Compounds n, n-substituted cyclic amine

 

The present invention relates to compounds N,N-substituted cyclic amine of formula (VIII)

in which a represents aryl group; E represents a group represented by the formula-CO-or a group represented by the formula

-SNON-; G represents an oxygen atom, sulfur or the group-NR10-; J represents an aryl group which may be substituted; R1represents a lower alkyl group; Alk is unbranched or branched lower alkylenes group; n, v, w, x and y are independent from each other and each represents 0 or 1, and p is 2 or 3, or their pharmacologically acceptable salts. Compounds of the present invention or their salts are effective for the treatment of diseases against which effective antagonism in relation to calcium. These diseases can include acute ischemic stroke, cerebral apoplexy, cerebral infarction, head injury, loss of cerebral nerve cells, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral circulatory metabolism, disturbance of cerebral function, pain, spasm, schizophrenia, m is, complications of type of dementia in AIDS, swelling, disruption of the type of anxiety (generalized type violation anxiety) and diabetic neuropathy. Also described pharmaceutical composition based compounds (VIII). 8 N., and 6 C.p. f-crystals, 8 ill., 7 table.

Industrial scope

This invention relates to new compounds N,N-substituted cyclic amine, which can be used as a calcium antagonist, particularly as selective in relation to the nerves of the calcium antagonist, specifically as an agent for the treatment and improvement of diseases against which effectively inhibitory effect on calcium channels P/Q-type or inhibitory effect on calcium channels, N-type, more specifically as an agent for inhibiting neuronal cell death or for the protection of cerebral nerve cells and more specifically as an agent for the treatment and improvement in nervous diseases and very specifically as an agent for prevention, treatment or improvement in acute ischemic stroke, cerebral apoplexy, cerebral infarction, head injury, death cerebral nerve is against cerebral circulatory metabolism, the disturbance of cerebral function, pain, spasm, schizophrenia, migraine, epilepsy, manic-depressive psychosis, nerve degenerative diseases, cerebral ischemia, complications of type of dementia in AIDS, swelling, violation type anxiety (generalized type violation anxiety) and diabetic neuropathy.

Prior art

In Japan, the number of patients with cerebral apoplexy is approximately 1.4 million or more a year, and it is estimated that the medical costs for this are approximately two billion yen. Cerebral apoplexy is the second cause of death after malignant tumors and is the main cause of the condition is bedridden human disease, often suffering from severe recurrent disease. The key to treatment of cerebral apoplexy are measures taken at the acute stage, and treatment in the acute stage affects the patient's life and functional prognosis for the patient and significantly affects the same disease again.

For the purpose of improving blood circulation in the currently approved or are not prohibited several drugs, such as ozagrel sodium (s arterial occlusion, t-PA (alteplase: tissue activator of plasminogen, which should be used within 3 hours after the start) as a thrombolytic agent, etc.

In the treatment of these drugs requires the following advanced techniques and careful assessment based on adequate knowledge and experience of a medical professional.

(1) In the case of cerebral infarction type of blood clot is first made by the respiratory regulation, regulation of blood pressure and the regulation of blood transfusion.

(2) Periodically measure the gas content in blood and blood pressure.

(3) In the acute stage monitor changing high blood pressure, but if you do not see complications in heart and kidney, treatment to lower blood pressure is not performed.

(4) Then, in the case of early acute stage without low range of absorption, the observed CT (computed tomography), use of thrombolytic agent “urokinase”.

(5) In the case in which these agents are not suitable, or when 24 hours or more has passed after the start, enter ozagrel sodium or enter argatroban. However, argatroban not suitable for heart attack gaps.

(6) to prevent the development of cerebral edema when fitting ispolzuemykh still, unsatisfactory and, in addition, there is a danger that their pharmacological effect often may be accompanied by bleeding.

Accordingly, there is a problem, which consists in the fact that it is difficult for anyone except specialists in the medical field, the use of these medicines.

In the Japan patent JP 62-167762 (EP 229623), JP 2-506694 (WO 90/13539), the German patent DE 4404249, the Japan patent JP 10-95758-A (EP 805147), etc. are described compounds containing compound is piperazine, which are entirely different in structure from the compounds of the number of N,N-substituted cyclic amines of the present invention.

Description of the invention

The authors of this invention have discovered a very safe drug, does not cause bleeding and providing excellent effect in the treatment and improvement in acute ischemic stroke, against which were not developed valuable medicines, and the inventors have focused on selective for the nerves, the antagonist of voltage-dependent calcium channels, which act directly on nerve cells, preventing the development of heart attack, and after that, the inventors conducted extensive research is Ilichevsky amines, having the following formula, or their pharmacologically acceptable salts have an excellent effect on the inhibition of neuronal cell death and protection of cerebral nerve cells, based on the inhibitory effect on calcium channels of type P/Q or calcium channels, N-type high security other medicines and can solve the problems described above, and the invention thereby has been completed.

Further, the invention is described in detail. Connection of a number of N,N-substituted cyclic amines (VIII) of this invention represented by the following formula:

where a represents an aryl group which may be substituted, a heteroaryl group which may be substituted, aracelio group which may be substituted, or heteroallyl group which may be substituted;

E represents a group represented by the formula-CO-, or a group represented by formula-NON-;

G represents an oxygen atom, a sulfur atom and a group represented by the formula-NR10- (where R10represents a hydrogen atom, a lower alkyl group, lower cycloalkyl group, a lower acyl group or a lower alkylsulfonyl formula-DUS, the group represented by the formula-CONR11- (where R11represents a hydrogen atom or a lower alkyl group), a group represented by the formula-NR12CO- (where R12represents a hydrogen atom or a lower alkyl group), a group represented by the formula-SO-, a group represented by the formula-SO2-, a group represented by formula-SONR13- (where R13represents a hydrogen atom or a lower alkyl group), a group represented by the formula-NR14SO- (where R14represents a hydrogen atom or a lower alkyl group), a group represented by the formula-SO2NR15- (where R15represents a hydrogen atom or a lower alkyl group), a group represented by the formula-NR16SO2- (where R16represents a hydrogen atom or a lower alkyl group), a group represented by the formula >C=N-OR17-(where R17represents a hydrogen atom or a lower alkyl group), a group represented by formula-NHCONH-, a group represented by formula-NHCSNH-, a group represented by formula-C(=NH)NH-, a group represented by the formula-NHC(=NH)-, a group represented by formula-OCOS-, a group represented by formula-SCOO-, a group represented by formula-LLC-, a group represented FPU, represented by the formula-SNON - or a group represented by formula-SNON(CH2)sO- (where s is 0 or an integer from 1 to 6);

J represents an aryl group which may be substituted, or a heteroaryl group which may be substituted;

R1represents a hydrogen atom, a halogen atom, a hydroxy-group, a lower alkyl group, lower alkenylphenol group, lower alkylamino group, lower cycloalkyl group, a lower hydroxyalkyl group, a lower alkoxyalkyl group, lower cyanoaniline group, a halogenated lower alkyl group, optionally N-substituted lower aminoalkyl group, a group represented by the formula-NR18R19(where R18and R19may be the same or different from each other and each represents a hydrogen atom or a lower alkyl group), aracelio group, morpholinyl group, thiomorpholine group, piperidino group, pyrrolidinyl group or piperazinilnom group;

Alk is unbranched or branched lower alkylenes group and

n, v, w, x and y are independent of each other and each equal to 0 or 1 and p is 2 or 3.

The present invention includes a pharmacologically als substituted, are phenyl group, naftalina group, etc. or these groups optionally substituted with at least one of, for example, halogen atom, hydroxy-group, lower alkyl groups, lower alkoxygroup, lower alkoxycarbonyl group, a lower hydroxyalkyl group, a halogenated lower alkyl group, hydroxykynurenine group, ceanography, nitro, optionally N-substituted amino group, optionally N-substituted carbamoyl group optionally N-substituted sulfamoyl group, lower dialkoxy, lower acyl groups, aromatic acyl groups, and so on,

Specific examples of the heteroaryl group which may be substituted, are Peregrina group, piratininga group, pyrimidinyl group, pyrrolidine group, imidazolidinyl group, pyrazolidine group, kinolinna group, izochinolina group, chinadaily group, phthalazinone group, khinoksalinona group, indolenine group, furilla group, thienyl group, thiazolidine group, etc. or these groups, optionally substituted.

Specific examples aranceles group which may be substituted, are the lower alkyl group, a substituted Ari is PA, naphthylethylene group, afterproperties group and so on, or such a group having aryl group, optionally substituted.

Specific examples heteroallyl group which may be substituted, are the lower alkyl group, a substituted heteroaryl group, for example pyridylmethylene group, personalitly group, pyrimidinylidene group, peralynna group, imidazolylalkyl group, parasaissetia group, hanalilolilo group, izochinolina group, purpurella group, thienylmethyl group, triazolylmethyl group and so on, or such a group having a heteroaryl group, optionally substituted.

Specific examples of the halogen atom include fluorine atom, chlorine atom, bromine atom or iodine atom.

Specific examples of the lower alkyl group is unbranched or branched alkyl group having from 1 to 6 carbon atoms, such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, tert-bucilina group, n-pencilina group, isopentyl group, tert-pencilina group, neopentylene group, exilda group, etc.

Specific Primerose from 2 to 6 carbon atoms, such as vinyl group (CH2=CH-), 1-protanilla group (CH3-CH=CH-), allyl group (CH2=SNSN2-), isopropylene (CH2=C(CH3)- ), and so on,

Specific examples of the lower alkenylphenol groups are groups formed from unbranched or branched alkynes having from 2 to 6 carbon atoms, such as etinilnoy group, 1-proponila group, 2-proponila group, etc.

Specific examples of the lower cycloalkyl groups are cyclic alkyl groups having 3 to 8 carbon atoms, such as cyclopropyl group, cyclobutyl group, cyclopentenone group, tsiklogeksilnogo group, cycloheptyl group, cyclooctyl group, etc.

Specific examples of the lower hydroxyalkyl group include groups having one or more hydroxy groups associated with the above-mentioned lower alkyl group, such as hydroxymethylene group, hydroxyethylene group, 2,3-dihydroxypropyl group, etc.

Specific examples of the lower cyanoaniline groups are groups having one or more cyano groups associated with the above-mentioned lower alkyl group, such as cyanomethylene group, cyanoethylene group, qi is PI, with one or more halogen atoms which can be the same or different from each other, connected with the above-mentioned lower alkyl group, such as permetrina group, deformational group, triptorelin group, chloromethylene group, 1-florachilena group, 2-florachilena group, 1,1-deperately group, 1,2-deperately group, 2,2-deperately group, 2,2,2-triptorelin group, etc.

Specific examples of the lower alkoxygroup are groups having the above-mentioned alkyl group attached to an oxygen atom, especially unbranched or branched alkoxygroup, such as a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, tert-butoxypropan, pentyloxy, hexyloxy etc.

Specific examples of the lower acyl groups are unbranched or branched acyl group, formed from fatty acids having from 1 to 6 carbon atoms, such as formyl group, acetyl group, propylaniline group, Butyrina group, isobutylene group, valerina group, isovaleryl group, pivellina group, hexanoyl group, etc.

Specific primerenou group, the lower acyl group, a lower alkylsulfonyl group and so on, and included a case in which the nitrogen atom is part of a cyclic amine. Especially can be offered to the amino group (-NH2), methylaminopropyl (-N3), dimethylaminopropyl (-N(CH3)2), atramentaria (-NHC2H5), diethylaminopropyl (-N(C2H5)2), methylethylamine (-N(CH3)C2H5), acetaminophe (CH3N-), propionamide (C2H5CONH-), methanesulfonamide (CH3SO2NH-), acanaloniidae (C2H5SO2NH-), pyrrolidinyl group, piratininga group, piperideine group, piperazinilnom group, 4-morpholinyl group, 4-thiomorpholine group, etc.

Specific examples carbamoyl group which may be substituted, are carnemolla group, which may be N-substituted lower alkyl group, etc. and included a case in which the nitrogen atom is part of a cyclic amine. Especially can be offered carnemolla group (-CONH2), N-methylcarbamoyl group (N3), N,N-dimethylcarbamoyl group (-CON(CH3)2), N-ethylcarbazole group (-CONHC3)2H5), 1-pyrrolidinylcarbonyl group, 1-PIR polycarbosilane group, 1-piperidinylcarbonyl group, 1-piperazinylcarbonyl group, 4-morpholinylcarbonyl group, 4-dimorpholinyldiethyl group, etc.

Specific examples sulfamoyl group which may be substituted, are Altamarena group, which may be N-substituted lower alkyl group, etc. and included a case in which the nitrogen atom is part of a cyclic amine. Especially can be offered Altamarena group (-SO2NH2), N-methylsulfanyl group (-SO2NHCH3), N,N-dimethylsulphamoyl group (-SO2N(CH3)2), N-ethylsulfonyl group (-SO2NHC2H5), N,N-diethylcarbamoyl group (-SO2N(C2H5)2), N-methyl-N-ethylsulfonyl group (-SO2N(CH3)C2H5), 1-pyrrolidinyl-ponilina group, 1-pyrazolecarboxylate group, 1-PI-pyridylsulfonyl group, 1-piperazinylcarbonyl group, 4-morpholinylcarbonyl group, 4-timeoforiginalfailure group, etc.

Specific examples of the lower dialkoxy are groups having the above-mentioned lower sub> and so on

Specific examples of the lower alkalinous groups are divalent group formed from unbranched or branched alkane having from 1 to 6 carbon atoms such as a methylene group (-CH2-), ethylene group (-CH2CH2-), utilizinga group (-CH(CH3)-), trimethylene group (-CH2CH2CH2-), isopropylidene group (-C(CH3)2-), propylene group (-CH(CH3)CH2-), tetramethylene group (-CH2CH2CH2CH2-), 1,2-butylene group (-CH(C2H5)CH2-), 1,3-butylene group (-CH(CH3)CH2CH2-), 2,3-butylene group (-CH(CH3)CH(CH3)-), isobutilene group (-C(CH3)2CH2- ), etc. in Addition, the position of the link (right side or left side) of the asymmetric alkalinous group is not limited.

Specific examples of the lower alkoxycarbonyl groups are carbonyl groups substituted by the above lower alkoxygroup, such as methoxycarbonyl group, ethoxycarbonyl group, etc.

Specific examples of the lower dialkoxy are groups having the above-mentioned lower alkyl GMS examples of the lower alkylsulfonyl groups are groups with the above lower alkyl group associated with sulfonyloxy group, such as methanesulfonyl group, acanaloniidae group, propanesulfonyl group, etc.

When the group R20or group, R21the structural formulas below, are connected to each other to form alicyclic ring, specific examples of this group are alicyclic condensed phenyl group, such as indayla group, tetralinyl group and so forth, or the group in which alicyclic group or a phenyl group optionally substituted.

When the group R20or group, R21are connected to each other with the formation of the heterocycle, specific examples of this series are a heterocycle condensed with a phenyl group, such as benzofuranyl group, chromadorina group, thrombilia group, indolinyl group, isoindolyl group, tetrahydropyridine group, tetrahydroisoquinoline group or groups in which a heterocycle or phenyl group optionally substituted.

When the group R20or group, R21contact each other to form alkylenedioxy, specific examples of the group having alwaysa additionally.

Here, specific examples of the aryl group which may be substituted, are a phenyl group, naftalina group, etc. or a group having these groups, optionally substituted.

Specific examples of the heteroaryl group which may be substituted, are Peregrina group, piratininga group, pyrimidinyl group, pyrrolidine group, imidazolidinyl group, pyrazolidine group, kinolinna group, izochinolina group, chinadaily group, phthalazinone group, khinoksalinona group, indolenine group, furilla group, thienyl group, thiazolidine group, etc. or a group having these groups, optionally substituted.

Specific examples aranceles group which may be substituted, are the lower alkyl group, a substituted aryl group such as benzyl group, penicilina group, phenylpropionate group, naphthylmethyl group, naphthylethylene group, afterproperties group, etc. or a group having the aryl group, optionally substituted.

Specific examples heteroallyl group which may be substituted, are the lower alkyl group, a substituted heteroaryl group, for example pyridiniomethyl group, parasaissetia group, hanalilolilo group, izochinolina group, purpurella group, thienylmethyl group, triazolylmethyl group and so on, or groups having the specified heteroaryl group, optionally substituted.

Specific examples of the lower alkyl groups are C1-C6is an alkyl group such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, tert-bucilina group, pencilina group, exilda group, etc.

Specific examples of the lower cycloalkyl groups are3-C8-cycloalkyl group, such as cyclopropyl group, cyclobutyl group, cyclopentenone group, tsiklogeksilnogo group, cycloheptyl group, cyclooctyl group, etc.

Specific examples of the halogen atom are a fluorine atom, chlorine atom, bromine atom or iodine atom.

Specific examples of the lower alkoxygroup is a group having the above-mentioned lower alkyl group linked to the oxygen atom, such as methoxy group, ethoxypropan, propoxylate etc.

Specific examples of the amino group which may be substituted, are the amino group of filamentgroup, atramentaria, dimethylaminopropyl, diethylaminopropyl, methylaminopropyl etc.

Specific examples of the lower alkoxycarbonyl group is a carbonyl group substituted by the above lower alkoxygroup, such as methoxycarbonyl group, ethoxycarbonyl group, etc.

Specific examples of the lower dialkoxy are the group that has the above-mentioned lower alkyl group, associated with the sulfur atom, such as methylthiourea, ethylthiourea, PropertyGroup etc.

Specific examples of the lower alkylsulfonyl group is a group having the above-mentioned lower alkyl group associated with sulfonyloxy group, such as methanesulfonyl group, acanaloniidae group, propanesulfonyl group, etc.

Specific examples of the lower acyl group is a group having the above-mentioned lower alkyl group, bonded to the carbonyl group such as acetyl group, propylaniline group, motirola group, etc.

The present invention includes as an embodiment of the connection of a number of N,N-substituted cyclic amine (I), represented by the following formula (I):

where a representation is the function group, which may be substituted, or heteroallyl group which may be substituted;

E represents a group represented by the formula-CO - or a group represented by formula-NON-;

G represents an oxygen atom, a sulfur atom and a group represented by the formula-NR10- (where R10represents a hydrogen atom, a lower alkyl group, a lower acyl group or a lower alkylsulfonyl group), a group represented by the formula-CO-, a group represented by the formula-COO-, a group represented by formula-OOS-, a group represented by the formula-CONR11- (where R11represents a hydrogen atom or a lower alkyl group), a group represented by the formula-NR12CO- (where R12represents a hydrogen atom or a lower alkyl group), a group represented by the formula-SO-, a group represented by the formula-SO2-, a group represented by formula-SONR13- (where R13represents a hydrogen atom or a lower alkyl group), a group represented by the formula-NR14SO- (where R14represents a hydrogen atom or a lower alkyl group), a group represented by the formula-SO2NR15- (where R15represents a hydrogen atom or a lower alkyl group), a group of ESCs), the group represented by the formula >C=N-OR17- (where R17represents a hydrogen atom or a lower alkyl group), a group represented by formula-NHCONH-, a group represented by formula-NHCSNH-, a group represented by formula-C(=NH)NH-, a group represented by the formula-NHC(=NH)-, a group represented by formula-OCOS-, a group represented by formula-SCOO-, a group represented by formula-LLC-, a group represented by formula-NHCOO-, a group represented by formula-OCONH-, group, represented by the formula-CO(CH2)sO-, a group represented by formula-SNON - or a group represented by formula-SNON(CH2)sO- (where s is 0 or an integer from 1 to 6);

J represents an aryl group which may be substituted, or a heteroaryl group which may be substituted;

R1represents a lower alkyl group, lower cycloalkyl group, a group represented by the formula-NR18R19(where R18and R19may be the same or different from each other and each represents a hydrogen atom or a lower alkyl group), morpholinyl group, thiomorpholine group, piperidino group, pyrrolidinyl group or piperazinilnom group;

R2, R3

m, o, q and r may be the same or different from each other and each is 0 or an integer from 1 to 6, n is 0 or 1 and p is 2 or 3.

Then, the invention includes as an embodiment of the compound N,N-substituted cyclic amine (II), represented by the following formula (II):

where a, E, G, J, R1, m, n, o, p, q and r have the same meanings as defined above.

Then, the invention includes as an embodiment of the compound N,N-substituted cyclic amine (III), represented by the following formula (III):

where A, G, J, R1, m, p and q have the same meanings as defined above.

Finally, the invention includes as an embodiment of the compound N,N-substituted cyclic amine (IV), represented by the following formula (IV):

where R1, m, p and q have the same meanings as defined above.

R20and R21are the same or different from each other and each represents a hydrogen atom, a halogen atom, a hydroxy-group, mercaptopropyl, a lower alkyl group, lower alkoxygroup, hydroxymethylene group, a nitrogroup, an amino group which may be substituted, lanagro the optimum group, the lower acyl group, a halogenated lower alkyl group, aryl group which may be substituted, a heteroaryl group which may be substituted, alloctype, aralkylated, lower alkoxycarbonylmethyl or lower hydroxyalkoxy group and R20or group, R21can form an alicyclic group which may be substituted, or a heterocyclic group, or alkylenedioxy, which may be substituted, and

j and t can be the same or different from each other and each is 0 or an integer from 1 to 5.

Compounds N,N-substituted cyclic amines (VIII) and (I) to (IV) of the present invention contain 1 or more asymmetric carbon atoms in the molecule, so that can be their optical isomers or meso-forms, but the invention is not limited and includes any of the optical isomers of meso-form and the racemate. In addition, they include not only anhydrides, but also hydrates and polymorphs.

When obtaining optically active compounds for asymmetric synthesis can be used optically active starting materials or the racemates can be divided into optical isomers column chromatography or forming compounds of the number of N,N-substituted cyclic amines (VIII) and (I) to (IV) of the present invention, specific examples are inorganic acid additive salts such as hydrochloride, sulfate, nitrate, Hydrobromic, hydroiodic, perchlorate, phosphate, etc. and organic acid additive salts such as oxalate, maleate, fumarate, succinate, etc., additive salts with sulfonic acids such as methanesulfonate, aconsultant, bansilalpet, p-toluensulfonate, camphorsulfonate, and additive salts with amino acids, among these preferred salts hydrochloride and oxalate.

More specific examples of the compounds N,N-substituted amine (VIII) and (I) to (IV) of the present invention include the following compounds, which should not be construed as limitations of this invention:

(1) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(2) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[3-(4-pertenece)propyl]piperazine

(3) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-pertenece)ethyl]homopiperazin

(4) 1-[(3-cyano-4-methyl-3-phenyl)pentyl]-4-[2-(4-pertenece)ethyl]homopiperazin

(5) 1-[(3-cyano-4-methyl-3-phenyl)pentyl]-4-[3-(4-pertenece)propyl]piperazine

(6) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(4-phenoxybutyl)piperazine

(7) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-phenoxyethyl)piperazine

(8) 1-[(4-cyan is phenoxy)ethyl]piperazine

(10) 1-[4-cyano-5-methyl-4-(4-chlorophenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(11) 1-[4-cyano-5-methyl-4-(4-methoxyphenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(12) 1-[4-cyano-5-methyl-4-(4-carbomethoxybiphenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(13) 1-[4-cyano-5-methyl-4-(4-hydroxymethylene)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(14) 1-[4-cyano-5-methyl-4-(4-hydroxyaminobuteroyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(15) 1-[4-cyano-5-methyl-4-(4-cyanophenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(16) 1-[4-cyano-5-methyl-4-(4-nitrophenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(17) 1-[4-cyano-5-methyl-4-(4-AMINOPHENYL)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(18) 1-[4-cyano-5-methyl-4-(4-acetamidophenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(19) 1-[4-cyano-5-methyl-4-(4-dimethylaminophenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(20) 1-{[4-cyano-5-methyl-4-(2-thienyl)hexyl]}-4-[2-(4-pertenece) ethyl]piperazine

(21) 1-{[4-cyano-5-methyl-4-(3-pyridyl)hexyl]}-4-[2-(4-pertenece)ethyl]piperazine

(22) 1-{[4-cyano-5-methyl-4-(2-forfinal)hexyl]}-4-[2-(4-pertenece)ethyl]piperazine

(23) 1-{[4-cyano-5-methyl-4-(3-forfinal)hexyl]}-4-[2-(4-pertenece)ethyl]piperazine

(24) 1-{[4-cyano-5-methyl-4-(4-forfinal)hexyl]}-4-[2-(4-pertenece)ethyl]piperazine

(25) 1-[)ethyl]piperazine

(27) 1-[(4-cyano-4-phenyl)heptyl]-4-[2-(4-pertenece)ethyl]piperazine

(28) 1-[(4-cyano-4-phenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(29) 1-[(4-cyano-4-phenyl)octyl]-4-[2-(4-pertenece)ethyl]piperazin

(30) 1-[(4-cyano-6-methyl-4-phenyl)heptyl]-4-[2-(4-pertenece)ethyl]piperazine

(31) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-pertenece)ethyl]piperazine

(32) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-pertenece)ethyl]piperazine

(33) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[3-(4-pertenece)pentyl]piperazine

(34) 1-[(4-cyano-5-methyl-4-phenyl)heptyl]-4-[3-(4-pertenece)ethyl]piperazine

(35) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3,4-divergence)ethyl]piperazine

(36) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-chlorophenoxy)ethyl]piperazine

(37) 1-{[(4-cyano-5-methyl-4-(3,4-dichlorophenyl)hexyl]}-4-[2-(4-pertenece)ethyl]piperazine

(38) 1-[(4-cyano-4-cyclohexyl-4-phenyl)butyl]-4-[2-(4-pertenece)ethyl]piperazine

(39) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-methoxyphenoxy)ethyl]piperazine

(40) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2,3-dimethoxyphenoxy)ethyl]piperazine

(41) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3,4-dimethoxyphenoxy)ethyl]piperazine

(42) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-aminophenoxy)ethyl]piperazine

(43) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-dimethylaminophenol is IANA-5-methyl-4-phenyl)hexyl]-4-[2-(4-methylthiophene)ethyl]piperazine

(46) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-cianfrocca)ethyl]piperazine

(47) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-cianfrocca)ethyl]piperazine

(48) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(benzyloxy)ethyl]piperazine

(49) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-forfinally)ethyl]piperazine

(50) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-perpenicular)ethyl]piperazine

(51) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-forgenerating)ethyl]piperazine

(52) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-forfinal)-N-methylamino]ethyl}piperazine

(53) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-forfinal)-N-acetylamino]ethyl}piperazine

(54) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-forfinal)-N-methanesulfonamido]ethyl}piperazine

(55) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(benzylamino)ethyl]piperazine

(56) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-acetyl-N-benzylamino)ethyl]piperazine

(57) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-methanesulfonyl-N-benzylamino)ethyl]piperazine

(58) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-benzyl-N-isopropylamino)ethyl]piperazine

(59) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-perbenzoic)ethyl]piperazine

(60) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[3-hydroxy-3-(4-forfinal)propyl]piperazine

(61) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-erasin

(63) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-ftorpolimernoj)ethyl]piperazine

(64) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-perbenzoate)ethyl]piperazine

(65) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[N-(4-forfinal)carbamoylmethyl] piperazine

(66) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-forbindelseshandtering)ethyl]piperazine

(67) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-forfinal)sulfamoyl]ethyl}piperazine

(68) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-forfinal)-N-methylcarbamoyl]ethyl}piperazine

(69) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-[N-methyl-4-forbindelseshandtering)ethyl]piperazine

(70) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[(4-forfinally)carbonyloxy]ethyl}piperazine

(71) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-pyridyloxy]ethyl]piperazine

(72) 1-(3-cyclohexyl-3-cyano-3-phenyl)propionyl 4-[2-(4-pertenece)ethyl]piperazine

(73) 1-(2-hydroxy-4-cyano-5-methyl-4-phenyl)hexyl-4-[2-(4-pertenece)ethyl]piperazine

(74) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-benzoylperoxy)ethyl]piperazine

(75) 1-[(4-cyano-5-hydroxy-5-methyl-4-phenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(76) 1-[5-(4-cyano-5-methyl-4-phenyl)hexenyl]-4-[2-(4-pertenece)ethyl]piperazine

(77) 1-[4-cyano-5-methyl-4-(4-hydroxyphenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperonyl)butyl]-4-[2-(4-pertenece)ethyl]piperazine

(80) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-ethoxycarbonylmethoxy-4-pertenece)ethyl]piperazine

(81) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-hydroxyethoxy-4-pertenece)ethyl]piperazine

(82) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-methoxy-4-pertenece)ethyl]piperazine

(83) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-isopropylaniline)ethyl]piperazine

(84) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-cyclohexylaniline)ethyl]piperazine

(85) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl-(4-isopropylaniline)ethyl]}piperazine

(86) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl-(3-isopropylaniline)ethyl]}piperazine

(87) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl-(2-isopropylaniline)ethyl]}piperazine

(88) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3,4-(methylendioxy)phenoxy]ethyl}piperazine

(89) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(6-hinomisaki)ethyl]piperazine

(90) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(5-athinaiki)ethyl]piperazine

(91) 1-[{2-(5-cyano-6-methyl-5-phenyl)heptyl}]-4-[2-(4-pertenece)ethyl]piperazine

(92) 1-{[4-(7-cyano-8-methyl-7-phenyl)nonyl]}-4-[2-(4-pertenece)ethyl]piperazine

(93) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-pyridyloxy)ethyl]piperazine

(94) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-pyridyloxy)ethyl]piperazine

(95) 1-[(4-cyano-5-METI the si)ethyl]piperazine

(97) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(1-naphthyloxy)ethyl]piperazine

(98) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-ethyl-2-(4-pertenece)ethyl]piperazine

(99) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-girasolereale)ethyl]piperazine

(100) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[4-(3-pyridyl)phenoxy]ethyl}piperazine

(101) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(3-pyridyl)phenoxy]ethyl}piperazine

(102) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-bromophenoxy)ethyl]piperazine

(103) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-bromophenoxy)ethyl]piperazine

(104) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-bromophenoxy)ethyl]piperazine

(105) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[4-(imidazol-1-yl)phenoxy]ethyl}piperazine

(106) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-pyrimidinone)ethyl]piperazine

(107) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[2-(3-pyridyl)phenoxy]ethyl}piperazine

(108) 1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(109) 1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(3-pertenece)ethyl]piperazine

(110) 1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-pertenece) ethyl]piperazine

(111) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(3-thienyl)phenoxy]ethyl}piperazine

(112) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[2-(6-methyl-2-pyridyl)vinylphenol] is l-4-phenyl)hexyl]-4-[2-(3-phenyleneoxy)ethyl]piperazine

(115) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(2-cyanovinyl)phenoxy]ethyl}piperazine

(116) 1-[(4-cyano-5-methyl-4-phenyl)hexanoyl]-4-[2-(4-pertenece)ethyl]piperazine and

(117) 1-[(4-cyano-4-phenyl)butyl]-4-[2-(4-pertenece)ethyl]piperazine.

Compounds of the present invention have very high values of LD50and very high security.

Among the above compounds of the present invention, for example, connection(1), (9), (10), (11), (20), (22), (23), (24), (36), (52), (75), (76), (79), (86), (88), (92), (95), (104), (107) (109) and (116) are preferred from the viewpoint of pharmacological activity and safety.

Next, the method of obtaining N,N-substituted cyclic amines of the present invention is not limited and, for example, can be performed as follows.

(1) preparation of N,N-substituted cyclic amine (VIII), where w>2 and the left side chain is a methylene group

In this case, the aldehyde compound (IX) and cyclic amine (X) is subjected to reaction in the presence of a reducing agent in accordance with generally accepted by reductive amination, for example, by the method described in Shin Jikken Called Koza 14-III, page 1373, published by Maruzen K. K. This reaction is carried out based on the following chemical scheme:

where a, E, G, J, Alk, R1

(2) Obtaining N,N-substituted cyclic amine (VIII), where w>2 and the left end group is a methylene group

In the way, other than (1), the target compound can be synthesized by adding active alkylsilane (XII) with a cyclic amine (XI) in the presence of a base. This reaction is carried out according to the following reaction scheme:

where A, E, G, J, Alk, R1, v, n, w, x, y and R have the same meanings as described above. L represents a leaving group such as halogen atom, methysulfonylmethane etc.

(3) Obtaining N,N-substituted cyclic amine (I), where o>2 and the terminal R4=R5=N

In this case, the aldehyde compound (V) and a cyclic amine (VI) is subjected to reaction in the presence of a reducing agent in accordance with generally accepted by reductive amination, for example, by the method described in Shin Jikken Called Koza 14-III, page 1373, published by Maruzen K. K. This reaction is carried out based on the following chemical scheme:

Hidetaka same values as specified above.

Reducing agent here is not the limit, because it is usually used for reductive N-alkylation, preferred examples include triacetoxyborohydride sodium, cyanoborohydride sodium, sodium borohydride, sociallyengaged etc.

(4) to Obtain N,N-substituted cyclic amine (I), where o>2 and the terminal R4=R5=N

In the method, different from (3), the target compound is synthesized by addition of active alkylsilane (VII) a cyclic amine (VI) in the presence of a base. This reaction is carried out based on the following chemical scheme:

where A, E, G, J, R1, R2, R3, R4, R5, R6, R7, R8R9, m, n, o, p, q and r have the same meanings as described above. L represents a leaving group such as halogen atom, methysulfonylmethane etc.

The form of the introduction of the compounds of the present invention includes, for example, oral pharmaceutical preparations such as powder, fine granules, granules, tablets, coated tablets and capsules, drugs for external use such as ointments, patches and suppositories, and injections. For the manufacture of pharmaceutical compositions can oral pharmaceutical compositions of N,N-substituted cyclic amines or their pharmacologically acceptable salts and fillers and, if necessary, binders, disintegrators, lubricants, coloring agents, amending the taste and smell of agents, etc. are mixed and molded in the usual way with the formation of powder, fine granules, granules, tablets, coated tablets, capsules, etc.

The fillers include, for example, lactose, corn starch, white sugar, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide and so on; binders include, for example, polyvinyl alcohol, polyvinyl simple ether, methylcellulose, ethylcellulose, Arabian gum, tragakant, gelatin, shellac, hypromellose, hydroxypropylcellulose, polyvinylpyrrolidone, block copolymers polypropylenglycol-polyoxyethylene, meglumin and so on; disintegrators include, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, calcium salt of carboxymethylcellulose, and so on; lubricants include, for example, magnesium stearate, talc, polyethylene glycol, silicon dioxide, utverjdenie vegetable oil; coloring agents include agents that are accepted to be added to pharmaceutical compositions, and correcting the taste and smell of agents vanoli can be covered charaterise coatings or any other materials, if necessary.

To obtain a pharmaceutical composition for injection is a common method to compounds N,N-substituted cyclic amines or their pharmacologically acceptable salts add agents for regulating the pH, agents, dissolving agents, giving isotonicity, etc. and, if necessary, agents, helps dissolve, stabilizers, etc.

A method of obtaining a pharmaceutical composition for external use is not limited, and can be accessed in the usual way. That is, the main raw materials used in pharmaceutical manufacturing, can be of different source materials commonly used in pharmaceutical compositions, non-pharmaceutical compositions, cosmetics, etc.

In particular, the basic source materials include, for example, such source materials as animal and vegetable oils, mineral oil, essential oil, waxes, higher alcohols, fatty acids, silicone oil, surfactants, phospholipids, alcohols, polyols, water-soluble polymers, clay minerals, purified water, etc. and, if necessary, pH regulators, antioxidants, chelating agents, preservatives, antifungal agents, okrania not limited to these materials, listed above. In addition, you can also enter components with an inducing effect on differentiation, activators of blood, disinfectants, anti-inflammatory agents, activators cells, vitamins, amino acids, moisturizers, carotenodermia agents and so on, the Number of these basic raw materials is generally defined as the number used in the preparation of drugs for external use.

In the present invention, the clinical dose of the compounds N,N-substituted cyclic amines or their pharmacologically acceptable salts is not limited, and the dosage varies depending on conditions, severity of disease, age of the patient, complications, etc. and the type of salt and route of administration. This dose is typically in the range from 0.01 to 1000 mg, preferably from 0.1 to 500 mg and more preferably from 0.5 to 100 mg per day for an adult, it is administered orally, intravenously, in the form of a suppository or subcutaneous.

Further excellent pharmacological action of the compounds of the present invention is specified as the action of the present invention.

For example in the following literature describes that connection, providing inhibitory DEH cells or for the protection of cerebral nerve cells, agent for the treatment and improvement in nervous diseases, an agent for treatment or improvement in acute ischemic stroke, head injury, neuronal cell death, Alzheimer's disease, cerebral circulatory metabolism, disorders of cerebral function or pain, antispastic agent, agent for the treatment or improvement in schizophrenia and agent for the prevention, treatment or improvement in migraine, epilepsy, manic-depressive psychosis, nerve degenerative diseases (Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, a disease of Huntington), cerebral ischemia, epilepsy, head injury, the complications of AIDS type of dementia, edema, violation type anxiety (generalized type violation anxiety) and diabetic neuropathy.

(1) Acute ischemic stroke: Annj. Rev. Physiol., 52, 543-559, 1990.

(2) head Injury: SCRIP, No. 2203, 24, 1997.

(3) Ischemia - cerebral death of nerve cells: Advances in Pharmacology, 22, 271-297, 1991.

(4) Alzheimer's Disease: Trends in Neuroscience, 16, 409, 1993.

(5) Disturbance of cerebral circulatory metabolism: Nichiyakurishi, 85, 323-328, 1985.

(6) Disturbance of cerebral function: Acta Neurol. Scand., 78:2, 14-200, 1998.

(9) Nerve degenerative diseases (Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, a disease of Huntigton), cerebral ischemia, epilepsy, head injury and complications of AIDS type of dementia: Revista de Neurologia., 24 (134), 1199-1209, 1996.

In addition, for example, in the following literature describes that compounds with inhibitory effect on calcium channels, N-type or P/Q-type, can serve as an agent for prevention, treatment or improvement in edema, violation type anxiety (generalized type violation anxiety, schizophrenia, diabetic neuropathy and migraine.

(10) Edema: Brain Research, 776, 140-145, 1997.

(11) Violation type anxiety (generalized type violation anxiety), schizophrenia: Jyunkan-seigyo (Circulation Control), 14(2), 139-145, 1993.

(12) Diabetic neuropathy: Shinkeinaika (Neurological Medicine), 50, 423-428, 1999.

(13) Migraine: Neurology, 50(4), 1105-1110, 1998.

Accordingly the present invention provides calcium antagonist comprising the compound N,N-substituted cyclic amines or their pharmacologically acceptable salts; for selective nerve calcium antagonist comprising the compound N,N-zamestnanosti diseases, against which effectively inhibitory effect on calcium channels P/Q-type, comprising the compound N,N-substituted cyclic amines or their pharmacologically acceptable salts; agent for prevention, treatment or improvement of diseases against which effectively inhibitory effect on calcium channels, N-type, including compounds N,N-substituted cyclic amines or their pharmacologically acceptable salts; agent for inhibiting neuronal cell death or to protect nerve cells in the brain, including the compounds N,N-substituted cyclic amines or their pharmacologically acceptable salts; agent for the prevention, cure or improvement in nervous diseases, comprising the compound N,N-substituted cyclic amines or their pharmacologically acceptable salts, where the disease of the nerve cells may be a disease selected from the group consisting of acute ischemic stroke, cerebral apoplexy, cerebral infarction, head injury, loss of cerebral nerve cells, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, a disease of Huntington, abnormalities of cerebral circulatory metabolism, disorders of cerebral fonzarelli, cerebral ischemia, complications of AIDS type of dementia, edema, disorders of the type of anxiety (generalized type violation anxiety) and diabetic neuropathy, which is a calcium antagonist composition comprising a pharmacologically effective amount of the compounds N,N-substituted cyclic amines or their pharmacologically acceptable salts and pharmaceutically acceptable carrier.

In addition, the present invention provides a method of treating diseases against which effective antagonism of calcium, which includes the introduction of a pharmacologically effective amount of the compounds N,N-substituted cyclic amines or their pharmacologically acceptable salts to a patient suffering from a specified disease, and the use of the compounds N,N-substituted cyclic amines or their pharmacologically acceptable salts for the manufacture of calcium antagonist.

Brief description of drawings

Fig.1 is a graph showing the effect of decreasing the volume of infarction compounds of the present invention (intravenous) in model rats with occlusion in the middle cerebral artery (represented by a mean ± (standard error)).

Fig.2 is heating) model rats with occlusion in the middle cerebral artery (represented by a mean ± (standard error)).

Fig.3 is a graph showing the effect of decreasing the volume of the infarction control connection (intravenous) in model rats with occlusion in the middle cerebral artery (represented by a mean ± (standard error)).

Fig.4 is a graph showing the analgesic effect of the compounds of the present invention (intravenous) in mice in the formalin test (represented by a mean ± (standard error)).

Fig.5 is a graph showing the analgesic effect of the compounds of the present invention (intravenous) in mice in the formalin test (represented by a mean ± (standard error)).

Fig.6 is a graph showing the analgesic effect of morphine (oral administration) on mice in the formalin test (represented by a mean ± (standard error)).

Fig.7 is a graph showing the analgesic effect of indomethacin (oral administration) on mice in the formalin test (represented by a mean ± (standard error)).

Fig.8 is a diagram of HPLC, showing that the compound obtained in example 1 was divided into optical connection example 75 and later coming (the last two) of the main peak shows a connection example 76).

Pharmacological experimental example 1. Measurement of the activity potential-dependent calcium channel by use of a fluorescent pigment (Fura 2)

(1) the Relationship between the model and the disease

At the present time “hypothesis glutamic acid-Sa is considered as the most important as a mechanism of infarction brain (loss of nerve cells due to ischemia). That is, if cerebral blood flow is reduced, anaerobic glycolysis, and ATP content in cerebral tissues is depleted. As a consequence of depletion of the energy gradient in the concentration of intracellular and extracellular ion may not be supported in order to generate a depolarization. In presynaptic potential-dependent calcium channels are activated due to depolarization, and is induced by excessive release of glutamate. In postsynaptic potential-dependent calcium channels are activated due to depolarization and intracellular levels of CA2+increase, while released in excess amounts of glutamic acid stimulates receptors glutamic acid, increasing the levels of intracellular CA2+. In this activates a large number of CA2+for whom zestawienie in this experimental system can be estimated inflow of CA2+in presynaptic.

(2) Obtaining synaptosome cortex

Synaptosome cortex receive the following way in accordance with Neuropharmacology, 32(11), 1195-1202, 1993.

The cerebral cortex was removed from the tissue sections of rat brain and roughly cut with scissors. The product was introduced into the homogenizer, homogenized in 0.3 M sucrose and centrifuged at 4°C (1500 g10 min). The resulting supernatant further centrifuged at 4°C (10000 g20 min). The resulting precipitates suspended in 0.3 M sucrose. The suspension was covered with a layer of 0.8 M sucrose and centrifuged (10000 g x 30 min). The resulting precipitates suspended in a solution (118 mm NaCl, 4.6 mm KCl, 1 mm CaCl2, 1 mm MgCl2, 1.2 mm Na2HPO4, 10 mm D-glucose, 20 mm HEPES-NaOH, pH of 7.4, with 0.1% BSA), receiving synaptosome cortex.

(3) Inhibitory effect on calcium channels

4 μm Fura/AM (Dojin Ltd) suspended in the solution And to obtain a solution for download. To a solution of synaptosome obtained by the method mentioned above, was added an equal volume of a solution for downloading and the mixture is incubated for 40 minutes at room temperature. After incubation, the solution is to download was removed by centrifugation of Britania, and the mixture is incubated for 10 minutes at room temperature. To the mixture was added 1/10 volume of a solution In (122,6 mm KCl, 1 mm CaCl2, 1 mm MgCl2, 1.2 mm Na2HPO4, 10 mm D-glucose, 20 mm HEPES-NaOH, pH of 7.4, with 0.1% BSA) for stimulation of calcium channels. The levels of intracellular calcium ion was determined by measurement at 2 wavelengths of 340 and 380 nm using ARUGUS-FDSS (Hamamatsu Photonics Co., Ltd) and determined the IC50each connection.

As a comparative control compounds used hydrochloride verapamil.

(4) Results

Example 2 pharmacological tests. Inhibitory effect on the release of glutamic acid

(1) the Relationship between the model and the disease

It is believed that this experimental system an experimental system in which the release of glutamic acid in presynaptic can be estimated graphically “hypothesis glutamic acid-Sa”.

(2) Obtaining tissue slices of the cerebral cortex

Tissue of the cerebral cortex were isolated from male rats strain SD (age 8 weeks) and used to obtain sections of 300 μm3 is the target (120 mm NaCl, 4 mm KCl, 10 mm gSO4, 16 mm Panso3, 10 mm glucose, 1 mm NaH2PO4, 10 mm HEPES-NaOH, pH of 7.4) in the presence of 95% O2/5% CO2. After that, the solution was replaced with fresh solution, followed by further incubation for 30 minutes.

(3) the Release of glutamic acid by stimulating highly concentrated KCl

Slices of the cerebral cortex were incubated in the plate for 24 wells for cell culture in advance method (Brain Res., 402, 255-263, 1987) and the release of glutamic acid induced with 50 mm KCl. Solution D (120 mm NaCl, 4 mm KCl, 1.2 mm CaCl2, 1 mm gSO4, 16 mm Panso3, 10 mm glucose, 1 mm NaH2PO4, 10 mm HEPES-NaOH, pH of 7.4) was aeronavali in an atmosphere of 95% O2/5% CO2and kept at 37°C and used in this experiment. Received 50 mm KCl, containing the same total number of K+and Na+. The tissue section corresponding to from 1 to 2 mg of protein, was placed on the upper Cup, provided at the bottom of the hole (mesh) in the lower well was injected 1.3 ml of solution containing 50 mm KCl solution and the upper Cup was transferred into a new well. 20 minutes before and 5 minutes after the reaction has been induced, to a solution of D or 50 mm KCl was added to test the connection.

(4) Quantitative luorescence detector (Ex. 330 nm, Em 450 nm). Used an eluting solvent was obtained by dilution with 150 ml of buffer citrate for automatic amino acid analyzer (Wako Pure Chemical Industries) 10 times with distilled water, then adding to the product of breeding MgCl2at a final concentration of 50 mm and then further diluted two times with acetonitrile. The flow rate was 2.0 ml/min was Used column Asahipak (ES-502N, Showa Denko K. K.). Glutamic acid was transformed into derived by adding 50 ál of sample 50 μm using a derived agent (10 mg o-phthalic aldehyde/500 ál Meon, 10 ál-mercaptopropionic acid, 0.15 M borate buffer, sodium, pH of 9.5, 100 μl), followed by stirring (Neuroscience Lett., 96, 202-206, 1989).

(5) Results

In a further decrease in the volume of infarction in the model rats with occlusion in the middle cerebral artery and analgesic effect on mice in the formalin test was determined using the compounds of the present invention to demonstrate the activity of a compound of the invention in vivo.

Pharmacological experimental example 3. Influence (I) to reduce the volume of infarction in the model rats with occlusion in the middle cerebral artery

On the basis of electrophysiological and pharmacological studies, the potential-dependent calcium channels present in the nerve cell is glutaminovoi acid from synaptosomes structures in the cerebral cortex of the rat (10, 11).

In accordance with the estimated protective effect of typical compounds of the present invention on the nerve cells against disturbances, induced by the emergence of local cerebral ischemia model in rats by occlusion of the middle cerebral artery.

(2) Experimental method

2-1) get sample

Connection example 1 were chosen as typical examples of the compounds of the present invention, this sample was dissolved in 5,28% mannitol to set the dose of 5 or 10 mg/kg/h immediately prior to use. The concentration of the sample was calculated based on the average weight of the animals, as shown in the following example. The average weight was determined by measuring the weights of all the animals had to be used in the experiment.

Example, in the case of 10 mg/kg/h

The concentration of sample=10 mgaverage weight (kg)/volume (0,616 ml), entered per hour.

2-2) Obtaining nylon pitch

For ambient occlusion in the middle cerebral artery was used embolus obtained from nylon yarn 4-0 of filaments (Ethicon, Inc., Somerville, NJ, USA). The end of the nylon of the pitch was previously rounded flame and the embolus was cut into fragments with a length of 25 mm, each fragment was recorded in Peter for intravenous injection

Implantation of the catheter for intravenous (Atom venous catheter 3Fr, Atom Medical Co., Ltd., Tokyo) was performed under anesthesia with a mixture of 70% laughing gas/2% halothane gas. A catheter filled with saline, was inserted through the femoral vein in his left leg.

2-4) Occlusion in the middle cerebral artery

Occlusion in the middle cerebral artery was performed according to the method of Longa et al. (12). Directly after the catheter has been implanted, the operation was performed under anesthesia with a mixture of 70% laughing gas/2% halothane gas. The rat was left to lie on his back and the cervical region it was opened by incision under stereoscopic microscope for operation, the part where the common carotid artery on the right side was divided into the external carotid artery and internal carotid artery was fixed. External carotid artery cut at the peripheral side and nylon embolus inserted over the end of the incised external carotid artery into the internal carotid artery. The embolus was inserted as long as the position at the distance of 17 mm from the end of the pitch has not reached the point where the external carotid artery was connected to the internal carotid artery, embolus recorded. To initiate blood flow again nylon embolus was removed 2 hours after to poop minutes after as the middle cerebral artery was occluded, each rat was holding up by the tail and rat, apparently having hemiplegia in the front paw (paralysis in the front paw on the opposite side from the resulting occlusion), were selected as the sample, where the middle cerebral artery was occluded, to successfully invoke a state of ischemia, and is selected animal was subjected to experiment.

2-6) Introduction environment and sample

The rat, who hemiplegia 30 minutes after middle cerebral artery was occluded, was placed in a cage element for regulating body temperature, and the rat had a probe for monitoring the temperature of the body, fixed on the rectum. Then the syringe containing the medium or sample attached to the catheter for intravenous and half (0,31 ml) dose, you need to enter infusion over 1 hour, was injected intravenously over 1 minute. After this, the environment or sample was injected continuously for 6 hours at a speed of 0,616 ml/h using a syringe pump for infusion (Razel Scientific Instruments, Inc., Stamford, CT, USA). During the introduction and within 2 hours after the infusion was completed, the rectal temperature was maintained in the range from 37,0 to 38.5°C in looking into the cage and kept for 1 day in a room to launch.

2-7) is a Measure of the volume of infarction

Staining of sections of brain tissue using TTS

Twenty-five hours after middle cerebral artery was occluded, the rat head was cut off and the brain was removed. The blood that clung to him, washed in ice physiological solution. The brain, from which the olfactory bulb was removed, cut at intervals of 2 mm from the end (6 slices and each slice was placed in a 2% solution of TTC, so that the rear side of the brain has been turned up. When using TTS was dissolved in physiological solution. The sample was left at room temperature for at least 1 hour in a solution of TTC and then measured the area of infarction.

Calculate the volume of infarction

The upper side (the rear side of the brain) of each slice was used to calculate the area of infarction. The image of the brain slice was entered into the computer (RM/100, Apple Japan, Tokyo) by use of a scanning image device color CCD camera, Sankei, Tokyo). The area of infarction of the cerebral cortex in the image was determined using software for image analysis (NIH image ver.1.60, National Institutes of Health, USA). Volume in the up>2
in each slice to size 2 (mm), which represents the thickness of the slice.

(2-8) data Analysis

The volume of infarction (mm3in the cerebral cortex were expressed as mean value ± standard error. Statistical significance between the average control group and each group of samples was determined by the method of multiple comparisons, Dunnett, and 5% of both of the parties was considered as the significance level. Reactivity dose were analyzed by regression analysis, and 5% one hand was considered as the significance level (reliability).

(3) Results

After middle cerebral artery was occluded for 2 hours nylon embolus, nylon embolus was removed to initiate blood flow again, and after 24 hours after middle cerebral artery was occludable, measured the amount of infarction. The results are shown in the following table 3 and Fig.1 (:p<0,05,:p<0,01). The volume of infarction (mm3in the cerebral cortex 24 hours after it was occluded middle cerebral artery

The volume of infarction in the cerebral cortex in the control group was 224,1±14.4 mm3; p<0.05) and 40% (135,5±26,2 mm3; p<0,01), respectively. In the regression analysis, it was found that the compounds of the present invention to restore the volume of a heart attack depends on the dose.

(4) CV

As described above, the compound of the present invention inhibits the influx induced high levels of KCl calcium ion in synaptosome in the cortex of the rat brain and inhibits the release of glutamate from cortical slices of rat brain. In addition, in the present experiment, the compound of the present invention has a protective effect on nerve cells against disturbances caused by local cerebral ischemia, and the introduction of 30 minutes after the generation of ischemia compound of the present invention exhibits a significant effect in reducing the volume of a heart attack, thus clarifying the efficacy of this compound against cerebral apoplexy after treatment.

These results are also confirmed reports (13, 14) that SNX-111 (CAS registration No. 107452-89-1), i.e., a peptide inhibitor for calcium channel N-type service of nerve cells in the model rats with local cerebral ischemia, and the message (15) that-agitoxin IVA, i.e., a peptide inhibitor of channels P/Q-type, has a protective effect on nerve cells in the model rats with local cerebral ischemia.

(5) References

(1) Schanne, F. A. H., Kane, A. C., Young, E. E., Farber, J. L. Calcium dependence of toxic cell death: a final common pathway. Science 206: 700-702 (1979).

(2) Kristian, T., Siesjo, B. K. Calcium in ischemic cell death. Stroke 29: 705-718 (1998).

(3) Graham, S. H., Shiraisi, C., Panter, S. S., Simon, R. P., Faden, A. I. Changes in increasing interest among amino acid neurotransmitters produced by focal cerebral ischemia. Neurosci. Lett. 110: 124-130 (1990).

(4) Rothman, S. M., Olney, J. W. Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann. Neurol. 19: 105-111 (1986).

(5) Siesjo, B. K., Bengtsson, F. Calcium influxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia, and spreading depression: A unifying hypothesis., J. Cereb. Blood Flow Metab. 9: 127-140 (1989).

(6) Mayer, M. L., Miller, R. J. Excitatory amino acid receptors, second messengers and regulation of intracellular Ca2+in mammalian neurons. Trends Pharmacol. Sci. 11: 254-260 (1990).

(7) Osuga, H., Hakim, A. M. Relationship between increasing interest among glutamate concentration and voltage-sensitive calcium channel function in focal cerebral ischemia in the rat. J. Cereb. Blood Flow Metab. 16: 629-636 (1996).

(8) Choi, D. W. Calcium-mediated neurotoxicity: Relationship to specific channel types and role in ischemic damage. Trends Neurosci., 11: 465-469 (1988).

(9) Randall, A. D., Tsien, R. W. Pharmacological dessection of multiple types of Ca2+channel currents in rat cerebellar granule neurons. J. Neurosci. 15: 2995-3012 (1995).

(10) Turner, T. J., Dunlap, K. Pharmacological characterization of presynaptic calcium channels using subsecond biochemical measurements of synaptosomal neurosecrf the voltage-dependent Ca2+channels present in synaptosomes from rat and chicken central nervous system. J. Neurochem. 64: 2544-2551 (1995).

(12) Longa, E. Z., Weinstein, P. R., Carlson, S., Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20: 84-91 (1989).

(13) Bowersox, S. S., Singh, T., Luther, R. R. Selective blockade of N-type voltage-sensitive calcium channels protects against brain injury after transient focal ischemia in rats, Brain Res. 747: 343-347 (1997).

(14) Takizawa, S., Matsushima, K., Fujita, H., Nanri, K., Ogawa, S., Shinohara, Y. A selective N-type calcium channel antagonist increasing interest among reduces glutamate release and infarct dementia volume in focal cerebral ischemia. J. Cereb. Blood flow Metab. 15: 611-618 (1995).

(15) Asakura, K., Matsuo, Y., Kanemasa, T., Ninomiya, M. P/Q - type Ca2+channel blocker-agatoxin IVA protect against brain injury after focal ischemia in rats. Brain Res. 7760: 140-145 (1997).

Pharmacological experimental example 4. The effect of (II) to reduce the volume of infarction model rats with occlusion in the middle cerebral artery

As a typical example of the compound of the present invention (the compound in example 1) was compared with the compounds described in JP 8-508037-A (WO 94/25469, US-A-5750525), which have an affinity for the AMPA receptors and is effective against cell necrosis after ischemia hypoxia and hypocalcemia.

Below are only dissimilar characteristic features in the experimental method,

(2) Experimental method

2-1) get sample

(a) a Typical example of the compounds of the present sore, to set the dose of 10 or 20 mg/kg/hour, immediately prior to use.

b) Control connection (JP 8-508037-A, example 6)

Chemical name: {[3,4-dihydro-7-(4-morpholinyl)-2,3-dioxo-6-(trifluoromethyl)-1-(2H)-honokalani]methyl}phosphonic acid (registration number CAS: 161605-73-8)

Common name: MPQX, ZK200775

The control compound was dissolved in physiological solution to establish the dose of 3 mg/kg/h immediately prior to use.

2-4) Occlusion in the middle cerebral artery

Occlusion in the middle cerebral artery was created according to the method described above. However, the middle cerebral artery was constantly occludable without removing the nylon of the pitch.

2-6) Introduction environment and sample

a) the Compound of the present invention

Two hours after middle cerebral artery was occluded, to a catheter for intravenous attach the syringe containing environment or sample (10 or 20 mg/kg/hour) and half dose (0,31 ml), which had to infusional for 1 hour, was injected intravenously over 1 minute. After this, the environment or sample was injected continuously for 6 hours at a speed of 0,616 ml/h using a syringe pump for infusion. During Bodensee from 37,0 to 38.5°C in the system to regulate body temperature. After the temperature regulation of the body was completed, the animal was returned to its cage and kept for 1 day in a room to launch.

b) the Control connection

Two hours after middle cerebral artery was occluded, to a catheter for intravenous attach the syringe containing environment or sample (3 mg/kg/hour), and the environment or sample was injected continuously for 6 hours at a speed of 0,616 ml/h using a syringe pump for infusion. During the introduction and within 2 hours after the infusion was completed, the temperature of the colon was maintained in the range from 37,0 to 38.5°C in the system to maintain the temperature of the body. After the temperature regulation of the body was completed, the animal was returned to its cage and kept for 1 day in a room to launch.

(3) Results

Middle cerebral artery was continuously occludable nylon emboli and the volume of infarction was measured 24 hours after was conducted occlusion.

a) Compound of the present invention

The volume of infarction in the cerebral cortex of the control group was 307,2±13,3 mm3(n=7). In the intravenous administration of the compounds of the present invention at the dose of 10 or 20 mg/kg/h the th brain was reduced to 260,7±13.1 mm3(n=8) and 215,4±21.3 mm3(n=7), respectively, in a dose-dependent way, and the volume of infarction in the group with the introduction of 20 mg/kg/h was statistically significantly lower (p<0,01) than the volume of infarction in the control group. Reducing the volume of infarction compound of this invention at doses of 10 and 20 mg/kg/hour were 15 and 30%, respectively.

The results are shown in the following table 4 and Fig.2. The volume of infarction (mm3in the cerebral cortex 24 hours after it was occluded middle cerebral artery

b) Control group

The volume of infarction in the cerebral cortex in the control group was 294,9±12.6 mm3(n=9). Although the control compound was injected intravenously at a dose of 3 mg/kg/hour in two hours after it was occluded middle cerebral artery, the volume of infarction in the cerebral cortex was 284,9±10,9 mm3(n=11), so that no differences from the control group.

The results are shown in the following table 5 and Fig.3. The volume of infarction (mm3in the cerebral cortex 24 hours after it was occluded middle cerebral artery

From the results described above, it is clear that joint is.

Pharmacological experimental example 5. Analgesic effect (I) on mice in the formalin test

(1) Prerequisite

Calcium channel N-type, which is one of the specific nerves calcium channels selectively inhibited by peptide SNX-111 with a low molecular weight. It is reported that in the formalin test, as one of the tests for analgesia, SNX-111 has analgesic properties when injected into the spinal cord (1, 2).

Analgesic effect typical example of the compounds of the present invention (example 1) with intravenous investigated in formalin test using mice (3).

(2) Method

2-1) Experimental animals

In this experiment used ddy mice (male, age 4 weeks), purchased from Nippon SLC Ltd.

Mice previously kept for 4 days (conditions: room temperature, 23±1°C; humidity 55±5%; the cycle of light and dark conditions at intervals of 12 hours). The group of about 20 animals were accomodative and maintained in polycarbonate cage 20 mice, in which was placed a bed of wood shavings (white flakes) (Charles River Co., Ltd., Tokyo). In the morning of that day, who conducted the experiment, the cell was transferred into laboratory without limitation tap water.

2-2) Test connection

As typical examples of the compounds of the present invention the compound of example 1 was used as the test compounds.

2-3) get sample

Was given to 20.4 mg of the test compound and were added to 10.2 ml 5,28% mannitol to obtain a solution of 2 mg/ml (20 mg/kg). Then 3.8 ml of a solution of 2 mg/ml was added to 3.8 ml 5,28% mannitol to obtain a solution of 1 mg/ml (10 mg/kg). Finally, 2.5 ml solution of 1 mg/ml) was added 2.5 ml 5,28% mannitol to obtain a solution of 0.5 mg/ml (5 mg/kg). This test compound was weighed and prepared on the day when we conducted an experiment.

2-4) Receiving reagent

30 ál from 35.0 to 38.0% commercial formaldehyde was added to 970 μl of saline. The resulting solution was used as a 3% formalin. Because the specified purity of the commercial formaldehyde is from 35.0 to 38.0%, 3% formalin produced and used at the present time, is a formalin with exact concentration from 2,84 up is 3.08%.

2-5) Grouping, the number of animals and dosage

Group processing in this test consisted of 4 groups, i.e. control group, group for the introduction of a 5 mg/kg of the test compounds of the group for the introduction of a 10 mg/kg and Geeta per 10 g of body weight. The test compound was administered at each concentration (0.5 mg/ml, 1 mg/ml and 2 mg/ml) in a volume of 0.1 ml per 10 g of body weight to 5 mg/kg group 10 mg/kg and group to 20 mg/kg, respectively.

2-6) test Method

5,28% mannitol was injected through the tail vein of each group, which gave the compound of the present invention, or the control group, animals were placed in a transparent plastic cage for observation. After 5 minutes in the bottom of the left hind paws of each mouse was subcutaneously injected 20 μl of 3% formalin. The duration of mouse behavior, oblizyvala left hind paw after injection of formalin, were measured for 5 minutes and used as an indicator of pain. Duration expressed in seconds.

2-7) Statistical analysis

For analysis of significance was performed parametric univariate analysis of variance framework for analysis and then were compared by the method of multiple comparisons type Dunnet (0,01<p<0,05,p<0,01 compared with the control group). For this analysis used an auxiliary system of statistical analysis with an integrated SAS 6.12 (SAS Institute Japan Ltd., Tokyo).

(3) Results

The effect of his hind legs (sec) and standard error (see Fig.4).

As is evident from the above results, groups that were given the compound of the present invention at doses of 5 mg/kg, 10 mg/kg and 20 mg/kg, was found a statistically significant reduction of time licking compared to the time licking the control group.

Like inhibitor calcium channel N-type, SNX-111, the connection of the present invention, i.e., specific for nerve inhibitor of calcium channels, shows analgesic effects in the formalin test, so it is obvious that the connection of the present invention can be used as an agent for the treatment and attenuation of acute pain.

(4) References

(1) Annika B. Malmberg, and Tony L. Yaksh (1994). Voltage-Sensitive Calcium Channels in Spinal Nociceptive Processing: Blockade of N - and P - Type Channels Inhibits Formalin-Induced Nociception. The Journal of Neuroscience 14 (8): 4882-4890.

(2) S. Scott Bowersox, Theresa Gadbois, Tejinder Singh, Mark Pettus, Yong-Xiang Wang and Robert R. Luther (1996). Selective N-type Neuronal Voltage-Sensitive Calcium Channel Blocker, SNX-111, Produces Spinal Antinociception in Rat Models of Acute, Persistent and Neuropathic Pain. The Journal of pharmacology and Experimental Therapeutics, 279(3): 1243-1249.

(3) Hunskaar S., Fasmer OB and Hole, K. (1985). Formalin test in mice, a useful technique for evaluating mild analgesics. Journal of Neuroscience Methods 14(1): 69-76.

Pharmacological experimental example 6. Analgesic effect (II) on mice in the formalin IMS and indomethacin in the same way, as in the above pharmacological experimental example 5.

Below are only dissimilar characteristic features of the experimental method.

(2) Experimental method

2-1) get sample

(a) a Typical example of the compounds of the present invention (the compound in example 1)

Was given to 20.4 mg of the compound of the present invention and to it were added to 10.2 ml 5,28% mannitol to obtain a solution of 2 mg/ml (20 mg/kg). Then 3.8 ml of a solution of 2 mg/ml was added to 3.8 ml 5,28% mannitol to obtain a solution of 1 mg/ml (10 mg/kg). Finally, 2.5 ml solution of 1 mg/ml) was added 2.5 ml 5,28% mannitol to obtain a solution of 0.5 mg/ml (5 mg/kg). This test compound was weighed and received on the day when we conducted an experiment.

b) the Control connection

b-1) Morphine

Weighed 17,0 mg of morphine, purchased as reagent, and to it was added 5,67 ml of physiological solution with formation of a solution of 3 mg/ml (30 mg/kg). Then 1.3 ml of a solution of 3 mg/ml was added to 2.6 ml of saline to obtain a solution of 1 mg/ml (10 mg/kg). Finally, to 0.9 ml solution of 1 mg/ml was added to 2.1 ml of saline to obtain a solution of 0.3 mg/ml (3 mg/kg). This test compound was weighed and received on the day when spend the Yali of 12.9 ml of 0.5% methylcellulose (MC) forming a suspension of 1 mg/ml (10 mg/kg). Then of 0.96 ml suspension of 1 mg/ml was added 2,24 ml of 0.5% MS to obtain a suspension of 0.3 mg/ml (3 mg/kg). Finally, to 0.8 ml of a suspension of 0.3 mg/ml was added to 1.6 ml of 0.5% MS to obtain a suspension of 0.1 mg/ml (1 mg/kg). This test compound was weighed and received on the day when we conducted an experiment.

2-5) Grouping, the number of animals and dosage

a) Compound of the present invention

The group is processed by the connection of the present invention, in this test consisted of 4 groups, i.e. control group, group for the introduction of a 5 mg/kg of the test compounds of the group for the introduction of a 10 mg/kg and group for the introduction of 20 mg/kg, and each group consisted of 5 animals.

The control group were given 0.1 ml 5,28% mannitol 10 g body weight via the tail vein. The compound of the present invention was administered via tail vein at each concentration (0.5 mg/ml, 1 mg/ml and 2 mg/ml) in a volume of 0.1 ml per 10 g of body weight in the group for the introduction of a 5 mg/kg group for the introduction of a 10 mg/kg and the group for the introduction of 20 mg/kg, respectively.

b-1) Morphine

The group treated with morphine, consisted of 4 groups, i.e. control group, group injection of 3 mg/kg morphine, group injection of 10 mg/kg morphine and groups injection of 30 mg/kg morphine, and each group consisted of the fin orally was administered at each concentration (0.3 mg/ml, 1 mg/ml and 3 mg/ml) in a volume of 0.1 ml per 10 g of body weight in the group for the introduction of 3 mg/kg group for the introduction of a 10 mg/kg and in group for injection 30 mg/kg, respectively.

b-2) Indomethacin

Group treatment with indomethacin consisted of 4 groups, i.e. control group, group introduction 1 mg/kg indomethacin, group injection of 3 mg/kg of indomethacin and groups administering 10 mg/kg indomethacin, and each group consisted of 5 animals.

The control group orally were given 0.1 ml of 0.5% MS per 10 g of body weight. Indomethacin oral was administered at each concentration (0.1 mg/ml, 0.3 mg/ml and 1 mg/ml) in a volume of 0.1 ml per 10 g of body weight in the group for the introduction of 1 mg/kg group for the introduction of 3 mg/kg and in group for introduction of 10 mg/kg, respectively.

2-6) test Method

a) Compound of the present invention

5,28% mannitol was injected through the tail vein of each group, which gave the compound of the present invention, or the control group, animals were placed in a transparent plastic cage for observation. After 5 minutes in the bottom of the left hind paws of each mouse was subcutaneously injected 20 μl of 3% formalin. The duration of mouse behavior, oblizyvala left hind paw after injection of formalin, were measured for 5 minutes and used as by introduced animals each morphine group or the control group and the animals were placed in a transparent plastic cage for observation. After 30 minutes in the bottom of the left hind paws of each mouse was subcutaneously injected 20 μl of 3% formalin. The following stages were the same as in the method of testing compounds of the present invention.

b-2) Indomethacin

0,5% MS oral was administered to each animal indomethacin group or the control group and the animals were placed in a transparent plastic cage for observation. After 90 minutes in the bottom of the left hind paws of each mouse was subcutaneously injected 20 μl of 3% formalin. The following stages were the same as in the method of testing compounds of the present invention.

(3) Results

The action of the compounds of the present invention in the formalin test, expressed in terms of the average time licking the left hind paws (sec) and standard error as follows.

A) the Action of the compounds of the present invention in the formalin test (see Fig.5).

From the above experimental results it is obvious that indomethacin does not have any effect, whereas the compound of the present invention has an excellent effect similar to morphine.

Further specifically described preparation examples get the source materials nastoyaschemuotkryl and so on, can be synthesized in accordance with the following literature:

(1) Compt. Rend., 256, 702 (1963).

(2) Compt. Rend., 256, 2632 (1963).

(3) Collect. Czech. Chem. Commun., 57, 1967 (1992).

PREPARATORY EXAMPLES

Preparatory example 1. Synthesis of 1-[2-(4-pertenece)ethyl]piperazine

1-Benzylpiperazine (8,3 g) and 2-(4-pertenece)ethylbromide (10.3 g) was dissolved in acetonitrile (100 ml) and to the solution was added potassium carbonate (6,51 g), the mixture is stirred overnight at a temperature of from 70 to 80°C. the Organic layer distributes the addition of an aqueous saturated sodium bicarbonate and ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system hexane/ethyl acetate) to give colorless oil (12.3 g). The obtained colorless oil (12.3 g) was dissolved in methanol (120 ml) and to the solution was added 10% palladium hydroxide/carbon, followed by stirring in a hydrogen atmosphere. The reaction solution is filtered and evaporated, whereby receive specified in the title compound (7.7 g, 73%) as a pale yellow oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 2,55 (width, 4H), 2,78 (t, J=6 Hz, 2H), piperazine

Piperazine (2.15 g) and 2-phenoxyethylamine (1,00 g) dissolved in tetrahydrofuran (30 ml), and the mixture is stirred at a temperature of from 40 to 60°C for 36 hours. The reaction solution is evaporated, to the residue add aqueous saturated sodium bicarbonate and diethyl ether and the aqueous layer was distributed. To the aqueous layer add methylene chloride and the organic layer evenly. The organic layer is dried over anhydrous sodium sulfate and evaporated, whereby receive specified in the title compound (664 mg, 65%).

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 2,56 (width, 4H), 2,80 (t, J=6 Hz, 2H), 2,92 (Shir.t, J=4.8 Hz, 4H), of 4.12 (t, J=6 Hz, 2H), 6,88-6,98 (m, 3H), 7,26-to 7.32 (m, 2H).

Preparatory example 3. Synthesis of 1-[2-(4-pertenece)propyl]piperazine

1-Formylpiperazine (2.8 g) and 2-(4-pertenece)propylchloride (4.7 g) was dissolved in dimethylformamide (60 ml) and the solution was added sodium iodide (3.2 g) and triethylamine (4.4 ml), the mixture is stirred overnight at a temperature of from 50 to 70°C. the Organic layer distributes the addition of water and ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and evaporated. Purify the residue chromatog is) and to the solution add 5 N. aqueous sodium hydroxide (10 ml) and then stirred for 1 hour at boiling under reflux. The reaction mixture is evaporated, and then the organic layer distributes the addition of water and ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation, purified by chromatography on a column of silica gel Cromatorex NH (system ethyl acetate/methanol), whereby receive specified in the title compound (2.2 g, 38%) as a pale yellow oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): of 1.93 (quintet, 7.2 Hz, 2H), 2,41 (width, 4H), 2,47 (t, J=7.2 Hz, 2H), 2,87 (Shir.t, J=5.0 Hz, 4H), of 3.94 (t, J=7.2 Hz, 2H), 6,79-6,85 (m, 2H), 6.90 to-6,97 (m, 2H).

Preparatory example 4. Synthesis of 1-(4-phenoxybutyl)piperazine

tert-Butyl-1-piperidinecarboxylate (1.0 g) and 4-phenoxybutyric (991 mg) dissolved in acetonitrile (50 ml) and to the solution is added triethylamine (1.5 ml) and sodium iodide (160 mg), the mixture is stirred overnight at a temperature of from 50 to 70°C. After concentrating the organic layer distributes the addition of water and ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and evaporated. The resulting residue is purified to colorless oil (222 mg) was dissolved in dichloromethane (10 ml) and to the solution add triperoxonane acid (1 ml), the mixture is stirred over night at room temperature. The organic layer distributes the addition of an aqueous saturated sodium bicarbonate and dichloromethane to the reaction mixture and dried over anhydrous sodium sulfate. The residue is evaporated, whereby receive specified in the title compound (190 mg, 15%) as a pale yellow oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 1,63-1,72 (m, 2H), 1,76 is 1.86 (m, 2H), 2,38 is 2.43 (m, 2H), 2,43-2,52 (width, 4H), 2,92 are 2.98 (m, 4H), 3.96 points-of 4.00 (m, 2H), 6.87 in-of 6.96 (m, 3H), 7,25-7,30 (m, 2H).

Next, the following compounds were synthesized according to preparation examples 1-4.

Preparatory example 5. 1-[2-(4-Pertenece)ethyl]homopiperazin

Free connection

1H NMR (400 MHz, CDCl3)(M. D.): 1,70-to 1.82 (m, 3H), 2,78-is 2.88 (m, 4H), 2,90-3,00 (m, 6N), a 4.03 (t, J=6 Hz), for 6.81-6.87 in (m, 2H), 6,93-7,00 (m, 2H).

Preparatory example 6. 1-[2-(4-Nitrophenoxy)ethyl]piperazine

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 2,35 (Shir. s, 4H), 2,62 (t, J=5.8 Hz, 2H), 2,65 is 2.75 (m, 4H), 4.00 points (t, J=5.8 Hz, 2H), 6,76 (d, J=9,2 Hz, 2H), 7,95 (d, J=9,2 Hz, 2H).

Similarly also receive 1-[4-(p is s, which, however, are not intended to limit the present invention.

EXAMPLES

Example 1. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

2-(1-Methylethyl)-5-oxo-2-phenylpentane (100 mg), 1-[2-(4-forfinal)ethyl]piperazine (104 mg) and acetic acid (0,13 ml) dissolved in dichloromethane (8.0 ml) and to this mixture triacetoxyborohydride sodium (196 mg), the mixture is stirred over night at room temperature. The organic layer distributes the addition of an aqueous saturated solution of sodium bicarbonate and dichloromethane, washed with water and dried over anhydrous sodium sulfate. Obtained by evaporation the residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate), obtaining mentioned in the title compound (168 mg, 86%) as a colourless oil. To a solution in methanol containing specified compound (168 mg), add a solution of 4 N. hydrogen chloride/ethyl acetate. After stirring for 10 minutes the solvent is evaporated, whereby receive hydrochloride (190 mg) specified in the connection header.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,7746-2,62 (m, 4H), 2,77 (t, J=5.8 Hz, 2H), Android 4.04 (t, J=5.8 Hz, 2H), 6,80-6,85 (m, 2H), 6,91-of 6.99 (m, 2H), 7,25-7,32 (m, 1H), 7,32-7,40 (m, 4H).

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,68 (d, J=6.6 Hz, 3H), 1,11 (d, J=6.6 Hz, 3H), 1,22-of 1.34 (m, 1H), 1,58-of 1.62 (m, 1H), 2.06 to 2,30 (m, 3H), 3,00-3,25 (m, 2H), 3,30-of 3.80 (m, 10H), 4,36 (Shir. s, 2H), 6,98-7,07 (m, 2H), 7,11-7,20 (m, 2H), 7,32-7,40 (m, 1H), 7,40-to 7.50 (m, 4H).

ESI-Macc: 424 (MH+).

Example 2. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[3-(4-pertenece)propyl]piperazine

Specified in the title compound (196 mg, 99%) was obtained as colorless oil from 2-(1-methylethyl)-5-oxo-2-phenylpentane (100 mg) and 1-[3-(4-forfinal)propyl]piperazine (111 mg) in the same manner as in example 1. This free compound (194 mg) is treated in the same manner as in example 1, obtaining hydrochloride (196 mg) specified in the connection header.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), of 1.05 to 1.19 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,84 is 2.00 (m, 3H), 2,07-to 2.18 (m, 2H), 2,23-to 2.55 (m, 13H), 3,92-to 3.99 (m, 2H), 6,79-6,85 (m, 2H), 6,91-of 6.99 (m, 2H), 7,25-7,32 (m, 1H), 7,32-7,40 (m, 4H).

Hydrochloride

1H NMR (400 MHz, DMSO-d3)(M. D.): 0,67 (d, J=6.6 Hz, 3H), 1,11 (d, J=6.6 Hz, 3H), 1,22-of 1.34 (m, 1H), 1.56 to 1,72 (m, 1H), 2.06 to 2,28 (m, 5H), 3.00 and-3,95 (m, N), 4,00-4,10 (m, 2H), 6,92-7,0-4-[2-(4-pertenece)ethyl]piperazine

Specified in the title compound (166 mg, 82%) was obtained as colorless oil from 2-(1-methylethyl)-5-oxo-2-phenylpentane (100 mg) and 1-[2-(4-forfinal)ethyl]homopiperazine (111 mg) in the same manner as in example 1. This free compound (166 mg) is treated in the same manner as in example 1, obtaining hydrochloride (169 mg) specified in the connection header.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,02-of 1.16 (m, 1H), 1,19 (d, J=6.8 Hz, 3H), 1,46-of 1.57 (m, 1H), 1.70 to 1.77 in (m, 2H), of 1.88 (dt, J=4.4 Hz, and 12.4 Hz, 1H), 2.06 to 2,19 (m, 2H), 2,33 at 2.45 (m, 2H), 2,53-to 2.57 (m, 4H), 2,74-of 2.81 (m, 4H), of 2.92 (t, J=6.2 Hz, 2H), 4.00 points (t, J=6.2 Hz, 2H), 6,80-6,86 (m, 2H), 6,92-7,00 (m, 2H), 7,26-7,33 (m, 1H), 7,33-7,40 (m, 4H).

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6, 6 Hz, 3H), 1,11 (d, J=6.6 Hz, 3H), 1.18 to 1,22 (m, 1H), 1,55-1,70 (m, 1H), 2.06 to 2,28 (m, 5H), 3,00-3,20 (m, 2H), 3,20-3,70 (m, 8H), 3,70-of 3.96 (m, 2H), 4,30-and 4.40 (m, 2H), 6,98-7,05 (m, 2H), 7,11-7,20 (m, 2H), 7,33-7,40 (m, 1H), 7,40-to 7.50 (m, 4H).

ESI-Macc: 438 (MH+).

Example 4. Synthesis of 1-[(3-cyano-4-methyl-3-phenyl)pentyl]-4-[2-(4-pertenece)ethyl]homopiperazine

Specified in the title compound (85 mg, 57%) was obtained as colorless oil from 2-(1-methylethyl)-4-oxo-2-phenylbutyramide (70 mg) and 1-[anywayt in the same way, as in example 1, obtaining hydrochloride (88 mg) specified in the connection header.

Free connection

1H NMR (400 MHz, CDCl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,20 (d, J=6.8 Hz, 3H), 1.70 to 1.77 in (m, 2H), 1,99-of 2.15 (m, 3H), 2,30-is 2.37 (m, 1H), 2,45-2,90 (m, N), 2,90 (t, J=6.2 Hz, 2H), 3,99 (t, J=6.2 Hz, 2H), 6,80-6,86 (m, 2H), 6,93-7,00 (m, 2H), 7,28-7,33 (m, 1H), 7,33-7,40 (m, 4H).

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,68 (d, J=6.6 Hz, 3H), of 1.13 (d, J=6.6 Hz, 3H), 1.26 in (m, 1H), 2,10-of 2.34 (m, 3H), of 2.51 was 2.25 (m, 2H), 3.00 and is-3.45 (m, 6N), 3,45-to 3.67 (m, 3H), 3,67-3,39 (m, 2H), 4,30-4,43 (m, 2H), 7,00-7,07 (m, 2H), 7,12-7,20 (m, 2H), was 7.36-7,44 (m, 1H), 7,44-7,51 (m, 4H).

ESI-Macc: 424 (MH+).

Example 5. Synthesis of 1-[(3-cyano-4-methyl-3-phenyl)pentyl]-4-[3-(4-pertenece)propyl]piperazine

Specified in the title compound (95 mg, 64%) was obtained as colorless oil from 2-(1-methylethyl)-4-oxo-2-phenylbutyramide (70 mg) and 1-[3-(4-pertenece)propyl]piperazine (83 mg) in the same manner as in example 1. This free compound (94 mg) is treated in the same manner as in example 1, obtaining hydrochloride (97 mg) specified in the connection header.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.6 Hz, 3H), 1,20 (d, J=6.6 Hz, 3H), 1,88-of 2.16 (m, 5H), 2,30-to 2.57 (m, N), 3,92-4,00 (m, 2),//img.russianpatents.com/chr/948.gif">(M. D.): 0,68 (d, J=6, 6 Hz, 3H), of 1.13 (d, J=6.6 Hz, 3H), 2,10-of 2.28 (m, 4H), 2.57 m)-2,70 (m, 2H), 3.00 and-3,90 (m, 11N), 4,00-4,10 (m, 2H), 6,93-7,00 (m, 2H), 7,10-7,17 (m, 2H), 7,37-7,44 (m, 1H), 7,46 is 7.50 (m, 4H).

ESI-Macc: 424 (MH+).

Example 6. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(4-phenoxybutyl)piperazine

Specified in the title compound (135 mg, 96%) was obtained as colorless oil from 2-(1-methylethyl)-5-oxo-2-phenylpentane (70 mg) and 1-(4-phenoxypropan)piperazine (76 mg) in the same manner as in example 1. This free compound (135 mg) is treated in the same manner as in example 1, obtaining hydrochloride (140 mg) specified in the connection header.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,78 (d, J=6.6 Hz, 3H), 1,05-1,17 (m, 2H), 1,20 (d, J=6.6 Hz, 3H), 1,24 of 1.28 (m, 1H), 1,50 is 1.58 (m, 1H), 1,61 was 1.69 (m, 1H), 1,73-to 1.82 (m, 2H), of 1.88 (dt, J=4.4 Hz, and 12.4 Hz, 1H), 2.05 is-to 2.18 (m, 2H), 2,20-of 2.50 (m, 11N), of 3.96 (t, J=6.4 Hz, 2H), to 6.88 (d, J=7.2 Hz, 2H), 6,92 (t, J=7.2 Hz, 1H), 7.23 percent-7,40 (m, 3H), 7,44-7,49 (m, 4H).

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.6 Hz, 3H), 1,11 (d, J=6.6 Hz, 3H), of 1.20 and 1.33 (m, 1H), 1,55-of 1.95 (m, 4H), 2,00-2,30 (m, 3H), 2.95 and is 3.25 (m, 4H), 3.25 to of 3.85 (m, N), 3,98 (t, J=6 Hz, 2H), 6,85-6,97 (m, 3H), 7,28 (Shir. t, J=8 Hz, 2H), 7,34-7,40 (m, 1H), 7,40-of 7.48 (m, 4H).

ESI-Macc: 434 (MH+).

Example 7. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl) what mg 64%) was obtained as colorless oil from 2-(1-methylethyl)-5-oxo-2-phenylpentane (429 mg) and 1-(2-phenoxyethyl)piperazine (644 mg) in the same manner as in example 1. This free compound (510 mg) is treated in the same manner as in example 1, obtaining hydrochloride (600 mg) specified in the connection header.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,02-of 1.16 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-to 1.61 (m, 1H), of 1.88 (dt, J=4.4 Hz, and 12.4 Hz, 1H), 2,08-to 2.18 (m, 2H), and 2.27 (Shir. t, J=7,6 Hz, 2H), 2,30 is 2.46 (m, 4H), 2,46-2,70 (m, 4H), 2,78 (t, J=5.8 Hz, 2H), 4,08 (t, J=5.8 Hz, 2H), 6,88-to 6.95 (m, 3H), 7.24 to 7,30 (m, 3H), 7,32-7,38 (m, 4H).

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.8 Hz, 3H), of 1.12 (d, J=6.8 Hz, 3H), 1,16-of 1.30 (m, 1H), 1,55-1,65 (m, 1H), 2.05 is was 2.25 (m, 3H), 2,90-the 3.65 (m, N), 4,20-and 4.40 (m, 2H), 6,69-of 6.99 (m, 3H), 7,29-7,33 (m, 2H), was 7.36-7,40 (m, 1H), 7,41-of 7.48 (m, 4H).

ESI-Macc: 406 (MH+).

Example 8. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-nitrophenoxy)ethyl]piperazine

Specified in the title compound (1.19 g, 71%) was obtained as yellow oil from 2-(1-methylethyl)-5-oxo-2-phenylpentane (800 mg) and 1-[2-(4-nitrophenoxy)ethyl]piperazine (1.40 g) in the same manner as in example 1. This free compound (225 mg) is treated in the same way the

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.4 Hz, 3H), 1,05-of 1.18 (m, 1H), 1,20 (d, J=6.4 Hz, 3H), 1,45-to 1.60 (m, 1H), of 1.88 (dt, J=5,0, at 13.0 Hz, 1H), 2,08-of 2.20 (m, 2H), 2,28 (Shir. t, J=7.5 Hz, 2H), 2,30 at 2.45 (m, 4H), 2,50-2,62 (m, 4H), 2,82 (t, J=5.8 Hz, 2H), 4,17 (t, J=5.8 Hz, 2H), 6,94-of 6.96 (m, 2H), 7,26-7,31 (m, 1H), was 7.36-7,37 (m, 4H), 8,18-to 8.20 (m, 2H).

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.8 Hz, 3H), of 1.12 (d, J=6.8 Hz, 3H), of 1.20 and 1.33 (m, 1H), 1.56 to to 1.70 (m, 1H), 2.05 is was 2.25 (m, 3H), 3.00 and-of 3.80 (m, N), 4,45-4,60 (m, 2H), 7.18 in-7,24 (m, 2H), 7,34-7,41 (m, 1H), 7,43-7,49 (m, 4H), by 8.22-of 8.28 (m, 2H).

ESI-Macc: 451 (MH+).

Example 9. Synthesis of 1-[4-cyano-5-methyl-4-(4-were)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

Specified in the title compound (376 mg, 59%) was obtained as colorless oil from 2-(1-methylethyl)-5-oxo-2-(4-were)pentenenitrile (334 mg) and 1-[2-(4-pertenece)ethyl]piperazine (360 mg) in the same manner as in example 1. This free compound (42 mg) is treated in the same manner as in example 1, obtaining hydrochloride (49 mg) specified in the connection header.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1.06 a-1,17 (m, 1H), 1,18 (d, J=6.8 Hz, 3H), 1,48-to 1.61 (m, 1H), of 1.85 (dt, J=4,4, 12,5 Hz, 1H), 2,03-of 2.16 (m, 2H), and 2.27 (t, J=7,1 Hz, 2H), 2,30 at 2.45 (m, 4H), of 2.34 (s, 3H), 2,45-to 2.65 (m, 4up>1
H NMR (400 MHz, D2O)(M. D.): 0,60 (d, J=6, 6 Hz, 3H), 1,01 (d, J=6.6 Hz, 3H), 1.18 to 1.32 to (m, 1H), 1,52-of 1.65 (m, 1H), 1,86 is 1.96 (m, 1H), 2.06 to 2,17 (m, 2H), measuring 2.20 (s, 3H), 2,90-3,00 (m, 1H), 3.04 from-3,13 (m, 1H), 3,22-of 3.48 (m, 10H), 4,18 (t, J=4.9 Hz, 2H), PC 6.82-6.87 in (m, 2H), 6,92-of 6.99 (m, 2H), 7,18 (d, J=8,2 Hz, 2H), 7.23 percent (d, J=8,2 Hz, 2H).

ESI-Macc: 438 (MH+).

Example 10. Synthesis of 1-[4-cyano-5-methyl-4-(4-chlorophenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

Specified in the title compound (599 mg, 63%) was obtained as colorless oil from 2-(1-methylethyl)-5-oxo-2-(4-chlorophenyl)pentenenitrile (496 mg) and 1-[2-(4-pertenece)ethyl]piperazine (490 mg) in the same manner as in example 1. This free compound (46 mg) is treated in the same manner as in example 1, obtaining hydrochloride (53 mg) specified in the connection header.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,13-of 1.16 (m, 1H), 1,19 (d, J=6.8 Hz, 3H), 1,48-to 1.61 (m, 1H), 1,84 (dt, J=4,4, 12,5 Hz, 1H), 2,03-2,19 (m, 2H), 2,28 (t, J=7,1 Hz, 2H), 2,30 is 2.46 (m, 4H), 2,46-of 2.64 (m, 4H), 2,77 (t, J=5.8 Hz, 2H), Android 4.04 (t, J=5.8 Hz, 2H), for 6.81-6,85 (m, 2H), 6,93-6,98 (m, 2H), 7,30 (d, J=8.6 Hz, 2H), 7,34 (d, J=8.6 Hz, 2H).

Hydrochloride

1H NMR (400 MHz, D2O)(M. D.): 0,60 (d, J=6, 6 Hz, 3H), of 1.02 (d, J=6.6 Hz, 3H), 1.18 to 1.30 on (m, 1H), 1,54-to 1.67 (m, 1H), 1,87 is 1.96 (m, 1H), 2.06 to of 2.20 (m, 2H), 2.95 and-3,0558 (MH+).

Example 11. Synthesis of 1-[4-cyano-5-methyl-4-(4-methoxyphenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

Specified in the title compound (404 mg, 63%) was obtained as colorless oil from 2-(1-methylethyl)-5-oxo-2-(4-methoxyphenyl)pentenenitrile (345 mg) and 1-[2-(4-pertenece)ethyl]piperazine (350 mg) in the same manner as in example 1. This free compound (59 mg) is treated in the same manner as in example 1, obtaining hydrochloride (68 mg) specified in the connection header.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,07-1,19 (m, 1H),1,18 (d, J=6.8 Hz, 3H), 1,48-to 1.61 (m, 1H), 1.77 in-to 1.87 (m, 1H), 2,03-of 2.15 (m, 2H), 2,28 (t, J=7,1 Hz, 2H), 2,30 is 2.46 (m, 4H), 2,46-to 2.65 (m, 4H), 2,77 (t, J=5.8 Hz, 2H), 3,81 (s, 3H), Android 4.04 (t, J=5.8 Hz, 2H), for 6.81-6,85 (m, 2H), to 6.88 (d, J=9.0 Hz, 2H), 6,93-6,97 (m, 2H), 7,26 (d, J=9.0 Hz, 2H).

Hydrochloride

1H NMR (400 MHz, D2O)(M. D.): 0,60 (d, J=6, 6 Hz, 3H), and 1.00 (d, J=6.6 Hz, 3H), 1,21-of 1.35 (m, 1H), 1,54 by 1.68 (m, 1H), 1,83 is 1.96 (m, 1H), 2,02-2,19 (m, 2H), 2,97-to 3.09 (m, 1H), 3,12-is 3.21 (m, 1H), 3,35-to 3.67 (m, 10H), 3,70 (s, 3H), 4,23 (Shir. t, J=4.9 Hz, 2H), PC 6.82-6.87 in (m, 2H), 6.90 to-6,99 (m, 3H), 7,27 (d, J=8,8 Hz, 2H).

ESI-Macc: 454 (MH+).

Example 12. Synthesis of 1-[4-cyano-5-methyl-4-(4-carbomethoxybiphenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

Ukazatel)pentenenitrile (59 mg) and 1-[2-(4-pertenece)ethyl]piperazine (53 mg) in the same way, as in example 1. This loose coupling (10 mg) is treated in the same manner as in example 1, obtaining hydrochloride (11 mg) specified in the connection header.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,76 (d, J=6.8 Hz, 3H), 1,10-of 1.13 (m, 1H),1,22 (d, J=6.8 Hz, 3H), 1,49-of 1.62 (m, 1H), 1.91 a (dt, J=4,4, 12,5 Hz, 1H), 2,09-of 2.24 (m, 2H), and 2.27 (t, J=7,1 Hz, 2H), 2,27 is 2.46 (m, 4H), 2,46-2,70 (m, 4H), 2,77 (t, J=5.8 Hz, 2H), 3,93 (s, 3H), Android 4.04 (t, J=5.8 Hz, 2H), for 6.81-6,85 (m, 2H), 6,93-6,98 (m, 2H), 7,46 (d, J=8,2 Hz, 2H), 8,04 (d, J=8,2 Hz, 2H).

Hydrochloride

1H NMR (400 MHz, D2O)(M. D.): 0,60 (d, J=6.6 Hz, 3H), of 1.05 (d, J=6.6 Hz, 3H), 1.18 to of 1.29 (m, 1H), 1,55-1,70 (m, 1H), 1,94-2,04 (m, 1H), 2,12 was 2.25 (m, 2H), 2,99-3,10 (m, 1H), 3,11-up 3.22 (m, 1H), 3,35-3,68 (m, 10H), of 3.80 (s, 3H), 4,22 (Shir. t, J=4.9 Hz, 2H), PC 6.82-6.87 in (m, 2H), 6,93-of 6.99 (m, 2H), of 7.48 (d, J=8,4 Hz, 2H), 7,94 (d, J=8,4 Hz, 2H).

ESI-Macc: 482 (MH+).

Example 13. Synthesis of 1-[4-cyano-5-methyl-4-(4-hydroxymethylene)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

The lithium borohydride (3 mg) are added to a solution in tetrahydrofuran (2 ml) containing 1-[4-cyano-5-methyl-4-(4-carbomethoxybiphenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine (64 mg) obtained in example 12, and the mixture is heated to boiling under reflux for 3 hours. The reaction mixture is cooled to room Tengri for 10 minutes. The organic layer distributes the addition of an aqueous saturated solution of sodium bicarbonate and ethyl acetate, washed with water and dried over anhydrous sodium sulfate. The residue obtained by evaporation, purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate), obtaining mentioned in the title compound (57 mg, 95%) as a colourless oil. To a solution of this free compound (27 mg) in methanol at room temperature is added a solution of 4 N. hydrogen chloride/ethyl acetate. The solution is stirred for 10 minutes and then the solvent is evaporated, whereby receive hydrochloride (31 mg) specified in the connection header.

Free connection

1H NMR (400 MHz, CDCl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,05-of 1.18 (m, 1H), 1,19 (d, J=6.8 Hz, 3H), 1,49-of 1.62 (m, 1H), 1,87 (dt, J=4,4, 12,5 Hz, 1H), 2,07-of 2.20 (m, 2H), and 2.27 (t, J=7,1 Hz, 2H), 2,29 is 2.44 (m, 4H), 2,46-2,61 (m, 4H), was 2.76 (t, J=5.8 Hz, 2H), a 4.03 (t, J=5.8 Hz, 2H), 4,69 (s, 2H), 4,70-4,72 (m, 1H), 6,79-6,85 (m, 2H), 6,92-6,98 (m, 2H), 7,33-7,40 (Shir. s, 4H).

Hydrochloride

1H NMR (400 MHz, D2O)(M. D.): 0,60 (d, J=6.6 Hz, 3H), of 1.03 (d, J=6.6 Hz, 3H), of 1.17 to 1.31 (m, 1H), 1,53 by 1.68 (m, 1H), 1,89 of 1.99 (m, 1H), 2,09-of 2.20 (m, 2H), 2,93-to 3.02 (m, 1H), 3,06 is 3.15 (m, 1H), 3,24-of 3.54 (m, 10H), 4,19 (t, J=4,9 Hz, 2H), 4,51 (s, 2H), PC 6.82-6.87 in (m, 2H), 6,93-of 6.99 (m, 2H), 7,32 (d, J=8,8 Il]-4-[2-(4-pertenece)ethyl]piperazine

DMSO (0.5 ml), triethylamine (0.5 ml) and a complex of a sulfur trioxide-pyridine (31 mg) are added to 1-[4-cyano-5-methyl-4-(4-hydroxymethylene)hexyl]-4-[2-(4-pertenece)ethyl]piperazine obtained in example 13, and the mixture is stirred at room temperature for 30 minutes. To the reaction mixture add the brine and simple ether, the organic layer is distributed, dried over anhydrous sodium sulfate and evaporated. The resulting residue is dissolved in ethanol (2 ml), then to the solution was added hydroxylamine hydrochloride (7 mg) and sodium acetate (9 mg) and the mixture is stirred at room temperature for 12 hours. To the reaction mixture is added aqueous saturated sodium bicarbonate and ethyl acetate, the organic layer is distributed, washed with water, dried over anhydrous sodium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel (system toluene/acetone), getting mentioned in the title compound (23 mg, 74%) as a colourless oil. To a solution of this free compound (8 mg) in methanol at room temperature is added a solution of 4 N. hydrogen chloride/ethyl acetate. The reaction mixture is stirred for 10 minutes and then the solvent is evaporated, through the NMR (400 MHz, CDCl3)(M. D.): 0,77 (d, J=6, 8 Hz, 3H), 1,19 (d, J=6.8 Hz, 3H), of 1.20 to 1.31 (m, 1H), 1,55-1,70 (m, 1H), 1,92 (dt, J=4,4, 12,5 Hz, 1H), 2,04-of 2.20 (m, 2H), 2,38 at 2.45 (m, 2H), 2,48-of 2.66 (m, 4H), 2,66-2,82 (m, 4H), to 2.85 (t, J=5.8 Hz, 2H), 4,08 (t, J=5.8 Hz, 2H), 6,79-6,84 (m, 2H), 6,92-6,97 (m, 2H), 7,37 (d, J=8,4 Hz, 2H), 7,50 (d, J=8,4 Hz, 2H), of 8.06 (s, 1H).

Hydrochloride

1H NMR (400 MHz, D2O)(M. D.): 0,61 (d, J=6.6 Hz, 3H), was 1.04 (d, J=6.6 Hz, 3H), of 1.17 to 1.31 (m, 1H), 1,53 by 1.68 (m, 1H), 1,90-2,00 (m, 1H), 2,10-of 2.23 (m, 2H), 2.91 in-a 3.01 (m, 1H), 3.04 from-3,14 (m, 1H), 3,22-of 3.46 (m, 10H), 4,18 (t, J=4,9 Hz, 2H), PC 6.82-6.87 in (m, 2H), 6,92-of 6.99 (m, 2H), 7,40 (d, J=8,2 Hz, 2H), 7,56 (d, J=8,2 Hz, 2H), 8,13 (s, 1H).

ESI-Macc: 467 (MH+).

Example 15. Synthesis of 1-[4-cyano-5-methyl-4-(4-cyanophenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

Carbonyldiimidazole (26 mg) are added to a solution of 1-[4-cyano-5-methyl-4-(4-hydroxyaminobuteroyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine (15 mg) obtained in example 14 in tetrahydrofuran (2 ml) and then the solution was stirred at 50°C for 12 hours. To the reaction mixture are added water and ethyl acetate and the organic layer is distributed, washed with water, dried over anhydrous sodium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel (system toluene/acetone) to give specified in the header of the connection (the temperature value add solution of 4 N. hydrogen chloride/ethyl acetate. The reaction mixture is stirred for 10 minutes and then the solvent is evaporated, whereby receive hydrochloride (10 mg) specified in the connection header.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 0,96-1,10 (m, 1H), 1,22 (d, J=6.8 Hz, 3H), 1,49-to 1.63 (m, 1H), 1,89 (dt, J=4,4, 12,5 Hz, 1H), 2,07 was 2.25 (m, 2H), 2,30 (t, J=7,0 Hz, 2H), 2,32 is 2.46 (m, 4H), 2,46-to 2.65 (m, 4H), 2,78 (t, J=5.8 Hz, 2H), of 4.05 (t, J=5.8 Hz, 2H), for 6.81-6,85 (m, 2H), 6,93-6,98 (m, 2H), 7,52 (d, J=8.6 Hz, 2H), 7,69 (d, J=8.6 Hz, 2H).

Hydrochloride

1H NMR (400 MHz, D2O)(M. D.): 0,59 (d, J=6.6 Hz, 3H), was 1.04 (d, J=6.6 Hz, 3H), 1,11-of 1.26 (m, 1H), 1,54 was 1.69 (m, 1H), 1.93 and-2,03 (m, 1H), 2,10-of 2.24 (m, 2H), 2,98-is 3.08 (m, 1H), 3,09-3,20 (m, 1H), 3,31-of 3.60 (m, 10H), is 4.21 (t, J=4,9 Hz, 2H), PC 6.82-6.87 in (m, 2H), 6,92-of 6.99 (m, 2H), 7,51 (d, J=8,4 Hz, 2H), 7,72 (d, J=8,4 Hz, 2H).

ESI-Macc: 449 (MH+).

Example 16. Synthesis of 1-[4-cyano-5-methyl-4-(4-nitrophenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

Specified in the title compound (356 mg, 90%) was obtained as colorless oil from 2-(1-methylethyl)-5-oxo-2-(4-nitrophenyl)pentenenitrile (219 mg) and 1-[2-(4-pertenece)ethyl]piperazine (210 mg) in the same manner as in example 1. This free compound (44 mg) is treated in the same manner as in example 1, obtaining G3)(M. D.): 0,78 (d, J=6.8 Hz, 3H), 0,96-1,10 (m, 1H), 1,24 (d, J=6.8 Hz, 3H), 1,50-to 1.63 (m, 1H), 1,92 (dt, J=4,4, 12,5 Hz, 1H), 2,11-of 2.26 (m, 2H), 2,28 (t, J=7,1 Hz, 2H), 2,30 is 2.44 (m, 4H), 2,46-of 2.66 (m, 4H), 2,77 (t, J=5.8 Hz, 2H), Android 4.04 (t, J=5.8 Hz, 2H), 6,80-6,85 (m, 2H), 6,93-6,98 (m, 2H), 7,58 (d, J=9.0 Hz, 2H), of 8.25 (d, J=9.0 Hz, 2H).

Hydrochloride

1H NMR (400 MHz, D2O)(M. D.): 0,61 (d, J=6.6 Hz, 3H), of 1.05 (d, J=6.6 Hz, 3H), 1,15-1,30 (m, 1H), 1,57-1,72 (m, 1H), 1,96-to 2.06 (m, 1H), 2,17-of 2.28 (m, 2H), 3,03-of 3.12 (m, 1H), 3,13-3,24 (m, 1H), 3,35-the 3.65 (m, 10H), 4,22 (Shir.t, J=4.9 Hz, 2H), PC 6.82-6.87 in (m, 2H), 6,92-of 6.99 (m, 2H), 7,58 (d, J=8,8 Hz, 2H), 8,18 (d, J=8,8 Hz, 2H).

ESI-Macc: 469 (MH+).

Example 17. Synthesis of 1-[4-cyano-5-methyl-4-(4-AMINOPHENYL)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

The catalyst is 10% palladium/charcoal (10 mg) are added to a solution of ethyl acetate (5 ml) containing 1-[4-cyano-5-methyl-4-(4-nitrophenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine (312 mg) obtained in example 16, and then the mixture is stirred for 5 hours at room temperature in a stream of hydrogen gas. The reaction mixture is filtered and the filtrate is evaporated. The resulting residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate), thereby obtaining specified in the title compound (87 mg, 30%) as a colourless oil. To a solution of gandevani the reaction mixture within 10 minutes the solvent is evaporated, whereby receive hydrochloride (32 mg) specified in the connection header.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,78 (d, J=6.8 Hz, 3H), of 1.16 (d, J=6.8 Hz, 3H), 1,47-to 1.61 (m, 1H), 1,77-of 1.85 (m, 2H), 1,99 with 2.14 (m, 2H), 2,28 (t, J=7,1 Hz, 2H), 2,30 at 2.45 (m, 4H), 2,46-to 2.67 (m, 4H), 2,77 (t, J=5.8 Hz, 2H), 3,68 (Shir.s, 2H), Android 4.04 (t, J=5.8 Hz, 2H), 6,66 (d, J=8,4 Hz, 2H), for 6.81-6,85 (m, 2H), 6,92-6,98 (m, 2H), 7,11 (d, J=8,4 Hz, 2H).

Hydrochloride

1H NMR (400 MHz, D2O)(M. D.): 0,59 (d, J=6, 6 Hz, 3H), of 1.02 (d, J=6.6 Hz, 3H), between 1.19 to 1.31 (m, 1H), 1.56 to 1.69 in (m, 1H), 1.93 and-2,04 (m, 1H), 2,09-of 2.23 (m, 2H), 3.04 from-3,14 (m, 1H), 3,15-3,24 (m, 1H), 3,39-and 3.72 (m, 10H), 4,24 (Shir.t, J=4.9 Hz, 2H), 6,83-6,87 (m, 2H), 6,93-of 6.99 (m, 2H), 7,35 (d, J=8.6 Hz, 2H), of 7.48 (d, J=8.6 Hz, 2H).

ESI-Macc: 439 (MH+).

Example 18. Synthesis of 1-[4-cyano-5-methyl-4-(4-acetamidophenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

Acetic anhydride (1 ml) are added to a solution of pyridine (2 ml) containing 1-[4-cyano-5-methyl-4-(4-AMINOPHENYL)hexyl]-4-[2-(4-pertenece)ethyl]piperazine (15 mg) obtained in example 17, and the mixture is stirred at room temperature for 12 hours. The reaction mixture is evaporated and the residue purified by chromatography on a column of silica gel (system toluene/acetone), thus obtaining specified in the header of the connection R 4 is H. hydrogen chloride/ethyl acetate. After stirring the reaction mixture for 10 minutes the solvent is evaporated, whereby receive hydrochloride (17 mg) specified in the connection header.

Free connection

1H NMR (400 MHz, CDCl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,10-1,22 (m, 1H), 1,18 (d, J=6.8 Hz, 3H), 1,49-to 1.63 (m, 1H), 1,87 (dt, J=4,0, to 12.8 Hz, 1H), 2,03-2,17 (m, 2H), 2,19 (s, 3H), 2,35 (t, J=7,1 Hz, 2H), 2,38-of 2.54 (m, 4H), 2,55 is 2.75 (m, 4H), of 2.81 (t, J=5.8 Hz, 2H), 4,06 (t, J=5.8 Hz, 2H), 6,79-6,85 (m, 2H), 6,93-of 6.99 (m, 2H), 7,29 (Shir. s, 1H), 7,31 (d, J=8,4 Hz, 2H), 7,52 (d, J=8,4 Hz, 2H).

Hydrochloride

1H NMR (400 MHz, D2O)(M. D.): 0,61 (d, J=6, 6 Hz, 3H), of 1.03 (d, J=6.6 Hz, 3H), of 1.20 and 1.35 (m, 1H), 1,54 was 1.69 (m, 1H), 1,86 of 1.99 (m, 1H), 2,03 (s, 3H), 2.05 is-2,22 (m, 2H), 2,96-of 3.06 (m, 1H), is 3.08-3,20 (m, 1H), 3.33 and-3,59 (m, 10H), 4,21 (Shir. t, J=4.9 Hz, 2H), 6,83-to 6.88 (m, 2H), 6,94-7,00 (m, 2H), 7,33 (d, J=9.0 Hz, 2H), was 7.36 (d, J=9.0 Hz, 2H).

ESI-Macc: 481 (MH+).

Example 19. Synthesis of 1-[4-cyano-5-methyl-4-(4-dimethylaminophenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

Paraformaldehyde (30 mg) and cyanoborohydride sodium (30 mg) are added to a solution in acetic acid (2 ml) containing 1-[4-cyano-5-methyl-4-(4-AMINOPHENYL)hexyl]-4-[2-(4-pertenece)ethyl]piperazine (21 mg) obtained in example 17, and the mixture is then stirred at room temp is saturated sodium bicarbonate and ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate), thereby obtaining specified in the title compound (12 mg, 56%) as a colourless oil. To a solution of this free compound (12 mg) in methanol is added a solution of 4 N. hydrogen chloride/ethyl acetate. After stirring the reaction mixture for 10 minutes the solvent is evaporated, whereby receive hydrochloride (14 mg) specified in the connection header.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,79 (d, J=6.8 Hz, 3H), of 1.16 (d, J=6.8 Hz, 3H), 1,17-1,24 (m, 1H), 1,49-of 1.62 (m, 1H), equal to 1.82 (dt, J=4,0, to 12.8 Hz, 1H), 1,99 with 2.14 (m, 2H), 2,28 (t, J=7,1 Hz, 2H), 2,30-2,47 (m, 4H), 2,47-to 2.65 (m, 4H), 2,77 (t, J=5.8 Hz, 2H), 2.95 and (C, 6N), Android 4.04 (t, J=5.8 Hz, 2H), of 6.68 (d, J=9.0 Hz, 2H), 6,80-6,85 (m, 2H), 6,92-6,98 (m, 2H), 7,19 (d, J=9.0 Hz, 2H).

Hydrochloride

1H NMR (400 MHz, D2O)(M. D.): 0,59 (d, J=6, 6 Hz, 3H), of 1.03 (d, J=6.6 Hz, 3H), 1,17-of 1.30 (m, 1H), 1,55-1,70 (m, 1H), 1,94-2,05 (m, 1H), 2,10-of 2.25 (m, 2H), 3,01-up 3.22 (m, 2H), 3,17 (s, 3H), 3,34-of 3.60 (m, 10H), 4,22 (Shir.t, J=4.9 Hz, 2H), 6,83-to 6.88 (m, 2H), 6,94-of 6.99 (m, 2H), 7,55 (Shir.s, 4H).

ESI-Macc: 467 (MH+).

Example 20. Synthesis of 1-{[4-cyano-5-methyl-4-(2-thienyl)hexyl]}-4-[2-(4-pertenece)ethyl]piperazine

Free connection

1H NMR (400 MHz, CDCl3)(M. D.): 0,90 (d, J=6.8 Hz, 3H), of 1.18 (d, J=6.8 Hz, 3H), 1,23-to 1.38 (m, 1H), 1,57 is 1.70 (m, 1H), 1.77 in (dt, J=4.0 Hz, 12.0 Hz, 2H), 2,00-2,10 (m, 1H), 2,11-of 2.20 (m, 1H), 2.26 and to 2.35 (m, 2H), 2,35-2,49 (m, 4H), 2,49-of 2.66 (m, 4H), 2,78 (t, J=5.8 Hz, 2H), Android 4.04 (t, J=5.8 Hz, 2H), 6,80-6,86 (m, 2H), 6,92-of 6.99 (m, 3H), 7,11 (DD, J=1.2 Hz, 3.6 Hz, 1H), 7.24 to 7,27 (m, 1H).

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,80 (d, J=6.8 Hz, 3H), of 1.07 (d, J=6.8 Hz, 3H), 1,40-of 1.55 (m, 1H), 1,66-to 1.82 (m, 1H), 1,87 of 1.99 (m, 1H), 2.06 to 2,30 (m, 2H), 3.00 and-4,0 (m, N), 4,34 (Shir.s, 2H), 6,98-was 7.08 (m, 3H), 7,10-to 7.18 (m, 3H), EUR 7.57 (DD, J=1.2 Hz, 4.8 Hz, 1H).

ESI-Macc: 430 (MH+).

Example 21. Synthesis of 1-{[4-cyano-5-methyl-4-(3-pyridyl)hexyl]}-4-[2-(4-pertenece)ethyl]piperazine

Specified in the title compound (325 mg, 54%) was obtained as colorless oil in the same manner as in example 1 from 2-(1-methylethyl)-5-oxo-2-(3-pyridyl)pentenenitrile (300 mg) synthesized from 3-pyridylacetonitrile, and 1-[2-(4-perfe 1, getting hydrochloride (300 mg) specified in the connection header.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,81 (d, J=6.8 Hz, 3H), 1,05-of 1.18 (m, 1H), 1,22 (d, J=6.8 Hz, 3H), 1,52-of 1.65 (m, 1H), 1,89 of 1.99 (m, 1H), 2,10-of 2.24 (m, 2H), 2,25 of-2.32 (m, 2H), 2,32 is 2.46 (m, 4H), 2,46-of 2.64 (m, 4H), 2,77 (t, J=5.8 Hz, 2H), Android 4.04 (t, J=5.8 Hz, 2H), 6,80-6,86 (m, 2H), 6,92-of 6.99 (m, 2H), 7,30 and 7.36 (m, 1H), 7,70 to 7.75 (m, 1H), 8,55-8,59 (m, 1H), 8,63-8,67 (m, 1H).

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0.69 (d, J=6,86 Hz, 3H), 1,11 (d, J=6.8 Hz, 3H), 1,22-of 1.39 (m, 1H), 1.60-to of 1.73 (m, 1H), 2,17-to 2.40 (m, 3H), 2.95 and-of 3.85 (m, N), or 4.31 was 4.42 (m, 2H), 6,97-7,06 (m, 2H), 7,09-to 7.18 (m, 2H), 7,84-a 7.92 (m, 1H), 8,28-at 8.36 (m, 1H), 8,78-8,88 (m, 2H).

ESI-Macc: 425 (MH+).

Example 22. Synthesis of 1-{[4-cyano-5-methyl-4-(2-forfinal)hexyl]}-4-[2-(4-pertenece)ethyl]piperazine

Specified in the title compound (67 mg, 12%) was obtained as colorless oil in the same manner as in example 1 from 2-(1-methylethyl)-5-oxo-2-(2-forfinal)pentenenitrile (290 mg), synthesized from 2-perforaciones, and 1-[2-(4-pertenece)ethyl]piperazine (278 mg). This free compound (67 mg) is treated in the same manner as in example 1, obtaining hydrochloride (60 mg) specified in the connection header.

Free connection

1H NMR (400 MHz, Dl3

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,73 (d, J=6.8 Hz, 3H), 1,11 (d, J=6.8 Hz, 3H), 1,20-of 1.39 (m, 1H), 1,57-of 1.73 (m, 1H), 2,08-of 2.20 (m, 2H), 2,30-to 2.42 (m, 1H), 3,30 of 3.75 (m, N), 4,29 (Shir.s, 2H), 6,97-7,03 (m, 2H), 7,10-7,17 (m, 2H), 7.24 to 7,32 (m, 2H), 7,42-7,53 (m, 2H).

ESI-Macc: 424 (MH+).

Example 23. Synthesis of 1-{[4-cyano-5-methyl-4-(3-forfinal)hexyl]}-4-[2-(4-pertenece)ethyl]piperazine

Specified in the title compound (258 mg, 45%) was obtained as colorless oil in the same manner as in example 1 from 2-(1-methylethyl)-5-oxo-2-(3-forfinal)pentenenitrile (300 mg) synthesized from 3-perforaciones, and 1-[2-(4-pertenece)ethyl]piperazine (289 mg). This free compound (258 mg) is treated in the same manner as in example 1, obtaining hydrochloride (80 mg) specified in the connection header.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,79 (d, J=6.8 Hz, 3H), 1.04 million-1,17 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-1,60 (m, 1H), of 1.85 (dt, J=4.4 Hz, to 13.6 Hz, 1H), 2,03-of 2.20 (m, 2H), 2,22-2,31 (m, 2H), 2,31 is 2.46 (m, 4H), 2,46-of 2.66 (m, 4H), 2,77 (t, J=6.0 Hz, 2H), Android 4.04 (t, J=6.0 Hz, 2H), 6,80-6,85 (m, 2H), 6,92? 7.04 baby mortality (m, 3H), 7,05-7,10 (m, 1H), 7,16-7,20 (m, 1H), 7,30-7,37 (m, 1H).

Hydrochloride

1

ESI-Macc: 424 (MH+).

Example 24. Synthesis of 1-{[4-cyano-5-methyl-4-(4-forfinal)hexyl]}-4-[2-(4-pertenece)ethyl]piperazine

Specified in the title compound (78 mg, 17%) was obtained as colorless oil in the same manner as in example 1 from 2-(1-methylethyl)-5-oxo-2-(4-forfinal)pentenenitrile (242 mg), synthesized from 4-perforaciones, and 1-[2-(4-pertenece)ethyl]piperazine (233 mg). This free compound (78 mg) is treated in the same manner as in example 1, obtaining hydrochloride (62 mg) specified in the connection header.

Free connection

1H NMR (400 MHz, CDCl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,02-of 1.18 (m, 1H), 1,19 (d, J=6.8 Hz, 3H), 1,48-of 1.62 (m, 1H), 1,80-1,89 (m, 1H), 2,02-2,19 (m, 2H), 2.23 to-2,31 (m, 2H), 2,31 is 2.46 (m, 4H), 2,46-of 2.66 (m, 4H), 2,77 (t, J=5.8 Hz, 2H), Android 4.04 (t, J=5.8 Hz, 2H), 6,79-6,86 (m, 2H), 6,93-of 6.99 (m, 2H), 7,02-to 7.09 (m, 2H), 7,31-7,37 (m, 2H).

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,66 (d, J=6.8 Hz, 3H), of 1.09 (d, J=6.8 Hz, 3H), 1,15-1,30 (m, 1H), 1,50-to 1.67 (m, 1H), 2.00 in 2,22 (m, 3H), 2.95 and-of 3.80 (m, N), 4,30 (Shir.s, 2H), 6,97-7,03 (m, 2H), 7,10-7,17 (m, 2H), 7.24 to 7,31 (m, 2H), 7,43-7,49 (m, 2H).

ESI-Macc: 424 (MH+).

Example 25. Synthesis of 1-[(3-cyano-4-methyl-3-phenyl)pokazanego in the title compound obtained as a colorless oil from 2-(1-methylethyl)-4-oxo-2-phenylbutyramide (0,12 mg) and 1-[2-(4-pertenece)ethyl]piperazine (0.12 g) in the same way, as in example 1.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,78 (d, J=6.8 Hz, 3H), 1,21 (d, J=6.8 Hz, 3H), 1,95-of 2.16 (m, 3H), 2,32-2,48 (m, 6N), 2,48-2,62 (m, 4H), 2,77 (t, J=6.0 Hz, 2H), a 4.03 (t, J=6.0 Hz, 2H), 6,79-6,85 (m, 2H), 6,92-6,98 (m, 2H), 7,26-7,34 (m, 1H), 7,34-7,40 (m, 4H).

The above free compound (0.17 g) is treated in the usual way, getting hydrochloride (0.18 g) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,66 (d, J=6.8 Hz, 3H), 1,11 (d, J=6.8 Hz, 3H), 2,18-of 2.26 (m, 1H), 2,54 of 2.68 (m, 2H), 3,40-of 3.80 (m, N), 4,32 (Shir.s, 2H), of 6.96-7.03 is (m, 2H), 7,10-to 7.18 (m, 2H), 7,34-7,42 (m, 1H), 7,42-of 7.48 (m, 4H).

ESI-Macc: 410 (MH+).

Example 26. Synthesis of 1-[(4-cyano-4-phenyl)pentyl]-4-[2-(4-pertenece)ethyl]piperazine

The free compound (0.35 g, 83%) indicated in the title compound obtained as a colorless oil from 2-methyl-5-oxo-2-phenylpentane (0.22 mg) and 1-[2-(4-pertenece)ethyl]piperazine (0.24 g) in the same manner as in example 1.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 1,33-of 1.45 (m, 1H), 1,60-1,70 (m, 1H), 1,72 (s, 3H), 1.91 a is 2.00 (m, 2H), 2,30 (t, J=6.8 Hz, 3H), 2,41 (Shir.s, 4H), 2.57 m (Shir.s, 4H), 2,78 (t, J=6.0 Hz, 2H), Android 4.04 (t, J=6.0 Hz, 2H), 6,80-6,86 (m, 2H), 6,92-of 6.99 (m, 2H), 7,27-7,33 (m, 1H), 7,33 was 7.45 (m, 4H).

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 1,48-1,50 (m, 1H), 1,68 (s, 3H), 1,72 is 1.86 (m, 1H), 1,95-2,05 (m, 2H), 3.04 from-3,18 (m, 1H), 3,20-of 3.80 (m, 11N), 4,33 (Shir.s, 2H), 6,97? 7.04 baby mortality (m, 2H), 7,10-to 7.18 (m, 2H), 7,33-7,37 (m, 1H), 7,40-7,51 (m, 4H).

ESI-Macc: 396 (MH+).

Example 27. Synthesis of 1-[(4-cyano-4-phenyl)heptyl]-4-[2-(4-pertenece)ethyl]piperazine

The free compound (0.35 g, 83%) indicated in the title compound obtained as a colorless oil from 5-oxo-2-phenyl-2-propylpentanoate (0.22 mg) and 1-[2-(4-pertenece)ethyl]piperazine (0.24 g) in the same manner as in example 1.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): of 0.87 (t, J=7.2 Hz, 3H), 1.06 a-1,20 (m, 1H), 1,22-of 1.33 (m, 1H), 1,42-and 1.54 (m, 1H), 1.60-to 1,72 (m, 1H), 1,80-2,05 (m, 4H), 2,28 (t, J=7.2 Hz, 2H), 2,39 (Shir.s, 4H), 2,56 (Shir.s, 4H), 2,77 (t, J=6.0 Hz, 2H), Android 4.04 (t, J=6.0 Hz, 2H), 6,80-6,86 (m, 2H), 6,92-of 6.99 (m, 2H), 7,26-7,32 (m, 1H), 7,34-7,40 (m, 4H).

The above free compound (0.35 g) is treated in the usual way, getting hydrochloride (0,37 g) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,82 (t, J=7.2 Hz, 3H), 0,92-of 1.05 (m, 1H), 1,24-to 1.37 (m, 1H), 1,37-1,50 (m, 1H), 1.70 to 1.85 to (m, 1H), 1.85 to to 1.98 (m, 2H), 1,98 is 2.10 (m, 2H), 3.00 and-3,18 (m, 2H), 3,20-of 3.80 (m, 10H), 4,33 (Shir.s, 2H), 6,97? 7.04 baby mortality (m, 2H), 7,10-is)ethyl]piperazine

The free compound (0.20 g, 83%) indicated in the title compound obtained as a colorless oil from 5-oxo-2-ethyl-2-phenylpentane (0,13 g) and 1-[2-(4-pertenece)ethyl]piperazine (0,13 g) in the same manner as in example 1.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,90 (t, J=7.2 Hz, 3H), of 1.23 to 1.34 (m, 1H), 1,59-1,71 (m, 1H), 1,88-of 2.09 (m, 4H), 2,28 (t, J=7.2 Hz, 2H), 2,39 (Shir.s, 4H), 2,56 (Shir.s, 4H), 2,77 (t, J=6.0 Hz, 2H), Android 4.04 (t, J=6.0 Hz, 2H), 6,80-6,86 (m, 2H), 6,92-of 6.99 (m, 2H), 7,27-7,33 (m, 1H), 7,34-7,40 (m, 4H).

The above free compound (0.20 g) is treated in the usual way, getting hydrochloride (0.14 g) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,77 (t, J=7.2 Hz, 3H), 1,38-of 1.52 (m, 1H), 1.70 to of 1.84 (m, 1H), 1,90-2,10 (m, 4H), 3.00 and-3,24 (m, 2H), 3,24-of 3.80 (m, 10H), 4,35 (Shir.s, 2H), 6,98? 7.04 baby mortality (m, 2H), 7,10-7,17 (m, 2H), 7,32-7,38 (m, 1H), 7,39-7,47 (m, 4H).

ESI-Macc: 410 (MH+).

Example 29. Synthesis of 1-[(4-cyano-4-phenyl)octyl]-4-[2-(4-pertenece)ethyl]piperazine

Free connection (0,22 g, 81%) indicated in the title compound obtained as a colorless oil from 2-butyl-5-oxo-2-phenylpentane (0.16 g) and 1-[2-(4-pertenece)ethyl]piperazine (0.14 g) in the same way,4 (t, J=7.2 Hz, 3H), of 1.03-1.14 in (m, 1H), 1,20-of 1.36 (m, 3H), 1,37-1,50 (m, 1H), 1,58-of 1.62 (m, 1H), 1,83-to 2.06 (m, 4H), 2,28 (t, J=7.2 Hz, 2H), 2,39 (Shir.s, 4H), 2,56 (Shir.s, 4H), 2,77 (t, J=6.0 Hz, 2H), Android 4.04 (t, J=6.0 Hz, 2H), 6,80-6,86 (m, 2H), 6,92-of 6.99 (m, 2H), 7,27-7,33 (m, 1H), 7,34-7,41 (m, 4H).

The above free connection (0,22 g) is treated in the usual way, getting hydrochloride (0,22 g) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,78 (t, J=7.2 Hz, 3H), 0.88 to 1.00 and (m, 1H), 1,17 is 1.34 (m, 3H), 1,35-1,49 (m, 1H), 1.70 to to 1.83 (m, 1H), 1,90-of 2.08 (m, 4H), 2,98-3,20 (m, 2H), 3,20-of 3.80 (m, 10H), 4,32 (Shir. s, 2H), 6,97-7,03 (m, 2H), 7,10-7,17 (m, 2H), 7,31-7,38 (m, 1H), 7,40-7,47 (m, 4H).

ESI-Macc: 438 (MH+).

Example 30. Synthesis of 1-[(4-cyano-6-methyl-4-phenyl)heptyl]-4-[2-(4-pertenece)ethyl]piperazine

Loose coupling (0,23 g, 85%) indicated in the title compound obtained as a colorless oil from 2-(2-methylpropyl)-5-oxo-2-phenylpentane (0.15 g) and 1-[2-(4-pertenece)ethyl]piperazine (0.14 g) in the same manner as in example 1.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,67 (d, J=6.4 Hz, 3H), 0,87-0,94 (m, 1H), and 0.98 (d, J=6.4 Hz, 3H), 1,14-of 1.30 (m, 1H), 1,55-1,72 (m, 2H), 1,84-2,05 (m, 3H), and 2.26 (t, J=7.2 Hz, 2H), 2,38 (Shir.s, 4H), 2,56 (Shir.s, 4H), 2,77 (t, J=6.0 Hz, 2H), Android 4.04 (t, J=6.0 Hz, 2H), 6,80-6,86 (m, 2H), 6,92-of 6.99 (m, 2H), 7,26-7,32 (m, Eid (0.21 g) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,62 (t, J=6.4 Hz, 3H), of 0.90 (d, J=6.4 Hz, 3H), of 1.33 to 1.48 (m, 2H), 1,33 is 2.10 (m, 5H), 2,97-3,18 (m, 2H), 3,20-of 3.80 (m, 10H), to 4.38 (Shir.s, 2H), 6,97? 7.04 baby mortality (m, 2H), 7,10-7,17 (m, 2H), 7,31-7,37 (m, 1H), 7,40-to 7.50 (m, 4H).

ESI-Macc: 438 (MH+).

Example 31. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-pertenece)ethyl]piperazine

The free compound (100 mg, 26%) indicated in the title compound obtained as a colorless oil from 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine (300 mg), 2-terfenol (408 mg), triphenylphosphine (263 mg) and a solution of 40% diethyl ester of azodicarboxylic acid/toluene (480 mg) in the same manner as in example 36-2).

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,05-of 1.18 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,49-to 1.61 (m, 1H), 1,89 (dt, J=4,4, to 13.6 Hz, 1H), 2.06 to 2,19 (m, 2H), 2,24-of 2.30 (m, 2H), 2,30 at 2.45 (m, 4H), 2,45-of 2.66 (m, 4H), 2,82 (t, J=6.0 Hz, 2H), 4,15 (t, J=6.0 Hz, 2H), 6,86-6,92 (m, 1H), 6,92-6,98 (m, 1H), 7,01-to 7.09 (m, 2H), 7,26-7,32 (m, 1H), 7,33-7,38 (m, 4H).

The above free compound (100 mg) is treated in the usual way, getting hydrochloride (117 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 ,33-7,40 (m, 1H), 7,41-7,49 (m, 4H).

ESI-Macc: 424 (MH+).

Example 32. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-pertenece)ethyl]piperazine

The free compound (204 mg, 53%) indicated in the title compound obtained as a colorless oil from 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine (300 mg), 3-terfenol (408 mg), triphenylphosphine (263 mg) and a solution of 40% diethyl ester of azodicarboxylic acid/toluene (480 mg) in the same manner as in example 36-2).

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,05-of 1.18 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,49-to 1.61 (m, 1H), of 1.88 (dt, J=4,4, and 12.4 Hz, 1H), 2,08-to 2.18 (m, 2H), 2,23-of 2.30 (m, 2H), 2,30 at 2.45 (m, 4H), 2,45-to 2.65 (m, 4H), 2,78 (t, J=5.8 Hz, 2H), 4,06 (t, J=5.8 Hz, 2H), 6,58-6,70 (m, 3H), 7,17-of 7.23 (m, 1H), 7,26-7,32 (m, 1H), 7,33-7,38 (m, 4H).

The above free compound (204 mg) is treated in the usual way, getting hydrochloride (234 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.4 Hz, 3H), of 1.12 (d, J=6.4 Hz, 3H), 1,16-of 1.30 (m, 1H), 1,52 by 1.68 (m, 1H), 2,00-2,30 (m, 3H), 3.00 and-3,70 (m, N), 4,20-and 4.40 (m, 2H), 6,78-of 6.90 (m, 3H), 7,30-7,39 (m, 2H), 7,42-of 7.48 (m, 4H).

ESI-Macc: 424 (MH+).

Example 33. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[3-(4-pertenece)pentyl]PI is s (1,94 g, 92%) indicated in the title compound obtained as a colorless oil from tert-butyl 1-piperidinecarboxylate (1.07 g) and 4-perteneciente (1,61 g) in the same manner as in preparatory example 4.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 1,50-1,90 (m, 10H), 2,34-of 2.50 (m, 4H), 2,90-2,96 (m, 2H), 3,88-of 3.96 (m, 2H), 6,79-6,85 (m, 2H), 6,93-of 6.99 (m, 2H).

33-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[3-(4-pertenece)pentyl]piperazine

The free compound (177 mg, 89%) indicated in the title compound obtained as a colorless oil from 2-(1-methylethyl)-5-oxo-2-phenylpentane (92 mg) and 1-[3-(4-forfinal)pentyl]piperazine (114 mg) in the same manner as in example 1.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,78 (d, J=6, 6 Hz, 3H), 1,05-1,20 (m, 1H), 1,20 (d, J=6.6 Hz, 3H), 1,40-1,90 (m, 10H), 2.05 is-of 2.20 (m, 2H), 2,20-of 2.50 (m, 10H), 3,85 is 3.40 (m, 2H), 6.75 in-6,85 (m, 2H), 6.90 to-7,00 (m, 2H), 7,25-7,40 (m, 5H).

The above free compound (175 mg) is treated in the usual way, getting hydrochloride (160 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,65 (d, J=6.6 Hz, 3H), of 1.09 (d, J=6.6 Hz, 3H), of 1.20 and 1.35 (m, 1H), 1,40-1,60 (m, 2H), 1,60-1,80 (m, ar 34. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)heptyl]-4-[3-(4-pertenece)ethyl]piperazine

The free compound (54 mg, 2.9 per cent) indicated in the title compound obtained as a colorless oil from 2-(1-methylethyl)-5-oxo-2-phenylhexanoic (928 mg) and 1-[3-(4-forfinal)ethyl]piperazine (104 mg) in the same manner as in example 1.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.4 Hz, 3H), 0,90-1,00 (m, 1H), 1,19 (d, J=6.4 Hz, 3H), 1.32 to to 1.42 (m, 1H), 1,45-of 1.52 (m, 1H), 1,80-1,90 (m, 1H), 2,05-of 2.20 (m, 2H), 2,20-of 2.27 (m, 2H), 2,30-of 2.50 (m, 4H), 2,50-to 2.65 (m, 4H), 2,78 (t, J=6.0 Hz, 2H), of 4.05 (t, J=6.0 Hz, 2H), 6,80-6,85 (m, 2H), 6.90 to-7,00 (m, 2H), 7,28-7,32 (m, 1H), 7,32-7,40 (m, 4H).

This free compound (54 mg) is treated in the usual way, getting hydrochloride (40 mg) specified in the connection header.

Hydrochloride

lH NMR (400 MHz, DMSO-d6)(M. D.): 0,66 (d, J=6.4 Hz, 3H), or 0.83 (m, 1H), 1,13 (d, J=6.4 Hz, 3H), 1,15-1,30 (m, 1H), 1,55-1,75 (m, 1H), 2,00-2,30 (m, 3H), 2.95 and-3,10 (m, 1H), 3,30-of 3.80 (m, 4H), 4,34 (m, 2H), 6,95-7,05 (m, 2H), 7,10-7,20 (m, 2H), 7,30-7,40 (m, 2H), 7,40-to 7.50 (m, 4H).

ESI-Macc: 438 (MH+).

Example 35. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3,4-divergence)ethyl]piperazine

The free compound (96 mg, 24%) specified in the connection header of orfanou (360 mg), triphenylphosphine (290 mg) and a solution of 40% diethyl ester of azodicarboxylic acid/toluene (440 mg) in the same manner as in example 36-2).

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1.04 million-of 1.18 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,48-to 1.61 (m, 1H), of 1.88 (dt, J=4,4, to 13.6 Hz, 1H), 2,08-to 2.18 (m, 2H), and 2.27 (Shir.t, J=7,6 Hz, 2H), 2,30 is 2.46 (m, 4H), 2,46-2,62 (m, 4H), was 2.76 (t, J=5.8 Hz, 2H), 4,01 (t, J=5.8 Hz, 2H), 6,55-6,60 (m, 1H), 6,68-6,74 (m, 1H), 7,00-7,07 (m, 1H), 7,26-7,31 (m, 1H), 7,34-7,38 (m, 4H).

The above free compound (96 mg) is treated in the usual way, getting hydrochloride (110 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.8 Hz, 3H), 1,11 (d, J=6.8 Hz, 3H), of 1.17 and 1.33 (m, 1H), 1,54 is 1.70 (m, 1H), 2.05 is was 2.25 (m, 3H), 3.00 and-of 3.80 (m, N), 4,25-and 4.40 (m, 2H), for 6.81-6.87 in (m, 1H), 7,12-7,20 (m, 1H), 7,34-7,42 (m, 2H), 7,42-7,49 (m, 4H).

ESI-Macc: 422 (MH+).

Example 36. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-chlorophenoxy)ethyl]piperazine

36-1) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine

The free compound (1.06 g, 75%) indicated in the title compound obtained as a colorless oil from 2-(1-methylethyl)-5-oxo-2-phenylpentane (1,00 g) and 1-piperazineethanol (1,21 g) in the same manner as in when, N), 1,06 is 1.20 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,49-to 1.63 (m, 1H), of 1.88 (dt, J=4.4 Hz, to 12.8 Hz, 1H), 2,08-2,19 (m, 2H), 2,22-of 2.30 (m, 2H), 2,30-to 2.41 (m, 4H), 2,41 is 2.55 (m, 4H), 2,52 (t, J=5.8 Hz, 2H), 3,57 (t, J=5.8 Hz, 2H), 7,26-7,32 (m, 1H), 7,34-7,39 (m, 4H).

ESI-Macc: 330 (MH+).

36-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-chlorophenoxy)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine (500 mg), 4-chlorophenol (390 mg) and triphenylphosphine (796 mg) dissolved in tetrahydrofuran (15.0 ml), and then to the solution was added a solution of 40% diethyl ester of azodicarboxylic acid/toluene (529 mg) in tetrahydrofuran (5 ml), and the mixture is stirred at room temperature overnight. The reaction mixture is evaporated and the residue purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate), whereby the free compound (47 mg, 7%) indicated in the title compound obtained as a colorless oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1.04 million-1,19 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-of 1.65 (m, 1H), of 1.88 (dt, J=4,4, to 12.8 Hz, 1H), 2,08-to 2.18 (m, 2H), and 2.27 (Shir.t, J=7.2 Hz, 2H), 2,30 is 2.43 (m, 4H), 2,50-2,62 (m, 4H), 2,77 (t, J=6.0 Hz, 2H), Android 4.04 (t, J=6.0 Hz, 2H), 6,80-6,84 (m, 2H), 7,19-of 7.23 (m, 2H), 7,25-7,31 (m, 1H), 7,33-7,38 (m, 4H).

The above free compound (47 mg) clicks the p>1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.8 Hz, 3H), 1,11 (d, J=6.8 Hz, 3H), 1,30-1,45 (m, 1H), 1,59-1,72 (m, 1H), 2,08 was 2.25 (m, 3H), 3.00 and is 4.35 (m, N), to 4.38 figure-4.49 (m, 2H), 7,07-7,34 (m, 2H), 7,34-7,40 (m, 3H), 7,42-of 7.48 (m, 4H).

ESI-Macc: 440 (MH+).

Example 37. Synthesis of 1-{[4-cyano-5-methyl-4-(3,4-dichlorophenyl)hexyl]}-4-[2-(4-pertenece)ethyl]piperazine

Specified in the title compound (390 mg, 68%) was obtained as colorless oil in the same manner as in example 1 from 2-(1-methylethyl)-5-oxo-2-(3,4-dichlorophenyl)pentenenitrile (330 mg), synthesized from 3,4-dichlorobenzonitrile, and 1-[2-(4-pertenece)ethyl]piperazine (312 mg).

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,79 (d, J=6.8 Hz, 3H), 1,02-1,15 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,49-of 1.65 (m, 1H), 1,78-1,89 (m, 1H), 2,02-of 2.20 (m, 2H), 2,22-2,48 (m, 6N), 2,48-of 2.66 (m, 4H), 2,78 (t, J= 5.8 Hz, 2H), Android 4.04 (t, J=5.8 Hz, 2H), 6,80-6,86 (m, 2H), 6,92-of 6.99 (m, 2H), 7.23 percent (DD, J=2 Hz and 8.4 Hz, 1H), 7,43-of 7.48 (m, 2H).

The above free compound (390 mg) is treated in the usual way, getting hydrochloride (348 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,66 (d, J=6.6 Hz, 3H), 1,10 (d, J=6.6 Hz, 3H), 1,16-of 1.30 (m, 1H), 1,531 by 1.68 (m, 1H), 2,02-of 2.30 (m, 3H), 2,97-3,74 (m, N), 4,24-to 4.38 (Shir.s, 2H), 6,97-7,03 (illogical-4-phenyl)butyl]-4-[2-(4-pertenece)ethyl]piperazine

The free compound (0.17 g, 67%) indicated in the title compound obtained as a colorless oil from 2-cyclohexyl-5-oxo-2-phenylpentane (0.16 g), 1-[2-(4-pertenece)ethyl]piperazine (0.12 g) in the same manner as in example 1.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,99-of 1.18 (m, 4H), of 1.18 to 1.34 (m, 3H), 1,48-1,77 (m, 4H), 1,82-of 1.92 (m, 2H), 2.05 is-of 2.23 (m, 2H), and 2.27 (t, J=6,8 Hz, 2H), 2,36 (Shir.s, 4H), 2,55 (Shir.s, 4H), 2,77 (t, J=6.0 Hz, 2H), Android 4.04 (t, J=6.0 Hz, 2H), 6,79-6,86 (m, 2H), 6,92-of 6.99 (m, 2H), 7,26-7,32 (m, 1H), 7,33-7,39 (m, 4H).

The above free compound (0.17 g) is treated in the usual way, getting hydrochloride (0,19 g) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): the 0.80 to 0.92 (m, 1H), of 0.96 to 1.34 (m, 6N), 1,52 by 1.68 (m, 3H), 1,72-to 1.87 (m, 2H), 2.00 in of 2.23 (m, 3H), 2,97 is 3.23 (m, 2H), 3,24-of 3.80 (m, 10H), 4,34 (Shir.s, 2H), 6,97? 7.04 baby mortality (m, 2H), 7,10-7,17 (m, 2H), 7,31-7,38 (m, 1H), 7,39-7,47 (m, 4H).

ESI-Macc: 464 (MH+).

Example 39. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-methoxyphenoxy)ethyl]piperazine

Loose coupling (877 mg, 85%) indicated in the title compound obtained as a colorless oil from 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine (780 mg)24 g) in the same way, as in example 36-2).

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1.06 a-1,18 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-of 1.65 (m, 1H), of 1.88 (dt, J=4,4, to 13.6 Hz, 1H), 2,07-of 2.20 (m, 2H), and 2.27 (Shir.t, J=7.2 Hz, 2H), 2,30 is 2.46 (m, 4H), 2,46-to 2.65 (m, 4H), was 2.76 (t, J=5.8 Hz, 2H), 3,76 (s, 3H), a 4.03 (t, J=5.8 Hz, 2H), 6,79-6,86 (m, 4H), 7,26-7,32 (m, 1H), 7,34-7,40 (m, 4H).

The above free connection (877 mg) is treated in the usual way, getting hydrochloride (995 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.8 Hz, 3H), of 1.12 (d, J=6.8 Hz, 3H), 1,15-1,30 (m, 1H), 1,55-to 1.67 (m, 1H), 2,03-of 2.27 (m, 3H), 2,96-of 3.85 (m, N), 3,70 (s, 3H), 4,16-to 4.33 (m, 2H), 6,85-of 6.96 (m, 4H), 7,34-7,41 (m, 1H), 7,42-7,49 (m, 4H).

ESI-Macc: 436 (MH+).

Example 40. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2,3-dimethoxyphenoxy)ethyl]piperazine

The free compound (112 mg, 26%) indicated in the title compound obtained as a colorless oil from 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine (300 mg), 2,3-dimethoxyphenol (720 mg), triphenylphosphine (290 mg) and a solution of 40% diethyl ester of azodicarboxylic acid/toluene (440 mg) in the same manner as in example 36-2).

Free connection

1H NMR (400 MHz, Dl3)

The above free compound (112 mg) is treated in the usual way, getting hydrochloride (129 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.8 Hz, 3H), of 1.12 (d, J=6.8 Hz, 3H), 1,20-1,32 (m, 1H), 1,57-1,71 (m, 1H), 2,05-of 2.26 (m, 3H), 3.00 and-3,90 (m, N), 3,68 (s, 3H), of 3.78 (s, 3H), 4.26 deaths was 4.42 (m, 2H), 6,68-6,74 (m, 2H), 7,01 (t, J= 8,4 Hz, 1H), 7,34-7,40 (m, 1H), 7,43-7,49 (m, 4H).

ESI-Macc: 466 (MH+).

Example 41. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3,4-dimethoxyphenoxy)ethyl]piperazine

The free compound (104 mg, 25%) specified in the title compound obtained as a colorless oil from 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine (300 mg), 3,4-dimethoxyphenol (720 mg), triphenylphosphine (290 mg) and 40% solution of diethyl ester of azodicarboxylic acid/toluene (440 mg) in the same manner as in example 36-2).

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,05-of 1.18 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-to 1.61 (m, 1H), of 1.88 (dt, J=4.4 Hz, to 13.6 Hz, 1H), 2,08-2,19 (m, 2H), 2,28 (s (d, J=2,8, 1H), 6,76 (d, J=8,8 Hz, 1H), 7,26-7,31 (m, 1H), 7,32-7,38 (m, 4H).

The above free compound (104 mg) is treated in the usual way, getting hydrochloride (119 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.8 Hz, 3H), of 1.12 (d, J=6.8 Hz, 3H), 1,15-1,32 (m, 1H), 1,55 by 1.68 (m, 1H), 2,03-of 2.27 (m, 3H), 3.00 and-of 3.85 (m, N), of 3.69 (s, 3H), 3,74 (s, 3H), 4,20 is 4.35 (m, 2H), 6.48 in (lat.DD, J=2,8 Hz and 8.8 Hz, 1H), 6,63 (Shir.d, J=2,8 Hz, 1H), 6,86 (d, J=8,8 Hz, 1H), 7,34-7,40 (m, 1H), 7,42-to 7.50 (m, 4H).

ESI-Macc: 466 (MH+).

Example 42. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-aminophenoxy)ethyl]piperazine

In an atmosphere of hydrogen 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-nitrophenoxy)ethyl]piperazine (925 mg) dissolved in methanol (20 ml), then to the solution was added 10% Pd/C (90 mg) and the mixture is stirred over night at room temperature. After removal of 10% Pd/C by filtration, the filtrate is evaporated, whereby the free compound (840 mg, 97%) indicated in the title compound obtained as a yellow oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,05-of 1.18 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-of 1.62 (m, 1H), of 1.88 (dt, J=4.4 Hz, to 12.8 Hz, 1H), 2,08-to 2.18 (m, 2H), and 2.27 (Shir.t, J=7.2 Hz, 2H), 2,30 at 2.45 (m, 4H is connected the free compound (272 mg) is treated in the same way, as in example 1, obtaining hydrochloride (332 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.8 Hz, 3H), 1,11 (d, J=6.8 Hz, 3H), 1,15-1,32 (m, 1H), 1,55-1,70 (m, 1H), 2.06 to to 2.25 (m, 3H), 2,97 of 3.75 (m, 14N), 4,30 was 4.42 (m, 2H), 7,07-7,13 (m, 2H), 7,32-7,40 (m, 3H), 7,43-of 7.48 (m, 4H).

ESI-Macc: 421 (MH+).

Example 43. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-dimethylaminoethoxy)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-aminophenoxy)ethyl]piperazine (243 mg) was dissolved in acetonitrile (5.0 ml) and 37% aqueous formaldehyde (1.0 ml), the solution add cyanoborohydride sodium (153 mg) and glacial acetic acid (0.2 ml) and the mixture is stirred over night at room temperature. The organic layer distributes the addition of an aqueous saturated sodium bicarbonate and ethyl acetate, washed with water and dried over anhydrous sodium sulfate, after removal of the drying agent by filtration, the filtrate is evaporated and the residue purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate) to give the free compound (210 mg, 81%) indicated in the title compounds as colorless oils.

Free connection

1H NMR (400 MHz, CDCl3)

The above free compound (210 mg) is treated in the usual way, getting hydrochloride (260 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.8 Hz, 3H), 1,11 (d, J=6.8 Hz, 3H), 1.18 to about 1.35 (m, 1H), 1,55-1,72 (m, 1H), 2,02-of 2.26 (m, 3H), of 3.07 (s, 6N), 3,00-3,90 (m, N), 4,30-4,50 (m, 2H), 7,10-7,20 (m, 2H), 7,32-of 7.48 (m, 5H), a 7.62 to 7.84 (m, 2H).

ESI-Macc: 449 (MH+).

Example 44. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-acetamidophenol)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-aminophenoxy)ethyl]piperazine (261 mg) was dissolved in acetic anhydride (2 ml) and pyridine (2 ml) and the mixture is stirred over night at room temperature. The organic layer is distributed by the addition of water and ethyl acetate, washed with water, dried over anhydrous sodium sulfate and, after drying agent removed by filtration, the filtrate is evaporated. The residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate) to give the free compound (2 mg, 1%) specified in the title compounds as colorless oils.6-1,19 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-of 1.62 (m, 1H), 1,89 (dt, J=4.4 Hz, and 12.4 Hz, 1H), 2,07-of 2.21 (m, 2H), of 2.15 (s, 3H), 2,28 (Shir.t, J=7.2 Hz, 2H), 2,30 is 2.46 (m, 4H), 2,46-to 2.65 (m, 4H), 2,77 (t, J=6.0 Hz, 2H), 4,06 (t, J=6.0 Hz, 2H), 6,82-to 6.88 (m, 2H), 7,09 (Shir.s, 1H), 7,25-7,32 (m, 1H), 7,32-7,41 (m, 6N).

The above free compound (2 mg) is treated in the usual way, getting hydrochloride (2 mg) specified in the title compound as an amorphous substance.

Hydrochloride

1H NMR (400 MHz, CD3OD)(M. D.): 0,74 (d, J=6.8 Hz, 3H), 1,21 (d, J=6.8 Hz, 3H), 1,30-1,50 (m, 1H), 1,70-1,90 (m, 1H), of 2.05 to 2.35 (m, 3H), of 2.08 (s, 3H), 3,10-to 4.15 (m, N), 4,30-4,50 (m, 2H), 6,97 (Shir. d, J=8,8 Hz, 2H), 7,30-7,38 (m, 1H), 7,39-to 7.50 (m, 7H).

ESI-Macc: 463 (MH+).

Example 45. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-methylthiophene)ethyl]piperazine

The free compound (122 mg, 30%) specified in the title compound obtained as a colorless oil from 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine (300 mg), 4-methylthiophenol (430 mg), triphenylphosphine (290 mg) and 40% solution of diethyl ester of azodicarboxylic acid/toluene (440 mg) in the same manner as in example 36-2).

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1.04 million-of 1.18 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-to 1.61 (m, 1H), of 1.88 (dt, J=4.4 G is 3-7,31 (m, 3H), 7,33-7,39 (m, 4H).

The above free compound (122 mg) is treated in the usual way, getting hydrochloride (141 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.8 Hz, 3H), of 1.12 (d, J=6.8 Hz, 3H), 1,16-of 1.30 (m, 1H), 1,54-to 1.67 (m, 1H), 2,03-of 2.26 (m, 3H), 2,42 (s, 3H), 2.95 and-of 3.80 (m, N), 4,20 is 4.36 (m, 2H), 6,93-of 6.99 (m, 2H), 7.23 percent-7,28 (m, 2H), 7,34-7,40 (m, 1H), 7,41-of 7.48 (m, 4H).

ESI-Macc: 452 (MH+).

Example 46. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-cianfrocca)ethyl]piperazine

46-1) 2-(2-Cianfrocca)ethylpiperazin

1-Formyl-4-(2-hydroxyethyl)piperazine (4,95 g) dissolved in tetrahydrofuran (100 ml), then to the solution was added triphenylphosphine (10,14 g) and 2-cyanoprop (3.57 g) and added dropwise to the mixture add a solution of 40% diethyl ester of azodicarboxylic acid/toluene (13.5 ml) specified in the title compound (1.60 g) are obtained in the same manner as in example 47-1).

1H NMR (400 MHz, CDCl3)(M. D.): 2,48-to 2.67 (m, 4H), 2,86-of 2.97 (m, 6N), 4,22 (t, J=5.8 Hz, 2H), 6,94? 7.04 baby mortality (m, 2H), 7,49-EUR 7.57 (m, 2H).

46-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-cyanate-noxy)ethyl]piperazine

2-(1-Methylethyl)-5-oxo-2-phenylpentane (150 mg), 1-[2-(4-cianfrocca)ethyl]PI is sybolized sodium (200 mg) and the mixture is stirred over night at room temperature. The reaction mixture was poured into aqueous saturated sodium bicarbonate solution, extracted with dichloromethane, washed with water and brine, dried and evaporated. The residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate) to give the free connection specified in the connection header in the form of butter.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,20 (d, J=6.8 Hz, 3H), 1,25-of 1.27 (m, 1H), 1,90-of 2.26 (m, 4H), 2.26 and-a 3.01 (m, N), 4,20-4,30 (m, 2H), 6,93-7,05 (m, 2H), 7,25-7,34 (m, 1H), was 7.36-7,40 (m, 4H), 7,49-7,58 (m, 2H).

The above free compound was dissolved in methanol and to the solution was added a solution of 4 N. hydrogen chloride/ethyl acetate. The solvent and excess hydrogen chloride is evaporated and the product recrystallized from methanol/simple ether, obtaining hydrochloride (168 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,68 (d, J=6.6 Hz, 3H), 1,11 (d, J=6.6 Hz, 3H), 1,16-1,32 (m, 1H), 1,57 is 1.60 (m, 1H), 2.06 to 2,30 (m, 3H), 3.00 and-3,70 (m, 14N), 4,51 (Shir. s, 2H), 7,12-to 7.18 (m, 1H), 7,27-7,31 (m, 1H), 7,33-7,40 (m, 1H), 7,43-of 7.48 (m, 4H), to 7.67-7,73 (m, 1H), 7,75-7,79 (m, 1H).

ESI-Macc: 431 (MH+).

Example 47. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-cianfrocca)ethyl]piperazine

1H NMR (400 MHz, CDCl3)(M. D.): 2,45-2,60 (m, 4H), of 2.81 (t, J=5.8 Hz, 2H), only 2.91 (t, J=5.8 Hz, 4H), 4,17 (t, J=5.8 Hz,/p>

2-(1-Methylethyl)-5-oxo-2-phenylpentane (150 mg), 1-[2-(4-cianfrocca)ethyl]piperazine (200 mg) and acetic acid (0.10 ml) dissolved in dichloromethane (15 ml), then the solution add triacetoxyborohydride sodium (200 mg) and the mixture is stirred over night at room temperature. The reaction mixture was poured into aqueous saturated sodium bicarbonate solution, extracted with dichloromethane, washed with water and brine and dried. After evaporation the residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate) to give the free connection specified in the connection header in the form of butter.

Free connection

lH NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,20 (d, J=6.8 Hz, 3H), 1,25-of 1.27 (m, 1H), 1,90-of 2.26 (m, 4H), 2.26 and-a 3.01 (m, N), 4,08-to 4.23 (m, 2H), 6,91-of 6.96 (m, 2H), 7,27-7,34 (m, 1H), 7,35-7,40 (m, 4H), 7,56-to 7.61 (m, 2H).

The above free compound was dissolved in methanol and to the solution was added a solution of 4 N. hydrogen chloride/ethyl acetate. The solvent and excess hydrogen chloride is evaporated, obtaining hydrochloride (134 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.6 Hz, 3H), 1,11 (d, J=6 2N).

ESI-Macc: 431 (MH+).

Example 48. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(benzyloxy)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine (442 mg) was dissolved in tetrahydrofuran (10 ml), then to the solution was added sodium hydride (54 mg) and after the mixture is stirred for 15 minutes at room temperature, there was added benzylbromide (250 mg), the mixture is further stirred for 3 hours at room temperature. The organic layer is distributed by the addition of water and ethyl acetate, washed with water, dried over anhydrous sodium sulfate and, after removal of the drying agent by filtration, the filtrate is evaporated and the residue purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate) to give the free compound (270 mg, 48%) indicated in the title compounds as colorless oils.

Free connection

1H NMR (400 MHz, CDCl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,05-of 1.18 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-of 1.62 (m, 1H), of 1.88 (dt, J=4.4 Hz, to 12.8 Hz, 1H), 2,07-to 2.18 (m, 2H), 2,20-of 2.30 (m, 2H), 2,30-to 2.41 (m, 4H), 2,41 is 2.55 (m, 4H), at 2.59 (t, J=5.8 Hz, 2H), of 3.56 (t, J=5.8 Hz, 2H), to 4.52 (c, 2H), 7,26-7,39 (m, 10H).

The above free compound (270 mg) is treated in the usual way, the ub>6
)(M. D.): 0,67 (d, J=6.8 Hz, 3H), of 1.12 (d, J=6.8 Hz, 3H), 1,15-1,30 (m, 1H), 1,55 by 1.68 (m, 1H), 2.00 in is 2.37 (m, 3H), 3.00 and-3,70 (m, N), 3,70-3,86 (m, 2H), to 4.52 (s, 2H), 7,28-7,34 (m, 1H), 7,34-7,39 (m, 5H), 7,42-of 7.48 (m, 4H).

ESI-Macc: 420 (MH+).

Example 49. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-forfinally)ethyl]piperazine

49-1) 2-Chloroethyl-4-florfenicol

According to J. O. C., 58, 4506, 1993, specified in the header connection (10,9 g, 98%) was obtained as yellow oil from 4-portifino (7,4 g) and 1,2-dichloroethane (58 ml).

1H NMR (400 MHz, Dl3)(M. D.): and 3.16 (t, J=8 Hz, 2H), to 3.58 (t, J=8 Hz, 2H), 7,03 (t, J=8,8 Hz, 2H), 7,41 (DD, J=5 Hz and 8.8 Hz, 2H).

49-2) 1-[2-(4-Forfinally)ethyl]piperazine and S-(4-forfinal)-1-(1-piperazinil)ethylthiourea

2-Chloroethyl-4-florfenicol (2,556 g), N-(tert-butoxycarbonyl)piperazine (2,686 g) and triethylamine (2 ml) dissolved in tetrahydrofuran (30 ml) and stirred over night at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, dried and evaporated. The residue is dissolved in ethanol (20 ml), then the solution add 5 N. Hcl (10 ml) and the mixture was stirred at 50°C for 1 hour. The reaction mixture vaporarium. The residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate), obtaining mentioned in the title compound (138 mg, 4% and 159 mg, 4%) as a colourless oil.

(1) 1-[2-(4-Forfinally)ethyl]piperazine

1H NMR (400 MHz, Dl3)(M. D.): 2,38-2,48 (Shir.s, 4H), 2,58 (t, J=7,6 Hz, 2H), 2,88 (t, J=5 Hz, 4H), of 3.00 (t, J=7,6 Hz, 2H), 6,99 (t, J=8,4 Hz, 2H), 6,99 (DD, J=5,2 Hz and 8.4 Hz, 2H).

(2) S-(4-Forfinal-1-(1-piperazinil)ethylthiourea

1H NMR (400 MHz, Dl3)(M. D.): 2,72-2,88 (Shir.s, 4H), 3,11 (t, J=6,8 Hz, 2H), 3,30-of 3.48 (m, 4H), to 4.23 (t, J=6,8 Hz, 2H), 7,39-the 7.43 (m, 2H).

49-3) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-perfe-NELTI)ethyl]piperazine

The free compound (205 mg, 82%) indicated in the title compound obtained as a colorless oil from 2-(1-methylethyl)-5-oxo-2-phenylpentane (124 mg) and 1-[2-(4-forfinally)ethyl]piperazine (138 mg) in the same manner as in example 1.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1.04 million-to 1.16 (m, 1H), 1,19 (d, J=6.4 Hz, 3H), 1,48 is 1.60 (m, 1H), 1,87 (dt, J=4.4 Hz, to 12.8 Hz, 1H), 2,07-2,17 (m, 2H), 2.21 are 2,52 (m, N), 2,54-of 2.58 (m, 2H), 2.95 and-2,99 (m, 2H), 6,98 (t, J=8.6 Hz, 2H), 7,26-7,38 (m, 7H).

The above free link the ID of the

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,65 (d, J=6.8 Hz, 3H), of 1.09 (d, J=6.8 Hz, 3H), 1.18 to 1.32 to (m, 1H), 1,55 by 1.68 (m, 1H), 2,04-2,22 (m, 3H), 2.95 and of 3.75 (m, 14N), 7,19 (t, J= 8,8 Hz, 2H), 7,32-7,44 (m, 5H), 7,47 (DD, J=5,2 Hz and 8.8 Hz, 1H).

ESI-Macc: 440 (MH+).

Example 50. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-perpenicular)ethyl]piperazine

50-1) 1-[2-(4-Perpenicular)ethyl]-4-(tert-butoxycarbonyl)piperazine

2-Chloroethyl-4-florfenicol (2.5 g), N-(tert-butoxycarbonyl)piperazine (2.3 g) and triethylamine (1.7 ml) dissolved in tetrahydrofuran (30 ml) and stirred over night at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate), obtaining mentioned in the title compound (4.4 g, yield quantitative) as a colourless oil.

1H NMR (400 MHz, CDCl3)(M. D.): the 1.44 (s, N), 2,30 (t, J=5 Hz, 4H), and 2.79 (t, J=7.2 Hz, 2H), 3,26-of 3.31 (m, 6N), 7,22-7,27 (m, 2H), 7,92-of 7.96 (m, 2H).

50-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-perfe-ylsulphonyl)ethyl]piperazine

1-[2-(4-Perpenicular)ethyl]-4-(tert-butoxycarbonyl)piperazine (4.4 g) rastvornuju the mixture is evaporated, alkalinized 5 N. aqueous NaOH and extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated. The free compound (80 mg, 46%) indicated in the title compound obtained as a colorless oil from part (101 mg) of the residue (2,567 g) and 2-(1-methylethyl)-5-oxo-2-phenylpentane (80 mg).

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,76 (d, J=6,8 Hz, 3,2 N) of 0.79 (d, 6.8 Hz, 3/2H), 1,01 is 1.13 (m, 1H), 1,19 (d, J=6,8 Hz, 3/2H), 1,21 (d, 6.8 Hz, 3/2H), 1,45-of 1.56 (m, 1H), of 1.85 (DDD, J=4.4 Hz, 12 Hz to 13.6 Hz, 1/2H), up to 1.98 (DDD, J=4.4 Hz, 12 Hz to 13.6 Hz, 1/2H), 2.06 to of 2.38 (m, N), is 2.74 (t, J=7.4 Hz, 2H), 3.27 to (t, J=7.4 Hz, 2H), 6,98 (t, J=8.6 Hz, 2H), 7,89-7,98 (m, 2H).

The above free the connection handle in the usual way, getting hydrochloride (35 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,64 (d, J=6.4 Hz, 3H), 0,91-of 1.33 (m, 5H), 1,55 by 1.68 (m, 1H), 2,03-of 2.23 (m, 4H), 2.95 and-to 3.52 (m, 10H), 4,85 to 4.92 (m, 2H), 7.29 trend was 7.45 (m, 5H), 7,52 (t, J=8,8 Hz, 2H), 7,98 (DD, J=7,8 Hz and 8.8 Hz, 2H).

ESI-Macc: 472 (MH+).

Example 51. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-forgenerating)ethyl]piperazine

51-1) 1-[2-(4-Forgenerating)ethyl]-4-benzylpiperazine

1-Benzyl-4-[N-(4-forfinal)carbamoylmethyl]piperazine (12,05 g) dissolved in , under reflux. After cooling, the reaction mixture was added to it in order water (1.4 ml), 5 N. NaOH (1.4 ml) and water (4,2 ml) and the insoluble matter is filtered through celite and the filtrate is evaporated. The residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate), obtaining mentioned in the title compound (10.2 g, 89%) as a yellow oil.

1H NMR (400 MHz, Dl3)(M. D.): 2,40-2,58 (Shir.s, 8H), 2,62 (t, J=6 Hz, 2H), 3,52 (s, 2H), 4,15-4,24 (Shir.s, 1H), 6,56 (DD, J=4.4 Hz, 8,8 Hz, 2H), to 6.88 (t, J=8,8 Hz, 2H), 7.23 percent-to 7.32 (m, 5H).

51-2) 1-[2-(4-Forgenerating)ethyl]piperazine

Specified in the title compound (1.45 g, quantitative yield) obtained as a colorless oil from 1-[2-(4-forgenerating)ethyl]-4-benzylpiperazine (2,05 g) in the same manner as in example 65-2).

1H NMR (400 MHz, Dl3)(M. D.): 2,40-2,55 (Shir.s, 4H), 2,61 (t, J=5.8 Hz, 2H), 2,90 (t, J=5 Hz, 4H), 3,11 (t, J=5.8 Hz, 2H), 4,13-4,30 (Shir.s, 1H), 6,56 (DD, J=4.4 Hz, 8,8 Hz, 2H), 6.89 in (t, J=8,8 Hz, 2H).

51-3) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-forgenerating)ethyl]piperazine

The free compound (411 mg, 69%) indicated in the title compound obtained as a colorless oil from 2-(1-methylethyl)-5-oxo-2-fenil the second connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1.06 a-to 1.16 (m, 1H), 1,20 (d, J=6.4 Hz, 3H), 1,50-of 1.62 (m, 1H), 1,89 (DDD, J=4,4, 12 Hz to 13.6 Hz, 1H), 2,08-of 2.50 (m, N), at 2.59 (t, J= 5.8 Hz, 2H), 3,05-of 3.12 (m, 2H), 4,10-4,20 (Shir.s, 1H), 6,53-to 6.57 (m, 2H), 6,85-6,91 (m, 2H), 7,26-7,37 (m, 5H).

The above free compound (95 mg) is treated in the usual way, getting hydrochloride (73 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,65 (d, J=6.8 Hz, 3H), of 1.09 (d, J=6.4 Hz, 3H), 1,20-1,32 (m, 1H), 1.56 to to 1.70 (m, 1H), 2.06 to of 2.21 (m, 3H), 3,05 of 3.75 (m, 14N), 6.73 x-to 6.80 (m, 2H), 6,99 (t, J=8,8 Hz, 2H), 7,31-the 7.43 (m, 5H).

ESI-Macc: 423 (MH+).

Example 52. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-forfinal)-N-methylamino]ethyl}piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl-4-[2-(4-forgenerating)ethyl]piperazine (121 mg) and paraformaldehyde (87 mg) was dissolved in acetic acid (5 ml), then the solution add triacetoxyborohydride sodium (246 mg) and the mixture is stirred over night at room temperature. To it was added saturated sodium bicarbonate and the product extracted with ethyl acetate, washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate), the e connection

lH NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,05-1,17 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-to 1.61 (m, 1H), of 1.88 (DDD, J=4,4, 12 Hz to 13.6 Hz, 1H), 2,08-of 2.50 (m, 14N), 2,89 (s, 3H), 3,39 (t, J=7,6 Hz, 2H), 6,61-only 6.64 (m, 2H), 6,88-6,94 (m, 2H), 7,27-7,37 (m, 5H).

The above free the connection handle in the usual way, getting hydrochloride (57 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,63 (d, J=6.4 Hz, 3H), of 1.09 (d, J=6.4 Hz, 3H), of 1.21 to 1.31 (m, 1H), 1,58 by 1.68 (m, 1H), 2.06 to 2,22 (m, 3H), of 2.86 (s, 3H), 3,03-to 3.73 (m, 14N), to 6.88 (DD, J=4.4 Hz, 8,8 Hz, 2H), 7,52 (t, J=8,8 Hz, 2H), 7,32-the 7.43 (m, 5H).

ESI-Macc: 437 (MH+).

Example 53. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-forfinal)-N-acetylamino]ethyl}piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl-4-[2-(4-forgenerating)ethyl]piperazine (97 mg) and triethylamine (0.06 ml) dissolved in tetrahydrofuran (4 ml) to the solution under cooling with ice add acetylchloride (0,03 ml) and the mixture is stirred for 1 hour. To the mixture is added saturated sodium bicarbonate and the product extracted with ethyl acetate, washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate), obtaining specified in the header tp://img.russianpatents.com/chr/948.gif">(M. D.): 0,77 (d, J=6.4 Hz, 3H), of 1.06-1.14 in (m, 1H), 1,19 (d, J=6.8 Hz, 3H), 1,48-to 1.59 (m, 1H), 1,80 (s, 3H), of 1.88 (DDD, J=4,4, 12 Hz to 13.6 Hz, 1H), 2,07-2,48 (m, 14N), of 3.78 (dt, J=2.4 Hz, 6.8 Hz, 2H), was 7.08 (t, J=8,8 Hz, 2H), 7,20 (DD, J=4,8 Hz and 8.8 Hz, 2H), 7,27 was 7.36 (m, 5H).

The above free the connection handle in the usual way, getting hydrochloride (62 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,65 (d, J=6.4 Hz, 3H), of 1.09 (d, J=6.4 Hz, 3H), of 1.20 and 1.35 (m, 1H), 1,58 is 1.60 (m, 1H), 1,71 (s, 3H), 2.05 is-of 2.21 (m, 3H), 3,00-4,00 (m, 14N), 7,28 (t, J=8.6 Hz, 2H), 7,32-the 7.43 (m, 5H), 7,63 (dt, J=4,8 Hz, 8.6 Hz, 2H).

ESI-Macc: 465 (MH+).

Example 54. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-forfinal)-N-methanesulfonamido]ethyl}piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl-4-[2-(4-forgenerating)ethyl]piperazine (98 mg) and triethylamine (0.2 ml) dissolved in tetrahydrofuran (4 ml) to the solution under cooling with ice add methanesulfonanilide (0.1 ml) and the mixture is stirred for 1 hour. To the mixture is added saturated sodium bicarbonate and the product extracted with ethyl acetate, washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate) to give the free compound (103 mg, 91%) specified in)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1.04 million-to 1.16 (m, 1H), 1,19 (d, J=6.4 Hz, 3H), 1,48-to 1.59 (m, 1H), of 1.88 (DDD, J=4,4, 12 Hz to 13.6 Hz, 1H), 2.06 to the 2.46 (m, N), 2,96 (s, 3H), of 3.73 (t, J=6,8 Hz, 2H), was 7.08 (t, J=8,4 Hz, 2H), 7,27 was 7.36 (m, 7H).

The above free the connection handle in the usual way, getting hydrochloride (63 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,65 (d, J=6.4 Hz, 3H), of 1.08 (d, J=6.4 Hz, 3H), 1,20-1,30 (m, 1H), 1,55 by 1.68 (m, 1H), 2,05-of 2.21 (m, 3H), 3,05 (s, 3H), 3,10-3,70 (m, N), a 4.03 (t, J=6,8 Hz, 2H), 7,27 (t, J=8,8 Hz, 2H), 7,31-7,37 (m, 1H), 7,40-the 7.43 (m, 4H), 7,52 (dt, J=5 Hz and 8.8 Hz, 2H).

ESI-Macc: 501 (MH+).

Example 55. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(benzylamino)ethyl]piperazine

55-1) 1-(2-amino-ethyl)-4-(tert-butoxycarbonyl)piperazine

N-(2-amino-ethyl)piperazine (24.4 g) and benzaldehyde (26,9 ml) dissolved in toluene (250 ml) using attached to the flask device, Dean-stark and the mixture is heated to boiling under reflux for 3 hours. After cooling to room temperature (10 ml) the reaction mixture is removed and concentrated, obtaining N-[2-(benzylidene)aminoethyl]piperazine (1.4 g). The remaining part (about 240 ml) the reaction mixture is added di(tert-butyl)dicarbonate (45 g) and the mixture paramashiva the mixture vigorously stirred for 5 hours at room temperature, the aqueous layer was distributed by the addition of diethyl ether. The aqueous layer was alkalinized by addition of sodium hydroxide (solid) and the organic layer is distributed by the addition of chloroform, washed with water, dried and evaporated, getting mentioned in the title compound (14.9 g).

55-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(benzylamino)ethyl]piperazine

The previously obtained N-[2-(benzylidene)aminoethyl]piperazine (1.4 g), 2-(1-methylethyl)-5-oxo-2-phenylpentane (808 mg) and acetic acid (0.9 ml) dissolved in dichloromethane (10 ml) and to the solution add triacetoxyborohydride sodium (2.5 g) and indicated in the title compound (311 mg, 20%) was obtained as colorless oil in the same manner as in example 1.

Free connection

lH NMR (400 MHz, CDCl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,05-1,17 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-1,60 (m, 1H), of 1.88 (m, 3H), 2.05 is-are 2.19 (m, 2H), 2,24 is 2.44 (m, N), 2,47 (t, J=6.0 Hz, 2H), 2,68 (t, J=6.0 Hz, 2H), of 3.78 (s, 2H), 7,22-7,37 (m, 10H).

The above free compound (300 mg) is treated in the usual way, getting hydrochloride (379 mg) specified in the title compounds as a colorless amorphous substance.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 6 (s, 2H), 7,34-7,40 (m, 2H), 7,42-7,44 (m, 6N), 7,56-to 7.59 (m, 2H), 9,39 (Shir.s, 2H).

ESI-Macc: 419 (MH+).

Example 56. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-acetyl-N-benzylamino)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl-4-[2-(benzylamino)ethyl]piperazine (51 mg) and triethylamine (0.2 ml) dissolved in tetrahydrofuran (5 ml) and to the solution add acetylchloride (0.1 ml), the mixture is stirred over night at room temperature. The organic layer is distributed by the addition of water (5 ml) and ethyl acetate, washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel Cromatorex NH (ethyl acetate), obtaining mentioned in the title compound (55 mg, 98%) as a colourless oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,11 (m, 1H), 1,19 (d, J=6.8 Hz, 3H), and 1.54 (m, 1H), 1,81 is 1.96 (m, 2H), 2,11 (s, 3H), of 2.25 (m, 3H), 2,30 (m, 3H), 2,39 (m, 3H), 2,42 (t, J=7.2 Hz, 2H), 2,48 (t, J=6,8 Hz, 2H), 3,30 (t, J=7,0 Hz, 1H), 3.46 in (m, 1H), 4,60 (t, J=17.6 Hz, 2H), 7,15 and 7.36 (m, 10 H).

The above free compound (20 mg) is treated in the usual way, getting hydrochloride (23 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.4 Hz, 3H), 0,86 (M70 (m, 2H).

ESI-Macc: 462 (MH+).

Example 57. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-methanesulfonyl-N-benzylamino)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(benzylamino)ethyl]piperazine (53 mg) and triethylamine (0.2 ml) dissolved in tetrahydrofuran (5 ml), the solution add methanesulfonanilide (0.1 ml) and the mixture is stirred over night. The organic layer is distributed by the addition of water (50 ml) and ethyl acetate, washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel Cromatorex NH (ethyl acetate), obtaining mentioned in the title compound (61 mg, 97%) as a colourless oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.6 Hz, 3H), of 1.12 (m, 1H), 1,19 (d, J=6.6 Hz, 3H), 1,49 is 1.58 (m, 1H), 1,73 (m, 1H), 1,85-1,90 (m, 1H), 2,07-of 2.30 (m, 8H), to 2.29-2.40 a (m, 5H), 2,98 (s, 3H), of 3.28 (t, J=6.4 Hz, 2H), of 4.11 (s, 2H), 7,25-7,40 (m, 10H).

The above free compound (20 mg) is treated in the usual way, getting hydrochloride (23 mg) specified in the title compounds as a colorless amorphous substance.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,19-of 1.23 (m, 3H), 0,83 is 2.33 (m, 7H), of 2.93 (s, 3H), 3.04 from-3,51 (m, 7H), 3,69-of 3.80 (m, 5H), and 4.40 (s,Ino) ethyl] piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(benzylamino)ethyl]piperazine (67 mg) and Isopropylamine (up 29.6 ml) dissolved in dimethylformamide (10 ml), then to the solution was added potassium carbonate (33,2 mg) and the mixture is heated at 100°C during the night. After the reaction mixture was cooled to room temperature, the organic layer distributes the addition of an aqueous saturated solution of sodium bicarbonate (7 ml) and ethyl acetate, washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate), obtaining mentioned in the title compound (15 mg, 20%) as a colourless oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 0,89 (m, 1H), 0,99 (d, J=6,8 Hz, 6N), 1,10 (m, 1H), 1,19 (d, J=6.8 Hz, 3H), 1.26 in (m, 1H), 1,53 (m, 1H), 1.69 in (m, 2H), 1,87 (TD, J=4.4 Hz, to 12.8 Hz, 1H), 2,07-of 2.16 (m, 2H), 2,23-of 2.26 (m, 2H), 2,28-is 2.37 (m, 6N), 2,53-to 2.57 (m, 2H), 2,90 (quintet, J=6,6 Hz, 1H), only 3.57 (s, 2H), 7,20 (m, J=7,0 Hz, 1H), 7,26 and 7.36 (m, N).

The above free compound (15 mg) is treated in the usual way, getting hydrochloride (18 mg) specified in the title compounds as a colorless amorphous substance.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)

ESI-Macc: 462 (MH+).

Example 59. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-perbenzoic)ethyl]piperazine

59-1) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(tert-butoxycarbonyl)piperazine

Specified in the title compound (671 mg, 89%) was obtained as colorless oil from 2-(1-methylethyl)-5-oxo-2-phenylpentane (400 mg) and N-(tert-butoxycarbonyl)piperazine (346 mg) in the same manner as in example 1.

1H NMR (400 MHz, Dl3)(M. D.): 0,76 (d, J=6.8 Hz, 3H), 1,08-of 1.18 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), of 1.44 (s, N), 1,50-1,60 (m, 1H), 1,87-of 1.95 (m, 1H), 2,08-2,31 (m, 8H), 3,35 is 3.40 (m, 4H), 7,16-7,31 (m, 5H).

59-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]piperazine

To 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(tert-butoxycarbonyl)piperazine (671 mg) is added 4 n solution of Hcl/ethyl acetate (20 ml) and the mixture was stirred at 50°C for 3 hours. The reaction mixture is evaporated, and then to the mixture is added saturated sodium carbonate and the product extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate), obtaining mentioned in the title compound (377 mg, 76%) in the m 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-1,60 (m, 1H), 1,89 (DDD, J=4.4 Hz, 12 Hz to 13.6 Hz, 1H), 2,07 of-2.32 (m, 8H), and 2.83 (t, J=5 Hz, 4H), 7,27-7,38 (m, 5H).

59-3) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-Farben-zoilus)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]piperazine (114 mg), 3-chloro-4-forpromotion (75 mg) and triethylamine (0.06 ml) dissolved in tetrahydrofuran (3 ml) and the mixture is stirred over night at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate) to give the free compound (99 mg, 56%) indicated in the title compounds as colorless oils.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1.06 a-1,18 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-1,60 (m, 1H), 1,89 (DDD, J=4.4 Hz, 12 Hz to 13.6 Hz, 1H), 2,08-of 2.56 (m, N), 2,80 (t, J=7,6 Hz, 2H), 3,14 (t, J=7,6 Hz, 2H), 7,13 (t, J=8,4 Hz, 2H), 7,26-7,37 (m, 5H), of 7.97 (DD, J=5.4 Hz, and 8.4 Hz, 2H).

The above free compound (30 mg) is treated in the usual way, getting hydrochloride (39 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,66 (d, J=6.8 Hz, 3H), 1,10 (d, J=6.8 Hz, 3H), 1,55-1,65 is-5-methyl-4-phenyl)hexyl]-4-[3-hydroxy-3-(4-forfinal)propyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-perbenzoic)ethyl]piperazine (64 mg) was dissolved in ethanol (1 ml), and then to the solution was added sodium borohydride (65 mg) and the mixture is stirred for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate), obtaining a free compound indicated in the title compound (64 mg, quantitative yield) as a colorless oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,08-of 1.18 (m, 1H), 1,20 (d, J=6.4 Hz, 3H), 1,50-1,60 (m, 1H), 1,79 (DD, J=6,6 Hz, 11 Hz, 2H), 3,76 (dt, J=4 Hz, 13 Hz, 1H), 2,08 was 2.76 (m, 14N), 4,88 (t, J=5.6 Hz, 1H), 7,01 (t, J=8,8 Hz, 2H), 7,27-7,37 (m, 7H).

The above free the connection handle in the usual way, getting hydrochloride (60 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,66 (d, J=6.8 Hz, 3H), of 1.09 (d, J=6.4 Hz, 3H), 1,15 of 1.28 (m, 1H), 1,52-to 1.67 (m, 1H), 1,90-2,22 (m, 5H), 2.95 and-of 3.80 (m, N), with 4.64 (K, 4 Hz, 1H), 7,15 (t, J=8,8 Hz, 2H), 7,33 was 7.45 (m, 7H).

ESI-Macc: 438 (MH+).

Example 61. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-terfenol the Noah acid (3,52 g) and heated to boiling under reflux for 1 hour. The reaction mixture is evaporated and the residue in a solution of tetrahydrofuran (5 ml) was added under ice cooling to a solution of 1-benzylpiperazine (3,65 g) and triethylamine (2.9 ml) in tetrahydrofuran (15 ml), followed by stirring for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, dried and evaporated. The residue is dissolved in ethanol (60 ml), then to the solution was added concentrated chlorotoluron acid (3 ml) and the catalyst 10% palladium/carbon (1.3 g) and the mixture is stirred over night at room temperature in a hydrogen atmosphere. After separation of the catalyst by filtration, the filtrate is evaporated, alkalinized 2 N. aqueous NaOH and extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate), obtaining mentioned in the title compound (4.09 g, 83%) as a pale brown oil.

1H NMR (400 MHz, Dl3)(M. D.): 2,82-2,87 (m, 4H), of 3.54 (t, J=5,2 Hz, 2H), 3,60 (t, J=5,2 Hz, 2H), of 4.66 (s, 2H), 6,88-7,00 (m, 4H).

61-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-pertenece)acetyl]piperazine

The free compound (140 mg, 98%) La (70 mg) and 2-(4-pertenece)acetylpiperidine (78 mg) in the same way, as in example 1.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.6 Hz, 3H), 1.06 a-1,17 (m, 1H), 1,20 (d, J=6.6 Hz, 3H), 1,48 is 1.60 (m, 2H), 1,89 (dt, J=4.4 Hz, 13,2 Hz, 1H), 2,07-of 2.20 (m, 3H), 2,22 of-2.32 (m, 4H), 3,48-to 3.64 (m, 4H), 4,63 (s, 2H), 6,70-to 6.80 (m, 2H), 6,85-7,00 (m, 2H), 7,28-7,34 (m, 1H), 7,34-7,38 (m, 4H).

The above free compound (140 mg) is treated in the usual way, getting hydrochloride (142 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.6 Hz, 3H), of 1.12 (d, J=6.6 Hz, 3H), 1,20-1,30 (m, 1H), 1,55-1,70 (m, 1H), 2,00-2,30 (m, 3H), 2,78-2,90 (m, 1H), 2,90-3,18 (m, 3H), 3,40-of 3.53 (m, 1H), 3,95 (Shir.d, J=12,6 Hz, 1H), 4,33 (Shir.d, J=12,6 Hz, 1H), 4.75 V-4,90 (m, 2H), 6.90 to-6,97 (m, 2H), 7,07-to 7.15 (m, 2H), 7,33-7,41 (m, 1H), 7,41-to 7.50 (m, 4H), 10,6 (m, 1H).

ESI-Macc: 438 (MH+).

Example 62. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-hydroxy-3-(4-pertenece)propyl]piperazine

62-1) 4-Fortunatelly ether

4-Terfenol (3.0 g) dissolved in dimethylformamide (50 ml), then to the solution was added sodium hydride (1.28 g, 50%) and the mixture is stirred for 45 minutes in an ice bath. To the reaction mixture add epibromohydrin (2.3 ml) and the mixture is stirred for 3 hours in an ice bath. The organic layer distribute dobavlenie.ok purified by chromatography on a column of silica gel (system hexane/ethyl acetate), obtaining a free compound (3.4 g, 75%) indicated in the title compounds as colorless oils.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 2,75 (DD, J=5.6 Hz, 3.2 Hz, 1H), 2,88 of 2.92 (m, 1H), 3,32-3,37 (m, 1H), 3,91 (DD, J=5.6 Hz, 11.2 Hz, 1H), 4,20 (DD, J=3.2 Hz, 11.2 Hz, 1H).

62-2) 1-(tert-Butoxy)carbonyl-4-[2-hydroxy-3-(4-pertenece)propyl]piperazine

1-(tert-Butoxycarbonyl)piperazine (1.8 g) and 4-fortunatelly ether (1.6 g) dissolved in 2-propanol (50 ml) and stirred for 2 hours while boiling under reflux. The solvent is evaporated and the residue purified by chromatography on a column of silica gel (system hexane/ethyl acetate) to give the free compound (2,48 g, 74%) indicated in the title compound as a colourless solid.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 1,47 (s, N), 2,35 at 2.45 (m, 2H), 2,50-of 2.58 (m, 2H), 2,58-of 2.66 (m, 2H), 3,36 of 3.56 (m, 2H), 3.72 points-of 4.00 (m, 2H), 4,06-to 4.14 (m, 1H), 6,84-of 6.90 (m, 2H), 6,94-7,01 (m, 2H).

62-3) Triptorelin 1-[2-hydroxy-3-(4-pertenece)propyl]piperazine

1-(tert-Butoxy)carbonyl-4-[2-hydroxy-3-(4-pertenece)propyl]piperazine (520 mg) was dissolved in dichloromethane (52 hours. After concentration of the mixture there was added toluene and the reaction mixture is again evaporated, getting triptorelin (450 mg) specified in the connection header.

Triptorelin

1H NMR (400 MHz, DMSO-d6)(M. D.): 3,20-of 3.60 (m, N), 3,95 (d, J=4,8 Hz, 2H), 4.26 deaths (m, 1H), 6,95-7,01 (m, 2H), 7,12-to 7.18 (m, 2H).

62-4) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-hydroxy-3-(4-pertenece)propyl]piperazine

The free compound (124 mg, 74%) indicated in the title compound obtained as a colorless oil in the same manner as in example 1 from 2-(1-methylethyl)-5-oxo-2-phenylpentane (80 mg), 1-[2-hydroxy-3-(4-pertenece)propyl]piperazine and trifenatate (274 mg) obtained in the above paragraph 3).

Free connection

1H NMR (400 MHz, CDCl3)(M. D.): 0,77 (d, J=6.6 Hz, 3H), 1,05-1,20 (m, 1H), 1,21 (d, J=6.6 Hz, 3H), 1,50-1,80 (m, 3H), 1,80-2,20 (m, 3H), 2,20-2,60 (m, 7H), 2,60-2,70 (m, 2H), 3,92 (d, J=5.6 Hz, 2H), Android 4.04 (m, 1H), 6,83-to 6.88 (m, 2H), 6,92-7,00 (m, 2H), 7,27-7,33 (m, 1H), 7,34-7,40 (m, 4H).

The above free compound (124 mg) is treated in the usual way, getting hydrochloride (110 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=5.5 H).

ESI-Macc: 454 (MH+).

Example 63. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-ftorpolimernoj)ethyl]piperazine

63-1) N-Acryloyl-4-ftoranila

4-Ftoranila (7 ml) and akriloilkhlorida (7.2 ml) dissolved in tetrahydrofuran (100 ml), then the solution is added triethylamine (15 ml) and the mixture is stirred over night at room temperature. The organic layer distributes the addition of an aqueous saturated solution of sodium bicarbonate and ethyl acetate, the organic layer washed with water and dried over anhydrous sodium sulfate and after removal by filtration of the drying agent, the filtrate is evaporated, whereby receive specified in the title compound (12.2 g, 100%) as a pale yellow solid.

1H NMR (400 MHz, Dl3)(M. D.): 5,76-5,79 (m, 1H), 6,24 (DD, J=10.4 Hz, is 16.8 Hz, 1H), 6,14-6,50 (m, 1H), 7,01-7,06 (m, 2H), 7,14 (m, 1H), 7,53-rate of 7.54 (m, 2H).

63-2) 1-Benzyl-4-[2-(4-ftorpolimernoj)ethyl]piperazine

N-Acryloyl-4-ftoranila (12.2 g) and 1-benzylpiperazine (19,7 g) dissolved in methanol (150 ml) and the mixture is stirred over night at room temperature. The reaction mixture is evaporated and the residue purified by chromatography on a column of net oil.

1H NMR (400 MHz, CDCl3)(M. D.): of 2.51 (t, J=5.8 Hz, 2H), 2.63 in (lat.s, 8H), of 2.72 (t, J=5.8 Hz, 2H) and 3.59 (s, 2H), 7,01 (m, J=8,8 Hz, 2H), 7,25-to 7.35 (m, 5H), 7,46 is 7.50 (m, 2H), 11,1 (Shir.s, 1H).

63-3) [2-(4-Ftorpolimernoj)ethyl]piperazine

1-Benzyl-4-[2-(4-ftorpolimernoj)ethyl]piperazine (2.9 g) was dissolved in acetic acid (100 ml), then to the solution was added the catalyst, 10% palladium/charcoal (7.2 g) and the mixture is stirred overnight in a hydrogen atmosphere. The catalyst is 10% palladium/charcoal is removed by filtration and the filtrate is evaporated, to the residue water is added, then alkalinized by addition of 1 N. aqueous sodium hydroxide solution, is subjected to extraction with chloroform, and the organic layer washed with water, dried and evaporated, whereby receive specified in the title compound (1.5 g, 70%) as a colourless oil.

1H NMR (400 MHz, Dl3)(M. D.): 1,84 (Shir.s, 2H), 2,53 (t, J=5.8 Hz, 2H), 2,60 (m, 4H), of 2.72 (t, J=5.8 Hz, 2H), 3,01 (t, J=4,8 Hz, 2H), 7,00 (m, J=8,8 Hz, 2H), of 7.48-7,52 (m, 2H), 11,1 (Shir.s, 1H).

63-4) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-ftorpolimernoj)ethyl]piperazine

Specified in the title compound (163 mg, 62%) was obtained as colorless maslia way as in example 66.

Free connection

1H NMR (400 MHz, CDCl3)(M. D.): 0,78 (d, J=6.8 Hz, 3H), of 1.18 (m, 1H), 1,21 (d, J=6.8 Hz, 3H), 1,58 (m, 1H), 1,78 (m, 1H), 1,92 (TD, J=13,0 Hz and 4.4 Hz, 1H), 2,13 (quintet, J=6,8 Hz, 1H), 2,15-of 2.21 (m, 1H), 2.26 and-of 2.38 (m, 3H), 2,44 (Shir.s, 3H), 2.50 each (t, J=6.0 Hz, 2H), 2,58 (Shir.s, 3H), 2,70 (t, J=6.0 Hz, 2H), 6,99 (m, J=8,8 Hz, 2H), 7,30 (m, 1H), 7,35-7,39 (m, 4H), 7,46 (DD, J=4,8 Hz, 6.8 Hz, 1H), 7,47 (DD, J=4,8 Hz, 7.0 Hz, 1H), 11,1 (Shir.s, 1H).

The above free compound (100 mg) is treated in the usual way, getting hydrochloride (189 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.8 Hz, 3H), 1,11 (d, J=6.8 Hz, 3H), 1.26 in (m, 1H), 1,59 at 2.45 (m, 5H), of 2.23 (t, J=6,8 Hz, 1H), 2,54-3,86 (m, 13H), to 7.15 (t, J=8,8 Hz, 2H), 7,37 (m, 1H), 7,44-7,46 (m, 4H), 7,58 to 7.62 (m, 2H).

ESI-Macc: 451 (MH+).

Example 64. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-perbenzoate)ethyl]piperazine

64-1) 1-[2-(4-Perbenzoate)ethyl]-4-(tert-butoxycarbonyl)piperazine

1-(2-amino-ethyl)-4-(tert-butoxycarbonyl)piperazine (1,33 g) obtained in example 58, and 4-perbenzoate (1.1 g) dissolved in tetrahydrofuran (20 ml), then the solution is added triethylamine (1.6 ml) and the mixture is stirred over night at room temperature. Organisoi washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate), whereby receive specified in the title compound (1.42 g, 70%) as a colourless oil.

1H NMR (400 MHz, Dl3)(M. D.): 1,47 (s, N), 2,44-of 2.26 (m, 4H), 2,62 (t, J=6.0 Hz, 2H), 3.46 in (t, J=5.0 Hz, 4H), 3,54 of 3.56 (m, 2H), of 6.71 (m, 1H), 7,12 (m, J=8,6 Hz, 2H), to 7.77-7,81 (m, 2H).

64-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-Farben-solumina)ethyl]piperazine

Specified in the title compound (102 mg, 40%) was obtained as colorless oil from 1-[2-(4-forbindelseshandtering)ethyl]-4-(tert-butoxycarbonyl)piperazine (159 mg) in the same manner as in example 66.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,78 (d, J=6, 8 Hz, 3H), of 1.13 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), and 1.56 (m, 1H), 1,78-of 1.94 (m, 3H), 2,09-2,19 (m, 2H), 2,23 is 2.33 (m, 2H), 2,34 (m, 3H), 2,48 (m, 3H), 2,58 (t, J=6.2 Hz, 2H), 3,51 (t, J=5.6 Hz, 2H), 6,76 (Shir.s, 1H), 7,11 (m, J=8,8 Hz, 2H), 7,29 (m, 1H), 7,32-7,38 (m, 4H), 7,75-7,80 (m, 2H).

The above free compound (100 mg) is treated in the usual way, getting hydrochloride (116 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.8 Hz, 3H)H), 7,95-to 7.99 (m, 2H).

ESI-Macc: 451 (MH+).

Example 65. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[N-(4-forfinal)carbamoylmethyl]piperazine

65-1) 1-Benzyl-4-[N-(4-forfinal)carbamoylmethyl]piperazine

N-Chloroacetyl-4-ftoranila (15,18 g), 1-benzylpiperazine (18,94 g) and triethylamine (15 ml) dissolved in dimethylformamide (200 ml) and the mixture is stirred over night at room temperature. The reaction mixture is evaporated and to it was added ethyl acetate. The organic layer was washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate), obtaining specified in the header connection (23,32 g, 86%) as a pale brown solid.

1H NMR (400 MHz, CDCl3)(M. D.): 2,48-2,60 (m, 4H), 2,62 of 2.68 (m, 4H), of 3.13 (s, 2H), 3,55 (s, 2H), 7,02 (t, J=8,8 Hz, 2H), 7.24 to 7,34 (m, 5H), 7,53 (DD, J=4,8 Hz and 8.8 Hz, 2H), 9,10-9,15 (Shir.s, 1H).

65-2) 4-[N-(4-Forfinal)carbamoylmethyl]piperazine

1-Benzyl-4-[N-(4-forfinal)carbamoylmethyl]piperazine (6,07 g) dissolved in ethanol (100 ml), then to the solution was added the catalyst, 10% palladium/carbon (1.3 g) and the mixture is stirred over night at room temperature in a hydrogen atmosphere. After the spacecraft is elem Cromatorex NH (system hexane/ethyl acetate), whereby specified in the header connection (4,21 g, 96%) was obtained as pale brown oil.

1H NMR (400 MHz, CDCl3)(M. D.): at 2.59 (t, J=1.8 Hz, 4H), 2,96 (t, J=4.8 Hz, 4H), 3,11 (s, 2H), 7,03 (t, J=8,8 Hz, 2H), 7,53 (DD, J=4,8 Hz and 8.8 Hz, 2H), 9,10-9,16 (Shir.s, 1H).

65-3) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[N-(4-forfinal)carbamoylmethyl]piperazine

The free compound (183 mg, 84%) indicated in the title compound obtained as a colorless oil from 2-(1-methylethyl)-5-oxo-2-phenylpentane (109 mg) and 4-[N-(4-forfinal)carbamoylmethyl]piperazine (120 mg) in the same manner as in example 1.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,78 (d, J=6.4 Hz, 3H), 1,09-1,19 (m, 1H), 1,21 (d, J=6.8 Hz, 3H), 1,50-to 1.61 (m, 1H), 1.91 a (DDD, J=4.4 Hz, and 12.2 Hz, and 13.4 Hz, 1H), 2,09 at 2.45 (m, 8H), of 2.56 2.63 in (lat.s, 4H), 3,10 (m, 2H), 7,01 (t, J=8,8 Hz, 2H), 7,27-7,38 (m, 5H), 7,51 (DD, J=4,8 Hz and 8.8 Hz, 2H), 9,07 (s, 1H).

The above free the connection handle in the usual way, getting hydrochloride (182 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,66 (d, J=6.4 Hz, 3H), 1,10 (d, J=6.8 Hz, 3H), 1.18 to 1.30 on (m, 1H), 1.56 to its 1.68 (m, 1H), 2,03-of 2.23 (m, 3H), 3.00 and-3,90 (m, 13H), 7,16 (t, J=8,8 Hz, 2H), 7,33-7,44 (m, 5H), 7 is phenylamino)ethyl]piperazine

66-1) 1-[2-(4-Forbindelseshandtering)ethyl]-4-(tert-botok-dicarbonyl)piperazine

1-(2-amino-ethyl)-4-(tert-butoxycarbonyl)piperazine (2,01 g) obtained in example 58, and 4-forbindelsesfaneblad (2,05 g) dissolved in tetrahydrofuran (20 ml), the solution is added triethylamine (2.4 ml) and the mixture is stirred over night at room temperature. To the reaction mixture are added water (50 ml), the mixture was then extracted with ethyl acetate and the organic layer washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate), thereby obtaining specified in the header connection (2,61 g, 77%) as a colourless oil.

1H NMR (400 MHz, Dl3)(M. D.): 1,45 (s, N), of 2.23 (t, J=5.2 Hz, 4H), 2,42 at 2.45 (m, 2H), 2,99-3,03 (m, 2H), 3,35 (t, J=5.2 Hz, 4H), to 5.17 (m, 1H), 7,20 (m, J=8.6 Hz, 2H), 7,22-7,37 (m, 2H).

66-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-forbindelseshandtering)ethyl]piperazine

1-[2-(4-Forbindelseshandtering)ethyl]-4-(tert-butoxycarbonyl)piperazine (260 mg) was dissolved in dichloromethane (2.0 ml), to the solution under stirring at 0°C. add triperoxonane acid (2 ml) and the mixture was stirred at 0°C for 1 is l)-5-oxo-2-phenylpentane (177 mg), acetic acid (0.10 ml) and triacetoxyborohydride sodium (261 mg), specified in the title compound (247 mg, 62%) was obtained as colorless oil in the same manner as in example 1.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,78 (d, J=6.8 Hz, 3H), 1,11 (m, 1H), 1,21 (d, J=6.8 Hz, 3H), of 1.53 (m, 1H), 1,74 is 1.91 (m, 2H), 1,96-2,19 (m, 2H), 2,25-of 2.45 (m, 10H), 2,39 (t, J=5.8 Hz, 2H), 2,98 (t, J=5.8 Hz, 2H), 7,16-of 7.23 (m, 2H), 7,29 (m, 1H), 7,34-7,39 (m, 4H), a 7.85 to $ 7.91 (m, 2H).

The above free compound (166 mg) is treated in the usual way, getting hydrochloride (191 mg) specified in the title compounds as a colorless amorphous substance.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.4 Hz, 3H), 1,11 (d, J=6.4 Hz, 3H), 1,25 (m, 1H), 1,62 (m, 1H), 2.06 to 2,24 (m, 3H), 3,17-is 3.21 (m, 6N), 3,33-3,51 (m, 10H), 7,33-7,39 (m, 1H), 7,41-7,49 (m, 6N), 7,89 (DD, J=5,2 Hz, 6.8 Hz, 1H), to $ 7.91 (DD, J=5,2 Hz, 7.2 Hz, 1H), 8,12 (Shir.s, 1H).

ESI-Macc: 487 (MH+).

Example 67. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-forfinal)sulfamoyl]ethyl}piperazine

67-1) 1-{2-[N-(4-Forfinal)sulfamoyl]ethyl}-4-(tert-butoxycarbonyl)piperazine

A solution of 4-foronline (3,41 g) and triethylamine (4.5 ml) in tetrahydrofuran (20 ml) is added dropwise to a solution of 2-floridasunmodels is mperature. To it was added 5 N. aqueous NaOH followed by extraction with ethyl acetate. The organic layer was washed with water, dried and evaporated. Part (3,81 g) residue (5,56 g) and N-(tert-butoxycarbonyl)piperazine (2.3 g) is dissolved in methylene chloride (20 ml) and stirred at room temperature for 2 hours. The reaction mixture is evaporated and purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate), thereby obtaining specified in the header connection (6,01 g, 82%) as a pale yellow oil.

1H NMR (400 MHz, Dl3)(M. D.): a 1.46 (s, N), the 2.46 (t, J=5 Hz, 4H), of 2.92 (t, J=6.4 Hz, 2H), 3,23 (t, J=6.4 Hz, 2H), 3,44 (t, J=5 Hz, 4H), 7,05 (t, J=8.6 Hz, 2H), 7,17-7,21 (m, 2H).

67-2) 1-{2-[N-(4-Forfinal)sulfamoyl]ethyl}piperazine

1-{2-[N-(4-Forfinal)sulfamoyl]ethyl}-4-(tert-butoxycarbonyl)piperazine (6,01 g) dissolved in ethanol (10 ml), then to the solution was added a solution of 4 N. HCl/ethyl acetate (40 ml) and the mixture was stirred at 50°C for 4 hours. The reaction mixture is evaporated, neutralized 5 N. aqueous NaOH and extracted with chloroform. The organic layer was washed with water, dried and evaporated, whereby receive specified in the header connection (3,52 g, 79%) as a light brown solid.

67-3) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-forfinal)sulfamoyl]ethyl}piperazine

The free compound (179 mg, 80%) indicated in the title compound obtained as a pale-yellow oil from 2-(1-methylethyl)-5-oxo-2-phenylpentane (100 mg) and 1-[2-(4-forfinal)propyl]piperazine (133 mg) in the same manner as in example 1.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.4 Hz, 3H), of 1.05 to 1.16 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,49 is 1.60 (m, 1H), of 1.88 (DDD, J =4.4 Hz, 12 Hz to 13.6 Hz, 1H), 2,08-of 2.56 (m, N), is 2.88 (t, J=6.4 Hz, 2H), 3,19 (t, J=6.4 Hz, 2H), 7,02 (t, J=8.6 Hz, 2H), 7,19 (dt, J=4.4 Hz, 8.6 Hz, 2H), 7,27-7,38 (m, 5H).

The above free compound (119 mg) is treated in the usual way, getting hydrochloride (120 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,65 (d, J=6.8 Hz, 3H), of 1.09 (d, J=6.8 Hz, 3H), 1,15 of 1.28 (m, 1H), 1,53-of 1.65 (m, 1H), 2,00-2,25 (m, 3H), 2.95 and of 3.75 (m, 14N), 7,17 (t, J=8,8 Hz, 2H), 7,25 (dt, J=4,8 Hz and 8.8 Hz, 2H), 7,32-the 7.43 (m, 5H), 10,00 (s, 1H).

ESI-Macc: 487 (MH+).

Example 68. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-forfinal)-N-methylcarbamoyl]ethyl}piperazine

To a solution of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4 ice cooling and the mixture is stirred for 30 minutes at room temperature. The reaction mixture was again cooled with ice, add methyliodide (0.01 ml) and the mixture is stirred for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate) to give the free compound (51 mg, 81%) indicated in the title compound as a pale yellow oil.

Free connection

1H NMR (400 MHz, CDCl3)(M. D.): 0,77 (d, J=6.6 Hz, 3H), of 1.05 to 1.16 (m, 1H), 1,20 (d, J=6.6 Hz, 3H), 1,50 is 1.58 (m, 1H), of 1.88 (DDD, J =4.4 Hz, 12 Hz to 13.6 Hz, 1H), 2,08-2,48 (m, N), 2,79-2,82 (m, 2H), 3,12-3,15 (m, 2H), and 3.31 (s, 3H), 7,02 (t, J=8.6 Hz, 2H), 7,16 (t, J=8.6 Hz, 2H), 7,27-7,38 (m, 7H).

The above free the connection handle in the usual way, getting hydrochloride (38 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,65 (d, J=6, 8 Hz, 3H), of 1.09 (d, J=6.8 Hz, 3H), 1,18-1,3 (m, 1H), 1,55 by 1.68 (m, 1H), 2,03-of 2.23 (m, 3H), 2.95 and-3,20 (m, 4H), of 3.25 (s, 3H), 3,35-of 3.80 (m, 10H), from 7.24 (t, J=8,8 Hz, 2H), 7,32-the 7.43 (m, 5H), 7,49 (DD, J=4,8 Hz and 8.8 Hz, 2H).

ESI-Macc: 501 (MH+).

Example 69. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-methyl-4-forbindelseshandtering)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)GE is 0°C with stirring sodium hydride (5.1 mg) and methyliodide (0.01 ml) and the mixture is stirred over night at room temperature. The reaction mixture is acidified by adding 5 M chlorotoluron acid and then evaporated. The residue is dissolved in dimethylformamide (5 ml) and to the solution add thiourea (7,3 mg), the mixture is heated at the boil under reflux overnight. After cooling the reaction mixture to room temperature the organic layer distributes the addition of water and ethyl acetate and the organic layer washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate), obtaining mentioned in the title compound (13 mg, 41%) as a colourless oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,08-to 1.14 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,25-of 1.55 (m, 3H), of 1.88 (dt, J=4,6 Hz, 13.0 Hz, 1H), 2,08-to 2.18 (m, 2H), 2.21 are of 2.27 (m, 2H), 2,27-2,38 (Shir.s, 3H), 2,38-2,48 (Shir.s, 3H), 2,52 (t, J=7,0 Hz, 2H), 2,78 (s, 3H), of 3.13 (m, 2H), 7,19 (m, J=8,4 Hz, 2H), 7,29 (m, 1H), 7,34-7,41 (m, 4H), 7,84-7,79 (m, 2H).

The above free compound (13 mg) is treated in the usual way, getting hydrochloride (14,8 mg) specified in the title compounds as a colorless amorphous substance.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,77 is 0.81 (m, 3H), 0,86-of 0.90 (m, 1H), 1,19-of 1.23 (m, 3H), 1 the Nile)hexyl]-4-{2-[(4-forfinally)carbonyloxy]ethyl}piperazine

The free compound (228 mg, 84%) indicated in the title compound obtained as a colorless oil from 2-(1-methylethyl)-5-oxo-2-phenylpentane (120 mg) and 1-(1-piperazinil)ethyl-S-(4-forfinal)thiocarbonate (159 mg) in the same manner as in example 1.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,78 (d, J=6.8 Hz, 3H), 1.06 a-1,18 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,49 is 1.60 (m, 1H), 1,90 (DDD, J =4.4 Hz, 12 Hz to 13.6 Hz, 1H), 2,08-of 2.28 (m, 8H), to 3.09 (t, J=6,8 Hz, 2H), 3,28-3,44 (m, 4H), 4,20 (t, J=6,8 Hz, 2H), 6,99 (t, J=8.6 Hz, 2H), 7,26-7,41 (m, 5H).

The above free the connection handle in the usual way, getting hydrochloride (88 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,65 (d, J=6.4 Hz, 3H), 1,10 (d, J=6.4 Hz, 3H), 1,16-of 1.26 (m, 1H), 1,54-of 1.66 (m, 1H), 2,04-of 2.24 (m, 3H), 2,78-3,37 (m, 13H), 4,10-4,18 (m, 2H), 7,17 (t, J=9 Hz, 2H), 7,33-7,37 (m, 1H), 7,40-7,46 (m, 6N).

ESI-Macc: 484 (MH+).

Example 71. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-pyridyloxy)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine (225 mg) and 2-bromopyridine (0.10 ml) dissolved in dimethylformamide (20 ml), then at room temperature to the solution was added sodium hydride (45 mg) and 2-bromopyridine (0,20 ml) and the mixture is heated at 75°C. The reaction mixture was poured into aqueous sodium bicarbonate, extracted with ethyl acetate, washed with water and brine and dried. After evaporation the residue is purified by chromatography on a column of silica gel Cromatorex NH (system hexane/ethyl acetate), whereby the free connection specified in the connection header receive in the form of butter.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,20 (d, J=6.8 Hz, 3H), 1,25-of 1.27 (m, 1H), 2,04-of 2.34 (m, 4H), 2,80-of 3.60 (m, 14N), of 6.71-6,76 (m, 1H), 6,85-6,91 (m, 1H), 7,27-7,34 (m, 1H), 7,35-7,42 (m, 4H), 7,54-to 7.61 (m, 1H), 8,10-to 8.14 (m, 1H).

The above free compound was dissolved in methanol and to the solution was added a solution of 4 N. hydrogen chloride/ethyl acetate. The solvent and excess hydrogen chloride is evaporated and the residue recrystallized from methanol/simple ether, whereby receive hydrochloride (55 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,68 (d, J=6.6 Hz, 3H), 1,11 (d, J=6.6 Hz, 3H), of 1.20 and 1.33 (m, 1H), 1.56 to to 1.70 (m, 1H), 2,04-of 2.30 (m, 3H), 3.00 and-3,82 (m, 14N), br4.61 (Shir.s, 2H), 6,86-of 6.90 (m, 1H), 7,02-7,07 (m, 1H), 7,34-7,40 (m, 1H), 7,42-of 7.48 (m, 4H), 7,73-7,79 (m, 1H), 8.17-a to 8.20 (m, 1H).

ESI-Macc: 407 (MH+).

Example 72. Synthesis of 1-(3-cyclohexyl-3-cyano-3-phenyl)propionyl sintezirovannyi in accordance with J. M. C., 35, 2210-2214, 1992, and sodium hydride (370 mg, 65%) was dissolved in dimethylformamide (35 ml) and the mixture was stirred at 60°C for 3 hours. The reaction mixture was left to reach room temperature and to this mixture ethylbromoacetate (1,67 g) and tetrahydrofuran (4 ml), the mixture is stirred overnight at a temperature of from 60 to 70°C. the Organic layer distributes the addition of water and a mixed solvent of simple ether/hexane, washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel (system hexane/ethyl acetate), whereby receiving ethyl-3-cyano-3-phenyl-3-cyclohexylpropionate (1.13 g) as a colourless oil.

This connection add ethanol (16 ml) and 8 n sodium hydroxide (2.0 ml), the mixture is stirred over night at room temperature. After neutralization with 5 N. chlorotoluron acid organic layer distribute a blend of simple ether/ethyl acetate, washed with water, dried and evaporated, getting 3-cyano-3-phenyl-3-cyclohexylpropionic acid (940 mg).

This carboxylic acid (205 mg) was dissolved in tetrahydrofuran (4.0 ml) and to the solution was added dimethylformamide (2 drops) and oxacillin (120 mg), the mixture is stirred for 10 minutes at room temperature is obtained 1-[2-(4-pertenece)ethyl]piperazine (215 mg) and triethylamine (120 mg) in tetrahydrofuran (5.0 ml). After stirring for 3 hours the organic layer distributes the addition of an aqueous saturated sodium bicarbonate and ethyl acetate, washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel (system hexane/ethyl acetate/methanol), whereby receive specified in the title compound (160 mg) as a colourless oil.

Free connection

1H NMR (400 MHz, CDCl3)(M. D.): of 1.05 to 1.40 (m, 5H), 1,60-1,70 (m, 3H), 1,83-1,90 (m, 1H), 1,95-2,15 (m, 2H), 2,30 at 2.45 (m, 4H), 2,77 (t, J=5.8 Hz, 2H), 3,01 (d, J=5 Hz, 2H), 3,13 (d, J=5 Hz, 2H), 3,20-to 3.35 (m, 2H), 3,42-to 3.50 (m, 2H), Android 4.04 (t, J=5.8 Hz, 2H), 6,80-6,85 (m, 2H), 6,91-of 6.99 (m, 2H), 7,22-the 7.43 (m, 4H).

Example 73. Synthesis of 1-(2-hydroxy-4-cyano-5-methyl-4-phenyl) hexyl]-4-[2-(4-pertenece)ethyl]piperazine

73-1) (3-Methyl-2-cyano-2-phenyl)mutilateral

3-Methyl-2-phenylbutyramide (4,19 g) synthesized in accordance with J. Chem. Soc. Perkin Trans, 1, 2845-2850, 1996, and 65% sodium hydride in oil (1,05 g) dissolved in dimethylformamide (90 ml) and the mixture was stirred at 60°C for 3 hours. The reaction mixture was left to reach room temperature and to it was added allylbromide (2.9 g) and tetrahydrofuran (3.0 ml), the mixture is stirred over night at 60°C. the Organic layer races is so The residue is purified by chromatography on a column of silica gel (system hexane/ethyl acetate), whereby receive (5-methyl-4-cyano-4-phenyl)-1-hexene (4.5 g, 86%) as a colourless oil.

This product (2.5 g) dissolved in dichloromethane (60 ml) and the solution was added sodium bicarbonate (2.35 g) and meta-chloroperbenzoic acid (2.76 g) under ice cooling, the mixture is stirred over night at room temperature. To the mixture ethanol (16 ml) and 8 n sodium hydroxide (2.0 ml) and the mixture is stirred over night at room temperature. To the reaction mixture is added aqueous saturated sodium bicarbonate solution and dichloromethane and the organic layer is distributed, washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel (system hexane/ethyl acetate), whereby receive previously suirvey the diastereoisomer (800 mg, 30%) specified in the connection header and later suirvey the diastereoisomer (390 mg, 14%) specified in the connection header.

The diastereoisomer 1 (suirvey earlier)

1H NMR (400 MHz, Dl3)(M. D.): 0,81 (d, J=6.8 Hz, 3H), 1,19 (d, J=6.8 Hz, 3H), of 2.05 (DD, J=7,2 Hz, 14 Hz, 1H), 2,16-of 2.24 (m, 1H), 2,44 (DD, J=12,8 Hz and 17.2 Hz, 1H), 2,58-of 2.64 (m, 1H), 2,64 of 2.68 (m, 1H), 2,70-to 2.74 (m, 1H), 7,30-to 7.50 (m, 5H).

Dia is C, 3H), 1,22 (d, J=6.8 Hz, 3H), of 1.92 (DD, J=6,4 Hz, 14.4 Hz, 1H), 2,17-of 2.26 (m, 1H), 2,48-2,78 (m, 1H), 2,64 of 2.68 (m, 2H), 2,810-2,874 (m, 1H), 7,30-to 7.50 (m, 5H).

73-2) 1-(2-Hydroxy-4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

Previously suirvey the diastereoisomer 1 (390 mg), 1-[2-(4-pertenece)ethyl]piperazine (450 mg) and the monohydrate ytterbium(III)triftormetilfullerenov acid (90 mg) are added to dichloromethane (2.5 ml) and the mixture is stirred over night at room temperature. The solvent is evaporated and the residue purified by chromatography on a column of silica gel (system hexane/ethyl acetate/methanol), getting mentioned in the title compound (320 mg, 40%).

1H NMR (400 MHz, Dl3)(M. D.): 0,76 (d, J=6.8 Hz, 3H), 1,21 (d, J=6.8 Hz, 3H), 2,10-of 2.24 (m, 3H), 2,27 is 2.43 (m, 3H), 2,43 is 2.51 (m, 7H), by 2.73 (t, J=6.0 Hz, 2H), 3,48-3,55 (m, 1H), a 4.03 (t, J=6.0 Hz, 2H), 6,79-6,85 (m, 2H), 6,92-6,98 (m, 2H), 7,26-7,34 (m, 1H), 7,34-7,40 (m, 4H).

Example 74. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-benzoylperoxy)ethyl]piperazine

N-[2-(Benzoylperoxy)ethyl]piperazine (169,9 mg), 2-(1-methylethyl)-5-oxo-2-phenylpentane (103 mg) and acetic acid (0.05 ml) dissolved in dichloroethane (5 ml), then the solution add triacetoxyborohydride sodium (160 mg) and the mixture treated is inane in the form of a colorless oil.

Free connection

1H NMR (400 MHz, CDCl3)(M. D.): 0,78 (d, J=6.2 Hz, 3H), 1.06 a-1,53 (m, 1H), 1,20 (d, J=6.2 Hz, 3H), 1,50-to 1.61 (m, 1H), 1.77 in (m, 1H), 1,88 (TD, J=4.4 Hz, and 12.6 Hz, 1H), 1,95-2,31 (m, 7H), 2,50 (Shir.s, 4H), to 2.75 (t, J=5.6 Hz, 2H), 3,06 (s, 2H), 4,06 (t, J=5.6 Hz, 2H), 6,83 (d, J=8,4 Hz, 1H), to 6.88 (t, J=7,4 Hz, 1H), 7,08-to 7.32 (m, 8H), 7,34-7,39 (m, 4H).

The above free compound (96 mg) is treated in the usual way, getting hydrochloride (110 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, Dl3)(M. D.): 0,79 (d, J=6.4 Hz, 3H), 1,24 (d, J=6.4 Hz, 3H), 1,25 (m, 1H), USD 1.43 (m, 1H), 1,78 (m, 1H), 2,04 (m, 1H), 2,16 (m, 2H), 2,33 (m, 1H), 2,87 (m, 1H), 2,90-3,10 (m, 2H), 3,25 (m, 1H), 3,35 (m, 2H), of 3.46 (m, 2H), 3,70 (m, 2H), 4.00 points (s, 2H), 4,43 (m, 2H), at 6.84 (d, J=6,8 Hz, 1H), 7,00-7,07 (m, 5H), 7,19-7,20 (m, 2H), was 7.36-7,44 (m, 6N).

ESI-Macc: 496 (MH+).

Finally, the described experimental examples, where the compound of example 1 are divided into optical isomers by using HPLC with an optically active column, as a preparative examples to obtain optically active compounds of the present invention (reference to Fig.8).

Conditions of HPLC analysis

Solid phase: Chiralcel OJ (0,46 cm25 cm, Daicel Chemical)

Mobile phase: n-hexane:isopropyl alcohol:ethanol = 850:100:50

Flow rate: 0.5 ml/min

rproxy)ethyl]piperazine

Specified in the header connection receive as previously elyuirovaniya faction in the above experimental example HPLC.

[]29D= -5,18 (C=1.0, ethanol).

Example 76. Hydrochloride(+)-1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

Specified in the header of the connection get as later elyuirovaniya faction in the above experimental example HPLC.

[]30D= +6,23 (C=1.0, ethanol).

In the same way optically active substances were obtained by separation of the compound of example 25.

Example 77. Hydrochloride(-)-1-[(3-cyano-4-methyl-3-phenyl)pentyl]-4-[2-(4-pertenece)ethyl]piperazine

[]27,8D= -6,552 (C=0.250, the ethanol).

Example 78. Hydrochloride(+)-1-[(3-cyano-4-methyl-3-phenyl)pentyl]-4-[2-(4-pertenece)ethyl]piperazine

[]27,6D= +4,118 (=0,267, ethanol).

In the same way optically active substances produced by separation of the compounds of example 38.

Example 79. Hydrochloride(-)-1-[(4-cyano-4-cyclohexyl-4-phenyl)butyl]-4-[2-(4-pertenece)ethyl]piperazine

[]27,4D= -5,717 (=1,833, ethanol).

Example 80. Hydrochloride(+)-1-[(4-cyano-4-cyclohexanol).

Example 81. Synthesis of 1-[(4-cyano-5-hydroxy-5-methyl-4-phenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

81-1) Ethyl-5-benzyloxy-2-cyano-2-phenylpentane

Sodium hydride are added to a solution of ethylvinylacetate (3 g) in dimethylformamide (20 ml) under ice cooling and the mixture is stirred at room temperature for 1 hour. The mixture was again cooled with ice, add to it benzyl-3-bromopropyl ether (4,2 ml) and the mixture is stirred at room temperature for 3 hours. After evaporation of the reaction mixture there was added water and the product extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel (system hexane/ethyl acetate), whereby receive specified in the header connection (2,892 g, 54%) as a colourless oil.

1H NMR (400 MHz, CDCl3)(M. D.): 1,22 (t, J=7.2 Hz, 3H), 1,65-of 1.84 (m, 2H), 2.23 to-2,31 (m, 1H), 2,44 is 2.51 (m, 1H), 3,49 (t, J=6.2 Hz, 2H), 4,14-4.26 deaths (m, 2H), 4,46 (s, 2H), 7.23 percent-7,41 (m, 8H), 7,54-7,56 (m, 2H).

81-2) 5-Benzyloxy-2-(1-hydroxy-1-methylethyl)-2-phenylpentane

3M methylmagnesium simple ether (8 ml) is added dropwise to a solution of ethyl-5-benzyloxy-2-. odny saturated ammonium chloride is added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, dried and evaporated. The residue is purified by chromatography on a column of silica gel (system hexane/ethyl acetate), whereby receive specified in the header connection (1,658 g, 60%) as a colourless oil.

1H NMR (400 MHz, Dl3)(M. D.): 1,22 (s, 3H), 1,35-1,45 (m, 1H), 1,37 (s, 3H), 1,67-to 1.77 (m, 1H), 2,17 was 2.25 (m, 1H), 2,38 at 2.45 (m, 1H), 3,47 (t, J=6.2 Hz, 2H), of 4.45 (s, 2H), 7.24 to 7,39 (m, 8H), 7,46-7,51 (m, 2H).

81-3) 2-(1-Hydroxy-1-methylethyl)-5-iodine-2-phenylpentane

The catalyst is 10% palladium/charcoal (250 mg) are added to a solution of 5-benzyloxy-2-(1-hydroxy-1-methylethyl)-2-phenylpentane (1,658 g) in ethanol (20 ml) and the mixture is stirred in hydrogen atmosphere for 5 hours. After filtering off the catalyst, the filtrate is evaporated. The residue and triethylamine (1.1 ml) dissolved in tetrahydrofuran (15 ml), the solution add methanesulfonanilide (0.6 ml) under ice cooling and the mixture is stirred at room temperature for 30 minutes. To the reaction mixture are added water and then extracted with ethyl acetate, the organic layer washed with water, dried and evaporated.reflux for 2 hours. The reaction mixture is evaporated, add it to water and the product extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated, the residue is purified by chromatography on a column of silica gel (system hexane/ethyl acetate), whereby specified in the header connection (1,493 g, 85%) was obtained as a yellowish brown oil.

1H NMR (400 MHz, Dl3)(M. D.): a 1.25 (s, 3H), of 1.42 (s, 3H), 1,50-1,60 (m, 1H), 1,91 is 2.01 (m, 1H), 2,20-of 2.27 (m, 1H), 2,45-2,52 (m, 1H), 3,12-3,26 (m, 2H), was 7.36-7,44 (m, 1H), 7,47-7,51 (m, 2H).

81-4) 1-[(4-Cyano-5-hydroxy-5-methyl-4-phenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

1-[2-(4-Pertenece)ethyl]piperazine (359 mg) and triethylamine (0,22 ml) are added to a solution of 2-(1-hydroxy-1-methylethyl)-5-iodine-2-phenylpentane (545 mg) in tetrahydrofuran (7 ml) and the mixture is stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel Chromatorex NH (system hexane/ethyl acetate), whereby specified in the title compound (406 mg, 56%) was obtained as a colorless oil.

Free connection

1H NMR (400 MHz, Dl3)(m2-7,42 (m, 3H), 7,46 is 7.50 (m, 2H).

The above free compound (125 mg) is treated in the usual way, getting hydrochloride (131 mg) specified in the connection header.

Hydrochloride

ESI-Macc: 440 (MH+).

Example 82. Synthesis of 1-[5-(4-cyano-5-methyl-4-phenyl)hexenyl]-4-[2-(4-pertenece)ethyl]piperazine

1-[(4-Cyano-5-hydroxy-5-methyl-4-phenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine (145 mg) was dissolved in thionyl chloride (1 ml) and heated to boiling under reflux for 5 minutes. The reaction mixture is added dropwise to 5 N. NaOH (10 ml) and the mixture was then extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel Chromatorex NH (system hexane/ethyl acetate), whereby specified in the title compound (98 mg, 70%) was obtained as a colorless oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 1,40-of 1.52 (m, 1H), 1,62 (s, 3H), 1,62-1,72 (m, 1H), 2,05-2,22 (m, 2H), a 2.36 (t, J=7.4 Hz, 2H), 2,36-of 2.66 (m, 8H), 2,78 (t, J=5.8 Hz, 2H), of 4.05 (t, J=5.8 Hz, 2H), 5,13 (s, 1H), 5,35 (s, 1H), for 6.81-6,85 (m, 2H), 6,93-6,98 (m, 2H), 7,28-7,42 (m, 5H).

The above free compound (98 mg) is treated in the usual way, getting hydrochloride (81 mg) specified in taxil]-4-[2-(4-pertenece)ethyl]piperazine

1-[4-Cyano-5-methyl-4-(4-methoxyphenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine (85 mg) obtained in example 11, was dissolved in dichloromethane (3 ml) and to the solution is added dropwise 1 M tribromide boron (solution in dichloromethane, 0.5 ml) under cooling with ice. After heating the mixture while boiling under reflux for 5 hours, it is cooled to room temperature and alkalinized water saturated solution of sodium bicarbonate under ice cooling. The mixture is extracted with ethyl acetate and the organic layer washed with water, dried over anhydrous sodium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system hexane/ethyl acetate), whereby receive specified in the title compound (30 mg, 36%) as a colourless oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.6 Hz, 3H), of 1.16 (d, J=6.6 Hz, 3H), 1,19-of 1.30 (m, 1H), 1,61-of 1.66 (m, 1H), 1,68-1,71 (m, 1H), 1,80 (TD, J=4.4 Hz, to 13.6 Hz, 1H), 1,99-2,05 (m, 1H), 2,08 (TD, J=4.4 Hz, to 12.8 Hz, 1H), 2,27-2,60 (m, N), 2,77 (t, J=5.6 Hz, 2H), 3,71 (m, 1H), a 4.03 (t, J=5.6 Hz, 2H), 6,64 of 6.66 (m, 2H), 6,80 (t, J=4.4 Hz, 1H), for 6.81 (DD, J=4.4 Hz, and 9.2 Hz, 1H), 6,94 (TM, J=8,8 Hz, 2H), 7,13 (m, 1H), 7,15 (m, 1H).

ESI-Macc: 440 (MH+).

Oxalic acid (equivalent) is added at room within 10 minutes the solvent is evaporated, whereby receive oxalate (16.1 mg) specified in the connection header.

Oxalate

ESI-Macc: 440 (MH+).

Example 84. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-hydroxy-4-pertenece)ethyl]piperazine

84-1) Ethyl-(2-acetyl-4-pertenece)acetate

5’-Fluoro-2’-hydroxyacetophenone (2.0 g), acilitated (4,16 g) and potassium carbonate (2.7 g) is added to the acetone (43 ml) under nitrogen atmosphere and the mixture is stirred over night while boiling under reflux with heating. After cooling to room temperature, the potassium carbonate is separated by filtration through celite and the filtrate is distributed by the addition of water and ethyl acetate. The organic layer is washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system hexane/ethyl acetate), whereby specified in the header of the connection (of 3.07 g, 99%) was obtained as a colorless oil.

1H NMR (400 MHz, Dl3)(M. D.): 1,31 (t, J=7.0 Hz, 3H), of 2.72 (s, 3H), 4,28 (K, J=7,0 Hz, 3H), 4,70 (s, 2H), for 6.81 (DD, J=4.0 Hz, and 9.2 Hz, 1H), 7,14 (DDD, J=3.2 Hz, 7.2 Hz, and 9.2 Hz, 1H), of 7.48 (DD, J=3.2 Hz, 8,8 Hz, 1H).

84-2) Ethyl-(2-acetoxy-4-pertenece)acetate

E who have to dichlormethane (10 ml) under nitrogen atmosphere and the mixture is stirred for 1 day while boiling under reflux with heating. The reaction mixture is cooled to room temperature, add to it 1 M aqueous sodium thiosulfate (5 ml), the mixture is stirred and distributed by the addition of water and dichloromethane. The organic layer is washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system hexane/ethyl acetate), whereby receive specified in the title compound (333 mg, 74%) as a colourless oil.

1H NMR (400 MHz, Dl3)(M. D.): of 1.30 (t, J=7,1 Hz, 3H), of 2.34 (s, 3H), 4.26 deaths (K, J=7,1 Hz, 2H), 4,57 (s, 2H), 6,82-6, 92 (m, 3H).

84-3) 1-(2-Hydroxy-4-forfinancial)pyrrolidin

Pyrrolidin (1,87 g) is added to ethyl(2-acetoxy-4-pertenece)acetate and the mixture is stirred over night. The reaction solution is distributed by the addition of water and ethyl acetate. The organic layer is washed with water and then saturated saline, dried over anhydrous magnesium sulfate and evaporated, whereby receive specified in the title compound (1.20 mg, 96%) as a brown oil.

1H NMR (400 MHz, Dl3)(M. D.): 1,82-2,04 (m, 4H), 3,26-of 3.32 (m, 2H), 3,50 of 3.56 (m, 2H), 4,50 (s, 2H), 6,46 (dt, J=3.1 Hz, and 8.9 Hz, 1H), to 6.67 (DD, J=data/79/794461.gif">

1-(2-Hydroxy-4-forfinancial)pyrrolidin (82 mg) was dissolved in N,N-dimethylformamide (12 ml) under nitrogen atmosphere and the solution was added 60% sodium hydride (21 mg) in oil and the mixture is stirred for 15 minutes, add benzylbromide (89 mg) and the mixture is stirred at room temperature. After 45 minutes, to the mixture of aqueous saturated solution of ammonium chloride and the mixture is stirred and distributed by the addition of water and ethyl acetate. The organic layer is washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (diethyl ether), whereby receive specified in the title compound (100 mg, 97%) as a pale yellow oil.

1H NMR (400 MHz, Dl3)(M. D.): 1,75-1,90 (m, 4H), of 3.48 (t, J=6,8 Hz, 4H), 4,63 (s, 2H), 5,09 (s, 2H), return of 6.58 (DDD, J=2,8 Hz, 8,8 Hz, 11.2 Hz, 1H), 6,69 (DD, J=2,8 Hz, 10.0 Hz, 1H), 6,94 (DD, J=5.6 Hz, 8,8 Hz, 1H).

84-5) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-benzyloxy-4-pertenece)ethyl]piperazine

1-(2-Benzyloxy-4-forfinancial)pyrrolidine (100 mg) dissolved in toluene (10 ml) under nitrogen atmosphere and the solution was added 3,4 M bis(2-methoxyethoxy)aluminiumtrihydrate in toluene (0,09 ml, fibre room temperature. After 15 minutes, to the mixture was added 1 N. chlorotoluron acid (1 ml), stirred and then distribute the addition of water and ethyl acetate. The organic layer is washed in order with water, aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated, getting aldehyde (65 mg). This product (65 mg), acetic acid (0.06 ml) and 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine (71 mg) was dissolved in dichloromethane (12.5 ml), the solution add triacetoxyborohydride sodium (107 mg) and the mixture is stirred at room temperature for 5 hours. The reaction mixture is distributed by addition of an aqueous saturated sodium bicarbonate and ethyl acetate. The organic layer is washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel NH (system hexane/ethyl acetate), whereby specified in the title compound (66 mg, 49%) was obtained as a pale yellow oil.

1H NMR (400 MHz, CDCl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), of 1.10-1.20 (m, 1H), 1,20 (d, J=6.6 Hz, 3H), 1,45-to 1.60 (m, 1H), 1,82-of 1.93 (m, 1H), 2,05-of 2.20 (m, 2H), 2,20-2,40 (m, 6N), 2,45-to 2.65 (m, 4H), 2,77 (t, J=5,9 Hz, 2H), 4,08 (t, J=5,9 Hz, 2H), is 5.06 (s, 2H), 6,57 (Shir. dt, J=3.2 Hz, 8,8 Hz, 1H), to 6.67 (DD, J=3.2 G is hydroxy-4-pertenece)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-benzyloxy-4-pertenece)ethyl]piperazine (66 mg) and 1,4-cyclohexadiene (0,23 ml) dissolved in ethanol (4 ml) and to the solution was added the catalyst, 10% palladium/carbon (6 mg), the mixture is stirred for 3 hours at boiling under reflux with heating. The reaction mixture was filtered through celite and evaporated. The residue is purified by chromatography on a column of silica gel NH (system hexane/ethyl acetate), whereby receive a free form (13 mg, 24%) indicated in the title compounds as colorless oils.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,78 (d, J=6.8 Hz, 3H), 1,05-1,20 (m, 1H), 1,20 (d, J=6.6 Hz, 3H), 1,50-to 1.63 (m, 1H), 1,80-of 1.93 (m, 1H), 2,05-of 2.20 (m, 2H), 2,28 to 2.35 (m, 2H), 2,35-2,70 (m, 8H), of 2.56 (t, J=5,2 Hz, 2H), a 4.03 (t, J=5,2 Hz, 2H), to 6.43 (Shir.dt, J=3.2 Hz, 8,8 Hz, 1H), 6,60 (DD, J=3.2 Hz, 10.4 Hz, 1H), 6,91 (DD, J=6,6 Hz and 8.8 Hz, 1H), 7,26-7,33 (m, 1H), 7,34-7,39 (m, 4H).

This compound (13 mg) is treated in the usual way, getting 11 mg hydrochloride specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.8 Hz, 3H), 1,11 (d, J=6.4 Hz, 3H), of 1.20 and 1.35 (m, 1H), 1,58 is 1.70 (m, 1H), of 2.05 to 2.35 (m, 3H), 3,30-of 3.80 (m, N), 4.26 deaths (Shir.s, 2H), 6,50-6,60 (m, 1H), 6,66 (who yl)butyl]-4-[2-(4-pertenece)ethyl]piperazine

85-1) 4-(1,3-Dioxolane-2-yl)-2-fluoro-2-phenylbutyramide

4-(1,3-Dioxolane-2-yl)-2-phenylbutyramide (1,00 g) synthesized in accordance with Heterocyclic Chem., 27, 307 (1990), dissolved in tetrahydrofuran (10 ml) and the solution in a nitrogen atmosphere at -78°injected With 1.0 M bis(trimethylsilyl)amide lithium in tetrahydrofuran (5,52 ml). The temperature of the mixture increases within 30 minutes to -20°C and then cooled to -78°C and injected into it a solution of N-forbindelsesfaneblad (2,18 g) in tetrahydrofuran (10 ml). The temperature is raised within 1 hour to -30°C and the solution was added aqueous saturated ammonium chloride and the solution extracted with ethyl acetate and then washed with brine. The extract is dried over anhydrous magnesium sulfate and evaporated. The residue is crystallized from ethanol, the insoluble part is separated by filtration and the filtrate is evaporated. The residue is purified by chromatography on a column of silica gel (system hexane/ethyl acetate), whereby receive specified in the title compound (0.55 g, 51%).

1H NMR (400 MHz, Dl3)(M. D.): 1,86-2,02 (m, 2H), 2,25-of 2.45 (m, 2H), 3,84-4,00 (m, 4H), is 4.93 (t, J=4.0 Hz, 1H), 7,40-7,52 (m, 5H).

85-2) 1-[(4-Cyano-4-fluoro-4-phenyl)butyl]-4-[2-(4-pertenece)ethyl]piperazine

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 1,62-1,90 (m, 2H), of 2.15 to 2.35 (m, 2H), 2,37 (t, J=7.2 Hz, 2H), 2,45 (Shir.s, 4H), 2,58 (Shir.s, 4H), and 2.79 (t, J=6.0 Hz, 2H), of 4.05 (t, J=6.0 Hz, 2H), 6,80-6,86 (m, 2H), 6,93-7,00 (m, 2H), 7,42-of 7.55 (m, 5H).

This free compound (0.14 g) is treated in the usual way, receiving 0.15 g of the hydrochloride specified in the connection header.

Hydrochloride

ESI-Macc: 400 (MH+).

Example 86. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-ethoxycarbonylmethoxy-4-pertenece)ethyl]piperazine

86-1) 2-(2-Acetyl-4-pertenece)ethanol

5’-Fluoro-2’-hydroxyacetophenone (5.0 g), 2-bromoethanol (between 6.08 g), potassium carbonate (13,4 g) and sodium iodide (7,28 g) dissolved in N,N-dimethylformamide (108 ml) and the solution stirred at 100°C during the night. The reaction mixture is cooled and then distributed by the addition of water and ethyl acetate. The organic layer is washed with water and then brine, dried on anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (systemacl.

1H NMR (400 MHz, Dl3)(M. D.): 2,36-to 2.40 (m, 1H), 2,64 (s, 3H), 3.96 points-was 4.02 (m, 2H), 4,16-4,20 (m, 2H), 6,95 (DD, J= 4.0 Hz, and 9.2 Hz, 1H), 7,16 (DDD, J=3.2 Hz and 7.6 Hz and 9.2 Hz, 1H), 7,43 (DD, J=3.2 Hz, 8,8 Hz, 1H).

86-2) 2-(2-Acetoxy-4-pertenece)ethanol

Specified in the title compound (96 mg, 68%) was obtained as colorless oil from 2-(2-acetyl-4-pertenece)ethanol (141 mg), sodium bicarbonate (107 mg) and meta-chloroperbenzoic acid (379 mg) in the same manner as in example 84-2).

1H NMR (400 MHz, Dl3)(M. D.): 2,45-2,52 (m, 1H), 2,33 (s, 3H), 3,84-3,90 (m, 2H), 4,12-4,16 (m, 2H), 6,80-6,86 (m, 1H), 6.90 to-of 6.96 (m, 2H).

86-3) 2-(2-Hydroxy-4-pertenece)ethanol

2-(2-Acetoxy-4-pertenece)ethanol (1,53 g) dissolved in a mixed solvent of tetrahydrofuran (10 ml) and water (5 ml), then to the solution was added monohydrate of lithium hydroxide (294 mg) and the mixture was stirred at 90°C. After stirring for 10 hours, the reaction mixture is cooled and distributed by the addition of water and ethyl acetate. The organic layer is washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system hexane/ethyl acetate), is 400 MHz, Dl3)(M. D.): 2,30-to 2.40 (m, 1H), 3.96 points-was 4.02 (m, 2H), 4,10-to 4.14 (m, 2H), 6,51 (DDD, J=3.0 Hz, 8,4 Hz and 8.8 Hz, 1H), 6,69 (DD, J=3.0 Hz, 9.6 Hz, 1H), 6,83 (DD, J=5,2 Hz and 8.8 Hz, 1H), 6.90 to-6,63 (m, 1H).

86-4) 2-(2-Ethoxycarbonylmethoxy-4-pertenece)ethanol

2-(2-Hydroxy-4-pertenece)ethanol (245 mg) and ethylbromoacetate (214 mg) was dissolved in N,N-dimethylformamide (5 ml) under nitrogen atmosphere and the solution was added sodium hydride (51 mg, 60% in oil). The mixture was stirred at 90°C for 1 hour and then distribute the addition of water and ethyl acetate. The organic layer is washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel NH (system hexane/ethyl acetate), whereby receive specified in the title compound (68 mg, 31%) as a colourless oil.

1H NMR (400 MHz, Dl3)(M. D.): 1,31 (t, J=7.2 Hz, 3H), 3.00 and-3,10 (m, 1H), 3,85-to 3.92 (m, 2H), 4,10-to 4.14 (m, 2H), 4,28 (K, J=7.2 Hz, 2H), 4,63 (s, 2H), 6,60 (DD, J=2,8 Hz, 9.6 Hz, 1H), 6,64-6,70 (m, 1H), 6,93 (DD, J=5.6 Hz, and 9.2 Hz, 1H).

86-5) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-ethoxycarbonylmethoxy-4-pertenece)ethyl]piperazine

2-(2-Ethoxycarbonylmethoxy-4-pertenece)ethanol (68 mg) and tritium is After stirring the mixture for 1 hour to it was added sodium iodide (47 mg) and 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine (90 mg) in acetonitrile (5 ml), the mixture is stirred for 2 hours at boiling under reflux with heating. The reaction mixture is distributed by the addition of water and ethyl acetate. The organic layer is washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (diethyl ether), whereby specified in the title compound (82 mg, 59%) was obtained as a colorless oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,05-1,20 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), of 1.27 and 1.33 (m, 3H), 1,50-to 1.63 (m, 1H), 1,70-1,90 (m, 1H), 2,05-of 2.20 (m, 2H), 2,25-of 2.30 (m, 2H), 2,30-2,60 (m, 8H), 2,78 (t, J=6.0 Hz, 2H), 3.15 in (s, 2H), 4,10 (t, J=6.0 Hz, 2H), 4,55-4,60 (m, 2H), 6,55 of 6.68 (m, 2H), 6,82-6,92 (m, 1H), 7,26-7,32 (m, 1H), 7,32-7,39 (m, 4H).

This product (28 mg) is treated in the usual way, getting hydrochloride (25 mg) specified in the connection header.

Hydrochloride

ESI-Macc: 526 (MH+).

Example 87. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-hydroxyethoxy-4-pertenece)ethyl]piperazine

1 M sociallyengaged in tetrahydrofuran (0,38 ml) are added to 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-ethoxycarbonylmethoxy-4-pertenece)ethyl]piperazine (20 mg) in tetrahydrofuran (4 modu and 2 N. aqueous sodium hydroxide. After removing the precipitate by filtration through celite, the filtrate is evaporated. The residue is purified by chromatography on a column of NH silica gel (ethyl acetate), whereby specified in the title compound (15 mg, 81%) was obtained as a colorless oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,05-1,20 (m, 1H), 1,20 (d, J=6.6 Hz, 3H), 1,45-to 1.63 (m, 1H), 1,82-of 1.93 (m, 1H), 2,05-of 2.20 (m, 2H), of 2.25 to 2.35 (m, 2H), 2.40 a-2,50 (m, 4H), 2,55-2,70 (m, 4H), 2,82 (t, J=6.0 Hz, 2H), 3,60-3,70 (m, 2H), 4,00-4,20 (m, 4H), 6,58 is 6.67 (m, 1H), of 6.68 (DD, J=2,8 Hz, 9.8 Hz, 1H), 6,86 (DD, J= 5.6 Hz, 8,8 Hz, 1H), 7,26-7,32 (m, 1H), 7,32-7,39 (m, 4H).

This product (15 mg) is treated in the usual way, getting hydrochloride (14 mg) specified in the connection header.

Hydrochloride

ESI-Macc: 484 (MH+).

Example 88. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-methoxy-4-pertenece)ethyl]piperazine

88-1) 1-(2-Methoxy-4-forfinancial)pyrrolidin

Specified in the title compound (90 mg, 69%) was obtained as colorless crystals of 1-(2-hydroxy-4-pertenece)acetylpyrrolidine (123 mg) and under the conditions (0.05 ml) in the same manner as in example 84-1).

1H NMR (400 MHz, Dl3)(M. D.): 1,80-1,90 (m, 2H), 1,90-2,00 (m, 2H), 3,48-ANO-5-methyl-4-phenyl)hexyl]-4-[2-(2-methoxy-4-pertenece)ethyl]piperazine

Specified in the title compound (39 mg, 24%) was obtained as a pale-yellow oil from 1-(2-methoxy-4-forfinancial)pyrrolidine (90 mg), 3,4 M bis(2-methoxyethoxy)aluminometasilicate in toluene (0.1 ml) and 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine (100 mg).

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,05-1,20 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-to 1.63 (m, 1H), 1,82-of 1.93 (m, 1H), 2,05-of 2.20 (m, 2H), of 2.25 to 2.35 (m, 2H), 2,30-to 2.65 (m, 8H), 2,80 (t, J=6.0 Hz, 2H), 3,82 (s, 3H), 4,08 (t, J=6.0 Hz, 2H), 6,55 (Shir. dt, J=2,8 Hz, 5.2 Hz, 1H), 6,62 (DD, J=2,8 Hz, 10.4 Hz, 1H), for 6.81 (DD, J= 5,2 Hz and 8.8 Hz, 1H), 7,26-7,33 (m, 1H), 7,32-7,39 (m, 4H).

This free compound (39 mg) is treated in the usual way, getting hydrochloride (33 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,68 (d, J=6, 6 Hz, 3H), 1,21 (d, J=6.6 Hz, 3H), 1,20-1,32 (m, 1H), 1,58-1,72 (m, 1H), of 2.05 to 2.35 (m, 3H), 3,30-OF 3.25 (2H), 3.25 to 3,70 (m, 10H), of 3.78 (s, 3H), 4,33 (Shir.s, 2H), of 6.71 (Shir.dt, J=3.0 Hz, 8.6 Hz, 1H), 6,95 (DD, J=3.0 Hz, a 10.6 Hz, 1H), 6,77 (DD, J=5.5 Hz, 8.6 Hz, 1H), 7,34 (m, 1H), 7,42-of 7.48 (m, 4H).

ESI-Macc: 454 (MH+).

Example 89. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-isopropylaniline)ethyl]piperazine

89-1) 2-(N-Isopropylaniline)ethanol

Informatica (14 ml) under nitrogen atmosphere and stirred at the boil under reflux with heating. After 1 hour the reaction mixture is cooled to room temperature and then distribute by adding water and diethyl ether, the organic layer washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system of hexane/diethyl ether) to give N-ethoxycarbonylmethyl-N-isopropylaniline (1,62 g). Part (550 mg) of this product is dissolved in tetrahydrofuran (10 ml) and to the solution was added 1 M sociallyengaged in tetrahydrofuran (2.5 ml) under cooling in an ice bath under nitrogen atmosphere. The mixture is stirred in an ice bath for 40 minutes and in the order specified, add water (0.1 ml), 2 N. aqueous sodium hydroxide (0.1 ml), water (0.3 ml) and diethyl ether (5 ml), the mixture is stirred. The insoluble part is separated by filtration through celite and the filtrate is evaporated. The residue is purified by chromatography on a column of silica gel (system hexane/ethyl acetate), whereby receive specified in the title compound (383 mg, 86%) as a colourless oil.

1H NMR (400 MHz, Dl3)(M. D.): to 1.16 (d, J=6,8 Hz, 6N), 1,84 is 1.91 (m, 1H), 3,32 (t, J= 6.0 Hz, 2H), 3,64-3,91 (m, 2H), 3,97 (Sept, J=6.8 Hz, 1H), 6,78-6,83 (m, 1H), 6,88-6,92 (m, 2H), 7,21-7,27 (m, 2H).

89-2) 1-[(4-CIaire nitrogen methanesulfonanilide (80 mg) are added to a solution of 2-(N-isopropylaniline)ethanol (125 mg) and triethylamine (of 0.24 ml) in acetonitrile (7 ml). After stirring the mixture for 1 hour to it was added sodium iodide (157 mg) and a solution of 1-[4-cyano-5-methyl-4-phenyl)hexyl]piperazine (100 ml) in acetonitrile (3 ml) and stirred for 4 hours at boiling under reflux with heating. The reaction solution is distributed by the addition of water and ethyl acetate and the organic layer washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel NH (system hexane/ethyl acetate), whereby specified in the title compound (80 mg, 25%) was obtained as a colorless oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), of 1.05 to 1.15 (m, 1H), 1,16 (d, J=6,4 Hz, 6N), 1,20 (d, J=6.4 Hz, 3H), 1,50-1,60 (m, 1H), of 1.88 (dt, J=4,8 Hz to 13.2 Hz, 1H), 2,07-to 2.18 (m, 2H), 2.21 are to 2.57 (m, N), 3,30 (Shir.t, J=8.0 Hz, 2H), 3,99-4.09 to (m, 1H), 6,64-6,70 (m, 1H), 6,74-of 6.78 (m, 2H), 7.18 in-of 7.23 (m, 2H), 7,27-7,31 (m, 1H), 7,34-7,38 (m, 4H).

This loose coupling (80 mg) is treated in the usual way, getting hydrochloride (70 mg) specified in the connection header.

Hydrochloride

ESI-Macc: 447 (MH+).

Example 90. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-cyclohexylaniline)ethyl]piperazine

90-1) 2-(N-Cyclohexylaniline)ethanol

1H NMR (400 MHz, Dl3)(M. D.): 1,05-of 1.18 (m, 1H), 1,26-of 1.44 (m, 4H), 1,63-1,71 (m, 1H), 1,80-to 1.87 (m, 5H), to 3.67 (t, J=6,7 Hz, 2H), 3,42 (m, 1H), 3,64-3,70 (m, 2H), 6,76-for 6.81 (m, 1H), 6,86-of 6.90 (m, 2H), 7,20-7,26 (m, 2H).

90-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-cyclohexylaniline)ethyl]piperazine

In the atmosphere of nitrogen methanesulfonanilide (80 mg) are added to a solution of 2-(N-cyclohexylaniline)ethanol (153 mg) and triethylamine (of 0.24 ml) in acetonitrile (7 ml). After stirring the mixture for 1 hour to it was added sodium iodide (157 mg) and a solution of 1-[4-cyano-5-methyl-4-phenyl)hexyl]piperazine (100 ml) in acetonitrile (3 ml) and stirred it at 70°C during the night. The mixture is distributed by the addition of water and ethyl acetate and the organic layer washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated.

The residue is purified by chromatography on a column of silica gel NH (system hexane/ethyl acetate), whereby specified in the title compound (172 mg, 50%) was obtained as a colorless oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6 is R. t, J=8.0 Hz, 2H), 3,50 of 3.56 (m, 1H), 6,61 of 6.68 (m, 1H), of 6.71-6,76 (m, 2H), 7,17-of 7.23 (m, 2H), 7,27-7,31 (m, 1H), 7,34-7,38 (m, 4H).

This free compound (172 mg) is treated in the usual way, getting hydrochloride (160 mg) specified in the connection header.

Hydrochloride

ESI-Macc: 487 (MH+).

Example 91. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl-(4-isopropylaniline)ethyl]}piperazine

91-1) 2-[N-methyl-(4-isopropylaniline)]ethanol

Methylchloroform (1,43 ml) are added to a solution of 4-isopropylaniline (2.5 g) and N,N-diisopropylethylamine (6,45 ml) in tetrahydrofuran (60 ml) under nitrogen atmosphere. After stirring for 3 hours the reaction solution is distributed by the addition of water and ethyl acetate. The organic layer is washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is dissolved in N,N-dimethylformamide (30 ml) and the solution in a nitrogen atmosphere while cooling in an ice bath, add sodium hydride (951 mg, 60% in oil). After stirring the mixture in an ice bath for 45 minutes and to it was added a solution of ethylbromoacetate (4,63 g) in N,N-dimethylformamide (10 ml). The reaction mixture is cooled to room temperature, stirred overnight and distribute the addition of water and ethyl acetate. Org is 53 g of residue. A portion (1.5 g) of the residue are dissolved in tetrahydrofuran (5 ml) and added dropwise to the previously obtained suspension sociallyengaged (305 mg) in tetrahydrofuran (10 ml) in an ice bath under nitrogen atmosphere. After complete addition, the mixture is heated for 2 hours at the boil under reflux. After cooling the reaction mixture to room temperature, thereto in this order with stirring, water (0.3 ml), 2 N. aqueous sodium hydroxide (0.3 ml), water (0.9 ml) and diethyl ether (15 ml). The insoluble portion removed by filtration through celite and the filtrate is evaporated. The residue is purified by chromatography on a column of silica gel (system hexane/ethyl acetate), whereby specified in the title compound (900 mg) obtained as a colorless oil.

1H NMR (400 MHz, Dl3)(M. D.): 1,22 (d, J=7,0 Hz, 6N), 1,80-1,90 (m, 1H), 2,83 (Sept., J=6,8 Hz, 1H), 2,80-to 2.85 (m, 1H), 2,92 (s, 3H), 3.43 points (t, J=5.5 Hz, 2H), 3,78-a-3.84 (m, 2H), 6,78 (d, J=8.6 Hz, 2H), 7,11 (d, J=8.6 Hz, 2H).

91-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl-(4-isopropylaniline)ethyl]}piperazine

In the atmosphere of nitrogen methanesulfonanilide (80 mg) are added to a solution of 2-[N-methyl-(4-isopropylaniline)]ethanol (135 mg) in a mixture of triethylamine (0,24 ml)/mg) and a solution of 1-[4-cyano-5-methyl-4-phenyl)hexyl]piperazine (100 mg) in acetonitrile (3 ml) and stirred it at 70°C during the night. The mixture is distributed by the addition of water and ethyl acetate. The organic layer is washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system methanol/ethyl acetate), whereby specified in the title compound (78 mg, 48%) was obtained as a colorless oil.

Free connection

1H NMR (400 MHZ, Dl3)(M. D.): 0,77 (d, J=6, 6 Hz, 3H), 1.04 million-of 1.18 (m, 1H), 1,20 (d, J=6.6 Hz, 3H), 1,21 (d, J=6,9 Hz, 6N), 1,48-of 1.62 (m, 1H), 1,84-of 1.94 (m, 1H), 2.06 to of 2.20 (m, 2H), 2,22-of 2.56 (m, N), 2,74-of 2.86 (m, 1H), 2,90 (s, 3H), 3.42 points (t, J=7,6 Hz, 2H), 6,65 (Shir.d, J=8.7 Hz, 2H), 7,08 (Shir.d, J=8.7 Hz, 2H), 7,26-7,32 (m, 1H), 7,33-7,38 (m, 4H).

This free compound (78 mg) is treated in the usual way, getting hydrochloride (70 mg) specified in the connection header.

Hydrochloride

ESI-Macc: 461 (MH+).

Example 92. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl-(3-isopropylaniline)ethyl]}piperazine

92-1) 2-[N-Methyl-(3-isopropylaniline)]ethanol

Specified in the title compound (900 mg) obtained from 3-isopropylaniline (2.5 g) in the same manner as in the above example.

1H NMR (400 MHz, Dl3)(M. D.): a 1.25 (d, J=6,8 Hz, 6N), 1,78-of 1.81 (m, 1H), 2,80-to 2.85 (m, {2-[N-methyl-(3-isopropylaniline)ethyl]}piperazine

In the atmosphere of nitrogen methanesulfonanilide (80 mg) are added to a solution of 2-[N-methyl-(3-isopropylaniline)]ethanol (135 mg) and triethylamine (of 0.24 ml) in acetonitrile (7 ml). After stirring the mixture for about 2 hours to it was added sodium iodide (157 mg) and a solution of 1-[4-cyano-5-methyl-4-phenyl)hexyl]piperazine (100 mg) in acetonitrile (3 ml) and stirred it at 70°C during the night. The mixture is distributed by the addition of water and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system methanol/ethyl acetate), whereby specified in the title compound (100 mg, 61%) was obtained as a colorless oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1.04 million-1,20 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), of 1.23 (d, J=6,8 Hz, 6N), 1,48-of 1.62 (m, 1H), 1,89 (dt, J=4.4 Hz, to 13.6 Hz, 1H), 2,07-of 2.20 (m, 2H), 2.26 and of-2.32 (m, 2H), 2,32-to 2.57 (m, 10H), 2,78-is 2.88 (m, 1H), 2,93 (s, 3H), 3,42-of 3.48 (m, 2H), 6,51-6,60 (m, 2H), 7,14 (Shir.t, J=8.0 Hz, 1H), 7.23 percent-7,31 (m, 2H), 7,35-7,38 (m, 4H).

This loose coupling (100 mg) is treated in the usual way, getting hydrochloride (98 mg) specified in the connection header.

Hydrochloride

ESI-Macc: 461 (Is) 2-(N-Methyl-2-isopropylaniline)ethanol

Specified in the title compound (950 mg) obtained from 2-isopropylaniline (2.5 g) in the same manner as in the above example.

1H NMR (400 MHz, CDCl3)(M. D.): 1,22 (d, J=7,0 Hz, 6N), 2,50-to 2.57 (m, 1H), 2,80-to 2.85 (m, 1H), 2,65 (s, 3H), to 3.09 (t, J=5.4 Hz, 2H), 3,51-3,62 (m, 1H), 3,62-3,70 (m, 2H), 7,01 (m, 4H), 7,18 (Shir.t, J=7.8 Hz, 1H).

93-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl-(2-isopropylaniline)ethyl]}piperazine

In the atmosphere of nitrogen methanesulfonanilide (80 mg) are added to a solution of 2-(N-methyl-2-isopropylaniline)ethanol (135 mg) and triethylamine (of 0.24 ml) in acetonitrile (7 ml). After stirring for about 2 hours the solution is added to sodium iodide (157 mg) and a solution of 1-[4-cyano-5-methyl-4-phenyl)hexyl]piperazine (100 ml) in acetonitrile (3 ml) and the mixture was stirred at 70°C during the night. The mixture is distributed by the addition of water and ethyl acetate and the organic layer washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel NH (system hexane/ethyl acetate), whereby specified in the title compound (154 mg, 95%) was obtained as a colorless oil.

Free connection

), of 1.87 (dt, J=4.4 Hz, to 13.6 Hz, 1H), 2,07-2,17 (m, 2H), 2,22-2,48 (m, N), to 2.65 (s, 3H), 2,99 totaling 3.04 (m, 1H), 3.46 in-to 3.58 (m, 2H), 7,10-7,17 (m, 3H), 7.23 percent-7,31 (m, 2H), 7,34-7,37 (m, 4H).

This free compound (154 mg) is treated in the usual way, getting hydrochloride (145 mg) specified in the connection header.

Hydrochloride

ESI-Macc: 461 (MH+).

Example 94. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3,4-(methylendioxy)phenoxy]ethyl}piperazine

94-1) 2-[3,4-Methylendioxy)phenoxy]ethylbromide

Sodium hydroxide (0.15 g) dissolved in water (6 ml), to the solution was added Sesamol (0.50 g) and 1,2-dibromethane (0,37 ml) and heated it to boiling under reflux for 12 hours. After cooling, to the mixture, water is added, the product extracted with ethyl acetate and then washed with brine. The product is dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel NH (system hexane/ethyl acetate), whereby receive specified in the header connection (0,30 g, 34%).

1H NMR (400 MHz, Dl3)(M. D.): 3,59 (t, J=6.4 Hz, 2H), 4,21 (t, J=6.4 Hz, 2H), of 5.92 (s, 2H), 6,33 (DD, J=2.4 Hz, J=8,4 Hz, 1H), 6,51 (d, J=2.4 Hz, 1H), 6,70 (d, J=8,4 Hz, 1H).

94-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3,4-(methylendioxy)phenoxy]ethyl}piperazine

in the form of oil treatment 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine (0,13 g) and 2-[3,4-(methylendioxy)phenoxy]ethylbromide (0.11 g) in the same way, as in the example 59-3).

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1.06 a-1,18 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-of 1.62 (m, 1H), 1,89 (dt, J=4.4 Hz, and 12.4 Hz, 1H), 2,07-2,19 (m, 2H), and 2.27 (t, J=7.2 Hz, 2H), 2,36 (Shir.s, 4H), 2,54 (Shir.s, 4H), to 2.74 (t, J=6.0 Hz, 2H), 4.00 points (t, J=6.0 Hz, 2H), 5,90 (s, 2H), 6.30-in (DD, J=2.4 Hz, J=8,4 Hz, 1H), of 6.49 (d, J=2.4 Hz, 1H), of 6.68 (d, J=8,4 Hz, 1H), 7,25-7,33 (m, 1H), 7,35-7,38 (m, 4H).

This free compound (0.12 g) is treated in the usual way, getting hydrochloride (0.14 g) specified in the connection header.

Hydrochloride

ESI-Macc: 450 (MH+).

Example 95. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(6-hinomisaki)ethyl]piperazine

Free form (0.10 g, 63%) indicated in the title compound obtained as oil from 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-chloroethyl)piperazine (0.12 g) and 6-hydroxyquinoline solution (0.25 g) in the same way as in example 99.

Free connection

1H NMR (400 MHz, CDCl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1.06 a-1,20 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-of 1.62 (m, 1H), 1,89 (dt, J=4.4 Hz, and 12.4 Hz, 1H), 2,03-of 2.20 (m, 2H), 2,28 (t, J=7.2 Hz, 2H), 2,39 (Shir.s, 4H), 2,60 (Shir.s, 4H), of 2.86 (t, J=6.0 Hz, 2H), 4,21 (t, J=6.0 Hz, 2H), 7,06 (d, J=2.4 Hz, 1H), 7,25-7,40 (m, 7H), to 7.99 (d, J=9,2 Hz, 1H), 8,02 (d, J=8,4 Hz, 1H), total of 8.74-8,78 (m, 1H).

This loose coupling (0,1 who reed

ESI-Macc: 457 (MH+).

Example 96. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(5-athinaiki)ethyl]piperazine

Free form (0.08 g, 51%) indicated in the title compound obtained as oil from 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-chloroethyl)piperazine (0.12 g) and 5-hydroxyquinoline solution (0.25 g) in the same way as in example 99.

Free connection

1H NMR (400 MHz, CDCl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1.06 a-1,20 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-of 1.62 (m, 1H), 1,89 (dt, J=4.4 Hz, and 12.4 Hz, 1H), 2,04-of 2.20 (m, 2H), 2,28 (t, J=6,8 Hz, 2H), 2,38 (Shir.s, 4H), 2,64 (Shir.s, 4H), 2.95 points (t, J=5.6 Hz, 2H), 4,27 (t, J=5.6 Hz, 2H), 6,98 (d, J=7,6 Hz, 1H), 7,25-7,33 (m, 1H), 7,33-7,38 (m, 4H), of 7.48 (t, J=8.0 Hz, 1H), 7,52 (t, J=8.0 Hz, 1H), 7,98 (d, J=6.0 Hz, 1H), charged 8.52 (d, J=6.0 Hz, 1H), 9,20 (s, 1H).

The above free compound (0.08 g) is treated in the usual way, getting hydrochloride (0.10 g) specified in the connection header.

Hydrochloride

ESI-Macc: 457 (MH+).

Example 97. Synthesis of 1-[{2-(5-cyano-6-methyl-5-phenyl)heptyl}]-4-[2-(4-pertenece)ethyl]piperazine

97-1) 4-Cyano-5-methyl-4-phenylhexanoic acid

2-(1-Methylethyl)-5-oxo-2-phenylpentane (6,00 g of 27.9 mmol) was dissolved in a mixed solvent of water (55 ml) of tert-butyl alcohol (200 ml) and then the solution is I (10.0 g, 111 mmol) in limited quantities and stirred for 2 hours. The reaction mixture is cooled with ice and acidified with 2 N. chlorotoluron acid. The mixture is then extracted with simple ether, washed with diluted chlorotoluron acid, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system ethyl acetate/hexane), whereby specified in the header connection (4,10 g of 17.7 mmol, 63.4 per cent) receive in the form of a white solid.

1H NMR (400 MHz, Dl3)(M. D.): 0,79 (d, J=is 6.78 Hz, 3H), of 1.23 (d, J=6,59 Hz, 3H), 1,94-to 2.06 (m, 1H), 2,08-of 2.23 (m, 2H), 2,38-of 2.54 (m, 2H), 7,29-7,42 (m, 5H).

ESI-Macc: 230 (MH-).

So pl. 82-84°C.

97-2) (N,O-Dimethylhydroxylamine)amide 4-cyano-5-methyl-4-phenylhexanoic acid

4-Cyano-5-methyl-4-phenylhexanoic acid (2,80 g, 12.1 mmol) was dissolved in tetrahydrofuran (70,0 ml) containing a small amount of N,N-dimethylformamide. Under ice cooling, to the solution is added dropwise oxalicacid (1,16 ml) and the temperature was raised to room temperature. The reaction mixture is evaporated and dissolved again in tetrahydrofuran (15.0 ml). Under ice cooling previously obtained the hydrochloride of N,O-dimethylhydroxylamine (6,00 ment of the mixture washed with brine, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel NH (system ethyl acetate/hexane), whereby specified in the header connection (2,72 grams for 9.90 mmol, 81,9%) was obtained as a pale yellow oil.

1H NMR (400 MHz, Dl3)(M. D.): 0,80 (d, J=is 6.78 Hz, 3H), of 1.23 (d, J=is 6.78 Hz, 3H), 1,95-of 2.08 (m, 1H), 2,08-2,22 (m, 1H), 2,22-of 2.34 (m, 1H), 2,42-2,63 (m, 2H), 3,11 (s, 3H), 3,52 (s, 3H), 7,26-7,42 (m, 5H).

97-3) 5-Cyano-6-methyl-5-phenylheptane-2-it

The above amide (140 mg, 0.51 mmol) dissolved in tetrahydrofuran (4,00 ml). Under ice cooling a solution of 1.05 M metallice simple ether (0,77 ml) is added dropwise to the obtained solution. The reaction mixture is distributed by addition of an aqueous saturated ammonium chloride and ethyl acetate and the organic layer washed with brine, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system ethyl acetate/hexane), whereby specified in the title compound (110 mg, 0.48 mol, 94,1%) was obtained as a colorless oil.

1H NMR (400 MHz, CDCl3)(M. D.): 0,78 (d, J=is 6.78 Hz, 3H), 1,22 (d, J=6,59 Hz, 3H), 2.00 in of 2.23 (m, 6N), 2,37 is 2.46 (m, 1H), 2,53-2,63 (m, 1H), 7,29-7,42 (m, 5H).

97-4) 1-[{2-(5-Cyano-6-tilgate-2-he is in the amount of 110 mg (0.48 mmol), 129 ml of 0.58 mmol) 1-[2-(4-pertenece)ethyl]piperazine and acetic acid (60 μl) dissolved in dichloroethane (3,00 ml). After 5 minutes the solution add triacetoxyborohydride sodium (153 mg). After 19 hours the reaction mixture is distributed by addition of an aqueous saturated sodium bicarbonate and ethyl acetate. The organic layer is washed again with aqueous saturated sodium bicarbonate and then brine, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system ethyl acetate/methanol), whereby specified in the title compound (20 mg, 46 μmol, 9,52%) was obtained as a colorless oil.

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,77 (d, J=is 6.78 Hz, 3H), 0,85-of 1.16 (m, 4H), 1,18-of 1.23 (m, 3H), 1,28-to 1.61 (m, 1H), 1.77 in-a 1.88 (m, 1H), 2.26 and-of 2.66 (m, N), 2,70 is 2.80 (m, 2H), 4,00-4,07 (m, 2H), for 6.81-6,86 (m, 2H), 6,92-of 6.99 (m, 2H), 7,26-7,33 (m, 1H), 7,33-7,39 (m, 4H).

ESI-Macc: 438 (MH+).

Example 98. Synthesis of 1-{[4-(7-cyano-8-methyl-7-phenyl)nonyl]}-4-[2-(4-pertenece)ethyl]piperazine

98-1) 4-Cyano-5-methyl-4-phenylhexanoic

4-Cyano-5-methyl-4-phenylhexanoic in the amount of 212 mg (0,92 mmol) described in example 2 or 3 JP 11-70613, dissolved in dichloromethane (9 ml). To the solution was added molecular sieves 4-n-Propylamine ((n3H7)4NRuO4, and 32.3 mg). After 1 hour the reaction mixture is evaporated. The residue is purified by chromatography on a column of silica gel (system ethyl acetate/hexane), whereby specified in the title compound (92 mg, 0.43 mmol, 46.4 per cent) obtained as a colorless oil.

1H NMR (400 MHz, Dl3)(M. D.): 0,80 (d, J=is 6.78 Hz, 3H), 1,24 (d, J=6,59 Hz, 3H), 2,08-of 2.24 (m, 3H), 2,43 of $ 2.53 (m, 1H), 2,56-of 2.66 (m, 1H), 7,30-the 7.43 (m, 5H), 9,65 (s, 1H).

98-2) 7-Cyano-8-methyl-7-phenylene-4-ol

4-Cyano-5-methyl-5-phenylhexanoic (92 mg, 0.43 mmol, 46.4 per cent) was dissolved in tetrahydrofuran (2 ml). The reaction mixture is cooled with ice and to it was added a solution of 2.0 M of propylaniline simple ether (0.5 ml). The reaction mixture is distributed by addition of an aqueous saturated ammonium chloride and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system ethyl acetate/hexane), whereby specified in the title compound (70 mg, 0.27 mmol, 62,8%) obtained as a colorless syrup.

1H NMR (400 MHz, Dl3)(M. D.): 0,79 (d, J=6,59 Hz, 3H), 0,84-of 0.91 (m, 3H), 0,94 is 1.58 (m, 8H) and 1.83-1.92 and 2,34 is 2.44 (m, total 1H), 2,08-2,19 (m, N-methyl-7-phenylene-4-ol (70 mg, 0.27 mmol) was dissolved in dimethyl sulfoxide (3,00 ml) and triethylamine (0,70 ml). To the solution is added a complex of sulfur trioxide - pyridine, or 64.7 mg). After 1 hour, to the mixture an additional quantity (80.0 mg) complex of a sulfur trioxide - pyridine. The reaction mixture is distributed by addition of an aqueous saturated sodium bicarbonate and ethyl acetate. The organic layer was washed with aqueous ammonium chloride and then with brine, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system ethyl acetate/hexane), whereby specified in the title compound (50 mg, 0,19 mmol, 72,0%) was obtained as colorless syrup.

1H NMR (400 MHz, Dl3)(M. D.): 0,78 (d, J=is 6.78 Hz, 3H), or 0.83 (d, J=7,42 Hz, 3H), 1,22 (d, J=is 6.78 Hz, 3H), 1,44-of 1.56 (m, 2H), 1,96-to 2.06 (m, 1H), 2,08 is 2.33 (m, 4H), 2,36 is 2.46 (m, 1H), 2,48 at 2.59 (m, 1H), 7,27-7,42 (m, 5H).

98-4) 1-{[4-(7-Cyano-8-methyl-7-phenyl)nonyl]}-4-[2-(4-pertenece)ethyl]piperazine

7-Cyano-8-methyl-7-phenylene-4-one (50 mg, 0,19 mmol), to 51.1 mg (0.23 mmol) of 1-[2-(4-pertenece)ethyl]piperazine and acetic acid (21,8 μl) dissolved in dichloromethane (2.00 ml). After 5 minutes the solution add triacetoxyborohydride sodium (80,5 mg). After 14 hours to it add an extra number shall maximalized sodium (40,0 mg). After 23 hours, the reaction mixture was distributed by addition of an aqueous saturated sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and then brine, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel Chromatorex NH (system ethyl acetate/hexane), whereby specified in the header connection (3,00 mg, 6,44 µmol, 3,39%) obtained as a colorless oil.

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,72-to 1.60 (m, 14N), 1,80-of 2.86 (m, 15 NM), 4,06 (t, J=5,86 Hz, H), for 6.81-6.87 in (m, 2H), 6,93-7,00 (m, 2H), 7,28-7,40 (m, 5H).

Example 99. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-pyridyloxy)ethyl]piperazine

99-1) 4-Cyano-5-methyl-4-phenylhexanoic

4-Cyano-5-methyl-4-phenylhexanoic in the amount of 5.00 g (23,0 mmol) described in example 2 or 3 JP 11-70613-And add to acetonitrile (150 ml) and triethylamine (3,53 ml) and dissolved in them. To the solution add methylchloride (1,96 ml, with 25.3 mmol). After 25 minutes of added sodium iodide (20.7 g). The reaction mixture is distributed by the addition of brine and ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate, then with brine, dried over magnesium sulfate and evaporated. The remainder ochischenie (of 5.89 g, 18.0 mmol, 78,2%) was obtained as a pale yellow oil.

1H NMR (400 MHz, Dl3)(M. D.): 0,79 (d, J=is 6.78 Hz, 3H), 1,22 (d, J=6,59 Hz, 3H), 1,37-1,49 (m, 1H), 1,82-of 1.94 (m, 1H), 1,98-of 2.26 (m, 3H), 3.04 from-3,18 (m, 2H), 7,28-7,42 (m, 5H).

99-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine

The above iodide (2,07 g, 6,32 mmol) dissolved in acetonitrile (40 ml). To the solution add triethylamine (0,88 ml) and 1-ethnoseparatism (1.07 g, by 8.22 mmol) and the mixture is heated at 50°C. the Reaction mixture is distributed by the addition of brine and ethyl acetate. The organic layer was washed with aqueous 1 N. NaOH and then brine, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel Chromatorex NH (ethyl acetate), whereby specified in the title compound (1.92 g, 5.83 mmol, 92,2%) was obtained as light yellow oil.

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=is 6.78 Hz, 3H), 1.06 a-1,18 (m, 1H), 1,20 (d, J=6,59 Hz, 3H), 1,49-of 1.62 (m, 1H), 1,84-of 1.94 (m, 1H), 2.06 to 2,62 (m, 14N), 3,61 (t, J=5,40, 2H), 7,26-7,40 (m, 5H).

99-3) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-chloroethyl)piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine (900 mg, 2,73 mmol) dissolved in dichloromethane under reflux and after 15 minutes, add the additional amount of thionyl chloride (2.00 ml). The reaction solution was poured slowly into a mixture of ice-water, then regulate pH to 11 with 1 N. aqueous NaOH solution and distribute the addition of ethyl acetate. The organic layer was washed with aqueous dilute solution of NaOH and then brine, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel Chromatorex NH (system ethyl acetate/hexane), whereby specified in the title compound (728 mg, of 2.09 mmol, 76,6%) obtained as a pale yellow oil.

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6,59 Hz, 3H), 1.06 a is 1.23 (m, 1H), 1,20 (d, J=6,59 Hz, 3H), 1,48-to 1.67 (m, 1H), 1,84-of 1.94 (m, 1H), 2,07-of 2.58 (m, N), a 2.71 (t, J=7,05, 2H), of 3.56 (t, J=7,05, 2H), 7,26-7,40 (m, 5H).

99-4) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-pyridyloxy)ethyl]piperazine

4 Hydroxypyridine (205 mg, of 2.16 mmol) suspended in toluene (4 ml) and to the suspension is added sodium hydride (86,4 mg of 2.16 mmol). The mixture is heated at 100°C and to it was added a solution of 150 mg (0.43 mmol) of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-chloroethyl)piperazine in toluene (1 ml). After 25 minutes, add the additional amount (2.00 ml) of dimethyl sulfoxide. After adding brine and achieve the pH of the reaction mixture to 11 using 1 N. aqueous solution NaOH, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel Chromatorex NH (system ethyl acetate/hexane), whereby specified in the header connection (43,0 mg, 0.11 mmol, 24,6%) was obtained as a pale yellow syrup.

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=is 6.78 Hz, 3H), 1,05-1,20 (m, 1H), 1,20 (d, J=is 6.78 Hz, 3H), 1,50-of 1.62 (m, 1H), 1,83-of 1.93 (m, 1H), 2.06 to to 2.65 (m, N), 2,80 (t, J=5,86, 2H), 4,12 (t, J=5,86, 2H), 6,78 (DD, J=1.65 Hz, was 4.76 Hz, 2H), 7,25-7,39 (m, 5H), to 8.41 (DD, J=1,47 Hz, was 4.76 Hz, 2H).

ESI-Macc: 407 (MH+).

Example 100. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-pyridyloxy)ethyl]piperazine

3 Hydroxypyridine (205 mg, of 2.16 mmol) suspended in toluene (2 ml). To the suspension is added sodium hydride (86,4 mg of 2.16 mmol), the mixture is heated at 100°C and then to it was added a solution of 150 mg (0.43 mmol) of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-chloroethyl)piperazine in toluene (1 ml). After 25 minutes, to the mixture an additional quantity (1,00 ml) of dimethyl sulfoxide. After adding brine to the reaction mixture and the establishment of the pH of the mixture to 11 using 1 N. aqueous solution of NaOH its distribute by adding ethyl acetate. The organic layer was washed with aqueous dilute solution of NaOH and then brine, dried over sulat/hexane), whereby specified in the header connection (93,0 mg, 0.23 mmol, 53,2%) was obtained as a pale yellow syrup.

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=is 6.78 Hz, 3H), 1,05-1,20 (m, 1H), 1,20 (d, J=6,59 Hz, 3H), 1,50-to 1.63 (m, 1H), 1,82-of 1.95 (m, 1H), 2.06 to 2,70 (m, N), of 2.81 (t, J=5,77, 2H), 4,12 (t, J=5,77, 2H), 4,12 (t, J=5,86 Hz, 2H), 7,16-7,40 (m, 7H), 8,20-8,23 (m, 2H), 8,29-of 8.33 (m, 2H).

ESI-Macc: 407 (MH+).

Example 101. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(5-hinomisaki)ethyl]piperazine

3-Hydroxyquinolin (313 mg, of 2.16 mmol) was dissolved in dimethyl sulfoxide (8 ml). To the solution was added sodium hydride (86,4 mg of 2.16 mmol), the mixture is heated at 100°C and then to it was added a solution of 150 mg (0.43 mmol) of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-chloroethyl)piperazine in toluene (1 ml). After adding brine to the reaction mixture and the establishment of the pH of the mixture to 11 using 1 N. aqueous solution of NaOH its distribute by adding ethyl acetate. The organic layer was washed with aqueous dilute solution of NaOH and brine, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel Chromatorex NH (system ethyl acetate/hexane), whereby specified in the header connection (77.0 mg, 0.11 mmol, 24,6%) was obtained as pale-yellow C is, N), 1,50-to 1.63 (m, 1H), 1,83-of 1.94 (m, 1H), 2.05 is is 2.75 (m, N), to 2.94 (t, J=5,68, 2H), 4,27 (t, J=5,68, 2H), at 6.84 (d, J=of 7.69 Hz, 1H), 7.24 to 7,40 (m, 5H), to 8.41 (DD, J=1,47 Hz, was 4.76 Hz, 2H).

ESI-Macc: 457 (MH+).

Example 102. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-triptoreline)ethyl]piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine (466 mg, of 1.41 mmol) was dissolved in N,N-dimethylformamide (15 ml). To the solution was added tert-piperonyl potassium (316 mg, 2.82 mmol). After stirring for 5 minutes, to the mixture is added 4-vorbestraften (0,32 ml, 2.54 mmol). After adding to the reaction mixture of brine and establishing the pH of the mixture to 11 using 1 N. aqueous solution of NaOH its distribute by adding ethyl acetate. The organic layer was washed with aqueous dilute solution of NaOH and brine, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel Chromatorex NH (system ethyl acetate/hexane), whereby specified in the title compound (432 mg, of 0.91 mmol, 64,7%) was obtained as colorless syrup.

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=is 6.78 Hz, 3H), 1,05-1,20 (m, 1H), 1,20 (d, J=is 6.78 Hz, 3H), 1,49-of 1.62 (m, 1H), 1,82-of 1.93 (m, 1H), 2.05 is-to 2.65 (m, N), 2,80 (t, J=5,86, 2H), 4,11 (t, J=5,86, 2H), 6,95 (d, J=8,42 Hz, 2H), 7,26-7,39 (m, 5H), 7,53 (d, J=8,61 Hz,

1-Naphthol (383 mg, of 2.66 mmol), 438 mg (1,33 mmol) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-hydroxyethyl)piperazine and 420 mg (1,60 mmol) of triphenylphosphine dissolved in tetrahydrofuran (15 ml). To the solution add diethylazodicarboxylate (0.25 ml, to 1.60 mmol). After adding to the reaction mixture of brine and establishing the pH of the mixture to 11 using 1 N. aqueous solution of NaOH, the mixture is distributed by the addition of ethyl acetate. The organic layer was washed with aqueous dilute solution of NaOH and brine, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel Chromatorex NH (system ethyl acetate/hexane), whereby specified in the title compound (123 mg, 0.27 mmol, 20,3%) was obtained as colorless syrup.

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=is 6.78 Hz, 3H), 1,05-1,20 (m, 1H), 1,20 (d, J=is 6.78 Hz, 3H), 1,50-1,70 (m, 1H), 1,84-of 1.95 (m, 1H), 2.05 is is 2.75 (m, N), 2,96 (t, J=5,68, 2H), 4,28 (t, J=5,68, 2H), 6,79 (DD, J=0,92, 6,59 Hz, 1H), 7,24-7,52 (m, N), 7,76-of 7.82 (m, 1H), 8,20-of 8.27 (m, 1H).

ESI-Macc: 456 (MH+).

Example 104. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-ethyl-2-(4-pertenece)ethyl]piperazine

104-1) 1-Benzyl-4-[2-vinyl-2-(4-pertenece)ethyl]piperazine

The butadiene monoxide (5.0 g) and 1-benzylpiperazine (10.5 g) was dissolved in owls. To the reaction mixture, water is added and the mixture is then extracted with chloroform, dried over anhydrous sodium sulfate and evaporated, getting 9,05 g of residue. The residue (720 mg), 4-terfenol (654 mg) and triphenylphosphine (1,53 g) dissolved in tetrahydrofuran (10 ml), the solution on a water bath add to 0.92 ml of diethylazodicarboxylate and the mixture is stirred over night. The mixture is distributed by the addition of water and ethyl acetate. The organic layer is washed successively with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel NH (system hexane/ethyl acetate), whereby specified in the header connection (919 mg, 92%) was obtained as a colorless oil.

1H NMR (400 MHz, Dl3)(M. D.): 2,40-of 2.50 (m, 4H), 2,50-to 2.65 (m, 4H), 2,60 (DD, J=4.0 Hz, a 13.4 Hz, 1H), 2,78 (DD, J=7.5 Hz, a 13.4 Hz, 1H), 3,49 (s, 2H), 4,48-4,72 (m, 1H), total of 5.21 (MD, J=a 10.6 Hz, 1H), 5,26 (DM, J=17.3 Hz, 1H), 5,86 (DDD, J=5,9 Hz, 10,6 GHz, 17.3 Hz, 1H), 6,80-to 6.88 (m, 2H), 6.90 to-6,97 (m, 2H), 7,20-to 7.35 (m, 5H).

104-2) 1-Benzyl-4-[2-(4-pertenece)butyl]piperazine

1-Benzyl-4-[2-vinyl-2-(4-pertenece)ethyl]piperazine (919 mg) is dissolved in ethanol (20 ml) and to the solution was added the catalyst of palladium hydroxide/carbon (50 mg, 51.5 per cent, in the raw state of the insoluble portion by filtration, the filtrate is evaporated and the residue purified by chromatography on a column of silica gel NH (system hexane/ethyl acetate), whereby specified in the header connection (717 mg, 77%) was obtained as a colorless oil.

1H NMR (400 MHz, Dl3)(M. D.): of 0.95 (t, J=7.5 Hz, 3H), 1.60-to 1,72 (m, 2H), 2,40-2,60 (m, 8H), of 2.51 (DD, J=4,6 Hz, 13.3 Hz, 1H), 2.63 in (DD, J=6,5 Hz, 13.3 Hz, 1H), 3,49 (s, 2H), 4,18-of 4.25 (m, 1H), 6,84-to 6.88 (m, 2H), 6.90 to-of 6.96 (m, 2H), 7,21-7,29 (m, 1H), 7,29-7,33 (m, 4H).

104-3) 1-[2-(4-Pertenece)butyl]piperazine

1-Benzyl-4-[2-(4-pertenece)butyl]piperazine (717 mg) is dissolved in dichloroethane (10 ml), to the solution was added 1-chloroethylphosphonic (598 mg) and the mixture is stirred for 2 hours at boiling under reflux with heating. After concentration of the reaction mixture there was added 10 ml of methanol and the mixture is stirred for 1 hour at boiling under reflux with heating. After evaporation of the mixture of its distribute by adding 2 N. chlorotoluron acid and the aqueous layer was neutralized 2 N. sodium hydroxide followed by extraction with ethyl acetate. The organic layer is successively washed with water and brine, dried over anhydrous magnesium sulfate and evaporated, whereby specified in the title compound (168 mg, 32%) was obtained as a colorless oil.

1H NMR (400 MHz, Dl3)

104-4) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-pertenece)butyl]piperazine

In nitrogen atmosphere 2-[1-methyl(ethyl)]-2-phenyl-5-hydroxypentanal (142 mg) and triethylamine (0,27 ml) dissolved in acetonitrile (10 ml) and to the solution add methanesulfonate (0.06 ml). After stirring the mixture for 1 hour to it was added sodium iodide (490 mg) and a solution of 1-[2-ethyl-2-(4-pertenece)ethyl]piperazine (165 mg) in acetonitrile (5 ml) and stirred at 70°C during the night. The reaction mixture is distributed by the addition of water and ethyl acetate. The organic layer is washed successively with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel NH (system hexane/ethyl acetate), whereby specified in the title compound (130 mg, 44%) was obtained as a colorless oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,76 (d, J=6.6 Hz, 3H), were 0.94 (t, J=7.5 Hz, 3H), of 1.05 to 1.15 (m, 1H), 1,19 (d, J=6.4 Hz, 3H), 1,55-1,75 (m, 2H), of 1.87 (dt, J=4,2 Hz to 13.2 Hz, 1H), 2.05 is-to 2.18 (m, 2H), 2,20-is 2.37 (m, 6N), 2,40-of 2.50 (m, 5H), 2,61 (DD, J=6,4 Hz to 13.6 Hz, 1H), 4,15-4,22 (m, 1H), 6,82-to 6.88 (m, 2H), 6,91-6,97 (m, 2H), 7.23 percent-7,30 (m, 1H), 7,30-7,38 (m, 4H).

The above free the tion.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.6 Hz, 3H), 0,86 (t, J=7.4 Hz, 3H), 1,11 (d, J=6.6 Hz, 3H), of 1.20 and 1.35 (m, 2H), 1,55-1,70 (m, 3H), 2.05 is was 2.25 (m, 3H), 3,00-4,00 (m, 11N), 4,75-of 4.90 (m, 1H), 7,05 for 7.12 (m, 2H), 7,12-7,17 (m, 2H), 7,35-7,40 (m, 1H), 7,50-of 7.70 (m, 4H).

ESI-Macc: 452 (MH+).

Example 105. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-girasolereale)ethyl]piperazine

Free form (0,059 g, 45%) specified in the header of the oil compound is obtained from 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-chloroethyl)piperazine (0.10 g) and 4-hydroxyquinazoline (0.21 g) in the same way as in example 99.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1.04 million-of 1.18 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,47 is 1.60 (m, 1H), of 1.88 (dt, J=4.4 Hz, J=12,4 Hz, 1H), 2,04-to 2.18 (m, 2H), 2,25 (t, J=7,6 Hz, 2H), 2,31 (Shir.s, 4H), 2.49 USD (Shir.s, 4H), 2,69 (t, J=6.0 Hz, 2H), 4,07 (t, J=6.0 Hz, 2H), 7,25-7,32 (m, 1H), 7,32-7,38 (m, 4H), 7,47-7,53 (m, 1H), 7.68 per for 7.78 (m, 1H), 8,04 (s, 1H), 8,29-8,32 (m, 1H).

The above free connection (0,059 g) is treated in the usual way, getting hydrochloride (0.05 g) specified in the connection header.

Hydrochloride

ESI-Macc: 458 (MH+).

Example 106. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[4-(3-pyridyl)phenoxy]ethyl}piperazine

106-1) 2-[4-(3-Pyridyl)phenoxy]ataman (509 mg), finely powdered potassium hydroxide (388 mg), bromide, Tetra-n-butylamine (74 mg) and complex tetranitroaniline (133 mg) are added to a tetrahydrofuran (10 ml) and the mixture is stirred at the boil under reflux with heating. After stirring for 2 hours the mixture is cooled to room temperature and distributed by the addition of water and ethyl acetate. The organic layer is washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system hexane/ethyl acetate), whereby receive specified in the title compound (233 mg, 50%) as pale yellow crystals.

1H NMR (400 MHz, CDCl3)(M. D.): 2,45 (t, J=6.2 Hz, 1H), 3,97-was 4.02 (m, 2H), 4,12-4,17 (m, 2H), 7,02 (Shir.d, J=8,8 Hz, 2H), to 7.32 and 7.36 (m, 1H), 7,51 (Shir.d, J=8,8 Hz, 2H), 7,80-a 7.85 (m, 1H), 8,53-8,56 (m, 1H), 8,78-8,82 (m, 1H).

ESI-Macc: 216 (MH+).

106-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[4-(3-pyridyl)phenoxy]ethyl}piperazine

In nitrogen atmosphere 2-[4-(3-pyridyl)phenoxy]ethanol (68 mg) and triethylamine (0,13 ml) dissolved in acetonitrile (6 ml) in an ice bath and to the solution add methanesulfonamide (40 mg). After stirring the mixture for 3 hours to her DOB is stirred for 5 hours while boiling under reflux. After cooling, the reaction solution is distributed by the addition of water and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel NH (system hexane/ethyl acetate), whereby specified in the title compound (17 mg, 11%) was obtained as a colorless oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,05-1,20 (m, 1H), 1,20 (d, J=6.6 Hz, 3H), 1,50-1,60 (m, 1H), 1,82-of 1.92 (m, 1H), 2,05-of 2.20 (m, 2H), 2,25-of 2.30 (m, 2H), 2,30 at 2.45 (m, 4H), 2,50-to 2.65 (m, 4H), 2,82 (t, J=5,9 Hz, 2H), 4,14 (t, J=5,9 Hz, 2H), 7,00 (d, J=8,8 Hz, 2H), 7,20-7,40 (m, 6N), 7,50 (d, J=8,8 Hz, 2H), 7,80-to 7.84 (m, 1H), 8,50-8,55 (m, 1H), 8,80-8,81 (m, 1H).

This free compound (17 mg) is treated in the usual way, getting hydrochloride (13 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.8 Hz, 3H), 1,11 (d, J=6.6 Hz, 3H), 1,20-1,30 (m, 1H), 1,55-1,70 (m, 1H), 2.05 is-is 2.30 (m, 3H), 3,00-3,25 (m, 2H), 3.25 to of 3.80 (m, 10H), 4,45-4,50 (m, 2H), 7,19 (d, J=8,8 Hz, 2H), 7,33-7,40 (m, 1H), 7,40-to 7.50 (m, 4H), 7,86 (d, J=8,8 Hz, 2H), of 7.96 (DD, J=5,5 Hz and 8.1 Hz, 1H), 8,68 (Shir.d, J=8,1 Hz, 1H), 8,77 (DD, J=1.1 Hz, 5.5 Hz, 1H), 9,15 (d, J=2.0 Hz, 1H).

ESI-Macc: 483 (MH+).

Example 107. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(3-pirinoa the title compound (435 mg, 88%) was obtained as pale-yellow crystals from 2-(3-bromophenoxy)ethanol (500 mg) in the same manner as in the above example.

1H NMR (400 MHz, CDCl3)(M. D.): 2,13 (t, J=6.2 Hz, 1H), 3,98-Android 4.04 (m, 2H), 4,14-4,20 (m, 2H), 6,95-7,00 (m, 1H), 7,12-to 7.15 (m, 1H), 7,17-7,22 (m, 1H), 7,34-7,44 (m, 2H), 7,84-of 7.90 (m, 1H), 8,58-to 8.62 (m, 1H), 8,82-8,86 (m, 1H).

ESI-Macc: 216 (MH+).

107-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(3-pyridyl)phenoxy]ethyl}piperazine

In nitrogen atmosphere 2-[3-(3-pyridyl)phenoxy]ethanol (68 mg) and triethylamine (0,13 ml) dissolved in acetonitrile (6 ml) in an ice bath and to the solution add methanesulfonamide (40 mg). After stirring the mixture for 3 hours there was added sodium iodide (142 mg) and a solution of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine (90 mg) in acetonitrile (3 ml) and the mixture is stirred for 5 hours while boiling under reflux. After cooling, the reaction mixture is distributed by the addition of water and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel NH (system hexane/ethyl acetate), whereby specified in the title compound (44 mg, 29%) was obtained as colorless is N), 1,05-1,20 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-1,60 (m, 1H), 1,82-of 1.92 (m, 1H), 2,05-of 2.20 (m, 2H), 2,25-of 2.30 (m, 2H), 2,30 at 2.45 (m, 4H), 2,45-to 2.65 (m, 4H), 2,82 (t, J=5,9 Hz, 2H), 4,15 (t, J=5,9 Hz, 2H), 6,91-6,98 (m, 1H), 7,10 for 7.12 (m, 1H), 7,14-to 7.18 (m, 1H), 7,25-7,32 (m, 1H), 7,32-7,40 (m, 6N), 7,83-7,87 (m, 1H), 8,56 (DD, J=1.5 Hz, 4.8 Hz, 1H), 8,23 (DD, J=0.7 Hz, 2.4 Hz, 1H).

This free compound (29 mg) is treated in the usual way, getting hydrochloride (23 mg) specified in the connection header.

Hydrochloride

lH NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.8 Hz, 3H), 1,11 (d, J=6.6 Hz, 3H), of 1.20 and 1.35 (m, 1H), 1,58-of 1.73 (m, 1H), 2.05 is was 2.25 (m, 3H), 3.00 and-of 3.85 (m, N), 4,50-4,56 (m, 2H), 7,13-to 7.18 (m, 1H), 7,33-7,40 (m, 1H), 7,42-rate of 7.54 (m, 7H), of 7.97 (DD, J=5,5 Hz and 8.2 Hz, 1H), 8,70 (Shir.d, J=8,2 Hz, 1H), 8,82 (DD, J=1.3 Hz, 5.5 Hz, 1H), 9,20 (d, J=1.8 Hz, 1H).

ESI-Macc: 483 (MH+).

Example 108. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-bromophenoxy)ethyl]piperazine

108-1) 2-(4-Bromophenoxy)ethanol

In nitrogen atmosphere 4-bromophenol (5.0 g), 2-bromoethanol (5,42 g) and potassium carbonate (12.0 g) is added to N,N-dimethylformamide (30 ml) and the mixture was stirred at 100°C. After 1 hour the mixture is cooled to room temperature and distribute by adding water and diethyl ether. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified chromaturia (5,15 g, 82%) was obtained as colorless crystals.

lH NMR (400 MHz, DMSO-d6)(M. D.): 1,95-2,00 (m, 1H), 3,94-to 3.99 (m, 2H), 4.04 the-4,07 (m, 2H), for 6.81 (Shir.d, J=9,2 Hz, 2H), 7,38 (Shir.d, J=9,2 Hz, 2H).

108-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-bromophenoxy)ethyl]piperazine

In nitrogen atmosphere 2-(4-bromophenoxy)ethanol (350 mg) and triethylamine (0.68 ml) dissolved in acetonitrile (16 ml) and to the solution add methanesulfonanilide (221 mg). After stirring the mixture for 1 hour to it was added sodium iodide (725 mg) and a solution of 1-[(4-cyano-5-methyl-4-phenyl)GEK-force]piperazine (460 mg) in acetonitrile (8 ml) and the mixture is stirred for 3 hours at boiling under reflux. After cooling, the reaction mixture is distributed by the addition of water and ethyl acetate and the organic layer washed with water and brine. It is dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel NH (system hexane/ethyl acetate), whereby specified in the title compound (587 mg, 75%) was obtained as a colorless oil.

Free connection

lH NMR (400 MHz, CDCl3)(M. D.): 0,77 (d, J=6, 6 Hz, 3H), 1,05-1,20 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-1,60 (m, 1H), 1,82-of 1.92 (m, 1H) (m, 6N).

This free compound (55 mg) is treated in the usual way, getting hydrochloride (50 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.6 Hz, 3H), 1,11 (d, J=6.6 Hz, 3H), 1,20-1,30 (m, 1H), 1,55-1,70 (m, 1H), 2.05 is-is 2.30 (m, 3H), 3.00 and-of 3.80 (m, N), 4,34 (Shir.s, 2H), 6,97 (d, J=8,8 Hz, 2H), 7,33-7,40 (m, 1H), 7,42-7,46 (m, 4H), of 7.48 (d, J=8,8 Hz, 2H).

ESI-Macc: 484 (M79VG]H+), 486 (M81Br]H+).

Example 109. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-bromophenoxy)ethyl]piperazine

109-1) 2-(3-Bromophenoxy)ethanol

In nitrogen atmosphere 3-bromophenol (5.0 g), 2-bromoethanol (5,42 g) and potassium carbonate (12.0 g) is added to N,N-dimethylformamide (30 ml) and the mixture was stirred at 100°C. After 1 hour the reaction mixture is cooled to room temperature and distribute by adding water and diethyl ether. The organic layer is washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system hexane/ethyl acetate), whereby specified in the header connection (4,85 g, 77%) was obtained as a colorless oil.

1H NMR (400 MHz, Dl3)(M. D.): 1,95-2,00 (m, 1H), 3,94-to 3.99 (m, 2H), 4.04 the-4 src="https://img.russianpatents.com/img_data/79/794517.gif">

In nitrogen atmosphere 2-(3-bromophenoxy)ethanol (350 mg) and triethylamine (0.68 ml) dissolved in acetonitrile (16 ml) and to the solution add methanesulfonanilide (221 mg). After stirring the mixture for 1 hour to it was added sodium iodide (725 mg) and a solution of 1-[(4-cyano-5-methyl-4-phenyl)hexyl] piperazine (460 mg) in acetonitrile (8 ml) and the mixture is stirred for 3 hours at boiling under reflux. After cooling, the reaction mixture is distributed by the addition of water and ethyl acetate. The organic layer is washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel NH (system hexane/ethyl acetate), whereby specified in the title compound (659 mg, 84%) was obtained as a colorless oil.

Free connection

1H NMR (400 MHz, CDCl3)(M. D.): 0,77 (d, J=6, 8 Hz, 3H), of 1.10-1.20 (m, 1H), 1,20 (d, J=6.6 Hz, 3H), 1,50-1,60 (m, 1H), 1,83-of 1.95 (m, 1H), 2,05-of 2.20 (m, 2H), 2,25-of 2.30 (m, 2H), 2,30 at 2.45 (m, 4H), 2,45-to 2.65 (m, 4H), 2,77 (t, J=5,9 Hz, 2H), of 4.05 (t, J=5,9 Hz, 2H), 6,80-6,84 (m, 1H),? 7.04 baby mortality-to 7.18 (m, 3H), 7,26-7,32 (m, 1H), 7,35-7,38 (m, 4H).

This free compound (71 mg) is treated in the usual way, getting hydrochloride (60 mg) specified in the connection header.

Hydrochloride

1H5-of 2.30 (m, 3H), 3.00 and-of 3.80 (m, N), to 4.38 (Shir.s, 2H), 6,98? 7.04 baby mortality (m, 1H), 7,15-7,30 (m, 3H), 7,33-7,40 (m, 1H), 7,42-to 7.50 (m, 4H).

ESI-Macc: 484 (M79VG]H+), 486 (M[81Br]H+).

Example 110. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-bromophenoxy)ethyl]piperazine

110-1) 2-(2-Bromophenoxy)ethanol

In nitrogen atmosphere 2-bromophenol (5.0 g), 2-bromoethanol (5,42 g) and potassium carbonate (12.0 g) is added to N,N-dimethylformamide (30 ml) and the mixture was stirred at 100°C. after About 2.5 hours the reaction mixture is cooled to room temperature and distribute by adding water and diethyl ether. The organic layer is washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system hexane/ethyl acetate), whereby specified in the header connection (5,09 g, 81%) was obtained as a colorless oil.

1H NMR (400 MHz, CDCl3);(M. D.) to 2.25 (t, J=6,6 Hz, 1H), 3.96 points-a 4.03 (m, 4H), 4,12-4,18 (m, 4H), 6.89 in (DDD, J=1.5 Hz, 7.5 Hz, 7.9 Hz, 1H), 6,93 (DD, J=1.5 Hz and 8.2 Hz, 1H), 7,27 (DDD, J=1.7 Hz, 7.5 Hz and 8.2 Hz, 1H), 7,55 (DD, J=1.7 Hz, 7.9 Hz, 1H).

110-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-brome-noxy)ethyl]piperazine

In nitrogen atmosphere 2-(2-bromophenoxy)ethanol (350 mg) and remesiana mixture for 1 hour to it was added sodium iodide (725 mg) and a solution of 1-[(4-cyano-5-methyl-4-phenyl)hexyl] piperazine (460 mg) in acetonitrile (8 ml) and the mixture is stirred for 3 hours at boiling under reflux. After cooling, the reaction mixture is distributed by the addition of water and ethyl acetate and the organic layer washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel NH (system hexane/ethyl acetate), whereby specified in the title compound (470 mg, 60%) was obtained as a colorless oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.6 Hz, 3H), 1,05-1,20 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-1,60 (m, 1H), 1,80-of 1.95 (m, 1H), 2,05-of 2.20 (m, 2H), 2,23-of 2.30 (m, 2H), 2,30 at 2.45 (m, 4H), 2,50-2,70 (m, 4H), of 2.86 (t, J=5.8 Hz, 2H), 4,14 (t, J=5.8 Hz, 2H), 6,80-of 6.90 (m, 2H), 7,21-to 7.32 (m, 2H), 7,33-7,38 (m, 4H), 7,52 (DD, J=1.5 Hz, 7.9 Hz, 1H).

This free product (61 mg) is treated in the usual way, getting hydrochloride (50 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.8 Hz, 3H), 1,11 (d, J=6.8 Hz, 3H), of 1.20 and 1.35 (m, 1H), 1,58 is 1.70 (m, 1H), of 2.05 to 2.35 (m, 3H), 3.00 and-of 3.85 (m, N), 4,67 (Shir.s, 2H), 6,92-6,98 (m, 1H), 7,14-to 7.18 (m, 1H), 7,34-7,40 (m, 2H), 7,42-of 7.48 (m, 4H), 7,60 (DD, J=1.6 Hz, 8.0 Hz, 1H).

ESI-Macc: 484 (M79Br]H+), 486 (M81Br]H+).

Example 111. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[4-(imidazol-1-yl)phenoxy]ethyl}piperazine

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,78 (d, J=6.8 Hz, 3H), 1.06 a-1,20 (m, 1H), 1,21 (d, J=6.8 Hz, 3H), 1,50-to 1.63 (m, 1H), 1,89 (dt, J=4.4 Hz, J=12,4 Hz, 1H), 2,05-of 2.20 (m, 2H), to 2.29 (t, J=7.2 Hz, 2H), 2,38 (Shir.s, 4H), 2.57 m (Shir.s, 4H), of 2.81 (t, J=6.0 Hz, 2H), 4,12 (t, J=6.0 Hz, 2H), 6,98 (d, J=8,8 Hz, 2H), 7,19 (d, J=8,8 Hz, 2H), 7,26-7,33 (m, 3H), 7,33-7,40 (m, 4H), of 7.75 (s, 1H).

The above free compound (0.05 g) is treated in the usual way, getting hydrochloride (0,052 g) specified in the connection header.

Hydrochloride

ESI-Macc: 472 (MH+).

Example 112. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-pyrimidinone)ethyl]piperazine

The free compound (0.03 g, 26%) indicated in the title compound obtained as oil from 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-chloroethyl)piperazine (0.10 g) and 2-hydroxypyrimidine (0,19 g) in the same way as in example 99.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,05-of 1.18 (m, 1H), 1,19 (d, J=6.8 Hz, 3H), 1,48 is 1.60 (m, 1H), 1,89 (dt, J=4.4 Hz, J=12.0 Hz, 1H), 2,07-is 2.37 (m, 8H), 2,46 (Shir.s, 4H), 2,70 (t, J=6.0 Hz, 2H), 3.96 points (t, J=6.0 Hz, 2H), of 6.26 (DD, J=4.0 Hz, 6.4 Hz, 1H), 7,26-7,33 (m, 1H), 7,33-7,49 (m, 4H), 7,66 (DD, J=2,8 Hz, 6.4 Hz, 1H), 8,56 (DD, J=2,8 Hz, J=4.0 Hz, 1H).

The above free connection (0,0 is reed

ESI-Macc: 408 (MH+).

Example 113. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[2-(3-pyridyl)phenoxy]ethyl}piperazine

113-1) 2-[2-(3-Pyridyl)phenoxy]ethanol

Specified in the title compound (111 mg, 22%) was obtained as pale-yellow crystals from 2-(2-bromophenoxy)ethanol (500 mg) in the same manner as in the above example.

1H NMR (400 MHz, Dl3)(M. D.): 3,89 (Shir.t, J=4.4 Hz, 2H), 4,11 (Shir.t, J=4.4 Hz, 2H), 7,03 (Shir.d, J=8.6 Hz, 1H), 7,06 for 7.12 (m, 1H), 7,30-7,40 (m, 3H), 7,86 (Shir.d, J=7.9 Hz, 1H), 8,40 at 8.60 (m, 1H), 8,65-of 8.90 (m, 1H).

ESI-Macc: 216 (MH+).

113-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[2-(3-pyridyl)phenoxy]ethyl}piperazine

In nitrogen atmosphere 2-[2-(3-pyridyl)phenoxy)ethanol (80 mg) and triethylamine (0,13 ml) dissolved in acetonitrile (6 ml) in an ice bath and to the solution add methanesulfonamide (40 mg). After stirring the mixture for 3 hours there was added sodium iodide (142 mg) and a solution of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine (90 mg) in acetonitrile (3 ml) and the mixture is stirred for 5 hours while boiling under reflux. After cooling, the reaction solution is distributed by the addition of water and ethyl acetate. The organic layer is washed with water and then Rogelim system (methanol/ethyl acetate), whereby specified in the title compound (46 mg, 26%) was obtained as a pale yellow oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,05-1,20 (m, 1H), 1,20 (d, J=6.9 Hz, 3H), 1,50-1,60 (m, 1H), 1,82-of 1.92 (m, 1H), 2,05-of 2.20 (m, 2H), 2,30-to 2.40 (m, 6N), 2,40-to 2.55 (m, 4H), 2,71 (t, J=5,9 Hz, 2H), 4.09 to (t, J=5,9 Hz, 2H), 6,98 (Shir.d, J=8.1 Hz), 7,02-was 7.08 (m, 1H), 7,25-7,38 (m, 8H), 7,86-a 7.92 (m, 1H), 8,53 (DD, J=1.6 Hz, 4.9 Hz, 1H), 8,76 (DD, J=0.7 Hz and 2.2 Hz, 1H).

This free compound (46 mg) is treated in the usual way, getting hydrochloride (30 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 0,67 (d, J=6, 6 Hz, 3H), 1,10 (d, J=6.6 Hz, 3H), of 1.20 and 1.35 (m, 1H), 1,55-1,70 (m, 1H), 2.05 is was 2.25 (m, 3H), 3.00 and-of 3.85 (m, N), 4,43-4,50 (m, 2H), 7,15-7,22 (m, 1H), 7,34-7,40 (m, 2H), 7,42-of 7.48 (m, 4H), 7,50-7,56 (m, 2H), 8,00-of 8.06 (m, 1H), 8,66-a total of 8.74 (m, 1H), 8,78-8,84 (m, 1H), 9,14 (Shir.s, 1H).

ESI-Macc: 483 (MH+).

Example 114. Synthesis of 1-[(4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

114-1) 3-Methyl-2-(2-thienyl)Botanical

2-Trilateral (15 g, 0.12 mol) dissolved in tetrahydrofuran (125 ml) and the solution added dropwise to a suspension of sodium amide (4,75 g, 0.12 mol) in tetrahydrofuran (250 ml) under cooling with ice. After paramesh the 5 ml). To the reaction mixture is added aqueous saturated solution of ammonium chloride and the mixture is then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system ethyl acetate/hexane), whereby specified in the header connection (5,56 g, 33.6 mmol, 28,0%) are obtained in the form of a yellow oil.

1H NMR (400 MHz, Dl3)(M. D.): 1,08 (d, J=to 6.80 Hz, 3H), of 1.12 (d, J=to 6.80 Hz, 3H), 2,14-of 2.24 (m, 1H), 3,95 (d, J=6,00 Hz, 1H), 6,99 (DD, J=4,00 Hz, 5,20 Hz, 1H), 7,05-was 7.08 (m, 1H), 7,27 (DD, J=1.20 Hz, from 5.29 Hz, 1H).

114-2) Ethyl-4-cyano-5-methyl-4-(2-thienyl)hexanoic

3-Methyl-2-(2-thienyl)Botanical (5,56 g, 33.6 mmol) and acrylate (4,00 ml, 37,0 mmol) dissolved in tetrahydrofuran (100 ml). To the solution at room temperature gradually add tert-piperonyl potassium (566 mg, 5,04 mmol). The heat continues during this stage. After stirring for 1 hour to the mixture successively added brine (100 ml) and aqueous saturated solution of ammonium chloride (150 ml) and the mixture extracted with simple ether (1 liter). The organic layer is successively washed with brine (500 ml) and water (500 ml), dried over anhydrous magnesium sulfate and viparis asanee the title compound (5,57 g, 21,0 mmol, 62.5%) and obtained as a yellow oil.

1H NMR (400 MHz, Dl3)(M. D.): 0,92 (d, J=is 6.78 Hz, 3H), 1,22 (d, J=7,14 Hz, 3H), of 1.23 (t, J=7,14, 3H), 2,01-2,19 (m, 3H), 2,41-of 2.58 (m, 2H), 4,01-to 4.15 (m, 2H), of 6.96 (DD, J=3,60 Hz, 5,13 Hz, 1H), 7,12 (DD, J=1.20 Hz, of 3.60 Hz, 1H), 7,29 (DD, J=1.20 Hz, 5,13 Hz, 1H).

114-3) 4-Cyano-5-methyl-4-(2-thienyl)hexanol

The above ester (5.50 g, of 20.7 mmol) dissolved in tetrahydrofuran (100 ml) and cooled to a temperature of from -30 to -40°C. To the solution was added dropwise a solution of 1 M sociallyengaged in tetrahydrofuran (150 ml), and the temperature rises within the hour to 0°C. the Reaction mixture is again cooled and successively added water (0,60 ml), 5 N. aqueous sodium hydroxide solution (0,60 ml) and water (1.80 ml) and the mixture is filtered through celite and evaporated. The residue is purified by chromatography on a column of silica gel (system ethyl acetate/hexane), whereby specified in the header connection (3,99 g of 17.9 mmol, 86,3%) are obtained in the form of a yellow oil.

1H NMR (400 MHz, Dl3)(M. D.): 0,92 (d, J=is 6.78 Hz, 3H), 1,19 (d, J=is 6.78 Hz, 3H), 1,33 of 1.46 (m, 1H), 1,65-to 1.77 (m, 1H), 1,80-1,90 (m, 1H), 2,08 (Sept., J=is 6.78 Hz, 1H), and 2.27 (DDD, J=4,40 Hz, 12.0 Hz, 13,2 Hz, 1H), 3,63 (Shir.DS, 2H), of 6.96 (DD, J=3,60 Hz, 5,20 Hz, 1H), 7,11-7,14 (m, 1H), 7,27 (DD, J=1,7.gif">

(where TBS is tert-butyldimethylsilyloxy group).

4-Cyano-5-methyl-4-(2-thienyl)hexanol (2.00 g, of 8.95 mmol) was dissolved in N,N-dimethylformamide (50 ml). To the solution at room temperature sequentially added imidazole (1,83 g, 26.9 mmol) and tert-butyldimethylchlorosilane (1.55 g, or 10.3 mmol). To the reaction mixture add the brine and the mixture is then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system ethyl acetate/hexane), whereby specified in the title compound (2.83 g, of 8.95 mmol, 100%) was obtained as a colorless oil.

1H NMR (400 MHz, Dl3)(M. D.): 0,01 (s, 3H), of 0.02 (s, 3H), 0.88 to (C, N), to 0.92 (d, J=is 6.78 Hz, 3H), of 1.18 (d, J=is 6.78 Hz, 3H), 1,27-of 1.41 (m, 1H), 1,59-1,71 (m, 1H) and 1.83 (DDD, J= 4,40 Hz and 12.4 Hz to 13.2 Hz, 1H), 2,07 (Sept., J=is 6.78 Hz, 1H), 2,22 (DDD, J=4,40 Hz and 12.4 Hz to 13.2 Hz, 1H) and 3.59 (t, J=6,04 Hz, 2H), 6,95 (DD, J=3,60 Hz, 5,20 Hz, 1H), 7,11 (DD, J=1.20 Hz, of 3.60 Hz, 1H), 7,26 (DD, J=1.20 Hz, 5,20 Hz, 1H).

114-5) [4-Cyano-5-methyl-4-(2-bromo-5-thienyl)hexyloxy]-tert-butyldimethylsilyl

[4-Cyano-5-methyl-4-(2-thienyl)hexyloxy]-tert-butyldimethylsilyl (2,72 g of 8.95 mmol) was dissolved in N,N-dimethylformamide (7 ml). To a solution of the th mixture add the brine and the mixture is then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system ethyl acetate/hexane), whereby specified in the header connection (2,56 g, x 6.15 mmol, 68.7 per cent) are obtained as a colourless oil.

1H NMR (400 MHz, Dl3)(M. D.): 0,02 (s, 3H), of 0.03 (s, 3H), 0.88 to (C, N), were 0.94 (d, J=is 6.78 Hz, 3H), of 1.17 (d, J=6,59 Hz, 3H), 1.32 to the 1.44 (m, 1H), 1,59-of 1.80 (m, 2H), 1,95-to 2.06 (m, 1H), 2,15 was 2.25 (m, 1H), 3,60 (t, J=5,86 Hz, 2H), to 6.88 (d, J=3,60 Hz, 1H), 6,91 (d, J=3,60 Hz, 1H).

114-6) [4-Cyano-5-methyl-4-(2-formyl-5-thienyl)hexyloxy]-tert-butyldimethylsilyl

A solution of [4-cyano-5-methyl-4-(2-bromo-5-thienyl)hexyloxy]-tert-butyldimethylsilyl (1.42 g, to 3.41 mmol) in tetrahydrofuran (20 ml) cooled to -70°C. To the solution is added dropwise a solution of 1.53 M utility in hexane (1,52 ml) and the mixture is stirred for 10 minutes. To the mixture of 1.52 ml of N,N-dimethylformamide and the temperature was raised to room temperature. To the reaction mixture is added aqueous saturated solution of ammonium chloride and brine, and the mixture was then extracted with simple ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on 41 mmol, 41,3%) was obtained as a yellow syrup.

1H NMR (400 MHz, Dl3)(M. D.): 0,01 (s, 3H), of 0.02 (s, 3H), 0,87 (s, N), of 0.93 (d, J=6,59 Hz, 3H), 1,21 (d, J=6,59 Hz, 3H), 1,22-of 1.36 (m, 1H), 1.60-to of 1.73 (m, 1H), 1,80-1,90 (m, 1H), 2,11 (Sept., J=6,59 Hz, 1H), 2,24-of 2.34 (m, 1H) and 3.59 (t, J=5,86 Hz, 2H), 7,26 (d, J=3,60 Hz, 1H), 7,65 (d, J=3,60 Hz, 1H), of 9.89 (s, 1H).

114-7) [4-Cyano-5-methyl-4-(2-cyano-5-thienyl)hexyloxy]-tert-butyldimethylsilyl

[4-Cyano-5-methyl-4-(2-formyl-5-thienyl)hexyloxy]-tert-butyldimethylsilyl (510 mg, of 1.39 mmol) dissolved in ethanol (5 ml), to the solution was added a solution of hydroxylamine hydrochloride (145 mg, of 2.09 mmol) and sodium acetate (228 mg, 2,78 mmol) in water (1.25 ml) and the mixture is heated at 80°C. To the reaction mixture add the brine and then extracted with simple ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated, getting oxime connection. This oxime compound is dissolved in N,N-dimethylformamide (10 ml) and cooled at 0°C followed by the addition of carbodiimide. After that, the mixture is heated at 60°C and after 20 minutes it add triethylamine. When cooled to the reaction mixture add the brine and then extracted with simple ether. The organic layer was washed with brine, dried over anhydrous is/hexane), whereby specified in the title compound (452 mg, 1.25 mmol, 89,9%) are obtained in the form of a yellow oil.

1H NMR (400 MHz, Dl3)(M. D.): 0,02 (s, 3H), of 0.03 (s, 3H), 0.88 to (C, N), of 0.93 (d, J=6,59 Hz, 3H), 1,20 (d, J=6,59 Hz, 3H), 1,23-of 1.36 (m, 1H), 1.60-to of 1.73 (m, 1H), 1,80-1,90 (m, 1H), 2,08 (Sept., J=6,59 Hz, 1H), 2,22 of-2.32 (m, 1H), 3,60 (t, J=ceiling of 5.60 Hz, 2H), 7,14 (d, J=3,60 Hz, 1H), 7,51 (d, J=3,60 Hz, 1H).

114-8) 4-Cyano-5-methyl-4-(2-cyano-5-thienyl)hexanol

[4-Cyano-5-methyl-4-(2-cyano-5-thienyl)hexyloxy]-tert-butyldimethylsilyl (452 mg, 1.25 mmol) dissolved in 10 ml of tetrahydrofuran and cooled at 0°C. To the solution was added dropwise a solution of 1 M tetrabutylammonium fluoride in tetrahydrofuran (1,38 ml) and then the temperature was raised to room temperature. To the reaction mixture is added aqueous saturated solution of ammonium chloride and brine and then extracted with simple ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system ethyl acetate/hexane), whereby specified in the title compound (273 mg, 1.10 mmol, 87.9 per cent) are obtained as a yellow syrup.

1H NMR (400 MHz, Dl3)(M. D.): 0,94 (d, J=6,59 Hz, 3H), 1,22 (d, J=6, is), 7,52 (d, J=3,60 Hz, 1H).

114-9) 1-[(4-Cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

4-Cyano-5-methyl-4-(2-cyano-5-thienyl)hexanol (273 mg, 1.10 mmol) was dissolved in acetonitrile (5,00 ml) and cooled at 0°C. To the solution is added triethylamine (0.16 ml) and methanesulfonamide (0.10 ml, to 1.21 mmol) and the temperature was raised to room temperature. After 1 hour, the mixture is distributed by adding a simple ether and brine. The organic layer was washed with aqueous saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated. Half (about 0.55 mmol) of the residue are dissolved in N,N-dimethylformamide (5,00 ml), to the solution was added 500 mg (3,34 mmol) of sodium iodide, 76,0 mg (0.55 mmol) of potassium carbonate and 202 mg (0.90 mmol) of 1-[2-(4-florfenicol)ethyl]piperazine and the mixture is heated at 60°C. To the reaction mixture are added water and the mixture extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel Chromatorex NH (system ethyl acetate/hexane), whereby specified in the title compound (215 mg, 0.47 mmol, 86,0%) was obtained as a yellow syrup.

1H NMR (400 MHz, CD,12 (m, 1H), 2,17-of 2.27 (m, 1H), 2,28 of 2.68 (m, 10H), and 2.79 (t, J=5,86 Hz, 2H), of 4.05 (t, J=5,86 Hz, 2H), to 6.80-6.87 in (m, 2H), 6,92-of 6.99 (m, 2H), 7,15 (d, J=3,80 Hz, 1H), 7,51 (d, J=3,80 Hz, 1H).

ESI-Macc: 455 (MH+).

Example 115. Synthesis of 1-[(4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(3-pertenece)ethyl]piperazine

Specified in the title compound is obtained using 1-[2-(3-pertenece)ethyl]piperazine in the same manner as in the above example.

1H NMR (400 MHz, Dl3)(M. D.): 0,92 (d, J=is 6.78 Hz, 3H), 1,21 (d, J=is 6.78 Hz, 3H), 1.18 to 1.32 to (m, 1H), 1,58-1,71 (m, 1H), 1,72-to 1.82 (m, 1H), 2.06 to (Sept., J=is 6.78 Hz, 1H), 2,17-of 2.27 (m, 1H), 2,28 of 2.68 (m, 10H), 2,80 (t, J=5,86 Hz, 2H), 4,07 (t, J=5,86 Hz, 2H), 6,68-of 6.71 (m, 3H), 7,15 (d, J=4,00 Hz, 1H), 7,17-7,24 (m, 1H), 7,51 (d, J=4,00 Hz, 1H).

ESI-Macc: 455 (MH+).

Example 116. Synthesis of 1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-pertenece)ethyl]piperazine

Specified in the title compound (yield of 86.9%, 336 mg) is obtained from 1-[2-(3-pertenece)ethyl]piperazine (323 mg) and 4-cyano-5-methyl-4-(2-thienyl)hexanol (200 mg) in the same manner as in example 114.

1H NMR (400 MHz, Dl3)(M. D.): 0,90 (d, J=6,59 Hz, 3H), of 1.18 (d, J=6,59 Hz, 3H), 1,25-to 1.38 (m, 1H), 1,58 is 1.70 (m, 1H), 1,72-to 1.82 (m, 1H), 2.06 to (Sept., J=6,59 Hz, 1H), 2,11-of 2.21 (m, 1H), 2,27-of 2.64 (m, 10H), and 2.79 (t, J=5,86 Hz, 2H), 4,07 (t, J=5,86 Hz, 2H), 6,58-6,70 p 117. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(3-thienyl)phenoxy)ethyl}piperazine

In nitrogen atmosphere 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-bromophenoxy)ethyl]piperazine (100 mg), thiophene-3-boronic acid (53 mg) and complex tetranitropentaerithrite (24 mg) was dissolved in toluene (4.0 ml) and to the solution was added 10% aqueous sodium bicarbonate solution, the atmosphere is replaced by nitrogen and the mixture is heated for 4 hours at boiling under reflux. The reaction mixture is cooled and then distributed by the addition of water and ethyl acetate. The organic layer is washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel NH (system hexane/ethyl acetate), whereby specified in the title compound (21 mg, 21%) was obtained as a colorless oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,05-1,20 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-to 1.63 (m, 1H), 1,83-of 1.95 (m, 1H), 2,05-of 2.20 (m, 2H), 2,23-of 2.30 (m, 2H), 2,30 at 2.45 (m, 4H), 2,45-2,60 (m, 4H), of 2.81 (t, J=6.0 Hz, 2H), 4,13 (t, J=6.0 Hz, 2H), 6,80-6,84 (m, 1H), 7,12-7,14 (m, 1H), 7,16-7,20 (m, 1H), 7,25-to 7.32 (m, 2H), 7,33-7,38 (m, 2H), 7,42 was 7.45 (m, 6N).

This free compound (21 mg) is treated with the usual who MHz, DMSO-d6)(M. D.): 0,67 (d, J=6.4 Hz, 3H), 1,11 (d, J=6.8 Hz, 3H), 1,20-1,30 (m, 1H), 1,55-1,70 (m, 1H), 2.05 is-is 2.30 (m, 3H), 3,20-of 3.80 (m, N), 4,42 (Shir.s, 2H), 6.90 to-to 6.95 (m, 1H), 7,30-7,40 (m, 4H), 7,40-to 7.50 (m, 4H), 7,55-7,58 (m, 1H), 7,62-7,66 (m, 1H), 7,88-a 7.92 (m, 1H).

ESI-Macc: 488 (MH+).

Example 118. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[2-(6-methyl-2-pyridyl)vinylphenol]ethyl}piperazine

In nitrogen atmosphere 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-bromophenoxy)ethyl]piperazine (100 mg), 6-vinyl-2-methylpyridine (49 mg), palladium acetate (4.6 mg) and Tris-(2-were)phosphine (12.5 mg) is dissolved in N,N-dimethylformamide (4.0 ml), the solution is added triethylamine (1 ml) and the mixture is stirred for 10 hours while boiling under reflux. The reaction mixture is cooled, filtered through celite and distribute by adding water and diethyl ether. The organic layer is washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel NH (system hexane/ethyl acetate), whereby specified in the title compound (115 mg, 100%) was obtained as a colorless oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.6 Hz, 3H), 1,05-1,20 (m, 1H), 16th (t, J=5,9 Hz, 2H), to 6.88 (d, J=8,4 Hz, 1H), 6,94-7,00 (m, 2H), 7.18 in-7,38 (m, 6N), 7,52 (t, J=7.7 Hz, 1H), 7,62-7,66 (m, 1H), 7,87 (d, J=16,7 Hz, 1H).

This free compound (115 mg) is treated in the usual way, getting hydrochloride (110 mg) specified in the connection header.

Hydrochloride

ESI-Macc: 523 (MH+).

Example 119. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-cianfrocca)ethyl]piperazine

In nitrogen atmosphere 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-bromophenoxy)ethyl]piperazine (100 mg), cyanide zinc (24 mg) and the complex tetranitroaniline (24 mg) was dissolved in N,N-dimethylformamide (4.0 ml), heated and stirred for 9 hours while boiling under reflux. The reaction mixture is cooled, filtered through celite and distribute adding water and diethyl ether. The organic layer is washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel NH (system hexane/ethyl acetate), whereby specified in the title compound (63 mg, 71%) was obtained as a colorless oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6, 8 Hz, 3H), 1,05-1,20 (m, 1H), 1,20 (d, J=6.6 Hz, 3H), 1,50-1,60 (m, 1H), 1,83-1,95>the data of the free compound (63 mg) is treated in the usual way, getting hydrochloride (58 mg) specified in the connection header.

Hydrochloride

ESI-Macc: 431 (MH+).

Example 120. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-phenyleneoxy)ethyl]piperazine

120-1) 2-(3-Phenyleneoxy)ethanol

In nitrogen atmosphere 3-phenylphenol (2.65 g), 2-bromoethanol (2,92 g) and potassium carbonate (6,51 g) dissolved in N,N-dimethylformamide (16 ml) and stirred at 100°C. After 5 hours the reaction mixture is cooled to room temperature and distribute by adding water and diethyl ether. The organic layer is washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system hexane/ethyl acetate), whereby specified in the title compound (1.78 g, 53%) was obtained as colorless crystalline substance.

1H NMR (400 MHz, CDCl3)(M. D.): 2,18-of 2.24 (m, 1H), 3.96 points-of 4.00 (m, 2H), 4,14 (t, J=4,8 Hz, 2H), 6,88-6,92 (m, 1H), 7,13-7,16 (m, 1H), 7.18 in-7,22 (m, 1H), 7,32-7,38 (m, 2H), 7,40 was 7.45 (m, 2H), 7,55-to 7.59 (m, 2H).

120-2) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-phenyleneoxy)ethyl]piperazine

In nitrogen atmosphere 2-(3-phenylphenols sulphonylchloride (40 mg). After stirring the mixture for 3 hours to a mixture of sodium iodide (142 mg) and a solution of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine (90 mg) in acetonitrile (3 ml), the mixture is stirred for 15 hours while boiling under reflux. After cooling, the reaction mixture is distributed by the addition of water and ethyl acetate. The organic layer is washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel NH (system hexane/ethyl acetate), whereby specified in the title compound (127 mg, 84%) was obtained as a colorless oil.

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.8 Hz, 3H), 1,05-1,20 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-1,60 (m, 1H), 1,82-of 1.92 (m, 1H), 2,05-of 2.20 (m, 2H), 2,25-of 2.30 (m, 2H), 2,30 at 2.45 (m, 4H), 2,45-to 2.65 (m, 4H), of 2.81 (t, J=5,9 Hz, 2H), 4,14 (t, J=5,9 Hz, 2H), 6,85-of 6.90 (m, 1H), 7,11-7,14 (m, 1H), 7,15-7,19 (m, 1H), 7,25 was 7.45 (m, N), 7,55-of 7.60 (m, 2H).

This free compound (127 mg) is treated in the usual way, getting hydrochloride (115 mg) specified in the connection header.

Hydrochloride

ESI-Macc: 482 (MH+).

Example 121. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(2-cyanovinyl)phenoxy]ethyl}piperazine

1-[(4-Citric-(2-were)phosphine (25 mg) dissolved in N,N-dimethylformamide (8.0 ml), to the solution is added triethylamine (2.0 ml) and the mixture is heated in a sealed vessel at 100°C for 12 hours. The reaction mixture is cooled and then filtered through celite and the filtrate is distributed by the addition of water and ethyl acetate. The organic layer is washed with water and then brine, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel NH (system hexane/ethyl acetate), whereby specified in the title compound (65 mg, 35%) was obtained as a colorless oil.

Free connection

lH NMR (400 MHz, Dl3)(M. D.): 0,77 (d, J=6.6 Hz, 3H), 1,05-1,20 (m, 1H), 1,20 (d, J=6.6 Hz, 3H), 1,50-1,60 (m, 1H), 1,82-of 1.92 (m, 1H), 2,05-of 2.20 (m, 2H), 2,25-of 2.30 (m, 2H), 2,30 at 2.45 (m, 4H), 2,45-to 2.65 (m, 4H), and 2.79 (t, J=5,9 Hz, 2H), 4.09 to (t, J=5,9 Hz, 2H), 5,85 (d, J=16,8 Hz, 1H), 6,64-7,40 (m, 10H).

This free compound (32 mg) is treated in the usual way, getting hydrochloride (30 mg) specified in the connection header.

Hydrochloride

ESI-Macc: 457 (MH+).

Example 122. Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexanoyl]-4-[2-(4-pertenece)ethyl]piperazine

Specified in the header connection (8.53 g, 85%) was obtained as colorless oil from 4-cyano-5-methyl-4-phenylhexanoic acid (5,28 g) and 1-[2-(4-f is Mr (400 MHz, Dl3)(M. D.): 0,78 (d, J=6.8 Hz, 3H), 1,22 (d, J=6.6 Hz, 3H), 1,80-of 1.93 (m, 1H), 2,10-of 2.20 (m, 1H), 2,25-to 2.55 (m, 7H), 2,77 (t, J=5.5 Hz, 2H), 3,20-3,40 (m, 2H), 3,45-3,70 (m, 2H), a 4.03 (t, J=5.5 Hz, 2H), 6,79-6,84 (m, 2H), 6,92-6,98 (m, 2H), 7,14-7,40 (m, 5H).

ESI-Macc: 438 (MH+).

Example 123. Synthesis of 1-[(4-cyano-4-phenyl)butyl]-4-[2-(4-pertenece)ethyl]piperazine

Specified in the header connection (874 mg, 67%) was obtained as a pale-yellow oil from (4-cyano-4-phenyl)butylaldehyde (720 mg) and 1-[2-(4-pertenece)ethyl]piperazine (689 mg) in the same manner as in example 1,

Free connection

1H NMR (400 MHz, Dl3)(M. D.): 1,60-1,70 (m, 2H), 1,86 is 2.00 (m, 2H), 2,37 (t, J=7.2 Hz, 2H), 2.40 a-to 2.54 (m, 4H), 2,54-of 2.66 (m, 4H), was 2.76-2.82 from (m, 2H), 3,84-3,88 (m, 1H), was 4.02-4,08 (m, 2H), for 6.81-6,86 (m, 2H), 6,93-6,98 (m, 2H), 7,30-7,40 (m, 5H).

This loose coupling (874 mg) is treated in the usual way, getting hydrochloride (890 mg) specified in the connection header.

Hydrochloride

1H NMR (400 MHz, DMSO-d6)(M. D.): 1,75-of 1.85 (m, 2H), 1.85 to 2,02 (m, 2H), 3,12-up 3.22 (m, 2H), 3,22-3,82 (m, 10H), 4,28-to 4.38 (m, 3H), 7,01-7,06 (m, 2H), 7,13-7,20 (m, 2H), 7,34-7,38 (m, 1H), 7,40-7,46 (m, 4H).

ESI-Macc: 382 (MH+).

Claims

1. N,N-substituted cyclic amine compounds represented with the traveler may be substituted, heteroaryl group which may be substituted, aracelio group which may be substituted;

E represents a group represented by the formula-CO-, or a group represented by formula-NON-;

G represents an oxygen atom, a sulfur atom or a group represented by the formula-NR10- (where R10represents a hydrogen atom, a C1-6alkyl group, a C3-8cycloalkyl,1-7acyl group, or With1-6alkylsulfonyl group), a group represented by the formula-CONR11- (where R11represents a hydrogen atom or a C1-6alkyl group), a group represented by the formula-NR12CO- (where R12represents a hydrogen atom or a C1-6alkyl group), a group represented by the formula-SO2-, a group represented by the formula-SO2NR15- (where R15represents a hydrogen atom or a C1-6alkyl group), a group represented by the formula-NR16SO2- (where R16represents a hydrogen atom or a C1-6alkyl group), a group represented by the formula-CO(CH2)sO-, a group represented by the formula-CHOH-, or a group represented by formula-SNON(CH2)sO- (where s is 0 or an integer from 1 to 6);

J presented the/p>R1represents a hydrogen atom, a halogen atom, a C1-6alkyl group, a C3-8cycloalkyl group, hydroxy1-6alkyl group;

Alk is unbranched or branched C1-6alkylenes group;

n, v, w, x and y are independent from each other and each is 0 or 1;

p represents 2 or 3;

where the aryl group is phenyl or naftalina group, heteroaryl group selected from thienyl, peredelnoj, pyrimidinyl, imidazolidine, chinadaily groups,

substituents selected from the group comprising halogen atom, a hydroxy-group, With1-6alkyl group, a C1-6alkoxygroup,1-6alkoxycarbonyl group optionally N-substituted by an amino group, cyano, C1-6dialkoxy,

or their pharmaceutically acceptable salts, provided that the following compounds are excluded:

1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-cianfrocca)ethyl]piperazine;

1-[4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexyl]-4-[2-(3-cianfrocca)ethyl]piperazine;

1-[4-cyano-4-(3-cyano-5-thienyl)-5-methylhexan]-4-[2-(3-cianfrocca)ethyl]piperazine;

1-[4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexyl]-4-[2-(3-cianfrocca)ethyl]piperazine;

1-[4-cyano-4-(5-cyano-2-thienyl)-5-petiatil)-N-benzylamino]pyrrolidin;

1-[4-cyano-4-(2-thienyl)-5-methylhexan]-(3S)-3-[N-(2-cyanoethyl)-N-(3-cyanobenzyl)amino]pyrrolidin;

4-[(4-cyano-5-methyl-4-phenyl)hexyl]-N-(4-forfinal)-N'-(2-methylpropyl)-1(2H)-pyrazinecarboxamide;

1-isopropyl-4-[4-(1-isobutyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-phenylbutazone;

1-[4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-(3-cianfrocca)ethyl]piperazine;

1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-cianfrocca)ethyl]piperazine;

1-[4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[3-(5-cyano-2-thienyl)propyl]piperazine;

1-[4-cyano-5-methyl-4-(3-thienyl)hexyl]-4-[2-(3-cianfrocca)ethyl]piperazine;

1-[4-cyano-5-methyl-4-[4-(2-cyano)thienyl]hexyl}-4-[2-(3-cianfrocca)ethyl]piperazine;

1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[(2-benzoxazolyl)amino]piperidine;

1-[4-cyano-4-(5-cyano-2-thienyl)-5-methylhexan]-(3S)-3-[N-(2-cyanoethyl)-N-benzylamino]pyrrolidin;

1-[4-cyano-4-(5-cyano-2-thienyl)-5-methylhexan]-(3R)-3-[N-(2-cyanoethyl)-N-benzylamino]pyrrolidin;

1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(benzothiazolyl)piperazine;

1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(6-methoxy)benzothiazolyl]piperazine;

1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-benzoxazolyl)piperazine;

1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-chinoline)piperazine

4-[4-(1-methyl-1H-benzo[d]imidazol-2-yl)-1,4-Diaz is butylene;

ethyl-4-(4-cyano-5-methyl-4-phenylhexa)-1-[2-(4-pertenece)ethyl]-2-piperidinecarboxylate;

1-[(2-oxo-1,2-dihydro-3-chinolin)methyl]-4-[(4-cyano-5-methyl-4-phenyl)hexyl]piperidine;

4-[(4-cyano-5-methyl-4-phenyl)hexyl]-1-{[2-(methanesulfonamido)phenyl]methyl}piperazine;

4-[(4-cyano-5-methyl-4-phenyl)hexyl]-1-{[2-(methanesulfonamido)phenyl]methyl}piperidine;

{1-[4-cyano-5-methyl-5-(2-thionyl)hexyl]piperazinil}amide(S)-3-phenyl-2-aminopropanoic acid;

4-[4-(4-phenylpiperidine)piperidinyl]-1-isopropyl-1-phenylbutazone;

4-[4-(4-cyano-4-phenylpiperidine)piperidinyl]-1-isopropyl-1-phenylbutazone; and

4-[4-(4-benzylpiperidine)piperidinyl]-1-isopropyl-1-phenylbutyramide.

2. Connection on p. 1, represented by the following formula (I):

in which a represents aryl group which may be substituted, a heteroaryl group which may be substituted, aracelio group which may be substituted, or heteroallyl group which may be substituted;

E represents a group represented by the formula-CO-, or a group represented by formula-NON-;

G represents an oxygen atom, a sulfur atom or a group represented by the formula-NR10- (where R10is a, is the group represented by the formula-CONR11- (where R11represents a hydrogen atom or a C1-6alkyl group), a group represented by the formula-NR12CO- (where R12represents a hydrogen atom or a C1-6alkyl group), a group represented by the formula-SO2-, a group represented by the formula-SO2NR15- (where R15represents a hydrogen atom or a C1-6alkyl group), a group represented by the formula-NR16SO2- (where R16represents a hydrogen atom or a C1-6alkyl group), a group represented by formula-OCOS-, a group represented by the formula-CO(CH2)sO-, a group represented by the formula-CHOH - or a group represented by formula-SNON(CH2)sO- (where s is 0 or an integer from 1 to 6);

J represents an aryl group which may be substituted, or a heteroaryl group which may be substituted;

R1is1-6alkyl, C3-8cycloalkyl group;

R2, R3, R4, R5, R6, R7, R8and R9may be the same or different from each other and each represents a hydrogen atom or a C1-6alkyl group;

m, o, q and r may be the same or R the PA represents phenyl or naftalina group, heteroaryl group selected from thienyl, peredelnoj, pyrimidinyl, imidazolidine, chinadaily groups,

substituents selected from the group comprising halogen atom, a hydroxy-group, With1-6alkyl group, a C1-6alkoxygroup,1-6alkoxycarbonyl group optionally N-substituted by an amino group, cyano, C1-6dialkoxy,

or its pharmaceutically acceptable salt.

3. Connection on p. 1, represented by the following formula (II):

in which a, E, G, J, R1, m, n, o, p, q and r have the same values as specified in paragraph 1,

or its pharmaceutically acceptable salt.

4. Connection on p. 1, represented by the following formula (III):

in which A, G, J, R1, m, p and q have the same values as specified in paragraph 1,

or its pharmaceutically acceptable salt.

5. Connection on p. 1, represented by the following formula (IV):

in which R1, m, p and q have the same values as specified in paragraph 1,

R20and R21are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxy-group, With1-6alkyl group, a C1-6alkoxygroup, alkoxygroup, aryl group which may be substituted, a heteroaryl group or a heterocyclic group, or alkylenedioxy, which may be substituted;

j and t can be the same or different and each is 0 or an integer from 1 to 5,

or its pharmaceutically acceptable salt.

6. Connection on p. 1, which is a compound selected from the group consisting of the following compounds:

(1) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(2) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[3-(4-pertenece)propyl]piperazine

(3) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-pertenece)ethyl]homopiperazin

(4) 1-[(3-cyano-4-methyl-3-phenyl)pentyl]-4-[2-(4-pertenece)ethyl]homopiperazin

(5) 1-[(3-cyano-4-methyl-3-phenyl)pentyl]-4-[3-(4-pertenece)propyl]piperazine

(6) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(4-phenoxybutyl)piperazine

(7) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-phenoxyethyl)piperazine

(8) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-nitrophenoxy)ethyl]piperazine

(9) 1-[4-cyano-5-methyl-4-(4-were)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(10) 1-[4-cyano-5-methyl-4-(4-chlorophenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(11) 1-[4-cyano-5-methyl-4-(4-methoxyphenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(12) 1-[4-cutifani)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(14) 1-[4-cyano-5-methyl-4-(4-hydroxyaminobuteroyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(15) 1-[4-cyano-5-methyl-4-(4-cyanophenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(16) 1-[4-cyano-5-methyl-4-(4-nitrophenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(17) 1-[4-cyano-5-methyl-4-(4-AMINOPHENYL)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(18) 1-[4-cyano-5-methyl-4-(4-acetamidophenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(19) 1-[4-cyano-5-methyl-4-(4-dimethylaminophenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(20) 1-{[4-cyano-5-methyl-4-(2-thienyl)hexyl]}-4-[2-(4-pertenece)ethyl]piperazine

(21) 1-{[4-cyano-5-methyl-4-(3-pyridyl)hexyl]}-4-[2-(4-pertenece)ethyl]piperazine

(22) 1-{[4-cyano-5-methyl-4-(2-forfinal)hexyl]}-4-[2-(4-pertenece)ethyl]piperazine

(23) 1-{[4-cyano-5-methyl-4-(3-forfinal)hexyl]}-4-[2-(4-pertenece)ethyl]piperazine

(24) 1-{[4-cyano-5-methyl-4-(4-forfinal)hexyl]}-4-[2-(4-pertenece)ethyl]piperazine

(25) 1-[(3-cyano-4-methyl-3-phenyl)pentyl]-4-[2-(4-pertenece)ethyl]piperazine

(26) 1-[(4-cyano-4-phenyl)pentyl]-4-[2-(4-pertenece)ethyl]piperazine

(27) 1-[(4-cyano-4-phenyl)heptyl]-4-[2-(4-pertenece)ethyl]piperazine

(28) 1-[(4-cyano-4-phenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(29) 1-[(4-cyano-4-phenyl)octyl]-4-[2-(4-pertenece)ethyl]piperazin

(30) 1-[(4-Cixi)ethyl]piperazine

(32) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-pertenece)ethyl]piperazine

(33) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[3-(4-pertenece)pentyl]piperazine

(34) 1-[(4-cyano-5-methyl-4-phenyl)heptyl]-4-[3-(4-pertenece)ethyl]piperazine

(35) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3,4-divergence)ethyl]piperazine

(36) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-chlorophenoxy)ethyl]piperazine

(37) 1-{[4-cyano-5-methyl-4-(3,4-dichlorophenyl)hexyl]}-4-[2-(4-pertenece)ethyl]piperazine

(38) 1-[(4-cyano-4-cyclohexyl-4-phenyl)butyl]-4-[2-(4-pertenece)ethyl]piperazine

(39) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-methoxyphenoxy)ethyl]piperazine

(40) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2,3-dimethoxyphenoxy)ethyl]piperazine

(41) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3,4-dimethoxyphenoxy)ethyl]piperazine

(42) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-aminophenoxy)ethyl]piperazine

(43) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-dimethylaminoethoxy)ethyl]piperazine

(44) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-acetamidophenol)ethyl]piperazine

(45) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-methylthiophene)ethyl]piperazine

(46) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-cianfrocca)ethyl]piperazine

(47) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-cianfrocca)ethyl]piperazine

(48) 1-[(4-ciio)ethyl]piperazine

(50) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-perpenicular)ethyl]piperazine

(51) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-forgenerating)ethyl]piperazine

(52) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-forfinal)-N-methylamino]ethyl}piperazine

(53) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-forfinal)-N-acetylamino]ethyl}piperazine

(54) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-forfinal)-N-methanesulfonamido]ethyl}piperazine

(55) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(benzylamino)ethyl]piperazine

(56) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-acetyl-N-benzylamino)ethyl]piperazine

(57) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-methanesulfonyl-N-benzylamino)ethyl]piperazine

(58) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-benzyl-N-isopropylamino)ethyl]piperazine

(59) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-perbenzoic)ethyl]piperazine

(60) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[3-hydroxy-3-(4-forfinal)propyl]piperazine

(61) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-pertenece)acetyl]piperazine

(62) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-hydroxy-3-(4-pertenece)propyl]piperazine

(63) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-ftorpolimernoj)ethyl]piperazine

(64) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-perbenzoate)ethyl]piperazine

(65) 1-4-[2-(4-forbindelseshandtering)ethyl]piperazine

(67) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-forfinal)sulfamoyl]ethyl}piperazine

(68) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-forfinal)-N-methylcarbamoyl]ethyl}piperazine

(69) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-methyl-4-forbindelseshandtering)ethyl]piperazine

(70) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[(4-forfinally)carbonyloxy]ethyl}piperazine

(71) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-pyridyloxy)ethyl]piperazine

(72) 1-(3-cyclohexyl-3-cyano-3-phenyl)propionyl 4-[2-(4-pertenece)ethyl]piperazine

(73) 1-(2-hydroxy-4-cyano-5-methyl-4-phenyl)hexyl-4-[2-(4-pertenece)ethyl]piperazine

(74) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-benzoylperoxy)ethyl]piperazine

(75) 1-[(4-cyano-5-hydroxy-5-methyl-4-phenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(76) 1-[5-(4-cyano-5-methyl-4-phenyl)hexenyl]-4-[2-(4-pertenece)ethyl]piperazine

(77) 1-[4-cyano-5-methyl-4-(4-hydroxyphenyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(78) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-hydroxy-4-pertenece)ethyl]piperazine

(79) 1-[(4-cyano-4-fluoro-4-phenyl)butyl]-4-[2-(4-pertenece)ethyl]piperazine

(80) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-ethoxycarbonylmethoxy-4-pertenece)ethyl]piperazine

(81) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-hydroxyethoxy-4-pertenece)at-methyl-4-phenyl)hexyl]-4-[2-(N-isopropylaniline)ethyl]piperazine

(84) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-cyclohexylaniline)ethyl]piperazine

(85) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl-(4-isopropylaniline)ethyl]}piperazine

(86) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl-(3-isopropylaniline)ethyl]}piperazine

(87) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl-(2-isopropylaniline)ethyl]}piperazine

(88) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3,4-(methylendioxy)phenoxy]ethyl}piperazine

(89) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(6-hinomisaki)ethyl]piperazine

(90) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(5-athinaiki)ethyl]piperazine

(91) 1-[{2-(5-cyano-6-methyl-5-phenyl)heptyl}]-4-[2-(4-pertenece)ethyl]piperazine

(92) 1-{[4-(7-cyano-8-methyl-7-phenyl)nonyl]}-4-[2-(4-pertenece)ethyl]piperazine

(93) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-pyridyloxy)ethyl]piperazine

(94) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-pyridyloxy)ethyl]piperazine

(95) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(5-hinomisaki)ethyl]piperazine

(96) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-triptoreline)ethyl]piperazine

(97) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(1-naphthyloxy)ethyl]piperazine

(98) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-ethyl-2-(4-pertenece)ethyl]piperazine

(99) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-girasolereale)ethyl]l-4-phenyl)hexyl]-4-{2-[3-(3-pyridyl)phenoxy]ethyl}piperazine

(102) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-bromophenoxy)ethyl]piperazine

(103) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-bromophenoxy)ethyl]piperazine

(104) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-bromophenoxy)ethyl]piperazine

(105) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[4-(imidazol-1-yl)phenoxy]ethyl}piperazine

(106) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-pyrimidinone)ethyl]piperazine

(107) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[2-(3-pyridyl)phenoxy]ethyl}piperazine

(108) 1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

(109) 1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(3-pertenece)ethyl]piperazine

(110) 1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-pertenece)ethyl]piperazine

(111) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(3-thienyl)phenoxy]ethyl}piperazine

(112) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[2-(6-methyl-2-pyridyl)vinylphenol]ethyl}piperazine

(113) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-cianfrocca)ethyl]piperazine

(114) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-phenyleneoxy)ethyl]piperazine

(115) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(2-cyanovinyl)phenoxy]ethyl}piperazine

(116) 1-[(4-cyano-5-methyl-4-phenyl)hexanoyl]-4-[2-(4-pertenece)ethyl]piperazine and

(117) 1-[(4-cyano-4-phenyl)butyl]-4-[2-(4-pertenece)-ethyl]-piperaceae amine compound according to any one of paragraphs.1-6 or its pharmacologically acceptable salt as an active ingredient.

8. Selective for the nerves calcium antagonist comprising N,N-substituted cyclic amine compound according to any one of paragraphs.1-6 or its pharmacologically acceptable salt as an active ingredient.

9. Agent for prevention, treatment and ameliorate diseases against which effectively inhibitory effect on calcium channel type, P/Q, including N,N-substituted cyclic amine compound according to any one of paragraphs.1-6 or its pharmacologically acceptable salt as an active ingredient.

10. Agent for prevention, treatment and ameliorate diseases against which effectively inhibitory effect on calcium channel type N, including N,N-substituted cyclic amine compound according to any one of paragraphs.1-6 or its pharmacologically acceptable salt as an active ingredient.

11. Agent for inhibiting neuronal cell death or to protect nerve cells in the brain, including N,N-substituted cyclic amine compound according to any one of paragraphs.1-6 or its pharmacologically acceptable salt as an active ingredient.

12. Agent for prevention, treatment or improvement in nervous disease, including N,N-substituted cyclic amine connection is UNT for the prevention, cure or improvement in nervous disease on p. 12, wherein the disease of the nerve cells is a disease from the group consisting of acute ischemic stroke, cerebral apoplexy, cerebral infarction, head injury, loss of cerebral nerve cells, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington disease, disorders of cerebral circulatory metabolism, disorders of cerebral function, pain, spasm, schizophrenia, migraine, epilepsy, manic-depressive psychosis, nerve degenerative diseases, cerebral ischemia, complications of type of dementia in AIDS, edema, violations type of anxiety (generalized type violation anxiety) and diabetic neuropathy.

14. The composition of the calcium antagonist comprising a pharmacologically effective amount of N,N-substituted cyclic amine compounds according to any one of paragraphs.1-6 or its pharmacologically acceptable salt of the pharmacologically acceptable carrier.

Priority points and attributes:

21.07.1998 on PP.1-5, 7-13, compounds 1 to 24 listed in paragraph 6;

01.10.1998 connection from 25 to 72 listed in paragraph 6;

21.07.1999 connection 73 to 117

 

Same patents:

Thrombin inhibitors // 2221808
The invention relates to compounds of formula I, the values of the radicals defined in the claims and their pharmaceutically acceptable salts

The invention relates to substituted cyclic aminoven compounds of formula (I)

< / BR>
where Ar represents thienyl, substituted pyridine, phenyl unsubstituted or substituted with halogen, hydroxy, alkoxy, C1-C4the alkyl, phenyloxy, NO2or phenyl; R1is NHOR2where R2is hydrogen; W is one or more hydrogen atoms; Y is independently one or more members of the group consisting of hydroxy, SR3, alkoxy, NR6R7where R6and R7independently selected from hydrogen, alkyl, pyridylethyl, SO2R8, COR9or R6and R7can be combined with the formation of the ring containing the nitrogen to which they relate, formulas

< / BR>
where Y' is CH2OH , SO2; R3represents hydrogen, alkyl, aryl, benzothiazolyl, pyrazinyl, N-methylimidazole; R8represents C1-C4alkyl, phenyl; R9represents hydrogen, alkyl, phenyl; Z is hydrogen; n = 1, and its optical isomer, diastereoisomer, or enantiomer, or its pharmaceutically acceptable salt

The invention relates to compounds of formula (I)

< / BR>
in which Ar1denotes a heterocyclic group, which represents a pyrazole which may be substituted by one or more radicals R1, R2or R3; Ar2denotes phenyl, naphthyl or tetrahydronaphthyl, each of which optionally is substituted by one to three groups R2; L denotes a saturated or unsaturated, branched or unbranched carbon C1-C10chain; in which one or more methylene groups are optionally independently replaced by O, NH or S, and in which the linking group is optionally substituted by 0-2 of doxography; Q has a value selected from a range of: a) phenyl, naphthyl, pyridine, imidazole, Piran, etc. b) tetrahydropyran, morpholine, thiomorpholine, thiomorpholine and t

The invention relates to new derivatives of benzothiadiazole, benzoxazoles and benzodiazines formula I in free base form or in the form of a pharmaceutically acceptable acid salt additive that can be used as an anxiolytic drug in the treatment of any condition, which is associated with increased endogenous levels of CRF or in which violated the regulation of the hPa system (hypothalamic - pituitary), or various diseases that are caused by CRF1or the manifestation of which contributes CRF1such as arthritis, asthma, allergies, anxiety, depression, etc

The invention relates to amide derivative of the formula I

< / BR>
where R3represents (1-6C)alkyl or halogen; m is 0, 1, 2 or 3; R1represents hydroxy, halogen, trifluoromethyl, nitro, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl] amino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino etc

The invention relates to new derivatives of phenyl - and aminobenzenesulfonamide formula

< / BR>
where a denotes (R1SO2NR2-), (R3R60NSO2NR2-); X represents-NH-, -CH2- or-OCH2-; Y represents 2-imidazoline, 2-oxazoline or 4-imidazole; R1means (NISS

The invention relates to new imidazole derivative of formula I and II

< / BR>
or

< / BR>
where 1, m, r, s, and t = 0 or 1; n = 1 or 2; provided that when 1 and m = 0, n = 2 Y - SO2or CH2; Z - CR12, NR32SO; NR13, NR36CO., OCONR15, SO2NR14; R1selected from the group consisting of hydrogen, alkyl, or aralkyl, the symbola single or double bond, R7, R8selected from the group consisting of hydrogen, aryl, - CN, halogen, and U-R44group, where U = O and R44and R11selected from the group consisting of hydrogen, alkyl, aralkyl, aryl; R32selected from the group consisting of hydrogen, lower alkyl, unsubstituted or substituted phenyl, and tanila; R9, R10, R12, R13, R14, R15, R36, R57and R58represent hydrogen or lower alkyl; one of R, S and T is CH2or CH(CH2)pQ, where Q denotes NR57R58; where p = 0,1 or 2; provided that when Y is - SO2, R11cannot be hydrogen; its enantiomers, diastereoisomers, pharmaceutically priemel the

The invention relates to new indole derivative of the formula I

< / BR>
where R1- H, halogen, CN; R2and R3the same or different is H, C1-C4alkyl, halogen; R4- H, C1-C4alkyl; And means cyanoaniline, aminosulphonylphenyl, aminopyridine, aminopyrimidine, halogenopyrimidines or cianciarulo group, provided that if all R1, R2and R3- N, when both R2and R3- N or when ring A - aminosulphonylphenyl group and both R1and R2the halogen atoms is excluded; and, in addition, when the ring a represents cyanophenyl group, 2-amino-5-pyridyloxy group or 2-halogen-5-pyridyloxy group, and R1represents a cyano or halogen group, at least one of R2and R3must not be a hydrogen atom

The invention relates to new derivatives of arylpiperazines General formula I, where X Is O or S1- C1-C4alkoxy, CF3, R2- C1-C6alkyl, saturated WITH3-C6cycloalkyl; heteroseksualci of 3-6 ring atoms, heteroatom of which is O, S or N, optionally N-substituted WITH1-C6by alkyl; phenyl, optionally substituted by F, Cl, Br, NH2CH3CF3or OCH3; 5-6-membered heteroaryl, the heteroatom of which is O, S or N, possibly substituted, or condensed heteroaromatic system containing 9 atoms

The invention relates to new and nitrate salts of heterocyclic compounds of formulas (a) and (b), where R is hydrogen, alkoxyl, R1- alkyl, alkoxyl, R2is hydrogen, alkyl, R3- alkyl, alkoxyl, X denotes N-R11or oxygen, R11means the free valence, Y represents N-R16, sulfur or alkyl, R16means hydrogen; other values radicals presented in the description of the invention

The invention relates to new indole derivative of the formula I

where two of R1a, Rlb, Rlc, Rldindependently from each other denote H, F, I, Cl, Br, (C1-C4)alkyl, phenyl, phenyl-(C1-WITH4)alkyl, (C1-C4)alkoxy, phenyl-(C1-C4)alkoxy, phenyloxy, HE, -NR5aR5b, -SOn-R6c, n is 1-2, and are the same or different, and two other mean N; where all residues R5a, R5b, R6cif present in the molecule more than once, are independent from each other and may be each the same or different; one of R2and R3means -(CH2)p-CO-R8and the other denotes H, F, Cl, Br, or -(CH2)p-CO-R8; p is 0, 1 or 2; R8means-NR9R10, -OR10; A represents the bivalent residue of(C1-C4)alkyl, which is saturated or which contains a triple bond, or -(C1-C4)alkyl-CO-NH-, where the nitrogen is associated with R4; R4means phenyl, which is substituted by one residue R15bor pyridyl, which is unsubstituted or substituted14on the nitrogen atom; all their stereozoom

The invention relates to new compounds of the formula (I) and their pharmaceutically acceptable salts and esters possessing inhibitory ability against endothelioma receptors, the Compounds can be used to treat diseases associated with abnormal vascular tone and endothelial dysfunction

The invention relates to new derivatives of 1,3-diaryl-2-pyridin-2-yl-3-(pyridine-2-ylamino)propanol of the formula (I)

where Z denotes-NH-(C1-C16-alkyl)-(C=O)-; -(C=O)-(C1-C16-alkyl)-(C=O)-;

-(C=O)-phenyl-(C=O)-; AND1AND2AND3AND4denote independently of each amino-acid residue, E represents-SO2-R4and-CO-R4; R1- phenyl, thiazolyl, oxazolyl, thienyl, thiophenyl and others, R2- N., HE, CH2HE, OMe; R3Is h, F, methyl, OMe; R4denotes -(C5-C16-alkyl), -(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylene)-NH-R5and others, R5denotes-COO-R6, -(C=O)-R6-(C1-C6-alkylen)-R7, phenyl, naphthyl and others, R6denotes H, -(C1-C6) alkyl; R7denotes H, -(C1-C7-cycloalkyl, phenyl, naphthyl and others, l, q, m, n, o, p denote 0 or 1, and l+q+m+n+o+p is greater than or equal to 1, and their pharmaceutically acceptable salts

The invention relates to arylpiperazines General formula I

< / BR>
where is phenyl, pyridyl or pyrimidyl; each R3- H, halogen, NO2, СООR, where R is H, C1-6alkyl, CN, CF3WITH1-6alkyl, -S - C1-6alkyl, -SO-Cl - C1-6alkyl, -SO2-Cl-C1-6alkyl, C1-6alkoxy and up to10aryloxy, n= 1, 2, or 3; R is a direct bond; And - piperazinil, X1and X2IS N; Y IS-SO2-; Z IS - N(OH)-CHO; Q - CH2-; R1- H, C1-6alkyl, C5-7cycloalkyl until10aryl, until10heteroaryl until1-2aralkyl or until12heteroallyl, R4- H, C1-6alkyl, and others; R2- H, C1-6alkyl, or together with R1- carbocyclic or heterocyclic Spiro 5-, 6 - or 7-membered ring containing at least one heteroatom selected from N, O or S, and the group Q can be associated either with R1or R2with the formation of 5,- 6 - or 7-membered alkyl or heteroalkyl ring that includes one or more O, S or N

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

The invention relates to compounds of formula (I)

< / BR>
in which Ar1denotes a heterocyclic group, which represents a pyrazole which may be substituted by one or more radicals R1, R2or R3; Ar2denotes phenyl, naphthyl or tetrahydronaphthyl, each of which optionally is substituted by one to three groups R2; L denotes a saturated or unsaturated, branched or unbranched carbon C1-C10chain; in which one or more methylene groups are optionally independently replaced by O, NH or S, and in which the linking group is optionally substituted by 0-2 of doxography; Q has a value selected from a range of: a) phenyl, naphthyl, pyridine, imidazole, Piran, etc. b) tetrahydropyran, morpholine, thiomorpholine, thiomorpholine and t
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