benzamide (108 mg, 87%).

1H NMR (400 MHz, D13) : 1,08 (3H, Shir. CH3CH2N-), 1,19 (3H, Shir. CH3CH2N), is 2.09 (1H, s, NH), of 2.25 (4H, Shir, piperidine-CH-), 2,84 (4H, Shir. piperidine-CH-), 3,23 (2H, Shir. CH3CH2N-), 3,47 (2H, Shir. CH3CH2N-), 6,74 (1H, m, AGN), 6,86 (2H, m, AGN), 7,06 (2H, d, J = 8.0 Hz, AGN), 7,18 (1H, m, AGN), of 7.24 (2H, d, J = 8.0 Hz, AGN).

Sol model HC1: so pl. > 70oWith (Razlog.).

IR (NaCl) 2978, 1605, 1478, 1432, 1290 cm-1.

Elemental analysis. Calculated for C23H27N2OF10,25 CH2Cl21,50 H2O: 61,89%; N, 7.04 PER CENT; N 6,21%. Found: 61,97%; N 6,95%; N To 6.22%.

(E) Scheme of the synthesis of the compound of example 26

The compound of example 26 was obtained by the method as shown in scheme 5.

(i) Obtaining 4'-iodoacetamide (compound 40)

To a solution of 4-iodoaniline (15 g, 69 mmol) in dry CH2Cl2(100 ml) was added acetic anhydride (14,09 g, 138 mmol) at room temperature, the reaction mixture then was stirred for 2 hours. Grey precipitate formed during the reaction, was filtered off, washed with simple ether and collected, the mother liquor is concentrated on the smoke substance, which is the target product (15,95 g, 88.7 per cent).

1H NMR (D13) : are 2.19 (3H, s, PINES3), 7,2 (1H, s, Shir. -NH), 7.23 percent (2H, m, Ar), to 7.61 (2H, m, Ar).

(ii) Obtaining 4-(4-acetamidobenzoyl)-N-tert-butoxycarbonylamino (compound 41)

To a solution of 4'-iodoacetamide (11,7 g, 45 mmol) in dry THF (200 ml) at 0oC was added NaH (1,62 g of 67.5 mmol), the reaction mixture was stirred for 30 min while the temperature was increased to room temperature, then slowly at -78oC was added n-BuLi (1.6 M in heptane, 54 mmol). The mixture was stirred for 15 min, then added dropwise through a syringe was added N-tert-butoxycarbonyl-N'-methyl-N'-methoxynicotinic (x 6.15 g, 30 mmol) in THF (10 ml). The reaction mixture was heated to room temperature and then extinguished in an aqueous solution of NH4Cl and extracted with ethyl acetate (2100 ml). The organic layer was washed with saturated (water) NH4Cl, brine, dried over MgSO4and concentrated give crude product which was further purified column chromatography on silica gel using MeOH-CH2Cl2(0:100 ~ 5:95), receiving target product (9,02 g, 87%).

1H NMR (CDCl3) : 1,47 (N, (CH3)3). 1,6-1,8 (4H, m, piperidine), of 2.21 (3H, WHAT P CLASS="ptx2">

(iii) Obtaining 4-(-hydroxy--(4-'N-tert-butoxycarbonylmethyl)-3-terbisil)acetanilide (compound 42)

According to the method described for connection 4, but replacing 1-bromonaphtalene 3-fluoro-1-iodobenzoyl got mentioned in the title compound (93%).

1H NMR (DMSO-D6) : 1,2-1,3 (4H, m, piperidine), 1,37 (N, with, (CH3)3), and 2.0 (3H, s, PINES3), to 2.65 (3H, Shir., piperidine), of 3.95 (2H, m, piperidine), 6,98 (1H, m, Ar), 7,21-to 7.50 (7H, m, Ar), 9.85 (1H, s, OC-NH).

(iv) obtaining the N-methyl-4-(-hydroxy--(4-N-tert-butoxycarbonylmethyl)-3-terbisil)acetanilide (compound 43)

To 2 M (water) NaOH solution (10 ml) was added tetrabutylammonium hydrosulfate (1.35 g, of 3.97 mmol) was then added 4--hydroxy--(4-N-tert-butoxycarbonylmethyl)-3-terbisil)acetanilide (825 mg, of 1.86 mmol) and methyliodide (769 mg, 5.4 mmol) in 10 ml of dichloromethane. The reaction mixture is then boiled under reflux for 1 hour, cooled to room temperature. The dichloromethane layer was collected and evaporated to a volume of about 1 ml was Added ethyl acetate and the precipitate was separated by filtration. The organic phase is washed with saline and dried over MgSO4concentrated, receiving the solid material which was further purified MPLC and with the S="ptx2">

1H NMR (D13) : 1.2 to 1.5 (4H, m, piperidine), 1,42 (N, with, (CH3)3) and 1.83 (3H, s, PINES3), 2,52 (1H, m, -CH-C-OH), 2,70 (2H, m, piperidine), 2,86 (1H, s, W, -HE), 3,21 (3H, s, NCH3), is 4.15 (2H, s, W, piperidine), of 6.90 (1H, m, Ar), 7,12-of 7.60 (7H, m, Ar).

Example 26

Obtaining N-methyl-4-(3-tortenelmietlen-4-ylidenemethyl)acetanilide (compound 44)

N-methyl-4--hydroxy--(4-N-tert-butoxycarbonylmethyl)-3-terbisil)acetanilide (300 mg, 0,657 mmol) in dry dichloromethane (5 ml) was added triperoxonane acid (50 ml) at room temperature. The reaction mixture is boiled under reflux for 4 hours and then concentrated. The residue was dissolved in AcOEt (50 ml). The resulting solution was washed 2 N. (water) NaOH (aqueous) NH4C1 and brine, dried over MgSO4. Removal of solvents gave the crude product, which was purified MPLC with elution MeOH-CH2Cl2-NH4HE (5: 95: 1) to give pure product (176 mg, 79%).

So pl. 235-237oWith (Razlog.).

IR (NaCl, film) (model HC1 salt),max:2961, 2722, 2480, 1658, 1608, 1580, 1507, 1429, 1381 cm-1.

1H NMR (CDCl3) : 1,89 (3H, s, PINES3), 1,95 (1H, s, -NH), 2,32 (4H, m, piperazine), of 2.92 (4H, m, piperazine), 3,26 (3H, s, N-CH3), for 6.81-7,28 (8H, m, Ar).

< 170,4.

Elemental analysis. Calculated for C21H23N2FOHC1: 67,28%; N 6,45%; N 7,47%. Found: 66,88%; N 6,44%; N, 7.16 Percent.

(F) Scheme of the synthesis of the compound of example 27

The compound of example 27 was obtained by the method as shown in scheme 6

(i) Obtaining N-tert-butoxycarbonyl-4-piperidone (compound 46)

A mixture of compound 45 (50 g, 0,325 mol) and di-tert-BUTYLCARBAMATE (71 g, 0,325 mol) in 300 ml dichloromethane was stirred at 0oWith dropwise adding triethylamine (133 g of 1.32 mol). The mixture was left to warm to room temperature and was stirred for 12 hours. The solvent is evaporated and the crude product was distributed between water (400 ml) and diethyl simple ether (400 ml). The aqueous phase was washed with additional portions of diethyl simple ether (400 ml). The combined ether was washed with water (400 ml) and brine (400 ml), dried over MgSO4. Removal of solvent gave compound 46 in the form of a pale yellow solid material (55,3 g, 85%).

H(400 MHz, D13): 1,50 (s, N), a 2.45 (t, 4H, J=6,1 Hz), and 3.72 (t, 4H, J=6,1 Hz).

(ii) Obtaining tert-butyl ester 4-(4-methoxycarbonylbenzyl)piperidine-1-carboxylic acid (compound 49)

Methyl-4-(methyl bromide)benzoate (compound 47) (11.2 g, 49 mmol) restock of trimethylphosphite was deleted by joint distillation with toluene, give crude methyl ester of 4-(dimethoxyphosphoryl)benzoic acid (compound 48).

H(400 MHz, D13): 3,20 (d, 2H, J=22 Hz), 3,68 (d, 3H, and 10.8 Hz), of 3.78 (d, 3H, 11.2 Hz), 3,91 (s, 3H), 7,38 (m, 2H), 8,00 (d, 2H, J=8 Hz).

The crude product (compound 48) was dissolved in dry THF (200 ml) in an atmosphere of N2and was cooled to -78oC. was added dropwise diisopropylamide lithium (32.7 ml, 1.5 M in hexano, 49 mmol). The solution was left to warm to room temperature. To the reaction mixture was added dropwise a solution of compound 46 (9,76 g, 49 mmol in 100 ml dry THF) and the mixture was stirred in an atmosphere of N2within 12 hours. To the reaction mixture were added water (300 ml) and ethyl acetate (300 ml) and was extracted. The aqueous phase was washed with ethyl acetate (2 300 ml). The combined ethyl acetate layers were dried over gS4and evaporated, to give crude product, which was purified by chromatography on silica gel (0-33% ethyl acetate in hexano) to give compound 49 as a white solid material (5,64 g, 35%).

H(400 MHz, D13): 1,44 (s, 1H), 2,31 (t, J=5.5 Hz, 2H), 2,42 (t, J= 5.5 Hz, 2H), 3,37 (t, J=5.5 Hz, 2H), 3,48 (t, J=5.5 Hz, 2H), a 3.87 (s, 3H), 6,33 (s, 1H), 7,20 (d, J=6,7 Hz, 2H), 7,94 (d, J=6,7 Hz, 2H);c-13(D13): 28,3, 29,2, 36,19, 51,9, 123,7, 127,8, 128,7, 129,4, 140,5, 142,1, 154,6, 166,8 M. D.

maxABOUT4: 68,86%; N 7,60%; H TO 4.23%. Found: From 69.1%; N 7,69%; N Of 4.25%.

(iii) Obtaining tert-butyl ester 4-bromo-4-[bromo-(4-ethoxycarbonylphenyl)methyl]piperidine-1-carboxylic acid (compound 50)

To a solution of compound 49 (5.2 g, 16 mmol) in dry dichloromethane (200 ml) was added TO a2CO3(1.0 g). Then dropwise at 0oWith solution was added bromine (2.9 g, 18 mmol in 30 ml of DCM and the mixture was stirred for 1.5 hours at room temperature. TO2CO3was removed by filtration and the solution evaporated to dryness. The crude product was dissolved in ethyl acetate (200 ml) and washed with water (200 ml), 0.5 M model HC1 (200 ml) and brine (200 ml), dried over MgSO4. The solvent is evaporated, give crude product, which was recrystallized from methanol, receiving compound 50 as a white solid material (6,07 g, 78%).

H(400 MHz, D13): of 1.28 (s, N), a 1.75 (m, 2H), 1,90 (m, 2H), 2,1 (m, 4H), is 3.08 (Shir. 4H), 3,90 (s, 3H), 4,08 (width, 4H), 5,14 (s, 1H), EUR 7.57 (d, J= 8,4 Hz, 2H), 7,98 (d, J=8,4 Hz, 2H);c-13(400 MHz, D13): 28,3, 36,6, 38,3, 40,3, 52,1, 63,2, 72,9, 129,0, 130,3, 130,4, 141,9, 154,4, 166,3 M. D.

max(NaCl) cm-1: 3425, 2969, 1725, 1669, 1426, 1365, 1279, 1243.

Elemental analysis. Calculated for C19H25Br2NO4: FROM 46.6%; N 5,13%; N 2.85 PERCENT. Found: 46,64%; N 5,16 is islote (compound 51)

To a solution of compound 50 (5,4 g, 11 mmol) in methanol (300 ml) at 40oWith added 2.0 M NaOH (100 ml). The reaction mixture was stirred for 3 hours at 40oC. the Crude salt was isolated by filtration. The solid material was dried overnight in vacuum. The dry salt was dissolved in 40% of a mixture of acetonitrile/water and the solution pH was brought to 2 using concentrated HCl. Target product (7) (3.8 g, 87%) was isolated as a white powder by filtration.

H(400 MHz, D13): 1,45 (s, N), 2,22 (DD, J=5,5 Hz and 6.1 Hz, 2H), 2,64 (DD, J=5,5 Hz and 6.1 Hz, 2H), 3,34 (DD, J=5,5 Hz and 6.1 Hz, 2H), 3,54 (DD, J=5,5 Hz and 6.1 Hz, 2H), 7,35 (d, J=6,7 Hz, 2H), 8,08 (d, J=6,7 Hz, 2H); c-13(400 MHz, D13): 28,3, 31,5, 34,2, 44,0, 115,3, 128,7, 129,4, 130,2, 137,7, 145,2, 154,6, 170,3.

Elemental analysis. Calculated for C18H22BrNO4: 54,56%; N CEILING OF 5.60%; N OF 3.53%. Found: 54,66%; N 5,68%; N 3,59%.

(v) Obtaining tert-butyl ester 4-[bromo-(4-diethylcarbamoyl)methylene]piperidine-1-carboxylic acid (compound 52)

To a solution of compound 51 (1.0 g, 2.5 mmol) in dry dichloromethane (10 ml) at -20oWith added isobutylparaben (450 mg, 3.3 mmol). After 20 min at -20oWith added diethylamine (4 ml) and the reaction mixture was left to warm to room temperature. 1.5 hours solvent is saline and was dried over MgSO4and the ethyl acetate was removed by evaporation. The crude product was purified by chromatography on silica gel (0-60% ethyl acetate in heptane) to give the product (compound 52) as white needles (800 mg, 73%).

H(400 MHz, D13): 1,13 (width, 3H), 1,22 (width, 3H), the 1.44 (s, N), 2,22 (t, J=5.5 Hz, 2H), 2,62 (t, J=5.5 Hz, 2H), and 3.31 (t, J=5.5 Hz, 2H), 3,52 (t, J= 5.5 Hz, 2H), 7,27 (d, J=7.9 Hz, 2H), 7,33 (d, J=7.9 Hz, 2H); c-13(400 MHz, D13): 12,71, 14,13, 28,3, 31,5, 34,2, 39,1, 43,2, 79,7, 115,9, 126,3, 129,3, 136,8, 137,1, 140,6, 154,6, 170,5.

Elemental analysis. Calculated for C22H31BrN2O3: 58,3%; N 6,92%; N 6,21%. Found: 58,62%; N 6,89%; N 6,21%.

Example 27

Obtaining N, N-diethyl-4-[piperidine-4-ilidene-(3-triptoreline)methyl] benzamide (compound 54 g AG = 3-triptoreline) (General method)

The combination of Suzuki connection 52 with different baronowie acids with subsequent removal of the protective group from the Deputy conducted in parallel on a small scale. Reaction and liquid-liquid extraction was performed in test tubes for crops with a size of 25 to 150 mm Technique typical reactions described below.

To a solution of compound 52 (25 mg, 57 μmol) and tetrakis(triphenylphosphine)palladium(0) (5 mg, 4.3 mmol) in xylenes (degassed, 0.5 ml) was added 3-triptoreline acid (28.5 mg, all to undergo reaction at 80oC for 1.5 hours in an atmosphere of Ar. The reaction mixture was diluted with water (1 ml) and diethyl simple ether (1 ml) and stirred with a twist. The organic phase was separated and evaporated, to give crude product (compound 9, AG=3-triptoreline).

The BOC-group was removed by treatment of the crude product of 1 ml TFU. After 30 minutes TFU evaporated at room temperature to give crude salt TFU. Salt was neutralized 1 M NH4OH (1.0 M) and was extracted with diethyl simple ether (2 x 1 ml). The ether phase was acidified 4.0 M model HC1 in dioxane (200 μl) and model HC1 salt was extracted with water (2 x 1 ml). An aqueous solution of the salt was washed diethyl simple ether (2 x 1 ml) and liofilizirovanny, receiving the product (compound 54, AG=3-triptoreline) as a white powder (10 mg, 39%).

1H NMR (D13) (ground) : 1,11 (width, 3H), 1,20 (width, 3H), and 2.26 (t, J= 5.6 Hz, 2H), 2,31 (t, J=5.6 Hz, 2H), 2,88-only 2.91 (m, 4H), 3.27 to (Shir. 2H), 3,52 (Shir. 2H), 7,10-7,47 (m, 8H).

Elemental analysis. Calculated for C24H28N2OF3Cl 1,80 H2O: 59,39%; N 6,56%; N 5,77%. Found: 59,39%; N 5,90%; N 5,77%.

Examples 28-52

According to the method described for compound 54 of example 27 but replacing 3-triftormetilfullerenov acid to the corresponding boranova acid were also paid (compound 55)

Used 3-nitrophenylarsonic acid.

< / BR>
1H NMR (D13) (ground) : 1,11 (Shir. 3H), 1,21 (Shir. 3H), 2,27-of 2.34 (m, 4H), of 2.92 (t, J=6.0 Hz, 4H), 3,26 (Shir. 2H), 3,52 (Shir. 2H), 7,10 (d, J= 8,4 Hz, 2H), 7,31 (d, J=8,4 Hz, 2H), 7,40-to 7.50 (m, 2H), 7.95 is-8,08 (m, 2H).

Example 29

N,N-Diethyl-4-(4-colorvitality-4-ylidenemethyl)benzamide (compound 56)

Used p-tolylboronic acid.

< / BR>
1H NMR (D13) (ground) : 1,10 (Shir. 3H), 1,19 (Shir. 3H), to 2.29 (s, 3H), 2.26 and-2,31 (m, 4H), 2,86-is 2.88 (m, 4H), 3,25 (W, 2H), 3,49 (Shir. 2H), 6,95-7,28 (m, 8H).

Example 30

N, N-Diethyl-4-(4-formylphenylboronic-4-ylidenemethyl)benzamide (compound 57)

Used 4-formylphenylboronic acid.

< / BR>
1H NMR (D13) (ground) : 1,10 (Shir. 3H), 1,20 (Shir. 3H), 2,28 is 2.33 (m, 4H), 2,89 of 2.92 (m, 4H), 3,25 (Shir. 2H), 3,50 (Shir. 2H), 7,08-7,79 (m, 8H), for 9.95 (s, 1H).

Example 31

N, N-Diethyl-4-(3-chloro-4-tortenelmietlen-4-ylidenemethyl)benzamide (compound 58)

Used 3-chloro-4-ftorhinolonovy acid.

< / BR>
1H NMR (D13) (ground) : 1,10 (Shir. 3H), 1,20 (Shir. 3H), 2.26 and-of 2.30 (m, 4H), 2,86-only 2.91 (m, 4H), 3,25 (Shir. 2H), 3,50 (Shir. 2H), 6,93-7,30 (m, 7H).

Example 32

N,N-Diethyl-4-(tortenelmietlen-4-ylidenemethyl)benzamide (compound 59)

Is (Shir. 3H in), 2.25 (s, 4H), 2,84 (s, 4H), 3,20 (Shir. 2H), 3,47 (Shir. 2H), 6,92 (m, 2H), 7,01 (m, 4H), of 7.23 (d, J=8,8 Hz, 2H).

Example 33

N, N-Diethyl-4-(2-tortenelmietlen-4-ylidenemethyl)benzamide (compound 60)

Used 2-ftorhinolonovy acid.

< / BR>
1H NMR (D13) (ground) : 1,11 (Shir. 3H), 1,15 (Shir. 3H), 2,10 (t, J= 5,2 Hz, 2H), and 2.27 (t, J=5,2 Hz, 2H), and 2.83 (m, 4H), 3,20 (Shir. 2H), 3.45 points (Shir. 2H), 6,94-7,03 (m, 3H), 7,10-of 7.23 (m, 5H).

Example 34

N,N-Diethyl-4-(2,4-dichloropyridine-4-ylidenemethyl)benzamide (compound 61)

Used 2,4-dichlorophenylamino acid.

< / BR>
1H NMR (DMSO) (model HC1 salt) : 1,07 (Shir. 6N), 2,24 (t, 2H), 2,50 (t, 2H), 3,10 (t, 2H), 3,30 (t, 2H), 3,31 (Shir. 2H), 3.43 points (Shir. 2H), 7,25 (d, J=8,4 Hz, 2H), 7,32 (d, J=8,4 Hz, 2H), 7,43 (d, J=8.0 Hz, 1H), 7,47 (d, J=8.0 Hz, 1H), 7,68 (s, 1H), 9,20 (Shir. 2H).

Example 35

N,N-Diethyl-4-(3,5-dichloropyridine-4-ylidenemethyl)benzamide (compound 62)

Used a 3.5-dichlorophenylamino acid.

< / BR>
1H NMR (DMSO) (model HC1 salt) : 1,03 (Shir. 6N), a 2.36-of 2.38 (m, 4H), to 3.0-3.2 (m, 4H), 3,2 (Shir. 2H), 3,38 (Shir. 2H), 7,19 (s, 1H), 7,21 (d, J=8.0 Hz, 2H), 7,29 (d, J=8.0 Hz, 2H), 7,49 (s, 2H), 9,10 (Shir. 2H).

Example 36

N, N-Diethyl-4-(3-acetylpiperidine-4-ylidenemethyl)benzamide (compound 63)

Used 3-acetylphenylalanine acid.

Example 37

N, N-Diethyl-4-(3,5-triftormetilfullerenov-4-ylidenemethyl)benzamide (compound 64)

Used a 3.5-triftormetilfullerenov acid.

< / BR>
1H NMR (DMSO) (model HC1 salt) : 1,06 (Shir. 3H), 1,08 (Shir. 3H), 2,33 (Shir. 2H), 2,41 (Shir. 2H), 3,12 (Shir. 6N), 3,38 (Shir. 2H), 7,24 (d, J=7,6 Hz, 2H), 7,30 (d, J=7,6 Hz, 2H), to 7.84 (s, 2H), 8,00 (s, 2H), 8,9 (Shir. 2H).

Example 38

N,N-Diethyl-4-(3-totenlieder-4-ylidenemethyl)benzamide (compound 65)

Used 3-thienylboronic acid.

< / BR>
1H NMR (DMSO) (model HC1 salt) : 1,10 (Shir. 6N), is 2.44 (t, 2H), 2,58 (t, 2H), 3,10-3,15 (m, 4H), 3,21 (Shir. 2H), 3,44 (Shir. 2H), 6,86 (d, J=4,8 Hz, 1H), 7,20 (d, J=8.0 Hz, 2H), 7,32 (d, J=8.0 Hz, 2H), 7,33 (s, 1H), 7,52 (d, J=4,8 Hz, 1H).

Example 39

N,N-Diethyl-4-(2-totenlieder-4-ylidenemethyl)Benjamin (compound 66)

Used 2-thienylboronic acid.

< / BR>
1H NMR (CDC13) (ground) : 1,12 (Shir. 3H), 1,20 (Shir. 3H), 2,24 (t, J= 5,2 Hz, 2H), 2,50 (t, J=5,2 Hz, 2H), 2,85 (t, J=5.6 Hz, 2H), 2,92 (t, J= 5.6 Hz, 2H), 3.27 to (Shir. 2H), 3,51 (Shir. 2H), 6.75 in (d, J=3.6 Hz, 1H), 6,93 (t, J=3,6 Hz, 1H), 7,16 (d, J=7.2 Hz, 2H), 7,21 (d, J=3.6 Hz, 1H), 7,30 (d, J=7.2 Hz, 2H).

Example 40

N-Diethyl-4-(4-methylthiophene">

< / BR>
1H NMR (D13) (ground) : 1,11 (Shir. 3H), 1,20 (Shir. 3H), 2,32 is 2.75 (m, 4H), of 2.45 (s, 3H), 2,90-2,87 (m, 4H), 3,26 (Shir. 2H), 3,51 (Shir. 2H), 7,01 (d, J=6.0 Hz, 2H), 7,10 (d, J=6.0 Hz, 2H), 7,15 (d, J=6,8 Hz, 2H), 7,27 (d, J=6,8 Hz, 2H).

Example 41

N, N-Diethyl-4-(3-aminopenicillin-4-ylidenemethyl)benzamide (compound 68)

Used 3-aminophenylarsonic acid.

< / BR>
1H NMR (D13) (ground) : 1,11 (Shir. 3H), 1,20 (Shir. 3H), 2,27 is 2.33 (m, 4H), 2,86-2,90 (m, 4H), 3.27 to (Shir. 2H), 3,51 (Shir. 2H), 3,57 (Shir. 2H), 3,68 (s, 1H), to 6.39 (s, 1H), of 6.52 (DD, J=1.6 Hz, J=7,6 Hz, 2H), 7,06 (t, J= 8.0 Hz, 1H), 7,12 (d, J=6,4 Hz, 2H), 7,26 (d, J=6,4 Hz, 2H).

Example 42

N, N-Diethyl-4-(4-triftormetilfullerenov-4-ylidenemethyl)benzamide (compound 69)

Used 4-triftormetilfullerenov acid.

< / BR>
1H NMR (DMSO) (Hcl salt) : 1,05 (Shir. 6N), to 2.35 (t, 2H), 2.40 a (t, 2H), 3,09 (m, 6N), 3,35 (Shir. 2H), 7,17 (d, J=8.0 Hz, 2H), 7,28 (d, J=8.0 Hz, 2H), 7,35 (d, J=8.0 Hz, 2H), to 7.67 (d, J=8.0 Hz, 2H), 8,71 (Shir. 2H).

Example 43

N,N-Diethyl-4-(4-methoxyphenylpiperazine-4-ylidenemethyl)benzamide (compound 70)

Used 4-methoxyphenylalanine acid.

< / BR>
1H NMR (Dl3) (ground) : 1,12 (Shir. 3H), 1,19 (Shir. 3H), to 2.29 (m, 4H), 2,87 (m, 4H), 3.27 to (Shir. 2H), 3,51 (Shir. 2N), of 3.77 (s, 3H), to 6.80 (m, 2H), 7,00 (m, 2H), 7,10 (d, J=8,4 Hz, 2H), 7,26 (d, J=8>Used 3,4-dichlorophenylamino acid.

< / BR>
1H NMR (DCl3) (ground) : 1,12 (Shir. 3H), 1,20 (Shir. 3H), 2,28 (t, J= 5.6 Hz, 4H), 2,89 (m, 4H), 3.27 to (Shir. 2H), 3,52 (Shir. 2H), 6,8-7,4 (m, 7H).

Example 45

N, N-Diethyl-4-(2-triftormetilfullerenov-4-ylidenemethyl)benzamide (compound 72)

Used 2-triftormetilfullerenov acid.

< / BR>
1H NMR (D13) (ground) : 1,05 (Shir. 3H), 1,16 (Shir. 3H), of 1.95 (m, 2H), 2,35-to 2.41 (m, 2H), 2,7-2,9 (m, 4H), 3,20 (Shir. 2H), 3,48 (Shir. 2H), 7,2-7,6 (m, 8H).

Example 46

N,N-Diethyl-4-(3-colorvitality-4-ylidenemethyl)benzamide (compound 73)

Used m-tolylboronic acid.

< / BR>
1H NMR (D13) (ground) : 1,11 (Shir. 3H), 1,19 (Shir. 3H), of 2.28 (s, 3H), to 2.29 (m, 4H), 2,89 (m, 4H), 3.27 to (Shir. 2H), 3,51 (Shir. 2N), of 6.8 to 7.3 (m, 8H).

Example 47

N,N-Diethyl-4-(2-methoxyphenylpiperazine-4-ylidenemethyl)benzamide (compound 74)

Used 2-methoxyphenylalanine acid.

< / BR>
1H NMR (D13) (ground) : 1,09 (Shir. 3H), 1,18 (Shir. 3H), 2,10 (kV, J= 4,8 Hz, 2H), 2,31 (kV, J=4,8 Hz, 2H), 2,8-2,9 (m, 4H), 3,25 (Shir. 2H), 3,50 (Shir. 2H), 3,68 (s, 3H), 6,83-of 6.90 (m, 2H), 7,0 (d, 1H), 7,15-7,25 (m, 5H).

Example 48

N, N-Diethyl-4-(3-formylphenylboronic-4-ylidenemethyl)benzamide (compound 75)

IP), 1,20 (Shir. 3H), 2.26 and-of 2.34 (m, 4H), 2,90 of 2.92 (m, 4H), 3,28 (Shir. 2H), 3,2 (Shir. 2H), 7,11-7,31 (m, 8H), 9,96 (s, 1H).

Example 49

N,N-Diethyl-4-(2-aftereverything-4-ylidenemethyl)benzamide (compound 76)

Used 2-NativeWindow acid.

< / BR>
lH NMR (D13) (ground) : 1,11 (Shir. 3H), 1,20 (Shir. 3H), 2,35-2,39 ( m, 4H), 2.91 in-2,96 (m, 4H), 3.27 to (Shir. 2H), 3,51 (Shir. 2H), 7,16-7,40 (m, 5H), 7,42-7,44 (m, 2H), EUR 7.57 (s, 1H), 7,72-7,79 (m, 2H).

Example 50

N, N-Diethyl-4-(2-formylpyridine-4-ylidenemethyl)benzamide (compound 77)

Used 2-formylphenylboronic acid.

< / BR>
1H NMR (Dl3) (ground) : 1,09 (Shir. 3H), 1,18 (Shir. 3H), 1.70 to 2,10 (m, 2H), 2.40 a-2,49 (m, 2H), was 2.76-2,84 (m, 2H), 2,85-of 2.97 (m, 2H), 3,23 (Shir. 2H), 3,48 (Shir. 2H), 7,13-7,40 (m, 6N), 7,53-of 7.55 (m, 1H), of 7.90 (d, J=7,6 Hz, 1H), 10,27 (s, 1H).

Example 51

N, N-Diethyl-4-(4-acetylpiperidine-4-ylidenemethyl)benzamide (compound 78)

Used 4-acetylphenylalanine acid.

< / BR>
1H NMR (D13) (ground) : 1,11 (Shir. 3H), 1,20 (Shir. 3H), of 2.30 to 2.35 (m, 4H), of 2.56 (s, 3H), of 2.92 (m, 4H), 3.27 to (Shir. 2H), 3,52 (Shir. 2H), 7,10-7,30 (m, 6N), 7,87 (d, J=7.2 Hz, 2H).

Example 52

N, N-Diethyl-4-(3-triftormetilfullerenov-4-ylidenemethyl)benzamide (compound 79)

Used 3-triftormetilfullerenov acid.

Example 53

Obtaining N, N-diethyl-4-([1-(2,6-diaminohexane)piperidine-4-ilidene]phenylmethyl)benzamide (compound 80)

< / BR>
L-Boc-lysine (Cbz) (0,38 g, 1.0 mmol) was dissolved in dry tetrahydrofuran (5 ml) in nitrogen atmosphere at -15oC. was Added N-methylmorpholine (of 0.11 ml, 1.0 mmol), then isobutylparaben made (0.13 ml, 1 mmol). After stirring for 10 minutes was added N,N-diethyl-4-(phenylpiperidine-4-ylidenemethyl)benzamide (compound 6) (0.35 g, 1.0 mmol) in tetrahydrofuran (1 ml) and the temperature was allowed to rise to 25oC for 2 hours. The reaction mixture was evaporated onto silica gel. MPLC on silica gel (0 to 100% ethyl acetate in heptane) gave, 0,4

The product (0.40 g, 0,56 mmol) was dissolved in methylene chloride (10 ml) and treated triperoxonane acid (3 ml) for 30 min, then the volatiles evaporated. The residue was dissolved in acetic acid (25 ml) and subjected to hydrogenolysis for 1.5 hours with hydrogen (1 ATM) over palladium on coal (10%, 0.10 g). The solvent is evaporated and the residue was purified by chromatography on a short column with reversed phase (RP-18), elwira 0-30% acetonitrile in water. The free amine was extracted with 5% solution of potassium carbonate/methylene chloride, produces the Oia gave dihydrochloride salt.

1H NMR (free amine, CD3D): 1,0-1,7 (m, N, amide-IU, piperidine-H, lysine-N), and 2.3-2.7 and 3.0 to 4.5 (m, 11N, amide-H, piperidine-H, lysine-N), and 4.8 (s, 4H, 2 NH2), 7,10-to 7.50 (m, M, ArH).

Elemental analysis. Calculated for C29H40N4O22,4 H2O 2 HCl: 58,76%; N Of 7.96%; N 9,43%. Found: 58,70%; N 7,51%; N Was 9.33%.

Example 54

Getting phosphonoacetate ester 4-[(4-diethylcarbamoyl)phenylmethylene]piperidine-1-carboxylic acid (compound 81)

< / BR>
N,N-Diethyl-4-(phenylpiperidine-4-ylidenemethyl)benzamide (compound 6) (0,62 g, 1.8 mmol) was dissolved in methylene chloride (10 ml) was added 1,8-bidimensionally (0,42 g, 2.0 mmol). The solution was cooled to 0oWith and was added dropwise chloromethylphosphonate (0.25 g, 2.0 mmol) in methylene chloride (1 ml). After incubation for 2 hours at 25oWith added an additional portion of first 1,8-mediamonitoring (0.21 g, 1.0 mmol), then chloromethylphosphonate (0.12 g, 1.0 mmol). After the total aging time of 4 hours, the solution washed with 1 M model HC1, brine, dried (MgSO4) and evaporated, getting to 0.62, the Residue was dissolved in toluene (25 ml), was added dimensionful silver (0,81 g, 2.1 mmol) and the mixture was heated 3 hours at 80oC. the Solution was filtered, then washed with 0 to 100% ethyl acetate in heptane) gave 0.66 g (0.96 mmol, 54%). The residue was dissolved in ethyl acetate (50 ml) and subjected to hydrogenolysis (1 ATM hydrogen) with palladium on coal (10%, 0.3 g) for 2 hours. After filtration and evaporation of the solvent the product was treated with two equivalents of sodium hydroxide in methanol/water. Lyophilization gave the disodium salt of the product as a white solid material.

1H NMR (D2O): 1,03, 1,20 (2 m, 6N, amide-IU), was 2.34 (m, 4H, piperidine-H), 3,19-3,61 (m, 8H, Amin-CH2, piperidine-H), 5,44 (d, J=13 Hz, 2H, och2O), 7,18 and 7.36 (m, M, ArH).

Connections 80 and 81, respectively, are suitable prodrugs of the compounds of formula (I).

(N) a Scheme for the synthesis of compounds of examples 55-57

The compounds of examples 55, 56 and 57 were obtained by the method of scheme 7.

(i) Obtaining tert-butyl-4-{bromo[4-(morpholinomethyl)phenyl]methylene}-1-piperidinecarboxylate (compound 82)

To a solution of compound 51, obtained according to scheme 6 (0.25 g, of 0.625 mmol), and freshly triethylamine (0.5 ml) in dichloromethane (12 ml) was added dropwise at room temperature oxalicacid (0,38 ml, 2.0 M, 0.75 mmol). The solution was stirred for 10 minutes at room temperature and the solvent and excess reagents were removed in vacuo, getting harangi the Morpholine (56 mg, of 0.65 mmol) was added to a solution of acid chloride (0,65 mmol) and triethylamine (0.5 ml) in dichloromethane (5 ml). The reaction mixture was left to undergo the reaction for one hour at room temperature. The solvent was then removed in vacuum. The crude product was distributed between ethyl acetate (25 ml) and water (25 ml). The aqueous layer was washed with ethyl acetate and the combined ethyl acetate layers were washed with 2 M NaOH (2 25 ml), 2 M model HC1 (2 25 ml), brine (1 25 ml) and dried over magnesium sulfate. The solvent was removed in vacuum, obtaining the product (compound 82) (294 mg, yield 97%).

1H NMR (D13, 400 MHz): 1,44 (s, N), of 2.21 (t, J=5.6 Hz, 2H), 2,62 (t, J= 5.6 Hz, 2H), and 3.31 (t, J=5.6 Hz, 2H), 3,52 (t, J=5.6 Hz, 2H), 3,69 (width, 8H), 7,31 (d, J=6,4 Hz, 2H), 7,37 (d, J=6,4 Hz, 2H).

(ii) Obtain tert-butyl 4-{bromo-[4-(piperidinylcarbonyl)phenyl]methylene} -1-piperidinecarboxylate (compound 83)

Used the same technique as described for connection 82, but using piperidine instead of the research.

1H NMR (D13, 400 MHz): 1,44 (s, N) and 1.51 (width, 2H), 1,66 (width, 4H), of 2.21 (t, J=5.6 Hz, 2H), 2,62 (t, J=5.6 Hz, 2H), and 3.31 (t, J=5.6 Hz, 2H), 3.33 and (width, 2H), 3,52 (t, J=5.6 Hz, 2H), 3,68 (width, 2H), 7,26 (d, J=8,4 Hz, 2H), 7,35 (d, J=8,4 Hz, 2H).

(iii) Obtain tert-butyl 4-{ bromo-[4-(tetrahydro-1H-1-pyrrolyl the La receiving the connection 82, but using pyrrolidine instead of the research.

1H NMR (D13, 400 MHz): 1,44 (s, N), 1,87 (K, J=6,8 Hz, 2H), 1,95 (K, J= 6,8 Hz, 2H), measuring 2.20 (t, J=5.6 Hz, 2H), 2,62 (t, J=5.6 Hz, 2H), and 3.31 (t, J= 5.6 Hz, 2H), 3.43 points (t, J=6,8 Hz, 2H), 3,52 (t, 5.6 Hz, 2H), 3,63 (t, J=6,8 Hz, 2H), 7,27 (d, J=8.0 Hz, 2H), 7,47 (d, J=8.0 Hz, 2H).

Example 55

Getting 4-[(3-forfinal)piperidine-4-ylmethyl]phenylmorpholine-4-ylmethanone (compound 85)

To a solution of compound 82 (37 mg, of 0.085 mmol) and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0,0043 mmol) in xylenes (degassed, 0.5 ml) was added 3-ftorhinolonovy acid (25 mg, 0.18 mmol) in ethanol (degassed, 0.5 ml), and then 150 μl of 2 M Na2SO4(water) (300 Microm). The reaction mixture was left to undergo reaction at 80oC for 2 hours in argon atmosphere. The reaction mixture was diluted with water (1 ml) and diethyl simple ether (1 ml) and stirred with a twist. The organic phase was separated and evaporated, to give crude product which was used without further purification.

The BOC-group was removed by treatment of the crude product of 1 ml TFU. After 30 minutes at room temperature TFU evaporated, obtaining the crude salt TFU. Salt was neutralized 1 M NH4OH (1.0 M) and was extracted with diethyl simple ether (21 ml). The ether phase is tilov simple ether (21 ml) and liofilizirovanny, receiving the product as a white powder.

1H NMR (D13, 400 MHz) : to 2.67 (m, 4H), 3,19 (m, 4H), 3.45 points (width, 2H), 3,68 (Shir. , 6N), to 6.75 (d, J=9.6 Hz, 1H), 6,85 (d, J=8.0 Hz, 1H), 6,95 (m, 1H), 7,11 (d, J=7,6 Hz, 2H), 7,25 (s, 1H), 7,35 (d, J=7,6 Hz, 2H).

Example 56

Getting 4-[(3-forfinal)piperidine-4-ylmethyl] phenylpiperidine-4-ylmethanone (compound 86)

Used the method described for connection 85, but using compound 83 as a source material.

1H NMR (D13, 400 MHz): 1,51 (width, 2H), 1,65 (width, 4H), 2,60 (width, 4H), 3,14 (width, 4H), 3.33 and (width, 2H), 3,68 (width, 2N), to 6.67 (d, J=8.0 Hz, 1H), 6,86 (d, J=8.0 Hz, 1H), 6,93 (t, J=8.0 Hz, 1H), was 7.08 (d, J=8,4 Hz, 2H), 7,25 (s, 1H), 7,32 (d, J=8,4 Hz, 2H).

Example 57

Getting 4-[(3-forfinal)piperidine-4-ylmethyl] phenylpyrrolidine-1 ylmethanone (compound 87)

Used the method described for connection 85, but using compound 84 as a source material.

1H NMR (CDCl3, 400 MHz) : 1,84-1,89 (m, 2H), 1,90-to 1.98 (m, 2H), 2,60 2.63 in (m, 4H), 3,13-3,17 (m, 4H), to 3.41 (t, J=6,8 Hz, 2H), 3,62 (t, J=6.8 Hz), 6.73 x (d, J=8,8 Hz, 1H), 6,86 (d, J=7.2 Hz, 1H), 6,93 (m, 1H), 7,10 (d, J=8.0 Hz, 2H), 7,25 (s, 1H), 7,45 (d, J=8.0 Hz, 2H).

(H) Scheme of the synthesis of compounds of examples 58-68

Connection examples 58-68 were obtained according to the methods yl)methyl]piperidine-1-carboxylic acid (compound 88)

To a mixture of compound 51, obtained according to scheme 6 (0.25 g, of 0.625 mmol) in toluene (5 ml) was added diphenylphosphoryl (0,192 g, 0.70 mmol) and triethylamine (0.1 ml, 0.7 mmol). After stirring the mixture in an argon atmosphere at 95oWith over two hours was added an excess of anhydrous ethanol (2 ml) and triethylamine (0.1 ml) and the solution was stirred at 95oC for an additional 5 hours. After cooling to room temperature the reaction mixture was distributed between water and diethyl ether. The ether layer was washed with water, dried over magnesium sulfate and evaporated in vacuum, obtaining the product (compound 88) in the form of a reddish-brown foam (300 mg, yield 99%).

1H NMR (400 MHz, D13): of 1.30 (t, J=7.2 Hz, 3H), of 1.44 (s, N), 2,22 (t, J= 6.0 Hz, 2H), 2,60 (t, J=6.0 Hz, 2H), and 3.31 (t, J=6.0 Hz, 2H), 3,51 (t, J= 6.0 Hz, 2H), 4,21 (kV, J=7.2 Hz, 2H), return of 6.58 (s, 1H), 7,19 (d, J=8,4 Hz, 2H), 7,33 (d, J=8,4 Hz, 2H).

(ii) Obtaining tert-butyl ester 4-[(4-ethoxycarbonylphenyl)-(3-forfinal)methyl]piperidine-1-carboxylic acid (compound 92)

The combination of Suzuki four vinylbital (connection 88-91) 3-ftorhinolonovy acid was performed in parallel. Reaction and liquid-liquid extraction was performed in test tubes for crops size 25 mm mm Method a typical R (50 mg) in toluene (degassed, 0.5 ml) was added 3-ftorhinolonovy acid (of 0.182 g, 1.3 mmol) in ethanol (degassed, 0.5 ml), and then 0.75 ml of 2 M Na2CO3water (1.5 mmol). The reaction mixture was left to undergo reaction at 80oC for 3 hours in argon atmosphere. The reaction mixture was diluted with water and diethyl simple ether and stirred with a twist. The organic phase was separated and evaporated, to give crude product. The crude product was purified by chromatography on silica gel (0-50% EtOAc in hexano) to give the product (compound 92) in the form of a white powder (0,166 g, yield 58%).

1H NMR (400 MHz, D13) : a 1.25 (t, J=7.2 Hz, 3H), of 1.44 (s, N), 2,27 is 2.33 (m, 4H), 3,41-3,44 (m, 4H), 4,20 (kV, J=7.2 Hz, 2H), of 6.52 (s, 1H), 6,76 (d, J= 10 Hz, 2H), 6,85-6,89 (m, 2H), 7,01 (d, J=8,8 Hz, 2H), 7,19-of 7.23 (m, 1H), 7,28 (d, J=8,8 Hz, 2H).

Example 58

Obtaining the ethyl ester of 4-[(3-forfinal)piperidine-4-ylmethyl] phenylcarbinol acid (compound 96)

Removal of the BOC-protective group is carried out on a small scale in parallel in test tubes for testing (13 mm mm). A typical procedure is described below.

The BOC-group was removed by treating compound 92 (50 mg, 0.11 mmol) model HC1 in dioxane (4.0 M, 2 ml). The mixture was stirred at room temperature for 30 minutes. The solvent and HCl were removed in vacuum, R (400 MHz, D13) : of 1.28 (t, J=7.2 Hz, 3H), 2,27-2,31 (m, 4H), 2,85-only 2.91 (m, 4H), 4,19 (kV, J=7.2 Hz, 2H), 6,50 (s, 1H), 6,76 (d, J=10 Hz, 1H), 6,85-6,89 (m, 2H), 7,01 (d, J=8,8 Hz, 2H), 7,19-of 7.23 (m, 1H), 7,28 (d, J=8,8 Hz, 2H).

Example 59

Obtaining the ethyl ester of 4-[(3-forfinal)piperidine-4-ylmethyl]feniletilfosfinovoi acid (compound 100)

Alkylation of the amide nitrogen was performed on a small scale in parallel in test tubes for testing (13 mm to 100 mm). A typical procedure is described below.

To a solution of compound 92 (50 mg, 0.11 mmol) in dichloromethane (1.5 ml) was added methyliodide (31 mg, 0.22 mmol), aqueous sodium hydroxide (1.0 ml, 2 M) and tetrabutylammonium sulfate (44 mg, 0.13 mmol). The solution was boiled under reflux for one hour. After cooling to room temperature, the dichloromethane layer was separated and evaporated. To the residue was added a simple ether and white tetrabutylammonium iodide was removed by filtration. The ether was removed in vacuum to give crude product connection 100 in the form of a light oil. The BOC-group was removed by treatment HC1 in dioxane as described above, when receiving the product as a white powder after lyophilization (17 mg, yield 42%).

1H NMR (400 MHz, CDC13) : of 1.23 (t, J=7.2 Hz, 3H), 2,27 is 2.33 (m, 4H), 2,85-only 2.91 (m, 4H), 3,26 (s, 3H), 4,15 (kV, J=7.2 Hz, 2H), 6,78 (d, J=10 Hz, 1H), 6,85-6,89 (m is a piperidine-4-yl)-(3-forfinal)methyl]phenylcarbamoyl acid (compound 116)

Benzylidene connection 100 spent on a small scale in parallel in test tubes for testing (13 mm to 100 mm). A typical procedure is described below.

Connection 100 in free base form was obtained by adding ammonium hydroxide (1 M, 0.5 ml) to the aqueous solution of compound 100 (0.046 mmol) and was extracted in a simple ether. The ether was removed in vacuum, obtaining oil, which was dissolved in dichloromethane and treated with benzylbromide (0,14 ml, 0.5 M in dichloromethane) and triethylamine (0.05 ml). The solution was stirred at room temperature for 5 hours. The solvent was removed in vacuum. The product was dissolved in a mixture of water/acetonitrile/Hcl (2:1:0.5 M) and liofilizirovanny, getting the product connection 108 in the form of a white powder.

1H NMR (400 MHz, D13) : of 1.28 (t, J=7.2 Hz, 3H), 2,33-of 2.36 (m, 4H), 2,38 is 2.46 (m, 4H), 3,51 (s, 2H), 4,19 (kV, J=7.2 Hz, 2H), 6,50 (s, 1H), 6,78 (d, J= 10 Hz, 1H), 6,85-6,89 (m, 2H), 7,05 (d, J=8.0 Hz, 2H), 7,19-7,30 (m, 7H).

Examples 61-68

Compounds were also obtained synthetic routes described in schemes 8(a)-(C).

In a preferred embodiment, the invention known at present, use connections 6, 7, 9, 10, 12, 26, 27, 34, 39, 44, 58, 59, 62, 69, 71, 104, 106 and 109.

Pharmaceutical compositions

But the social, intraperitoneally, intraorale, intravenously, epidurally, vnutriobolochechnoe, intracerebroventricularly and by injection into the joints.

The preferred route of administration oral, intravenous or intramuscular.

The dose will depend on the method of administration, severity of disease, age and weight of the patient, and other factors normally considered by the attending physician, when determining the individual regimen and dose of the medication, the most suitable for a particular patient.

To obtain pharmaceutical compositions of the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Drugs in solid form include powders, tablets, dispersible granules, capsules, sachets and suppositories.

A solid carrier can be one or more substances, which can act as diluents, corrigentov, solubilization, lubricants, suspendida agents, binding agents or agents that loosen up the tablets; it may also be kapsulirujushchej material.

In powders, the carrier is a finely ground solid material, which is smim vital properties, in suitable proportions and pressed to obtain the desired shape and size.

To obtain compositions in the form of suppositories, viscoplastic wax 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 then poured into molds of the conventional size and leave for cooling and solidification.

Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragakant, methylcellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter and the like.

Pharmaceutically acceptable salts are the acetate, bansilalpet, benzoate, bicarbonate, bitartrate, bromide, calculatedat, camsylate, carbonate, chloride, citrate, dihydrochloride, ethylenediaminetetraacetate, edisylate, estolate, Eilat, fumarate, gluceptate, gluconate, glutamine, glycoli-arsanilic, hexylresorcinol, geranamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, malate, maleate, mandelate, mesilate, bromide, methylnitrate, methyl sulfate, mukat, napsylate, nitrate, pamoate (embonate), pannal, sulfate, tannat, tartrate, teoclate, triethiodide, salt Bettina, 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 refers to the finish of the preparative form of the active component with kapsulirujushchej material as a carrier providing formation of a capsule in which the active component (with other carriers or without them) is surrounded by carrier, which, thus, is associated with him. Similarly includes Sasha.

As solid dosage forms suitable for oral administration, you can use pills, powders and capsules.

Compositions in liquid form include solutions, suspensions and emulsions. As examples of liquid preparations suitable for parenteral administration include solutions of the active compounds in sterile water or a mixture of water/ propylene glycol. Liquid compositions can also be manufactured in an aqueous solution of polyethylene glycol.

Aqueous solutions for oral administration can be obtained rastvoritelei, if you want to. Aqueous suspensions for oral use can be prepared by dispersing finely ground active component in water with viscous material, such as natural and synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other suspendresume agents known in the field of pharmaceutical finished preparative forms.

Preferred pharmaceutical compositions is a unit dosage form. In this form, the composition is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package contains a discrete number of drugs, such as packaged tablets, capsules, and powders in vials or ampoules. The unit dosage form may itself also be a capsule, sachet or tablet or she may submit an appropriate number of any of these packaged forms.

Biological assessment

A) in vitro Model

Cell culture

293S cells of the person expressing the cloned receptors person , and resistant to neomycin, were grown in suspension at 37oC in an atmosphere with 5% CO

The preparation of membranes

Cells were collected as a precipitate after centrifugation and re-suspended in buffer for lysis (50 mm Tris, pH 7.0, 2.5 mm EDTU with PMSF added directly before use to 0.1 mm 0.1 M initial solution in ethanol), incubated on ice for 15 min, then homogenized with Poltrona within 30 seconds. The suspension was centrifuged at 1000 g (max) for 10 min at 4oC. the Supernatant was kept on ice and the precipitate is re-suspended and centrifuged as described previously. Supernatant two zentrifugenbau were combined and centrifuged at 46000 g (max) for 30 minutes the Precipitate is re-suspended in cold Tris buffer (50 mm Tris/CL, pH 7.0) and centrifuged again. The final precipitate is re-suspended in the buffer to membranes (50 mm Tris, Of 0.32 M sucrose, pH 7.0). Aliquots (1 ml) in a polyethylene test tubes were frozen in the system dry ice/ethanol and kept at -70oWith to use. Protein concentration was determined by the modified Lowry analysis with LTOs.

Analyses of binding

Membranes were thawed at 37oC, cooled on ice, passed 3 times through a 25 G needle and bred in batrouny through the filter of 0.22 m and to which only added to 5 μg/ml fresh Aprotinin, 10 μm of bestatin, 10 μm diprolene And without DTT). In chilled on ice polypropylene tubes size 1275 mm containing 100 µl of the appropriate radioactive ligand (see table 1) and 10 µl of the tested peptides at various concentrations were added to aliquots of 100 μl (1 μg protein, see table 1). Overall (OS) and nonspecific (NS) binding was determined in the absence and presence of 10 μm naloxone, respectively. The tubes were shaken by vortex and incubated at 25oFor 60-75 minutes, after this time the contents were rapidly filtered under vacuum and washed with about 12 ml/tube ice buffer for washing (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) remaining on the filters was measured by a beta counter after soaking the filters for at least 12 hours in minimule containing 6-7 ml of scintillation fluid. If the analysis was carried out in tablets with 96 deep wells, filtration was performed through a 96-seat single filter, pre-soaked in the PAYS, which were washed in buffer 31 for washing and dried in a drying Cabinet at 55oIn tachininae liquid MS-20/well.

Data analysis

Specific binding (SS), calculated as an OS-NS and SS in the presence of different subjects peptides, expressed as a percentage of the SS from the control. The value of the IC50and the hill coefficient (nHfor ligands and overset specifically bound radioactive ligand was calculated by logarithmic schedule or program to build curves, such as Ligand, GraphPad Prism, SigmaPlot or RecepyorFit. The value Kiwas calculated by the equation of Cheng-Prussoff. The mean values of the standard error for IC50TOiand nHcited for the tested ligands, at least on the basis of three curves of displacement.

Experiments on saturation of receptors

The value K of the radioactive ligand was determined by analysis of binding at cellular membranes with suitable radioactive ligands at concentrations in the range from 0.2 to 5-fold concentrations estimated K (up to 10-fold, if there are such quantities of the desired radioactive ligand). Specific binding of the radioactive ligand was expressed as pmol/mg of membrane protein. The values K andmaxfrom separate experiments were obtained from the nonlinear dependence of the specific wired is clothed.

In the biological model (model in vivo)

Mechano-allodynia in rats, induced complete adjuvant's adjuvant (PAF) and the cuff is placed on the sciatic nerve

Animals

Used male rats Sprague-Dawley (Charles River, St-Constant, Canada) weighing 175-200 g at the time of surgery. They were housed in groups of three individuals in the boxes in which thermostatically maintained 20oWith and have established a daily cycle of light/dark 12:12, and the rats were provided free access to feed and water. After placing in boxes, animals were left to acclimatize for at least 2 days before surgery. The experiments were approved by the Medical Ethical Committee for animal studies.

EXPERIMENTAL TECHNIQUE

FULL BETA-BLOCKERS

Rats were first anestesiologi in a cell halothane gas, then in the dorsal region of the left foot, between the second and third outer fingers were subcutaneously injected with 10 μl of PAF. Animals were then left to recover from anesthesia under the supervision over them in the cage.

CUFF FOR SCIATIC NERVE

Animals were prepared according to the method described Mosconi and Kruger (1996). Rats were anestesiologi intraperitoneally with a mixture of ketamine/xylazine (2 ml/kg) and p is englih muscles were prepared separately using a needle to release the sciatic nerve, around which were placed a plastic cuff (tube D 60, length 2 mm). The wound was then sutured in two layers with 3-0 wikilove and silk suture materials.

DETERMINATION OF THE MECHANICAL AND ALLODYNIA USING TEST VON FREY

The test was carried out between 08:00 and 16:00 hours, using the method described by Chaplan et al. (1994). Rats were placed in cages made of plexiglass on top of the base of wire mesh, which provided access to the foot, and left for addiction 10-15 minutes the Test area was sredneplastichnye part of the left rear legs, thereby avoiding the use of less sensitive pads of the feet. Paw touched the hairs from the group of 8 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, III, USA). Hair von Frey applied from below the mesh floor perpendicular to the plantar surface with a force sufficient to cause the weak curl of hair on legs, and this effort was supported for about 6-8 seconds. A positive response was noted when the paw was abruptly dragged aside. Wince immediately after the removal of hair is also considered as a positive response. Moving rats was seen as unclear receational day 1 for PAF-treated group and at postoperative day 7 for the group with the cuff of the sciatic nerve. the 50% threshold straightening was determined using the method of Dixon up-down" (1980). The test started with hair 2,04 g, average in the series. Stimulation was always performed consistently regardless of whether they were increasing or decreasing. In the absence of the reaction of otdergivanija paws on the originally selected hair gave a stronger incentive; in the case of straightening the legs have selected the following, weaker stimulus. The calculation of the optimal threshold in this way requires 6 responses in the immediate vicinity of the 50% threshold, and counting these 6 responses started, when was the first change in response, for example, when the threshold was first crossed. In cases where the thresholds were outside stimuli, were assessed value 25,14 (normal sensitivity) or 0,41 (maximum allodynia), respectively. The results of positive and negative responses were presented in tables 1 and 2 using the standard method, X=without otdergivanija, 0= OTDELENIE, and 50% threshold otdergivanija was interpolable using the formula:

the 50% threshold, g=10(XF series+kd)/10000,

where xf is the value of the last used volume vo is eacci and d - the average difference between the stimuli (log-units). Here d=0,224.

Thresholds von Frey were converted into a percentage of the maximum possible effect (% PHE) by Chaplan et al., 1994. To calculate % PHE was using the following equation:

< / BR>
THE INTRODUCTION OF THE TEST SUBSTANCE

Rats were administered by injection (subcutaneously, intraperitoneally or administered orally) test connection to test according to the method of von Frey, the time between the introduction of the test compounds and test according to the method of von Frey varied depending on the nature of the test compounds.

The following abbreviations have the following values:

Ac = acetyl

AG = aryl

t-BOC = tertiary butoxycarbonyl

t-Bu =tertiary butyl

Et = ethyl

iPr = isopropyl

Me = methyl

Ph = phenyl

WG = cut

r.t = room temperature

TFU = triperoxonane acid

THF = tetrahydrofuran

TMEDA = N,N,N, N'-tetramethylethylenediamine

1. Derivatives of piperidine derivatives of General formula I

< / BR>
where R1selected from hydrogen, branched or unbranched C1-C6-alkyl, C2-C6-alkenyl, C3-C8-cycloalkyl, C4-C8-(alkylcyclohexane), where alkyl is C1- is>-alkyl)-(C6-C10-aryl, where the aryl may be substituted by 1 or 2 substituents selected from CH3, OR5or halogen, where R5represents C1-C6-alkyl, (C1-C2-alkyl) heteroaryl, and the heteroaryl portion has 5 to 10 atoms selected from C, S, N and O; groups

< / BR>
where R18and R19represent hydrogen, C1-C6-alkyl; groups

< / BR>
and

< / BR>
R2and R3represent hydrogen;

And choose from

< / BR>
< / BR>
< / BR>
where R8, R9and R12represent hydrogen or C1-C6-alkyl;

R13represents C1-C6-alkyl or C1-C6-alkoxyl;

Z1and Z2represent hydrogen;

Q represents a 5 - or 6-teleny a heterocycle containing, as heteroatom O and/or N;

In represents C6-C10-aryl or C5-C10-heteroaryl containing as heteroatoms of S, N or O, and aryl may be substituted by 1 or 2 substituents selected from CH3, CF3, NO2, halogen, HE, COR4, NR4R5THE CO3or S3where R4and R5represent hydrogen or C1-C6-alkyl,

or their pharmaceutical

where R8, R9and R12represent hydrogen or C1-C6-alkyl;

R13represents C1-C6-alkyl or C1-C6-alkoxyl;

Z1and Z2represent hydrogen;

Q is chosen from the research, piperidine and pyrrolidine,

R1selected from hydrogen, branched or unbranched1-C4-alkyl, C3-C5-cycloalkyl, C4-C8-(alkylcyclohexane), where alkyl is C1-C2-alkyl and cycloalkyl represents C3-C6-cycloalkyl; C6-C10-aryl, (C1-C2-alkyl)-(C6-C10-aryl, where the aryl may be substituted by 1 or 2 substituents selected from CH3, OR5or halogen, where R represents a C1-C6-alkyl;

Choose from phenyl, naphthyl, benzofuranyl, chinoline, thiophenyl, and the phenyl or naphthyl may be substituted by 1 or 2 substituents selected from CH3, CF3, NO2HE, halogen, COR4, NR4R5THE CO3or S3where R4and R5represent hydrogen or C1-C6-alkyl.

3. The compound of formula I on p. 2, where a represents the

< / BR>
where R8and R9predstavlen2-CH-CH2, -CH2-cyclopropyl, -CH2-aryl;

Choose from phenyl, naphthyl, benzofuranyl, chinoline, thiophenyl, and the phenyl or naphthyl may be substituted by 1 or 2 substituents selected from CH3, CF3, NO2, halogen, COR4, NR4R5THE CO3or S3where R4and R5represent hydrogen or C1-C6-alkyl.

4. The compound of formula I under item 1, which is (see graphic part).

5. Connection on p. 1, which is chosen from:

< / BR>
and

< / BR>
6. The compound according to any one of the preceding paragraphs in the form of his cleaners containing hydrochloride, sulfate, tartrate or citrate salt.

7. Pharmaceutical composition having analgesic activity, comprising a compound of formula I under item 1 as an active ingredient together with a pharmacologically and pharmaceutically acceptable carrier.

8. The method of obtaining compounds of formula I on p. 1, including:

a) interaction of the ketone of the formula I

< / BR>
where R1, R2and R3are specified in paragraph 1 values and where R1can also be tert-butoxycarbonyl;

X represents a leaving group,

with metalloorganic represent metal-containing group,

in the presence of, if necessary, solvent to obtain compounds of formula h

< / BR>
where a, b, R1, R2and R3are specified in paragraph 1 values and where R1can also be tert-butoxycarbonyl;

b) dehydration of the compounds of formula h with obtaining the compounds of formula I under item 1.

9. The compound of the formula h

< / BR>
where a, b, R2and R3are specified in paragraph 1 values;

Vos denotes tert-butoxycarbonyl.

10. The compound of the formula h on p. 9, where it is

< / BR>
where R8and R9represent ethyl;

and Z1and Z2represent hydrogen.

11. Connection on p. 10, which represents (see graphic part).

Priority points and features:

20.12.1996 on PP. 1-3, 6-10, when R1, R2, R3, R4, R5, R8, R9, R12, R13, R18, R19, A, B, Z1Z2have the specified values, except when R1group:

< / BR>
and

< / BR>
except when In-aryl, which is substituted by 1 or 2 substituents selected from NR2or S3; thiophenyl; except when the a - team:

< / BR>
p. 4 for the first 22 of the texts in this paragraph;

09.12.1997 (on the date of filing of the international application) - PP. 1-3, 6-10, when R1group:

< / BR>
and

< / BR>
when In - aryl, which is substituted by 1 or 2 substituents selected from the NO2or S3; when A - team:

< / BR>
p. 4 for connection 23-33, 36-60 in the course of their statement in this paragraph, p. 5.

 

Same patents:

The invention relates to trehzameshchenny phenyl derivative of the General formula (1) in which Y represents a group or SIG1where R1represents a C1-C6alkyl group, optionally substituted by up to three halogen atoms; R2represents a C1-C6alkyl or C3-C8cycloalkyl provided that Y and-OR2are not both methoxypropane; R3represents a hydrogen atom or a hydroxy-group; R4and R5that may be the same or different, represent a group -(CH2)nAr, where n = 0 or 1 and Ar is a phenyl or heteroaryl group containing one or two 5 - and/or 6-membered ring containing up to three heteroatoms selected from oxygen, sulfur and nitrogen, where Ar is optionally substituted with halogen, C1-C6the alkyl, C1-C6hydroxyalkyl,1-C6alkoxy, C1-C6alkoxy-C1-C6the alkyl, C1-C6halogenation, amino,

di-(C1-C6)alkylamino-C1-C6by alkyl, hydroxyl, formyl, carboxyla,1-C6alkoxycarbonyl,1-C6alkanoyloxy, thiol, carboxamido,1-C6alkanolamine,

The invention relates to new piperidine derivative of the formula I, where R1means sensational, benzofuranyl, naphthyl which may be substituted with halogen, C1-C6-alkyl, C1-C6-alkoxygroup, substituted thienyl or substituted furanyl, which is substituted by halogen, C1-C6-alkyl, C3-C6-cycloalkyl or1-C6-alkenyl, R2means halogen and R3means1-C6-alkyl or C3-C6-cycloalkenyl, or their pharmaceutically acceptable salt, or solvate

The invention relates to new derivatives benzoylpyridine General formula (I), where R1means alkyl with 1-8 carbon atoms, a represents a group represented by the formula of the invention, means (-CH2-)aor (-CO-)band means an integer of 0 to 8, preferably 1, 2, 3 or 4, b means of 0,1 or 2, preferably 1, R2means unsubstituted or substituted alkyl with 1-8 carbon atoms, unsubstituted phenyl, NR3R4or preferably the five-membered heterocycle represented in the claims, in which U, V, W, X and Z can mean CH, NH, O or S, R3and R4denote alkyl with 1-8 carbon atoms

The invention relates to new Bermatingen compounds, the United propylenebis communication, General formula I where Ar represents a radical of formula (a) or (b), R1is-OR6or-COR7, R2represents a polyether radical, comprising 1 to 6 carbon atoms and 1 to 3 atoms of oxygen or sulfur, and if in the latter case, R4represents a linear or branched C1-C20alkyl, he is in ortho - or meta-position relative to X-Ar connection, R3represents lower alkyl, or R2or R3taken together form a 6-membered ring, optionally substituted by at least one of the stands and/or optional split the atom of oxygen or sulfur, R4represents H, linear or branched C1-C20alkyl or aryl, R5represents H or-OR8, R6represents H, R7represents H, -OR10or-N(r)r (r) r are H, lower alkyl or taken together with the nitrogen atom form a ring of morpholino, R8represents H or lower alkyl, R10represents H, linear or branched C1-C20alkyl, X represents a divalent radical, which is from right to left or Vice versa has the formula (d), R11Fri carboxylic acid and the optical and geometrical isomers of the above compounds of formula (I)

The invention relates to the derivatives of thiophene of the General formula I, in which R1is the formula A1- X1- R3; R2is perhaps the formula A2- X2- R4; ring b is 4-10-membered nitrogen-containing cycloalkyl ring or 5 - or 6-membered nitrogen-containing unsaturated heterocycle; Ar represents an aryl ring or heteroaryl ring; A1, A2and A3may be the same or different and each represents a bond or lower alkylenes group; X1and X2may be the same or different and each represents a bond or a formula-O-, -S-; R3and R4may be the same or different, and each represents a hydrogen atom, cyclic aminogroup or a lower alkyl group, aryl group or aracelio group, or its pharmaceutically acceptable salt

The invention relates to new derivatives of chloropyridinyl formula I where Het is a group of formula a, b, C, d or e, R1is hydrogen, unsubstituted or substituted C1- C6alkyl, and the substituents selected from the group comprising halogen, phenyl, cyano, C1- C4alkoxy, C1- C4alkylthio,1- C4alkylsulphonyl; C2- C4alkenyl, unsubstituted or substituted C1- C4alkoxygroup; phenyl or unsubstituted or substituted 1 or 21- C4alkoxygroup, n = 1 or 2, and their acid additive salts

The invention relates to new N-substituted azaheterocyclic carboxylic acids f-crystals (I) or their salts, in which R1and R2independently represent a hydrogen atom, halogen atom, trifluoromethyl, C1-C6-alkyl or C1-C6-alkoxy: Y is the grouporin which only the underlined atom participates in the cyclic system; X is a group-O-, -S-, -CR7R8, -CH2-CH2-, -CH=CH-CH2-, -CH2-CH=CH-, -CH2CH2CH2-, -CH=CH-, -NR9-(C= O)-, -O-CH2-, -(C= O)- or -(S=O)-, where R7, R8and R9independently represent a hydrogen atom or a C1-C6-alkyl; z = 1, 2, or 3; m = 1 or 2, n = 1 when m = 1 and n = 0 when m = 2; R4and R5each represents a hydrogen atom or, when m = 2, can both work together to develop a bond; R6is hydroxyl or C1-C8-alkoxygroup, or its pharmaceutically acceptable salt, provided that is not included compound 10-(3-(3-carbomethoxy-1-piperidyl) propyl) phenothiazines and 10-(3-(3-carborexics-1-piperidyl) propyl) phenothiazines

The invention relates to new derivatives of 1-[2-(substituted vinyl)]-5H-2,3-benzodiazepine, method of production thereof, pharmaceutical composition, method thereof and method of treating diseases of the Central nervous system

The invention relates to a new use of derivatives of imidazole, to new derivatives of imidazole, the way they are received, to the new obtained intermediate products and to pharmaceutical compositions based on derivatives of imidazole

The invention relates to new derivatives of 4-hydroxypiperidine formula I

< / BR>
where X represents-O-, -NH-, -CH2-, -CH=, -SNON - or-CO-; R1-R4independently from each other denote hydrogen, a hydroxy-group, (lower) alkylsulfonyl or acetaminoph; R5-R8independently from each other denote hydrogen, a hydroxy-group, (lower)alkyl, halogen, (lower)alkoxygroup, trifluoromethyl or cryptometrics; a and b may denote a double bond, provided that when a represents a double bond, b is unable to designate a double bond; n = 0-2; m = 1-3; p = 0 or 1, and their pharmaceutically acceptable additive salts

The invention relates to new piperidine derivative of the formula I, where R1means sensational, benzofuranyl, naphthyl which may be substituted with halogen, C1-C6-alkyl, C1-C6-alkoxygroup, substituted thienyl or substituted furanyl, which is substituted by halogen, C1-C6-alkyl, C3-C6-cycloalkyl or1-C6-alkenyl, R2means halogen and R3means1-C6-alkyl or C3-C6-cycloalkenyl, or their pharmaceutically acceptable salt, or solvate

The invention relates to new derivatives of 2- (iminomethyl) aminobenzoyl General formula (I) where a represents either a radical represented by the formula of the invention in which R1and R2denote, independently, a hydrogen atom, a group HE, a linear or branched alkyl or alkoxy having from 1 to 6 carbon atoms, R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4, R4means a linear or branched alkyl with 1-6 carbon atoms, or radicals represented by the formula of the invention, R5means a hydrogen atom, a group HE or linear or branched alkyl or alkoxy with 1-6 carbon atoms, means thienyl, X means Z1-, -Z1-CO-, -Z1-NR3-CO, -CH=CH-CO - or a simple bond, Y represents a radical chosen from the radicals Z2-Q, piperazinil, homopiperazine, -NR3-CO-Z2-Q-, -NR3-O-Z2-, -O-Z2Q-in which Q means a simple bond, -O-Z3and-N(R3)-Z3-, Z1, Z2and Z3means independently a simple link or a linear or branched alkylene with 1-6 carbon atoms, preferably Z1, Z2and Z3means -(CH2)m-, and m is an integer, R

The invention relates to new derivatives benzoylpyridine General formula (I), where R1means alkyl with 1-8 carbon atoms, a represents a group represented by the formula of the invention, means (-CH2-)aor (-CO-)band means an integer of 0 to 8, preferably 1, 2, 3 or 4, b means of 0,1 or 2, preferably 1, R2means unsubstituted or substituted alkyl with 1-8 carbon atoms, unsubstituted phenyl, NR3R4or preferably the five-membered heterocycle represented in the claims, in which U, V, W, X and Z can mean CH, NH, O or S, R3and R4denote alkyl with 1-8 carbon atoms

The invention relates to new Bermatingen compounds, the United propylenebis communication, General formula I where Ar represents a radical of formula (a) or (b), R1is-OR6or-COR7, R2represents a polyether radical, comprising 1 to 6 carbon atoms and 1 to 3 atoms of oxygen or sulfur, and if in the latter case, R4represents a linear or branched C1-C20alkyl, he is in ortho - or meta-position relative to X-Ar connection, R3represents lower alkyl, or R2or R3taken together form a 6-membered ring, optionally substituted by at least one of the stands and/or optional split the atom of oxygen or sulfur, R4represents H, linear or branched C1-C20alkyl or aryl, R5represents H or-OR8, R6represents H, R7represents H, -OR10or-N(r)r (r) r are H, lower alkyl or taken together with the nitrogen atom form a ring of morpholino, R8represents H or lower alkyl, R10represents H, linear or branched C1-C20alkyl, X represents a divalent radical, which is from right to left or Vice versa has the formula (d), R11Fri carboxylic acid and the optical and geometrical isomers of the above compounds of formula (I)

The invention relates to pharmaceutical compositions containing two or more compounds having anti-HIV activity
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