Compounds, pharmaceutical composition, method of preventing neuronal cell death, the method of prevention

 

The present invention relates to a new compound, which is characterized by a high degree of antagonism in relation to calcium, in particular neurovisualising antagonism in relation to calcium. This invention relates to a compound according to the following formula, its salt or hydrate.

In this formula, Ar denotes optionally substituted 5 to 14-membered aromatic ring and the like; ring a is any ring, selected from piperazine, homopiperazine, piperidine and the like; ring b is optionally substituted C3-14hydrocarbon ring, and the like; E. means a simple link, a group of the formula-CO -, and the like; X is a simple bond, oxygen atom and the like; R1means a hydrogen atom, halogen atom, hydroxyl group and the like; D1D2, W1and W2have identical or different meanings and represent each simple bond or optionally substituted C1-6alkylenes chain. 4 C. and 46 C.p. f-crystals, 3 ill., 1 PL.

The technical field,

The present invention relates to a new compound useful as antiobesity, containing a specified substance; in particular, this invention relates to a new compound, which is neionizirovanny a calcium antagonist, in particular a new compound has inhibitory activity against calcium channel P/Q-type and/or N-type, and so on,

Background of the invention

Bleeding in the brain diagnosed each year in Japan at 1.4 million or more persons, and estimated costs for the treatment of this disease are approximately two billion yen. Mortality from bleeding in the brain occupies the second place after cancer, and also bleeding in the brain is the main reason that people (patients) are bedridden, suffering from serious secondary diseases. A distinctive feature of the treatment of bleeding in the brain is the need for rapid response to acute stage of the disease, and the effectiveness of treatment at this stage depends on the preservation of life and vital functions of the patient, as well as the prevention of secondary diseases.

As medicines to improve blood flow recommended several drugs, such as ozagrel sodium (inhibitor of thromboxane-with the t-PA (alteplaza: activator tissue plasminogen you need to type in the first 3 hours after hemorrhage), which is a thrombolytic agent, and others. However, modern methods of treatment described in the publications (1)-(6) are very complex and depend on the subjective assessment of the specialist on the basis of his knowledge and experience. Namely, in the case of a heart attack brain due to the formation of a blood clot, you should first check the function of the respiratory organs, measure blood pressure and to produce a blood transfusion (1). It is necessary to periodically measure the gas content in blood and blood pressure (2). In the acute stage of the disease is high blood pressure, but in the absence of complications on heart and kidney treatment aimed at lowering blood pressure, does not hold (3). Then if in computed tomography is not observed range of weak absorption in the early acute stage of the disease, use of thrombolytic agent "urokinase" (4). In case of contraindications to the use of these funds upon expiration of 24 hours after hemorrhage, needy entity type "ozagrel sodium" or "argatroban". However, argatroban contraindicated in case of heart attack gaps (5). To prevent the development of edema EOS used drugs is poor, often there is a risk of increasing bleeding due to the pharmacological action of such funds. Therefore, to correctly apply these funds can only highly qualified medical specialists.

On the other hand, in the scientific literature there is evidence that compounds with inhibitory activity against calcium channels M-type or P/Q-type, can be used as a means of preventing neuronal cell death or protecting the nerve cells of the brain, the means to treat or suppress symptoms (improvement) in the case of nervous diseases, acute ischemic stroke, head trauma, Alzheimer's disease, metabolic disorders of brain blood flow, dysfunction of the brain or of pain, as an antispasmodic means, tools for the treatment or suppression of symptoms in schizophrenia, means for prevention, treatment or suppression condition in the case of migraine, epilepsy, manic-depressive psychosis, nerve degenerative diseases (Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease), cerebral ischemia, epileptica) and diabetic neuropathy, and means to prevent, treat or suppress symptoms of brain edema, state of fear, schizophrenia, diabetic neuropathy and migraine.

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

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

(3) Ischemia - loss of nerve cells in the brain: Advances in Pharmacology, 22, 271-297, 1991.

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

(5) Metabolic disorder of brain blood flow: Nichiyakurishi, 85, 323-328, 1985.

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

(7) an Analgetic: Drug of the Future, 23(2), 152-160, 1998.

(8) cerebral Ischemia, migraine, epilepsy, manic-depressive psychosis: Casopis Lekau Ceskych., 130 (22-23), 625-630, 1991.

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

(10) Swelling of the brain: Brain Research, 776, 140-145, 1997.

(11) State of fear (generalized state of fear), schizophrenia: Jyunkanseigyo (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.

Description of the invention

With Uch is, the which has an excellent effect in the treatment and decrease the intensity of symptoms of acute ischemic stroke brain, for which there is no known suitable drug, and which is safe because it does not cause bleeding, purposefully acting on neuroanatomically antagonist of voltage-dependent calcium channel, impacting directly on nerve cells and prevents future development of myocardial infarction. In the result of the research, the authors of the present invention have synthesized a new nitrogen-containing compound of the formula (I), its salt and a hydrate and then unexpectedly found that these compounds, their salts or hydrates effectively prevent the death of nerve cells and protects the nerve cells of the brain due to antagonism against calcium channel P/Q-type or N-type, while they are much less cause myocardial cells, are characterized by low toxicity and are excellent in safety in comparison with known antagoniste calcium.

In the formula AG means (1) C6-14aromatic hydrocarbon cyclic group which may be samegroup, substituted C6-14aromatic hydrocarbon cyclic group which may be substituted, or (4) C1-6alkyl group, substituted 5 to 14-membered aromatic heterocyclic group which may be substituted; ring a represents pieperazinove ring, homopiperazine ring, piperidine ring, homopiperazine ring, pyrolidine ring or diazabicyclo[2,2,1]heptane ring, which may be respectively substituted; ring b means (1) With the3-14hydrocarbon ring which may be substituted, or (2) 5-14-membered heterocyclic ring which may be substituted; E means (1) a simple link, a group of the formula (2) -CO - or (3) -CH(OH)-; X is (1) a direct link, (2) an oxygen atom, (3) a sulfur atom, (4) C1-6alkylenes chain which may be substituted, a group of the formula (5) -NR2- (where R2means a hydrogen atom or a C1-6alkyl group, a C3-8cycloalkyl group, a lower acyl group or a C1-6alkylsulfonyl group which may be substituted), (6) -CO-, (7) -COO-, (8) -OOS-, (9) -CONR3- (where R3means a hydrogen atom or a C1-6alkyl group which may be substituted), (10) -NR4CO- (where R4means a hydrogen atom or C1-6alkyl group which may be substituted), (14) -NR6SO- (where R6means a hydrogen atom or a C1-6alkyl group which may be substituted), (15) -SO2NR7- (where R7means a hydrogen atom or a C1-6alkyl group which may be substituted), (16) -NR8SO2- (where R8means a hydrogen atom or a C1-6alkyl group which may be substituted), (17) >C=N-OR9(where R9means a hydrogen atom or a C1-6alkyl group which may be substituted), (18) -NR10W3-O- (where R10means a hydrogen atom or a C1-6alkyl group, a C3-8cycloalkyl group, a lower acyl group or a C1-6alkylsulfonyl group which may be substituted, and W3means C1-6alkylenes group which may be substituted), (19) -NH-CO-NH-, (20) -NH-CS-NH-, (21) -C(=NR15)NR16- (where R15and R16have identical or different meanings and represent a hydrogen atom, a nitrile group, a C1-6alkyl group, a C2-6alkenylphenol group3-8cycloalkyl group or3-8cycloalkenyl group), (22) -NHC(=NH)-, (23) -O-CO-S-, (24) -S-CO-O-, (25) -LLC-, (26) -NHCOO-, (27) -OCONH-, (28) -CO(CH2)mO- (where m is 0 or a whole which means (1) a hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) C1-6alkyl group which may be substituted by one or more groups selected from hydroxyl group, halogen atom and nitrile group, (5)2-6alkenylphenol group which may be substituted by one or more groups selected from hydroxyl group, halogen atom and nitrile group, (6) C2-6alkylamino group which may be substituted by one or more groups selected from hydroxyl group, halogen atom and nitrile group, (7)3-8cycloalkyl group which may be substituted by one or more groups selected from hydroxyl group, halogen atom and nitrile group, (9) C1-6alkoxy-C1-6alkyl group, (10) amino-C1-6alkyl group in which the nitrogen atom may be substituted, (11) a group of the formula-N(R11R12- (where R11and R12have identical or different meanings and represent a hydrogen atom or a C1-6alkyl group), (12) Uralkaliy group, (13) morpholinyl group, (14) thiomorpholine group, (15) piperidino group, (16) pyrrolidinyloxy group, or (17) piperazinilnom group; and D1D2, W1and W2and which may be substituted; provided that the above definition excluded 1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine; 1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(3-pertenece)ethyl]piperazine and 1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-pertenece)ethyl]piperazine.

The first object of the present invention is 1), the compound of the above formula (I), its salt or hydrate, where 2) AG mean6-14aromatic hydrocarbon ring or a 5 to 14-membered aromatic heterocyclic ring which may be substituted, 3) AG can mean a thiophene ring or benzene ring which may be substituted, 4) AG mean6-14aromatic hydrocarbon ring or a 5 to 14-membered aromatic heterocyclic ring which may be substituted by one or more groups selected from nitrile group and halogen atom, 5) AG can mean a thiophene ring or benzene ring which may be substituted by one or more groups selected from nitrile group and halogen atom respectively, 6) ring And can be piperazinone ring, homopiperazine ring or piperidinyl ring, 7) ring And can be piperazinone ring may be substituted by one or more groups, selected from hydroxyl group, halogen atom, ceanography, C1-6alkyl group which may be substituted, C2-6alkenylphenol group which may be substituted With2-6alkenylphenol group which may be substituted, C1-6CNS group which may be substituted With2-6alkenylacyl, which may be substituted, C1-6alkylcarboxylic group which may be substituted With2-6alkenylamine group which may be substituted, C1-6alkoxycarbonyl group which may be substituted, and C2-6alkenylcarbazoles group which may be substituted, 9) ring In mean6-14aromatic hydrocarbon ring or a 5 to 14-membered aromatic heterocyclic ring which may be substituted, 10) ring can mean a benzene, thiophene, pyridine, 1,4-benzodioxan, indole, benzothiazole, benzoxazole, benzimidazole, 2-keto-1-benzimidazole, thiazole, oxazole, isoxazol, 1,2,4-oxadiazole, indanan, benzofuran, quinoline, 1,2,3,4-tetrahydroquinolin, naphthalene or 1,2,3,4-tetrahydronaphthalen, which may be substituted, 11) ring In mean6-14aromatic hydrocarbon ring or a 5 to 14-membered aromatic heteros is from a halogen atom, nitrile group, a C1-6alkyl group, a lower acyl group, a C1-6alkylsulfonyl group and aranceles group, 12) D1and D have identical or different meanings and can mean (1) a simple link or (2) C1-6alkylenes chain which may be substituted by one or more groups selected from hydroxyl group, halogen atom, nitrile group, a C1-6alkyl group, a C2-6alkenylphenol group and C1-6CNS group, 13) E can mean a simple link, 14) D1and D2can be C1-6alkylenes chain and E can mean a simple link, 15) partial structure of-D1-E-D2- can be C1-4alkylenes group 16) W1and W2can have identical or different meanings and represent (1) a simple link or (2) C1-6alkylenes chain which may be substituted by one or more groups selected from hydroxyl group, halogen atom, nitrile group, a C1-6alkyloxy and C2-6alkenylacyl, 17) W1can mean (1) a simple link or (2) C1-6alkylenes chain which may be substituted by one or more groups selected from (i) nitrile group, (ii) C1-6al is Inoi group and2-6alkenylacyl, and (iii)2-6alkenylphenol group; and W2may mean a simple link, 18) W1and W2can have the same or different values, and each of them represents C1-6alkylenes chain, substituted by one or more groups selected from C1-6alkyl groups and C2-6alkenylphenol group, in addition, the above C1-6an alkyl group and/or C2-6Alchemilla group can be connected to each other to form a ring or C1-6an alkyl group or2-6Alchemilla group can be connected with the ring or X with the formation of rings 19) X can mean (1) a simple link, (2) an oxygen atom, a group of the formula (3) -NR2- (where R2means a hydrogen atom, a C1-6alkyl group, a C3-8cycloalkyl group, a lower acyl group or a C1-6alkylsulfonyl group which may be substituted), (4) -NR10-W3-O- (where R10means a hydrogen atom, a C1-6alkyl group, a C3-8cycloalkyl group, a lower acyl group or a C1-6alkylsulfonyl group which may be substituted; and W3means C1-6alkylenes group which may be substituted) or (5) -NH-SO2-, 20) X is lilou group, With3-8cycloalkyl group, a lower acyl group or a C1-6alkylsulfonyl group which may be substituted) or (3) -NH-SO2-, 21) partial structure-W1-X-W2- can be C1-6alkylenes group which may be substituted, 22) W1means C1-6alkylenes chain which may be substituted; W2means of a simple bond; and X is oxygen or a group of the formula-NR2- (where R2has the above values), 23) W1may be substituted for any one or more of any group selected from (1) nitrile group, (2) C1-6alkyl group which may be substituted C1-6alkyloxyaryl or2-6alkenylacyl, and (3) C2-6alkenylphenol group; and R2can be C1-6alkyl group which may be substituted, 24) R1can be C1-6alkyl group, 25) R1could mean a methyl group, ethyl group, n-sawn group or isopropyl group, 26) the compound of the above formula 1) is a compound of the formula:

where R1has the above meanings; R13and R14have identical or different meanings and represent the which may be substituted by one or more groups, chosen from hydroxyl groups and halogen atom, (6) C1-6CNS group which may be substituted by one or more groups selected from hydroxyl group, halogen atom and C1-6alkoxycarbonyl group, (7) a nitro-group, (8) an amino group which may be substituted, (9) cyano, (10) carboxyl group, (11) C1-6alkoxycarbonyl group, (12) C1-6tolkatelnye group, (13) C1-6alkylsulfonyl group, (14) a lower acyl group, (15)6-14aromatic hydrocarbon cyclic group which may be substituted, (16) 5 to 14-membered aromatic heterocyclic group which may be optionally substituted, (17) alloctype or (18) aralkylated or (19) are elements of R13or R14can be connected to each other with the formation of (i) aliphatic ring which may be substituted, (ii) heterocyclic ring which may be substituted, or (iii) alkylenedioxy; n indicates 0 or an integer from 1 to 3; R denotes an integer from 1 to 6; q indicates an integer from 1 to 6 and r is 0 or an integer from 1 to 5; provided, which of the above definitions excluded 1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(4-tometal-4-(2-thienyl)hexyl]-4-[2-(3-pertenece)ethyl]piperazine; 27) the compound of the above formula 1) is a compound of the formula:

where R1and R2have the values indicated above; R13and R14have identical or different meanings and represent (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) mercaptopropyl, (5) C1-6alkyl group which may be substituted by one or more groups selected from hydroxyl groups and halogen atom, (6) C1-6CNS group which may be substituted by one or more groups selected from hydroxyl group, halogen atom and C1-6alkoxycarbonyl group, (7) a nitro-group, (8) an amino group which may be substituted, (9) cyano, (10) carboxyl group, (11) C1-6alkoxycarbonyl group, (12) C1-6tolkatelnye group, (13) C1-6alkylsulfonyl group, (14) a lower acyl group, (15)6-14aromatic hydrocarbon cyclic group which may be substituted, (16) 5 to 14-membered aromatic heterocyclic group which may be substituted, (17) alloctype, (18) aralkylated or (19) are elements of R13or R14can be connected to each other with the formation of (i the but or (iii) alkylenedioxy; n indicates 0 or an integer from 1 to 3; R denotes an integer from 1 to 6; q indicates an integer from 1 to 6; r is 0 or an integer from 1 to 5, and 28) the compound of the above formula 1) is any compound selected from the group including

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]Pipa is indolinyl)piperazine

4-[4-(1-methyl-1H-benzo[d]imidazol-2-yl)-1,4-diazepan-1-yl]-1-isopropyl-1-phenylbutazone;

4-[4-(1-ethyl-1H-benzo[d]imidazol-2-yl)-1,4-diazepan-1-yl]-1-isopropyl-1-phenylbutazone;

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-phenylbutyramide and

4-[4-(4-benzylpiperidine)piperidinyl]-1-isopropyl-1-phenylbutyramide.

The second object of the present invention is 29) a pharmaceutical composition comprising a compound of the formula:

where AG means (1) With the6-14aromatic hydrocarbon cyclic group which may be substituted, (2) 5-14-membered aromatic heterocyclic group which may be substituted, (3)1-6alkyl group, samisen the alkyl group, substituted 5 to 14-membered aromatic heterocyclic group which may be substituted; ring a represents respectively pieperazinove ring, homopiperazine ring, piperidine ring, homopiperazine ring, pyrolidine ring or diazabicyclo[2,2,1]heptane ring which may be substituted; ring b is (1) C3-14hydrocarbon ring which may be substituted, or (2) 5-14-membered heterocyclic ring which may be substituted; E means (1) a simple link, a group of the formula (2) -CO - or (3) -SN(OH); X indicates (1) a simple link, (2) an oxygen atom, (3) a sulfur atom, (4) C1-6alkylenes chain which may be substituted, a group of the formula (5) -NR2- (where R2means a hydrogen atom or a C1-6alkyl group, a C3-8cycloalkyl group, a lower acyl group or a C1-6alkylsulfonyl group which may be substituted), (6) -CO-, (7) -COO-, (8) -OOS-, (9) -CONR3- (where R3means a hydrogen atom or a C1-6alkyl group which may be substituted), (10) -NR4CO- (where R4means a hydrogen atom or a C1-6alkyl group which may be substituted), (11) -SO-, (12) -SO2-, (13) -SONR5- (where R5means a hydrogen atom ia or C1-6alkyl group which may be substituted), (15) -SO2NR7(where R7means a hydrogen atom or a C1-6alkyl group which may be substituted), (16) -NR8SO2- (where R8means a hydrogen atom or a C1-6alkyl group which may be substituted), (17) >C=N-OR9(where R9means a hydrogen atom or a C1-6alkyl group which may be substituted), (18) -NR10W3-O- (where R10means a hydrogen atom or a C1-6alkyl group, a C3-8cycloalkyl group, a lower acyl group or a C1-6alkylsulfonyl group which may be substituted, and W3means C1-6alkylenes group which may be substituted), (19) -NH-CO-NH-, (20) -NH-CS-NH-, (21) -C (=NR15)NR16- (where R15and R16have identical or different meanings and represent a hydrogen atom, a nitrile group, a C1-6alkyl group, a C2-6alkenylphenol group3-8cycloalkyl group or3-8cycloalkenyl group), (22) -NHC(=NH)-, (23) -O-CO-S-, (24) -S-CO-O-, (25) -LLC-, (26) -NHCOO-, (27) -OCONH-, (28)- (CH2)mO- (where m is 0 or an integer from 1 to 6), (29) -SNON - or (30) -SNON(CH2)nO- (where n is 0 or an integer from 1 to 6); R1o be substituted by one or more groups, selected from hydroxyl group, halogen atom and nitrile group, (5)2-6alkenylphenol group which may be substituted by one or more groups selected from hydroxyl group, halogen atom and nitrile group, (6) With2-6alkylamino group which may be substituted by one or more groups selected from hydroxyl group, halogen atom and nitrile group, (7)3-8cycloalkyl group which may be substituted by one or more groups selected from hydroxyl group, halogen atom and nitrile group, (9) C1-6alkoxy-C1-6alkyl group, (10) amino-C1-6alkyl group in which the nitrogen atom may be substituted, (11) a group of the formula-N(R11R12- (where R11and R12have identical or different meanings and represent a hydrogen atom or a C1-6alkyl group), (12) Uralkaliy group, (13) morpholinyl group, (14) thiomorpholine group, (15) piperidino group, (16) pyrrolidinyloxy group, or (17) piperazinilnom group; and D1D2, W1and W2have identical or different meanings and represent (1) a simple link or (2) C1-6alkylenes chain which may be substituted; PR is noxi)ethyl]piperazine; 1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(3-pertenece)ethyl]piperazine and 1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-pertenece)ethyl]piperazine; its salt or hydrate, and the above composition 29) can be 30) a calcium antagonist, 31) neionizirovanny a calcium antagonist, 32) inhibitor calcium channel P/Q-type and/or N-type, 33) means for treatment, prevention and suppression of disease symptoms, susceptible to inhibition of calcium channel P/Q-type and N-type, 34) means preventing neuronal cell death and protects the nerve cells of the brain, 35) means for treatment, prevention or suppression of symptoms of nervous diseases, such as 36) acute ischemic stroke, brain hemorrhage, heart attack, brain, head injury, loss of nerve cells in the brain, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, a metabolic disorder of brain blood flow, impaired brain function, pain, spasm, schizophrenia, migraine, epilepsy, manic-depressive syndrome, degenerative nerve diseases, cerebral ischemia, dementia caused by AIDS, brain swelling, the condition of the country is 37) analgetikom.

The present invention relates to a method for prevention, treatment or suppression of symptoms of sablania, in which the effective antagonism in relation to calcium, neionizirovanny antagonism in relation to calcium and / or inhibitory activity against calcium channel P/Q-type and/or N-type by introducing the patient a pharmacologically effective amount of the compounds of formula (I), its salt or hydrate.

The present invention relates to a method for prevention, treatment or suppression of symptoms of nervous disease or pain.

In addition, the present invention relates to the use of compounds of formula (I), its salt or hydrate to obtain a calcium antagonist, neurovisualising a calcium antagonist, an inhibitor of calcium channel P/Q-type and/or N-type, the means for the treatment, prevention or suppression of disease symptoms, susceptible to the inhibitory activity against calcium channel P/Q-type and/or N-type, and means preventing neuronal cell death or protecting the nerve cells of the brain.

In addition, the present invention relates to the use of compounds of formula (I), its salt or hydrate for the manufacture of tools designed to lelanda any of the diseases, selected from such as acute ischemic stroke, brain hemorrhage, heart attack, brain, head injury, loss of nerve cells in the brain, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, a metabolic disorder of brain blood flow, impaired brain function, pain, spasm, schizophrenia, migraine, epilepsy, manic-depressive syndrome, degenerative nerve diseases, cerebral ischemia, dementia caused by AIDS, brain swelling, state of fear, diabetic neuropathy, dementia due to vascular lesions of the brain and multiple sclerosis.

Below is the meaning of the symbols and terms used in the description of the invention to this application, and provides a detailed description of the present invention.

For convenience of description in this application, the structural formula of the compound represents a specific isomer, but in the scope of the present invention includes all geometric isomers that exist within the structure of this compound, optical isomers based on asymmetric carbons, stereoisomers, tautomers and the like as well as mixtures of isomers. Nastoi mixture. Therefore, compounds of the present invention may include optically active and racemic forms having in a molecule an asymmetric carbon atom, but are not limited to these forms. In addition, the compounds of the present invention are characterized by the presence of crystalline polymorphism, but are not limited to these forms, and these compounds may exist in crystalline form in crystal form or a mixture of crystals and may be a hydrate, in addition to the anhydride. The so-called metabolite, which is formed as a result of decomposition in vivo of the compounds of the present invention, is also in the scope of the present invention.

The term "and/or" in the description to this application includes as is "and" and is "or". For example, "a and/or b" has two meanings, "and" and "or", and can be used any of the listed values.

The term "nervous disease" in the description to this application mainly means acute ischemic stroke, brain hemorrhage, heart attack, brain, head injury, loss of nerve cells in the brain, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclera the main brain pain, spasm, schizophrenia, migraine, epilepsy, manic-depressive syndrome, degenerative nerve diseases, cerebral ischemia, dementia caused by AIDS, brain swelling, state of fear, diabetic neuropathy, dementia due to vascular lesions of the brain and multiple sclerosis.

The term "analgetic" in the description to this application means a drug that reduces or relieves pain by altering perception of stimulation of pain receptors and without causing drug stunning and unconsciousness.

The term "halogen atom" in the description to this application means atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, preferably fluorine atom, chlorine atom and bromine atom, more preferably a fluorine atom and a chlorine atom.

The term "C1-6alkyl group" in the description to this application means an alkyl group having 1-6 carbon atoms, and preferred examples of such groups include alkyl groups with linear or branched chain such as methyl, ethyl, n-sawn, ISO-propyl, n-bucilina, isobutylene, second-bucilina, tert-bucilina, n-pencilina, 1,1-d is, -methyl-2-ethylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1-popypropylene, 1-methylbutyl, 2-methylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl and 3-methylpentyl group.

The term "C2-6Alchemilla group" in the description to this application means alkenylphenol group having 2-6 carbon atoms, preferably a linear or branched chain, such as vinyl, allyl, 1-protanilla, 2-protanilla, Isopropenyl, 2-methyl-1-protanilla, 3-methyl-1-protanilla, 2-methyl-2-protanilla, 3-methyl-2-protanilla, 1-bucinellina, 2-bucinellina, 3-bucinellina, 1-penttila, 1-examilia, 1,3-hexadienyl and 1,6-hexadienyl group.

The term "C2-6Alchemilla group" in the description to this application means alkylamino group having 2-6 carbon atoms, preferably a linear or branched chain, such as etinilnoy, 1-proponila, 2-proponila, 1-Butyrina, 2-Butyrina, 3-Butyrina, 3-methyl-1-proponila, 1-ethinyl-2-proponila, 2-methyl-3-proponila 1-penicilina, 1-hexylamine, 1,3-hexadienyl and 1,6-hexadienyl the>-6alkyloxy", in which the oxygen atom is associated with a group that has the values specified above for C1-6alkyl group, and preferred examples of such groups are methoxy, ethoxy, n-propoxy, isopropoxy, sec-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentylamine, sec-pentyloxy, n-hexyloxy, isohexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropylene, 2-ethylpropoxy, 1-methyl-2-ethylpropoxy, 1-ethyl-2-methylpropoxy, 1,1,2-trimethylpropane, 1,1-Dimethylbutane, 1,2-Dimethylbutane, 2,2-Dimethylbutane, 2,3-dimethylbutylamino, 1,3-dimethylbutylamino, 2-ethylbutane, 1,3-Dimethylbutane, 2-methylpentane, 3 methylpentane, hexyloxy and other groups.

The term "C1-6alkenylacyl" in the description of the invention of the present application means a group in which an oxygen atom is associated with a group that has the values specified above for C1-6alkenylphenol group, and preferred examples of such groups are vinyloxy, allyloxy, 1 propenyloxy, 2-propenyloxy, isopropanolamine, 2-methyl-1-propenyloxy, 3-methyl-1-propenyloxy, 2-methyl-2-propenyloxy, 3-methyl-2-propenyloxy, 1 butenyloxy, 2-butenyloxy, 3 butenyloxy, 1 pentyloxy, 1 hexenoate, 1,3-Gex is retene to this application means cycloalkyl group, in which the ring is formed of 3-8 carbon atoms, and preferred examples of such groups are cyclopropyl, cyclobutyl, cyclopentamine, tsiklogeksilnogo, cycloheptyl, cyclooctyl and other groups. In addition, the term "C3-8cycloalkane" in the description to this application means a ring (cyclic connection), corresponding to the above With3-8cycloalkyl group.

The term "C3-8cycloalkenyl group" in the description to this application means3-8cycloalkenyl group in which the ring is formed of 3-8 carbon atoms, and examples of such groups are groups of the formula:

The term "aromatic cyclic group" in the description to this application means6-14aromatic hydrocarbon tsiklicheskimi uglevodorodno cyclic group" include monocyclic, dziklicska or tricyclic6-14aromatic hydrocarbon groups such as phenyl, angenlina, 1-naftalina, 2-naftalina, atulananda, heptylaniline, biphenylene, Indianola, acenaphthylene, fluoroaniline, phenylaniline, phenanthroline, antarctilyne, Cyclopentasiloxane, benzocyclobutene and similar groups.

(2) examples of the "5 to 14-membered aromatic heterocyclic group" include monocyclic, disilicate or tricyclic 5 to 14-membered aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen atoms, sulfur and oxygen, and are, for example:

(i) aromatic heterocyclic rings containing nitrogen, such as pyrrolidine, perederina, pyridinoline, pyrimidinyl, piratininga, triazoline, tetrataenia, benzotriazolyl, pyrazolidine, imidazolidine, benzimidazolinone indayla, isoindoline, indolizinyl, polylina, indazolinone, kinolinna, izochinolina, hyalinella, talasila, naphthylidine, khinoksalinona, chinadaily, indolenine, peridiniella, imidazolidinyl, pirazinamida, accidenily, phenanthridinone, imidazopyrimidines and pyrazolopyrimidine groups;

(ii) aromatic heterocyclic ring containing sulfur, such as thienyl and benzothiazoline groups;

(iii) aromatic heterocyclic ring containing oxygen, such as furilla, Pernilla, cyclopentadienyls, benzofuranyl and isobenzofuranyl group, and

(iv) an aromatic heterocyclic ring containing 2 or more different heteroatoms selected from nitrogen atoms, sulfur and oxygen, such as thiazolidine, isothiazolinone, benzothiazoline, benzothiadiazole, phenothiazinyl, isoxazolyl, furazolidine, phenoxystyrene, oxazolidine, benzoxazolinone, oxadiazolidine, pyrazoloacridine, imidazothiazole, thienopyrimidine, properally, pyridoxamine group.

The term "C3-14hydrocarbon ring" in the description to this application means3-8cycloalkane,3-8cycloalken or6-14aromatic hydrocarbon ring having the values specified above for C3-8cycloalkane,3-8cycloalkene and C6-14aromatic hydrocarbon ring.

The term "5 to 14-membered heterocyclic ring" in the description of sobratema, selected from nitrogen atoms, sulfur and oxygen, and this definition includes aromatic heterocyclic rings and non-aromatic heterocyclic ring. In this case, (1) the "5 to 14-membered aromatic heterocyclic ring" has the values given above for 5 to 14-membered aromatic heterocyclic ring. In addition, (2) the preferred "5 to 14-membered non-aromatic heterocyclic ring" include 5 to 14-membered non-aromatic heterocyclic ring, as pyrolidine, pyrrolinone, piperidino, pieperazinove, imidazoline, pyrazolidine, imidazolidine, morpholine, tertrahydrofuran ring, tetrahydropyrrole, aziridine, oxirane, oxathiolane, Spiridonova and other ring, and condensed rings, such as phthalimide, operations and other rings.

The term "hydrocarbon group" in the description to this application means C1-6alkyl group, a C2-6alkenylphenol group2-6alkylamino group3-8cycloalkyl group3-8cycloalkenyl group or6-14aromatic hydrocarbon cyclic group, which have the above values.

Values of Ah

In Narodnoy cyclic group, which may be substituted, (2) 5-14-membered aromatic heterocyclic group which may be substituted, (3)1-6alkyl group, substituted C6-14aromatic hydrocarbon cyclic group which may be substituted, or (4) C1-6alkyl group, substituted 5 to 14-membered aromatic heterocyclic group which may be substituted.

Examples of the above "C6-14aromatic hydrocarbon cyclic group" are preferably phenyl, pentylaniline, angenlina, naftalina, 1,2,3,4-tetrahydronaphthalene, atulananda, heptylaniline, benzocyclobutene, terranella, phenanthroline and other groups, more preferably phenyl, naftalina and other groups.

Preferred examples of the "5 to 14-membered aromatic heterocyclic group" are pyrrolidine, perederina, pyridinoline, pyrimidinyl, piratininga, triazoline, tetrataenia, benzotriazolyl, pyrazolidine, imidazolidine, benzimidazolyl, indayla, isoindoline, indolizinyl, polylina, indazolinone, kinolinna, izochinolina, hyalinella, talasila, naphthylidine, khinoksalinona, chinadaily, CIGNA, garbatella, carbazolyl, pyrimidinyl, phenanthroline, ventimilia, imidazopyridine, imidazopyrimidines pyrazolopyrimidinone, thienyl, benzothiazoline, furilla, Pernilla, cyclopentadienyls, benzofuranyl, isobenzofuranyl, thiazolidine, isothiazolinone, benzothiazoline, benzothiadiazole, phenothiazinyl, isoxazolyl, furazolidine, phenoxystyrene, oxazolidine, benzoxazolinone, oxadiazolidine, pyrazoloacridine, imidazothiazole, thienopyrimidine, properally, pyridoxamine and other groups, more preferred thienyl, Peregrina and other groups and the most preferred thienyl group.

When AG means "optionally substituted C6-14aromatic hydrocarbon cyclic group or optionally substituted 5 to 14-membered aromatic heterocyclic group", examples of "substituents" are (i) hydroxyl group, (ii) halogen atom (e.g. fluorine atom, chlorine, bromine and iodine), (iii) nitrile group, (iv) C1-6an alkyl group (preferably methyl, ethyl, n-sawn, ISO-propyl, n-bucilina, isobutylene, second-bucilina, tert-bucilina, n-pentyl is strong, 1-methyl-2-ethylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1-popypropylene, 1-methylbutyl, 2-methylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl and other groups), (v)2-6Alchemilla group (preferably vinyl, allyl, 1-protanilla, 2-protanilla, Isopropenyl, 2-methyl-1-protanilla, 3-methyl-1-protanilla, 2-methyl-2-protanilla, 3-methyl-2-protanilla, 1-bucinellina, 2-bucinellina, 3-bucinellina, 1-penttila, 1-examilia, 1,3-hexadienyl, 1,6-hexadienyl and other groups), (vi) C2-6Alchemilla group (preferably etinilnoy, 1-proponila, 2-proponila, 1-Butyrina, 2-Butyrina, 3-Butyrina, 3-methyl-1-proponila, 1-ethinyl-2-proponila, 2-methyl-3-proponila, 1-penicilina, 1-hexylamine, 1,3-hexadienyl, 1,6-hexadienyl and other groups), (vii) C1-6CNS group (preferably methoxy, ethoxy, n-propoxy, isopropoxy, sec-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentylamine, sec-pentyloxy, n-hexyloxy, isohexyl, 1,1-dimethylpropyl, 1,2-DIMETHYLPROPANE, is ethylbutane, 1,2-Dimethylbutane, 2,2-Dimethylbutane, 2,3-dimethylbutylamino, 1,3-dimethylbutylamino, 2-ethylbutane, 1,3-Dimethylbutane, 2-methylpentane, 3 methylpentane, hexyloxy and other groups), (viii) C1-6allylthiourea (preferably methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutyric, sec-butylthio, tert-butylthio, n-pentylthio, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1 ethylpropyl, 2-ethylpropyl, n-hexylthio, 1-methyl-2-ethylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1 profileproperty, 1 methylbutyl, 2-methylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 2-methylphenylthio, 3 methylphenylthio and other groups), (ix) C1-6alkoxycarbonyl group, (x) hydroxyl-C1-6alkyl group, (xi) halogen-substituted C1-6alkyl group, (xii) hydroxyimino-C1-6alkyl group, (xiii) nitro-group, (xiv) amino group in which the nitrogen atom may be substituted, (xv) carnemolla group in which the nitrogen atom may be substituted, (xvi) Altamarena group in which the nitrogen atom may be substituted, (xvii) lower acyl group, (xviii) an aromatic acyl group, (xix) C1-6alkylsulfonyl (a) a hydroxyl group, (b) halogen atom, (C) nitrile group, (d) C1-6alkyl group, (e) C1-6alkylsulfonyl group, (f) C1-6CNS group, (g) C1-6allylthiourea etc., more preferably a nitrile group or a halogen atom (e.g. fluorine atom, and so on).

Examples of preferred "C6-14aromatic hydrocarbon cyclic group which may be substituted" or "5 to 14-membered aromatic heterocyclic group which may be substituted" in the definition of Hypertension include thiophene, pyridine, benzene or naphthalene ring which may be substituted by one or more groups selected from a halogen atom and ceanography. The most preferred example is a thiophene ring which may be substituted by one or more groups selected from a halogen atom and ceanography, namely the ring of the formula:

where R13a, R13band R13chave identical or different meanings and represent a hydrogen atom, halogen atom or cyano.

In those cases, when in the compound of formula (I) according to the present invention Ah means "C1-6alkyl group, substituted C6-14aromatic uglevodorov the aromatic heterocyclic group, which may be substituted", "C6-14aromatic hydrocarbon cyclic group which may be substituted", or "5 to 14-membered aromatic heterocyclic group which may be substituted" have the meanings specified above for C6-14aromatic hydrocarbon cyclic group which may be substituted, or 5 to 14-membered aromatic heterocyclic group which may be substituted, respectively. C1-6alkyl group substituted by such groups, means C1-6alkyl group substituted by the above groups. In this case, preferred examples of the "C1-6alkyl groups are methyl, ethyl, n-sawn, ISO-propyl, n-bucilina, isobutylene, second-bucilina, tert-bucilina, n-pencilina, 1,1-dimethylpropylene, 1,2-dimethylpropylene, 2,2-dimethylpropylene, 1-ethylpropyl, 2-ethylpropyl, n-exilda, 1-methyl-2-ethylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1-popypropylene, 1-methylbutyl, 2-methylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl and other groups. Predpochitayutsa benzyl, penicilina, phenylpropionate, naphthylethylene, naphthylethylene, naphtylamine, pyridylmethylene, personalitly, pyrimidinylidene, peralynna, imidazolylidene, parasaissetia, hanalilolilo, izochinolina, purpurella, thienylmethyl, triazolylmethyl and other groups which may be optionally substituted by one or more groups selected from nitrile group, halogen atom (e.g. fluorine atom, chlorine, bromine, iodine and so on) and similar groups.

Preferred examples of "C1-6alkoxycarbonyl group" in the definition of AG are methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, second-propoxycarbonyl, n-butoxycarbonyl, solutionline, second-butoxycarbonylmethylene, tert-butoxycarbonylmethylene, n-ventilatsiooniga, isobutylacetophenone, second-ventilatsiooniga, tert-ventilatsiooniga, n-hexyloxymethyl, isohexadecane, 1,2-dimethylpropyleneurea, 2-ethylpropylamine, 1-methyl-2-ethylpropylamine, 1-ethyl-2-ethylpropylamine, 1,1,2-trimethylhexamethylene, 1,1-dimethylphosphoramidocyanidate, 3-methylbenzyloxycarbonyl and other groups.

Preferred examples of the above hydroxy-C1-6alkyl groups are C1-6alkyl group with a linear or branched chain, such as hydroxymethylene, 1-hydroxyethylene, 2-hydroxyethylene, 3-hydroxy-n-through hydroxyisopropyl, hydroxy-sec-through, hydroxy-n-bucilina, hydroxyisobutyrate, hydroxy-sec-bucilina, hydroxy-tert-bucilina, hydroxy-n-pencilina, hydroxyisophthalate, hydroxy-n-exilda and hydroxyisohexyl group.

The above-mentioned "halogen-substituted C1-6alkyl group" represents a group in which one or more identical or different halogen atoms associated with "C1-6alkyl group having the above values, and preferred examples of such groups are permetrina, deformational, triptoreline, chlormethine, 1-florachilena, 2-florachilena, 1,1-deperately, 1,2-deperately, 2,2-deperately, 2,2,2-triptoreline and other groups.

The above "hydroxyimino-C1-6alkyl group" represents a group in which hydroxyimino associated with a group, have the values specified above for C1-6Ala formula-N(R15R16- (where R15and R16have identical or different meanings and represent (1) hydrogen atom, (2) C1-6alkyl group, a C1-6alkenylphenol group or a C1-6alkylamino group which may be substituted respectively with one or more groups selected from a halogen atom, a C3-8cycloalkyl group3-8cycloalkenyl group and C1-6CNS group, (3)3-8cycloalkyl group or3-8cycloalkenyl group which may be substituted by a halogen atom, (4) a carbonyl group substituted with any group selected from C1-6alkyl group, a C1-6alkenylphenol group, C1-6alkenylphenol group3-8cycloalkyl group3-8cycloalkenyl group, C1-6CNS group6-14aromatic hydrocarbon cyclic group, a 5 to 14-membered aromatic heterocyclic group, and a 5-14-membered non-aromatic heterocyclic group which may be substituted by a halogen atom, (5) karbamoilnuyu group, substituted with any group selected from C1-6alkyl group, a C1-6alkenylphenol group, C1-6alkenylphenol group, C6-14aromatic carbohydrate is sennou any group, selected from C1-6alkyl group, a C1-6alkenylphenol group and C1-6alkenylphenol group, or (7) R15and R16can be connected to each other to form 3-10-membered nonaromatic heterocyclic group containing the nitrogen atom to which they are attached, and the specified heterocyclic group may be substituted by one or more groups selected from hydroxyl group, halogen atom, a C1-6CNS group, and so on).

Examples of preferred amino groups are unsubstituted amino group, methylaminopropyl, dimethylaminopropyl, atramentaria, diethylaminopropyl, methylaminopropyl, acetamide (CH3N-) group, propylene, methanesulfonamido, acanaloniidae, pyrrolidinyl, piratininga, piperidinyl, piperazinilnom, 4-morpholinyl, 4-thiomorpholine and other groups. Preferable examples of the "amino group which may be substituted" is an amino group which may be substituted by one or two groups selected from C1-6alkyl group, a C2-6alkenylphenol group2-6alkenylphenol group3-8cycloalkyl group and3-8cycloalkenyl group.

1-6alkyl group, a C2-6alkenylphenol group2-6alkenylphenol group3-8cycloalkyl group and3-8cycloalkenyl group. Carnemolla group is also the group in which the nitrogen atom is part of a cyclic amine. Preferred examples of "carbamoyl group in which the nitrogen atom may be substituted" are unsubstituted carnemolla group, N-methylcarbamoyl group, N,N-dimethylcarbamoyl group, N-ethylcarbazole group, N,N-diethylcarbamoyl group, N-methyl-N-ethylcarbazole group, 1-pyrrolidinylcarbonyl group, 1-pyrazolecarboxylate group, 1-piperidinylcarbonyl group, 1-piperazinylcarbonyl group, 4-morpholinylcarbonyl group, 4-dimorpholinyldiethyl and other groups.

The above "Altamarena group in which the nitrogen atom may be substituted" is sulfamoyl group in which the nitrogen atom may be optionally substituted by a group selected from C1-6alkyl group, a C2-6alkenylphenol group2-6alkenylphenol group3-8cycloalkyl group3-8cycloalkenyl and other groups who predpochtitelnye examples "sulfamoyl group, in which the nitrogen atom may be substituted" are unsubstituted Altamarena group (-SO2NH2), N-methylsulfanyl group (-SO2NH3), 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)2H5), 1-pyrrolidinylcarbonyl group, 1-pyrazolecarboxylate group, 1-piperidinylcarbonyl group, 1-piperazinylcarbonyl group, 4-morpholinylcarbonyl group, 4-timeoforiginalfailure group, etc.

The above-mentioned "lower acyl group" represents an acyl group with a linear or branched chain derived from a fatty acid with 1-6 carbon atoms, and preferred examples of this group are formyl, acetyl, propylaniline, Butyrina, isobutylene, valerina, isovaleryl, bialoleka, hexanoyl and other groups.

The value of the ring And

In the compound of the above formula (I) according to the present invention, ring a is any ring, selected from piperazinovogo rings, homopiperazine rings, Pieper is reamers ring And preferably include pieperazinove ring, homopiperazine ring, piperidine ring, homopiperazine ring, pyrolidine ring, more preferably piperidine ring, pieperazinove ring and most preferably pieperazinove ring. When the ring And means pieperazinove ring, piperidine ring, pyrolidine ring or diazabicyclo[2,2,1]heptane ring, preferred is a structure of the formula:

in which the ring And attached connecting chain D2and W1and the preferred structure has the formula:

Values ring

In the compound of the above formula (I) according to the present invention ring b is (1) C3-14hydrocarbon ring which may be substituted, or (2) 5-14-membered heterocyclic ring which may be substituted.

(1) "C3-14hydrocarbon ring" in the definition of ring means With3-8cycloalkane,3-8cycloalken or C6-14aromatic hydrocarbon ring. When the ring is In "C3-8cycloalkane", examples of such rings preferably include a 3-8-membered cycloalkanes such as cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, ciceco In is "C3-8cycloalken", examples of such rings include a 3-8-membered cycloalkene, such as cyclopropene, cyclobutene, cyclopentene, cyclohexene and cycloheptene, as well as non-aromatic unsaturated hydrocarbon ring in which a carbon-carbon double bond of the aromatic hydrocarbon ring is partially saturated. More preferred are cyclopropene, cyclobutene, cyclopentene, cyclohexene, etc. When the ring is In "C6-14aromatic hydrocarbon ring, such a ring is preferably a benzene ring, pentalene ring, indene ring, naphthalene ring, 1,2,3,4-tetrahydronaphthalene ring, Aslanova ring, heptenophos ring, benzocyclobutene ring, phenanthrene ring and other, and the ring3-8cycloalkane condensed with an aromatic hydrocarbon ring, and the ring3-8cycloalkene condensed with an aromatic hydrocarbon ring, are also included in the definition of "C6-14aromatic hydrocarbon ring".

(2) "5-14-Membered heterocyclic ring" in the definition of ring means 5 to 14-membered non-aromatic heterocyclic ring or a 5 to 14-membered aromatic heterocyclic calctitle is pyrolidine ring, pyrrolinone ring, pieperazinove ring, imidazoline ring, pyrazolidine ring, imidazolidine ring, morpholine ring, tetrahydropyran ring, aziridine ring, oxirane ring, phthalimide ring, operations ring, etc. When the ring is In the "5 to 14-membered aromatic heterocyclic ring, preferred ring is pyrrole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazinone ring, pyrazol ring, imidazole ring, indole ring, isoindole ring, indolizine ring, purine ring, indazol ring, quinoline ring, isoquinoline ring, chinolinowe ring, phthalazinone ring, naphthylidine ring, hinoksolinov ring, hintline ring, benzimidazole ring, cinnoline ring, pteridine ring, imidazothiazole ring, pyrazinamidase ring, acridine ring, phenanthridinium ring, carbazole ring, carbazoles ring, pyrimidinone ring, phenanthroline ring, finalname ring, thiophene ring, benzothiophene ring, furan ring, pernovae ring, cyclopentadiene ring, benzopyrrole ring, Isobel is ICO, phenothiazine ring, isoxazole ring, furazane ring, phenoxazine ring, pyrazoloquinoline ring, imidazothiazole ring, thienopyrrole ring, foraperle ring, pyridoxine ring, 1,4-benzodioxane ring, benzoxazole ring, 2-keto-1-imidazole ring, oxazoline ring, 1,2,4-oxadiazole ring, indanone ring, 1,2,3,4-tetrahydroquinoline ring and so on

Examples of the "substituent" "C3-14hydrocarbon ring which may be substituted" or "5 to 14-membered heterocyclic ring which may be substituted" in the ring include one or more groups selected from (1) hydroxyl group, (2) halogen atom (e.g. fluorine atom, chlorine, bromine, iodine and others), (3) nitrile group, (4) C1-6alkyl group which may be substituted (for example, C1-6alkyl group which may be substituted by one or more groups selected from hydroxyl group, halogen atom, nitrile group, hydroxyimino and others), (5)2-6alkenylphenol group which may be substituted (for example,2-6alkenylphenol group which may be substituted by one or more groups selected from hydroxyl group may be substituted (for example, C1-6CNS group which may be substituted by one or more groups selected from hydroxyl group, halogen atom, nitrile group, hydroxyimino and other), (7) C1-6allylthiourea, which may be substituted, (8) C1-6alkoxycarbonyl group, (9) nitro, (10) amino group in which the nitrogen atom may be substituted, (11) carbamoyl group in which the nitrogen atom may be substituted, (12) sulfamoyl group in which the nitrogen atom may be substituted, (13) a lower acyl group, (14) an aromatic acyl group, (15) C1-6alkylsulfonyl group (for example, methylsulfonyl group, ethylsulfonyl group and others), (16)6-14aromatic hydrocarbon cyclic group, (17) 5-14-membered aromatic heterocyclic group and (18) Uralkaliy group (e.g. benzyl group, fenetylline group and other), and the preferred group is (i) hydroxyl group, (ii) halogen atom (e.g. fluorine atom, chlorine, bromine, etc.), (iii) nitrile group, (iv) C1-6alkyl group (e.g. methyl, ethyl, n-sawn, ISO-propyl, n-bucilina, isobutylene, tert-bucilina and other groups), (v) C6-14aromatic titelnoj is a nitrile group, a fluorine atom, a chlorine atom, and others.

The most preferred ring is respectively6-14aromatic hydrocarbon ring or a 5 to 14-membered aromatic heterocyclic ring which may be substituted. Typical examples include benzene ring, thiophene ring, pyridine ring, 1,4-benzodioxane ring, indole ring, benzothiazoline ring, benzoxazole ring, benzimidazole ring, 2-keto-1-imidazole ring, thiazole ring, oxazole ring, isoxazole ring, 1,2,4-oxadiazole ring, indanone ring, benzopyrrole ring, quinoline ring, 1,2,3,4-tetrahydroquinoline ring, naphthalene ring, 1,2,3,4-tetrahydronaphthalene ring and others that may be substituted by one or more groups selected from nitrile group, halogen atom (e.g. fluorine atom, chlorine bromine and other)6-14aromatic hydrocarbon cyclic group (for example, phenyl, naftilos and other groups), a 5 to 14-membered aromatic heterocyclic group (for example, peredelnoj, thienyl, shriley and other groups), C1-6alkyl groups (e.g. methyl, ethyl, n-sawn, ISO-propyl, isobutylene and ylsulphonyl and other groups).

The values of E

In the compound of the above formula (I) according to the present invention connecting chain E represents a simple bond, a group of the formula-CO - or-CH(OH)-. The most preferred value of E is a simple link.

Values X

In the compound of the above formula (I) according to the present invention connecting the chain X is (1) simple communication, (2) an oxygen atom, (3) a sulfur atom, (4) C1-6alkylenes chain which may be substituted, a group of the formula (5) -NR2- (where R2means a hydrogen atom or a C1-6alkyl group, a C3-8cycloalkyl group, a lower acyl group or a C1-6alkylsulfonyl group which may be substituted), (6) -CO-, (7) -COO-, (8) -OOS-, (9) -CONR3- (where R3means a hydrogen atom or a C1-6alkyl group which may be substituted), (10) -NR4CO- (where R4means a hydrogen atom or a C1-6alkyl group which may be optionally substituted), (11) -SO-, (12) -SO2-, (13) -SONR5- (where R5means a hydrogen atom or a C1-6alkyl group which may be substituted), (14) -NR6SO- (where R6means a hydrogen atom or a C1-6alkyl group which may be substituted), (15) -SO2NR7- (where R- (where R8means a hydrogen atom or a C1-6alkyl group which may be substituted), (17) >C=N-OR9(where R9means a hydrogen atom or a C1-6alkyl group which may be substituted), (18) -NR10W3-O-(where R10means a hydrogen atom, a C1-6alkyl group, a C3-8cycloalkyl group, a lower acyl group or a C1-6alkylsulfonyl group which may be substituted; and W3means C1-6alkylenes group which may be substituted), (19) -NH-CO-NH-, (20) -NH-CS-NH-, (21) -C (=NR15) NR16- (where R15and R16have identical or different meanings and represent a hydrogen atom, a nitrile group, a C1-6alkyl group, a C2-6alkenylphenol group3-8cycloalkyl group or3-8cycloalkenyl group), (22) -NHC(=NH)-, (23) -O-CO-S-, (24) -S-CO-O-, (25) -LLC-, (26) -NHCOO-, (27) -OCONH-, (28)- (CH2)mO- (where m is 0 or an integer from 1 to 6), (29) -SNON - or (30) -SNON(CH2)nO- (where n is 0 or an integer from 1 to 6).

When X represents C1-6alkylenes chain which may be substituted", the term "C1-6Allenova circuit" means a circuit obtained from C1-6alkane with a linear or branched chain, and primer, 1,3-butylene, 2,3-butylene, isobutylene, etc.

In the definition of X the most preferred example, "C1-6alkyl group which may be substituted" indicated by R2-R10is C1-6alkyl group (e.g. methyl, ethyl, n-sawn, ISO-propyl and other groups), which may be substituted by one or more groups selected from hydroxyl group, halogen atom (e.g. fluorine atom, chlorine, bromine, iodine, etc.), nitrile group, nitro, C1-6CNS group (for example, methoxy, ethoxy, n-propoxy, isopropoxy and other groups), and so on,

In the definition of X the preferred examples of "C3-8cycloalkyl groups denoted by R2and R10are cyclopropylamine, cyclobutylamine, cyclopentadiene, cyclohexadiene, cycloheptadiene and other groups, and this group is more preferable is cyclopropylamino, cyclobutadiene, cyclopentadiene, cyclohexadiene and other groups.

In the definition of X the preferred examples of "lower acyl group" denoted by R2and R10are formyl, acetyl, propylaniline, Butyrina, isobutylene, valerina, isovaleryl>alkylsulfonyl groups denoted by R2and R10are methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylaniline, second-propylsulfonyl, n-butylsulfonyl, isobutyronitrile, second-butylsulfonyl, tert-butylsulfonyl, n-pentylaniline, isopentenyladenine, second-pentylaniline, tert-pentylaniline, n-hexylaniline, isohexanol, 1,2-dimethylpropyleneurea, 2-ethylpropylamine, 1-methyl-2-ethylpropylamine, 1-ethyl-2-methylpropylsulfonic, 1,1,2-trimethylphenylsulfonyl, 1,1,2-trimethylphenylsulfonyl, 1,1-dimethylbutylamino, 2,2-dimethylbutylamino, 2-ethylbutylamine, 1,3-dimethylbutylamine, 2-methylphenylsulfonyl, 3-methylphenylsulfonyl and other groups.

R15and R16in the definition of X are identical or different meanings and represent a hydrogen atom, a nitrile group, a C1-6alkyl group, a C2-6alkenylphenol group3-8cycloalkyl group or3-8cycloalkenyl group. Preferred groups for both radicals are identical or different meanings and represent a hydrogen atom, nitrile the affected group. More preferably R15means nitrile, ethyl, n-sawn, ISO-propyl or tsiklogeksilnogo group, and R16means a hydrogen atom. The most preferred group of the formula-C(=NR15)NRl6- chain is expressed by the formula-C(=NCN)NH-.

The values of the respective groups listed in the definition of X described above. (1) the Preferred values of X are simple bond, oxygen atom, sulfur atom, C1-6Allenova chain which may be substituted, a group of the formula-NR2- (where R2means a hydrogen atom, a C1-6alkyl group, a C3-8cycloalkyl group, a lower acyl group or a C1-6alkylsulfonyl group which may be substituted), -CO-, -NR10-W3-O- (where R10means a hydrogen atom, a C1-6alkyl group, a C3-8cycloalkyl group, a lower acyl group or a C1-6alkylsulfonyl group which may be substituted, and W3means C1-6alkylenes group which may be substituted) and-NH-SO2-. (2) the preferred values of X are oxygen atom, a C1-6Allenova chain which may be substituted, a group of the formula-NR2- (where R2means a hydrogen atom, a Cis the function group, which may be substituted), -CO-, -NR10-W3-O- (where R10means a hydrogen atom or a C1-6alkyl group, a C3-8cycloalkyl group, a lower acyl group or a C1-6alkylsulfonyl group which may be substituted; and W3means C1-6alkylenes group which may be substituted) and-NH-SO2-. (3) Even more preferred values of X are oxygen atom, a C1-6Allenova chain which may be substituted, a group of the formula-NR2- (where R2means a hydrogen atom, a C1-6alkyl group, a C3-8cycloalkyl group, a lower acyl group or a C1-6alkylsulfonyl group which may be substituted), -CO - and-NH-SO2-. (4) the Most preferred value of X is an oxygen atom or a group of the formula-NR2- (where R2means a hydrogen atom, a C1-6alkyl group, a C3-8cycloalkyl group, a lower acyl group or a C1-6alkylsulfonyl group which may be substituted).

Values of R1

The group, designated as R1in the above formula (I), represents (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4)1-6alkyl group which may b the th group, (5)2-6alkenylphenol group which may be substituted by one or more groups selected from hydroxyl group, halogen atom and nitrile group, (6) With2-6alkylamino group which may be substituted by one or more groups selected from hydroxyl group, halogen atom and nitrile group, (7)3-8cycloalkyl group which may be substituted by one or more groups selected from hydroxyl group, halogen atom and nitrile group, (9) C1-6alkoxy-C1-6alkyl group, (10) amino-C1-6alkyl group in which the nitrogen atom may be substituted, (11) a group of the formula-N(R11R12- (where R11and R12have identical or different meanings and represent a hydrogen atom or a C1-6alkyl group), (12) Uralkaliy group, (13) morpholinyl group, (14) thiomorpholine group, (15) piperidino group, (16) pyrrolidinyloxy group, or (17) piperazinilnom group.

The above-mentioned "halogen atom" means preferably a fluorine atom, chlorine and bromine, more preferably fluorine atom and chlorine atom.

"C1-6alkyl group" in the definition of R1preferably includes methyl, ethyl, n-propylen is entrusted methyl, ethyl, n-sawn and ISO-propyl group, more preferably n-sawn and ISO-propyl group, and most preferably ISO-propyl group.

"C2-6Alchemilla group" in the definition of R1preferably includes vinyl, allyl, 1-propenyloxy, Isopropenyl, 1-butene-1-ilen, 1-butene-2-ilen, 1-butene-3-ilen, 2-butene-1-ilen, 2-butene-2-ilen and other groups, more preferably vinyl, allyl, Isopropenyl and other groups.

Preferred examples of "C2-6alkenylphenol group" in the definition of R1are etinilnoy, 1-proponila, 2-proponila, Butyrina, pantanella, hexylamine and other groups.

Preferred examples of "C3-8cycloalkyl group" in the definition of R1are cyclopropylamine, cyclobutylamine, cyclopentadiene, cyclohexadiene and other groups.

Preferred examples of "C1-6alkoxy-C1-6alkyl group" in the definition of R1are C1-6alkyl group substituted by a group having the values specified above for C1-6CNS group, and the preferred group is methoxymethyl, ethoxymethylene, 1-methoxyaniline, 2-methoxyaniline, 1-articlename examples, "C1-6alkyl groups, substituted nitrile group" in the definition of R1are cyanomethylene, 2-cyanoaniline, 3-cyano-n-through 2-cyanocobala, 2-cyano-n-bucilina, 2-cyano-second-bucilina, 2-cyano-tert-bucilina, 2-cyano-n-pencilina, 3-cyano-n-exilda and other groups.

Preferred examples of "amino-C1-6alkyl group in which the nitrogen atom may be substituted" in the definition of R1are aminomethyl, methylaminomethyl, dimethylaminomethyl, ethylaminomethyl, diethylaminomethyl, methylaminomethyl, acetamidomethyl, pyrrolidinedione, 2-pyrazolidinone, 1-piperidinedione, piperazinylmethyl and other groups.

Preferred examples of "Uralkaliy group" in the definition of R1are benzyl, fenetylline, phenylpropionate, naphthylethylene, naphthylethylene, afterproperties and other groups.

The values of the respective groups, the above definition of R1described above and the preferred values of R1are a hydrogen atom, halogen atom, hydroxyl group, C1-6alkyl group, a C2-6Alchemilla group2-6Alchemilla group3-8cycloalkyl group, guide the PAP and C1-6alkyl group substituted by a halogen atom. The preferred values of R1are halogen atom, a hydroxyl group, a C1-6alkyl group, a C2-6Alchemilla group and C2-6Alchemilla group, still more preferred value of R1is C1-6alkyl group (particularly, methyl, ethyl, n-sawn, ISO-propyl group).

The values of D1D2, W1and W2

In the compound of the above formula (I) according to the present invention D1D2, W1and W2have the same or different values of and, respectively, represent (1) a simple link or (2) optionally substituted C1-6alkylenes chain.

Preferred values of C1-6alkalinous chain" in the above "C1-6alkalinous chain which may be substituted" are methylene, ethylene, utilizinga, trimethylene, isopropylidene, propylene, tetramethylene, 1,2-butylene, 1,3-butylene, 2,3-butylene, isobutilene and other circuits.

Further, the circuit is asymmetrical in relation to the left and right orientation, is also included in the above definition of C1-6alkilinity circuits, but in this case, the direction of education St. the Preferred "Deputy" in the above "C1-6alkalinous chain which may be substituted" is (i) hydroxyl group, (ii) halogen atom (e.g. fluorine atom, chlorine, bromine, iodine etc.), (iii) nitrile group, (iv) C1-6alkyl group (e.g. methyl, ethyl, n-sawn, ISO-propyl, n-bucilina, tert-bucilina and other groups), (v) C2-6Alchemilla group (for example, vinyl, allyl, 1-protanilla, 2-protanilla, Isopropenyl, 2-methyl-1-protanilla, 3-methyl-1-protanilla, 2-methyl-2-protanilla and other groups), (vi) C1-6CNS group (for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and other groups), and so on,

Further, when the "Deputy" is C1-6an alkyl group and/or C2-6Alchemilla group, these substituents may be linked together with education 5-14-membered ring, and in the case of W1and W2these substituents may be connected with the ring or X education 5-14-membered ring.

In the preferred case, D1D2, W1and W2have identical or different meanings and represent (1) a simple link or (2) a methylene, ethylene, ethylidene, trimethylene, isopropylidene, propylene, tetramethylaniline substituted by one or more groups, selected from hydroxyl group, halogen atom and nitrile group.

The above-described corresponding values of E, X, D1D2, W1and W2. The preferred values of the partial structure of-D1-E-D2- are the ethylene chain (-CH2-CH2-), utilizinga chain (-CH(CH3)-), trimethylene chain (-(CH2)3-), isopropylidenebis chain (-CH(CH3)2), propylene chain (-CH(CH3)CH2-), tetramethylene chain (-(CH2)4), 1,2-butylene chain (-CH(C2H5)CH2-), 1,3-butylene chain (-CH(CH3)CH2CH2-), 2,3-butylene chain (-CH(CH3)CH(CH3)-), isobutilene chain (-CH(CH3)3CH2-) and others. More preferred values are trimethylene chain (-(CH2)3-), isopropylidenebis chain (-CH(CH3)2-), propylene chain (-CH(CH3)CH2-), tetramethylene chain (-(CH2)4-), 1,2-butylene chain (-CH(C2H5)CH2and others, particularly preferred values include tetramethylene chain (-(CH2)3-) and others. The preferred values of the partial patterns-W1-X-W2- are simple communication and air>2-.

Variants of the compounds of the above formula (I) according to the present invention have no particular restrictions, and the person skilled in the art can easily join the group above in the definitions AG, ring A, ring b, E, X, R1D1D2, W1and W2and to receive all incoming connections in the scope of this invention. More preferred options is one where AG denotes optionally substituted 5 to 14-membered aromatic heterocyclic group; ring a represents pieperazinove ring, piperidine ring or pyrolidine ring; ring b means C6-14aromatic hydrocarbon group or a 5-14-membered aromatic heterocyclic group which may be substituted; E means a simple bond; X is a simple bond, oxygen atom, optionally substituted C1-6alkylenes group or a group of the formula-NR2- (where R2has the above values). Another preferred variant is a compound of the formula:

or

(where the symbols have the above values), its salt or hydrate.

The compounds obtained in the OPI is typical led connection:

4-[(4-cyano-5-methyl-4-phenyl)hexyl]-N-(4-forfinal)-N’-(2-methylpropyl)-1(2H)-pyrazinecarboxamide;

1-isopropyl-4-[4-(1-isobutyl-1N-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-diazepan-1-yl]-1-isopropyl-1-phenylbutazone;

4-[4-(1-ethyl-1H-benzo[d]imidazol-2-yl)-1,4-diazepan-1 is rboxylic;

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-phenylbutyramide and

4-[4-(4-benzylpiperidine)piperidinyl]-1-isopropyl-1-phenylbutyramide.

The compound of the above formula (I) according to the present invention, its salt or hydrate can be obtained by known manufacturing methods or the methods described in this application. As known ways of getting listed, for example, the production method, described in JP-A 2000-169462 (the production method, described in paragraph "0054"-"0065" publications), and the production method, described in JP-A 2000-12207, 2000-12208 and 2000-12209.

Starting compound used for obtaining the compound (I) may be in the form of a salt or hydrate and do not have any restrictions, unless such connection does not prevent the interaction. Upon receipt of the compound (I) by infusion. asnie isomers (for example, geometric isomers, optical isomers based on asymmetric nitrogen atom, stereoisomers, tautomers and the like) obtained for compound (I) of the present invention, it is possible to purify and isolate by conventional methods of separation (for example, by recrystallization, by a method based on the salt of the diastereoisomer, by the method of enzymatic separation, different chromatographic methods and the like).

The term "salt" in the description to this application does not have any specific restrictions, unless it is formed with the compound of the present invention and acceptable in pharmacological terms, such a salt is preferably the salt of the halogen acids (for example, hydroptere, hydrochloride, hydrobromide, hydroiodide, and the like), a salt of an inorganic acid (e.g., sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate and the like), salt of organic carboxylic acid (e.g., salt of acetic acid, salt triperoxonane acid, salt of oxalic acid, a salt of maleic acid, salt, tartaric acid salt, fumaric acid salt of citric acid, and the like), salt of organic sulfonic acid (e.g., meanswhen is), salt of the amino acids (e.g., salt, aspartic acid salt, glutamic acid and the like), a salt of the Quaternary ammonium salt of an alkali metal (e.g. sodium salt, potassium salt and the like), salts of alkaline-earth metal (e.g. magnesium salt, calcium salt and the like) and others. More preferred is the hydrochloride salt of oxalic acid, salt triperoxonane acid and the like.

The compound of the above formula (I), its salt or hydrate can be produced in the form of drugs, which include tablets, powders, granules, fine granules, coated tablets, capsules, syrups, lozenges, aerosols, suppositories, injection solutions, pastes, eye ointments, eye drops, nose drops, ear drops, poultices, lotions and the like. In the manufacture of drugs commonly used excipients, binders, disintegrators, lubricants, colorants, flavoring agents and, if necessary, stabilizers, emulsifiers, accelerators suction, surfactants, pH regulators, antiseptics, antioxidants and the like. Ingredients commonly used as starting substances in pharmaceutical preparations, the vegetable oil, such as soybean oil, tallow and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane and solid paraffin; ester oils such as octyldodecyl and isopropylmyristate; higher alcohols, such as cetosteatil alcohol and beganby alcohol; silicone resins; silicone oils; surfactants such as esters of fatty acids and polyoxyethylene, ester of fatty acid and sorbitan, ester of fatty acid and glycerol, ester of fatty acid and polyoxyethylenesorbitan, utverjdenie a polyoxyethylene castor oil and a block copolymer of polyoxyethylene and polyoxypropylene; water-soluble polymers, such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, poly(vinyl pyrrolidone) and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropyleneglycol and sorbitol; sugars such as glucose and dextrose; inorganic powders such as silicic anhydride, aluminum silicate and magnesium aluminum silicate; purified water and the like. As fillers usually used lactose, corn starch, white sugar, textst use polyvinyl alcohol, polyvinylether, methylcellulose, ethylcellulose, Arabian gum, tragakant, gelatin, shellac, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, block-copolymer polypropylenglycol and polyoxyethylene, meglumine, calcium citrate, dextrin, pectin and the like; as the disintegrator, the use of starch, agar, poroshkovaya gelatin, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, calcixerollic and the like; lubricants use magnesium stearate, talc, polyethylene glycol, silicon dioxide, utverjdenie vegetable oil and the like; as dyes use any pigments, suitable for introduction in the pharmaceutical compositions; as flavourings use cocoa powder, menthol, aromatic powder, peppermint oil, borneol, cinnamon powder and the like; as the use of antioxidants ascorbic acid-tocopherol and similar substances, which are recognized to be suitable for introduction in the pharmaceutical composition.

For example, (1) preparations for oral administration get in the form of powders, fine granules, the largest of the invention, its salt or hydrate fillers and adding, if necessary, binders, disintegrators, lubricants, colorants, flavors, etc. (2) In the manufacture of tablets and granules they are coated with sugar and gelatin and, if necessary, additional suitable material. (3) In the manufacture of syrups, intravenous solutions, eye drops and similar structures use pH regulators, dissolving agents, agents for isotonic solution and the like and, if necessary, add substances that contribute to the dissolution, stabilizers, buffers, suspendresume tools, antioxidants and the like, and then get the desired composition in a known manner. In the case of drugs for injection you can get freeze-drying and used for intravenous, subcutaneous and intramuscular injection. Preferred examples suspendida agents include methylcellulose, Polysorbate 80, hydroxyethylcellulose, Arabian gum, poroshkovaya tragakant, sodium carboxymethyl cellulose, monolaurin of polyoxyethylenesorbitan and the like; preferable examples of the solvents are utverjdenie a polyoxyethylene red examples of the stabilizer include sodium sulfite, metasulfite sodium, diethyl ether and the like; preferable examples of preservatives are methyl-p-oxybenzoic, ethyl-p-oxybenzoic, sorbic acid, phenol, cresol, chlorocresol and the like. (4) for the production of preparations for external use, there are no restrictions, and these drugs can be obtained in the usual way. As starting substances for the main medicines you can use various substances commonly used in pharmacology, quatercentennial tools, cosmetics and the like. For example, in the pharmaceutical composition can be added such source materials as animal and vegetable oils, mineral oil, essential oil, waxes, higher alcohols, fatty acids, silicone oil, surfactants, phosphatides, alcohols, polyhydric alcohols, water-soluble polymers, minerals class of clay, purified water, and similar substances. Depending on requirements can be added as a pH regulator, antioxidant, helatoobrazovatel, antiseptic and fungicide, dye, flavor, and similar substances. In addition, if necessary, the pharmaceutical composition can be entered ingredi is the means, anti-inflammatory agents, activators cells, vitamins, amino acids, humectants, keratolytic tools and the like. The dose of the pharmaceutical of the present invention may vary depending on the severity of symptoms, age, sex, body weight, route of administration, type of salt, different susceptibility to the drug, method of exposure, but for an adult by oral administration of single or multiple dose usually ranges from about 30 μg to 1000 mg per day, preferably from 100 μg to 500 mg and more preferably from 100 μg to 100 mg For administration by injection single or multiple dose of the pharmaceutical preparation is about 1-3000 μg/kg, preferably 3-1000 mg/kg

The compound of the above formula (I) according to the present invention, its salt or hydrate useful as antagonists of calcium, in particular neionizirovannykh calcium antagonists. The compound of the present invention is a novel compound inhibiting calcium channel P/Q-type and N-type, and can be used as a means for the treatment or prevention of disease, susceptible to inhibition of calcium channel P/Q-type and N-type. In addition,the effect on the cells compared with the known antagonists and are safe with calcium antagonists with reduced toxicity. Thus, the connection of the present invention, its salt or hydrate is useful as substances that prevent the death of nerve cells and reduces the irritation of the nerve cells of the brain, for the treatment or prophylaxis of nervous diseases and analgesics. In particular, these compounds are suitable as means for treatment, prevention or suppression of symptoms of acute ischemic stroke, hemorrhage, infarction of the brain, head injury, loss of nerve cells in the brain, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, metabolic disorders of brain blood flow, disturbance of brain function, pain, spasms, schizophrenia, migraine, epilepsy, manic-depressive syndrome, degenerative nerve diseases, cerebral ischemia, dementia caused by AIDS, cerebral edema, state of fear, diabetic neuropathy, dementia due to vascular lesions of the brain, multiple sclerosis, etc.

Brief description of drawings

In Fig.1 shows HPLC obtained in reference example 97.

In Fig.2 shows a graph of HPLC, obtained the CTD No. 2 obtained in reference example 101.

In Fig.3 shows a graph HPLC obtained in reference example 103.

EXAMPLES

The following examples are preferred variant implementation of the present invention, the following reference examples (working) examples (methods of obtaining pharmaceutically acceptable salt or hydrate and pharmaceutical compositions containing these substances) and test examples are only illustrative, and compounds of the present invention is not considered limited to the examples. Specialists in this field can make various changes in the following examples, but the scope covered by the claims in this patent application with the purpose of the widest possible implementation of this invention, all such modifications are included in the scope of the claims presented in the description of the present patent application.

The symbol Z is used as a reference or working examples means benzyloxycarbonyloxy group and HPLC means high performance liquid chromatography.

Reference example 1

2-[(4-Cyano-5-methyl-4-phenyl)hexyl]-5-benzyl-2,5-diazabicyclo[2,2,1]heptane

Specified in the reasons of the (400 MHz, CDCl3)0,78 (d, J=6.8 Hz, 3H), 1.04 million-to 1.16 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,45-of 1.57 (m, 1H), 1,64 (DD, J=9.6 Hz, J=33.6 Hz, 2H), was 1.94 (dt, J=4.4 Hz, J=12,4 Hz, 1H), 2,07-of 2.23 (m, 2H), 2,30-of 2.38 (m, 1H), 2,50-a 2.71 (m, 5H), 3,19 (d, J=14 Hz, 2H), 3,66 (kV, J=14 Hz, 2H), 7,19-7,40 (m, 10H).

Reference example 2

3-Methyl-2-(2-naphthyl)butyronitrile

3.00 g (to 17.9 mmol) of 2-naphthylacetamide dissolved in 10 ml of dimethyl sulfoxide and alternately add 2,43 g (19,7 mmol) of 2-bromopropane, 330 mg (0.90 mmol, catalyst) iodide, Tetra-n-butylamine and 10 ml of 50% potassium hydroxide. After the reaction add a saturated salt solution and the mixture extracted with ether. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 150 g of silica gel (ethyl acetate:hexane = 1:10), while receiving 2,42 g (11.6 mmol, 64.6 per cent) indicated in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3)of 1.07 (d, J=6.8 Hz, 3H), 1,11 (d, J=6.8 Hz, 3H), 2,10-of 2.30 (m, 1H), 3,84 (d, J=3,84 Hz, 1H), 7,38 (DD, J=1,8 Hz, 8.6 Hz, 1H), of 7.48-of 7.55 (m, 2H), 7,79-7,88 (m, 4H).

Reference example 3

4-Cyano-5-methyl-4-(2-naphthyl)hexanol

to 1.00 g (4,78 mmol) 3-methyl-2-(2-naphthyl)butyronitrile restores cooled to room temperature and added with 0.93 ml (4.00 mmol) (3-bromopropane)-tert-butyldimethylsiloxy. After the reaction add a saturated solution of salt and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 50 g of silica gel (ethyl acetate:hexane = 1:18) and get a mixture of 1.40 g of the target product, the starting materials and impurities. The resulting mixture is used in the following reaction without purification. Namely, 1.40 g of the above crude 4-cyano-5-methyl-5-(2-naphthyl)hexaoxa-tert-butyldimethylsilyl dissolved in 20 ml of tetrahydrofuran and add 5 ml (5 mmol) of fluoride tetraamine. After the reaction add a saturated solution of salt and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride and saturated salt solution, dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 50 g of silica gel (ethyl acetate:hexane = 1:4), while receiving 590 mg (2.21 mmol, 46,2%, stage 2) is specified in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3)to 0.80 (d, J=6.8 Hz, 3H), 1,10-1,30 (m, 1H), 1.27mm (d, J=6.8 Hz, 3H), 1,57 was 1.69 (m, 1H), 2,02-2,12 (m, 1H), 2,20-is 2.37 (m, 1H), to 3.58 (t, J=6.2 for the-4-phenyl)hexyl]-3-tert-butoxycarbonylamino

2.76 g (8,44 mmol) 4-cyano-5-methyl-4-phenylhexanoic dissolved in a 50.0 ml of acetonitrile, add 1,29 ml (9.28 are mmol) of triethylamine and 1.88 g (10.1 mmol) of 3-tert-butoxycarbonylmethylene and heat the mixture to 60°C. After the reaction mixture is distributed between ethyl acetate and a saturated solution of salt. The organic layer is dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 50 g of silica gel Cromatorex NH (ethyl acetate:hexane = 2:1), while receiving 2,97 g (7,76 mmol, 91.3 percent) specified in the title compounds as a pale yellow syrup.

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.8 Hz, 3H), 1,21 (d, J=6.8 Hz, 3H), 1,05-1,25 (m, 1H), USD 1.43 (s, N), 1,50-of 1.65 (m, 2H), 1,88 is 2.00 (m, 1H), 2.00 in 2,28 (m, 4H), 2,28-2,60 (m, 4H), 2,65-2,70 (m, 1H), 4,05-4,20 (Shir.Dr. s, 1H), 4,82-4,95 (Shir.Dr. s, 1H), 7,26-to 7.59 (m, 5H).

Reference example 5

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-3-aminopyrrolidine

of 2.36 g (6.12 mmol) of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-3-tert-butoxycarbonylmethylene dissolved in a mixed solution of 5 ml of tetrahydrofuran and 10 ml of methanol and added a 4 n solution of hydrogen chloride in ethyl acetate. After the reaction mixture is alkalinized 2 N. aqueous solution of the hydroxide is ω 1.66 g (of 5.82 mmol, 95,1%, orange syrup) crude product.

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.4 Hz, 3H), 1,20 (d, J=6.8 Hz, 3H), 1,08-1,24 (m, 1H), 1,42-of 1.62 (m, 2H), 1,84 is 2.00 (m, 3H), 2,08-of 2.28 (m, 4H), 2,32-2,48 (m, 3H), 2,58-to 2.67 (m, 2H), 3,42-3,51 (m, 1H), 7,26-7,40 (m, 5H).

Reference example 6

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-3-[N-(2-cyanoethyl)amino]pyrrolidin

700 mg (2.45 mmol) of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-3-aminopyrrolidine dissolved in 15 ml of methanol, add to 0.19 ml (2,85 mmol) of Acrylonitrile and heat the mixture under reflux. After the reaction mixture is evaporated and get the crude product. The crude product is treated with 20 g of silica gel Cromatorex NH (ethyl acetate 100%), while receiving 775 mg (to 2.29 mmol, 93.5 per cent) indicated in the title compound as an orange syrup.

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 1,07-1,24 (m, 1H), 1,20 (d, J=6.4 Hz, 3H), 1,08-1,24 (m, 1H), 1,46-of 1.62 (m, 2H), 1,86 is 1.96 (m, 1H), 2,04-of 2.24 (m, 4H), 2,28 is 2.46 (m, 4H), 2,46-2,62 (m, 2H), 2.49 USD (t, J=6,8 Hz, 2H), to 2.85 (t, J=6,8 Hz, 2H), 3,22-3,30 (m, 1H), 7,26-7,40 (m, 5H).

Reference example 7

3-Perteneciente

a 2.00 g (17.8 mmol) of m-terfenol dissolved in 50 ml of dimethylformamide, alternately add 785 mg (19,6 mmol, 60 wt.%, mineral hydride NAT is make a saturated salt solution and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 105 g of silica gel Cromatorex NH (ethyl acetate:hexane = 1:40), while receiving 3,17 g (a 13.9 mmol, 78,1%) specified in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3)1,25 (t, J=7,0 Hz, 6N), 3,55-3,82 (m, 4H), 3,99 (d, J=5.0 Hz, 2H), 4,82 (t, J=5.0 Hz, 1H), 6,61-6,72 (m, 3H), 7,17-7,25 (m, 1H).

1.68 g (7,38 mmol) obtained above acetal is dissolved in 30 ml of acetone and 20 ml of 2.5 n hydrochloric acid and the mixture is heated. After the reaction mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated, while receiving 800 mg of crude product, which contains below the target connection. The crude product is subjected to the above reaction without purification.

Reference example 8

1-Benzyl-3-[N-(2-cyanoethyl)amino]pyrrolidin

of 4.00 g (22.7 mmol) of 1-benzyl-3-aminopyrrolidine dissolved in 70 ml of methanol, add 1,49 ml (22.7 mmol) of Acrylonitrile and heat the mixture to 70°C. After the reaction, the reaction solution mpariwa the ol, 88,4%) specified in the title compound as a yellow oil.

1H-NMR (400 MHz, Dl3)1,54-of 1.66 (m, 1H), 2,10-2,22 (m, 1H), 2,40-2,60 (m, 2H), 2.49 USD (t, J=6,8 Hz, 2H), 2,67-2,78 (m, 2H), 2,86 (t, J=6,8 Hz, 2H), 3,30-to 3.38 (m, 1H), 3,57-to 3.73 (m, 2H), 7,22 and 7.36 (m, 5H).

Reference example 9

1-Benzyl-3-[N-(2-cyanoethyl)-N-{2-(4-cianfrocca)ethyl}amino]pyrrolidin

2,03 g (8,87 mmol) 1-benzyl-3-[(N-(2-cyanoethyl)amino]pyrrolidine dissolved in 50 ml of dichloroethane and alternately add of 1.30 g (of 8.06 mmol) separately synthesized 4-cyanobenzaldehyde, of 1.02 ml (about 17.7 mmol) of acetic acid and of 2.56 g (12.1 mmol) of triacetoxyborohydride sodium. After the reaction mixture is alkalinized to the main reaction 2 N. aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 250 g of silica gel Cromatorex NH (ethyl acetate:hexane = 2:3), while receiving 2,39 g (6.38 mmol, 79,2%) specified in the title compound as a yellow syrup.

1H-NMR (400 MHz, CDCl3)1,70-of 1.84 (m, 1H), 2,03 with 2.14 (m, 1H), 2,40-of 2.54 (m, 1H), 2,47 (t, J=6,8 Hz, 2H), 2,55 of 2.68 (m, 2H), was 2.76-is 2.88 (m, 1H), 2.91 in-to 3.09 (m, 4H), 3,48-3,68 (m, 2H), 3,64-3,72-(4-cianfrocca)ethyl}amino]pyrrolidin

1-Benzyl-3-[(N-(2-cyanoethyl)-N-{2-(4-cianfrocca)ethyl}amino]pyrrolidine dissolved in dichloroethane add l (from 0.84 ml, 7,66 mmol) and heat the mixture under reflux. After approximately one hour add AceCl (0,12 ml) and continue to heat the mixture. After the reaction mixture evaporated. To the residue add 30 ml of methanol and then heated under reflux. After one hour the reaction solution is evaporated. The residue is extracted with 2 N. a solution of hydrochloric acid, washed with ether and adjusted to pH 11-12 by adding 2 N. aqueous sodium hydroxide solution. The mixture is extracted with ethyl acetate, dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 50 g of silica gel Cromatorex NH (ethyl acetate:methanol 1:0 to 3:1), while receiving 1.12 g (3.93 mmol, 61,6%) specified in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3)1,64 to 1.76 (m, 1H), 1,94-to 2.06 (m, 1H), 2,52 (t, J=6,8 Hz, 2H), 2,56-2,70 (m, 2H), 2.77-to of 2.86 (m, 1H), 2.91 in-3,20 (m, 5H), 3,36-3,51 (m, 1H), 4,08 (t, J=5.6 Hz, 2H), of 6.96 (t, J=9,2 Hz, 2H), 7,60 (t, J=9,2 Hz, 2H).

Reference example 11

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

to 1.00 g (3.50 mmol) of 1-[(4-cyanogenia ice added dropwise to 0.35 ml (of 3.85 mmol) methylpropanoate. After the reaction add a saturated solution of salt and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 50 g of silica gel Cromatorex NH (ethyl acetate:hexane = 1:2), while receiving 1.22 g (3,41 mmol, 97.5 per cent) indicated in the title compound as an orange oil.

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 1,05-1,20 (m, 1H), 1,20 (d, J=6.4 Hz, 3H), 1,48-of 1.64 (m, 1H), 1,84-of 1.93 (m, 1H), 2.06 to to 2.18 (m, 2H), 2,24-2,31 (m, 2H), 2,31 is 2.46 (m, 4H), 2,46-2,60 (m, 4H), 3,19 (s, 2H), 3,71 (s, 3H), 7,24-7,39 (m, 5H).

Reference example 12

3-Forbesautos.com

To 200 ml of a solution of 10.0 g (82,6 mmol) 3-formentioned in ethanol add 8,61 g (124 mmol) of hydroxylamine hydrochloride and 22.8 g (165 mmol) of potassium carbonate and heating the mixture under reflux. After the reaction mixture evaporated. To the residue is added saturated salt solution and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 100 g of silica gel (ethyl acetate:hexane = 1:2-1:4), while receiving 8.00 g (51,9 mmol, 62.8% of) "https://img.russianpatents.com/chr/948.gif">4,75-4,85 (m, 2H), 7,09-to 7.59 (m, 4H).

Reference example 13

N-Z-4-Piperidinemethanol

4,70 g cases (36.4 mmol) of 4-piperidinemethanol and 10.0 g (72,8 mmol) of potassium carbonate dissolved in ether (50 ml) and water (50 ml). Under ice cooling ZCl (of 4.44 ml to 25.0 mmol) dissolved in 30 ml of ether and the resulting solution was added dropwise to the reaction mixture. The physical properties of the resulting specified in the connection header is shown below. After the reaction add a saturated solution of salt and the mixture is extracted with simple ether. The organic layer was washed with saturated salt solution and saturated aqueous ammonium chloride, dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 100 g of silica gel (ethyl acetate:hexane = 1:2), while receiving of 5.48 g (20,8 mmol, 57.2 per cent) indicated in the title compounds as colorless oils.

1H-NMR (400 MHz, Dl3)1,05-1,25 (m, 2H), 1,40 is 1.75 (m, 5H), 2,70-to 2.85 (m, 2H), 3,71 (t, J=6,59 Hz, 2H), 4,10-of 4.25 (m, 2H), 5,12 (s, 2H), 7,28-7,39 (m, 5H).

Reference example 14

1-Benzyloxycarbonyl-4-[2-(4-pertenece)ethyl]piperidine

a 2.00 g (7,60 mmol) N-Z-4-piperidinemethanol, 1.70 g (15,2 mmol) of 4-terfenol and 2,39 g (dobavlaut of 1.44 ml (9,12 mmol) of diethylazodicarboxylate and then stirred the mixture at room temperature. After the reaction add a saturated solution of salt and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 100 g of silica gel (ethyl acetate:hexane = 1:3), while receiving 2,19 g (6.12 mmol, 80,6%) specified in the title compounds as colorless oils.

1H-NMR (400 MHz, Dl3)1,10-1,30 (m, 2H), of 1.65 and 1.80 (m, 5H), 2,70-2,90 (m, 2H), 3.96 points (t, J=6.0 Hz, 2H), 4,10-to 4.28 (m, 2H), 5,13 (s, 2H), 6,79-6,84 (m, 2H), 6,93-of 6.99 (m, 2H), 7,28-7,38 (m, 5H).

Reference example 15

4-[2-(4-Pertenece)ethyl]piperidine

2,19 g (6.12 mmol) of 1-benzyloxycarbonyl-4-[2-(4-pertenece) ethyl]piperidine was dissolved in 40 ml of methanol, add 300 mg of 10% palladium on coal and replace the atmosphere of hydrogen. After the reaction the mixture is filtered and the filtrate evaporated, to give crude product. The crude product is treated with 50 g of silica gel Cromatorex NH (ethyl acetate:hexane = 1:3 ethyl acetate:methanol = 6:1), while receiving of 1.30 g (of 5.82 mmol, 95,1%) specified in the title compound as a yellow oil.

1H-NMR (400 MHz, Dl3)1,10-of 1.23 (m, 2H), 1.60-to 1.77 in (m, 5H), 2,59 (dt, J=2,4 Hz and 12.2 Hz, 2H), 3.96 points (t, J=6.0 Hz, 2H), 4,1 shall pyridin

to 5.00 g (of 36.4 mmol) 3-pyridinemethanol dissolved in 150 ml of acetonitrile, add 4,55 ml (to 38.3 mmol) benzylbromide and heat the mixture at 70°C. After 2 hours, the heating is stopped and the mixture evaporated. The residue is dissolved in 100 ml of methanol and the mixture is cooled to 0°C. Then added to the mixture of 4.12 g (109 mmol) of sodium borohydride. After the reaction, add 50 ml of water and the mixture evaporated. The residue is distributed between ethyl acetate and a saturated solution of salt. The organic layer is dried over magnesium sulfate and the mixture is evaporated, give crude product. The crude product is treated with 150 g of silica gel Cromatorex NH (ethyl acetate:hexane = 1:6-1:1), while receiving 6,48 g (28,0 mmol, 77,0%) specified in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3)1,65-of 1.74 (m, 2H), 2,02 and 2.13 (m, 4H), to 2.55 (t, J=6.0 Hz, 2H), 2.93 which are 2.98 (m, 2H), only 3.57 (s, 2H), to 3.64 (t, J=6.4 Hz, 2H), 5,38-5,42 (m, 1H), 7,22-7,37 (m, 5H).

Reference example 17

1-Benzyl-4-hydroxypropiophenone

6,48 g of 1-benzyl-4-hydroxypropyl-1,2,5,6-tetrahydropyridine is dissolved in 60 ml of methanol, add 88 mg PtO2and replace the atmosphere of hydrogen. After the reaction the mixture is filtered and the filtrate is evaporated while>
)of 1.16 and 1.33 (m, 5H), 1,33-1,41 (Shir.Dr. s, 1H), 1,53-of 1.74 (m, 4H), 1,87-to 1.98 (m, 2H), 2,83-2,90 (m, 2H), 3,48 (s, 2H), 3,62 (t, J=6.4 Hz, 2H), 7,16-7,27 (m, 5H).

Reference example 18

1-Benzyl-4-methanesulfonylaminoethyl

2.58 g (11.1 mmol) of 1-benzyl-4-hydroxypropylamino and 3.26 ml (by 23.4 mmol) of triethylamine are dissolved in 50 ml of tetrahydrofuran and added dropwise to 1.67 ml (21.6 mmol) of methanesulfonamide. After the reaction mixture is distributed between ethyl acetate and a saturated solution of salt. The organic layer is dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 50 g of silica gel Cromatorex NH (ethyl acetate:hexane = 1:1), while receiving 2,90 g (9,31 mmol, 83,9%) specified in the title compound as a yellow oil. Physico-chemical data of the target compounds is shown below.

1H-NMR (400 MHz, Dl3)of 1.18 to 1.37 (m, 5H), 1,58 by 1.68 (m, 2H), 1,71 and 1.80 (m, 2H), 1,88-of 1.97 (m, 2H), 2,84-2,90 (m, 2H), 3.00 and (s, 3H), of 3.48 (s, 2H), 4,21 (t, J=6,8 Hz, 2H), 7,13-to 7.32 (m, 5H).

Reference example 19

4-[(4-Cyano-5-methyl-4-phenyl)hexyl]piperidine

2,43 g (of 6.49 mmol) 1-benzyl-4-[(4-cyano-5-methyl-4-phenyl) hexyl]piperidine was dissolved in 30 ml of 1,2-dichloroethane, add 0,85 30 ml of methanol and again heat the mixture under reflux. After the reaction mixture is evaporated, extracted with water and washed with ether. The obtained aqueous layer was alkalinized and distribute the mixture between ethyl acetate and a saturated solution of salt. The organic layer is dried over magnesium sulfate and evaporated, thus obtaining of 1.62 g (5,69 mmol, 87.7 per cent) yellow crude product. Physico-chemical data specified in the connection header is shown below.

1H-NMR (400 MHz, Dl3)of 0.77 (d, J=6.8 Hz, 3H), 0,86 of-1.04 (m, 3H), 1,07 of 1.28 (m, 3H), 1,19 (d, J=6.4 Hz, 3H), 1,29-of 1.44 (m, 1H), 1,48 is 1.58 (m, 2H), 1,74-of 1.85 (m, 1H), 2,04 with 2.14 (m, 2H), 2.49 USD (dt, J=2.4 Hz, 12.0 Hz, 2H), 2.95 and-to 3.02 (m, 2H), 7,26-7,40 (m, 5H).

Reference example 20

3-Cyano-3-(2-thienyl)propanol

In the atmosphere of nitrogen borohydride sodium (650 mg) is added to the bath with ice to a solution (25 ml) thiophene-2-acetonitrile (1 g), and (3 bromopropane)-tert-butyldimethylsiloxy from 2.06 g) in DMF. After 20 minutes, the organic layer is separated, by adding a saturated aqueous solution of ammonium chloride, and added ethyl acetate. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the mixture evaporated. The resulting residue is dissolved in acetonitrile (20 ml), add the ur. After 18 hours the organic layer was separated by adding water and ethyl acetate. The obtained organic layer was washed with water and saturated salt solution and dried over magnesium sulfate. The drying agent is filtered off and the mixture evaporated. The resulting residue is purified by chromatography on a column of silica gel (system hexane:ethyl acetate), obtaining mentioned in the title compound as a red oil (637 mg, 43%).

1H-NMR (400 MHz, Dl3)2,08-of 2.16 (m, 1H), is 3.08 (t, J=7,0 Hz, 2H), 3,75 (t, J=7,0 Hz, 2H), 4,15-4,20 (m, 1H), 7,14 (DD, J=3.8 Hz, 4.8 Hz, 1H), 7,65 (DD, J=0.8 Hz, 4.8 Hz, 1H), of 7.75 (DD, J=0.8 Hz, 3.8 Hz, 1H).

Reference example 21

2-[(3-Cyano-3-phenyl)propyl]-1,3-dioxolane

In nitrogen atmosphere sodium amide (1,11 g) are added to a solution (25 ml) phenylacetonitrile (3 g) in tetrahydrofuran. After 30 minutes, to the reaction solution via addition funnel add solution (25 ml) of 2-(2-bromacil)-1,3-dioxolane (with 4.64 g) in tetrahydrofuran. The mixture is stirred for 2 hours, add saturated aqueous solution of ammonium chloride and ethyl acetate to separate an organic layer. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The drier Sistema hexane:ethyl acetate), while receiving specified in the header connection (3,47 g, 62%).

1H-NMR (400 MHz, Dl3)a 1.75-1,90 (m, 2H), 1,95-2,10 (m, 2H), 3,80-4,00 (m, 5H), 4,91 (t, J=4.4 Hz, 1H), 7,30-7,42 (m, 5H).

Reference example 22

Ethyl-4-methyl-3-phenylpentane

In the atmosphere of nitrogen ethyltrimethylammonium (5,19 g) is added at -78°C. to the solution (1.5 M solution of 21.6 ml) diisopropylamide lithium in tetrahydrofuran (100 ml). After 20 minutes, add a solution (10 ml) isobutyrophenone (4.0 g) in tetrahydrofuran and leave the mixture to warm to room temperature. After stirring for 18 hours, add the monohydrate of sodium bisulfate (0.6 g) and continue to mix. After 10 minutes, separate the organic layer, adding of 0.2 n hydrochloric acid (250 ml) and ethyl acetate (200 ml). The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the mixture evaporated. 756 mg of the obtained crude product (7.9 g) was dissolved in methanol (5 ml), add a catalytic amount of 10% palladium on coal (9.5 mg) and the mixture is stirred in hydrogen atmosphere. After 4 hours the catalyst is filtered off and the filtrate concentrated. About the and this is mentioned in the title compound as a colorless oil (350 mg).

1H-NMR (400 MHz, Dl3)of 0.75 (d, J=6.4 Hz, 3H), of 0.95 (d, J=6.8 Hz, 3H), of 1.06 (t, J=7.2 Hz, 3H), 1,80-1,90 (m, 1H), 2,58 (DD, J=10 Hz, 15.2 Hz, 1H), 2,77 (DD, J=5.6 Hz, 15.2 Hz, 1H), 2,84-only 2.91 (m, 1H), 7,12-7,29 (m, 5H).

Reference example 23

4-Methyl-3-phenylpentane

In nitrogen atmosphere ethyl-4-methylpentanoate (350 mg) was dissolved in tetrahydrofuran (10 ml) at -78°C., add a solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 1,58 ml) and the mixture is stirred. The mixture is left to warm to room temperature with stirring, for 1.5 hours alternately add water (0.05 ml), 2 N. aqueous sodium hydroxide solution (0.05 ml) and water (0.15 ml), after which the mixture is stirred. Then to the mixture is added diethyl ether, then the resulting insoluble matter is filtered off and the filtrate evaporated. The resulting residue is purified by chromatography on a column of silica gel (system hexane:ethyl acetate), obtaining mentioned in the title compound as a colourless oil (257 mg, 42%, stage 2).

1H-NMR (400 MHz, Dl3)to 0.73 (d, J=6.8 Hz, 3H), of 0.97 (d, J=6.4 Hz, 3H), 1,78-of 1.88 (m, 2H), 2,04 with 2.14 (m, 1H), 2,36 is 2.46 (m, 1H), 3,34-of 3.54 (m, 2H), 7,20-7,16 (m, 2H), 7,17-7,22 (m, 1H), 7,25-7,31 (m, 2H).

Reference example 24

4-Methyl-3-phenylpentane to a solution (30 ml) of tert-butyldiethanolamine (4.9 g) in tetrahydrofuran. The mixture is left to warm to room temperature over 10 minutes and stirred. After 1 hour, add a solution (10 ml) isobutyrophenone (4.0 g) in tetrahydrofuran. The mixture is stirred for 13 hours and separate the organic layer, adding water and ethyl acetate. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the mixture evaporated. of 5.48 g of the obtained crude product (6,1 g) dissolved in methanol (30 ml), add a catalytic amount of 10% palladium on coal (250 mg) and the mixture is subjected to interaction under hydrogen pressure (3,9 kg/cm2). After 1.3 hours the catalyst is filtered off and the filtrate concentrated. The resulting residue is purified by chromatography on a column of silica gel (system hexane:ethyl acetate). The resulting product (3.0 g) dissolved in acetone (50 ml) and 5 N. the solution of hydrochloric acid (20 ml) and the mixture is stirred for 3 hours while heating under reflux. The solution is evaporated, thus obtaining specified in the title compound in the form of a reddish-yellow oil (1,96 g, 58% in 3 stages).

1H-NMR (400 MHz, Dl3)of 0.75 (d, J=6.8 Hz, 3H), were 0.94 (d, J=6.8 Hz, 3H), 1,80 is 1.91 (m, 1H)example 25

N-Methyl-N-methoxy-4-methyl-3-phenylpentane

In nitrogen atmosphere, the solution diethylthiophosphate (1.97 g) and triethylamine (1,63 ml) in dimethylformamide added at 0°C. to the solution (24 ml) of 4-methyl-3-phenylpentane acid (1,96 g) of the hydrochloride of N,O-dimethylhydroxylamine (1.18 g) and triethylamine (1,63 ml) in tetrahydrofuran. After 19 hours, the organic layer is separated, by adding diethyl ether and a saturated aqueous solution of ammonium chloride. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the mixture evaporated. The resulting residue is purified by chromatography on a column of silica gel (system hexane:ethyl acetate), obtaining mentioned in the title compound (1.13 g, 47%).

1H-NMR (400 MHz, Dl3)0,76 (d, J=6.6 Hz, 3H), of 0.97 (d, J=6.6 Hz, 3H), 1,84 is 1.96 (m, 1H), 2,74-of 2.86 (m, 2H), 2,97 was 3.05 (m, 1H), 3,06 (s, 3H), of 3.57 (s, 3H), 7,15-7,21 (m, 3H), 7.24 to 7,29 (m, 2H).

Reference example 26

4-Methyl-3-phenylpentane

In nitrogen atmosphere N-methyl-N-methoxy-4-methyl-3-phenylpentane (215 mg) was dissolved in tetrahydrofuran (9.1 ml) at -78°C. and add a solution of hydride diisobutylaluminum in toluene (1,leave, return to warm to room temperature with continuous stirring. The organic layer is separated, by adding to a mixture of diethyl ether, water and 1 N. aqueous solution of hydrochloric acid. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the mixture is evaporated, thus obtaining specified in the title compound as a colourless oil (200 mg). The compound obtained using the following reaction without purification.

1H-NMR (400 MHz, Dl3)of 0.77 (d, J=6.6 Hz, 3H), 0.95 d, J=6.8 Hz, 3H), 1,82-of 1.92 (m, 1H), 2,70-2,84 (m, 2H), 2,90 are 2.98 (m, 1H), 7,13-to 7.32 (m, 5H), 9,59-being 9.61 (m, 1H).

Reference example 27

4-Methyl-3-phenylhexane

Under nitrogen atmosphere a solution of n-utility in tetrahydrofuran (1.53 M, 1.2 ml) are added to a solution of the chloride (methoxymethyl)triphenylphosphine (627 mg) in tetrahydrofuran at -78°C, after which the temperature of the mixture was raised to 0°C. After 20 minutes, the external temperature is reduced to -78°C. and add 4-methyl-3-phenylpentane (200 mg) with tetrahydrofuran (4 ml). The mixture is left to warm to room temperature over 45 minutes and continue to stir for another 20 minutes. The organic layer is separated, by adding to a mixture of diethyl ether and nassali and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the mixture is evaporated, thus obtaining specified in the title compound as a colourless oil (200 mg). The compound obtained is dissolved in isopropanol (2 ml) and water (2 ml), add n-toluensulfonate acid (6 mg) and the reaction mixture is subjected to interaction for 8.5 hours under reflux. The organic layer is separated, by adding to a mixture of diethyl ether and a saturated aqueous solution of ammonium chloride. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the mixture evaporated. The residue is purified by chromatography on a column of silica gel NH (system hexane:ethyl acetate), obtaining mentioned in the title compound as a colorless oil (103 mg, 59%, stage 3).

1H-NMR (400 MHz, Dl3)to 0.72 (d, J=6.8 Hz, 3H), 0,99 (d, J=6.6 Hz, 3H), 1,76-1,90 (m, 2H), 2,12-of 2.28 (m, 4H), 7,07-7,10 (m, 2H), 7.18 in-7,22 (m, 1H), 7,26-7,35 (m, 2H), 9,63 of-9.65 (m, 1H).

Reference example 28

1-[(2-Vinyl-2-(4-pertenece)ethyl]piperazine

Specified in the title compound synthesized by the method according to example 104, described in JP-A 11-206862.

1H-NMR (400 MHz, Dl3)

Reference example 29

Dimethylacetal 4-bromo-2-thiophenecarbaldehyde

(90%) 4-bromo-2-thiophenecarbaldehyde (10.0 g) is dissolved in methanol (50 ml) and add ion-exchange resin Amberlite IR120B (5 g). The mixture is heated under reflux for 10 hours, allowed to cool to room temperature and then filtered ion exchange resin. The filtrate is evaporated and the resulting residue purified by chromatography on a column of silica gel (NH) (hexane), while receiving specified in the title compound as a pale yellow oil (8,93 g, 72%).

1H-NMR (400 MHz, Dl3)to 3.36 (s, 6N), 5,59 (d, J=0.8 Hz, 1H), 7,00 (DD, J=0.8 Hz, J=1.6 Hz, 1H), 7,20 (d, J=1.6 Hz, 1H).

Reference example 30

3-Cyano-5-thiophenecarbaldehyde

Method 1

Dimethylacetal 4-bromo-2-thiophenecarbaldehyde (6,82 g) dissolved in DMF (50 ml) and added copper cyanide (4,29 g). The mixture is heated under reflux for 3 hours, cooled to room temperature and add ethyl acetate. The mixture is then washed with an aqueous solution of ammonia, water, 0.1 G. of aqueous solution of hydrochloric acid and the Ute in 80% aqueous acetic acid solution (100 ml) and stirred the mixture at 0°C for one hour. The mixture is then washed with a saturated solution of salt. The reaction mixture is allowed to cool to room temperature and then add ethyl acetate. The mixture was washed with saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel (system: hexane/ethyl acetate) and recrystallized from ethyl acetate/hexane, thus obtaining specified in the title compound as pale yellowish white crystals (2,44 g, 62%).

Method 2

4-Bromo-2-thiophenecarbaldehyde (5,00 g) dissolved in DMF (40 ml) and added copper cyanide (3,52 g). The mixture is heated under reflux for 3 hours and allowed to cool to room temperature, then add ethyl acetate. The mixture is washed with an aqueous solution of ammonia, water, 0.1 G. of aqueous solution of hydrochloric acid and then with saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel (system: hexane/ethyl acetate) and recrystallized from ethyl acetate/hexane, thus obtaining specified in the title compound in the form of pale yellowish-white is 1H-NMR (400 MHz, Dl3)7,94 (d, J=1.2 Hz, 1H), 8,27 (d, J=1.2 Hz, 1H), 9,95 (d, J=1.2 Hz, 1H).

Reference example 31

3-Cyano-5-(1-hydroxy-2-methylpropyl " thiophene

3-Cyano-5-thiophenecarbaldehyde (2.00 g) was dissolved in anhydrous ether (100 ml) and anhydrous tetrahydrofuran (THF) (20 ml) and add a solution (10.9 ml) (2.0 M) chloride Isopropylamine in the air. The mixture is stirred at 0°C for 2 hours and add ethyl acetate. The mixture was washed with saturated aqueous ammonium chloride and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel (system: hexane/ethyl acetate), obtaining mentioned in the title compound as a pale yellow oil (1.25 g, 47%).

1H-NMR (400 MHz, Dl3)of 0.91 (d, J=6.8 Hz, 3H), and 1.00 (d, J=6.8 Hz, 3H), 1,99 (Sextus, J=6,8 Hz, 1H), 2,42 (d, J=4 Hz, 1H), and 4.68 (DD, J=4 Hz, J=6 Hz, 1H), 7,08-7,10 (m, 1H), a 7.85 (d, J=1.6 Hz, 1H).

Reference example 32

3-Cyano-5-(1-oxo-2-methylpropyl " thiophene

Oxalicacid (0,70 ml) dissolved in methylene chloride (10 ml) and cooled the mixture to a temperature of from -60 to -50°C. To the mixture is added dimethyl sulfoxide (0,57 ml) and re is the methylene chloride at a temperature of from -60 to -50°C and stirred the mixture for 15 minutes. Then to the mixture is added triethylamine (4,65 ml) and left to warm to room temperature. Then add ethyl acetate and the mixture washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The resulting residue is recrystallized from ethanol, thus obtaining specified in the title compound as pale yellowish white crystals (0,59 g). The filtrate is purified by chromatography on a column of silica gel (system: hexane/ethyl acetate), thus obtaining specified in the header connection (0,41 g, total yield of 1.00 g, 84%).

1H-NMR (400 MHz, Dl3)of 1.27 (d, J=6,8 Hz, 6N), 3,36 (Queen, J=6,8 Hz, 1H), 7,86 (d, J=1.2 Hz, 1H), 8,18 (d, J=0.8 Hz, 1H).

Reference example 33

[1-Cyano-1-(3-cyano-5-thienyl)-2-methylpropyl]diethylphosphate

3-Cyano-5-(1-oxo-2-methylpropyl " thiophene (0,90 g) dissolved in THF (50 ml) and add to 30.1 ml (0.5 M) of lithium cyanide and (90%) diethylthiophosphate (2,29 ml) in DMF. The mixture is stirred at room temperature for 30 minutes and add ethyl acetate and hexane. The mixture is then washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a number of the on-yellow oil (1,72 g, quantitative yield).

1H-NMR (400 MHz, Dl3)of 0.96 (d, J=6.8 Hz, 3H), of 1.27 to 1.34 (m, N), 2,49 (Queen, J=6,8 Hz, 1H), 4,00-is 4.21 (m, 4H), 7,56 (d, J=1.2 Hz, 1H), 8,04 (d, J=1.6 Hz, 1H).

Reference example 34

3-Cyano-5-(1-cyano-2-methylpropyl " thiophene

[1-Cyano-1-(3-cyano-5-thienyl)-2-methylpropyl]diethylphosphate (45 mg) was dissolved in ethyl acetate (5 ml), add (10%) palladium on coal (20 mg) and the mixture hydronaut at room temperature and normal pressure for 2 hours. The catalyst is filtered off and the filtrate evaporated. The resulting residue is purified preparative thin-layer chromatography on a column of silica gel (system: hexane/ethyl acetate), obtaining mentioned in the title compound as a pale yellow oil (22 mg, 88%).

1H-NMR (400 MHz, Dl3)of 1.09 (d, J=6.8 Hz, 3H), 1.14 in (d, J=6.8 Hz, 3H), 2,20 (Sextus, J=6,8 Hz, 1H), 3.96 points (d, J=6,8 Hz, 1H), 7,26 (s, 1H), to $ 7.91 (d, J=1.6 Hz, 1H).

Reference example 35

Ethyl-4-cyano-4-(3-cyano-5-thienyl)-5-methylhexane

tert-Piperonyl potassium (35 mg) are suspended in DMF (5 ml) and add a solution (5 ml) of 3-cyano-5-(1-cyano-2-methylpropyl)thiophene (0,60 g) in DMF. The mixture is stirred at room temperature for 3.5 is placed a solution of salt, dried over anhydrous magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel (system: hexane/ethyl acetate), obtaining mentioned in the title compound as a pale yellow oil (0.55 g, 60%).

1H-NMR (400 MHz, Dl3)of 0.94 (d, J=6.8 Hz, 3H), of 1.23 (d, J=6.8 Hz, 3H), 1,24 (t, J=6.8 Hz, 3H), 2,04-of 2.15 (m, 3H), 2,45-2,60 (m, 2H), 4.04 the-4,17 (m, 2H), 7,30 (d, J=1.2 Hz, 1H), to 7.93 (d, J=1.6 Hz, 1H).

Reference example 36

4-Cyano-4-(3-cyano-5-thienyl)-5-methylhexane

Ethyl-4-cyano-4-(3-cyano-5-thienyl)-5-methylhexane (0.55 g) was dissolved in THF (10 ml), add borohydride lithium (46 mg) and the mixture heated under reflux for 1.5 hours. After cooling to room temperature, add 1 N. aqueous solution of hydrochloric acid and water at 0°C and the mixture extracted with ethyl acetate. The mixture is then washed with saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel (system: hexane/ethyl acetate), obtaining mentioned in the title compound as a pale yellow oil (1.25 g, 47%). The catalyst is filtered off and the filtrate evaporated. Formed statocracy when this is mentioned in the title compound as a pale yellow oil (0.39 g, 83%).

1H-NMR (400 MHz, Dl3)of 0.93 (d, J=6.8 Hz, 3H), 1,21 (d, J=6.8 Hz, 3H), 1,19-of 1.41 (m, 1H), 1,45 is 1.70 (m, 1H), 1,65-to 1.77 (m, 1H), of 1.88 (dt, J=4 Hz, J=13,2 Hz, 1H), 2,09 (Queen, J=6,8 Hz, 3H), 2,30 (dt, J=4 Hz, J=12,4 Hz, 1H), 3,66 (t, J=6.4 Hz, 2H), 7,30 (d, J=1.2 Hz, 1H), 7,92 (s, 1H).

Reference example 37

N-(2-Cyanoethyl)-N-(2-Iodate)aniline

a 2.00 g (10.5 mmol) of N-(2-cyanoethyl)-N-(2-hydroxyethyl)aniline are dissolved in 60,0 ml of acetonitrile and to the solution alternately add 2,20 ml (15.8 mmol) of triethylamine and 0.90 ml (11.6 mmol) of methylchloride. After the reaction add a saturated solution of salt and the desired product extracted with ether. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated, give crude product. The crude product is dissolved in acetone and added 12.0 g (80,1 mmol) of sodium iodide. After the reaction add a saturated solution of salt and the desired product extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and get the crude product. The crude product is treated with silica gel (elution with ethyl acetate:hexane = 1:3), while receiving 2,78 g (9,26 mmol, 88,2%) decree/img> 2,62 (t, J=7,0 Hz, 2H), 3,26 (t, J=8.0 Hz, 2H), 3,71-3,81 (m, 4H), 6,66-6,72 (m, 2H), for 6.81-6,86 (m, 1H), 7,25-to 7.32 (m, 2H).

Reference example 38

1-{2-[N-(2-Cyanoethyl)aniline]ethyl}piperazine

2,78 g (9,26 mmol) of the above iodide dissolved in a 50.0 ml of acetonitrile, alternately add 2.5 g (13,4 mmol) 1-tert-butoxycarbonylamino and 1.29 ml (to 13.4 mmol) of triethylamine and the mixture is heated to 60°C. After the reaction add a saturated solution of salt and the desired product extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and get the crude product. The crude product is dissolved in 40 ml of methanol and add 30 ml of 4 n solution of hydrogen chloride in ethyl acetate. After the reaction, water is added and 10 ml of 5 n Hcl solution and washed with a mixture of ethyl acetate. the pH of the aqueous layer was adjusted to 11, add 5 N. aqueous sodium hydroxide solution and then the desired product is extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated, thus obtaining 1,81 g (7,01 mmol, 75.7 percent) specified in the title compound as a yellow syrup, which is crude product.

1H-NMR (400 MHz, Dl3)<, N), 3,71 (t, J=7.2 Hz, 2H), 6,65-6,72 (m, 2H), 6.73 x-6,79 (m, 1H), 7,22-7,29 (m, 2H).

Reference example 39

3-(1,3-Dioxolane-2-yl)thiophene

of 20.3 g (181 mmol) of 3-tiefenanzeige, 50 ml of ethylene glycol and 2.00 g (of 7.96 mmol) of PPTS are dissolved in 230 ml of toluene and dehydration in the office of Dean-stark. After the reaction mixture is extracted with ethyl acetate. The extract is washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and get the crude product. The crude product is treated with silica gel (ethyl acetate:hexane = 1:10), while receiving 12,1 g (77,3 mmol, 86.7 per cent) indicated in the title compound as a yellow oil.

1H-NMR (400 MHz, Dl3)3,97-to 4.15 (m, 4H), 5,91 (s, 2H), 7,16 (DDD, J=0.4 Hz, 1.2 Hz, 5.2 Hz, 1H), 7,32 (DD, J=2,8 Hz, 5.2 Hz, 1H), 7,42 (DDD, J=0.4 Hz, 1.2 Hz, 2.8 Hz, 1H).

Reference example 40

3-(1,3-Dioxolane-2-yl)-2-thiophenecarbaldehyde

to 5.00 g (32,0 mmol) of 3-(1,3-dioxolane-2-yl)thiophene are dissolved in 100 ml of THF. To the mixture are added dropwise to 24.5 ml (1.5 mol/l) n-utillity. The mixture is stirred for 0.5 hour, cooled to -70°C, add 3,10 ml (40.0 mmol) of DMF and transfer the mixture to the bath with ice. The mixture is then stirred for about 2 cassena salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and get the crude product. The crude product is treated with silica gel (ethyl acetate:hexane = 1:2), while receiving 3,68 g (20.0 mmol, 62.4 per cent) indicated in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3)3,97-to 4.15 (m, 4H), 5,91 (s, 2H), 7,16 (DDD, J=0.4 Hz, 1.2 Hz, 5.2 Hz, 1H), 7,32 (DD, J=2,8 Hz, 5.2 Hz, 1H), 7,42 (DDD, J=0.4 Hz, 1.2 Hz, 2.8 Hz, 1H).

Reference example 41

3-(1,3-Dioxolane-2-yl)-2-thiophenecarbonitrile

20 ml of a solution of 4.49 g (40.0 mmol) of tert-butoxide potassium in THF cooled to a temperature of from -45 to -30°C and alternately add 20 ml 3,90 g (20.0 mmol) of TOSmic reagent in THF and 20 ml 3,68 g (20.0 mmol) of 3-(1,3-dioxolane-2-yl)-2-thiophenecarbaldehyde in THF. After 40 minutes, add 60 ml of methanol at -15°C. the Mixture is heated under reflux for 15 minutes, add saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The extract is washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and get the crude product. The crude product is treated with silica gel Cromatorex NH (ethyl acetate:hexane = 1:4), while receiving 1,43 g (to 7.32 mmol, 36.6 percent) specified in the title compound as a yellow oil.

Reference example 42

2-[3-(1,3-Dioxolane-2-yl)-2-thienyl]-4-methylbutyronitrile

1,43 g (to 7.32 mmol) of 3-(1,3-dioxolane-2-yl)-2-thiophenecarbonitrile dissolved in 2 ml of dimethyl sulfoxide and alternately add 1,08 g (8,78 mmol) of 2-bromopropane, 100 mg (catalyst) iodide, Tetra-n-butylamine and 3 ml of 50% potassium hydroxide. After 25 minutes, add 300 mg of 2-bromopropane, then after 50 minutes, add 1 ml of 50% potassium hydroxide and 2 ml of DMSO. After the reaction add a saturated solution of salt and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and evaporated, to give crude product. The crude product is treated with 100 g of silica gel (ethyl acetate:hexane = 1:8), while receiving 853 mg (3,59 mmol, 49.1 per cent) indicated in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3)of 1.03 (d, J=6.8 Hz, 3H), 1,19 (d, J=6.4 Hz, 3H), 2,17-of 2.27 (m, 1H), 3,97 is 4.13 (m, 4H), or 4.31 (d, J=8.0 Hz, 1H), 7,06 (d, J=5,2 Hz, 2H), 7,24 (d, J=5,2 Hz, 2H).

Reference example 43

2-(3-Formyl-2-thienyl)-4-methylbutyronitrile

2.16 g (9,10 mmol) 2-[3-(1,3-dioxolane-2-yl)-2-thienyl]-4-methylbutyronitrile dissolved in 40 ml of acetone, add 115 ml of 5 N. the salt and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 75 g of silica gel (ethyl acetate:hexane = 1:2), while receiving 1.66 g (8,58 mmol, 94,3%) specified in the title compound as a brown oil.

1H-NMR (400 MHz, Dl3)of 1.12 (d, J=6.8 Hz, 3H), 1.14 in (d, J=6.8 Hz, 3H), 2,18-to 2.29 (m, 1H), equal to 4.97 (d, J=6,4 Hz, 1H), 7,34 (d, J=5,2 Hz, 2H), 7,44 (d, J=5,2 Hz, 2H), 10,01 (s, 1H).

Reference example 44

2-(3-Cyano-2-thienyl)-4-methylbutyronitrile

1.66 g (8,58 mmol) of 2-(3-formyl-2-thienyl)-4-methylbutyronitrile dissolved in 40 ml of ethanol, add 10 ml of an aqueous solution containing 894 mg (12.9 mmol) of hydroxylamine hydrochloride and 1.41 g (17,2 mmol) of sodium acetate and heated the mixture at 80°C. After the reaction add a saturated solution of salt and the desired product extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and receive crude oxime. The oxime is dissolved in 50 ml of dimethylformamide and added to 5.56 g (to 34.3 mmol) carbodiimide. Then the mixture is heated at 60°C and 50 minutes later, add to 2.40 ml (17,2 mmol) of triethylamine. After the eye is tatom. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and get the crude product. The crude product is treated with silica gel (elution with ethyl acetate:hexane = 1:9), while receiving 1.07 mg (vs. 5.47 mmol, 63.7 per cent) indicated in the title compound as an orange oil.

1H-NMR (400 MHz, Dl3)of 1.10 (d, J=6.8 Hz, 3H), 1,19 (d, J=6.8 Hz, 3H), 2,27-of 2.38 (m, 1H), 4,20 (d, J=7.2 Hz, 1H), 7,22 (d, J=5.6 Hz, 2H), 7,40 (d, J=5.6 Hz, 2H).

Reference example 45

Ethyl-4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexanoate

1.07 g (vs. 5.47 mmol) of 2-(3-cyano-2-thienyl)-4-methylbutyronitrile and 0.71 ml (6,56 mmol) acrylate is dissolved in 30 ml of tetrahydrofuran. To the resulting solution was gradually added 123 mg (1,09 mmol, catalyst) tert-butoxide potassium at room temperature. After the reaction alternately add a saturated solution of salt, saturated aqueous solution of ammonium chloride and 2 n Hcl solution and the desired product extracted with ethyl acetate. The organic layer is washed twice with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and get the crude product. The crude product is treated with silica gel (Elya is the IDA yellow oil.

1H-NMR (400 MHz, Dl3)of 0.94 (d, J=6.8 Hz, 3H), 1,24 (t, J=7.2 Hz, 3H), of 1.29 (d, J=6.4 Hz, 3H), 2,04-of 2.26 (m, 1H), 2,46-to 2.74 (m, 4H), 4,07-4,16 (m, 2H), 7,29 (d, J=5.3 Hz, 2H), 7,31 (d, J=5.3 Hz, 2H).

Reference example 46

4-Cyano-5-methyl-4-(3-cyano-2-thienyl)hexanol

500 mg (1,72 mmol) ethyl-4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexanoate dissolved in 10 ml of THF, add 37.5 mg (1,72 mmol) of lithium borohydride and the mixture is heated under reflux. After 1 hour 20 minutes stop heating and cooling with ice add 2 n Hcl solution. The mixture is extracted with ethyl acetate, the extract was successively washed with a saturated solution of salt and water and dried over anhydrous magnesium sulfate. The solvent is evaporated and get the crude product. The crude product is treated with silica gel (elution with ethyl acetate:hexane = 35:65), while receiving 244 mg (0.98 mmol, 57.1 per cent) indicated in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3)of 0.94 (d, J=6.4 Hz, 3H), of 1.26 (d, J=6.8 Hz, 3H), 1,24-of 1.39 (m, 1H), 1,68-to 1.82 (m, 1H), 2,28-2,48 (m, 2H), 2,59-2,70 (m, 1H), 3,64-and 3.72 (m, 2H), 7,28-7,29 (m, 2H).

Reference example 47

4-Cyano-5-methyl-4-(3-cyano-2-thienyl)hexalite

244 mg (0.98 mmol) of 4-cyano 83,6 ál (1,08 mmol) methylchloride. After about 5 minutes add 1.47 g (9,80 mmol) of sodium iodide. After the reaction add a saturated salt solution and ethyl acetate, an ethyl acetate layer was washed with aqueous sodium thiosulfate solution and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated, to give crude product. The crude product is treated with silica gel (elution with ethyl acetate:hexane = 1:10), while receiving 334 mg (0,93 mmol, 95,1%) specified in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3)of 0.93 (d, J=6.8 Hz, 3H), 1.27mm (d, J=6.8 Hz, 3H), 1,49-of 1.62 (m, 1H), 1,98 is 2.10 (m, 1H), 2,27-of 2.36 (m, 1H), 2,42-2,52 (m, 1H), 2,60-a 2.71 (m, 1H), 3,12-up 3.22 (m, 2H), 7,29-7,31 (m, 2H).

Reference example 48

4-Cyano-5-methyl-4-(5-cyano-2-thienyl)hexalite

1,05 g (to 4.23 mmol) 4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexanol dissolved in 40 ml of acetonitrile and 0.80 ml (5,71 mmol) of triethylamine. To the resulting mixture of 0.39 ml (5,07 mmol) methylchloride. After about 10 minutes add 6,34 g (of 42.3 mmol) of sodium iodide. After the reaction add a saturated salt solution and ethyl acetate. An ethyl acetate layer was washed with aqueous sodium thiosulfate solution and saturated salt solution, dried over magnesium sulfate and upar is getting 1.39 g (3.88 mmol, 91,7%) specified in the title compound as a yellow oil.

1H-NMR (400 MHz, Dl3)of 0.93 (d, J=6.8 Hz, 3H), 1.27mm (d, J=6.8 Hz, 3H), 1,49-of 1.62 (m, 1H), 1,98 is 2.10 (m, 1H), 2,27-of 2.36 (m, 1H), 2,42-2,52 (m, 1H), 2,60-a 2.71 (m, 1H), 3,12-up 3.22 (m, 2H), 7,29-7,31 (m, 2H).

Reference example 49

Methyl-3-(5-bromo-2-thienyl)propanoate

3.50 g (to 20.6 mmol) methyl-3-(2-thienyl)propanoate, synthesized by the method described in the journal J. Med.Chem., 1992, 35(21), 3870, dissolved in 20 ml of DMF, add of 3.85 g (21.6 mmol) of NBS, dissolved in 10 ml of DMF, and the mixture is heated at 80°C. After 2 hours, add a saturated salt solution and the mixture extracted with ether. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with silica gel (ethyl acetate:hexane = 1:9), while receiving to 4.62 g (to 18.6 mmol, 90,1%) specified in the title compounds as a pale yellow oil.

1H-NMR (400 MHz, Dl3)to 2.65 (t, J=7.4 Hz, 2H), is 3.08 (t, J=7.4 Hz, 2H), 3,69 (s, 3H), return of 6.58 (d, J=3.6 Hz, 1H), 6,85 (d, J=3.6 Hz, 1H).

Reference example 50

Methyl-3-(5-cyano-2-thienyl)propanoate

to 4.62 g (to 18.6 mmol) methyl-3-(5-bromo-2-thienyl)propanoate, 1,75 g (14.9 mmol) of Zn(CN)2 and the mixture is heated at 120°C. After 2 hours the mixture is cooled and extracted with ether. The organic layer was washed with a saturated solution of salt and 2 N. Hcl solution, dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with silica gel (ethyl acetate:hexane = 1:9), while receiving 2,96 g (to 18.6 mmol, 100%) specified the title compound as a green oil.

1H-NMR (400 MHz, CDCl3)a 2.71 (t, J=7.4 Hz, 2H), 3,19 (t, J=7.4 Hz, 2H), 3,71 (s, 3H), 6,85 (d, J=3.6 Hz, 1H), 7,46 (d, J=3.6 Hz, 1H).

Reference example 51

3-(2-Thienyl)propanol

1,32 g (of 7.75 mmol) methyl-3-(2-thienyl)propanoate dissolved in 50 ml of THF. The mixture is cooled to -20°C and added to 6.00 ml LiAlH4(1.0 M solution). After the reaction mixture is quenched with water and 5 N. NaOH solution and filtered through celite. The filtrate is concentrated and the resulting crude product is treated with silica gel (ethyl acetate:hexane = 1:1), while receiving 1,05 g (7,38 mmol, 95.2 per cent) indicated in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3)of 1.29 (t, J=6.0 Hz, 1H), 1,90-2,00 (m, 2H), 2.95 points (t, J=7,6 Hz, 2H), and 3.72 (q, J=6.0 Hz, 2H), 6,80-6,83 (m, 1H), 6,91-6,94 (m, 1H), 7,11-7,14 (m, 1H).

Reference example 52

3-(5-Cyano-2-thienyl)disappear THF, add 450 mg (to 18.6 mmol) of lithium borohydride and the mixture is heated under reflux. After one hour stop heating and cooling with ice to a mixture of 2 N. the model HC1 solution. The mixture is extracted with ethyl acetate, the extract was successively washed with a saturated solution of salt and water and dried over anhydrous magnesium sulfate. The solvent is evaporated and get the crude product. The crude product is treated with silica gel (elution with ethyl acetate:hexane, 25:75 to 50:50), while receiving of 1.37 g (8,19 mmol, 44,0%) specified in the title compound as a green oil.

1H-NMR (400 MHz, Dl3)of 1.32 to 1.37 (m, 1H), 1,90-2,00 (m, 2H), 2,99 (t, J=7,6 Hz, 2H), 3,68 is 3.76 (m, 2H), at 6.84 (d, J=3.6 Hz, 1H), 7,47 (d, J=3.6 Hz, 1H).

Reference example 53

tert-Butyl 4-[3-(2-thienyl)propyl]-1-piperidinecarboxylate

1,05 g (7,38 mmol) 3-(2-thienyl)propanol are dissolved in 60 ml of acetonitrile and added to a solution of 2.58 ml (18.5 mmol) of triethylamine and 0.63 ml (8,12 mmol) methylchloride. After 25 minutes, add 2,07 g (11.1 mmol) of tert-butyl 1-piperidinecarboxylate, of 3.32 g (22.7 mmol) of sodium iodide and 6 ml of water and heat the mixture to 60°C. After the reaction add a saturated solution of salt and the desired product extracted with atilas ritel is evaporated and get the crude product. The crude product is treated with silica gel Cromatorex NH (elution with ethyl acetate:hexane = 2:8), while receiving 1,94 g (of 6.25 mmol, 84.7 per cent) indicated in the title compounds as a pale yellow oil.

1H-NMR (400 MHz, Dl3)of 1.46 (s, N), 1,83 is 1.91 (m, 2H), 2,35-to 2.42 (m, 2H), 2,87 (t, J=7,6 Hz, 2H), 3,40-of 3.46 (m, 4H), 6,77-to 6.80 (m, 1H), 6,91 (DD, J=3.2 Hz, 5.2 Hz, 1H), 7,11 (DD, J=1.2 Hz, 5.2 Hz, 1H).

Reference example 54

tert-Butyl 4-[3-(5-cyano-2-thienyl)propyl]-1-piperidinecarboxylate

Specified in the title compound is synthesized analogously to the way to obtain tert-butyl 4-[3-(2-thienyl)propyl]-1-piperidinecarboxylate in reference example 53 (exit 74,2%).

1H-NMR (400 MHz, Dl3)of 1.46 (s, N), 1,83 is 1.91 (m, 2H), 2,34-to 2.41 (m, 6N), only 2.91 (t, J=7,6 Hz, 2H), 3,41-of 3.46 (m, 4H), for 6.81 (d, J=4.0 Hz, 1H), 7,46 (d, J=4.0 Hz, 1H).

Reference example 55

1-[3-(2-Thienyl)propyl]piperazine

of 1.94 g (of 6.25 mmol) of tert-butyl 4-[3-(2-thienyl)propyl]-1-piperidinecarboxylate dissolved in 20 ml of methanol and add 15 ml of 4 n solution of hydrogen chloride in ethyl acetate. After the reaction mixture evaporated. The residue was adjusted to pH 11 by adding 2 N. aqueous sodium hydroxide solution, the desired product is extracted CHL%) specified in the title compound as a yellow oil, which of the crude product.

1H-NMR (400 MHz, Dl3)1,84-of 1.92 (m, 2H), 2,35-2,48 (m, 6N), 2,83-of 2.93 (m, 6N), 6,77-to 6.80 (m, 1H), 6,91 (DD, J=3.2 Hz, 5.2 Hz, 1H), 7,11 (DD, J=1.2 Hz, 5.2 Hz, 1H).

Reference example 56

1-[3-(5-Cyano-2-thienyl)propyl]piperazine

Specified in the title compound is synthesized analogously to the way to obtain 1-[3-(2-thienyl)propyl]piperazine in reference example 55 (exit 96,0%).

1H-NMR (400 MHz, Dl3)1,83 is 1.91 (m, 2H), 2,33 is 2.44 (m, 6N), 2,87-to 2.94 (m, 6N), for 6.81 (d, J=4.0 Hz, 1H), 7,46 (d, J=4.0 Hz, 1H).

Reference example 57

2-(Chloromethyl)benzoxazole

Specified in the title compound is obtained by a method described in SYNTHETIC COMMUNICATION, 19(16), 2921-2924 (1989) (yield quantitative).

1H-NMR (400 MHz, Dl3)of 4.77 (s, 2H), 7,34-the 7.43 (m, 2H), 7,54-7,58 (m, 1H), 7,73-to 7.77 (m, 1H).

Reference example 58

Benzyl-4-[(2-benzoxazolyl)methyl]-1-piperidinecarboxylate

a 2.00 g (11.9 mmol) of 2-(chloromethyl)benzoxazole dissolved in 50 ml of acetonitrile, add of 1.66 ml (to 11.9 mmol) of triethylamine and 3.15 g (of 14.3 mmol) benzyl-1-piperidinecarboxylate and the mixture is stirred at 80°C. After 2 hours the reaction solution is concentrated and add the second salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and get the crude product. The crude product is treated with silica gel Cromatorex NH (eteltetet:hexane = 25:75), while receiving 3.57 g (10.2 mmol, 85.7 percent) specified in the title compound as a yellow syrup.

1H-NMR (400 MHz, Dl3)2,56 of 2.68 (Shir. d, 4H), 3,56-3,62 (m, 4H), to 3.89 (s, 2H), 5,12 (s, 2H), 7,28-7,37 (m, 7H), 7,52-of 7.55 (m, 1H), 7,70-7,74 (m, 1H).

Reference example 59

1-[(2-Benzoxazolyl)methyl]piperazine

3.57 g (10.2 mmol) of benzyl 4-[(2-benzoxazolyl)methyl]-1-piperidinecarboxylate dissolved in 50 ml of methanol and added 400 mg of 10% Pd-C. Atmosphere replaced with hydrogen and the mixture is stirred. After the reaction, the reaction solution is filtered and evaporated, thus obtaining 2.15 g (of 9.89 mmol, 97,0%) specified in the title compound as a yellow oil, which is unrefined product.

1H-NMR (400 MHz, Dl3)2,56-of 2.66 (m, 4H), 2,96 are 2.98 (m, 4H), a 3.87 (s, 2H), 7,31 and 7.36 (m, 2H), 7,51-7,56 (m, 1H), 7,69-7,74 (m, 1H).

Reference example 60

2-(Chloromethyl)-5-cyanobenzoate

Specified in the title compound synthesized by the method described in SYNTHETIC COMMUNICATION, 19(16), 2921-2924 (1989) (the yield of 79.8%).

1H-NMR (400 MHz, Dl3)

Specified in the title compound is synthesized analogously to method of obtaining benzyl-4-[(2-benzoxazolyl)methyl]-1-piperidinecarboxylate in reference example 58 (exit 85,6%).

1H-NMR (400 MHz, Dl3)to 2.57-2,70 (Shir.d, 4H), 3,56 - 3,63 (m, 4H), to 3.92 (s, 2H), 5,13 (s, 2H), 7,30-7,38 (m, 5H), 7,62-to 7.68 (m, 2H), 8,04-with 8.05 (m, 1H).

Reference example 62

1-[{2-(5-Cyanobenzoate)}methyl]piperazine

Specified in the title compound synthesized by the method described in reference example 59 (exit 58,0%).

1H-NMR (400 MHz, Dl3)2,59-of 2.66 (m, 4H), 2.93 which is 3.00 (m, 4H), 3,90 (s, 2H), 7,62-to 7.67 (m, 2H), 8,03-with 8.05 (m, 1H).

Reference example 63

Ethyl-4-cyano-5-methyl-4-(3-thienyl)hexanoic

3-Methyl-2-(3-thienyl)Botanical (6,23 g), obtained using 3-trilaterally in as the starting material in the method of example 114, described in JP-A 11-206862, and acrylate (4,53 g) dissolved in dimethylformamide (15 ml) and at room temperature are added to a solution of tert-butoxide potassium (423 mg) in a solution of dimethylformamide (60 ml). The mixture is stirred for 5 hours and the separated organic layer by adding saturated aq is a thief salt and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the filtrate evaporated. The residue is purified by chromatography on a column of silica gel (system: hexane/ethyl acetate), obtaining mentioned in the title compound as a yellow oil (6,66 g, 67%).

1H-NMR (400 MHz, Dl3)of 0.85 (d, J=6.8 Hz, 3H), 1,19 (d, J=6.8 Hz, 3H), 1,22 (t, J=7.2 Hz, 3H), 2.00 in to 2.18 (m, 3H), 2,38-of 2.50 (m, 2H), was 4.02-to 4.14 (m, 2H), 6,94 (DD, J=1.4 Hz, 5.0 Hz, 1H), 7,29 (DD, J=1.4 Hz, 2.8 Hz, 1H), 7,37 (DD, J=2,9 Hz, 5.0 Hz, 1H).

Reference example 64

4-Cyano-5-methyl-4-(3-thienyl)hexanol

Solution (35 ml) of ethyl-4-cyano-5-methyl-4-(3-thienyl)hexanoate (6,66 g) in tetrahydrofuran is added dropwise to a solution (50 ml) of lithium aluminum hydride (686 mg) in tetrahydrofuran. The mixture is stirred for 2 hours, add 2 N. aqueous solution of NaOH and water and filter the precipitate. The resulting filtrate is evaporated and the residue purified by chromatography on a column of silica gel (system ethyl acetate/hexane), while receiving specified in the title compound as a yellow oil (5.30 g, 95%).

1H-NMR (400 MHz, Dl3)of 0.85 (d, J=6.8 Hz, 3H), of 1.17 (d, J=6.6 Hz, 3H), 1.18 to 1,22 (m, 1H), 1,22-of 1.36 (m, 1H), 1.56 to 1,72 (m, 1H), 1,90 (DDD, J=4,6 Hz, 12.1 Hz, and 13.4 Hz, 1H), 2,04-2,12 (m, 1H), 2,14-2,22 (m, 1H), to 3.58-the 3.65 (m, 2H), 6,95 (DD, J=1.5 Hz, 5.1 Hz, is an

In the atmosphere of nitrogen methanesulfonanilide (0,20 ml) are added to a solution (9.0 ml) of 4-cyano-5-methyl-4-(3-thienyl)hexanol (400 mg) and triethylamine (0.75 ml) in acetonitrile at room temperature and the resulting mixture is stirred. After 2 hours, add water and ethyl acetate and the separated organic layer. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the filtrate evaporated. The resulting residue is dissolved in acetone (18 ml), add sodium iodide (2,68 g) and the mixture was stirred at 40°C for 2 hours. The organic layer was separated by adding water and ethyl acetate. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the filtrate is evaporated, getting mentioned in the title compound as a yellow oil (670 mg).

1H-NMR (400 MHz, Dl3)of 0.85 (d, J=6.8 Hz, 3H), of 1.18 (d, J=6.6 Hz, 3H), 1,46 is 1.60 (m, 1H), 1,86 is 2.00 (m, 1H), 2,02-of 2.20 (m, 2H), 3,05-3,20 (m, 2H), 6,95 (DD, J=1.2 Hz, 5.2 Hz, 1H), 7,28 (DD, J=1.2 Hz, 2.8 Hz, 1H), 7,37 (DD, J=2,8 Hz, 5,2 Hz, 1H).

Reference example 66

Ethyl-4-cyano-5-methyl-4-[4-(2-cyano)thienyl]hexanoate

1H-NMR (400 MHz, Dl3 is, J=1.6 Hz, 1H), 7,58 (d, J=1.6 Hz, 1H).

Reference example 67

4-Cyano-5-methyl-4-(2-cyano-4-thienyl)hexanol

Specified in the title compound obtained as a yellow oil by the above method recovery LiBH4(30%).

1H-NMR (400 MHz, Dl3)0,86 (d, J=6.8 Hz, 3H), of 1.18 (d, J=6.8 Hz, 3H), of 1.20 and 1.33 (m, 1H), 1.60-to 1,72 (m, 1H), 1,86 is 1.96 (m, 1H), 2.00 in a 2.12 (m, 1H), 2,16-of 2.26 (m, 1H), 3,60-3,68 (m, 2H), of 7.48 (d, J=1.6 Hz, 1H), EUR 7.57 (d, J=1.6 Hz, 1H).

Reference example 68

1-Iodine-4-cyano-5-methyl-4-[4-(2-cyano)thienyl]hexane

Specified in the title compound is synthesized in the form of a yellow oil by the methods described in reference examples 63, 64 and 65 (91%).

1H-NMR (400 MHz, Dl3)0,86 (d, J=6.8 Hz, 3H), 1,19 (d, J=6.8 Hz, 3H), 1,20-1,30 (m, 1H), 1,40-of 1.55 (m, 1H), 1,90-2,00 (m, 1H), 2.00 in a 2.12 (m, 1H), 2,16-of 2.26 (m, 1H), 3,06-3,17 (m, 1H), 3,17-of 3.23 (m, 1H), of 7.48 (d, J=1.6 Hz, 1H), EUR 7.57 (d, J=1.6 Hz, 1H).

Reference example 69

2-(2-Cyano-4-pertenece)ethylpiperazin

In nitrogen atmosphere tert-piperonyl potassium (869 mg) are added to a solution (10 ml), benzyl-4-(2-hydroxyethyl)-1-piperidinecarboxylate (1.86 g) in tetrahydrofuran in a bath with ice. The reaction system is stirred for one hour,1,09 g) in tetrahydrofuran (5 ml). The reaction system is stirred for 2 hours, allowing it to warm to room temperature, then add saturated aqueous solution of ammonium chloride and diethyl ether and separate the organic layer. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the filtrate evaporated. The residue is purified by chromatography on a column of silica gel (system hexane:ethyl acetate) and receive a colorless oil, which is an intermediate substance (1.10 g, 46%). The intermediate compound (1.10 g) was dissolved in methanol (10 ml), add 10% palladium on coal (100 mg) and the mixture is stirred at room temperature in a hydrogen atmosphere. After 1.5 hours, the catalyst of the reaction is filtered through celite and the filtrate evaporated. Specified in the title compound (647 mg, 80%) used in the following reaction without purification.

Loose coupling:

1H-NMR (400 MHz, Dl3)to 2.55 2.63 in (m, 4H), 2,87 (t, J=5.7 Hz, 2H), 2,89 of 2.92 (m, 4H), 4,19 (t, J=5.7 Hz, 2H), 6,93 (DD, J=4 Hz and 8.8 Hz, 1H), 7,21-7,29 (m, 2H).

Reference example 70

4-Cyano-5-methyl-4-[4-(2,5-dibromo)thienyl]hexanol

In nitrogen atmosphere 4-cyano-5-methyl-4-(3-enterprise is the atur. The mixture is stirred at 100°C for one hour, add water and diethyl ether, and the separated organic layer. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the filtrate evaporated. The resulting residue is purified by chromatography on a column of silica gel (system hexane:ethyl acetate), obtaining mentioned in the title compound as a yellow oil (670 mg, 78%).

1H-NMR (400 MHz, Dl3)to 0.92 (d, J=6.8 Hz, 3H), of 1.18 (d, J=6.8 Hz, 3H), 1,31-of 1.44 (m, 1H), 1.60-to around 1.74 (m, 1H), 2,08 (DDD, J=4.3 Hz, 12.1 Hz, to 13.6 Hz, 1H), 2,43 (DDD, J=4,6 Hz, 12.3 Hz, to 13.6 Hz, 1H), 2,59 (Sept, J=6.8 Hz, 2H), 7,05 (s, 1H).

Reference example 71

2-(4-Methylsulfinylphenyl)ethylpiperazin

In nitrogen atmosphere 4-(methylthio)phenol (4,2 g) and bromoethanol (5.6 g) was dissolved in a solution of dimethylformamide (60 ml), add potassium carbonate (12.4 g) and stirring, heat the mixture at 100°C. After 3 hours the mixture is cooled to room temperature and separate the organic layer by adding diethyl ether and water. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The drying of hoteltravel is the best (4 methylthiophene)ethanol (3.55 g, 64%) as white crystals. The product (1.0 g) dissolved in dichloromethane (50 ml), the mixture is cooled in a bath with a mixture of dry ice / methanol, add meta-chloroperbenzoic acid (3.6 g) and the mixture is stirred. The reaction mixture is allowed to cool to room temperature for 2 hours and then add 1 N. aqueous sodium bicarbonate solution and 1 n solution of Na2S2O3. The mixture is stirred, extracted with dichloromethane and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the mixture evaporated. The residue is dissolved in acetonitrile (18 ml), add triethylamine (2.3 ml) and methanesulfonamide (0.5 ml) and stirred the mixture at room temperature. After 1.5 hours, add sodium iodide (4.9 g) and tert-butyl-1-piperidinecarboxylate (1.2 g) and stirring, heat the mixture at 60°C. the Reaction mixture is stirred for 4.5 hours and the separated organic layer by adding ethyl acetate and water. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the mixture evaporated. The residue is purified by chromatography on a column of silica gel (system: hexane/ethyl acetate), thus obtaining tert-butyl-2-(4-methylthiophene)ethyl-1-piperazinylcarbonyl 4 N. the solution of hydrochloric acid in ethyl acetate (30 ml) in a bath with ice. The mixture is stirred at room temperature overnight, the resulting white crystals are collected by filtration and washed with diethyl ether. To the crystals was added 1 N. aqueous sodium hydroxide solution and dichloromethane and separated the organic layer. The obtained organic layer is evaporated, thus obtaining specified in the title compound as a yellow oil (820 mg, 53%, stage 3).

1H-NMR (400 MHz, Dl3)2,52-2,60 (m, 4H), and 2.83 (t, J=5.8 Hz, 2H), 2,93 (Shir.t, J=4.8 Hz, 4H), 3,03 (s, 3H), 4,18 (t, J=5.8 Hz, 2H), 7,03 (Shir.d, J=9.0 Hz, 2H), 7,86 (Shir.d, J=9.0 Hz, 2H).

Reference example 72

2-(3-Acetylphenol)ethylpiperazin

In nitrogen atmosphere 3-hydroxyacetophenone (4.1 g) and octabromodiphenyl ethanol (5.6 g) was dissolved in a solution of dimethylformamide (60 ml), add potassium carbonate (12.4 g) and stirring, heat the mixture at 100°C. After 3 hours the mixture is cooled to room temperature and separate the organic layer, adding water and diethyl ether. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the mixture evaporated. The mod is ol (3.28 g, 61%) as white crystals. Product (977 mg) dissolved in acetonitrile (18 ml), add triethylamine (2.3 ml) and methanesulfonamide (0.5 ml) and the mixture is stirred at room temperature. After 1.5 hours, add sodium iodide (4.9 g) and tert-butyl-1-piperidinecarboxylate (1.2 g) and stirring, heat the mixture at 60°C. the Reaction mixture is stirred for 4.5 hours and separate the organic layer, adding water and ethyl acetate. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the mixture evaporated. The residue is purified by chromatography on a column of silica gel (system: hexane/ethyl acetate) to give tert-butyl 2-(3-acetylphenol)ethyl-1-piperidinecarboxylate (1,33 g) as a yellow oil. Product (1,33 g) dissolved in methanol (10 ml) and the solution is added to 4 N. the solution of hydrochloric acid in ethyl acetate (30 ml). The mixture is stirred at room temperature overnight, the resulting white crystals are collected by filtration and washed with diethyl ether. The organic layer is separated, adding to the crystals 1 N. aqueous sodium hydroxide solution and dichloromethane. The obtained organic layer is evaporated, thus obtaining specified in if">2,52-2,60 (m, 4H), 2,60 (s, 3H), 2,82 (t, J=5.8 Hz, 2H), 3,93 (Shir.t, J=4.9 Hz, 4H), to 4.16 (t, J=5.8 Hz, 2H), 7,12 (DDD, J=1.1 Hz, 2.6 Hz and 8.2 Hz, 1H), 7,34-7,40 (m, 1H), 7,50 (DD, J=1.5 Hz, 2.6 Hz, 1H), 7,54 (DDD, J=1.1 Hz, 1.5 Hz, 7.5 Hz, 1H).

Reference example 73

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

tert-Butyl-1-piperidinecarboxylate (540 mg) is added to the solution (11 ml) 1-iodine-4-cyano-5-methyl-4-(2-thienyl)hexane (744 mg) and triethylamine (0,93 ml) synthesized in example 84, acetonitrile and the mixture is stirred at 50°C for 5 hours in nitrogen atmosphere. The reaction solution is evaporated and the crude product is purified by chromatography on a column of silica gel (system: hexane/ethyl acetate) to give colorless oil (705 mg, 81%). The resulting product (705 mg) was dissolved in methanol (5 ml), added with 4 n hydrochloric acid in ethyl acetate (15 ml) and the mixture is stirred for 10 hours. To the mixture is added diethyl ether and ethyl acetate and stirred in a bath with ice. Hydrochloride is indicated in the title compound collected by filtration (white crystals, 490 mg, 75%). The resulting hydrochloride is extracted with dichloromethane and saturated aqueous sodium bicarbonate is converted into the free compound and use the following RHC, 3H), 1.30 and of 1.55 (m, 1H), 1,60 of-1.83 (m, 1H), 1,83 is 2.00 (m, 1H), 2,22-of 2.30 (m, 2H), 3.00 and-of 3.80 (m, 10H), 7,07 (DD, J=5,1 Hz, 3.5 Hz, 1H), 7,11 (DD, J=3.5 Hz, 1.3 Hz, 1H), to 7.59 (DD, J=5,1 Hz, 1.3 Hz, 1H), of 9.30-9,70 (m, 2H).

ESI-MS (m/e): 292 (M+H).

Reference example 74

1-[3-Cyano-4-methyl-3-(2-thienyl)pentyl]piperazine

Specified in the title compound synthesized by the method according to reference example 73.

Loose coupling:

1H-NMR (400 MHz, Dl3)of 0.91 (d, J=6.6 Hz, 3H), 1,19 (d, J=6.8 Hz, 3H), 1,50-1,60 (m, 1H), 1,88-to 1.98 (m, 1H), 2,20-to 2.18 (m, 2H), 2,28-2,52 (m, 6N), 2,83-2,90 (m, 4H), 6,94-6,98 (m, 1H), 7,10-7,13 (m, 1H), 7,25-7,30 (m, 1H).

Reference example 75

4-(1,4-Diazepan-1-yl)-1-isopropyl-1-phenylbutyramide

Specified in the title compound synthesized from tert-butyl 1-homopiperazines the method according to reference example 73.

Loose coupling:

1H-NMR (400 MHz, Dl3)0,78 (d, J=6.8 Hz, 3H), 1,02-1,20 (m, 1H), 1,20 (d, J=6.6 Hz, 3H), 1,44-of 1.62 (m, 1H), 1,64-of 1.74 (m, 2H), 1.85 to 1,95 (m, 1H), 2.06 to of 2.20 (m, 2H), 2,36-2,48 (m, 2H), 2,50 at 2.59 (m, 4H), 2,80-of 2.86 (m, 2H), 2,89 (t, J=6,1 Hz, 2H), 7,25-7,34 (m, 1H), was 7.36-7,40 (m, 4H).

Reference example 76

1-(Vinylsulphonyl)piperidine

1H-NMR (400 MHz, Dl3)1,47-1p>

1,2,3,4-Tetrahydro-1-finelinenation

1H-NMR (400 MHz, Dl3)1,95-2,05 (m, 2H), of 2.81 (t, J=6,8 Hz, 2H), 3.75 to of 3.85 (m, 2H), 5,91 (d, J=10.4 Hz, 1H), 6,23 (d, J=16.4 Hz, 1H), 6,46 (DD, J=16.4 Hz, 10.4 Hz, 1H), 7,00-7,20 (m, 3H), of 7.65 (d, J=8,4 Hz, 1H).

Reference example 78

5-(2,5-Dihydro-1H-1-pyrrolyl)-2-isopropyl-5-oxo-2-(2-thienyl)pentenenitrile

In nitrogen atmosphere diethylthiophosphate (618 mg) is added at room temperature to a solution (15 ml) of 3-pyrroline (262 mg) and 4-cyano-4-(2-thienyl)-5-methylhexanoic acid (692 mg) in tetrahydrofuran and the mixture is stirred over night. Then the reaction solution is evaporated and the crude product is purified by chromatography on a column of silica gel (system: hexane/ethyl acetate), obtaining mentioned in the title compound as a yellow oil (440 mg).

1H-NMR (400 MHz, Dl3)to 0.92 (d, J=6.8 Hz, 3H), 1,22 (d, J=6.6 Hz, 3H), 2,00-2,30 (m, 3H), 2,40-2,60 (m, 2H), 4,00-4,30 (m, 4H), 5,70-5,80 (m, 1H), 5,80-5,90 (m, 1H), 6.87 in-7,00 (m, 1H), 7,15 (m, 1H), 7.23 percent-7,26 (m, 1H).

Physico-chemical data the following compounds include values NMR measured for free connection, and values ESI-MC measured for hydrochloride. Hydrochloride get way, op is relaminarization

867 mg (3,49 mmol) 4-cyano-4-(5-cyano-2-thienyl)-5-methylhexane dissolved in 20 ml of acetonitrile. Type of 0.58 ml (1.20 equiv.) of triethylamine and 0.30 ml (1,10 EQ.) methylchloride. After 10 minutes, add a saturated solution of salt and the desired product extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and get the crude product. The product is dissolved in 30 ml of acetonitrile, add of 1.57 g (3.00 EQ.) sodium iodide, 0.54 ml (1,10 EQ.) of triethylamine and 845 mg (of 4.54 mmol) of (3R)-3-tert-butoxycarbonylmethylene and the mixture is heated at 60°C. After the reaction add a saturated solution of salt and the desired product extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and get the crude product. The crude product is treated with 100 g of silica gel Cromatorex NH (ethyl acetate:hexane = 25-35% ethyl acetate), obtaining of 1.34 g (3,21 mmol, 92,0%) specified in the title compound as a yellow oil. Physicochemical data of the compounds are shown below.

1H-NMR (400 MHz, Dl3)to 0.92 (d, J=6.4 Hz, 3H), 1,21 (d, J=6.8 Hz, 3H), 1,1, ,70-4,82 (lat.d, 1H, 7,15 (d, J=3.6 Hz, 1H), 7,52 (d, J=3.6 Hz, 1H).

Reference example 80

1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexan]-(3R)-3-aminopyrrolidine

1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexan]-(3R)-3-tert-butoxycarbonylamino (1,34 g is 3.21 mmol) obtained in reference example 79, dissolved in 10 ml of methanol and add 10 ml of 4 n solution of hydrochloric acid in ethyl acetate. After the reaction mixture is alkalinized 5 N. solution of sodium hydroxide and extracted with chloroform. The organic layer is dried over magnesium sulfate and evaporated, thus obtaining 998 mg (3,15 mmol, 99.5% pure, red oil) crude product. Physicochemical data of the compounds are shown below.

1H-NMR (400 MHz, Dl3)to 0.92 (d, J=6.8 Hz, 3H), 1,21 (d, J=6.4 Hz, 3H), 1.18 to 1.32 to (m, 1H), 1,39-1,71 (m, 2H), 1,75-of 1.85 (m, 1H), 2,01-2,19 (m, 2H), 2,19-to 2.29 (m, 2H), 2,32-to 2.41 (m, 2H), 2,42 is 2.51 (m, 1H), 2.57 m)-2,66 (m, 2H), 3,45-to 3.52 (m, 1H), 7,15 (d, J=3.6 Hz, 1H), 7,52 (d, J=3.6 Hz, 1H).

Reference example 81

Obtaining 1-[4-cyano-4-(5-cyano-2-thienyl)-5-methylhexan]-(3R)-3-[N-(2-cyanoethyl)amino]pyrrolidine

998 mg (3,15 mmol) 1-[4-cyano-4-(5-cyano-2-thienyl)-5-methylhexan]-(3R)-3-aminopyrrolidine obtained in reference example 80, dissolved in 25 m is. the donkey the end of the reaction the mixture is evaporated and get the crude product. The crude product is treated with 5 g of silica gel Cromatorex NH (100% etilatsetata), while receiving 1.01 g (2,73 mmol, 86.7 per cent) indicated in the title compound as an orange oil. Physicochemical data of the compounds are shown below.

1H-NMR (400 MHz, Dl3)to 0.92 (d, J=6.4 Hz, 3H), 1,21 (d, J=6.4 Hz, 3H), of 1.20 to 1.31 (m, 1H), 1,48-1,71 (m, 2H), 1,76 is 1.86 (m, 1H), 2,02-of 2.15 (m, 2H), 2,18-to 2.29 (m, 1H), 2,30-2,39 (m, 3H), 2,43-of 2.56 (m, 4H), 2,56-of 2.64 (m, 1H), 2,86 (t, J=6,4 Hz, 2H), 3.25 to to 3.33 (m, 1H), 7,16 (d, J=4.0 Hz, 1H), 7,52 (d, J=4.0 Hz, 1H).

Reference example 82

1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexan]piperazine

1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexan]-4-(tert-butoxycarbonyl)piperazine synthesized from 4-cyano-4-(5-cyano-2-thienyl)-5-methylhexanoate and tert-butyl-1-piperidinecarboxylate the method according to example 77. Specified in the header of the get connection, removing the protection of the BOC-group by the method described in reference example 79. Physicochemical data of the compounds are shown below.

1H-NMR (400 MHz, Dl3)to 0.92 (d, J=6.4 Hz, 3H), 1,21 (d, J=6.8 Hz, 3H), 1,20-1,32 (m, 1H), 1,59 of-1.83 (m, 2H), 2,01-2,11-of 1.80 (m, 1H), 2,17-to 2.40 (m, 7H), 2,80 of 2.92 (m, 4H), to 7.15 (d, J=4.0 Hz, 1H), 5,71 (d, J=4.0 Hz, 1H).

Reference example, the connection information synthesized by the method according to reference example 73.

Loose coupling:

1H-NMR (400 MHz, Dl3)of 0.77 (d, J=6, 8 Hz, 3H), 1,08-1,17 (m, 1H), 1,19 (d, J=6.6 Hz, 3H), 1,52-of 1.62 (m, 1H), 1,81-1,89 (m, 1H), 2,04-to 2.18 (m, 2H), 2,22-to 2.29 (m, 6N), 2,83-2,87 (m, 4H),? 7.04 baby mortality-was 7.08 (m, 2H), to 7.32 and 7.36 (m, 2H).

Reference example 84

1-[4-Cyano-5-methyl-4-(3-forfinal)hexyl]piperazine

Specified in the title compound synthesized by the method according to reference example 73.

Loose coupling:

1H-NMR (400 MHz, Dl3)of 0.79 (d, J=6.6 Hz, 3H), 0,81-1,19 (m, 1H), 1,21 (d, J=6.6 Hz, 3H), 1,54-to 1.59 (m, 1H), 1,81-1,89 (m, 1H), 2.05 is-to 2.29 (m, 8H), 2,83-2,87 (m, 4H), 6,97-7,03 (m, 1H), 7,06-7,10 (m, 1H), 7,17-7,20 (m, 1H), 7,32-7,37 (m, 1H).

Reference example 85

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

Specified in the title compound synthesized by the method according to reference example 73.

Loose coupling:

1H-NMR (400 MHz, Dl3)to 0.80 (d, J=6.8 Hz, 3H), 1,10-of 1.16 (m, 1H), 1,22 (d, J=6.6 Hz, 3H), 1,55-of 1.64 (m, 1H), 2,03-2,11 (m, 1H), 2,17-of 2.34 (m, 7H), 2,43-of 2.50 (m, 1H), 2,80-2,87 (m, 4H), 7,01-7,06 (m, 1H), 7,13-7,17 (m, 1H), 7,26-7,34 (m, 1H), 7,56-to 7.61 (m, 1H).

Reference example 86

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

Specified in the header connection /img.russianpatents.com/chr/948.gif">0,86 (d, J=6.8 Hz, 3H), 1,10-1,24 (m, 1H), 1,18 (d, J=6.8 Hz, 3H), 1,50-of 1.64 (m, 1H), 2,02 with 2.14 (m, 1H), 2,14-of 2.30 (m, 1H), 2,20-2,40 (m, 6N), a 2.36-of 2.54 (m, 1H), 2,50 (s, 3H), 2,78-2,90 (m, 4H), 7,10-7,24 (m, 3H), 7,46-7,56 (m, 1H).

Reference example 87

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

Specified in the title compound obtained as a colorless oil by the method according to reference example 73.

1H-NMR (400 MHz, Dl3)of 0.75 (d, J=6.4 Hz, 3H), 1,00-1,20 (m, 1H), 1,18 (d, J=6.8 Hz, 3H), 1,45-to 1.60 (m, 1H), 1,90-2,00 (m, 1H), 2,20-2,40 (m, 6N), 2,35-of 2.50 (m, 1H), 2,65 is 2.75 (m, 1H), 2,75-2,90 (m, 4H), of 3.80 (s, 3H), 6.87 in (d, J=8,4 Hz, 1H), 6,95 (t, J=7,6 Hz, 1H), 7.24 to 7,32 (m, 1H), 7,55 (d, J=7,6 Hz, 1H).

Reference example 88

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

Specified in the title compound obtained as a colorless oil by the method according to reference example 73.

1H-NMR (400 MHz, Dl3)of 0.77 (d, J=6.8 Hz, 3H), 1,02-of 1.18 (m, 1H), 1,23 (d, J=6.8 Hz, 3H), 1,45-to 1.60 (m, 1H), 1,95-2,10 (m, 1H), 2,20-2,40 (m, 6N), 2,64 was 2.76 (m, 1H), 2,80-2,90 (m, 4H), 2,88-to 3.02 (m, 1H), 7,22-to 7.32 (m, 2H), 7,34-7,40 (m, 1H), 7,71-to 7.77 (m, 1H).

Reference example 89

1-Benzyl-4-[3-[1-(4-forfinal)cyclohexyl]-1-oxopropyl]piperazine

Methyl-4-perforateed (10.0 g) is dissolved in t the Institute ice for 10 minutes and within one hour added dropwise a 1.5-dibromethane (11.3 ml). Then the mixture is stirred over night at room temperature, add a mixture of ice water and extracted with ethyl acetate. The extract is washed with saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel (n-hexane/ethyl acetate), while receiving 7,37 g (53%) of oil.

The above oil (7,37 g) dissolved in tetrahydrofuran (100 ml) and added dropwise 1.0 M solution (18.7 ml) of lithium aluminum hydride in diethyl ether at a temperature of from -50 to -40°C. the Mixture is stirred at the same temperature for 20 minutes and under ice cooling, water is added, 5 N. aqueous sodium hydroxide solution and an additional amount of water. The insoluble matter is filtered off through celite and the filtrate evaporated. The resulting residue is purified by chromatography on a column of silica gel (n-hexane/ethyl acetate), while receiving 3,43 g (53%) of oil.

Oxalicacid (1,05 ml) dissolved in methylene chloride (25 ml) and added dropwise a solution (5 ml) of dimethyl sulfoxide (0,85 ml) in methylene chloride at a temperature of from -60 to -50°C. the Mixture is stirred for 2 minutes and within 5 minutes added dropwise a solution (10 ml) obtained above oil (2,08 g) in meloney the mixture continued to stir for another 5 minutes and allowed to warm to room temperature. The mixture is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated, thus obtaining 1,91 g (93%) of oil.

60% sodium hydride (0.55 g) is suspended in tetrahydrofuran (10 ml) and under ice cooling are added dropwise triethylphosphate (2,73 ml) in tetrahydrofuran (5 ml). The mixture is stirred for 15 minutes under cooling with ice and added dropwise a solution (15 ml) obtained above oil (1.89 g) in tetrahydrofuran. The reaction mixture is stirred for 15 minutes at the same temperature and continue to stir one hour at room temperature. To the mixture is added saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The extract is washed with saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel (n-hexane/ethyl acetate), while receiving 2,07 g (82%) of oil.

The above oil (1,02 g) dissolved in ethanol (20 ml), add 10% palladium on coal (0.2 g) and hydronaut at room temperature and normal pressure for 30 minutes. The catalyst is filtered off and the filtrate evaporated. The resulting residue is purified by chromatography on a column of silica gel (n-hexane/et the Ute 2 N. an aqueous solution of sodium hydroxide (50 ml). The mixture is heated under reflux for 2 hours, cooled to room temperature and evaporated. The resulting residue is suspended in ethyl acetate and the mixture is brought to pH 2 by adding 5 n hydrochloric acid. The mixture is dried over anhydrous magnesium sulfate and evaporated. The resulting residue is recrystallized from ethyl acetate/n-hexane, thus obtaining 6,45 g (79%) of white crystals.

1-Benzylpiperazine (2,82 g) dissolved in N,N-dimethylformamide (40 ml) and add the above crystals (4.0 g) and 1-hydroxybenzotriazole (2.16 g). Under ice cooling are added dropwise a solution (30 ml) of 1,3-dicyclohexylcarbodiimide (3,63 g) in N,N-dimethylformamide. The mixture is stirred over night at room temperature, the insoluble matter is filtered off and the filtrate is extracted with ethyl acetate and 1 N. a solution of hydrochloric acid. The extract was washed with 2 N. aqueous sodium hydroxide solution and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel (n-hexane/ethyl acetate), while receiving 6,23 g (95%) indicated in the title compound in the form of butter.

ESI-MS: 409 (MH+).

Reference example 90

1-Benzyl-4-[3-[1-(4-forfinal)cyclohexyl]propyl]piperazine

1-Benzyl-4-[3-[1-(4-forfinal)cyclohexyl]-1-oxopropyl]piperazine (5,90 g) dissolved in tetrahydrofuran (100 ml) and cooled with ice add 80% of alumoweld lithium (1,03 g). The mixture is heated under reflux for 1.5 hours and allowed to cool to room temperature. While cooling with ice to the mixture add water, 1 N. aqueous sodium hydroxide solution and an additional amount of water and the insoluble matter is filtered off. The filtrate is evaporated and the resulting residue is recrystallized from ethanol, thus obtaining 4,48 g (79%) indicated in the title compound as white crystals.

1H-NMR (400 MHz, Dl3)1,06-of 1.15 (m, 2H), 1,28 is 1.58 (m, N), 1,98-to 2.06 (m, 2H), and 2.14 (t, J=8 Hz, 2H), 2,20-of 2.54 (m, 8H), 3,47 (s, 2H), 6,93-7,00 (m, 2H), 7,20-to 7.32 (m, 7H).

ESI-MS: 395 (MH+).

Reference example 91

4-[3-[1-(4-Forfinal)cyclohexyl]propyl]piperazine

1-Benzyl-4-[3-[1-(4-forfinal)cyclohexyl]propyl]piperazine (4.0 g) dissolved in methanol (100 ml)flax pressure for 6 hours. The catalyst is filtered off and the filtrate is evaporated, thus obtaining 3,09 g specified in the title compound as an oil (quantitative yield).

1H-NMR (400 MHz, Dl3)1,07-1,17 (m, 2H), 1,28-to 1.60 (m, 10H), 1,75 (Shir.s, 1H), 1,99-2,07 (m, 2H), 2,12 (t, J=8 Hz, 2H), 2,25 (Shir.s, 4H), 2,82 (t, J=4,8 Hz, 2H), 6,94-7,01 (m, 2H), 7,21-7,27 (m, 2H).

ESI-MS: 305 (MN+).

Reference example 92

Ethyl-4-(4-cyano-5-methyl-4-phenylhexa)-2-piperidinecarboxylic

Ethyl-1-benzyl-4-(4-cyano-5-methyl-4-phenylhexa)-2-piperidinecarboxylate (857 mg) is dissolved in ethanol (15 ml) and added 770 mg of 10% Pd-C. Atmosphere replaced with hydrogen and the mixture is stirred. After the reaction solution is evaporated, thus obtaining 639 mg (93%) indicated in the title compound as crude product.

Loose coupling:

1H-NMR (400 MHz, Dl3)of 0.77 (d, J=6.6 Hz, 3H), 1,08 is 1.16 (m, 1H), 1,20 (d, J=6.6 Hz, 3H), 1,22-of 1.29 (m, 3H), 1,53-of 1.64 (m, 1H), 1,86-of 1.95 (m, 1H), 2.05 is is 2.33 (m, 6N), 2,41-2,49 (m, 1H), 2,74-and 2.83 (m, 2H), 2,97 totaling 3.04 (m, 1H), 3,47-to 3.52 (m, 1H), 4,14-is 4.21 (m, 2H), 7,26-7,31 (m, 1H), 7,34-7,39 (m, 4H).

Reference example 93

Ethyl-4-[2-(4-pertenece)ethyl]-2-piperidinecarboxylate

Ethyl-1-benzyl-4-[2-(4-pertenece)ethyl]-2-piperidinecarboxylate (977 mg of 10% Pd-C. The atmosphere replaced with hydrogen and the mixture is stirred. After the reaction solution is evaporated, thus obtaining 752 mg (100%) specified the title compound as crude product.

Loose coupling:

1H-NMR (400 MHz, Dl3)1,24 of 1.28 (m, 3H), 2,33-of 2.34 (m, 1H), 2,48-of 2.50 (m, 1H), 2,72-only 2.91 (m, 4H), 3.04 from-3,10 (m, 2H), 3,56-3,59 (m, 1H), 4.04 the-4,08 (m, 2H), 4,16-4,22 (m, 2H), 6,82-6,86 (m, 2H), 6,94-of 6.99 (m, 2H).

Intermediate compounds used to obtain the compounds of the present invention, can be also obtained in the form of optically active intermediate compounds by known methods and their modifications, as well as, for example, the following ways.

Reference example 94

3-Methyl-2-(2-thienyl)Botanical

47,6 g (to 0.39 mol) of 2-thiophenecarbonitrile and to 57.0 g (0.46 mol) of 2-bromopropane dissolved in 100 ml of DMSO and the resulting solution was added dropwise a 50% aqueous solution of KOH. After the reaction, water is added and the mixture is extracted with toluene. The reaction mixture is washed with saturated salt solution and saturated aqueous ammonium chloride, dried over magnesium sulfate and evaporated, to give crude product. The crude product is distilled under reduced pressure (2-3 mm Od, 132-137°C), half the data link given below.

1H-NMR (400 MHz, Dl3)a 1.08 (d, J=6.8 Hz, 3H), of 1.12 (d, J=6.8 Hz, 3H), 2,14-of 2.24 (m, 1H), 3,95 (d, J=6.0 Hz, 1H), 6,99 (DD, J=4.0 Hz, 5,20 Hz, 1H), 7,05-was 7.08 (m, 1H), 7,27 (DD, J=1.2 Hz, 5.2 Hz, 1H).

Reference example 95

Ethyl-4-cyano-5-methyl-4-(2-thienyl)hexanoate

1,49 g (13.3 mmol, catalyst) tert-butoxide potassium dissolved in 120 ml of DMF and mixed solution 43,9 g (0.27 mol) of 3-methyl-2-(2-thienyl)Botanical and 30.2 ml (0.28 mol) acrylate ponemnogu added to the obtained solution at room temperature. (In the case of incomplete dissolution of the original substance add a further quantity of ethyl acrylate and tert-butoxide potassium). During the addition is exothermic reaction. After the reaction alternately add 100 ml of saturated salt solution and 200 ml of a saturated aqueous solution of ammonium chloride and the desired product is extracted with 500 ml of hexane. The organic layer was washed with 400 ml of saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and get 67,0 g crude product as a yellow oil, which is a complex ether (ethyl-4-cyano-5-methyl-4-(2-thienyl)hexanoate). Physicochemical data of the compounds are shown below.

1H-NMR (400 MG to 4.15 (m, 2N), of 6.96 (DD, J=3,6 Hz, 5.1 Hz, 1H), 7,12 (DD, J=1.2 Hz, 3.6 Hz, 1H), to 7.99 (DD, J=1.2 Hz, 5.1 Hz, 1H).

Reference example 96

Salt cyclohexylamine d1-4-cyano-4-(2-thienyl)-5-methylhexanoic acid

67,0 g obtained above of ester are dissolved in 500 ml of tetrahydrofuran, are added to a solution of 200 ml of 5 n NaOH solution and 50 ml of ethanol and stirred the mixture. After the reaction solution is evaporated. The aqueous layer containing the desired product, 4 times washed with 200 ml of toluene. Then the pH was adjusted to 1-2 by adding 320 ml of 5 n Hcl solution, and the target product is extracted with 750 ml of toluene. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated, receiving of 55.6 g (yellow oil) crude carboxylic acid. Carboxylic acid are dissolved in 150 ml of toluene and added to 22.5 g (0.23 mol) of cyclohexylamine. The resulting white crystals are collected by filtration, thus obtaining 55,6 g (to 0.17 mol) specified in the connection header. Physicochemical data of the compounds are shown below.

1H-NMR (400 MHz, Dl3)to 0.92 (d, J=6.8 Hz, 3H), 1,20 (d, J=6.4 Hz, 3H), 1,20-1,40 (m, 6N), 1,57-to 1.67 (m, 1H), 1,72-of 1.81 (m, 2H), 1,92-2,11 (m, 3H), 2,30-to 2.42 (m, 1H), 2,44-of 2.54 (m, 1H), 2,85-2,96 (m, 1H), 6,95 (DD, J=3.2 Hz, 5.2 Hz, 1H), )-5-methylhexanoic acid

55 g (0.16 mol) of salt cyclohexylamine d1-4-cyano-4-(2-thienyl)-5-methylhexanoic acid are suspended in 100 ml of 5 n Hcl solution and 50 ml of water and the mixture is extracted with 300 ml of toluene. The extract was washed with 2 N. Hcl solution and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and the gain of 38.7 g of the crude carboxylic acid. of 38.7 g of crude d1-4-cyano-4-(2-thienyl)-5-methylhexanoic acid are dissolved in 120 ml of toluene. To a solution of carboxylic acid add a solution of 18.8 g (0.14 mol, 0.85 EQ.) (S)-1-(4-were)ethylamine in 40 ml of toluene. Then added to the mixture crystals (6 mg) obtained earlier specified in the connection header and the mixture is allowed to cool. Received diastereomers Sol (Sol 1) is collected by filtration. Salt 1 dissolve when heated in 250 ml of toluene and stirring, cool the mixture to room temperature. Received diastereomers Sol (Sol 2: optical purity 90,5%, excluding errors) is collected by filtration, thus obtaining 21,3 g (57,2 mmol, 35.1 per cent) (optical purity 90,5%, excluding errors) specified in the connection header.

Example 2

dl-4-Cyano-4-(2-thienyl)-5-methylhexanoic acid (96,6 mmol) turn into salt by the above method split the Skye purity 95%, excluding errors) specified in the connection header. Physicochemical data of the compounds are given below. In addition, the following are the conditions of HPLC analysis and data analysis (graph HPLC) shown in Fig.1.

1H-NMR (400 MHz, Dl3)of 0.91 (d, J=6.8 Hz, 3H), 1,19 (d, J=6.4 Hz, 3H), of 1.42 (d, J=6.8 Hz, 3H), 1,95-2,11 (m, 3H), of 2.33 (s, 3H), 2,30-of 2.50 (m, 2H), 3,74 (Shir.Dr. s, 3H), 6,95 (DD, J=3,6 Hz, 5.2 Hz, 1H), 7,10 (DD, J=1.2 Hz, 3.6 Hz, 1H), 7,14 (d, J=8,4 Hz, 2H), 7,21 (d, J=8,4 Hz, 2H), 7,25-7,29 (m, 1H).

Conditions of HPLC analysis:

Column: Daicel Chemical Industries, Ltd. CHIRALCEL OJ, 4, 6250 mm

Mobile phase: 20% ().

(A) a Mixed solution of n-hexane/triperoxonane acid (1000:1).

(B) a Mixed solution of n-hexane/isopropanol/triperoxonane acid (500:500:1).

Flow rate: 0.5 ml/min

Detector: UV 231 nm.

Retention time: 15,5 minutes

Reference example 98

Salt (S)-1-phenethylamine 4-cyano-4-(2-thienyl)-5-methylhexanoic acid

Optically active salt of (S)-1-phenethylamine 4-cyano-4-(2-thienyl)-5-methylhexanoic acid (to 107.7 g, 39%) (white crystals, optical purity 96.9 percent, excluding errors) can also be obtained with the processing of dl-4-cyano-4-(2-thienyl)-5-methylhexanoic acid (168, 8mm g) (S)-1-phenethylamine (6p>

1H-NMR (400 MHz, CD3OD)of 0.94 (d, J=7 Hz, 3H), of 1.23 (d, J=7 Hz, 3H), of 1.65 (d, J=7 Hz, 3H), 2,02 (DDD, J=15 Hz, 12 Hz, 4 Hz, 1H), and 2.14 (DDD, J=14 Hz, 12 Hz, 4 Hz, 1H), 2,18 (kV kV, J=7 Hz, 7 Hz, 1H), 2,33 (DDD, J=15 Hz, 12 Hz, 4 Hz, 1H), 2,52 (DDD, J=14 Hz, 12 Hz, 4 Hz, 1H), of 4.44 (q, J=7 Hz, 1H),? 7.04 baby mortality (DD, J=5 Hz, 3 Hz, 1H), 7,14 (DD, J=3 Hz, 1 Hz, 1H), 7,44 (DD, J=5 Hz, 1 Hz, 1H), 7,40-to 7.50 (m, 5H).

ESI-MS (m/z): 135, 177, 195, 273 (M+).

Melting point 136-144°C.

Conditions of HPLC analysis:

Column: Daicel Chemical Industries, Ltd. (Tokyo) CHIRALCEL OJ.

Mobile phase: 10% ().

(A) n-hexane/triperoxonane acid (1000:1).

(B) n-hexane/2-propanol/triperoxonane acid (500:500:1).

Flow rate: 0.5 ml/min

Detector: UV 231 nm.

Retention time: 26,2 minutes

Reference example 99

Salt (R)-1-phenethylamine 4-cyano-4-(2-thienyl)-5-methylhexanoic acid

Specified in the title compound obtained as white crystals by the method in reference example 98, using (R)-1-phenylethylamine and dl-4-cyano-4-(2-thienyl)-5-methylhexanoic acid.

Melting point 136-144°C.

Conditions of HPLC analysis:

Column: Daicel Chemical Industries, Ltd. (Tokyo) CHIRALCEL OJ.

Mobile phase: 10% ().

(A) n-hexane/triperoxonane acid (1000:1).

(B) n-hexane/2-propria: 19,9 minutes

Reference example 100

Salt (S)-1-(4-were)ethylamine 4-cyano-4-(3-thienyl)-5-methylhexanoic acid

5.6 g (optical purity was 86.7%, excluding errors) specified in the title compound obtained as white crystals of dl-4-cyano-4-(3-thienyl)-5-methylhexanoic acid (11.4 g) and (S)-1-(4-were)ethylamine (of 5.45 g) the method according to reference examples 96 and 97. Physicochemical data of the compounds are given below. In addition, the following are the conditions of HPLC analysis and data analysis (graph HPLC) shown in Fig.2.

Loose coupling: 4-cyano-4-(3-thienyl)-5-methylhexanoic acid

1H-NMR (400 MHz, Dl3)of 0.85 (d, J=6, 8 Hz, 3H), 1,19 (d, J=6.6 Hz, 3H), 2,02-to 2.18 (m, 3H), 2,38-of 2.58 (m, 2H), 6,94 (DD, J=3.1 Hz, 1.5 Hz, 1H), 7,30 (DD, J=3.1 Hz, 1.5 Hz, 1H), 7,38 (DD, J=5,1 Hz, 3.1 Hz, 1H).

Salt: salt (S)-1-(4-were)ethylamine 4-cyano-4-(3-thienyl)-5-methylhexanoic acid

1H-NMR (400 MHz, Dl3)of 0.83 (d, J=6.8 Hz, 3H) and 1.15 (d, J=6.6 Hz, 3H), of 1.42 (d, J=6.6 Hz, 3H), 1,80-2,10 (m, 3H), 2,27-to 2.42 (m, 2H), 2,33 (s, 3H), 4,14 (kV, J=6,8 Hz, 1H), 6,91 (DD, J=5,1 Hz, 1.5 Hz, 1H), 7,13 (Shir.d, J=8.0 Hz, 2H), 7,20 (Shir.d, J=8.0 Hz, 2H), 7,24 (DD, J=3.1 Hz, 1.5 Hz, 1H), 7,33 (DD, J=5,1 Hz, 3.1 Hz, 1H).

Melting point 140-143°C.

Conditions perform anal flow: 0.5 ml/min

Detector: UV at 235 nm.

Retention time: 15,7 minutes

Reference example 101

Optically active 4-cyano-4-(3-thienyl)-5-methylhexanoic acid

Specified in the header of the free compound (3.94 g) receiving, processing salt (S)-1-(4-were)ethylamine 4-cyano-4-(3-thienyl)-5-methylhexanoic acid (5.6 g) in an aqueous solution of hydrochloric acid by the method according to reference example 97. Physicochemical data of the compounds are given below. In addition, the following are the conditions of HPLC analysis, and data analysis (graph HPLC) shown in Fig.2.

1H-NMR (400 MHz, Dl3)of 0.85 (d, J=6.8 Hz, 3H), 1,19 (d, J=6.6 Hz, 3H), 2,02-to 2.18 (m, 3H), 2,38-of 2.58 (m, 2H), 6,94 (DD, J=3.1 Hz, 1.5 Hz, 1H), 7,30 (DD, J=3.1 Hz, 1.5 Hz, 1H), 7,38 (DD, J=5,1 Hz, 3.1 Hz, 1H).

Reference example 102

Salt (R)-1-(4-were)ethylamine 4-cyano-4-(3-thienyl)-5-methylhexanoic acid

Specified in the title compound (35%, optical purity 88.5 percent, excluding errors) are obtained as white crystals by the method in example 97 using (R)-1-(4-were)ethylamine and d1-4-cyano-4-(3-thienyl)-5-methylhexanoic acid.

Melting point 140-143°C.

Conditions of HPLC analysis:

The coin.

Detector: UV at 235 nm.

Retention time: 12,8 minutes

Reference example 103

Salt (R)-1-(4-were)ethylamine 4-cyano-4-(2-thienyl)-5-methylhexanoic acid

Specified in the header connection get the method according to reference example 97 using (R)-1-(4-were)ethylamine and dl-4-cyano-4-(2-thienyl)-5-methylhexanoic acid. Conditions of HPLC analysis are presented below, and data analysis (graph HPLC) shown in Fig.3.

Conditions of HPLC analysis:

Column: Daicel Chemical Industries, Ltd. CHIRALCEL OJ, 4,6250 mm

Mobile phase: 20% ().

(A) a Mixed solution of n-hexane/triperoxonane acid (1000:1).

(B) a Mixed solution of n-hexane/isopropanol/triperoxonane acid (500:500:1).

Flow rate: 0.5 ml/min

Detector: UV 231 nm.

Retention time: 12,8 minutes

Reference example 104

4-Cyano-4-(2-thienyl)-5-methylhexane (optically active compound)

Salt (S)-1-(4-were)ethylamine 4-cyano-4-(2-thienyl)-5-methylhexanoic acid obtained in reference example 97, converted into the free carboxylic acid by the method according to reference example 97. 8,31 g (35,0 mmol) of the obtained compound was dissolved in 140 ml of t is the solution added dropwise 3.5 ml (of 40.3 mmol) oxalicacid, warmed to room temperature and stirred for 1.5 hours. The solvent is evaporated, add 80 ml of tetrahydrofuran and the solution again cooled with ice. To the solution was added 75 ml of methanol and 6,10 ml (range 43.8 mmol) of triethylamine and stirring, allowed to warm to room temperature. After the reaction solution is extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate and saturated salt solution and dried over magnesium sulfate. The solvent is evaporated and the resulting crude product was then purified by chromatography on a column of silica gel (system: hexane/ethyl acetate), to thereby obtain 8.0 g (of 31.8 mmol, 90,9%) complicated methyl ester. 8.00 g (of 31.8 mmol, 90,9%) of ester are dissolved in 50 ml of tetrahydrofuran. The solution is added dropwise to a suspension of 845 mg (22,3 mmol) of lithium aluminum hydride in THF, cooled to ambient temperature from -50 to -40°C, and heated to ambient temperature -20°C for 0.5 hour. After the reaction solution was again cooled, alternately add 0.9 ml of water, 0.9 ml of 5 n NaOH solution and 2.70 ml of water and filtered through celite. The filtrate is evaporated and the resulting crude product was then purified by chromatography on a column of silica gel (n-hexane/ethyl acetate), obtaining the connections shown below.

Carboxylic acid:

1H-NMR (400 MHz, Dl3)of 0.93 (d, J=6.8 Hz, 3H), 1,21 (d, J=6.4 Hz, 3H), 2,01-of 2.23 (m, 3H), 2,47-of 2.58 (m, 2H), 6,97 (DD, J=3,6 Hz, 5.2 Hz, 1H), 7,12 (DD, J=1.2 Hz, 3.6 Hz, 1H), 7,29 (DD, J=1.2 Hz, 5.2 Hz, 1H).

Methyl ester derived from a carboxylic acid And:

1H-NMR (400 MHz, Dl3)to 0.92 (d, J=6.8 Hz, 3H), 1,22 (d, J=6.4 Hz, 3H), 2,03-of 2.20 (m, 3H), 2,43-of 2.58 (m, 2H), to 3.64 (s, 3H), of 6.96 (DD, J=3,6 Hz, 5.2 Hz, 1H), 7,12 (DD, J=1.2 Hz, 3.6 Hz, 1H), 7,29 (DD, J=1.2 Hz, 5.2 Hz, 1H).

Alcohol:

1H-NMR (400 MHz, Dl3)to 0.92 (d, J=6.8 Hz, 3H), 1,19 (d, J=6.8 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=6.8 Hz, 1H), and 2.27 (DDD, J=4.4 Hz, 12.0 Hz, 13,2 Hz, 1H), 3,63 (Shir.Dr. s, 2H), of 6.96 (DD, J=3,6 Hz, 5.2 Hz, 1H), 7,11-7,14 (m, 1H), 7,27 (DD, J=1.2 Hz, 5.2 Hz, 1H).

Reference example 105

4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexane (optically active compound)

Bromination and subsequent cyanidation carry out the method according to example 80, using as the starting material alcohol As obtained in reference example 104. In particular, optically active 4-cyano-4-(5-bromo-2-thienyl)-5-methylhexane synthesize bromirovanii and then without cleaning subjected to cyanidation, while receiving specified in the header soy )of 0.94 (d, J=6,59 Hz, 3H), 1,22 (d, J=is 6.78 Hz, 3H), 1,28-of 1.42 (m, 1H), 1,66-of 1.78 (m, 1H), 1,83-of 1.93 (m, 1H), 2,03-of 2.16 (m, 1H), 2,32 (DDD, J=4,40 Hz and 12.4 Hz to 13.2 Hz, 1H), to 3.58-3,74 (m, 2H), 7,16 (d, J=3,60 Hz, 1H), 7,52 (d, J=3,60 Hz, 1H).

Example 1

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

Specified in the title compound synthesized by the method according to example 86-5) described in JP-A 11-206862.

1H-NMR (400 MHz, CDCl3)of 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), 1,80-of 1.95 (m, 1H), 2,05-of 2.20 (m, 2H), of 2.25 to 2.35 (m, 2H), 2,35-2,48 (m, 4H), 2,48-to 2.65 (m, 4H), at 2.59 (s, 3H), of 2.81 (t, J=5.8 Hz, 2H), 4,13 (t, J=5.8 Hz, 2H), 7,08-7,13 (m, 1H), 7,26-7,32 (m, 1H), 7,34-7,40 (m, 5H), 7,46 is 7.50 (m, 1H), 7,52-7,56 (m, 1H).

Then free the connection handle in the method of example 20 described in JP-A 11-206862, and receive hydrochloride specified in the connection header.

ESI-MS: 448 (MN+).

Example 2

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

In acetonitrile (3 ml) is dissolved 1-benzyl-2-pyrrolidin.ethanol (83 mg) and add triethylamine (of 0.18 ml) and methylchloride (0.037 ml). The mixture is stirred at room temperature for one hour and add a solution (3 ml) of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine (124 mg) in azet the temperature. To the mixture are added ethyl acetate and washed with water and saturated salt solution. The mixture is dried over anhydrous magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel (NH) (system: hexane/ethyl acetate), obtaining mentioned in the title compound as a pale yellow oil (58 mg, 29%). Then loose coupling is transformed into a hydrochloride in a known manner, thus obtaining the hydrochloride specified in the connection header.

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 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-of 1.73 (m, 4H), 1,83 is 2.00 (m, 3H), 2,07-to 2.18 (m, 2H), 2,20-of 2.64 (m, 13H), 2,87-of 2.93 (m, 1H), 3,23 (d, J=12,8 Hz, 1H), 4,19 (d, J=12,8 Hz, 1H), 7,19-7,39 (m, 10H).

Hydrochloride:

ESI-MS: 459 (MN+).

Example 3

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

In 1,2-dichloroethane (6 ml) is dissolved 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine (0,19 g) and add benzofuran-2-carbaldehyde (0.11 g), acetic acid (0,095 ml) and triacetoxyborohydride sodium. The mixture is stirred for 3 hours at room temperature, add ethyl acetate and washed with water and saturated salt solution. The reaction mixture is dried by Nadel (NH) (system: hexane/ethyl acetate), while receiving specified in the title compound as a pale yellow oil (0.28 g, quantitative yield). Then loose coupling is converted into the hydrochloride in the usual way, thus obtaining hydrochloride specified in the connection header.

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,76 (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), 1,87 (dt, J=4.4 Hz, J=12 Hz, 1H), 2,07-2,17 (m, 2H), and 2.27 (t, J=7.2 Hz, 2H), 2,38 (Shir.s, 4H), 2,52 (Shir.s, 4H), 3,66 (s, 2H), to 6.57 (s, 1H), 7,17-7,30 (m, 3H), 7,32-7,37 (m, 4H), 7,44-7,53 (m, 2H).

Hydrochloride:

ESI-MS: 416 (MN+).

Example 4

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

Specified in the title compound obtained as a pale yellow oil by the method according to example 3 (86%). Hydrochloride specified in the header of free connections receive the usual way.

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 1,05-of 1.18 (m, 1H), 1,19 (d, J=6.8 Hz, 3H), 1,47 is 1.60 (m, 1H), 1,90 (dt, J=4.4 Hz, J=12,4 Hz, 1H), 2,05-of 2.38 (m, 8H), 2,50 (Shir.s, 4H), 3,79 (s, 2H), of 3.84 (s, 3H), 7,21-7,40 (m, 8H), 7,71 to 7.75 (m, 1H).

Hydrochloride:

ESI-MS: 430 (MN+).

Example 5

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(3-indolyl)methyl]n the CSOs oil method according to example 3 (76%). Hydrochloride specified in the header of free connections receive the usual way.

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,76 (d, J=6.8 Hz, 3H), 1.04 million-of 1.18 (m, 1H), 1,18 (d, J=6.8 Hz, 3H), 1,47 is 1.60 (m, 1H), 1,86 (dt, J=4.4 Hz, J=12,4 Hz, 1H), 2,03-of 2.16 (m, 2H), 2,22 of-2.32 (m, 2H), 2,33 (Shir.s, 4H), 2.49 USD (Shir.s, 4H), 3,70 (s, 2H), 7,05-7,20 (m, 4H), 7.23 percent-of 7.48 (m, 5H), of 7.70 (d, J=6,8 Hz, 1H), 8,25-to 8.40 (m, 1H).

Hydrochloride:

ESI-MS: 415 (MH+).

Example 6

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

Specified in the title compound obtained as a pale yellow oil by the method according to example 3 (62%). Hydrochloride specified in the header of free connections receive the usual way.

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 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), 1,90 (dt, J=4.4 Hz, J=12 Hz, 1H), 2,07-to 2.18 (m, 2H), 2,24 to 2.35 (m, 2H), 2,38 (Shir.s, 4H), 2,54 (Shir.s, 4H), 3,82 (s, 2H), 7.24 to 7,30 (m, 1H), 7,32-7,38 (m, 4H), 7,51 (d, J=8 Hz, 1H), 7,60 (d, J=8,4 Hz, 1H), 7,66-7,72 (m, 1H), 7,79 (d, J=8 Hz, 1H), of 8.06 (d, J=8,4 Hz, 1H), 8,10 (d, J=8,4 Hz, 1H).

Hydrochloride:

ESI-MS: 427 (MN+).

Example 7

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(4-phenyl-3-pyridyl)methyl]piperazine

Specified in zag is the head of the free connections receive the usual way.

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,76 (d, J=6.8 Hz, 3H), 1.04 million-of 1.18 (m, 1H), 1,19 (d, J=6.8 Hz, 3H), 1,47-to 1.59 (m, 1H), 1,87 (dt, J=4 Hz, J=12 Hz, 1H), 2.06 to of 2.34 (m, 8H), 2,34 (Shir.s, 4H), 3,39 (s, 2H), 7,18 (d, J=4,8 Hz, 1H), 7,25-7,46 (m, 10H), charged 8.52 (d, J=4,8 Hz, 1H), 8,63 (s, 1H).

Hydrochloride:

ESI-MS: 427 (MN+).

Example 8

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(1,2,3,4-tetrahydro-2-naphtol)piperazine

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]piperazine (150 mg) is dissolved in N,N-dimethylformamide (5 ml). To the mixture was added 1-hydroxybenzotriazole (71 mg), 1,2,3,4-tetrahydro-2-naphthenic acid (93 mg) and a solution (2 ml) dicyclohexylcarbodiimide (120 mg) in N,N-dimethylformamide. The mixture is stirred over night at room temperature, the insoluble matter is filtered off and added to the ethyl acetate filtrate. Then add a small amount of 1 n hydrochloric acid and the mixture is stirred. The reaction mixture was washed with saturated aqueous sodium carbonate and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel (NH) (system n-hexane/ethyl acetate), thus obtaining specified in the header connect the usual way.

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.8 Hz, 3H), 1.04 million-1,20 (m, 1H), 1,21 (d, J=6.8 Hz, 3H), 1,50-to 1.63 (m, 1H), 1,86-2,04 (m, 3H), 2,09-of 2.23 (m, 2H), 2,24-of 2.36 (m, 6N), 2,75-to 2.94 (m, 4H), 3,03-of 3.12 (m, 1H), 3,49 (t, J=4,8 Hz, 2H), 3,56-3,68 (m, 2H), 7,06-7,13 (m, 4H), 7,27-7,40 (m, 5H).

Hydrochloride:

ESI-MS: 444 (MN+).

Example 9

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(1,2,3,4-tetrahydro-2-naphthyl)methyl]piperazine

In tetrahydrofuran (5 ml) is dissolved 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(1,2,3,4-tetrahydro-2-naphtol)piperazine (150 mg) and cooled with ice add 1.0 M solution of the complex of borane in tetrahydrofuran (1.35 ml). The mixture is stirred at room temperature for 5 hours and evaporated. To the residue is added methanol (5 ml) and 2 n hydrochloric acid (5 ml) and stirred at 80°C for one hour. The mixture is allowed to cool to room temperature and evaporated. To the mixture are added ethyl acetate and washed with saturated aqueous sodium carbonate and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The resulting residue is purified preparative thin-layer chromatography on a column of silica gel (methylene chloride/methanol), while receiving pointed to by the connection receive the usual way.

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.8 Hz, 3H), 1.04 million-1,20 (m, 2H), 1,20 (d, J=6.8 Hz, 3H), 1,29 was 1.43 (m, 2H), 1,51-to 1.63 (m, 2H), 1,65-of 1.73 (m, 1H), 1,90 (dt, J=4.4 Hz, J=12 Hz, 1H), 1,90-2,00 (m, 4H), 2,08-2,19 (m, 2H), 2,25-2,48 (m, 7H), 2,77 of 2.92 (m, 3H),? 7.04 baby mortality-7,10 (m, 4H), 7,26-of 7.48 (m, 5H).

Hydrochloride:

ESI-MS: 430 (MN+).

Example 10

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

Specified in the title compound obtained as a pale yellow oil by the method according to example 8 (86%). Hydrochloride specified in the header of free connections receive the usual way.

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.8 Hz, 3H), 1,08-1,20 (m, 1H), 1,21 (d, J=6.8 Hz, 3H), 1,51-to 1.63 (m, 1H), 1,92 (dt, J=4.4 Hz, J=12 Hz, 1H), 2,09-of 2.23 (m, 2H), 2,25-to 2.40 (m, 6N), 3,49 is 3.57 (m, 2H), 3,63 is 3.76 (m, 2H), 4,30 (DD, J=8 Hz, J=12 Hz, 1H), 4,46 (DD, J=2,8 Hz, J=12 Hz, 1H), 4,79 (DD, J=2,8 Hz, J=8 Hz, 1H), 6,83-6,91 (m, 4H), 7,27-7,40 (m, 5H).

Hydrochloride:

ESI-MS: 448 (MN+).

Example 11

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

Specified in the title compound obtained as a pale yellow oil by the method according to example 9 (56%). Hydrochloride specified in the header /img.russianpatents.com/chr/948.gif">0,78 (d, J=6.8 Hz, 3H), 1,16-1,20 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-of 1.62 (m, 1H), 1,89 (dt, J=4.4 Hz, J=12,8 Hz, 1H), 2,08-2,19 (m, 2H), 2,24-of 2.34 (m, 2H), 2,36 (Shir.s, 4H), 2,52 (Shir.s, 4H), 2,61 (DDD, J=5.6 Hz, J=13,2 Hz, J=40,4 Hz, 2H), 3.96 points (DD, J=7,6 Hz, J=11,6 Hz, 1H), 4,24-or 4.31 (m, 2H), 6,79-6,89 (m, 4H), 7,26-7,39 (m, 5H).

Hydrochloride:

ESI-MS: 434 (MN+).

Example 12

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

Specified in the title compound obtained as a pale yellow oil by the method according to example 8 (82%). Hydrochloride specified in the header of free connections receive the usual way.

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.8 Hz, 3H), 1,08-1,20 (m, 1H), 1,21 (d, J=6.8 Hz, 3H), 1,50-of 1.62 (m, 1H), 1,87-of 1.97 (m, 1H), 2,08-2,22 (m, 2H), 2,28-of 2.38 (m, 6N), and 3.72 (Shir.s, 4H), 3,81 (s, 3H), 6,56 (s, 1H), 7,10-7,16 (m, 1H), 7,25-7,39 (m, 7H), to 7.61 (d, J=8 Hz, 1H).

Hydrochloride:

ESI-MS: 443 (MN+).

Example 13

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

Specified in the title compound obtained as a pale yellow oil by the method according to example 9 (40%). Hydrochloride specified in the header of free connections receive the usual way.

Loose coupling:

1H-NMR (400 MHz, CDCl17 (m, 2H), 2.21 are is 2.37 (m, 6N), 2,44 (Shir.s, 4H), of 3.60 (s, 2H), 3,76 (s, 3H), 6,34 (s, 1H), 7,07 (t, J=8 Hz, 1H), 7,18 (t, J=8 Hz, 1H), 7,25-7,38 (m, 6N), 7,54 (d, J=8 Hz, 1H).

Hydrochloride:

ESI-MS: 429 (MN+).

Example 14

2-[(4-Cyano-5-methyl-4-phenyl)hexyl]-5-[2-(4-pertenece)ethyl]-2,5-diazabicyclo[2,2,1]heptane

In methanol (5 ml) was dissolved 2-[(4-cyano-5-methyl-4-phenyl)hexyl]-5-benzyl-2,5-diazabicyclo[2,2,1]heptane (37 mg). To the mixture are added 20% palladium hydroxide on coal (10 mg) and hydronaut at room temperature and normal pressure for 8 hours. The catalyst is filtered off and the filtrate is evaporated, receiving the remainder in the form of a pale yellow oil (29 mg). The residue is dissolved in N,N-dimethylformamide (3 ml) and add a solution (2 ml) of triethylamine (0,027 ml) and 2-(4-pertenece)ethylbromide (25 mg) in N,N-dimethylformamide.

The solution is stirred over night at 50°C and allowed to cool to room temperature. To the mixture are added ethyl acetate and washed with water and saturated salt solution. The reaction mixture was dried over anhydrous magnesium sulfate and evaporated. The resulting residue is purified preparative thin-layer chromatography on a column of silica gel (methylene chloride/methanol), while receiving specified in the title compound as a pale p>

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.8 Hz, 3H), 1.06 a-1,20 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,45-of 1.57 (m, 1H), 1,66-of 1.73 (m, 2H), 1,95 (dt, J=4.4 Hz, J=12 Hz, 1H), 2,11 (Queen, J=6,8 Hz, 1H), 2,14-of 2.23 (m, 1H), 2,32-to 2.40 (m, 1H), of 2.51-2,61 (m, 2H), 2,63-of 2.81 (m, 3H), 2.91 in (d,Queen, J=6 Hz, J=40,4 Hz, 2H), 3,21 (s, 1H), 3,36 (s, 1H), 3,94-a 4.03 (m, 2H), 6,79-6,85 (m, 2H), 6,92-7,00 (m, 2H), 7,26-7,40 (m, 5H).

Hydrochloride:

ESI-MS: 436 (MN+).

Example 15

8-[(4-Cyano-5-methyl-4-phenyl)hexyl]-1-phenyl-1,3,8-diazaspiro[4,5]Decan-4-one

In acetonitrile (6 ml) was dissolved 4-cyano-5-methyl-4-phenylhexane (120 mg) and add triethylamine (0,23 ml) and methylchloride (0,051 ml) at room temperature. The mixture is stirred at room temperature for one hour and add a solution (3 ml) of 1-phenyl-1,3,8-diazaspiro[4,5]Decan-4-it (140 mg) in acetonitrile. The resulting solution was heated under reflux for 2.5 hours and allowed to cool to room temperature. Then to the mixture are added ethyl acetate and washed with water and saturated salt solution. The reaction mixture was dried over anhydrous magnesium sulfate and evaporated. The resulting residue is purified preparative thin-layer chromatography on a column of silica gel (system: hexane/ethyl acetate), obtaining the lowke free connections receive the usual way.

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.79 (d, J=6.4 Hz, 3H), 1,22 (d, J=6.4 Hz, 3H), of 1.26 (t, J=7.2 Hz, 2H), 1,55-of 1.73 (m, 3H), 1,94-2,05 (m, 1H), 2,08 was 2.25 (m, 2H), 2,38-2,52 (m, 2H), 2,60-2,90 (m, 6N), 4,72 (s, 2H), 6,85 (t, J=7.2 Hz, 1H), make 6.90 (d, J=8 Hz, 2H), 7.24 to 7,31 (m, 2H), 7,33-7,41 (m, 4H), 7.62mm (Shir.s, 1H).

Hydrochloride:

ESI-MS: 431 (MN+).

Example 16

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-keto-1-benzimidazolinyl)piperidine

Specified in the title compound obtained as a pale yellow oil by the method according to example 15 (23%). Hydrochloride specified in the header of free connections receive the usual way.

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.79 (d, J=6.8 Hz, 3H), 1,11-of 1.34 (m, 2H), 1,23 (d, J=6.8 Hz, 3H), 1,55-to 1.67 (m, 1H), 1,73-to 1.82 (m, 2H), 1,90-2,05 (m, 2H), 2,08-of 2.23 (m, 3H), 2,30-2,52 (m, 4H), 2,88-to 3.02 (m, 2H), 4,28-to 4.38 (m, 1H), 7,00-7,07 (m, 2H), 7,09-7,13 (m, 1H), 7,22-to 7.32 (m, 2H), 7,33-the 7.43 (m, 4H), 10,12-10,30 (m, 4H).

Hydrochloride:

ESI-MS: 417 (MN+).

Example 17

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(2-benzoxazolyl)amino]piperidine

Specified in the title compound obtained as a pale yellow oil by the method according to example 15 (30%). Hydrochloride specified in the header of the free compounds produces the d, J=6,8 Hz, 3H), 1,08-1,19 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,47-of 1.62 (m, 3H), 1.75 of of-1.83 (m, 1H), 1,89 (dt, J=4.4 Hz, J=13,6 Hz, 1H), 2.00 (evens Shire.t, J=12,4 Hz, 1H), 2,04-of 2.20 (m, 4H), 2,25-2,31 (m, 2H), 2,72 (Shir.t, J=11,6 Hz, 2H), 3,69-of 3.80 (m, 1H), 4.92 in-5,02 (m, 1H), 6,99-7,05 (m, 1H), 7,13-7,17 (m, 1H), 7,20-7,25 (m, 1H), 7,25-7,32 (m, 1H), 7,33-7,40 (m, 5H).

Hydrochloride:

ESI-MS: 417 (MN+).

Example 18

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(2-benzothiazolyl)aminopiperidin

Specified in the title compound obtained as a pale yellow oil by the method according to example 15 (52%). Hydrochloride specified in the header of free connections receive the usual way.

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.8 Hz, 3H), 1.06 a-1,20 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,46-of 1.62 (m, 3H), 1.77 in (lat.s, 1H), 1.85 to was 1.94 (m, 1H), 1,96-2,05 (m, 1H), 2.05 is-to 2.18 (m, 4H), 2,25 of-2.32 (m, 2H), 2,70 (Shir.t, J=12,4 Hz, 2H), 3,56-3,66 (m, 1H), 5,24 (Shir.d, J=6,8 Hz, 1H),? 7.04 baby mortality-to 7.09 (m, 1H), 7,25-to 7.32 (m, 2H), 7,33-7,39 (m, 4H), 7,50-7,58 (m, 2H).

Hydrochloride:

ESI-MS: 433 (MH+).

Example 19

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(2-benzothiazolyl)(methyl)amino]piperidine

Specified in the title compound obtained as a pale yellow oil by the method according to example 15 (30%). Hydrochloride specified in the header of free connections get obygn, 3H), 1,08-1,20 (m, 1H), 1,21 (d, J=6.8 Hz, 3H), 1,51-of 1.64 (m, 1H), 1,74-of 2.20 (m, N), 2,30 (t, J=7.2 Hz, 2H), 2,82-of 2.93 (m, 2H), 3,05 (s, 3H), 3,94-of 4.05 (m, 1H), 7,01-7,06 (m, 1H), 7.24 to 7,33 (m, 2H), 7,34-7,40 (m, 4H), 7,51-to 7.59 (m, 2H).

Hydrochloride:

ESI-MS: 447 (MN+).

Example 20

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(2-benzothiazolyl)(2-propyl)amino]piperidine

In N,N-dimethylformamide (3 ml) is dissolved 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[(2-benzothiazolyl)amino]piperidine (50 mg) synthesized in example 18, and added 60% sodium hydride (7 mg). The reaction mixture was stirred at 50°C for one hour and add 2-bromopropane (0,012 ml). The mixture continued to stir at 50°C over night and add an additional amount of 2-bromopropane (0,012 ml). The mixture is then stirred at 50°C for another 6 hours and add an additional amount of 60% sodium hydride (7 mg). The solution continued to stir at 50°C. overnight and allowed to cool to room temperature. To the mixture are added ethyl acetate and washed with water and saturated salt solution. The reaction mixture was dried over anhydrous magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel (NH) (system: hexane/ethyl acetate), thus obtaining specified in the header suchaut in the usual way.

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.4 Hz, 3H), 1,08-1,20 (m, 1H), 1,20 (d, J=6.4 Hz, 3H), 1,50 (d, J=6,8 Hz, 6N), 1,69-of 2.34 (m, 13H), 2,63-to 2.74 (m, 2H), 2,81-2,90 (m, 1H), 6,86-6,91 (m, 1H), of 6.96-7,02 (m, 1H), 7,11-7,16 (m, 1H), 7,25-to 7.32 (m, 2H), 7,33-7,41 (m, 4H).

Hydrochloride:

ESI-MS: 475 (MN+).

Example 21

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(1-methyl-2-benzimidazolyl)amino]piperidine

Specified in the title compound obtained as a pale yellow oil by the method according to example 15 (12%). Hydrochloride specified in the header of free connections receive the usual way.

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.8 Hz, 3H), 1.06 a-1,20 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,42-to 1.61 (m, 3H), 1,84-of 1.93 (m, 1H), 1,98-of 2.20 (m, 6N), and 2.27 (t, J=7.2 Hz, 2H), 2,69 was 2.76 (m, 2H), 3.45 points (s, 3H), 3,86-4,01 (m, 2H), 7,01 for 7.12 (m, 3H), 7,26-7,31 (m, 1H), 7,33-7,39 (m, 4H), 7,45 (d, J=7,6 Hz, 1H).

Hydrochloride:

ESI-MS: 430 (MN+).

Example 22

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[[1-(2-propyl)-2-benzimidazolyl]amino]piperidine

Specified in the title compound obtained as a pale yellow oil by the method according to example 15 (54%). Hydrochloride specified in the header of free connections receive the usual way, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,40-of 1.55 (m, 3H), of 1.57 (d, J=6,8 Hz, 6N), 1,85-of 1.93 (m, 2H), 2,02-of 2.20 (m, 5H), 2,28 (t, J=7.2 Hz, 2H), 2,67 is 2.75 (m, 2H), 3,85-4,00 (m, 2H), 4,33 (Queen, J=6,8 Hz, 1H), 6,97-7,10 (m, 2H), 7,20-to 7.32 (m, 2H), 7,34-7,39 (m, 4H), 7,46-of 7.48 (m, 1H).

Hydrochloride:

ESI-MS: 458 (MN+).

Example 23

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpiperidine

Specified in the title compound obtained as a pale yellow oil by the method according to example 15 (30%). Hydrochloride specified in the header of free connections receive the usual way.

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.8 Hz, 3H), 1,08-of 1.36 (m, 4H), 1,20 (d, J=6.8 Hz, 3H), 1,38-of 1.95 (m, 8H), 2,08-to 2.18 (m, 2H), 2,18 of-2.32 (m, 2H), 2,65-and 2.83 (m, 4H), up 3.22 (DD, J=8 Hz, J=17.6 Hz, 1H), 3,90 (s, 3H), of 3.96 (s, 3H), 6,86 (s, 1H), 7,16 (s, 1H), 7,26-7,41 (m, 5H).

Hydrochloride:

ESI-MS: 489 (MH+).

Example 24

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[[2-(4-pertenece)ethyl](2-cyanoethyl)amino]piperidine

Specified in the title compound obtained as a pale yellow oil (21%) by the method described in the following example 35. Hydrochloride specified in the header of free connections receive the usual way.

1H-NMR (400 MHz, CDCl3)

Hydrochloride:

ESI-MS: 491 (MH+).

Example 25

1-[4-Cyano-5-methyl-4-(2-naphthyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

In acetonitrile (5 ml) dissolved 310 mg (1,16 mmol) 4-cyano-5-methyl-4-(2-naphthyl)hexanol and add 190 µl (about 1.36 mmol) of triethylamine and 105 μl (about 1.36 mmol) methylchloride. After metilirovaniya to the reaction mixture of 1.11 g (7,38 mmol) of sodium iodide, 255 mg (of 1.85 mmol) of potassium carbonate, 414 mg (of 1.85 mmol) 1-[2-(4-pertenece)ethyl]piperazine and 5 ml of dimethylformamide and 1 ml of water and heated to 60°C. After the reaction to the mixture is added a saturated solution of salt and the desired product extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and get the crude product. The crude product is treated with silica gel (NH) (elution with ethyl acetate/hexane, 2/3), while receiving 384 mg (0.81 mmol, 69.9 per cent) indicated in the title compound as a yellow syrup.

1H-NMR (400 MHz, CDCl3)of 0.79 (d, J=6.8 Hz, 3H), of 1.05 to 1.15 (m, 1H), 1,26 (d, J=6.8 Hz, 3H), 1,50-of 1.65 (m, 1H), 1.93 and-2,05 (m, 1H), 2,18-2,60 (m, N), a 2.75 (t, /p>ESI-MS: 474 (M+N+).

Example 26

1-[4-Cyano-5-methyl-4-(1-naphthyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

Specified in the title compound obtained as a colorless oil by the method according to example 25 (exit 57,8%).

1H-NMR (400 MHz, CDCl3)0,70-0,90 (m, 3H), 0,95-1,10 (m, 1H), 1,20-1,40 (m, 4H), 1,50-of 1.65 (m, 1H), 1.93 and-2,05 (m, 1H), 2,10-of 2.56 (m, 10H), 2,56-2,70 (m, 1H), 2,73 (t, J=5.8 Hz, 1H), 2,90-3,00 (m, 1H), 4,01 (t, J=5.8 Hz, 2H), 6,78-6,83 (m, 2H), 6,91-6,97 (m, 2H), 7,40-to 7.50 (m, 3H), 7,78-a 7.92 (m, 3H), by 8.22-8,31 (Shir.Dr. s, 1H).

ESI-MS: 474 (M+N+).

Example 27

1-[4-Cyano-5-methyl-4-(2-pyridyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

4-Cyano-5-methyl-4-(2-pyridyl)hexanol, synthesized by the method according to example 25, oxidizes SO3-pyridine in the usual way. The resulting crude aldehyde is subjected to hydroamination described below by way of example 42 and synthesize thus the target compound as colorless oil (yield 69,1%).

1H-NMR (400 MHz, CDCl3)to 0.74 (d, J=6.8 Hz, 3H), 0,90-1,10 (m, 1H), 1,20 (d, J=6.4 Hz, 3H), 1,24-of 1.30 (m, 1H), 1,53-of 1.66 (m, 1H), 2,03-of 2.23 (m, 2H), 2,24-to 2.74 (m, 10H), of 2.81 (t, J=5.4 Hz, 2H), 4,06 (t, J=5.4 Hz, 2H), 6,79-6,85 (m, 2H), 6,92-6,98 (m, 2H), 7,21 (DDD, J=1.2 Hz, 4.8 Hz, 8.0 Hz, 1H), EUR 7.57 (dt, J=1.2 Hz, 8.0 Hz, 1H), 7,69 (dt, J=2.0 Hz, 8.0 G is Il]piperazine

Specified in the title compound obtained as a yellow oil by the method according to example 25 (yield 70%).

1H-NMR (400 MHz, CDCl3)of 0.79 (d, J=6.8 Hz, 3H), 1,00-1,20 (m, 1H), 1,22 (d, J=6.4 Hz, 3H), 1,50-of 1.64 (m, 1H), 1.85 to 2,00 (m, 1H), 2,08 was 2.25 (m, 2H), 2.26 and is 2.75 (m, 10H), 2,82 (t, J=5.4 Hz, 2H), 4,07 (t, J=5.4 Hz, 2H), 6,79-6,85 (m, 2H), 6,92-6,98 (m, 2H), 7,31 (DD, J=1.6 Hz, 4.4 Hz, 2H), 8,63 (DD, J=1.6 Hz, 4.4 Hz, 2H).

ESI-MS: 425 (M+H+).

Example 29

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-phenylpiperazin

In acetonitrile (2 ml) dissolve 100 mg (0.30 mmol) of 4-cyano-5-methyl-5-phenylhexanoic. To the resulting mixture are added 55 mg (0.36 mmol) of potassium carbonate and 60 mg (0.36 mmol) phenylpiperazine and heated to 60°C. After the reaction solution was distributed between ethyl acetate and a saturated solution of salt. The organic layer is dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 2 g of silica gel Chromatorex NH (ethyl acetate/hexane, 1/5), while receiving 137 mg (quantitative yield) specified in the title compounds as a colorless syrup. Physico-chemical data specified in the connection header is shown below.

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6,4 Hz, 3 6,88-6,92 (m, 2H), 7,22-to 7.32 (m, 4H), 7,34-7,40 (m, 3H).

ESI-MS: 362 (M+N+).

Example 30

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

Specified in the title compound synthesized by the method according to example 29, using 1-(2-phenylethyl)piperazine (yield 100%, colorless oil).

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.4 Hz, 3H), 1,08-1,20 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-to 1.63 (m, 1H), 1,84-of 1.93 (m, 1H), 2,07-2,19 (m, 2H), 2,24-2,60 (m, N), 2,74-2,82 (m, 2H), 7,16-7,21 (m, 3H), 7.24 to 7,31 (m, 3H), 7,35-7,38 (m, 4H).

ESI-MS: 390 (M+N+).

Example 31

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(3-phenylpropyl)piperazine

Specified in the title compound synthesized by the method according to example 29, using 1-(3-phenylpropyl)piperazine (yield 100%, colorless oil).

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 1.04 million-1,20 (m, 1H), 1,20 (d, J=6.4 Hz, 3H), 1,50-of 1.62 (m, 1H), 1,74-of 1.92 (m, 3H), 2.06 to to 2.18 (m, 2H), 2,20-of 2.50 (m, N), 2,61 (t, J=7,6 Hz, 2H), 7,14-7,19 (m, 3H), 7.23 percent-7,31 (m, 3H), 7,34-7,37 (m, 4H).

ESI-MS: 404 (M+N+).

Example 32

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-3-[N-(2-cyanoethyl)-N-{2-(3-pertenece)ethyl}amino]pyrrolidin

In dichloromethane (7 ml) dissolve 250 mg (0,74 mmol) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-3-[N-(2-what maldehyde, 0,08 ml (1.48 mmol) of acetic acid and 235 mg (1.11 mmol) of triacetoxyborohydride sodium. After the reaction solution is alkalinized 2 N. a sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 25 g of silica gel Chromatorex NH (ethyl acetate/hexane, 1/3), while receiving 290 mg (0.61 mmol, 82.2 per cent) indicated in the title compounds as a colorless syrup.

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 1,05-1,25 (m, N) of 1.20 (d, J=6.8 Hz, 3H), 1,47 and 1.80 (m, 2H), 1.85 to 2,28 (m, 4H), 2,29-2,70 (m, 6N), 2,48 (t, J=6,8 Hz, 2H), 2,90-of 3.25 (m, 4H), 3,40-3,55 (m, 1H), 3,98 (t, J=5.6 Hz, 2H), 6,56-6,62 (m, 1H), 6,63-of 6.90 (m, 3H), 7.18 in-7,25 (m, 1H), 7,26-7,40 (m, 5H).

ESI-MS: 477 (M+N+).

Example 33

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-3-[N-(2-cyanoethyl)-N-{2-(3-cianfrocca)ethyl}amino]pyrrolidin

In dichloromethane (7 ml) dissolve 250 mg (0,74 mmol) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-3-[N-(2-cyanoethyl)amino]pyrrolidine and alternately add 179 mg (1.11 mmol) of 3-cyanobenzaldehyde synthesized separately similar to the method of obtaining 3-perfeccionamiento, and 0.08 ml (1.48 mmol) of acetic acid and 235 mg (1.11 mmol) trucktrailer with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 25 g of silica gel Cromatorex NH (ethyl acetate/hexane, 1/3), while receiving 318 mg (0.66 mmol, 88,9%) specified in the title compounds as a colorless syrup.

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 1,05-1,25 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,47 and 1.80 (m, 2H), 1.85 to 2,28 (m, 4H), 2,29-of 2.72 (m, 6N), 2,48 (t, J=6,8 Hz, 2H), 2,90 was 3.05 (m, 4H), 3,42-3,55 (m, 1H), 4,01 (t, J=5.6 Hz, 2H), 7,11-to 7.15 (m, 2H), 7.23 percent-7,40 (m, 7H).

ESI-MS: 484 (M+N+).

Example 34

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-3-[N-(2-cyanoethyl)-N-{2-(2-cianfrocca)ethyl}amino]pyrrolidin

In dichloromethane (7 ml) dissolved 263 mg (0.78 mmol) of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-3-[N-(2-cyanoethyl)amino]pyrrolidine and alternately add 251 mg (1.56 mmol) separately synthesized 3-cyanobenzaldehyde, and 0.09 ml (1.56 mmol) of acetic acid and 247 mg (1,17 mmol) triacetoxyborohydride sodium. After the reaction solution is alkalinized 2 N. a sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated, to give crude product. The crude product clicks the connection information in the form of a yellow syrup.

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 1,05-1,25 (m, 1H), 1,19 (d, J=6.4 Hz, 3H), of 1.45 and 1.80 (m, 2H), 1.85 to of 2.16 (m, 3H), 2,16-2,70 (m, 7H), of 2.54 (t, J=6,8 Hz, 2H), 2,90-of 3.12 (m, 4H), 3.45 points-of 3.60 (m, 1H), 4,11 (t, J=6,8 Hz, 2H), 6,40? 7.04 baby mortality (m, 2H), 7,26-7,40 (m, 5H), 7,50-7,58 (m, 2H).

ESI-MS: 484 (M+N+).

Example 35

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-3-[N-(2-cyanoethyl)-N-{2-(4-cianfrocca)ethyl}amino]pyrrolidin

In acetonitrile (5,00 ml) dissolved 217 mg (1.00 mmol) 4-cyano-5-methyl-5-phenylhexane and the resulting solution was cooled to 0°C. To the mixture add 320 ál (2,30 EQ.) of triethylamine and 85 μl (1,10 EQ.) methylchloride and warmed to room temperature. After 15 minutes add 450 mg (3.00 EQ.) sodium iodide and 370 mg (1,30 mmol) 3-[N-(2-cyanoethyl)-N-{2-(4-cianfrocca)ethyl}amino]pyrrolidine and heat the mixture to 60°C. After the reaction to the mixture is added a saturated solution of salt and the desired product extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and get the crude product. The crude product is treated with 37 g of silica gel Cromatorex NH (ethyl acetate/hexane, 1/1), while receiving 316 mg (of 0.65 mmol, 65%) indicated in the title compound as a yellow syrup.

the), of 1.65-1.77 in (m, 1H), 1,78-of 1.97 (m, 1H), 1,98-2,17 (m, 2H), 2,19-of 2.30 (m, 1H), 2,30-by 2.73 (m, 6N), 2,48 (t, J=6,8 Hz, 2H), 2,90-of 3.07 (m, 4H), 3.43 points of 3.56 (m, 1H), Android 4.04 (t, J=5.8 Hz, 2H), 6,94 (d, J=9,2 Hz, 2H), 7,27-7,34 (m, 1H), 7,34-7,40 (m, 4H), to 7.59 (d, J=9,2 Hz, 2H).

ESI-MS: 484 (M+N+).

Example 36

1-[((4-Cyano-5-methyl-4-(2-thienyl))hexyl]-3-[N-(2-cyanoethyl)-N-{2-(4-cianfrocca)ethyl}amino]pyrrolidin

Specified in the title compound synthesized by the method according to example 35 using 4-cyano-5-methyl-5-(2-thienyl)hexanol (yield 38%, pale yellow syrup).

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.8 Hz, 3H), of 1.18 (d, J=6.4 Hz, 3H), 1,25-1,40 (m, 1H), 1,55-of 1.85 (m, 2H), 1,98-2,12 (m, 3H), 2,18-2,78 (m, 7H), 2,48 (t, J=6,8 Hz, 2H), 2,90-3,10 (m, 4H), 3,44-to 3.58 (m, 1H), of 4.05 (t, J=5.6 Hz, 2H), 6,92-6,98 (m, 3H), 7,10-7,13 (m, 1H), 7,25-7,29 (m, 1H), to 7.59 (d, J=8,8 Hz, 2H).

ESI-MS: 490 (M+N+).

Example 37

1-[(4-Cyano-5-methyl-4-(2-thienyl))hexyl]-3-[N-(2-cyanoethyl)-N-{2-(3-cianfrocca)ethyl}amino]pyrrolidin

Specified in the title compound synthesized by the method according to example 35 using 4-cyano-5-methyl-5-(2-thienyl)hexanol and 3-cyanobenzaldehyde (yield 98%, pale yellow syrup).

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.4 Hz, 3H), of 1.18 (d, J=6.4 Hz, 3H), 1,28-of 1.45 (m, 1H), 1,58-1,90 (m, 2H), 2.00 in to 2.15 (m, 3H), 2,20-2,31 (m, 1H), 2,32-2,80 (, =7,8 Hz, 9.0 Hz, 1H).

ESI-MS: 490 (M+N+).

Example 38

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(6-vinylpyridin-3-yl)methyl]piperazine

(6-Vinylpyridin-3-yl)methanol (185 mg, 1.00 mmol) and triethylamine (0,29 ml) dissolved in 5 ml of acetonitrile and added dropwise 85,1 μl (1.10 mmol) of methanesulfonamide. After the disappearance of the original substance, which is confirmed by the data of thin-layer chromatography, the reaction solution at room temperature is added 340 mg (1,19 mmol) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine, then alternately add 899 mg of sodium iodide, 5 ml of dimethylformamide and 1 ml of water. The mixture is then heated to 80°C. After the reaction to the mixture is added a saturated salt solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 50 g of silica gel Cromatorex NH (ethyl acetate/hexane, 1/2), while receiving 300 mg (0.66 mmol, 66.3 per cent) indicated in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 1.06 a-1,26 (m, 1H), 1,20 (d, J=6.4 Hz, 3H), 1,48-of 1.64 (m, 1H), 1,84-of 1.97 (m, 1H), 2.06 to 2,22 (m, 2H), 2.23 to-2,60 (m, 10H), of 3.54 (s, 2H), 7.24 to to 7.32 (t, 1H), 7,32-7,43 (Il-4-phenyl)hexyl]-4-[(5-phenylisoxazol-3-yl)methyl]piperazine

(5-Phenylisoxazol-3-yl)methanol (61,3 mg, 0.35 mmol) and triethylamine (0.10 ml) dissolved in 3 ml of acetonitrile and added dropwise 27,1 μl (0.35 mmol) of methanesulfonamide. After the disappearance of the original substance, which is confirmed by the data of thin-layer chromatography, the reaction solution at room temperature was added 100 mg (0.35 mmol) of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine, then alternately add 262 mg of sodium iodide and 2 ml of dimethylformamide. The mixture is then heated to 70°C. After the reaction to the mixture is added a saturated salt solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 15 g of silica gel Cromatorex NH (ethyl acetate/hexane, 2/3), while receiving 45 mg (0.10 mmol, 29.0 percent) specified in the title compound as a yellow syrup.

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 1.06 a-1,26 (m, 1H), 1,20 (d, J=6.4 Hz, 3H), 1,48-of 1.64 (m, 1H), 1,86-to 1.98 (m, 1H), 2.06 to of 2.20 (m, 2H), 2,25-2,70 (m, 10H), 3,63 (s, 2H), is 6.54 (s, 1H), 7.24 to 7,32 (m, 1H), 7,32-7,39 (m, 4H), 7,39-7,49 (m, 3H), 7,74-7,79 (m, 2H).

ESI-MS: 443 (M+N+).

Example 40

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(2-phenylthiazol-4-yl)Melina dissolved in 3 ml of acetonitrile and added dropwise 27,1 μl (0.35 mmol) of methanesulfonamide. After the disappearance of the original substance, which is confirmed by the data of thin-layer chromatography, the reaction solution at room temperature was added 100 mg (0.35 mmol) of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine. Then to the resulting mixture 262 mg of sodium iodide, 2 ml of dimethylformamide and 2 ml of acetonitrile and heated to 70°C. After the reaction to the mixture is added a saturated salt solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 15 g of silica gel Cromatorex NH (ethyl acetate/hexane, 1/2) to give 63 mg (0.14 mmol, 40,0%) specified in the title compounds as a colorless syrup.

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 1,05-1,25 (m, 1H), 1,20 (d, J=6.4 Hz, 3H), 1,48-of 1.64 (m, 1H), 1,82-to 1.98 (m, 1H), 2,05-2,22 (m, 2H), 2,23 is 2.80 (m, 10H), 3,74 (s, 2H), 7,13 (s, 1H), 7,25-7,32 (m, 1H), 7,32-7,39 (m, 4H), 7,39 was 7.45 (m, 3H), to $ 7.91 to 7.75 (m, 2H).

ESI-MS: 459 (M+N+).

Example 41

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

(2-Phenyloxazol-4-yl) methanol (61,3 mg, 0.35 mmol) and 0.10 ml of triethylamine are dissolved in 3 ml of acetonitrile and added dropwise 27,1 ál (0,35 nematollahi, to the reaction solution at room temperature was added 100 mg (0.35 mmol) of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine. Then added to the mixture 262 mg of sodium iodide and 2 ml of dimethylformamide and heated to 70°C. After the reaction to the mixture is added a saturated salt solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 15 g of silica gel Cromatorex NH (ethyl acetate/hexane, 2/3), while receiving 41 mg (0.09 mmol, 26.5 per cent) indicated in the title compounds as a colorless syrup.

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 1,07-1,24 (m, 1H), 1,19 (d, J=6.8 Hz, 3H), 1,49-of 1.64 (m, 1H), 1,84 is 1.96 (m, 1H), 2.06 to of 2.20 (m, 2H), 2.26 and-to 2.74 (m, 10H), of 3.54 (s, 2H), 7.24 to 7,32 (m, 1H), 7,32-7,39 (m, 4H), 7,41-7,46 (m, 3H), 7,58 (s, 1H), 8,01-of 8.06 (m, 2H).

ESI-MS: 443 (M+N+).

In the above examples (6-vinylpyridin-3-yl)methanol and (5-phenylisoxazol-3-yl)methanol synthesized by the method described in journal of Med. Chem., 1998, 41, 2390-2410, (2-phenyloxazol-4-yl)methanol synthesized by the method described in journal of Org. Chem., 1996, 61, 6496-6497, and (2-phenylthiazol-4-yl)methanol synthesized by the method described in the journal Bull. Chem. Soc. Jpn., 71, 1391-1396 (1998).

Example 42

1-[(4-Cyano-5-methyl-4-phenyl)gel 2-(4-phenyl-2-oxo-3-oxazolidinyl)acetaldehyde dissolved in 5 ml of acetone, add 6 ml of 2.5 n hydrochloric acid and the mixture is heated. After the reaction mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated, receiving 300 mg of crude product, which is 2-(4-phenyl-2-oxo-3-oxazolidinyl)acetaldehyde. The crude product is used in the following reaction without purification. Namely, 2-(4-phenyl-2-oxo-3-oxazolidinyl)acetaldehyde dissolved in 5 ml of dichloroethane and alternately add 300 mg (of 1.46 mmol) obtained above 2-(4-phenyl-2-oxo-3-oxazolidinyl)acetaldehyde, of 0.11 ml (2.00 mmol) of acetic acid and 318 mg (1.50 mmol) of triacetoxyborohydride sodium. After the reaction solution is alkalinized 2 N. a sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 50 g of silica gel Cromatorex NH (ethyl acetate/hexane, 1/1), while receiving 477 mg (0,94 mmol, 94.2 percent) specified in the title compounds as a colorless syrup.

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 1,08-1,22 (m, 1H), 1,20 (d, J=6.4 Hz, 3H), 1,48-to 1.63 (m, 1H), 1.85 to a 1.96 (m, 1H), 2.06 to to 2.18 (m, 2H), 2,20-2,52 (m 7,34-the 7.43 (m, 8H).

ESI-MS: 475 (M+N+).

Example 43

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(3-phenyl-2-oxo-5-oxazolidinyl)methyl]piperazine

5-(Hydroxymethyl)-3-phenyl-2-oxoacetate synthesized by the method described in the journal J. Med.Chem., 989, 673-1681. 5-(Hydroxymethyl)-3-phenyl-2-oxoacetate (1.00 mmol, 193 mg) and of 0.29 ml of triethylamine dissolved in 5 ml of acetonitrile and added dropwise 85,1 μl (1.10 mmol) of methanesulfonamide. After the disappearance of the original substance, which is confirmed by the data of thin-layer chromatography, the reaction solution at room temperature is added 340 mg (1,19 mmol) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine, then alternately add 899 mg of sodium iodide, 5 ml of dimethylformamide and 1 ml of water. The mixture is then heated to 60°C. After the reaction to the mixture is added a saturated salt solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 50 g of silica gel Cromatorex NH (ethyl acetate/hexane, 1/1), while receiving 110 mg (0.24 mmol, 23,9%) specified in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3)0, which, 1H), 4,70-4,80 (m, 1H), 7,11-7,16 (m, 1H), 7,27-7,33 (m, 1H), 7,33-7,40 (m, 6N), 7,51-7,56 (m, 2H).

ESI-MS: 461 (M+N+).

Example 44

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]piperazine

In tetrahydrofuran (3 ml) dissolve to 95.3 mg (0.70 mmol) benzamidoxime and molecular sieve 4 angstroms (400 mg). To the mixture is first added 32 mg (0.8 mmol) of sodium hydride and then another 20 mg and heated to 60°C. After 10 minutes, add 3 ml of a solution of 500 mg (1,40 mmol) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[(methoxycarbonyl)methyl]piperazine in tetrahydrofuran and heat the mixture under reflux. After the reaction to the mixture is added a saturated salt solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated, to give crude product. The crude product is purified by preparative chromatography (ethyl acetate: 10%) and then treated with 25 g of silica gel Cromatorex NH (ethyl acetate/hexane, 3:5), while receiving 127 mg (0.29 mmol, 40.9 per cent) indicated in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.4 Hz, 3H), 1.04 million-1,20 (m, 1H), 1,19 (d, J=6.4 Hz, 3H), 1,45-to 1.60 (m, 1H), 1,80-of 1.92 (m, 1H), 2.05 is-to 2.18 (m, 2H), 2,22-2,31 (m, 2H), 2,31-of 2.50 (m, 4H), 2,55/sup>).

Example 45

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(5-(3-forfinal)-1,2,4-oxadiazol-3-yl)methyl]piperazine

Specified in the title compound is synthesized using 3-forbesautos.com, similar to the way to obtain 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]piperazine in example 44 (yield 26%, pale yellow syrup).

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 1.06 a-1,22 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-of 1.62 (m, 1H), 1,83 is 1.96 (m, 1H), 2,05-of 2.20 (m, 2H), 2,20-of 2.54 (m, 6N), 2,55 was 2.76 (m, 4H), 3,90 (s, 2H), 4,06 (t, J=8,8 Hz, 1H), 4,70-4,80 (m, 1H), 7,17-7,25 (m, 1H), 7,25-7,32 (m, 1H), 7,32-7,38 (m, 4H), 7,42-of 7.48 (m, 1H), to 7.77-of 7.82 (m, 1H), 7,86-of 7.90 (m, 1H).

ESI-MS: 462 (M+N+).

Example 46

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(2-(4-pertenece)ethyl]piperidine

In acetonitrile (2 ml) dissolve 100 mg (0.30 mmol) of 4-cyano-5-methyl-4-phenylhexanoic. To the mixture is added 55 mg (0.36 mmol) of sodium carbonate and 80 mg (0.36 mmol) 4-[(2-(4-pertenece)ethyl]piperidine and heated to 60°C. After the reaction mixture is distributed between ethyl acetate and a saturated solution of salt. The organic layer is dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 40 g of silica gel Cromatorex NH (a syrup. Physico-chemical data specified in the connection header is shown below.

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), of 1.05 to 1.24 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,22-of 1.32 (m, 2H), 1,42 and 1.80 (m, 7H), 1,81-of 1.92 (m, 2H), 2,07-to 2.18 (m, 2H), 2,20-of 2.28 (m, 2H), 2.70 height is 2.80 (m, 2H), 3,93 (t, J=6,8 Hz, 2H), 6,78-6,83 (m, 2H), 6,92-6,98 (m, 2H), 7,25-7,38 (m, 5H).

ESI-MS: 423 (M+N+).

Example 47

1-Benzyl-4-[(4-cyano-5-methyl-4-phenyl)hexyl]piperidine

In DMF (70 ml) dissolved 2,39 g (15.0 mmol) of 3-methyl-2-phenylpentane. To a mixture of 600 mg (60 wt.%, 15.0 mmol) of sodium hydride and heated to 60°C. After 30 minutes the reaction solution is cooled to room temperature, add 2,90 g (9,31 mmol) 1-benzyl-4-methanesulfonylaminoethyl dissolved in 10 ml of DMF, and the mixture is again heated. After the reaction mixture is distributed between ethyl acetate and a saturated solution of salt. The organic layer is dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 100 g of silica gel (ethyl acetate/hexane, from 1/100 to 1/0), while receiving to 2.57 g (6,86 mmol, 73,7%) specified in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 0,85-0,98 (m, 1H), 1,06-of 1.26 (m, 6N), of 1.18 (d,(4 Fervency)ethyl]-4-[(4-cyano-5-methyl-4-phenyl)hexyl]piperidine

In acetonitrile (5 ml) was dissolved 200 mg (0.70 mmol) of 4-[(4-cyano-5-methyl-4-phenyl)hexyl]piperidine. To the mixture is added 69 mg (0.50 mmol) of potassium carbonate and 110 mg (0.50 mmol) 4-fortunecity.com and heated to 60°C. After the reaction mixture is distributed between ethyl acetate and a saturated solution of salt. The organic layer is dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 40 g of silica gel Cromatorex NH (ethyl acetate/hexane, 1/7), while receiving 160 mg (0.38 mmol, 76,0%) specified in the title compounds as a colorless syrup. Physico-khimicheskie connection information below.

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 0,85-0,98 (m, 1H), 1,10-1,30 (m, 5H), 1,19 (d, J=6.8 Hz, 3H), 1.30 and USD 1.43 (m, 1H), 1,50-of 1.66 (m, 2H), 1,74-of 1.85 (m, 1H), 1,92-2,03 (m, 2H), 2.05 is with 2.14 (m, 2H), 2,72 (t, J=6.0 Hz, 2H), 2,88-2,95 (m, 2H), a 4.03 (t, J=6.0 Hz, 2H), 6,79-6,84 (m, 2H), 6,92-6,98 (m, 2H), 7,26-7,38 (m, 5H).

ESI-MS: 423 (M+N+).

Example 49

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

Specified in the header loose coupling is obtained as yellow oil from 3-cyano-3-(2-thienyl)propanol (114 mg) and 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine (90 mg) (see formula (l, J=6,8 Hz, 3H), 1,05-1,20 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-of 1.73 (m, 2H), 1,82-of 1.95 (m, 2H), 1,95-of 2.08 (m, 2H), 2,08-to 2.18 (m, 2H), 2,20-of 2.45 (m, 10H), 4,10-to 4.15 (m, 1H), 6.90 to-6,99 (m, 1H),? 7.04 baby mortality-7,06 (m, 1H), 7,26-7,30 (m, 1H), 7,35-7,40 (m, 5H).

63 mg) obtained above in the header of the free connection handle in the usual way and get 60 mg of the hydrochloride.

Hydrochloride:

ESI-MS: 449 (MH+).

Example 50

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(4-cyano-4-(4’-forfinal)butyl]piperazine

2-[(3-Cyano-3-phenyl)propyl]-1,3-dioxolane (1.77 g) was dissolved in 2 N. a solution of Hcl (15 ml) in tetrahydrofuran (15 ml). The mixture is stirred at room temperature for 13 hours, add 2 n NaOH solution (15 ml) and ethyl acetate and the separated organic layer. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the mixture evaporated. 99 mg of the resulting residue (5-oxo-2-phenylpropionitrile), 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine (99 mg) and acetic acid (0.1 ml) dissolved in dichloromethane (3.5 ml) and add triacetoxyborohydride sodium (147 mg). The mixture is stirred at room temperature for 18 hours and 30 minutes, neutralized by adding a saturated aqueous solution bicarbonate filtered off and the mixture evaporated. The resulting residue is purified by chromatography on a column of NH silica gel (system: hexane/ethyl acetate), obtaining mentioned in the title compound (136 mg, 88% yield calculated on the basis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine).

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 1.04 million-1,19 (m, 1H), 1,19 (d, J=6.8 Hz, 3H), 1,50-1,70 (m, 3H), 1,80-2,00 (m, 3H), 2,08-of 2.20 (m, 2H), 2,20-of 2.45 (m, N), 3,80-3,88 (m, 1H), 7,25-7,40 (m, N).

136 mg) obtained above in the header of the free connection handle in the usual way and obtain 141 mg of the hydrochloride.

Hydrochloride:

ESI-MS: 461 (MN+).

Example 51

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[4-hydroxym-4-(4’-forfinal)butyl]piperazine

A solution (10 ml) of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine (100 mg), 4-chloro-4’-verbalization (91 mg) and triethylamine (0.1 ml) in acetonitrile is stirred by heating under reflux. After 6 hours the reaction solution is cooled to room temperature and separate the organic layer, adding water and ethyl acetate. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the filtrate evaporated. The resulting OS is l-4-phenyl)hexyl]-4-[4-(4-forfinal)butane-1-it]piperazine, a precursor of the desired compound (56 mg). 27 mg of the product is dissolved in ethanol (2 ml), add chloride of hydroxyamine (8,3 mg) and sodium acetate (9.8 mg) and the mixture stirred with heating under reflux. After 2 hours the solution is cooled to room temperature and separate the organic layer, adding water and ethyl acetate. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the filtrate evaporated. The resulting residue is purified by chromatography on a column of silica gel (system methanol/ethyl acetate), obtaining mentioned in the title compound as a colourless oil (17 mg).

1H-NMR (400 MHz, CDCl3)0,76 (d, J=6.8 Hz, 3H), 1.06 a-1,20 (m, 1H), 1,18 (d, J=6.8 Hz, 3H), 1,50-of 1.62 (m, 1H), 1,75-to 1.82 (m, 2H), 1,82-of 1.92 (m, 1H), 2,05-of 2.20 (m, 2H), 2,22 is 2.55 (m, N), 2,72-2,78 (m, 2H), 6,99-7,05 (m, 2H), 7,25-7,30 (m, 1H), 7,31 and 7.36 (m, 4H), 7,58 to 7.62 (m, 2H).

17 mg) obtained above in the header of the free connection handle in the usual way and obtain 14 mg of the hydrochloride.

Hydrochloride:

ESI-MS: 465 (MN+).

Example 52

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(4-methyl-3-phenylpentane)piperazine

Specified the Association:

1H-NMR (400 MHz, CDCl3)of 0.71 (d, J=6.6 Hz, 3H), 0,76 (d, J=6.8 Hz, 3H), of 0.92 (d, J=6.8 Hz, 3H), 1,03 is 1.16 (m, 2H), 1,18 (d, J=6.8 Hz, 3H), 1,46 is 1.60 (m, 3H), 1.70 to of 2.16 (m, 6N), 2,18-to 2.42 (m, 10H), 7,07-7,13 (m, 2H), 7,14-to 7.18 (m, 1H), 7,20-to 7.32 (m, 4H), 7,33 and 7.36 (m, 4H).

Hydrochloride (80 mg) specified in the connection header receiving, processing loose coupling method of example 1.

Hydrochloride:

ESI-MS: 446 (MN+).

Example 53

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(4-methyl-3-phenylhexane)piperazine

Specified in the header of the compound obtained by the method of example 1 described in JP-A 11-206862 (150 mg, yield 94%).

Loose coupling:

1H-NMR (400 MHz, CDCl3)0.69 (d, J=6,86 Hz, 3H), 0,76 (d, J=6.8 Hz, 3H), of 0.92 (d, J=6.6 Hz, 3H), 1,03 is 1.16 (m, 2H), 1,19 (d, J=6.6 Hz, 3H), 1,18 of 1.28 (m, 2H), 1,65-1,90 (m, 4H), 2.05 is with 2.14 (m, 3H), 2,14 is 2.44 (m, 10H), 7,07-7,13 (m, 2H), 7,14-to 7.18 (m, 1H), 7,20-to 7.32 (m, 3H), 7,33 and 7.36 (m, 4H).

Hydrochloride get, the processing specified in the header of the loose coupling method of example 1.

Hydrochloride:

ESI-MS: 460 (MN+).

Example 54

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

Specified in the title compound obtained as a pale yellow oil (183 mg, 38%) https://img.russianpatents.com/chr/948.gif">of 0.77 (d, J=6.8 Hz, 3H), 1.04 million-1,19 (m, 1H), 1,19 (d, J=6.6 Hz, 3H), 1,50-of 1.64 (m, 1H), 1,82-of 1.92 (m, 1H), 2.06 to to 2.18 (m, 2H), 2,22-of 2.28 (m, 2H), 2,28-to 2.40 (m, 4H), 2,48-of 2.64 (m, 5H), to 2.75 (DD, J=7,7 Hz, and 13.4 Hz, 1H), 4,65-to 4.73 (m, 1H), 5,20 (d, J=a 10.6 Hz, 1H), 5.25-inch (d, J=17,4 Hz, 1H), to 5.85 (DDD, J=5.8 Hz, a 10.6 Hz, to 17.4 Hz, 1H), for 6.81-to 6.88 (m, 2H), 6,88-6,97 (m, 2H), 7,25-7,31 (m, 1H), 7,32-7,40 (m, 4H).

Hydrochloride get, the processing specified in the header of the loose coupling method of example 1.

Hydrochloride:

ESI-MS: 450 (MN+).

Example 55

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

Specified in the title compound obtained as a colorless oil (67 mg, 62%) by the method according to example 104, described in JP-A 11-206862.

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 1,05-of 1.18 (m, 1H), 1,19 (d, J=6.4 Hz, 3H), 1,48-of 1.66 (m, 1H), 1,48 (dt, J=4.4 Hz, and 12.4 Hz, 1H), 2.06 to to 2.18 (m, 2H), 2,22-to 2.40 (m, 6N), 2,44-of 2.54 (m, 1H), 2,68-to 2.74 (m, 2H), 2.93 which is 3.00 (m, 1H), 3.95 to 3,98 (m, 2H), 4,06 (d, J=5,2 Hz, 2H), 5,16 (Shir.d, J=10.4 Hz, 1H), 5,24 (DD, J=1,6 Hz and 17.2 Hz, 1H), 5,81-of 5.92 (m, 1H), 6,80-6,97 (m, 4H), 7.24 to 7,33 (m, 1H), 7,34-7,39 (m, 4H).

Hydrochloride get, the processing specified in the header of the loose coupling method of example 1.

Hydrochloride:

ESI-MS: 494 (MH+).

Example 56

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[3-(n-propanone)-2-(4-ftoh exyl]-4-[3-allyloxy-2-(4-pertenece)propyl]piperazine (85 mg) was dissolved in ethanol (3.5 ml) at room temperature. To the mixture is added 10% palladium on coal (10 mg) and stirred. After 3 hours 20 minutes palladium on coal is separated by filtration and the filtrate evaporated. The resulting residue is purified by chromatography on a column of NH silica gel (system: hexane/ethyl acetate), obtaining mentioned in the title compound (34 mg, 40%).

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.6 Hz, 3H), 0.88 to (dt, J=2.7 Hz, 7.2 Hz, 3H), 1,05-1,20 (m, 1H), 1,19 (d, J=6.6 Hz, 3H), 1,50-1,60 (m, 4H), 1,82-of 1.92 (m, 1H), 2,05-of 2.20 (m, 3H), 2,20-2,60 (m, N), 2,66-2,78 (m, 2H), 3,31-to 3.41 (m, 2H), 3,61 (d, J=5.5 Hz, 1H), 4,06 (d, J=5,1 Hz, 1H), for 6.81-6,98 (m, 4H), 7,25-7,32 (m, 1H), 7,32-7,40 (m, 4H).

Hydrochloride get, the processing specified in the header of the loose coupling method of example 1.

Hydrochloride:

ESI-MS: 496 (MN+).

Example 57

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

In tetrahydrofuran (5 ml) is dissolved 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[3-allyloxy-2-(4-pertenece)propyl]piperazine (125 mg) and add borohydride sodium (14.4 mg) and then a solution of iodine (64 mg) in tetrahydrofuran (2 ml). The mixture is stirred for one hour and separated the organic layer by adding ethyl acetate and water. The obtained organic layer is up and the filtrate evaporated. The residue is purified by chromatography on a column of NH silica gel (system: hexane/ethyl acetate), obtaining mentioned in the title compound as a pale yellow oil (70 mg, 61%). Hydrochloride get, the processing specified in the header of the loose coupling method of example 1.

Hydrochloride:

ESI-MS: 436 (MH+).

Example 58

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

Specified in the title compound is obtained from 1,2,3,4-tetrahydroquinoline method of example 89, described in JP-A 11-206862 (34%).

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 1,05-1,20 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-of 1.66 (m, 1H), 1.85 to to 1.98 (m, 2H), 2.05 is-of 2.20 (m, 2H), 2,24-of 2.56 (m, 1H), 2,73 (Shir.t, J=6.4 Hz, 2H), 3,29 (Shir.t, J=5.6 Hz, 3H), 3,36-to 3.41 (m, 2H), 3,39 (Shir.t, J=7.8 Hz, 2H), 3.45 points-to 3.52 (m, 2H), 6,52-6,59 (m, 2H), 6.90 to-6,94 (m, 1H), 7,00-to 7.15 (m, 1H), 7,26-7,32 (m, 1H), 7,34-7,38 (m, 4H).

Hydrochloride get, the processing specified in the header of the loose coupling method of example 1.

Hydrochloride:

ESI-MS: 445 (MH+).

Example 59

4-[(4-Cyano-5-methyl-4-phenyl)hexyl]-N-(4-forfinal)-N’-(2-methylpropyl)-1(2H)-pyrazinecarboxamide

In a nitrogen atmosphere to a solution of 1-(forfinal)-chetyrehpostovye carbon (948 mg) in dichloromethane (4 ml). After 45 minutes the reaction solution is cooled to room temperature and separate the organic layer, adding water and dichloromethane. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the filtrate evaporated. The resulting residue was immediately purified by chromatography on a column of NH silica gel (system: hexane/ethyl acetate) to give carbodiimide in the form of a colorless oily intermediate compounds. Carbodiimide and 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine (100 mg) dissolved in 2-propanol (10 ml) and stirred with heating under reflux. After 2 hours the solvent is evaporated and the resulting residue purified by chromatography on a column of NH silica gel (system: hexane/ethyl acetate), obtaining mentioned in the title compound as a colourless solid (174 mg, 25%, stage 2).

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 0.88 to of 0.91 (m, 6N), 1,05-of 1.18 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,50-of 1.65 (m, 2H), 1,67 and 1.80 (m, 2H), 1,88-to 1.98 (m, 1H), 2.06 to of 2.20 (m, 2H), 2,22-of 2.36 (m, 4H), 2,79 (Shir.d, J=6,8 Hz, 1H), 3,05 (DD, J=6.0 Hz, 6.8 Hz, 1H), 3,14-3,20 (m, 1H), 4,82-4,91 (m, 1H), 6,52 return of 6.58 (m, 1H), 6,72-of 6.78 (m, 1H), 6,91? 7.04 baby mortality (m, 3H), 7,22-7,31 (m, 4H), 7,35-7,38 (m, >/p>Hydrochloride:

ESI-MS: 478 (MN+).

Example 60

4-[(4-Cyano-5-methyl-4-phenyl)hexyl]-N-(4-terbisil)-N’-(2-methylpropyl)-1(2H)-pyrazinecarboxamide

Specified in the title compound obtained as a colorless oil by the method according to example 59 (62%).

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 0,80-0,88 (m, 6N), 1,05-of 1.18 (m, 1H), 1,20 (d, J=6.4 Hz, 3H), 1,43 is 1.60 (m, 1H), 1,84-of 1.95 (m, 1H), 2,05-of 2.20 (m, 2H), 2,25-to 2.40 (m, 6N), 2,87-2,95 (m, 2H), 3,22-to 3.38 (m, 4H), 3,49 (s, 2H), 4,35 is 4.45 (m, 2H), 7,02-to 7.09 (m, 2H), 7,27-7,34 (m, 3H), 7,34-7,41 (m, 4H).

Hydrochloride get, the processing specified in the header of the loose coupling method of example 1.

Hydrochloride:

ESI-MS: 492 (MN+).

Example 61

4-[(4-Cyano-5-methyl-4-phenyl)hexyl]-N,N’-dicyclohexylcarbodiimide

Specified in the title compound obtained as a colorless oil by the method according to example 59 (62%).

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.8 Hz, 3H), 1.04 million of 1.46 (m, N), to 1.21 (d, J=6.8 Hz, 3H), 1,46-of 1.74 (m, 6N), 1,74 is 1.86 (m, 6N), 1,86-to 1.98 (m, 2H), 2,07-2,22 (m, 2H), 2,24-to 2.40 (m, 6N), 3,05-and 3.16 (m, 2H), 3,23-of 3.32 (m, 4H), 3,41-to 3.52 (m, 1H), 7,28-7,34 (m, 1H), 7,35-7,42 (m, 4H).

Hydrochloride receive processing indicated the emer 62

N-Cyano-4-[(4-cyano-5-methyl-4-phenyl)hexyl]-N’-[(4-pertenece)ethyl]pyrazinecarboxamide

In nitrogen atmosphere N-cyano-N’-ethyl-(4-pertenece)-O-phenylazomethine (168 mg) and 1-[(4-cyano-5-methyl-4-phenyl)hexyl]piperazine (100 mg) dissolved in 2-propanol (5 ml) and the mixture stirred with heating under reflux. After 24 hours the solvent is evaporated and the resulting residue purified by chromatography on a column of silica gel (system: hexane/ethyl acetate), obtaining mentioned in the title compound as a colourless solid (98 mg, 71%).

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.6 Hz, 3H), of 1.08 (d, J=6.6 Hz, 3H), of 1.20 to 1.34 (m, 1H), 1,50-1,70 (m, 1H), 1,92 (DDD, J=4,9 Hz and 11.6 Hz to 13.6 Hz, 1H), 2,05-of 2.23 (m, 2H), 2,24-of 2.38 (m, 6N), 3,43-to 3.50 (m, 2H), 3,78-3,82 (m, 2H), Android 4.04-4.09 to (m, 2H), 5,00-of 5.05 (m, 1H), 6,80-6,85 (m, 2H), 6,92-7,01 (m, 2H), 7,27-7,32 (m, 1H), 7,34-7,39 (m, 4H).

Hydrochloride get, the processing specified in the header of the loose coupling method of example 1.

Hydrochloride:

ESI-MS: 491 (MN+).

Example 63

(2-Thienyl)-[(4-cyano-5-methyl-4-phenyl)hexylpyridine]metonymy

Specified in the title compound obtained as a colorless oil by the method according to the C, 3H), 1,05-1,20 (m, 1H), 1,20 (d, J=6.6 Hz, 3H), 1,50-of 1.64 (m, 1H), 1,88-of 2.08 (m, 1H), 2,08-2,22 (m, 2H), 2,28-of 2.38 (m, 6N), 3,32-3,44 (m, 4H), 7,00 (DD, J=3,6 Hz, 5.2 Hz, 1H), 7,14 (DD, J=1.2 Hz, 3.6 Hz, 1H), 7,26-7,32 (m, 1H), 7,34 (DD, J=1.2 Hz, 5.2 Hz, 1H), 7,35-7,39 (m, 4H).

Hydrochloride specified in the connection header receiving, processing loose coupling method of example 1.

Hydrochloride:

ESI-MS: 345 (MN+).

Example 64

1-Isopropyl-4-[4-isobutyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-phenylbutyramide

2-Chloro-1-isobutyl-1H-benzo[d]imidazole (4 g) and 1-[(4-cyano-5-methyl-4-hexyl]piperazine (5 g) dissolved in tetrahydrofuran (10 ml) and stirred at an oil bath at 150°C for 6 hours in an open system. The reaction product is purified by NH silica gel (system ethyl acetate/hexane), while receiving specified in the title compound as a brown oil (6.8 g, 85%).

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.8 Hz, 3H), or 0.83 (d, J=6.8 Hz, 3H), from 0.84 (d, J=6.4 Hz, 3H), of 1.20 and 1.35 (m, 1H), 1,21 (d, J=6.8 Hz, 3H), 1,52-to 1.67 (m, 1H), 1,95-2,07 (m, 1H), 2,08-of 2.23 (m, 1H), 2,23 is 2.43 (m, 4H), 2,43-of 2.50 (m, 4H), 3,21-of 3.25 (m, 4H), 3,80 (d, J=7,6 Hz, 2H), 7,08-to 7.64 (m, N).

Hydrochloride get, the processing specified in the header of the loose coupling method of example 1.

Hydrochloride:

ESI-MS: 458 (M>/p>In nitrogen atmosphere thionyl chloride (4 ml) are added to (4-cyano-5-methyl-4-phenyl)hexanol (2,33 g) under ice cooling and stirring, is heated under reflux. After 2 hours the mixture is evaporated. The resulting residue is purified by chromatography on a column of silica gel (system: hexane/ethyl acetate) to give (4-cyano-5-methyl-4-phenyl)vexilloid (2.35 g, 93%) as a yellow oil. The obtained chloride (454 mg), [(4-cyano-5-methyl-4-phenyl)hexyl]piperazine (166 mg) and sodium iodide (289 mg) was dissolved in acetonitrile (5 ml) and stirring, heat the solution to reflux. After 2 hours the mixture is cooled to room temperature and separate the organic layer by adding ethyl acetate and water. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the mixture evaporated. The residue is purified by chromatography on a column of NH silica gel (hexane/ethyl acetate), obtaining mentioned in the title compound as a pale yellow oil (213 mg, 23%).

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 1,02-of 1.16 (m, 2H), 1,19 (d, J=6,8 Hz, 6N), 1,46 is 1.60 (m, 2H), 1,80-of 1.92 (m, 2H), 2.40 a-2,17 (m, 4H), 2,17-of 2.36 (m, N), 7.23 percent-7,31 (m, 2H), 7,33-7,37 (m, 8H).

Hydrochlori

ESI-MS: 485 (MH+).

Example 66

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

Specified in the title compound obtained as a pale yellow oil by way of example 65 (yield 52%).

1H-NMR (400 MHz, CDCl3)0,76 (d, J=6.8 Hz, 3H), 0,765 (d, J=6.4 Hz, 3H), 1.00 and-of 1.18 (m, 1H), 1,18 (d, J=6.4 Hz, 3H), 1,19 (d, J=6.8 Hz, 3H), 1,44 is 1.60 (m, 1H), 1,80-2,00 (m, 4H), 2.00 in to 2.18 (m, 4H), 2,18 is 2.44 (m, 10H), 7,26-to 7.32 (m, 2H), 7,33-7,40 (m, 8H).

Hydrochloride specified in the connection header receiving, processing loose coupling method of example 1.

Hydrochloride:

ESI-MS: 471 (MN+).

Example 67

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(1’,2’-methylenedioxyphenyl)ethyl]piperidine

Specified in the title compound is obtained by way of example 49 (51% yield).

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 1,10-1,30 (m, 3H), 1,20 (d, J=6.4 Hz, 3H), 1,48 to 1.76 (m, 7H), 1,80-of 1.94 (m, 2H), 2.06 to to 2.18 (m, 2H), 2,18-of 2.28 (m, 2H), 2,53-2,60 (m, 2H), 2.70 height is 2.80 (m, 2H), of 5.92 (s, 2H), 6,82-6,70 (m, 2H), 6,70-of 6.78 (m, 1H), 7,26-7,40 (m, 5H).

Hydrochloride get, the processing specified in the header of the loose coupling method of example 1.

Hydrochloride:

ESI-MS: 433 (MH+).

In acetonitrile (5 ml) was dissolved 4-cyano-4-(3-cyano-5-thienyl)-5-methylhexane (0,13 g). To the mixture add triethylamine (of 0.21 ml) and methylchloride (0,048 ml) and stirred at room temperature for one hour. To the reaction mixture, water is added, extracted with ethyl acetate and washed with a saturated solution of salt. The mixture is dried over anhydrous magnesium sulfate and evaporated, obtaining a pale yellow oil. The oil obtained is dissolved in DMF (2 ml) and add a solution (4 ml) of 1-[2-(4-cianfrocca)ethyl]piperazine (0.14 g), triethylamine (of 0.21 ml) and sodium iodide (0.15 g) in DMF. The mixture was stirred at 60°C over night, add ethyl acetate and washed with water and saturated salt solution. The mixture is then dried over anhydrous magnesium sulfate, the solvent is evaporated and the resulting residue purified by chromatography on a column of NH silica gel (system: hexane/ethyl acetate), obtaining mentioned in the title compound as a pale yellow oil (0.09 g, 33%).

Loose coupling:

1H-NMR (400 MHz, CDCl3)to 0.92 (d, J=6.8 Hz, 3H), 1,20 (d, J=6.8 Hz, 3H), of 1.21 to 1.31 (m, 1H), 1.60-to of 1.73 (m, 1H), 1.77 in (dt, J=4 Hz to 13.2 Hz, 1H), 2.06 to (Queen, J=6,8 Hz, 1H), measuring 2.20 (dt, J=4 Hz to 13.2 Hz, 1H), 2,33 (t, J=7,6 Hz, 2H), 2,42 (Shir.s, 4H), 2,58 (Shir.s, 4H), 2,82 (t, J=5.6 Hz, 2H), 4,13 (t, J=5.6 Hz, 2H)passed in the header of the free connection in the usual way.

Hydrochloride:

ESI-MS: 462 (MN+).

Example 69

1-[(4-Cyano-4-(3-cyano-5-thienyl)-5-methylhexan]-4-[2-(3-cianfrocca)ethyl]piperazine

Specified in the title compound obtained as a pale yellow oil (0.15 g, 58%) of 4-cyano-4-(Z-cyano-5-thienyl)-5-methylhexane and 1-[2-(3-cianfrocca)ethyl]piperazine by the method according to example 68.

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.93 (d, J=6.8 Hz, 3H), 1,21 (d, J=6.8 Hz, 3H), 1,22-1,32 (m, 1H), 1.60-to of 1.73 (m, 1H), 1,79 (dt, J=4 Hz and 12.4 Hz, 1H), 2,07 (Queen, J=6,8 Hz, 1H), of 2.21 (dt, J=4 Hz and 12.4 Hz, 1H), 2,34 (t, J=7.2 Hz, 2H), 2,43 (Shir.s, 4H), 2,59 (Shir.s, 4H), 2,82 (t, J=5.6 Hz, 2H), 4,11 (t, J=5.6 Hz, 2H), 7,12-7,40 (m, 5H), to $ 7.91 (s, 1H).

Hydrochloride get, the processing specified in the header loose connection in the usual way.

ESI-MS: 462 (MH+).

Example 70

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

In acetonitrile (10.0 ml) was dissolved 400 mg (1,61 mmol) 4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexanol and cooling the mixture to 0°C. To this mixture of 0.26 ml of 1.85 mmol) of triethylamine and 0.14 ml (1.77 mmol) of methylchloride and warmed to room temperature. After 20 minutes add a simple ether and a saturated solution of salt. Essential Ritel is evaporated and get the crude product. Half of the amount (about 0.1 mmol) of the crude mesyl compound dissolved in 8,00 ml of dimethylformamide. To this mixture 724 mg (a 4.83 mmol) of sodium iodide, 111 mg (0.81 mmol) of potassium carbonate and 243 mg (1.05 mmol) of 1-[2-(3-cianfrocca)ethyl]piperazine and heated to 60°C. After the reaction to the mixture is added a saturated solution of salt and the desired product extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and get the crude product. The crude product is treated with silica gel Cromatorex NH (elution with ethyl acetate/hexane, 1/1), to thereby obtain 289 mg (0,63 mmol, 77.3 per cent) indicated in the title compound as a yellow syrup.

1H-NMR (400 MHz, CDCl3)to 0.92 (d, J=6.8 Hz, 3H), 1,21 (d, J=6.4 Hz, 3H), 1,20-to 1.38 (m, 1H), 1,60 is 1.86 (m, 2H), 2,01-2,12 (m, 1H), 2,18-of 2.30 (m, 1H), 2,30-of 2.75 (m, HE), 2,80-2,90 (m, 2H), 4,08-4,18 (m, 2H), 7,11-to 7.18 (m, 3H), of 7.23-7,28 (m, 1H), 7,34-7,40 (m, 1H), 7,52 (d, J=3,60 Hz, 1H).

ESI-MS: 462 (MN+).

Example 71

1-[(4-Cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-{N-(2-cyanoethyl)anilino}ethyl]piperazine

Specified in the title compound is synthesized using [2-{N-(2-cyanoethyl)of aniline}ethyl]piperazine, similar to the way Poluchenie oil).

1H-NMR (400 MHz, CDCl3)to 0.92 (d, J=6.4 Hz, 3H), of 1.20 and 1.33 (m, 1H), 1,21 (d, J=6.4 Hz, 3H), 1,58-of 1.73 (m, 1H), 1,73-of 1.84 (m, 1H), 2,02-2,11 (m, 1H), 2,23 (dt, J=4.0 Hz, to 12.8 Hz, 1H), 2,31-of 2.64 (m, N), 2,68 (t, J=7.2 Hz, 2H), 3,51 (t, J=6,8 Hz, 2H), 3,69 (t, J=7.2 Hz, 2H), to 6.67 (d, J=8.0 Hz, 3H), 6,76 (t, J=7,4 Hz, 1H), 7,15 (d, J=4,00 Hz, 1H), 7.23 percent-7,30 (m, 2H), 7,52 (d, J=4.0 Hz, 1H).

ESI-MS: 489 (M+N+).

Example 72

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

In 1.5 ml of acetonitrile was dissolved 111 mg (0.31 mmol) of 4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexylidene. To the mixture of 56.2 μl (0.40 mmol) of triethylamine and 109 mg (0.47 mmol) of 1-(3-cyanobenzoate)piperazine and stirred for 3 days. The organic layer was separated by adding ethyl acetate and saturated salt solution, the reaction solution is dried over magnesium sulfate and evaporated, to give crude product. The crude product is treated with 12.5 g of silica gel Cromatorex NH (ethyl acetate/hexane, 1/2), while receiving 144 mg (quantitative yield) specified in the title compound as a yellow syrup.

1H-NMR (400 MHz, CDCl3)to 0.92 (d, J=6.4 Hz, 3H), 1,15 of 1.28 (m, 1H), 1,26 (d, J=6.4 Hz, 3H), 1,60-1,75 m, 1H), 2,17-of 2.27 (m, 1H), 2,27-2,70 (m, N), of 2.81 (t, J=6.0 Hz, 2H), 4,10 (t, J=6 Hz, 2H), 7,11-7,16 (m, 2H), 7,22-7,26 (m, 1H), 7,26-7,28 (m, 2H), 7,33-7,39 (m, erasin

Specified in the title compound synthesized by the method according to example 72 (yield 82.3 per cent).

1H-NMR (400 MHz, CDCl3)to 0.92 (d, J=6.4 Hz, 3H), 1,15-of 1.29 (m, 1H), 1,26 (d, J=6.8 Hz, 3H), 1.60-to around 1.74 (m, 1H), 2,17-of 2.27 (m, 1H), 2,27-2,70 (m, N), 2,80 (t, J=6.0 Hz, 2H), 4,08 (t, J=6.0 Hz, 2H), 6,59-6,70 (m, 3H), 7,16-7,24 (m, 1H), 7,26-7,28 (m, 2H).

ESI-MS: 455 (M+N+).

Example 74

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

Specified in the title compound synthesized by the method according to example 72 (exit 70.2 per cent).

1H-NMR (400 MHz, CDCl3)to 0.92 (d, J=6.8 Hz, 3H), 1,14-of 1.29 (m, 1H), 1,26 (d, J=6.8 Hz, 3H), 1.60-to around 1.74 (m, 1H), 2,17-of 2.27 (m, 1H), 2,27-2,70 (m, N), 2,78 (t, J=6.0 Hz, 2H), of 4.05 (t, J=6.0 Hz, 2H), for 6.81-6,85 (m, 2H), 6,93-6,98 (m, 1H), 7,26-7,28 (m, 2H).

ESI-MS: 455 (M+N+).

Example 75

1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-cianfrocca)ethyl]piperazine

Specified in the title compound synthesized by the method according to example 72, using 4-cyano-5-methyl-4-(2-thienyl)hexolite (output 94,7%).

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.6 Hz, 3H), of 1.18 (d, J=6.8 Hz, 3H), 1,20-to 1.38 (m, 1H), 1,55-1,72 (m, 1H), 1,73 of-1.83 (m, 1H), 2,02-2,12 (m, 1H), 2,12-2,22 (m, 1H), 2,28 to 2.35 (m, 2H), 2,35-to 2.65 (m, 8H), of 2.81 (t, J=5,9, Giano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(4-cianfrocca)ethyl]piperazine

Specified in the title compound synthesized by the method according to example 72, using 4-cyano-5-methyl-4-(2-thienyl)hexolite (output of 40.9%).

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.8 Hz, 3H), of 1.18 (d, J=6.8 Hz, 3H), 1,22-to 1.38 (m, 1H), 1.56 to to 1.70 (m, 1H), 1,72-of 1.81 (m, 1H), 2,01 is 2.10 (m, 1H), 2,10-of 2.21 (m, 1H), 2,27-of 2.34 (m, 2H), 2,34-2,62 (m, 8H), of 2.81 (t, J=6.0 Hz, 2H), of 4.12 (t, J=6.0 Hz, 2H), 6,92-of 6.96 (m, 3H), 7,11 (DD, J=1.2 Hz, 3.6 Hz, 1H), 7.24 to 7,27 (m, 2H), EUR 7.57 (d, J=8,8 Hz, 2H).

ESI-MS: 437 (M+N+).

Example 77

1-[4-Cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[3-(5-cyano-2-thienyl)propyl]piperazine

In acetonitrile (3 ml) was dissolved 200 mg (0,56 mmol) 4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexylidene. To this mixture 78,0 ál (0,56 mmol) of triethylamine and 178 mg (from 0.76 mmol) of 1-[3-(5-cyano-2-thienyl)propyl]piperazine and stirred at 55°C. After 5 hours the reaction solution is concentrated and the residue is treated with silica gel Cromatorex NH (ethyl acetate/hexane, 1/2), while receiving 243 mg (0.52 mmol, 92,8%) specified in the title compound as a yellow syrup.

1H-NMR (400 MHz, CDCl3)to 0.92 (d, J=6.8 Hz, 3H), of 1.18 to 1.31 (m, 1H), 1,21 (d, J=6.8 Hz, 3H), 1.60-to 1,72 (m, 1H), 1,73 is 1.91 (m, 3H), 2,00-2,10 (m, 1H), 2,17-of 2.27 (m, 1H), 2,28-of 2.50 (m, N), is 2.88 (t, J=7,6 Hz, 2H), 6,80 (d, J=4.0 Hz, 1H), 7,15 (d, what enyl)hexyl]-4-[3-(2-thienyl)propyl]piperazine

Specified in the title compound synthesized by the method described in example 77 (exit 96,4%).

1H-NMR (400 MHz, CDCl3)to 0.92 (d, J=6.8 Hz, 3H), between 1.19 to 1.31 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1.60-to 1,72 (m, 1H), 1,72-of 1.81 (m, 1H), 1,82 is 1.91 (m, 2H), 2,00-2,10 (m, 1H), 2,17-of 2.24 (m, 1H), 2,27-of 2.54 (m, N), 2,85 (t, J=7,6 Hz, 2H), is 6.78 (DD, J=0.8 Hz, 3.6 Hz, 1H), 6,91 (DD, J=3,6 Hz, 5.2 Hz, 1H), 7,10 (DD, J=0.8 Hz, 5.2 Hz, 1H), 7,14 (d, J=4.0 Hz, 1H), 7,51 (d, J=4.0 Hz, 1H).

ESI-MS: 441 (M+N+).

Example 79

1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-[3-(5-cyano-2-thienyl)propyl]piperazine

Specified in the title compound synthesized by the method in example 77, using 4-cyano-5-methyl-4-(2-thienyl)hexolite (output 96,4%).

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.8 Hz, 3H), of 1.18 (d, J=6.4 Hz, 3H), of 1.23 to 1.37 (m, 1H), 1,60-1,70 (m, 1H), 1,72-1,90 (m, 3H), 2,02-of 2.09 (m, 1H), 2,11-of 2.20 (m, 1H), 2.26 and-2,52 (m, N), is 2.88 (t, J=7,6 Hz, 2H), 6,80 (d, J=3.6 Hz, 1H), 6,94 (DD, J=3,6 Hz, 5.2 Hz, 1H), 7,11 (DD, J=1.2 Hz, 3.6 Hz, 1H), 7,26 (DD, J=1.2 Hz, 5.2 Hz, 1H), 7,45 (d, J=3.6 Hz, 1H).

ESI-MS: 441 (M+N+).

Example 80

1-[4-Cyano-5-methyl-4-(4-cyano-2-thienyl)hexyl]-4-[3-(2-thienyl)propyl]piperazine

Specified in the header connection receive under the conditions described below, the synthesis of tert-butyl 4-[3-(2-tie persin, synthesized by the method according to example 69 (exit 23,6%).

1H-NMR (400 MHz, CDCl3)to 0.92 (d, J=6.8 Hz, 3H), 1,20 (d, J=6.8 Hz, 3H), 1,22-1,32 (m, 1H), 1,59-1,72 (m, 1H), 1,72 is 1.91 (m, 3H), 2,02-2,12 (m, 1H), 2,15-of 2.24 (m, 1H), 2,28-of 2.56 (m, N), 2,85 (t, J=7,6 Hz, 2H), 6,77-to 6.80 (m, 1H), 6,91 (DD, J=3,6 Hz, 5.2 Hz, 1H), 7,11 (DD, J=1.2 Hz, 5.2 Hz, 1H), 7,28 (d, J=1.2 Hz, 1H), 7,89 (d, J=1.2 Hz, 1H).

ESI-MS: 441 (M+N+).

Example 81

1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-[(2-benzoxazolyl)methyl]piperazine

In acetonitrile (5 ml) was dissolved 230 mg (0.82 mmol) of 1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]piperazine synthesized similarly to the above 1-[3-(5-cyano-2-thienyl)propyl]piperazine. To a mixture of 120 mg (0,72 mmol) of 2-(chloromethyl)benzoxazole and 0.10 ml (to 0.72 mmol) of triethylamine and heated to 50°C. After 5 hours the reaction solution is concentrated and the residue is treated with silica gel Cromatorex NH (ethyl acetate/hexane, 1/2), while receiving 244 mg (of 0.58 mmol, 80.5 per cent) indicated in the title compound as a yellow syrup.

1H-NMR (400 MHz, CDCl3)to 0.89 (d, J=6.8 Hz, 3H), of 1.18 (d, J=6.4 Hz, 3H), 1,20-to 1.38 (m, 1H), 1,55 was 1.69 (m, 1H), 1,71-of 1.81 (m, 1H), 2,00-2,09 (m, 1H), 2,10-2,19 (m, 1H), 2,28 of $ 2.53 (m, 6N), 2,55-by 2.73 (m, 4H), 3,86 (s, 2H), 6,93 (DD, J=3,6 Hz, 5.2 Hz, 1H), 7,10 (DD, J=1.2 Hz, 3.6 Hz, 1H), 7,24 (DD, J=1.2 Hz, 5.2 Hz, 1H), 7,30 and 7.36 (m, 2H), 7,50-7,55 (azolyl)methyl]piperazine

In acetonitrile (3 ml) was dissolved 200 mg (0,56 mmol) 4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexylidene. To this mixture 78,0 ál (0,56 mmol) of triethylamine and 146 mg (0.67 mmol) of 1-[(2-benzoxazolyl)methyl]piperazine and stirred at 55°C. After 14 hours the reaction solution is concentrated and the residue is treated with silica gel Cromatorex NH (ethyl acetate/hexane, 1/2), while receiving 237 mg (0,53 mmol, 94,6%) specified in the title compound as a yellow syrup.

1H-NMR (400 MHz, CDCl3)of 0.91 (d, J=6.8 Hz, 3H), 1,20 (d, J=6.8 Hz, 3H), 1,20-1,30 (m, 1H), 1,59 is 1.70 (m, 1H), 1,70-1,80 (m, 1H), 2,00-2,09 (m, 1H), 2,15 was 2.25 (m, 1H), 2,33 (t, J=7.2 Hz, 2H), 2,37-2,52 (m, 4H), 2.57 m-2,72 (m, 4H), a 3.87 (s, 2H), 7,14 (d, J=4.0 Hz, 1H), 7,30 and 7.36 (m, 2H), 7,50 (d, J=4.0 Hz, 1H), 7,51-of 7.55 (m, 1H), 7.68 per-7,73 (m, 1H).

ESI-MS: 448 (M+H+).

Example 83

1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-[{2-(5-cyanobenzoate)}methyl]piperazine

Specified in the title compound synthesized by the method described in example 82 (exit 89.3 per cent).

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.4 Hz, 3H), of 1.18 (d, J=6.8 Hz, 3H), 1,22-of 1.36 (m, 1H), 1.56 to to 1.70 (m, 1H), 1,71 and 1.80 (m, 1H), 2,00-2,09 (m, 1H), 2,10-2,19 (m, 1H), 2,29-of 2.36 (m, 2H), 2,36-2,52 (m, 4H), 2,56-a 2.71 (m, 4H), to 3.89 (s, 2H), 6,93 (DD, J=3,6 Hz, 5.2 Hz, 1H), 7,10 (DD, J=1.2 Hz, 3.6 Hz, 1H), 7,25 (exil]-4-[2-(3-pertenece)ethyl]piperazine

1-[2-(4-Pertenece)ethyl]piperazine (50 mg) synthesized by the method described in example 1 of JP-A 11-206862, add at room temperature in a nitrogen atmosphere to a solution (3 ml), 1-iodine-4-cyano-5-methyl-4-(3-thienyl)hexane (50 mg) and triethylamine (0.06 ml) in acetonitrile. The mixture is stirred at 50°C for 4 hours, the solvent is evaporated and the resulting residue purified by chromatography on a column of silica gel Cromatorex NH (system: hexane/ethyl acetate), obtaining mentioned in the title compound as a yellow oil (62 mg, 96%).

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.83 (d, J=6.8 Hz, 3H), of 1.16 (d, J=6.6 Hz, 3H), 1,55-1,65 (m, 1H), 1,74-of 1.84 (m, 1H), 2,02-2,12 (m, 2H), to 2.29 (t, J=7.2 Hz, 2H), 2,30-2,47 (m, 4H), 2,47-to 2.65 (m, 4H), and 2.79 (t, J=6.0 Hz, 2H), 4,07 (t, J=6.0 Hz, 2H), 6,58-6,70 (m, 3H), 6,92 (DD, J=1.5 Hz, 5.0 Hz, 1H), 7,17-7,24 (m, 1H), 7,26-7,28 (m, 1H), 7,33 (DD, J=3.0 Hz, 5.0 Hz, 1H).

62 mg) obtained above in the header of the free compound was dissolved in methanol and add an excess of 4 n hydrochloric acid in ethyl acetate. The mixture is stirred and evaporated. To the resulting residue, water is added and the aqueous solution freeze, immersing in a bath with a mixture of dry ice / methanol. The solvent is removed by drying in the e substance 62 mg).

Hydrochloride:

ESI-MS: 430 (MN+).

Example 85

1-[4-Cyano-5-methyl-4-(3-thienyl)hexyl]-4-[2-(3-cianfrocca)ethyl]piperazine

Specified in the title compound obtained as a colorless oil by the method described in example 84 (85%).

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.83 (d, J=6.8 Hz, 3H), of 1.16 (d, J=6.6 Hz, 3H), 1,15-1,30 (m, 1H), 1,54-of 1.66 (m, 1H), 1,75-of 1.85 (m, 1H), 2,02-of 2.15 (m, 2H), 2,25 is 2.33 (m, 2H), 2,33-2,48 (m, 4H), 2,48-to 2.65 (m, 4H), 2,80 (t, J=5.7 Hz, 2H), 4,10 (t, J=5.7 Hz, 2H), 6,93 (DD, J=1.3 Hz, 5.1 Hz, 1H), 7,10-7,30 (m, 2H), 7,20-7,26 (m, 1H), 7,26-7,28 (m, 1H), 7,32-7,39 (m, 2H).

Hydrochloride specified in the header of the free compounds produced by the method described in example 84.

Hydrochloride:

ESI-MS: 437 (MH+).

Example 86

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

Specified in the title compound obtained as a colorless oil by the method described in example 84 (76%).

Loose coupling:

1H-NMR (400 MHz, CDCl3)from 0.84 (d, J=6.8 Hz, 3H), 1,01-1,02 (m, 1H), 1,17 (d, J=6.6 Hz, 3H), 1,50-1,70 (m, 1H), 1,75-of 1.85 (m, 1H), 2.00 in of 2.08 (m, 1H), 2,08-to 2.18 (m, 1H), 2,27 is 2.33 (m, 2H), 2,33-2,48 (m, 4H), 2,48-of 2.66 (m, 4H), 2,80 (t, J=5.8 Hz, 2H), 4,07 (t, J=5.8 Hz, 2H), 6,59-6,70 (m, 3H), 7,17-7,2 the way, described in example 84.

ESI-MS: 455 (MN+).

Example 87

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

Specified in the title compound obtained as a colorless oil by the method described in example 84 (78%).

Loose coupling:

1H-NMR (400 MHz, CDCl3)from 0.84 (d, J=6.8 Hz, 3H), 1,01-1,02 (m, 1H), 1,17 (d, J=6.6 Hz, 3H), 1,50-of 1.65 (m, 1H), 1,75-of 1.85 (m, 1H), 2,00-2,09 (m, 1H), 2,09-to 2.18 (m, 1H), 2,27 is 2.33 (m, 2H), 2,33-2,48 (m, 4H), 2,48-of 2.66 (m, 4H), of 2.81 (t, J=5.8 Hz, 2H), 4,10 (t, J=5.8 Hz, 2H), 7,12-7,16 (m, 2H), 7.23 percent-7,28 (m, 1H), was 7.36 (dt, J=0.8 Hz, 7.8 Hz, 1H), 7,46 (d, J=1.6 Hz, 1H), 7,56 (d, J=1.6 Hz, 3H).

Hydrochloride specified in the header of the free compounds produced by the method described in example 84.

ESI-MS: 462 (MN+).

Example 88

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

Specified in the title compound obtained as a colorless oil by the method described in example 84 (72%).

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.8 Hz, 3H), of 1.18 (d, J=6.6 Hz, 3H), 1,22-to 1.38 (m, 1H), 1,52 is 1.70 (m, 1H), 1,73 of-1.83 (m, 1H), 2,00-2,11 (m, 1H), 2,11-of 2.20 (m, 1H), 2,27 is 2.33 (m, 2H), 2,33 is 2.51 (m, 4H), of 2.51-2,70 (m, 4H), of 2.86 (t, J=5.8 Hz, 2H), 4,17 (t, J=5.8 Hz, 2H), 6.89 in-6,97 (m, is written in example 84.

ESI-MS: 455 (MN+).

Example 89

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

Specified in the title compound obtained as a colorless oil by the method described in example 84 (72%).

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.83 (d, J=6.8 Hz, 3H), of 1.16 (d, J=6.6 Hz, 3H), 1,16-1,20 (m, 1H), 1,50-of 1.66 (m, 1H), 1,76 is 1.86 (m, 1H), 2,01 and 2.13 (m, 2H), 2,24 is 2.33 (m, N), 2,33 is 2.51 (m, 4H), of 2.51-2,70 (m, 4H), 2,87 (t, J=5.8 Hz, 2H), to 4.17 (t, J=5.8 Hz, 2H), 6.89 in-6,97 (m, 2H), 7,20-7,30 (m, 3H), 7,33-7,38 (m, 1H).

Hydrochloride specified in the header of the free compounds produced by the method described in example 84.

ESI-MS: 455 (MN+).

Example 90

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

Specified in the title compound obtained as a colorless oil by the method according to example 84 (64%), using as the starting material 2-(4-cyano-2-pertenece)ethyl]piperazine, synthesized by the method according to reference example 69.

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.6 Hz, 3H), of 1.18 (d, J=6.8 Hz, 3H), 1,22-to 1.38 (m, 1H), 1,52 is 1.70 (m, 1H), 1,72-to 1.82 (m, 1H), 2,00-2,10 (m, 1H), 2,11-of 2.20 (m, 1H), 2,27 is 2.33 (m, 2H), 2,33 is 2.51 (m, 4H), of 2.51-2,70 (the d, J=1.9 Hz, 10.4 Hz, 1H), 7,38-7,42 (m, 1H).

Hydrochloride target get connection with the processing of loose coupling by way of example 84.

ESI-MS: 455 (MN+).

Example 91

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

Specified in the title compound obtained as a colorless oil by the method according to example 84 (64%), using as the starting material 2-(4-cyano-2-pertenece)ethylpiperazin, synthesized by the method according to reference example 69.

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.83 (d, J=6.8 Hz, 3H), of 1.16 (d, J=6.8 Hz, 3H), 1,22-to 1.38 (m, 1H), 1,52 is 1.70 (m, 1H), 1,74-of 1.84 (m, 1H), 2.00 in to 2.13 (m, 2H), 2,25 is 2.33 (m, 2H), 2,33-2,49 (m, 4H), 2,49 of 2.68 (m, 4H), 2,85 (t, J=5.8 Hz, 2H), 4,20 (t, J=5.8 Hz, 2H), 6,92 (DD, J=1.5 Hz, 5.1 Hz, 1H), 7,00 (t, J=8,4 Hz, 1H), 7,25-7,28 (m, 1H), 7,32-7,37 (m, 2H), 7,40 (DDD, J=1.3 Hz, 1,8 Hz and 8.4 Hz, 1H).

Hydrochloride specified in the header of the free compounds produced by the method described in example 84.

ESI-MS: 455 (MN+).

Example 92

1-{4-Cyano-5-methyl-4-[(2,5-dibromo)-3-thienyl]hexyl}-4-[2-(3-cianfrocca)ethyl]piperazine

Specified in the title compound obtained as a colorless oil by the method described in example 84 (78%).

Free, 1,52 is 1.70 (m, 1H), 1,82-2,02 (m, 1H), 2,30 of $ 2.53 (m, 8H), 2,53 of 2.68 (m, 4H), of 2.81 (t, J=5.8 Hz, 2H), 4,10 (t, J=5.8 Hz, 2H),? 7.04 baby mortality (s, 1H), 7,11-7,20 (m, 2H), 7,22-7,29 (m, 1H), 7,34-7,39 (m, 1H).

Hydrochloride specified in the header of the free compounds produced by the method described in example 84.

ESI-MS: 593, 595, 597 (MN+).

Example 93

1-{4-Cyano-5-methyl-4-(2-bromo-5-cyano-3-thienyl)hexyl}-4-[2-(3-cianfrocca)ethyl]piperazine

1-{4-Cyano-5-methyl-4-[(2,5-dibromo)-3-thienyl]hexyl}-4-[2-(3-cianfrocca)ethyl]piperazine (145 mg) is dissolved under nitrogen atmosphere in a mixed solution of cyanide of zinc (57,3 mg) and 1,1’-bis(diphenylphosphino)ferrocene (13.5 mg) in dimethylformamide (10 ml)/water (0.1 ml). To the obtained mixture is added a complex of palladium and dibenzylideneacetone in (8.9 mg), three times replace a nitrogen atmosphere and stirred the solution at 120°C for 4 hours. To the mixture add water, diethyl ether and an aqueous solution of ammonia and separate the organic layer. The obtained organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent is filtered off, the filtrate evaporated and the residue purified LC-MS (column ODS; the system acetonitrile/water), while receiving specified in the title compound as a yellow oil (8 mg, 6.7 per cent).

Free soede by 1.68 (m, 1H), 2,00-2,10 (m, 1H), 2,30-2,70 (m, N), and 2.83 (t, J=5.7 Hz, 2H), 4,11 (t, J=5.7 Hz, 2H), 7,11-7,17 (m, 2H), 7,22-7,27 (m, 1H), 7,34-7,39 (m, 1H), 7,55 (s, 1H).

Hydrochloride specified in the header of the free compounds produced by the method described in example 84.

ESI-MS: 540, 542 (MN+).

Example 94

1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(4-methylthiophene)ethyl]piperazine

Specified in the title compound obtained as a colorless oil by the method according to example 45, described in JP-A 11-206862 (64%).

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.8 Hz, 3H), of 1.18 (d, J=6.8 Hz, 3H), 1,22-to 1.38 (m, 1H), 1,55-1,70 (m, 1H), 1,71-to 1.82 (m, 1H), 2,02 is 2.10 (m, 1H), 2,11-of 2.21 (m, 1H), and 2.27 to 2.35 (m, 2H), 2,35-of 2.50 (m, 4H), of 2.44 (s, 3H), 2,50-to 2.65 (m, 4H), 2,78 (t, J=5,9 Hz, 2H), 4,07 (t, J=5,9 Hz, 2H), 6,84 (Shir.d, J=8,8 Hz, 2H), 6,94 (DD, J=3,7 Hz, 4.9 Hz, 1H), 7,11 (Shir.d, J=3,7 Hz, 1H), 7,22-7,29 (m, 3H).

Hydrochloride specified in the header of the free compounds produced by the method described in example 84.

ESI-MS: 456 (MN+).

Example 95

1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(4-methylsulfinylphenyl)ethyl]piperazine

Specified in the title compound obtained as a colorless oil by the method described in example 84 (85%).

Loose coupling:

1H-NMR (4000 (m, 1H), 2,11-of 2.21 (m, 1H), and 2.27 to 2.35 (m, 2H), 2,35-of 2.50 (m, 4H), 2,50-to 2.65 (m, 4H), and 2.83 (t, J=5.8 Hz, 2H), 3,03 (s, 3H), of 4.16 (t, J=5.8 Hz, 2H), 6,84 (Shir.d, J=8,8 Hz, 2H), 6,94 (DD, J=3,7 Hz, 4.9 Hz, 2H), 7,11 (Shir.d, J=3,7 Hz, 1H), 7,22-7,29 (m, 3H).

Hydrochloride specified in the header of the free compounds produced by the method described in example 84.

ESI-MS: 490 (MN+).

Example 96

1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-acetylphenol)ethyl]piperazine

Specified in the title compound obtained as a colorless oil by the method described in example 84 (72%).

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.8 Hz, 3H), of 1.18 (d, J=6.6 Hz, 3H), 1,22-to 1.38 (m, 1H), 1,55-1,71 (m, 1H), 1,71-to 1.82 (m, 1H), 2,02 is 2.10 (m, 1H), 2,11-of 2.21 (m, 1H), 2,28 to 2.35 (m, 2H), 2,35-of 2.50 (m, 4H), 2,50-to 2.65 (m, 4H), 2,59 (s, 3H), 2,82 (t, J=5.8 Hz, 2H), 4,14 (t, J=5.8 Hz, 2H), 6,94 (DD, J=3.5 Hz, 4.9 Hz, 1H), 7,09-7,13 (m, 2H), 7.24 to 7,28 (m, 1H), was 7.36 (t, J=7.9 Hz, 1H), 7,47-to 7.50 (m, 1H), 7,54 (Shir.d, J=7.9 Hz, 1H).

Hydrochloride specified in the header of the free compounds produced by the method described in example 84.

ESI-MS: 454 (MN+).

Example 97

1-[4-Cyano-5-methyl-4-(3-thienyl)hexyl]-4-[2-(3-acetylphenol)ethyl]piperazine

Specified in the title compound obtained as a colorless oil by the method described in the note is to 1.16 (d, J=6,8 Hz, 3H), 1,16-of 1.30 (m, 1H), 1,50 by 1.68 (m, 1H), 1,75-of 1.84 (m, 1H), 2,02 and 2.13 (m, 2H), of 2.25 to 2.35 (m, 2H), 2,35-2,47 (m, 4H), 2,47 of 2.68 (m, 4H), at 2.59 (s, 3H), of 2.81 (t, J=5,9 Hz, 2H), 4,14 (t, J=5,9 Hz, 2H), 6,92 (DD, J=1.4 Hz, 4.9 Hz, 1H), 7,09-7,13 (m, 1H), 7,25-7,28 (m, 1H), 7,32-7,38 (m, 2H), 7,47-to 7.50 (m, 1H), 7,51-7,56 (m, 1H).

Hydrochloride specified in the header of the free compounds produced by the method described in example 84.

ESI-MS: 454 (MN+).

Example 98

1-[4-Cyano-5-methyl-4-(3-thienyl)hexyl]-4-[2-(4-cianfrocca)ethyl]piperazine

Specified in the title compound obtained as a colorless oil by the method described in example 84 (55%).

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.83 (d, J=6.8 Hz, 3H), of 1.16 (d, J=6.8 Hz, 3H), 1,16-of 1.30 (m, 1H), 1,50 by 1.68 (m, 1H), 1,72-of 1.84 (m, 1H), 2,02-2,12 (m, 2H), of 2.25 to 2.35 (m, 2H), 2,35 at 2.45 (m, 4H), 2,45-to 2.65 (m, 4H), of 2.81 (t, J=5.8 Hz, 2H), of 4.12 (t, J=5.8 Hz, 2H), 6.90 to-6,97 (m, 3H), 7.23 percent-to 7.32 (m, 1H), 7,32 and 7.36 (m, 1H), EUR 7.57 (d, J=8.6 Hz, 2H).

Hydrochloride specified in the header of the free compounds produced by the method described in example 84.

ESI-MS: 437 (MH+).

Example 99

1-[4-Cyano-5-methyl-4-(3-thienyl)hexyl]-4-[2-(4-methylthiophene)ethyl]piperazine

Specified in the title compound obtained as a colorless oil by the method according to example 45, described in JP-A 11-,50-1,68 (m, 1H), 1,72-of 1.84 (m, 1H), 2,02-2,12 (m, 2H), of 2.25 to 2.35 (m, 2H), 2,35-2,48 (m, 4H), of 2.44 (s, 3H), 2,48-to 2.65 (m, 4H), 2,78 (t, J=5,9 Hz, 2H), 4,06 (t, J=5,9 Hz, 2H), 6,84 (Shir.d, J=6.6 Hz, 2H), 6,92 (DD, J=1.5 Hz, 5.1 Hz, 1H), 7,22-7,28 (m, 3H), 7,33 (DD, J=3.0 Hz, 5.1 Hz, 1H).

Hydrochloride specified in the header of the free compounds produced by the method described in example 84.

ESI-MS: 456 (MH+).

Example 100

1-[4-Cyano-5-methyl-4-(3-thienyl)hexyl]-4-[2-(4-methylsulfinylphenyl)ethyl]piperazine

Specified in the title compound obtained as a colorless oil by the method described in example 84 (56%).

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.83 (d, J=6.6 Hz, 3H), of 1.16 (d, J=6.8 Hz, 3H), 1,16-of 1.30 (m, 1H), 1,50 by 1.68 (m, 1H), 1,74-of 1.84 (m, 1H), 2,02-2,12 (m, 2H), of 2.25 to 2.35 (m, 2H), 2,35-2,48 (m, 4H), 2,48-to 2.65 (m, 4H), 2,82 (t, J=5,9 Hz, 2H), 3,03 (s, 3H), of 4.16 (t, J=5,9 Hz, 2H), 6,92 (DD, J=1.5 Hz, 5.1 Hz, 1H), 7,02 (Shir.d, J=8,8 Hz, 2H), 7.24 to 7,29 (m, 1H), 7,33 (DD, J=3.0 Hz, 5.1 Hz, 1H), 7,86 (Shir.d, J=8,8 Hz, 2H).

Hydrochloride specified in the header of the free compounds produced by the method described in example 84.

ESI-MS: 490 (MH+).

Example 101

1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-bromophenoxy)ethyl]piperazine

Specified in the title compound obtained as a colorless oil by the way, apicad, J=6.6 Hz, 3H), of 1.18 (d, J=6.6 Hz, 3H), 1,20-1,40 (m, 1H), 1,55-1,70 (m, 1H), 1,72-to 1.82 (m, 1H), 2,00-2,10 (m, 2H), 2,10-2,22 (m, 2H), of 2.25 to 2.35 (m, 2H), 2,35-of 2.50 (m, 4H), 2,50-to 2.65 (m, 4H), 2,78 (t, J=5.8 Hz, 2H), 4,06 (t, J=5.8 Hz, 2H), 6,80-6,85 (m, 1H), 6,94 (Shir.DD, J=3.5 Hz, 5.0 Hz, 1H),? 7.04 baby mortality-to 7.15 (m, 4H), 7.24 to 7,28 (m, 1H).

Hydrochloride specified in the header of the free compounds produced by the method described in example 84.

ESI-MS: 490, 492 (MN+).

Example 102

1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-(2-phenoxyethyl)piperazine

Specified in the title compound obtained as a colorless oil by the method described in example 84 (97%).

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.6 Hz, 3H), of 1.18 (d, J=6.6 Hz, 3H), 1,20-1,40 (m, 1H), 1,55-1,70 (m, 1H), 1,72-to 1.82 (m, 1H), 2,00-2,10 (m, 2H), 2,10-2,22 (m, 2H), of 2.25 to 2.35 (m, 2H), 2,35-of 2.50 (m, 4H), 2,50-to 2.65 (m, 4H), 2,80 (t, J=5.8 Hz, 2H), 4.09 to (t, J=5.8 Hz, 2H), 6.87 in-6,97 (m, 4H), 7,08 for 7.12 (m, 1H), 7.23 percent-7,30 (m, 2H).

Hydrochloride specified in the header of the free compounds produced by the method described in example 84.

ESI-MS: 412 (MH+).

Example 103

1-[4-Cyano-5-methyl-4-(2-bromo-5-thienyl)hexyl]-4-[2-(3-cianfrocca)ethyl]piperazine

Using [4-cyano-5-methyl-4-(2-bromo-5-thienyl)hexyloxy]-tert-butyldimethylsilyl (700 mg) obtained in example 114-5), privo example 114-8), described in JP-A 11-206862. 105 mg of the obtained compound and 96 mg of 2-(3-cianfrocca) ethylpiperazine synthesize specified in the title compound as a colorless oil by the method described in example 84 (138 mg, 62%).

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.93 (d, J=6.8 Hz, 3H), of 1.18 (d, J=6.8 Hz, 3H), 1,20-1,40 (m, 1H), 1,55-1,70 (m, 1H), 1,90-2,05 (m, 1H), 2,05-of 2.20 (m, 2H), 2,30-of 2.38 (m, 2H), 2,38-of 2.50 (m, 4H), 2,50-to 2.65 (m, 4H), of 2.81 (t, J=5.8 Hz, 2H), 4,10 (t, J=5.8 Hz, 2H), 6.90 to (DD, J=3.8 Hz, 8.6 Hz, 2H), 7,10-7,17 (m, 2H), 7,22-7,30 (m, 1H), 7,33-7,40 (m, 1H).

Hydrochloride specified in the header of the free compounds produced by the method described in example 84.

ESI-MS: 515, 517 (MH+).

Example 104

1-[4-Cyano-4-(3-cyano-5-thienyl)-5-methylhexan]-4-[2-(4-methylsulfinylphenyl)ethyl]piperazine

From 4-cyano-4-(3-cyano-5-thienyl)-5-methylhexane and 1-[2-(4-methylsulfinylphenyl)ethyl]piperazine synthesize specified in the title compound as a pale yellow oil by way of example 68 (39%). Hydrochloride get, the processing specified in the header loose connection in the usual way.

Loose coupling:

1H-NMR (400 MHz, CDCl3)to 0.92 (d, J=6.8 Hz, 3H), 1,20 (d, J=6.8 Hz, 3H), of 1.21 to 1.31 (m, 1H), 1.60-to 1,72 (m, 1H), 1,78 (dt, J=4 Hz to 13.2 G is of 4.16 (t, J=5.6 Hz, 2H), 7,02 (d, J=8,8 Hz, 1H), 7,29 (d, J=1.2 Hz, 1H), 7,86 (d, J=8,8 Hz, 2H), of 7.90 (d, J=1.2 Hz, 1H).

Hydrochloride:

ESI-MS: 515 (MN+).

Example 105

1-[4-Cyano-4-(3-cyano-5-thienyl)-5-methylhexan]-4-[2-(3-acetylphenol)ethyl]piperazine

From 4-cyano-4-(3-cyano-5-thienyl)-5-methylhexane and 1-[2-(3-acetylphenol)ethyl]piperazine get mentioned in the title compound as a pale yellow oil by way of example 68 (yield 38%). Hydrochloride get, the processing specified in the header loose connection in the usual way.

Loose coupling:

1H-NMR (400 MHz, CDCl3)to 0.92 (d, J=6, 8 Hz, 3H), 1,20 (d, J=6.8 Hz, 3H), 1,21-1,32 (m, 1H), 1.60-to around 1.74 (m, 1H), 1,78 (dt, J=4 Hz to 13.2 Hz, 1H), 2,07 (Queen, J=6,8 Hz, 1H), measuring 2.20 (dt, J=4 Hz to 13.2 Hz, 1H), 2,29-is 2.37 (m, 2H), 2,43 (Shir.s, 4H), 2,59 (Shir.s, 4H), 2,60 (s, 3H), and 2.83 (t, J=5.6 Hz, 2H), 4,15 (t, J=5.6 Hz, 2H), 7,10-7,13 (m, 1H), 7,29 (d, J=1.2 Hz, 1H), 7,37 (t, J=8 Hz, 1H), 7,49 (DD, J=1.6 Hz, 2.8 Hz, 1H), 7,52-of 7.55 (m, 1H), of 7.90 (d, J=1.2 Hz, 1H).

Hydrochloride:

ESI-MS: 479 (MN+).

Example 106

1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-[{2-(5-cyanobenzoyl)}methyl]piperazine

Using 1-[{2-(5-cyanobenzoyl)}methyl]piperazine, synthesize specified in the header of the connection method of example 75 (yield 100%).

0 (m, 1H), 2,00-2,09 (m, 1H), 2,10-2,19 (m, 1H), 2,32 (t, J=7.2 Hz, 2H), 2,35-to 2.65 (m, 8H), 3,70 (s, 2H), 6,65 (Shir.Dr. s, 1H), 6,93 (DD, J=3.2 Hz, 5.2 Hz, 1H), 7,10 (DD, J=1.2 Hz, 3.2 Hz, 1H), 7,24 (DD, J=1.2 Hz, 5.2 Hz, 1H), 7,52-rate of 7.54 (m, 2H), a 7.85-7,87 (m, 1H).

ESI-MS: 447 (M+N+).

Example 107

1-[4-Cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-(2-phenoxyethyl)piperazine

Using 1-[2-phenoxyethyl]piperazine, synthesize the target compound in the method of example 77 (exit 96,5%). Physico-chemical data specified in the connection header is shown below.

1H-NMR (400 MHz, CDCl3)to 0.92 (d, J=6.8 Hz, 3H), 1,21 (d, J=6.4 Hz, 3H), 1,20-1,32 (m, 1H), 1.60-to 1,72 (m, 1H), 1,72-to 1.82 (m, 1H), 2.00 in a 2.12 (m, 1H), 2,17-of 2.27 (m, 1H), 2,33 (t, J=7.2 Hz, 2H), 2,32-2,48 (m, 4H), 2,50-2,70 (m, 4H), of 2.81 (t, J=6.0 Hz, 2H), 4,10 (t, J=6.0 Hz, 2H), 6,88-6,97 (m, 3H), 7,15 (d, J=4.0 Hz, 1H), 7,25-7,30 (m, 2H), 7,51 (d, J=4.0 Hz, 1H).

ESI-MS: 437 (M+N+).

Example 108

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

Using 1-[2-(3-bromophenoxy)ethyl]piperazine, synthesize specified in the header of the connection method of example 77 (exit 83,5%). Physico-chemical data specified in the connection header is shown below.

1H-NMR (400 MHz, CDCl3)of 0.93 (d, J=6.4 Hz, 3H), 1,22 (d, J=6.8 Hz, 3H), 1,26,81-6,86 (m, 1H), 7,05-7,10 (m, 2H), 7,10-7,14 (m, 1H), 7,16 (d, J=3.6 Hz, 1H), 7,52 (d, J=3.6 Hz, 1H).

ESI-MS: 515, 517 (M+N+).

Connection examples 110, 111, 112, 113, 114, 115, 116, 117, 118, 119 and 120 are synthesized by the methods described in examples 1, 89 or 99 in JP-A 11-206862, or similarly specified ways.

Example 109

1-[4-Cyano-5-methyl-4-(2-bromo-5-thienyl)hexyl]-4-[2-(3-cianfrocca)ethyl]piperazine

Specified in the title compound obtained as a pale brown oil by the method of example 1 described in JP-A 11-206862.

Hydrochloride:

ESI-MS (m/e): 515, 517 (M+H).

Example 110

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

Loose coupling:

1H-NMR (400 MHz, CDCl3)to 0.92 (d, J=6.6 Hz, 3H), 1,21 (d, J=6.6 Hz, 3H), 1,21-1,32 (m, 1H), 1,55-of 1.73 (m, 2H), 2.00 in a 2.12 (m, 1H), 2,15-of 2.30 (m, 1H), 2,30-of 2.38 (m, 2H), 2,38 at 2.45 (m, 4H), 2,50-to 2.65 (m, 4H), 2,80 (t, J=5.8 Hz, 2H), 4,07 (t, J=5.8 Hz, 2H), 6,76-PC 6.82 (m, 1H), 6,88-to 6.95 (m, 1H), 7,13-7,21 (m, 3H), 7,51 (d, J=3.8 Hz, 1H).

Hydrochloride:

ESI-MS (m/e): 471 (M+H).

Example 111

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

Loose coupling:

1H-NMR (400 MHz, CDCl3)to 0.92 (d, J=6, 6 Hz, 3H), 1,21 (d, J=6J=5.8 Hz, 2H), 6,86-6,99 (m, 1H), of 6.96-7,01 (m, 1H), 7,15 (d, J=3.8 Hz, 1H), 7,25-7,30 (m, 2H), 7,51 (d, J=3.8 Hz, 1H).

Hydrochloride:

ESI-MS (m/e): 563 (M+H).

Example 112

1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-{N-[(3-cyanophenyl)-N-isopropylamino]ethyl}piperazine

Hydrochloride:

ESI-MS (m/e): 478 (M+H).

Example 113

1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-{N-[(3-cyanophenyl)-N-methylamino]ethyl}piperazine

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.6 Hz, 3H), of 1.18 (d, J=6.6 Hz, 3H), 1,20-1,40 (m, 1H), 1,45 is 1.70 (m, 1H), 1.70 to to 1.82 (m, 1H), 2,00-2,10 (m, 1H), 2,10-of 2.20 (m, 1H), 2,24-2,60 (m, N), of 3.00 (s, 3H), of 3.46 (t, J=7.4 Hz, 2H), 6,84-6,98 (m, 4H), 7,11 (DD, J=3.5 Hz, 1.1 Hz, 1H), 7.23 percent-7,33 (m, 2H).

Hydrochloride:

ESI-MS (m/e): 450 (M+H).

Example 114

Synthesis of 1-[3-cyano-4-methyl-5-(2-thienyl)pentyl]-4-[2-(3-cianfrocca)ethyl]piperazine

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.91 (d, J=6.8 Hz, 3H), 1,19 (d, J=6.6 Hz, 3H), 1.85 to to 1.98 (m, 1H), 2.00 in of 2.20 (m, 2H), 2,30-2,70 (m, 10H), 2,80 (t, J=5,9 Hz, 2H), 4.09 to (t, J=5,9 Hz, 2H), 6,95 (DD, J=5,1 Hz and 3.7 Hz, 1H), 7,10-to 7.15 (m, 3H), 7,22-7,29 (m, 2H), 7,33-7,39 (m, 1H).

Hydrochloride:

ESI-MS (m/e): 423 (M+H).

Example 115

1-[3-Cyano-4-methyl-5-(2-thienyl)pentyl]-4-[2-(4-pertenece)ethyl]piperazine

Hydrochloride:

ESI-MS (m/e): 416 (M+H).

Example 116

1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-(cyclohexylmethyl)piperazine

Triptorelin:

ESI-MS (m/e): 388 (M+H).

Example 117

4-[4-(4-Phenylpiperidine)piperidinyl]-1-isopropyl-1-phenylbutyramide

Loose coupling:

Rf=0,5 (manifesting solvent: ethyl acetate:hexane=2:1, Fuji Silysia Chemical Ltd. TCX on silica gel NH).

Hydrochloride:

ESI-MS (m/e): 444 (M+H).

Example 118

4-[4-(4-Cyano-4-phenylpiperidine)piperidinyl]-1-isopropyl-1-phenylbutyramide

Loose coupling:

Rf=0.4 (of manifesting solvent: ethyl acetate:hexane=2:1, Fuji Silysia Chemical Ltd. TCX on silica gel NH).

Hydrochloride:

ESI-MS (m/e): 469 (M+H).

Example 119

4-[4-(4-Benzylpiperidine)piperidinyl]-1-isopropyl-1-phenylbutyramide

Loose coupling:

Rf=0,5 (manifesting solvent: ethyl acetate:hexane=2:1, Fuji Silysia Chemical Ltd. TCX on silica gel NH).

Hydrochloride:

ESI-MS (m/e): 458 (M+H).

Example 120

1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-{2-[N-the head of the compound synthesized by the methods in examples 63 or 67, described in JP-A 11-206862, or similarly specified ways.

Triptorelin:

ESI-MS (m/e): 515 (M+H).

Example 121

1-[3-Cyano-4-methyl-5-(2-thienyl)pentyl]-4-{2-[N-(1,2,3,4-tetrahydro-1-chinoline)sulfamoyl]ethyl}piperazine

Specified in the title compound synthesized by the methods in examples 63 or 67, described in JP-A 11-206862, or similarly specified ways.

Triptorelin:

ESI-MS (m/e): 501 (M+H).

Example 122

1-[4-Cyano-5-methyl-4-(2-thienyl)hexyl]-4-{2-[N-(piperidinyl)sulfamoyl]ethyl}piperazine

Specified in the title compound synthesized by the methods in examples 63 or 67, described in JP-A 11-206862, or similarly specified ways.

Hydrochloride:

ESI-MS (m/e): 467 (M+H).

Example 123

Bis-1,4-[(3-cyano-4-methyl-3-phenyl)pentyl]piperazine

3-Methyl-2-(2-oxoethyl)-2-phenylbutanoate (100 mg) and anhydrous piperazine (22 mg) is dissolved in methylene chloride (5 ml). To the mixture of acetic acid (of 0.085 ml) and triacetoxyborohydride sodium (158 mg) and stirred overnight at room temperature. The organic layer is separated, by adding saturated aqueous sodium bicarbonate solution and methylene chloride, washed with water, dried over be the m Chromatorex NH (system: hexane/ethyl acetate), while receiving specified in the title compound as a colourless oil (81 mg, 71%). Hydrochloride (89 mg) specified in the connection header receiving, processing free connection in the usual way.

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,76 (d, J=6,8 Hz, 6N), of 1.10-1.20 (m, 2H), 1,19 (d, J=6,8 Hz, 6N), 1,50-1,60 (m, 2H), 1,90-of 2.15 (m, 6N), 2,00 at 2.45 (m, 8H), 7,25-7,42 (m, 10H).

Hydrochloride:

ESI-MS (m/e): 457 (M+H).

Specified in the title compound in examples 124-126 synthesized by the method described in example 123.

Example 124

Bis-1,4-[(3-cyano-4-methyl-3-phenyl)pentyl]homopiperazin

Hydrochloride:

ESI-MS (m/e): 471 (M+H).

Example 125

Bis-1,4-[(3-cyano-4-methyl-3-phenyl)hexyl]homopiperazin

Hydrochloride:

ESI-MS (m/e): 499 (M+H).

Example 126

Bis-1,4-[(3-cyano-4-methyl-3-(2-thienyl)pentyl]piperazine

Hydrochloride:

ESI-MS (m/e): 469 (M+H).

Example 127

{1-[(4-Cyano-5-methyl-4-phenyl)hexyl]piperazinil}amide (S)-3-phenyl-2-aminopropanoic acid

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]piperazine (14 mg) and N-(tert-butoxycarbonyl)-L-phenylalanine (10 mg) dissolved in methylene chloride (0.5 ml), dobavlja room temperature. The solution is purified by chromatography on a column of silica gel (diethyl ether) and remove the solvent by blowing with nitrogen.

The resulting residue is dissolved in methylene chloride (0.4 ml), add triperoxonane acid (0.2 ml) and the mixture is stirred at room temperature for 9 hours. The reaction solvent is removed, leaving the mixture to stand at 35°C while purging with nitrogen during the night, and thus receive the hydrochloride (21 mg, 91%) specified in the connection header.

Hydrochloride:

ESI-MS (m/e): 433 (M+H).

Specified in the title compound in examples 128 and 129 are synthesized by the method described in example 127.

Example 128

{1-[(4-Cyano-5-methyl-5-(2-thionyl)hexyl]piperazinil}amide (S)-3-phenyl-2-aminopropanoic acid

Hydrochloride:

ESI-MS (m/e): 439 (M+H).

Example 129

{1-[(3-Cyano-4-methyl-4-(2-thionyl)hexyl]piperazinil}amide (S)-3-phenyl-2-aminopropanoic acid

Hydrochloride:

ESI-MS (m/e): 425 (M+H).

Example 130

5-[3-(Benzylamino)-4-hydroxycitrate-1H-1-pyrrolyl]-2-isopropyl-5-oxo-2-(2-thienyl)pentenenitrile

In nitrogen atmosphere 5-(2,5-dihydro-1H-1-pyrrolyl]-2-isopropyl-5-oxo-2-(2-teniposide (2 ml) and water (0.1 ml). To the mixture is added N-bromosuccinimide (177 mg) and stirred over night. The reaction solution was distributed between ethyl acetate and water, the organic layer is dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel (system: ethyl acetate/hexane) to give colorless oily intermediate compound (140 mg). The intermediate compound (20 mg) dissolved in tetrahydrofuran (0.05 ml), add 1 N. aqueous sodium hydroxide solution (0.06 ml) and the mixture is stirred at room temperature. The mixture is stirred for 45 minutes, add a solution of benzylamine (11 mg) in tetrahydrofuran (0.05 ml) and continue stirring at 70°C during the night. The reaction solution is cooled to room temperature and distributed between ethyl acetate and water. The resulting organic layer is dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel Cromatorex NH (system ethyl acetate/hexane), while receiving specified in the title compound as a colourless oil (20 mg).

Hydrochloride:

ESI-MS (m/e): 412 (M+H).

Specified in the title compound in examples 131-136 synthesized by the method described in example 130.

Example 131

5-[3-(232D/img_data/78/782419.gif">

Hydrochloride:

ESI-MS (m/e): 426 (M+H).

Example 132

5-[3-(2-Titilation)-4-hydroxycitrate-1H-1-pyrrolyl]-2-isopropyl-5-oxo-2-(2-thienyl)pentenenitrile

Hydrochloride:

ESI-MS (m/e): 432 (M+H).

Example 133

5-[3-(N-Phenylpiperazine)-4-hydroxycitrate-1H-1-pyrrolyl]-2-isopropyl-5-oxo-2-(2-thienyl)pentenenitrile

Triptorelin:

ESI-MS (m/e): 467 (M+H).

Example 134

5-{3-[4-(2,3-Dihydro-1H-1-indolyl)piperazine derivatives]-4-hydroxycitrate-1H-pyrrolyl}-2-isopropyl-5-oxo-2-(2-thienyl)pentenenitrile

Triptorelin:

ESI-MS (m/e): 507 (M+H).

Example 135

5-[3-(3-Pyridylmethylene)-4-hydroxycitrate-1H-pyrrolyl]-2-isopropyl-5-oxo-2-(2-thienyl)pentenenitrile

Triptorelin:

ESI-MS (m/e): 427 (M+H).

Example 136

5-{3-[4-(1H-1-Indolyl)piperidino]-4-hydroxycitrate-1H-pyrrolyl}-2-isopropyl-5-oxo-2-(2-thienyl)pentenenitrile

Triptorelin:

ESI-MS (m/e): 505 (M+H).

Specified in the title compound in examples 137-172 synthesized by the method described in the example above 64.

Example 137

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

.gif">0,78 (d, J=6.8 Hz, 3H), 1,10-1,30 (m, 1H), 1,21 (d, J=6.6 Hz, 3H), 1,50-1,70 (m, 1H), 1,87-1,20 (m, 1H), 2,08-of 2.24 (m, 2H), 2,30-of 2.38 (m, 1H), 2.40 a-2,48 (m, 4H), 3,52-to 3.64 (m, 4H),? 7.04 baby mortality-7,10 (m, 1H), 7,24-7,34 (m, 2H), 7,35-7,40 (m, 4H), 7,50-to 7.61 (m, 2H).

Hydrochloride:

ESI-MS (m/e): 449 (M+H).

Example 138

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(6-methoxy)benzothiazolyl]piperazine

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.8 Hz, 3H), 1,10-1,30 (m, 1H), 1,21 (d, J=6.6 Hz, 3H), 1,50-1,70 (m, 1H), 1,87-1,20 (m, 1H), 2,08-of 2.24 (m, 2H), 2,30-of 2.38 (m, 1H), 2,38-2,48 (m, 4H), 3,50-3,62 (m, 4H), 3,82 (s, 3H), 6,86-6,92 (m, 1H), 7,12-to 7.15 (m, 1H), 7,22-7,35 (m, 3H), 7,35-7,40 (m, 3H), 7,43-of 7.48 (m, 1H).

Hydrochloride:

ESI-MS (m/e): 419 (M+H).

Example 139

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

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.8 Hz, 3H), 1,10-1,30 (m, 1H), 1,21 (d, J=6.6 Hz, 3H), 1,50-1,70 (m, 1H), 1.77 in-1,20 (m, 1H), 2,08 was 2.25 (m, 2H), 2,28-of 2.38 (m, 1H), 2,38-2,48 (m, 4H), 3,60-and 3.72 (m, 4H), 6,98? 7.04 baby mortality (m, 1H), 7,12-to 7.18 (m, 1H), 7,22-7,28 (m, 1H), 7,28-the 7.43 (m, 5H).

Hydrochloride:

ESI-MS (m/e): 403 (M+H).

Example 140

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

Loose coupling:

Rf=0.6 for manifesting solvent: diethyl ether, TLC on salicyl)piperazine

Loose coupling:

Rf=0.45 in (manifesting solvent: diethyl ether, TLC on silica gel Merck 60F254).

Hydrochloric salt:

ESI-MS (m/e): 413 (M+H).

Example 142

4-[4-(1-Isobutyl-1H-benzo[d]imidazol-2-yl)-1,4-diazepan-1-yl]-1-isopropyl-1-phenylbutyramide

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.8 Hz, 3H), 0,81 (d, J=8,1 Hz, 6N), 1,08-of 1.30 (m, 1H), 1,20 (d, J=7,0 Hz, 3H), 1,50-1,70 (m, 1H), 1.77 in-1,20 (m, 2H), 2,00 of-2.32 (m, 4H), 2.40 a-2,52 (m, 2H), 2,60-to 2.67 (m, 2H), 2,67-by 2.73 (m, 2H), 3,48-of 3.60 (m, 4H), 3,81 (d, J=7,3 Hz, 2H), 7,07-to 7.18 (m, 3H), 7,25-7,42 (m, 5H), 7,51-7,56 (m, 1H).

Hydrochloride:

ESI-MS (m/e): 472 (M+H).

Example 143

4-[4-(1-Isobutyl-1H-benzo[d]imidazol-2-yl)-1,4-diazepan-1-yl]-1-isopropyl-1-(2-chlorophenyl)butylene

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.8 Hz, 3H), 0,81 (d, J=8,1 Hz, 6N), 1,08-of 1.30 (m, 1H), 1,20 (d, J=7,0 Hz, 3H), 1,50-1,70 (m, 1H), 1.77 in-1,20 (m, 2H), 2,00 of-2.32 (m, 4H), 2.40 a-2,52 (m, 2H), 2,60-to 2.67 (m, 2H), 2,67-by 2.73 (m, 2H), 3,48-of 3.60 (m, 4H), 3,81 (d, J=7,3 Hz, 2H), 7,05-to 7.35 (m, 5H), 7,3035-7,40 (m, 1H), 7,51-7,56 (m, 1H), 7,72-7,79 (m, 1H).

Hydrochloride:

ESI-MS (m/e): 506 (M[34Cl]+H), 508 (M[36Cl]+H).

Example 144

1--4-[4-(1H-[d]ao-2-)]-1-"https://img.russianpatents.com/chr/948.gif">0,78 (d, J=6.8 Hz, 3H), 1.04 million-1,25 (m, 1H), 1,20 (d, J=6.6 Hz, 3H), 1,50-1,70 (m, 1H), 1,87 of 1.99 (m, 1H), 2,05-of 2.23 (m, 2H), 2,25-to 2.40 (m, 2H), 2.40 a-2,47 (m, 4H), 3,42-to 3.58 (m, 4H), 7,00-7,40 (m, N).

Hydrochloride:

ESI-MS (m/e): 402 (M+H).

Example 145

1-Isopropyl-4-[4-(1-methyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-phenylbutyramide

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.8 Hz, 3H), 1,10-1,30 (m, 1H), 1,21 (d, J=6.8 Hz, 3H), 1,50-1,70 (m, 1H), 1,92-2,03 (m, 1H), 2,08 was 2.25 (m, 2H), 2,28 at 2.45 (m, 2H), 2,45-of 2.56 (m, 4H), of 3.25 to 3.35 (m, 4H) and 3.59 (s, 3H), 7,02 to 7.62 (m, N).

Hydrochloride:

ESI-MS (m/e): 416 (M+H).

Example 146

1-Isopropyl-4-[4-(1-ethyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-phenylbutyramide

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.8 Hz, 3H), 1,10-1,30 (m, 1H), 1,21 (d, J=6.8 Hz, 3H), of 1.44 (t, J=7,3 Hz, 3H), 1,50-1,70 (m, 1H), 1,92-2,03 (m, 1H), 2,08 was 2.25 (m, 2H), 2,28 at 2.45 (m, 2H), 2,45-of 2.56 (m, 4H), 3,20-to 3.35 (m, 4H), a 4.03 (q, J=7,3 Hz, 2H), 7,14-to 7.64 (m, N).

Hydrochloride:

ESI-MS (m/e): 430 (M+H).

Example 147

4-[4-(1-Ethyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-isopropyl-1-(2-thienyl)butylene

Loose coupling:

Rf=0.35 in (manifesting solvent: ethyl acetate:hexane = 1:1, Fuji Silysia Chemical Ltd. TCX on silica gel NH).

-(2-thienyl)butylene

Loose coupling:

Rf=0.4 (of manifesting solvent: ethyl acetate:hexane = 1:1, Fuji Silysia Chemical Ltd. TCX on silica gel NH).

Hydrochloride:

ESI-MS (m/e): 464 (M+H).

Example 149

1-Isopropyl-4-[4-(1-isopropyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-phenylbutyramide

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.6 Hz, 3H), 1,10-1,25 (m, 1H), 1,21 (d, J=6.6 Hz, 3H), 1.50 is by 1.68 (m, 7H), 1,90-2,04 (m, 1H), 2,05-of 2.24 (m, 2H), 2,25-of 2.45 (m, 2H), 2,45 of $ 2.53 (m, 4H), 3.15 and is 3.25 (m, 4H), 4,56-and 4.68 (m, 1H), 7,09-7,19 (m, 2H), 7,25-7,33 (m, 1H), 7,34-7,42 (m, 5H), 7,60-to 7.64 (m, 1H).

Hydrochloride:

ESI-MS (m/e): 444 (M+H).

Example 150

4-[4-(1H-Benzo[d]imidazol-2-yl)-1,4-diazepan-1-yl]-1-isopropyl-1-phenylbutyramide

Loose coupling:

1H-NMR (400 MHz, CDCl3)to 0.74 (d, J=6, 6 Hz, 3H), 1.00 and-1,15 (m, 1H), 1,14 (d, J=6.6 Hz, 3H), of 1.40-1.50 (m, 1H), 1,78-of 1.93 (m, 3H), 2.00 in 2,17 (m, 2H), 2,30-to 2.40 (m, 2H), 2,45 is 2.55 (m, 2H), 2.57 m-of 2.64 (m, 2H), 3,57-3,63 (m, 4H), of 6.96-7,52 (m, N).

Hydrochloride:

ESI-MS (m/e): 416 (M+H).

Example 151

4-[4-(1-Methyl-1H-benzo[d]imidazol-2-yl)-1,4-diazepan-1-yl]-1-isopropyl-1-phenylbutyramide

Loose coupling:

1H-NMR (400 MHz, CDCl3)

Hydrochloride:

ESI-MS (m/e): 430 (M+H).

Example 152

4-[4-(1-Ethyl-1H-benzo[d]imidazol-2-yl)-1,4-diazepan-1-yl]-1-isopropyl-1-phenylbutyramide

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 1, 05-1,17 (m, 1H), 1,19 (d, J=6.6 Hz, 3H), of 1.40 (t, J=7.2 Hz, 3H), 1,47-of 1.62 (m, 1H), 1,76-of 2.23 (m, 5H), 2.40 a-2,50 (m, 2H), 2,60-to 2.67 (m, 2H), 2,68 was 2.76 (m, 2H), 3,51-3,63 (m, 4H)that was 4.02 (d, J=7.2 Hz, 3H), 7,06-rate of 7.54 (m, N).

Hydrochloride:

ESI-MS (m/e): 444 (M+H).

Example 153

1-Isopropyl-4-[4-(1-ethyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-(4-forfinal)butylene

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.8 Hz, 3H), 1,13-of 1.23 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), of 1.44 (t, J=7,1 Hz, 3H), 1.56 to of 1.66 (m, 1H), 1,89-of 1.97 (m, 1H), 2,04-2,22 (m, 2H), 2,34-to 2.41 (m, 2H), 2,50 is 2.51 (m, 4H), 3,26 be 3.29 (m, 4H), 4,01-4,07 (m, 2H), 7,05-7,10 (m, 2H), 7,14-7,25 (m, 3H), 7,34-7,38 (m, 2H), 7,60 to 7.62 (m, 1H).

Example 154

1-Isopropyl-4-[4-(1-benzyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-(4-forfinal)butylene

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6, 6 Hz, 3H), 1,08-1,15 (m, 1H), 1,18 (d, J=6.6 Hz, 3H), 1,53-of 1.57 (m, 1H), 1.85 to of 1.93 (m, 1H), 2,02-2,19 (m, 2H), 2,29-of 2.38 (m, 2H), 2,42 (m, 4H), 3,21-3,24 (m, 4H), 5.2 azole-2-yl)piperazine derivatives]-1-(4-forfinal)butylene

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6.8 Hz, 3H), 0,82-0,85 (m, 6N), 1,12-1,25 (m, 1H), 1,20 (d, J=6.6 Hz, 3H), 1,57-to 1.63 (m, 1H), 1,90-to 1.98 (m, 1H), 2,04-2,12 (m, 1H), 2,14-to 2.42 (m, 4H), 2,48 (m, 4H), 3,23-of 3.25 (m, 4H), 3,81 (d, J=7,3 Hz, 2H), 7,05-7,20 (m, 2H), 7,21-of 7.23 (m, 3H), 7,33-7,38 (m, 2H), 7,60-7,63 (m, 1H).

Example 156

1-Isopropyl-4-[4-(1-isobutyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-(3-forfinal)butylene

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,77-0,89 (m, N), 1,13-of 1.26 (m, 1H), 1,21 (d, J=6.6 Hz, 3H), 1,58-of 1.65 (m, 1H), 1,90-to 1.98 (m, 1H), 2,04-to 2.41 (m, 5H), 2,41-of 2.50 (m, 4H), 3,23-of 3.25 (m, 4H), 3,80 (d, J=7.5 Hz, 2H), 6,98-7,03 (m, 1H), 7,08-of 7.23 (m, 5H), 7,33-7,39 (m, 1H), 7,60-7,63 (m, 1H).

Example 157

1-Isopropyl-4-[4-(1-isobutyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-(2-forfinal)butylene

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,80-0,88 (m, N), 1,15-1,25 (m, 1H), 1,23 (d, J=6.6 Hz, 3H), 1,58-of 1.64 (m, 1H), 2,04-of 2.16 (m, 1H), 2,25 is 2.51 (m, N), 3,22-of 3.25 (m, 4H), 3,80 (d, J=7.5 Hz, 2H), 7,02-was 7.08 (m, 1H), 7,13-7,21 (m, 4H), 7,29-7,33 (m, 1H), 7,58 to 7.62 (m, 2H).

Example 158

1-Isopropyl-4-[4-(1-methyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-(3-forfinal)butylene

Free connection,58-1,66 (m, 1H), 1,89-of 1.97 (m, 1H), 2,01-of 2.24 (m, 2H), 2,34-to 2.41 (m, 2H), of 2.51 of $ 2.53 (m, 4H), 3,29-of 3.32 (m, 4H) and 3.59 (s, 3H), 6,98? 7.04 baby mortality (m, 1H), 7,08-7,21 (m, 5H), 7,33-7,39 (m, 1H), 7,58-to 7.61 (m, 1H).

Example 159

1-Isopropyl-4-[4-(1-ethyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-(3-forfinal)butylene

Loose coupling:

1H-NMR (400 MHz, CDCl3)to 0.80 (d, J=6.8 Hz, 3H), 1,13-of 1.28 (m, 1H), 1,22 (d, J=6.8 Hz, 3H), of 1.44 (t, J=7,1 Hz, 3H), 1,58-of 1.66 (m, 1H), 1,89-of 1.97 (m, 1H), 2,04-of 2.24 (m, 2H), 2,33-to 2.41 (m, 2H), of 2.51-2,52 (m, 4H), 3.27 to 3.30 is (m, 4H), 4,01-4,07 (m, 2H), 6,98? 7.04 baby mortality (m, 1H), 7,08-7,27 (m, 5H), 7,33-7,39 (m, 1H), to 7.59 to 7.62 (m, 1H).

Example 160

1-Isopropyl-4-[4-(1-benzyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-(3-forfinal)butylene

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,78 (d, J=6, 6 Hz, 3H), 1,08-of 1.18 (m, 1H), 1,20 (d, J=6.8 Hz, 3H), 1,54-of 1.65 (m, 1H), 1,84-of 1.92 (m, 1H), 2,04-of 2.20 (m, 2H), 2,28-of 2.36 (m, 2H), 2,38 is 2.43 (m, 4H), 3,22-of 3.25 (m, 4H), 5,20 (s, 2H), of 6.96-7,01 (m, 2H), 7,05-7,10 (m, 2H), 7,14-7,21 (m, 4H), 7,26 and 7.36 (m, 4H), 7,63-to 7.64 (m, 1H).

Example 161

1-Isopropyl-4-[4-(1-ethyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-(2-forfinal)butylene

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,81 (d, J=6.8 Hz, 3H), 1,15 of 1.28 (m, 1H), 1,23 (d, J=6.8 Hz, 3H), of 1.44 (t, J=7,1 Hz, 3H), 1,59 by 1.68 (m

Synthesis of 1-isopropyl-4-[4-(1-methyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-(2-tolyl)butylene

Oxalate:

1H-NMR (400 MHz, DMSO-d6)of 0.77 (d, J=6.8 Hz,3H), of 1.07 (d, J=6.8 Hz, 3H), 1,25-1,40 (m, 1H), 1,53 is 1.70 (m, 1H), 1,97 is 2.10 (m, 1H), measuring 2.20 to 2.35 (m, 1H), 2.40 a-2,50 (m, 1H), 2,47 (s, 3H), 3,05-3,20 (m, 2H), 3,10-3,30 (m, 4H), 3.33 and-a 3.50 (m, 4H) and 3.59 (s, 3H), 7,07-to 7.15 (m, 2H), 7,20-7,29 (m, 3H), 7,34-7,46 (m, 3H).

Example 163

1-Isopropyl-4-[4-(1-methyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-(4-forfinal)butylene

Oxalate:

1H-NMR (400 MHz, DMSO-d6)0,66 (d, J=6.4 Hz, 3H), 1,10 (d, J=6.4 Hz, 3H), 1,10-1,30 (m, 1H), 1,50-to 1.67 (m, 1H), 1,95-of 2.30 (m, 2H), 2,15-of 2.27 (m, 1H), 2.95 and-3,20 (m, 2H), 3,10-3,30 (m, 4H), 3,35-to 3.50 (m, 4H) and 3.59 (s, 3H), 7,07-to 7.15 (m, 2H), 7,28 (t, J=8,8 Hz, 2H), 7,34-7,46 (m, 2H), 7,43-to 7.50 (m, 2H).

Example 164

1-Isopropyl-4-[4-(1-ethyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-(2-chlorophenyl)butylene

Oxalate:

1H-NMR (400 MHz, DMSO-d6)to 0.73 (d, J=6.8 Hz, 3H), of 1.12 (d, J=6.8 Hz, 3H), 1,10-of 1.35 (m, 1H), 1,30 (t, J=7.2 Hz, 3H), 1.50 is by 1.68 (m, 1H), 2.00 in to 2.15 (m, 1H), 2,50-2,70 (m, 1H), 2,78-2,90 (m, 1H), 3,00-3,20 (m, 2H), 3,05-3,30 (m, 4H), of 3.25 to 3.45 (m, 4H), 4,06 (kV, J=7.2 Hz, 2H), 7,06-to 7.15 (m, 2H), 7,38-7,49 (m, 4H), 7,54 (DD, J=7,6 Hz, 2.0 Hz, 1H), 7,65 (DD, J=7,6 Hz, 2.0 Hz, 1H).

Example 165

1-From the">

Oxalate:

1H-NMR (400 MHz, DMSO-d6)of 0.75 (d, J=6,8 Hz, N), of 1.12 (d, J=6.4 Hz, 3H), 1,15-of 1.45 (m, 1H), 1,50-1,70 (m, 1H), 2,00-2,25 (m, 2H), 2,50-to 2.65 (m, 1H), 2,75-2,90 (m, 1H), 3.00 and-3,30 (m, 2H), 3.00 and-3,30 (m, 4H), 3,20 is-3.45 (m, 4H), a 3.87 (d, J=7.2 Hz, 2H), 7,00-to 7.18 (m, 2H), 7,38-of 7.48 (m, 4H), 7,54 (d, J=7,6 Hz, 1H), to 7.64 (d, J=7,6 Hz, 1H).

Example 166

1-Isopropyl-4-[4-(1-methyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-(2-methoxyphenyl)butylene

Oxalate:

1H-NMR (400 MHz, DMSO-d6)of 0.68 (d, J=6.8 Hz, 3H), of 1.09 (d, J=6.8 Hz, 3H), 1,10-1,30 (m, 1H), 1,50-of 1.65 (m, 1H), 1,90-2,05 (m, 1H), 2,35-of 2.50 (m, 1H), 2.57 m)-2,70 (m, 1H), 2.95 and-3,20 (m, 2H), 3,05-of 3.25 (m, 4H), 3,30-to 3.50 (m, 4H) and 3.59 (s, 3H), 3,81 (s, 3H), 6,98? 7.04 baby mortality (m, 1H), 7,07-to 7.15 (m, 3H), 7,33-the 7.43 (m, 4H).

Example 167

1-Isopropyl-4-[4-(1-ethyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-(2-methoxyphenyl)butylene

Oxalate:

1H-NMR (400 MHz, DMSO-d6)of 0.67 (d, J=6.4 Hz, 3H), of 1.08 (d, J=6.8 Hz, 3H), 1,10-1,30 (m, 1H), 1,30 (t, J=7.2 Hz, 3H), 1,45-to 1.60 (m, 1H), 1,90-2,05 (m, 1H), 2,35-of 2.50 (m, 1H), 2,58-2,70 (m, 1H), 2,90-3,10 (m, 2H), 3,00-3,20 (m, 4H), of 3.25 to 3.45 (m, 4H), 3,81 (s, 3H), 4,06 (kV, J=7.2 Hz, 2H), 7,01 (t, J=7,6 Hz, 1H), 7,06-7,14 (m, 3H), of 7.36 (t, J=7,6 Hz, 1H), 7,35-7,45 (m,3H).

Example 168

1-Isopropyl-4-[4-(1-isobutyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-(2-methoxyphenyl)butylene

Example 169

1-Isopropyl-4-[4-(1-benzyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-(2-methoxyphenyl)butylene

Oxalate:

1H-NMR (400 MHz, DMSO-d6)of 0.67 (d, J=6.8 Hz, 3H), of 1.08 (d, J=6.8 Hz, 3H), 1,10-1,25 (m, 1H), 1,45-of 1.65 (m, 1H), 1,90-2,00 (m, 1H), 2,33 at 2.45 (m, 1H), 2,55-2,70 (m, 1H), 2,90-3,20 (m, 2H), 3,10-of 3.25 (m, 4H), of 3.25 to 3.45 (m, 4H), 3,79 (s, 3H), and 5.30 (s, 2H), 6,97-7,20 (m, 7H), 7,21-7,47 (m, 6N).

Example 170

1-Isopropyl-4-[4-(1-ethyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-(2-were)butylene

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.87 (d, J=6.8 Hz, 3H), 1,19 (d, J=6.8 Hz, 3H), 1,20 of 1.28 (m, 1H), 1,44 (d, J=7,3 Hz, 3H), 1,55-1,70 (m, 1H), 2.06 to of 2.20 (m, 1H), 2,35 at 2.45 (m, 4H), 2,45-of 2.58 (m, 7H), of 3.25 to 3.35 (m, 4H), Android 4.04 (q, J=7,3 Hz, 2H), 7,15-of 7.23 (m, 6N), EUR 7.57-to 7.68 (m, 1H), to 7.59-of 7.60 (m, 1H).

Hydrochloride:

ESI-MS (m/e): 444 (M+H).

Example 171

1-Isopropyl-4-[4-(1-benzyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-(2-were)butylene

Loose coupling:

1H-NMR (400 MHz, Dl3, ,19-3,24 (m, 4H), 5,19 (s, 2H), 6,99-7,01 (m, 1H), 7,08-7,21 (m, 8H), 7,27-7,38 (m, 2H), 7,43-of 7.55 (m, 1H), 7,63-the 7.65 (m, 1H).

Hydrochloride:

ESI-MS (m/e): 506 (M+H).

Example 172

1-Isopropyl-4-[4-(1-isobutyl-1H-benzo[d]imidazol-2-yl)piperazine derivatives]-1-(2-were)butylene

Loose coupling:

1H-NMR (400 MHz, Dl3)of 0.83 (d, J=4.0 Hz, 3H), of 0.85 (d, J=4.0 Hz, 3H), of 0.87 (d, J=6,b Hz, 3H), 1,19 (d, J=6.6 Hz, 3H), 1,20-of 1.29 (m, 1H), 1,54-of 1.65 (m, 1H), 2,05-of 2.16 (m, 1H), 2,24 is 2.51 (m, N), 2,52 (s, 3H), 3,20-of 3.25 (m, 4H), 3,80 (d, J=7.5 Hz, 2H), 7,12-7,22 (m, 6N), of 7.48-7,56 (m, 1H), to 7.59-of 7.60 (m, 1H).

Hydrochloride:

ESI-MS (m/e): 472 (M+H).

Example 173

1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexan]-(3R)-3-[N-(2-cyanoethyl)-N-benzylamino]pyrrolidin

In dichloromethane (8 ml) was dissolved 300 mg (0.81 mmol) of 1-[4-cyano-4-(5-cyano-2-thienyl)-5-methylhexan]-(3R)-3-[N-(2-cyanoethyl)amino]pyrrolidine obtained in reference example 81, and alternately add the 98.9 mg (0,93 mmol) of benzaldehyde, and 0.09 ml of 1.62 mmol) of acetic acid and 258 mg (1,22 mmol) triacetoxyborohydride sodium. After the reaction, the reaction solution is alkalinized 5 N. the sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and upar is Tata), while receiving 220 mg (0.48 mmol, 59.1 per cent) indicated in the title compounds as a colorless syrup. Physicochemical data of the compounds are shown below.

1H-NMR (400 MHz, Dl3)of 0.90 (d, J=6, 4 Hz, 3H), 1,19 (d, J=6.4 Hz, 3H), 1,16-of 1.29 (m, 1H), 1,54-of 1.66 (m, 1H), 1.70 to of 1.84 (m, 2H), 1,91-of 2.08 (m, 2H), 2,17-is 2.37 (m, 5H), 2,38 is 2.51 (m, 2H), of 2.51-of 2.58 (m, 1H), 2,61 of 2.68 (m, 1H), 2,78-to 2.94 (m, 2H), 3,40-to 3.50 (m, 1H), 3,60 (d, J=14 Hz, 1H), 3,71 (d, J=14 Hz, 1H), 7,13 (d, J=3.6 Hz, 1H), 7,32-7,39 (m, 5H), 7,50 (d, J=3.6 Hz, 1H).

The diastereoisomer specified in the connection header is produced by way of example 173 4-cyano-4-(5-cyano-2-thienyl)-5-methylhexane (hereinafter referred to as "alcohol"), synthesized by the method according to reference examples 104 and 105 of 4-cyano-4-(2-thienyl)-5-methylhexanoic acid obtained in reference example 103, and (3R)-3-tert-butoxycarbonylmethylene. Similarly, the mirror isomer is specified in the header of the compounds synthesized by the method according to example 173 of alcohol and (3S)-3-tert-butoxycarbonylmethylene.

Example 174

1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexan]-(3R)-3-[N-(2-cyanoethyl)-N-(2-thienylmethyl)amino]pyrrolidin

Specified in the title compound synthesized by the method according to example 173 1-[4-cyano-4-(5-cyano-2-thienyl)-5-methylhexan]-(3R)-3-[N-(RCM data link given below.

The yield of 46.7%.

1H-NMR (400 MHz, Dl3)of 0.90 (d, J=6.8 Hz, 3H), 1,19 (d, J=6.4 Hz, 3H), 1,16-of 1.29 (m, 1H), 1,54-to 1.67 (m, 1H), 1,67-of 1.84 (m, 2H), 1,95-of 2.09 (m, 2H), 2,17 to 2.35 (m, 3H), 2,35-of 2.56 (m, 5H), 2,61-2,70 (m, 1H), 2,80-2,96 (m, 2H), 3,44-of 3.54 (m, 1H), 3,84 (d, J=to 15.0 Hz, 1H), 3,92 (d, J=to 15.0 Hz, 1H), 6,92? 7.04 baby mortality (m, 2H), 7,13 (d, J=4.0 Hz, 1H), 7.23 percent-7,31 (m, 1H), 7,51 (d, J=4.0 Hz, 1H).

Example 175

1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexan]-(3S)-3-[N-(2-cyanoethyl)-N-benzylamino]pyrrolidin

Specified in the title compound is synthesized as described below in two ways (the ways of synthesis of a and b).

The method of synthesis And

(1) (3S)-3-[N-(2-Cyanoethyl)-N-benzylamino]pyrrolidin

(3S)-3-[N-(2-Cyanoethyl)-N-benzylamino]-1-(tert-butoxycarbonyl)pyrrolidin synthesize ways in reference example 81 and example 173 from (3S)-3-amino-1-(tert-butoxycarbonyl)pyrrolidine. Specified in the header of the get connection, removing the protection of the BOC-group by the method according to reference example 80 (exit 78,2%, 3 phase). Physicochemical data of the compounds are shown below.

Physico-chemical data (3S)-3-[N-(2-cyanoethyl)-N-benzylamino]-1-(tert-butoxycarbonyl)pyrrolidine:

1H-NMR (400 MHz, CDCl3)of 1.46 (s, N), 1,77-of 1.95 (m, 1H), 1,98-2,12 (m, 1H), 2,32 (t, J=6,8 Hz, Idina:

1H-NMR (400 MHz, CDCl3)1,66-of 1.78 (m, 1H), 1,88-2,02 (m, 1H), 2,31 (t, J=6,8 Hz, 2H), 2,78-2,95 (m, 4H), 3,02-of 3.12 (m, 2H), 3,32-to 3.41 (m, 1H), 2,87 (t, J=6,8 Hz, 2H), 3,64 (d, J=14 Hz, 1H), 3,71 (t, J=14 Hz, 1H), 7,27-7,38 (m, 5H).

(2) 1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexan]-(3S)-3-[N-(2-cyanoethyl)-N-benzylamino]pyrrolidin

Optically active compound, 4-cyano-4-(5-cyano-2-thienyl)-5-methylhexanoate (iodide, optically active substance) are synthesized from the alcohol In the method of example 77(1). Specified in the title compound synthesized by the method according to example 77(2) of the iodide and (3S)-3-[N-(2-cyanoethyl)-N-benzylamino]pyrrolidine obtained in stage (1). Physicochemical data of the compounds are shown below.

The yield of 90.6%.

ESI-MS: 460 (M+N)+.

1H-NMR (400 MHz, CDCl3)of 0.91 (d, J=6.8 Hz, 3H), 1,19 (d, J=6.8 Hz, 3H), 1,16-of 1.30 (m, 1H), 1.56 to its 1.68 (m, 1H), 1.70 to is 1.81 (m, 2H), 1.93 and is 2.10 (m, 2H), 2.21 are of 2.44 (m, 7H), to 2.57-to 2.67 (m, 2H), 2,80-2,95 (m, 2H), 3,39-of 3.48 (m, 1H), 3,62 (d, J=14 Hz, 1H), 3,69 (d, J=14 Hz, 1H), 7,15 (d, J=4.0 Hz, 1H), 7.23 percent-7,37 (m, 5H), 7,52 (d, J=4.0 Hz, 1H).

The method of synthesis In

Specified in the title compound synthesized by the method according to example 173 of the above iodide (or alcohol) and (3S)-3-tert-butoxycarbonylmethylene.

Example 176

1-[4-Cyano-4-(2-thienyl)-5-methylhexan]-(3S)-3-[N-(2-cyanoethyl)-N-benzilpinicilin (iodide D, optically active substance) are synthesized from alcohol And method of example 77(1). Specified in the title compound synthesized by the method according to example 75 from iodide D and (3S)-3-[N-(2-cyanoethyl)-N-benzylamino]pyrrolidine obtained in the method of synthesis of A (1) example 175. Physico-chemical data specified in the connection header is shown below.

Yield 97%.

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.8 Hz, 3H), of 1.17 (d, J=6.4 Hz, 3H), of 1.20 and 1.35 (m, 1H), 1,55 by 1.68 (m, 1H), 1,69-to 1.82 (m, 2H), 1,92 is 2.10 (m, 2H), 2,17 is 2.43 (m, 7H), 2,54-of 2.66 (m, 2H), 2,87 (t, J=6,8 Hz, 2H), 3,37-of 3.46 (m, 1H), 3,62 (d, J=14 Hz, 1H), 3,68 (d, J=14 Hz, 1H), 6,95 (DD, J=3,6 Hz, 5.2 Hz, 1H), 7,15 (DD, J=1.2 Hz, 3.6 Hz, 1H), 7.23 percent-7,39 (m, 6N).

Example 177

1-[4-Cyano-4-(2-thienyl)-5-methylhexan]-(3S)-3-[N-(2-cyanoethyl)-N-(3-cyanobenzyl)amino]pyrrolidin

Specified in the title compound synthesized by the method according to example 75 from iodide D and (3S)-3-[N-(2-cyanoethyl)-N-(3-cyanobenzyl)amino]pyrrolidine obtained in the method of synthesis of A (1) example 175. Physicochemical data of the compounds are shown below.

Yield 82%.

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.4 Hz, 3H), of 1.16 (d, J=6.8 Hz, 3H), 1,22-of 1.34 (m, 1H), 1,54-to 1.67 (m, 1H), 1,67 and 1.80 (m, 2H), 1.93 and-of 2.09 (m, 2H), 2,16-of 2.27 (m, 2H), 2,27 is 2.43 (m, 5H), 2,59-of 2.72 (m, 2H), 2,88 (t, J=6,8 Hz, 2H), 3,34-of 3.43 (m, 1H), 3,68 (m, 1H), 7,62-7,66 (m, 2H).

Example 178

1-[4-Cyano-4-(2-thienyl)-5-methylhexan]-4-[{3-methoxy-(2R)-2-(2-pyridyloxy)}propyl]piperazine

Specified in the title compound synthesized by the method according to example 75 from iodide D and 1-[{3-methoxy-(2R)-2-(2-pyridyloxy)}propyl]piperazine. Physico-chemical data obtained of the target compounds is shown below.

1H-NMR (400 MHz, CDCl3)to 0.89 (d, J=6.8 Hz, 3H), of 1.17 (d, J=6.4 Hz, 3H), 1,21-of 1.35 (m, 1H), 1,55 was 1.69 (m, 1H), 1,70-1,80 (m, 1H), 2.00 in to 2.18 (m, 2H), 2,20-2,62 (m, 10H), 2,62-of 2.72 (m, 2H), 3,38 (s, 3H), 3,60-3,70 (m, 2H), 5,47-of 5.55 (m, 1H), of 6.71-of 6.78 (m, 1H), for 6.81-6.87 in (m, 1H), 6,94 (DD, J=3,6 Hz, 5.2 Hz, 1H), 7,10 (DD, J=1.6 Hz, 3.6 Hz, 1H), 7,25 (DD, J=1.6 Hz, 5.2 Hz, 1H), 7,50-7,58 (m, 1H), 8,09-8,13 (m, 1H).

Example 179

1-(6-Bromo-2-pyridyl)-(3R)-3-{N-[4-cyano-4-(2-thienyl)-5-methylhexan]amino}pyrrolidin

Specified in the title compound synthesized by the method according to example 75 of iodide With (optically active compound) and (3R)-3-{N-[4-cyano-4-(2-thienyl)-5-methylhexan]amino}pyrrolidine.

Physicochemical data of the compounds are shown below.

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.8 Hz, 3H), of 1.18 (d, J=6.8 Hz, 3H), 1,23-of 1.36 (m, 1H), 1,57 is 1.70 (m, 1H), 1,73 of-1.83 (m, 2H), 2,00-2,10 (m, 1H), 2,10-of 2.24 (m, 2H), 2,56-a 2.71 (m, 2H), 3,14-up 3.22 (m, 1H), 3,34-3,44 (m, 2H), 3,49-3,Hz, 1H), 7,26 (DD, J=1.2 Hz, 5.2 Hz, 1H).

Example 180

1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexan]-4-[2-(5-chlorobenzoxazole)methyl]piperazine

Specified in the title compound synthesized by the method according to example 77 1-[4-cyano-4-(5-cyano-2-thienyl)-5-methylhexan]piperazine and 2-chloromethyl-5-chlorobenzoxazole obtained by the method in example 83. Physicochemical data of the compounds are shown below.

1H-NMR (400 MHz, CDCl3)of 0.91 (d, J=6.8 Hz, 3H), 1,20 (d, J=6.4 Hz, 3H), 1,20-1,30 (m, 1H), 1,58-1,71 (m, 1H), 1,71-of 1.81 (m, 1H), 2,00-2,10 (m, 1H), 2,16-of 2.26 (m, 1H), 2,34 (t, J=6,8 Hz, 2H), 2,37-of 2.54 (m, 4H), 2,54-by 2.73 (m, 4H), 3,86 (s, 2H), 7,14 (d, J=4.0 Hz, 1H), 7,31 (DD, J=2.0 Hz, and 8.4 Hz, 1H), 7,45 (d, J=8,4 Hz, 1H), 7,51 (d, J=4.0 Hz, 1H), 7,68 (d, J=2.0 Hz, 1H).

Example 181

1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexan]-4-[2-(5-methylbenzimidazolyl)methyl]piperazine

Analogously to example 180 1-[4-cyano-4-(5-cyano-2-thienyl)-5-methylhexan]piperazine and 2-chloromethyl-5-methylbenzoate obtained by the method according to example 83, synthesize specified in the header, connection method for example 77. Physicochemical data of the compounds are shown below.

1H-NMR (400 MHz, CDCl3)of 0.91 (d, J=6.8 Hz, 3H), 1,20 (d, J=6.4 Hz, 3H), 1,20-1,30 (m, 1H), 1,58 is 1.70 (m, 1H), 1,Hz, 1H), 7,39 (d, J=8,4 Hz, 1H), 7,47-7,49 (m, 1H), 7,51 (d, J=4.0 Hz, 1H).

Example 182

1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexan]-4-[2-benzothiazolyl]piperazine

Analogously to example 180 indicated in the title compound synthesized by the method according to example 77 1-[4-cyano-4-(5-cyano-2-thienyl)-5-methylhexan]piperazine obtained in example 180, and 2-chloromethylthiazole obtained in example 83. Physicochemical data of the compounds are shown below.

1H-NMR (400 MHz, CDCl3)to 0.92 (d, J=6.8 Hz, 3H), 1,21 (d, J=6.8 Hz, 3H), 1,20-1,32 (m, 1H), 1,59-1,72 (m, 1H), 1,72 of-1.83 (m, 1H), 2,01 is 2.10 (m, 1H), 2,18-of 2.28 (m, 1H), 2,35 (t, J=7.4 Hz, 2H), 2,35-2,52 (m, 4H), 2,54-to 2.74 (m, 4H), of 3.95 (s, 2H), 7,14 (d, J=3.6 Hz, 1H), 7,33-7,39 (m, 1H), 7,42-of 7.48 (m, 1H), 7,51 (d, J=3.6 Hz, 1H), 7,84-7,88 (m, 1H), 7,94-to 7.99 (m, 1H).

Example 183

1-[4-Cyano-4-(2-thienyl)-5-methylhexan]-4-[2-(5-trifluoromethyl-2-pyridyloxy)ethyl]piperazine

The target compound synthesized by the method according to example 75, from 4-cyano-[4-(2-thienyl)-5-methylhexan]iodide and 1-[2-(5-trifluoromethyl-2-pyridyloxy)ethyl]piperazine. Physicochemical data of the compounds are shown below.

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.4 Hz, 3H), of 1.18 (d, J=6.4 Hz, 3H), 1,20-to 1.38 (m, 1H), 1,55-1,70 (m, 1H), 1,71-to 1.82 (m, 1H), 2.00 in the, J=3,6 Hz, 5.2 Hz, 1H), 7,11 (DD, J=1.2 Hz, 3.6 Hz, 1H), of 7.75 (DD, J=2,4 Hz and 8.8 Hz, 1H), 8,39-8,44 (m, 1H).

Example 184

1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexan]-4-[2-(5-trifluoromethyl-2-pyridyloxy)ethyl]piperazine

Specified in the title compound synthesized by the method according to example 77 4-cyano-4-(5-cyano-2-thienyl)-5-methylhexanoate and 1-[2-(5-trifluoromethyl-2-pyridyloxy)ethyl]piperazine. Physicochemical data of the compounds are shown below.

1H-NMR (400 MHz, CDCl3)to 0.92 (d, J=6.4 Hz, 3H), 1,21 (d, J=6.4 Hz, 3H), of 1.20 to 1.31 (m, 1H), 1.60-to is 1.82 (m, 2H), 2,00-2,10 (m, 1H), 2,17-of 2.28 (m, 1H), 2,28-2,48 (m, 6N), 2,48-to 2.65 (m, 4H), and 2.79 (t, J=6.0 Hz, 2H), 4,49 (t, J=6.0 Hz, 2H), 6,83 (d, J=8,8 Hz, 1H), 7,15 (d, J=4.0 Hz, 1H), 7,51 (d, J=4.0 Hz, 1H), 7,76 (DD, J=2,4 Hz and 8.8 Hz, 1H), 8,40-8,44 (m, 1H).

Example 185

1-[4-Cyano-4-(2-thienyl)-5-methylhexan]-4-[2-(5-chloro-3-pyridyloxy)ethyl]piperazine

Specified in the title compound synthesized by the method according to example 75, from 4-cyano-4-(2-thienyl)-5-methylhexanoate and 1-[2-(5-chloro-3-pyridyloxy)ethyl]piperazine. Physicochemical data of the compounds are shown below.

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.8 Hz, 3H), of 1.18 (d, J=6.4 Hz, 3H), of 1.20 to 1.37 (m, 1H), 1,55-1,71 (m, 1H), 1,71-to 1.82 (m, 1H), 2,00-2,10 (m, 1H), 2,10-of 2.21 (m, 1H), 2,25-2,49 (m, 6N), 2,49-to 2.65 (m, N Hz, 1H), to 8.20 (d, J=2.0 Hz, 1H).

Example 186

1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexan]-4-[2-(5-chloro-3-pyridyloxy)ethyl]piperazine

Specified in the title compound synthesized by the method according to example 77 4-cyano-4-(5-cyano-2-thienyl)-5-methylhexanoate and 1-[2-(5-chloro-3-pyridyloxy)ethyl]piperazine. Physicochemical data of the compounds are shown below.

1H-NMR (400 MHz, CDCl3)to 0.92 (d, J=6.4 Hz, 3H), 1,21 (d, J=6.4 Hz, 3H), 1,20-1,30 (m, 1H), 1.60-to 1,72 (m, 1H), 1,72-to 1.82 (m, 1H), 2,00-2,11 (m, 1H), 2,17-of 2.28 (m, 1H), 2,28-2,48 (m, 6N), 2,49-to 2.65 (m, 4H), of 2.81 (t, J=5.6 Hz, 2H), of 4.13 (t, J=5.6 Hz, 2H), 7,15 (d, J=4.0 Hz, 1H), 7,21-of 7.23 (m, 1H), 7,51 (d, J=4.0 Hz, 1H), 8,19 (d, J=1.6 Hz, 1H), to 8.20 (d, J=2,8 Hz, 1H).

Example 187

1-[4-Cyano-4-(2-thienyl)-5-methylhexan]-4-[2-(5-chloro-3-pyridyloxy)ethyl]piperidine

Specified in the title compound synthesized by the method according to example 75, from 4-cyano-4-(2-thienyl)-5-methylhexanoate and 4-[2-(5-chloro-3-pyridyloxy)ethyl]piperidine. Physicochemical data of the compounds are shown below.

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.8 Hz, 3H), of 1.18 (d, J=6.8 Hz, 3H), 1,20-to 1.38 (m, 2H), 1,40-of 1.56 (m, 1H), 1.60-to of 1.93 (m, N), 2,00-of 2.20 (m, 2H), of 2.25 to 2.35 (m, 2H), 2.77-to 2,87 (m, 2H), was 4.02 (t, J=6.4 Hz, 2H), 6,95 (DD, J=3,6 Hz, 5,2 Hz, 1H), 7,11 (DD, J=1.2 Hz, 3.6 Hz, 1H), 7,17-7,20 (m, 1H), 7,24-tp://img.russianpatents.com/img_data/78/782477.gif">

Specified in the title compound synthesized by the method according to example 75, from 4-cyano-4-(2-thienyl)-5-methylhexanoate and 4-(3-pyridylamino)piperidine. Physicochemical data of the compounds are shown below.

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.8 Hz, 3H), of 1.18 (d, J=6.8 Hz, 3H), 1,24-to 1.38 (m, 1H), 1,38 of 1.50 (m, 2H), 1,58-1,71 (m, 1H), 1,73 of-1.83 (m, 1H), 1,95-of 2.21 (m, 5H), 2,29-of 2.36 (m, 2H), 2,72-of 2.81 (m, 2H), 3,20-of 3.31 (m, 1H), 3,48 of 3.56 (m, 1H), for 6.81-6,86 (m, 2H), 6,94 (DD, J=3,6 Hz, 5.2 Hz, 1H), 7,05 (DD, J=4,8 Hz to 12.8 Hz, 1H), 7,11 (DD, J=1.2 Hz, 3.6 Hz, 1H), 7,26 (DD, J=1.2 Hz, 5.2 Hz, 1H), 7,92 (DD, J=1.6 Hz, 4.8 Hz, 1H), 7,99 (d, J=2.1 Hz, 1H).

Example 189

1-[4-Cyano-4-(2-thienyl)-5-methylhexan]-4-[2-{N-isopropyl-N-(2-pyridyl)amino}ethyl]piperazine

Specified in the title compound synthesized by the method according to example 75, from 4-cyano-4-(2-thienyl)-5-methylhexanoate and 1-[2-{N-isopropyl-N-(2-pyridyl)amino}ethyl]piperazine. Physicochemical data of the compounds are shown below.

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.8 Hz, 3H), 1,14-to 1.21 (m, N), 1,24-to 1.38 (m, 1H), 1,58 is 1.70 (m, 1H), 1,72-to 1.82 (m, 1H), 2,00-2,10 (m, 1H), 2,10-of 2.21 (m, 1H), 2,28-of 2.66 (m, N), to 3.41 (t, J=8.0 Hz, 2H), 4,74-4,84 (m, 1H), 6,47-6,53 (m, 2H), 6,94 (DD, J=3,6 Hz, 5.2 Hz, 1H), 7,11 (DD, J=1.2 Hz, 3.6 Hz, 1H), 7.24 to 7,29 (m, 1H), 7,37-7,44 (m, 1H), 8,12-8,16 (m, 1H).

Example 190

1-[4-Cyano-4-(2-thienyl)-5-methylhexan]the compound synthesized by the method according to example 75, from 4-cyano-4-(2-thienyl)-5-methylhexanoate and 1-[2-(6-methoxymethyl-2-pyridyloxy)ethyl]piperazine. Physicochemical data of the compounds are shown below.

ESI-MS: 457 (M+N)+.

Example 191

1-[4-Cyano-4-(2-thienyl)-5-methylhexan]-4-[2-(6-vermeil-2-pyridyloxy)ethyl]piperazine

Specified in the title compound synthesized by the method according to example 75, from 4-cyano-4-(2-thienyl)-5-methylhexanoate and 1-[2-(6-vermeil-2-pyridyloxy)ethyl]piperazine. Physicochemical data of the compounds are shown below.

ESI-MS: 445 (M+N)+.

Example 192

1-[4-Cyano-4-(2-thienyl)-5-methylhexan]-4-[2-(6-bromo-2-pyridyloxy)ethyl]piperazine

Specified in the title compound synthesized by the method according to example 75, from 4-cyano-4-(2-thienyl)-5-methylhexanoate and 1-[2-(6-bromo-2-pyridyloxy)ethyl]piperazine. Physicochemical data of the compounds are shown below.

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.4 Hz, 3H), of 1.18 (d, J=6.4 Hz, 3H), 1,22-to 1.38 (m, 1H), 1,58 is 1.70 (t, 1H), 1,71-to 1.82 (m, 1H), 2,00-2,10 (m, 1H), 2,10-of 2.20 (m, 1H), 2,25-to 2.65 (m, 10H), was 2.76 (t, J=6.0 Hz, 2H), 4,42 (t, J=6.0 Hz, 2H), 6,69 (d, J=8.0 Hz, 1H), 6,94 (DD, J=3,6 Hz, 5.2 Hz, 1H),? 7.04 baby mortality (d, J=8.0 Hz, 1H), 7,11 (DD, J=1.6 Hz, 3.6 Hz, 1H), 7.24 to 7,28 (m, 1H), 7,40 (t, J=8.0 Hz, 1H).

Example 193

1-[4-Cyano-4-(2-thienyl)-5-methylhexan]-4-[2-(6-fluoro-2-pyridyloxy)ethyl]piperazine

Alazani-2-pyridyloxy)ethyl]piperazine. Physicochemical data of the compounds are shown below.

ESI-MS: 431 (M+N)+.

Example 194

1-[4-Cyano-4-(2-thienyl)-5-methylhexan]-4-[2-(2-pyridyloxy)ethyl]piperazine

Specified in the title compound synthesized by the method according to example 75, from 4-cyano-4-(2-thienyl)-5-methylhexanoate and 1-[2-(2-pyridyloxy)ethyl]piperazine. Physicochemical data of the compounds are shown below.

ESI-MS: 413 (M+N)+.

Example 195

1-[4-Cyano-4-(2-thienyl)-5-methylhexan]-4-[2-(6-methyl-2-pyridyloxy)ethyl]piperazine

Specified in the title compound synthesized by the method according to example 75, from 4-cyano-4-(2-thienyl)-5-methylhexanoate and 1-[2-(6-methyl-2-pyridyloxy)ethyl]piperazine. Physicochemical data of the compounds are shown below.

1H-NMR (400 MHz, CDCl3)of 0.90 (d, J=6.8 Hz, 3H), of 1.18 (d, J=6.8 Hz, 3H), 1,22-to 1.38 (m, 1H), 1,58 is 1.70 (m, 1H), 1,71-to 1.82 (m, 1H), 2,00-2,10 (m, 1H), 2,10-of 2.21 (m, 1H), 2,27-2,70 (m, 10H), 2,42 (s, 3H), 2,77 (t, J=6.0 Hz, 2H), to 4.41 (t, J=6.0 Hz, 2H), 6,51-6,55 (m, 1H), 6,67-6,72 (m, 1H), 6,94 (DD, J=3,6 Hz, 5.2 Hz, 1H), 7,11 (DD, J=1.6 Hz, 3.6 Hz, 1H), 7,25 (DD, J=1.6 Hz, 5.2 Hz, 1H), 7,43 (DD, J=7,2 Hz and 8.4 Hz, 1H).

Example 196

1-[4-Cyano-4-(2-thienyl)-5-methylhexan]-4-[2-(6-cyano-2-pyridyloxy)ethyl]piperazine

Ukazannoe-2-pyridyloxy)ethyl]piperazine. Physicochemical data of the compounds are shown below.

ESI-MS: 438 (M+N)+.

Example 197

1-[4-Cyano-4-(5-cyano-2-thienyl)-5-methylhexan]-4-[2-(6-cyano-2-pyridyloxy) ethyl]piperazine

Specified in the title compound synthesized by the method according to example 75, from 4-cyano-4-(5-cyano-2-thienyl)-5-methylhexanoate and 1-[2-(6-cyano-2-pyridyloxy)ethyl]piperazine. Physicochemical data of the compounds are shown below.

ESI-MS: 463 (M+N)+.

Example 198

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[N-[2-(4-pertenece)ethyl]-N-2-cyanoethyl]aminopiperidin

Specified in the title compound synthesized by the method according to example 35.

Hydrochloride:

ESI-MS: 491 (MN+).

Example 199

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

Specified in the header of the compound obtained by the method in example 3.

Hydrochloride:

ESI-MS: 406 (MN+).

Example 200

1-[[4-Cyano-5-methyl-4-(2-thienyl)]hexyl]-4-[3-[1-(4-forfinal)cyclohexyl]propyl]piperazine

Specified in the header of the compound obtained by the method in example 70, using the above 4-[3-[1-(4-forfinal) cyclohexyl]propyl]piperazine.

Specified in the header of the compound obtained by the method in example 70.

Hydrochloride:

ESI-MS: 487 (MN+).

Example 202

1-[[4-Cyano-5-methyl-4-(3-benzothiazyl)]hexyl]-4-benzylpiperazine

Specified in the header of the compound obtained by the method in example 70.

Hydrochloride:

ESI-MS: 432 (MN+).

Example 203

1-[[4-Cyano-5-methyl-4-(3-benzothiazyl)]hexyl]-4-(3-cyanobenzyl)piperazine

Specified in the header of the compound obtained by the method in example 3.

Hydrochloride:

ESI-MS: 457 (MH+).

Example 204

1-[[4-Cyano-5-methyl-4-(3-benzothiazyl)]hexyl]-4-[(2-thienyl)methyl]piperazine

Specified in the header of the compound obtained by the method in example 3.

Hydrochloride:

ESI-MS: 438 (MN+).

Example 205

1-[[4-Cyano-5-methyl-4-(3-benzothiazyl)]hexyl]-4-[(4-cyano-2-thienyl)methyl]piperazine

Specified in the header of the compound obtained by the method in example 3.

Hydrochloride:

ESI-MS: 463 (MN+).

Example 206

1-[[4-Cyano-5-methyl-4-(3-benzothiazyl)]hexyl]-4-[6-methyl-2-picolyl]piperazine

Specified in Saga-Cyano-5-methyl-4-(1-methyl-2-pyrrolyl)]hexyl]-4-[2-(3-cianfrocca)ethyl]piperazine

Specified in the header of the compound obtained by the method in example 70.

Oxalate:

ESI-MS: 434 (MN+).

Example 208

1-[[4-Cyano-5-methyl-4-(5-methyl-2-thienyl)]hexyl]-4-[N-[2-(4-pertenece)ethyl]-N-2-cyanoethyl]aminopiperidin

Specified in the title compound is obtained by way of example 35.

Hydrochloride:

ESI-MS: 522 (MN+).

Example 209

1-[[4-Cyano-5-methyl-4-(2-thienyl)]hexyl]-4-[N-[2-(4-pertenece)ethyl]-N-2-cyanoethyl]aminopiperidin

Specified in the title compound is obtained by way of example 35.

Hydrochloride:

ESI-MS: 497 (MN+).

Example 210

1-[[4-Cyano-5-methyl-4-(2-thienyl)]hexyl]-4-[(2-benzoxazolyl)amino]piperidine

Specified in the title compound is obtained by way of example 17.

Hydrochloride:

ESI-MS: 423 (MN+).

Example 211

1-[[4-Cyano-5-methyl-4-(5-cyano-2-thienyl)]hexyl]-4-[(2-benzoxazolyl)amino]piperidine

Specified in the title compound is obtained by way of example 17.

Hydrochloride:

ESI-MS: 448 (MN+).

Example 212

1-[[4-Cyano-5-methyl-4-(2-furyl)]hexyl]-4-[2-(3-cianfrocca)ethyl]piperazin/p>Hydrochloride:

ESI-MS: 421 (MN+).

Example 213

1-[[4-Cyano-5-methyl-4-(2-furyl)]hexyl]-4-[(2-benzoxazolyl)amino]piperidine

Specified in the title compound is obtained by way of example 17.

Oxalate:

ESI-MS: 407 (MN+).

Example 214

1-[[4-Cyano-5-methyl-4-(2-thienyl)]hexyl]-4-[N-(2-benzoxazolyl)-N-(2-cyanoethyl)amino]piperidine

Specified in the title compound is obtained by way of example 35.

Hydrochloride:

ESI-MS: 476 (MH+).

Example 215

1-[[4-Cyano-5-methyl-4-(2-furyl)]hexyl]-4-[N-(2-benzoxazolyl)-N-(2-cyanoethyl)amino]piperidine

Specified in the title compound is obtained by way of example 35.

Oxalate:

ESI-MS: 460 (MN+).

Example 216

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

Specified in the header of the compound obtained by the method in example 70.

Hydrochloride:

ESI-MS: 363 (MN+).

Example 217

1-[[4-Cyano-5-methyl-4-(2-thienyl)]hexyl]-4-(2-pyridyl)piperazine

Specified in the header of the compound obtained by the method in example 70.

Hydrochloride:

ESI-MS: 369 (MN+).

Example 218

Oxalate specified in the title compound obtained as colorless solid by the method according to example 3.

Oxalate:

1H-NMR (400 MHz, DMSO-d6)of 0.64 (d, J=6.8 Hz, 3H), of 1.09 (d, J=6.4 Hz, 3H), 1,00-1,20 (m, 1H), 1,40-1,60 (m, 1H), 1,95-2,15 (m, 1H), 2,10-of 2.25 (m, 1H), 2,60 was 3.05 (m, 11N) and 3.59 (s, 2H), 7,17 (t, J=7.2 Hz, 1H), 7,29 (d, J=8,4 Hz, 1H), 7,30-7,38 (m, 1H), 7,35 is 7.50 (m, 5H), a 7.62 (DD, J=8.0 Hz, 1.2 Hz, 1H), 7,89 (s, 1H), 11,88 (s, 1H).

Example 219

1-[(2-Oxo-1,2-dihydro-3-chinolin)methyl]-4-[(4-cyano-5-methyl-4-phenyl)hexyl]piperidine

Oxalate specified in the title compound obtained as colorless solid by the method according to example 3.

Oxalate:

1H-NMR (400 MHz, DMSO-d6)0,63 (d, J=6.8 Hz, 3H), 0,70-0,85 (m, 1H), 1,00-of 1.45 (m, 6N), of 1.09 (d, J=6.8 Hz, 3H), 1,60 (Shir.d, J=2,8 Hz, 2H), 1,87-of 2.08 (m, 2H), 2,10-of 2.23 (m, 1H), 2,75-2,95 (m, 2H), 3,20-to 3.35 (m, 2H), 4,08 (s, 2H), 7,19-7,25 (m, 1H), 7,28-7,44 (m, 6N), 7,53-7,58 (m, 1H), 7,65-of 7.70 (m, 1H), 8,13 (s, 1H), 12,13 (s, 1H).

Example 220

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(4-cyano-5-methyl-4-phenyl)hexyl]piperidine

Oxalate specified in the title compound obtained as colorless solid by the method according to example 3.

Oxalate:

1H-NMR (400 MHz, DMSO-d6)

Example 221

1-[(5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(4-cyano-5-methyl-4-phenyl)hexyl]piperidine

Oxalate specified in the title compound obtained as colorless solid by the method according to example 3.

Oxalate:

1H-NMR (400 MHz, DMSO-d6)0,63 (d, J=6.8 Hz, 3H), 0,70-0,85 (m, 1H), 1,00-1,40 (m, 6N), of 1.09 (d, J=6.4 Hz, 3H), 1,53 (Shir.d, J=13,2 Hz, 2H), 1,87-of 2.08 (m, 2H), 2,10-of 2.23 (m, 1H), 2,40-2,60 (m, 2H), 3.04 from (Shir.d, J=11,6 Hz, 2H), 3,68 (s, 2H), 7,25-7,35 (m, 1H), was 7.36-7,44 (m, 4H), to 7.59 (d, J=2,8 Hz, 1H), 7,66 (d, J=2.4 Hz, 1H).

Example 222

4-[(4-Cyano-5-methyl-4-phenyl)hexyl]-1-{[2-(methanesulfonamido)phenyl]methyl}piperazine

Oxalate specified in the title compound obtained as colorless solid by the method according to example 3.

Oxalate:

1H-NMR (400 MHz, DMSO-d6)of 0.64 (d, J=6.4 Hz, 3H), 0,80-1,20 (m, 1H), 1,09 (d, J=6.8 Hz, 3H), 1,40-1,60 (m, 1H), 1,90-of 2.15 (m, 1H), 2,10-of 2.25 (m, 1H), 2,60-3,10 (m, 11N), 3,03 (s, 3H), of 3.65 (s, 2H), 7,13 (t, J=7.2 Hz, 1H), 7,26-7,47 (m, 8H).

Example 223

4-[(4-Cyano-5-methyl-4-phenyl)hexyl]-1-{[2-(p-toluensulfonyl)phenyl]methyl}piperazine

Oxalate:

1H-NMR (400 MHz, DMSO-d6)of 0.65 (d, J=6.4 Hz, 3H), 0,80-1,20 (m, 1H), 1,09 (d, J=6.8 Hz, 3H), 1,45-to 1.60 (m, 1H), 1,95-2,15 (m, 1H), 2,10-of 2.25 (m, 1H), 2,33 (s, 3H), 2,60 was 3.05 (m, 11N), to 3.34 (s, 2H), 7,05 for 7.12 (m, 2H), 7,16-7,24 (m, 2H), to 7.32 (d, J=7,6 Hz, 2H), 7,29-7,37 (m, 1H), 7,37-7,46 (m, 4H), 7,58 (d, J=8.0 Hz, 2H).

Example 224

4-[(4-Cyano-5-methyl-4-phenyl)hexyl]-1-{[2-(methanesulfonamido)phenyl]methyl}piperidine

Specified in the title compound obtained as a colorless oil by the method according to example 3.

1H-NMR (400 MHz, CDCl3)to 0.80 (d, J=6.8 Hz, 3H), 0,85-1,05 (m, 1H), of 1.05 to 1.45 (m, 6N), 1,22 (d, J=6.4 Hz,3H), 1.50 is by 1.68 (m, 2H), 1,73-of 1.88 (m, 1H), 1,90-2,05 (m, 2H), 2.00 in of 2.20 (m, 2H), 2,75-2,90 (m, 2H), 3.04 from (s, 3H), of 3.60 (s, 2H), of 6.96-7,11 (m, 2H), 7,24 and 7.36 (m, 2H), 7,34-7,44 (m, 4H), 7,46-7,52 (m, 1H).

Example 225

4-[(4-Cyano-5-methyl-4-phenyl)hexyl]-1-{[2-(p-toluensulfonyl)phenyl]methyl}piperidine

Specified in the title compound obtained as a colorless oil by the method according to example 3.

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 0,85-1,02 (m, 1H), 1,08-of 1.30 (m, 5H), 1,25-of 1.44 (m, 1H), 1,19 (d, J=6.4 Hz, 3H), 1.57 in (lat.t, J=13,6 Hz, 2H), 1,76-1,90 (m, 3H), 2.06 to of 2.16 (m, 2H), is 2.37 (s, 3H), 2,68 (Shir.d, J=11.2 Hz, 2H), 3,13 (s, 2H), 6,91 (d, J=7.2 Hz, 1H), 6,95 (t, J=7,6 Hz, 1H), 7,19 (d, J=8,4 Hz, 2H), 7,16-7,22 (m, Enoki)ethyl]piperazine

Oxalate specified in the title compound obtained as colorless solid by the method according to example 48.

Oxalate:

1H-NMR (400 MHz, DMSO-d6)to 0.72 (d, J=6.8 Hz, 3H), 1,10 (d, J=6.8 Hz, 3H), 1,00-1,25 (m, 1H), 1,42 is 1.60 (m, 1H), 1,95-2,10 (m, 1H), 2,45-to 2.65 (m, 1H), 2,60-3,10 (m, 13H), 4.09 to (t, J=5,2 Hz, 2H), 6.89 in-6,99 (m, 2H), 7,10 (t, J=8,8 Hz, 2H), 7,37-7,46 (m, 2H), 7,51 (DD, J=7,6 Hz, 1.6 Hz, 1H), 7.62mm (DD, J=7,6 Hz, 1.6 Hz, 1H).

Example 227

1-[4-Cyano-5-methyl-4-(o-tolyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine

Oxalate specified in the title compound obtained as colorless solid by the method according to example 48.

Oxalate:

1H-NMR (400 MHz, DMSO-d6)0,76 (d, J=6.4 Hz, 3H), of 1.05 (d, J=6.4 Hz, 3H), 1,10-1,30 (m, 1H), 1,43 is 1.60 (m, 1H), 1.93 and-2,07 (m, 1H), 2,15-of 2.30 (m, 1H), 2,38 of $ 2.53 (m, 1H), of 2.45 (s, 3H), 2,65 was 3.05 (m, N), 4,07 (t, J=5,2 Hz, 2H), 6,89-of 6.96 (m, 2H), 7,10 (t, J=8.0 Hz, 2H), 7.18 in-7,27 (m,3H), 7,38-7,44 (m, 1H).

Example 228

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

Oxalate specified in the title compound obtained as colorless solid by the method according to example 48.

Oxalate:

1H-NMR (400 MHz, DMSO-d6)

Example 229

N-{1-[(4-Cyano-5-methyl-4-phenyl)hexyl]piperidine-4-yl}-p-toluensulfonate

Specified in the title compound obtained as a pale brown oil by the method according to example 15.

1H-NMR (400 MHz, Dl3)0,76 (d, J=6.8 Hz, 3H), 0.95 to-1,15 (m, 1H), 1,18 (d, J=6.8 Hz, 3H), 1,30-1,45 (m, 2H), 1,35-of 1.55 (m, 1H), 1,63 is 1.75 (m, 2H), 1,75-of 1.95 (m, 5H), 2.00 in to 2.15 (m, 2H), 2,15 was 2.25 (m, 2H), 2,45-to 2.65 (m, 2H), of 3.00-3.15 in (m, 1H), 7,29 (d, J=8.0 Hz, 2H), 7,31-7,40 (m, 5H), of 7.75 (d, J=7,6 Hz, 2H).

Example 230

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

Oxalate specified in the title compound obtained as colorless solid by the method according to example 15.

Oxalate:

1H-NMR (400 MHz, DMSO-d6)of 0.64 (d, J=6.8 Hz, 3H), of 1.09 (d, J=6.8 Hz, 3H), 1,00-1,40 (m, 1H), 1,43 is 1.60 (m, 1H), 1.93 and-of 2.15 (m, 2H), 2,10-of 2.25 (m, 1H), 2,60-3,20 (m, 11N), 3,45-of 3.60 (m, 2H), Android 4.04 (d, J=5.6 Hz, 2H), 6,88-of 6.96 (m, 3H), 7,26 (t, J=7,6 Hz, 1H), 7,30-7,38 (m, 1H), was 7.36-7,46 (m, 4H).

Example 231

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-(3-cyanobenzyl)piperidine

Oxalate specified in the title compound obtained as p://img.russianpatents.com/chr/948.gif">of 0.64 (d, J=6.8 Hz, 3H), 1,11 (d, J=6.4 Hz, 3H), 1,63 and 1.80 (m, 2H), 1.85 to 2,00 (m, 2H), 2,13-of 2.27 (m, 1H), 2,30 at 2.45 (m, 1H), 2,35 is 2.55 (m, 1H), 2,75-3,00 (m, 4H), 3,00-3,20 (m, 2H), 3,50-3,60 (m, 1H), to 4.52 (s, 2H), 7,33-7,40 (m, 1H), 7,40-of 7.48 (m, 4H), 7,54 (t, J=8.0 Hz, 1H), 7,66 (d, J=8.0 Hz, 1H), 7,74 (d, J=8.0 Hz, 1H), to 7.77 (m, 1H).

Example 232

4-[(3-Cyano-4-methyl-3-phenyl)pentyl]-1-{2-[3-(p-toluensulfonyl)phenoxy]ethyl}piperazine

Oxalate specified in the title compound obtained as colorless solid by the method according to example 3.

Oxalate:

1H-NMR (400 MHz, DMSO-d6)of 0.64 (d, J=6.8 Hz, 3H), 1,11 (d, J=6.4 Hz, 3H), 2.13 and costs 2.50 (m, 1H), 2,20-of 2.50 (m, 2H), is 2.37 (s, 3H), 2,45-of 2.50 (m, 2H), 2,50-2,60 (m, 2H), 2,60 is 2.80 (m, 4H), 2.70 height is 3.00 (m, 4H), 3,63 (t, J=6.4 Hz, 2H), 6,41 (DD, J=8.0 Hz, 2.0 Hz, 1H), 6,47 (d, J=2.0 Hz, 1H), 6,70 (DD, J=8.0 Hz, 2.4 Hz, 1H), to 7.09 (t, J=8.0 Hz, 1H), was 7.36 (d, J=8,4 Hz, 2H), 7,32-7,40 (m, 1H), 7,38-of 7.48 (m, 4H), 7,46 (d, J=8.0 Hz, 2H).

Example 233

4-[(4-Cyano-5-methyl-4-phenyl)hexyl]-1-{2-[3-(p-toluensulfonyl)phenoxy]ethyl}piperazine

Oxalate specified in the title compound obtained as a pale brown solid by the method according to example 15.

Oxalate:

1H-NMR (400 MHz, DMSO-d6)of 0.64 (d, J=6.4 Hz, 3H), of 1.09 (d, J=6.4 Hz, 3H), 1,00-1,20 (m, 1H), 1,43 is 1.60 (m, 1H), 1,90 and 2.13 (m, 2H), 2,15 was 2.25 (m, 1 (d, J=8,4 Hz, 2H), 7,30-7,40 (m, 1H), was 7.36-of 7.48 (m, 4H), 7,45 (d, J=8,4 Hz, 2H).

Example 234

1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{[3-(p-toluensulfonyl)phenoxy]methyl}piperidine

Specified in the title compound obtained as a yellow amorphous substance by the method according to example 15.

1H-NMR (400 MHz, CDCl3)of 0.75 (d, J=6.8 Hz, 3H) and 1.15 (d, J=6.4 Hz, 3H), 1,05-1,30 (m, 3H), 1,30-1,45 (m, 1H), 1,45-of 1.65 (m, 1H), 1,65 (Shir.d, J=12,4 Hz, 2H), of 1.65 and 1.80 (m, 1H), 1,75-of 1.95 (m, 2H), 2.00 in to 2.18 (m, 2H), and 2.26 (t, J=7.2 Hz, 2H), 2.40 a (s, 3H), 2,67 is 2.80 (m, 2H), and 3.31 (d, J=7,6 Hz, 2H), to 6.43 (d, J=8.0 Hz, 1H), 6,56 (d, J=2.0 Hz, 1H), 6,67-6,76 (m, 1H), was 7.08 (t, J=8.0 Hz, 1H), 7,22 (d, J=6,8 Hz, 2H), 7,20-7,40 (m, 5H), was 7.45 (d, J=8.0 Hz, 2H).

Example 235

1-[(3-Cyano-4-methyl-3-phenyl)pentyl]-4-{[3-(p-toluensulfonyl)phenoxy]methyl}piperidine

Specified in the title compound obtained as a pale brown amorphous substance by the method according to example 3.

1H-NMR (400 MHz, CDCl3)to 0.73 (d, J=6.8 Hz, 3H), 1.14 in (d, J=6.4 Hz, 3H), 1,15-1,30 (m, 2H), 1,35-of 1.52 (m, 1H), 1,68 (Shir.d, J=12,4 Hz, 2H), 1,73-2,05 (m, 3H), 2.00 in to 2.18 (m, 2H), 2,30 is 2.43 (m, 2H), 2.40 a (s, 3H), 2,70-2,90 (m, 2H), 3,20-to 3.38 (m, 2H), 6,38 (DD, J=8.0 Hz, 2.0 Hz, 1H), return of 6.58 (d, J=1.6 Hz, 1H), 7,00 (DD, J=8.0 Hz, 2.0 Hz, 1H), 7,07 (t, J=8.0 Hz, 1H), 7,22 (d, J=7,6 Hz, 2H), 7,25-7,40 (m, 5H), the 7.43 (d, J=8,4 Hz, 2H).

Example 236

the frame in the title compound obtained as colorless solid by the method according to example 48.

Oxalate:

1H-NMR (400 MHz, DMSO-d6)0,63 (d, J=6.8 Hz, 3H), 0,70-0,85 (m, 1H), 1,00-1,30 (m, 5H), of 1.08 (d, J=6.4 Hz, 3H), of 1.20 and 1.35 (m, 1H), 1,58 (Shir.d, J=12,8 Hz, 2H), 1,87-of 2.08 (m, 2H), 2,10-of 2.23 (m, 1H), 2,61 (Shir.t, J=11.2 Hz, 2H), 3,11 (Shir.d, J=10,8 Hz, 2H), 4,10 (s, 2H), 7,28-7,33 (m, 1H), 7,34-7,44 (m, 4H), to 7.61 (t, J=7,6 Hz, 1H), 7,76 (d, J=7,6 Hz, 1H), 7,84-of 7.90 (m, 2H).

Example 237

1-[(5-Phenyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(4-cyano-5-methyl-4-phenyl)hexyl]piperidine

Specified in the title compound obtained as a pale yellow oil by the method according to example 3.

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), of 0.85 to 1.00 (m, 1H), 1,10-of 1.45 (m, 4H), 1,19 (d, J=6.8 Hz, 3H), 1,50-of 1.65 (m, 2H), 1.60-to of 2.20 (m, 5H), 2,80-3,00 (m, 2H), 3,54 (s, 2H), 7.24 to of 7.48 (m, 10H), to 7.64-of 7.70 (m, 1H), 7,78-to 7.84 (m, 1H).

Example 238

Ethyl-1-benzyl-4-(4-cyano-5-methyl-4-phenylhexa)-2-piperidinecarboxylate

Specified in the title compound synthesized by the method according to example 15 using 1-benzyl-2-(etoxycarbonyl)piperazine (Synthesis, 318, 1991).

Loose coupling:

1H-NMR (400 MHz, CDCl3)0,76 (d, J=6.6 Hz, 3H), 1,05-1,10 (m, 1H), of 1.18 to 1.31 (m, 6N), 1,50-to 1.63 (m, 1H), 1,86-of 1.94 (m, 1H), 2,04-of 2.15 (m, 2H), 2.21 are of 2.54 (m, 7H), 2,96 (m, 1H), 3,22-of 3.27 (m, 1H), 3,51 (m, 1H), 3,86-3,90 (m, 1H), 4,12-to 4.23 (m, 2H), 7,21-7,37 (m, 10="https://img.russianpatents.com/img_data/78/782528.gif">

Specified in the title compound synthesized by the method according to example 48, using ethyl-4-(4-cyano-5-methyl-4-phenylhexa)-2-piperidinecarboxylate.

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), 1.06 a-1,11 (m, 1H), 1,17-of 1.29 (m, 6N) and 1.51-of 1.62 (m, 1H), 1,86 is 1.91 (m, 1H), 2,05-2,11 (m, 2H), 2,22-of 2.36 (m, 4H), 2,52 is 2.55 (m, 3H), 2,94-a 3.01 (m, 2H), 3,13-and 3.16 (m, 1H), 3,38-3,39 (m, 1H), 4,01-a 4.03 (m, 2H), 4,14-4,22 (m, 2H), 6,78-PC 6.82 (m, 2H), 6,92-6,97 (m, 2H), 7,26-7,31 (m, 1H), was 7.36-7,37 (m, 4H).

Example 240

1-(4-Cyano-5-methyl-4-phenylhexa)-3-hydroxymethyl-4-[2-(4-pertenece)ethyl]piperazine

To a solution (5.0 ml) of lithium aluminum hydride (20 mg) in diethyl ether under ice cooling are added dropwise a solution (3.0 ml) 213 mg of ethyl-4-(4-cyano-5-methyl-4-phenylhexa)-1-[2-(4-pertenece)ethyl]-2-piperidinecarboxylate in diethyl ether. The mixture is stirred under ice cooling for one hour and alternately add water (0.1 ml), 1 N. aqueous sodium hydroxide solution (0.1 ml) and water (0.2 ml). To the reaction solution was added anhydrous magnesium sulfate and filtered by-product. The solvent is evaporated, thus obtaining specified in the title compound (194 mg).

Loose coupling:

1H-NMR (400 MHz, CDCl3)

Example 241

Ethyl-1-benzyl-4-[2-(4-pertenece)ethyl]-2-piperidinecarboxylate

Specified in the title compound synthesized by the method according to example 48 using 1-benzyl-2-(etoxycarbonyl)piperazine (Synthesis, 318, 1991).

Loose coupling:

1H-NMR (400 MHz, CDCl3)1,24 of 1.28 (m, 3H), 2,36-2,12 (m, 1H), 2,54-2,61 (m, 2H), 2.71 to and 2.83 (m, 4H), to 3.02 (m, 1H), 3,31-to 3.34 (m, 1H), 3,53 of 3.56 (m, 1H), 3,89-to 3.92 (d, J=16.6 Hz, 1H), 3,99-of 4.05 (m, 2H), 4,11-4,24 (m, 2H), 6,79-6,83 (m, 2H), 6,93-6,98 (m, 2H), 7.23 percent-7,34 (m, 5H).

Example 242

Ethyl-1-(4-cyano-5-methyl-4-phenylhexa)-4-[2-(4-pertenece)ethyl]-2-piperidinecarboxylate

Specified in the title compound synthesized by the method according to example 15, using ethyl-4-[2-(4-pertenece)ethyl]-2-piperidinecarboxylic.

Loose coupling:

ESI-MS (m/e): 496 (M+H).

Ethyl-4-[2-(4-pertenece)ethyl]-2-piperidinecarboxylate

receive in the form of a crude product (752 mg, 100%), and ethyl-1-benzyl-4-[2-(4-pertenece)ethyl]-2-piperidinecarboxylate (977 mg) synthesized by the method in example 241, dissolved in ethanol (15 ml), added 210 mg of 10% Pd-C, replace almosteveryone:

1H-NMR (400 MHz, CDCl3)1,24 of 1.28 (m, 3H), 2,33-of 2.34 (m, 1H), 2,48-of 2.50 (m, 1H), 2,72-only 2.91 (m, 4H), 3.04 from-3,10 (m, 2H), 3,56-3,59 (m, 1H), 4.04 the-4,08 (m, 2H), 4,16-4,22 (m, 2H), 6,82-6,86 (m, 2H), 6,94-of 6.99 (m, 2H).

Example 243

1-(4-Cyano-5-methyl-4-phenylhexa)-2-hydroxymethyl-4-[2-(4-pertenece)ethyl]piperazine

Specified in the title compound synthesized by the method according to example 240 using ethyl-1-(4-cyano-5-methyl-4-phenylhexa)-4-[2- (4-pertenece)ethyl]-2-piperidinecarboxylate.

Loose coupling:

1H-NMR (400 MHz, CDCl3)of 0.77 (d, J=6.8 Hz, 3H), of 1.07-1.14 in (m, 1H), 1,20 (d, J=6.6 Hz, 3H), 1,43-of 1.56 (m, 1H), 1,79-1,90 (m, 1H), 2,04-and 2.83 (m, 13H), 3,47-3,51 (m, 1H), 3,83-3,91 (m, 1H), 4,01-4,10 (m, 2H), 6,80-6,84 (m, 2H), 6,94-6,98 (m, 2H), 7,26-7,40 (m, 5H).

Test examples

In the following examples describe tests of the compounds of the present invention on the inhibition of calcium in vitro (test example 1), the reduction of lesion infarction in in vivo models with occlusion of the middle cerebral artery of the brain in rats (test example 2) and analgesic effect in the induction of the response to formalin in mice (test example 3). Below are the testing methods and results.

Test example 1

Measurement ingibiruemaya importance as a mechanism of infarction brain (neuronal cell death due to ischemia), is attributed to the assumption "glutamic acid - Sa. Namely, when the reduction of blood flow in the brain is anaerobic glycolysis, which causes depletion of adenosine triphosphate (ATP) in the brain. The result of the exhaustion of the energy potential is disturbed concentration gradient of ions inside and outside the cells, which leads to depolarization. The activation of voltage-dependent calcium channel in presence due to depolarization, which causes excessive release of glutamic acid. Activation of voltage-dependent calcium channel in postsynaptic due to depolarization causes an increase in the concentration of CA2+in the cell, with excessive release of glutamic acid stimulates receptor glutamic acid, which increases the concentration of CA2+in the cage. As a result, these enzymes as carpain and phospholipase dependent on the concentration of CA2+activated and cause the death of nerve cells. Experimental system according to this application allows you to evaluate the influx of CA2+in presynapses in the above-described process scheme.

oxine GVIA, which is the inhibitor calcium channel N-type, and 1 μm w-agitoxin IVA, which is the inhibitor calcium channel P/Q-type, inhibit the influx of CA2+respectively 16%, 18% and 64% (see the following reference to the literature). Therefore, this system is suitable for assessing the inhibition of calcium channel N-type and P/Q-type.

References

D. Bowman, S. Alexander and D. Lodge, Pharmacological characterization of the calcium channels coupled to the plateau phase of KCl-induced intracellular free Ca2+elevation in chicken and rat synaptosomes, Neutopharmacology, 32 (11), 1195-1202 (1993).

(1) Obtaining the synaptosomes structures of the cerebral cortex

Synaptosome cortex receive the following method described in "Neuropharmacology, 32(11), 1195-1202, 1993". Namely, the cerebral cortex is separated from the brain decapitated rats and shredded with scissors. Shredded cortex of the brain is placed in a homogenizer, homogenize in 3 M sucrose and centrifuged (1500 g10 minutes) at 4°C. the Resulting supernatant is again centrifuged (10000 g20 minutes) at 4°C. To the obtained precipitate add 0.3 M sucrose and the mixture is suspended. The suspension is stratified in 0.8 M sucrose and centrifuged (10000 g30 minutes). The obtained precipitate suspend the EPES-NaOH, a pH of 7.4, with 0.1% BSA), thus obtaining synaptosome cortex.

(2) Inhibition of calcium channel

4 mm dye fura2/AM (Doujin) suspended in the above solution And receive a solution to boot. The specified solution in equal quantities are added to a solution of the synaptosomes structures obtained as described above, and the mixture is incubated for 40 minutes at room temperature. After incubation, the solution is to load removed by centrifugation and washed 2 times with solution A. To the resulting solution was added a solution containing the compound of the present invention, and the mixture is incubated for 10 minutes at room temperature. Calcium channel stimulate, adding to the resulting solution 1/10 "solution" (122,6 mm KCl, 1 mm CaCl2, 1 mm MgClz, 1.2 mm Na2HPO4, 10 mm D-glucose, 20 mm HEPES-NaOH, pH of 7.4, with 0.1% BSA). The concentration of calcium ions in the cell determine measured two wavelengths equal to 340 and 380 nm, in the apparatus ARUGUS-FDSS (HAMAMATSU-PHOTONICS Co.), and set the IC50for the respective test compounds. As a reference compound for comparison with test compounds use of verapamil hydrochloride.

Test example 2

Decrease

Calcium ions present in the cell, play an important role in different functions of the cell. But a significant increase in the concentration of calcium ions causes damage to cells (see references (1) and (2)). As an example, damage to the nervous cells stimulating amino acid in the case when cerebral ischemia causes an excessive increase in the concentration of calcium ions in the cell (3) and (4). As a result of local cerebral ischemia (3) under the action of stimulating amino acids violated mechanism for maintaining membrane potential, there is a depolarization of the membrane (5) and increases the influx of calcium ions into the cell through potentsialzavisimye calcium channel (6) and (7). In light of the above, we can assume that the hypothesis about the death of nerve cells under the action of stimulating amino acids is consistent with the hypothesis that the loss of nerve cells is associated with an increased concentration of calcium ions in the cell and the activation of voltage-dependent calcium channel contributes to the induction of death of nerve cells (8). Voltage gated calcium channels present in the nerve cell can be classified into 6 subtypes on the basis of electrophysiological and Farmak the order his glutamic acid from synaptosomes structures of the cerebral cortex of the rat (10) and (11). Therefore, the typical compounds of the present invention evaluate protective action in respect of the affected nerve cells after local cerebral ischemia, on the model of blockage of the middle cerebral artery of the brain in rats.

(1) get sample

The compound of the above formula (I) according to the present invention is dissolved in physiological solution and the resulting solution is used for doses equal to 1.5, 5 and 15 mg/kg per hour. The concentration of the sample calculated in the calculation of the average body weight of the animal. In addition, calculate the average mass of a body by measuring the body weight of all animals used in the experiment. For example, a dose equal to 5 mg/kg per hour, is calculated as follows: concentration of sample = 5 mgthe average body weight (kg)/injected volume (0,616 ml) per hour.

(2) the Manufacture of nylon of the pitch

Occlusion of the middle cerebral artery of the brain called embolus, made of nylon monofilament 4-0 (Ethicon, Inc., Somerville, NJ, USA). To get nylon embolus, the thread end upravlyaut flame in the form of a ball, cut off part of the thread length 25 mm and an oil marker make a mark at the distance of 17 mm from the end of the thread.

(3) Implantation of a catheter for intravenous injection

The catheter is nitrogen with 2% halothane gas. A catheter filled with saline solution, injected into the femoral vein of the left paw of the rat.

(4) Blockage of the middle cerebral artery of the brain

Central artery of the brain overlap method described by long and others (12). Do surgery under General anesthesia with a mixture of 70% nitrous oxide with 2% halothane gas immediately after implantation of the catheter. Before surgery, the rat lay on his back under a stereoscopic microscope, dissect the neck and determine the place where the right common carotid artery branches into the external carotid artery and internal carotid artery. External carotid artery cut off from the peripheral side and end of the external carotid artery, separated from the internal carotid artery, nylon insert embolus. The embolus is injected to the position when the mark at a distance of 17 mm from its end corresponds to the point of bifurcation of the external and internal carotid arteries, and fix. Nylon embolus is removed from the Central artery of the brain 2 hours to resume blood flow.

(5) the Selection of animals with symptoms of ischemia

30 minutes after occlusion of the middle cerebral artery in rat brain caught and lifted by the tail; for experiment select animals with obvious signs of unilateral paralysis of the anterior l is dressed occlusion of middle cerebral artery of the brain with symptoms of ischemia.

(6) the Introduction of the substrate and preparation

Rats are experiencing symptoms of unilateral paralysis after 30 minutes after occlusion of the middle cerebral artery of the brain, is placed in a cell equipped with a device for measuring body temperature, and injected into the rectum probe for measuring body temperature. A syringe filled with substrate or product, is inserted into the catheter for intravenous and within one minute intravenous half dose (0,34 ml), which should be introduced within 1 hour. Then the infusion of produce at the rate 0,682 ml/hour for 24 hours using a syringe pump for infusion (Razel Scientific Instruments, Inc. Stamford, CT, USA). During the introduction and within 2 hours after injection using a system for measuring the body temperature measure the temperature in the rectum, which is in the range from 37,0 to 38.5°C.

(7) the measurement of the lesion heart (staining of brain slice chloride, 2,3,5-triphenyltetrazolium (IDT))

24 hours after occlusion of the middle cerebral artery in rat brain decapitate, the brain removed and the blood is washed off cooled ice saline solution. From brain to remove olfactory bulb and make a slice thickness of 2 mm (6 slices), palacesonwheels.com solution. Slices left in the TTC solution for one hour or more at room temperature and then used to determine the magnitude of the lesion heart.

(8) calculate the volume of the lesion heart

The upper part of each slice (the rear surface of the brain) is used to calculate the size of the lesion heart. Images of brain slices get in the computer (RM/100, Apple Japan, Tokyo) using a photographic device color CCD camera, SANKEI Inc., Tokyo). Lesions myocardial cortex on the obtained images was measured using software for image analysis (NIH image ver. 1,60, National Institutes of Health, USA). The volume of the lesion heart of one of the animal is calculated as the total amount (unit of measure = mm3for 6 slices by multiplying the square (unit of measure = mm2) lesion of the infarct related sections 2 (unit of measure = mm) that is equal to the thickness of the slice.

(9) Method of data analysis

Volume (unit = mm3) lesion myocardial cortex expressed as mean value ± standard error. Statistical significance relative to the control group, which introduced the substrate, to the comparative analysis method Dannetta and the level of significance set equal to 5% for both sides. Reactivity dose determined by regression analysis and the significance level set equal to 5% for one side.

(10) Results

Central artery of the brain overlap of nylon embolus, which is removed after 2 hours to resume blood flow, and 24 hours after occlusion of the middle cerebral artery of the brain to measure the volume of the lesion heart. As a result of the experiment found that the compound of the present invention significantly reduces the volume of the lesion myocardial cortex, while the regression analysis confirms the interdependence between injected dose and reduction of lesion heart when using the compounds of the present invention. For example, the compound from example 70 reduces the volume of the lesion myocardial cortex respectively 4% (128,9±12.5 mm3n=16), 20% (108,0±14,9 mm3, n=15) and 44% (75,7±11.2 mm3, n=12; p<0,01) when administered intravenously at doses of 1.5, 5 and 15 mg/kg/h after 30 minutes after occlusion of the middle cerebral artery of the brain compared with the volume of the lesion myocardial cortex, equal 134,3±12.3 mm3(n=19) for the control group. Connection example 75 reduces energy is3, n=14; p<0.01) and 49% (83,7±21.3 mm3, n=11; p<0,01) when administered intravenously at doses of 1.5, 5 and 15 mg/kg per hour after 30 minutes after occlusion of the middle cerebral artery of the brain compared with the volume of the lesion myocardial cortex, equal 162,9±8.4 mm3(n=15) for the control group.

Namely, the compound of the present invention inhibits the inflow of calcium ions in synaptosome cortex of the rat brain induced by a high concentration of KCl, and prevents separation of glutamic acid from a slice of the cerebral cortex of the rat. In addition, the compound of the present invention protects nerve cells from damage caused by local ischemia of the brain in this experiment, and significantly reduces lesion heart with the introduction of 30 minutes after the occurrence of ischemia. Thus, the connection of the present invention provides effective action even after introduction of a brain hemorrhage in man.

The obtained results confirmed the reports that SNX-111 (CAS Registration No. 107452-89-1), a peptide inhibiting calcium channel N-type, prevents the release of glutamic acid from the cerebral cortex and prevents subsequent defeat tp://img.russianpatents.com/chr/969.gif">-agitoxin IVA, which is a peptide inhibiting calcium channel P/Q-type, has a protective effect on nerve cells in an animal model of local ischemia of the cerebral cortex in rats (15).

Links

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 neurosecretion. Neuropharmacology 34: 1469-14up>channels present in synaptosomes from rat and chicken central nervous system. J. Neurochem. 64: 2544-2551 (1995).

12) Longa, E. Z., Weinstein, P. P., 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).

Test example 3

Analgesic effect (I) in the induction of the response to formalin in mice

Calcium channel N-type, which is one of neurospecific calcium channels, it is possible to selectively inhibit drug SNX-111, which is a low molecular weight polypeptide. In addition, it is known that SNX-111 has analgesic effect when injected into the spinal cord in response caused by the formalin response, which is one of the test methods analgesic actions (1) and (2). Therefore, the compounds of the present invention evaluate the analgesic effect in the induction of the response to formalin in mice (3).

(1) LC With. Mice adapt for 4 days or more (conditions: room temperature 23±1°C, humidity 55±5%, the cycle of alternation of light and darkness every 12 hours). Mice are housed groups, consisting of about 20 mice, cells from polycarbonate floor, with the capacity of 20 mice (White Flake, Charles River Co., Ltd. Tokyo), and feed. On the morning of the test mice are transferred to the laboratory. Mouse without limitation receive food MF (Oriental Yeast Co., Tokyo). In addition, they without limitation collect drinking water.

(2) Test connection

As the test compounds used connection examples 7, 20, 47, 49, 58, 63, 64, 198, 199, 209, 189, 123, 124, 219 and 221. As a control drug use known analgesics, such as morphine, which is a strong narcotic analgetika, and indomethacin, which is anti-inflammatory analgetikom.

(3) Preparation of the test compounds

The compound of the present invention is dissolved in 5,28% mannitol concentration 1 mg/ml (10 mg/kg). Compound is weighed and prepared for the day of the experiment. Morphine was dissolved in physiological solution with a concentration of 3 mg/ml (30 mg/kg) and indomethacin suspended in 0.5% medically is eagent

Select 30 μl of commercially produced 35,0-38,0% solution of formaldehyde and add to 970 μl of saline. The resulting solution was used as a 3% formalin. Formalin is a 37% formaldehyde solution, and as the purity of the used solution of formaldehyde equal to 35.0-38,0%, 3% formaldehyde, obtained for use in this experiment, represents precisely 2,84-is 3.08% formalin.

(5) Dose, route of administration, number of samples

Intravenous 10 mg/kg of the compounds of the present invention (0.1 ml of solution with a concentration of 1 mg/ml per 10 g of body weight). Orally administered 30 mg/kg of morphine (0.1 ml of solution with a concentration of 3 mg/ml per 10 g of body weight). In addition, orally administered 10 mg/kg indomethacin (0.1 ml of a suspension with a concentration of 1 mg/ml per 10 g of body weight). As the control of substances intravenously or orally administered 0.1 ml of the appropriate solvent per 10 g of body weight. In each group experiencing five different samples.

(6) test Method

The tail vein injected with 10 mg/kg of the compounds of the present invention, orally administered 30 mg/kg of morphine and 10 mg/kg indomethacin. After 5, 30 and 90 minutes after a proper introduction prozrachnogo plastic. After injection of formalin for 5 minutes to determine the exposure time, during which the mouse licks his left hind paw, and the result is viewed as an indicator of pain. Appropriate solvents are injected the same way as control substances. Taking the time licking with the introduction of the control of substances as 100%, the following formula calculate the degree of reduction of pain (%) of the compound of the present invention.

Formula:

The degree of reduction of pain (%) = (time licking with the introduction of a control substance - time licking with the introduction of the test compound)/(time licking with the introduction of the control of substances) x 100

(7) Results

The compound of the present invention at a statistically significant level reduces the amount of time licking, compared with the control group, and the degree of reduction of pain is within 33-88%. In particular, the analgesic effect of the compounds according to example 189 corresponds to a 59% decrease in pain. On the other hand, the analgesic effect of morphine corresponds to a 54% decrease in pain, and the degree of reduction of pain in what nhibition calcium channel, the compound of the present invention has analgesic effect, such SNX-111, which is an inhibitor of calcium channel N-type, and morphine, which is a strong narcotic analgetika even in comparison with known analgesics, and has a much stronger analgesic effect than indomethacin, which is anti-inflammatory analgetikom. Thus, the connection of the present invention is extremely useful for the treatment and alleviating pain.

Links

1) Annika C. 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 O. C. and Hole, K. (1985) Formalin test in mice, a useful technique for evaluating mild analgesics. Journal of Neuroscience Methods 14 (1): 69-76.

Claims

1. The compound of formula (I), its salt or hydrate:

where Ar means6-14aromatic hydrocarbon cyclic group which may be substituted, 5-14-is responsible pieperazinove ring, homopiperazine ring, piperidine ring, pyrolidine ring or diazabicyclo[2,2,1]heptane ring, which respectively may be substituted;

the ring is In3-14hydrocarbon ring which may be substituted, or a 5-14-membered heterocyclic ring which may be substituted;

E. means a simple bond or a group of the formula-CO-;

X is a simple bond, oxygen atom, With1-6alkylenes chain which may be substituted, a group of formula-CO-, -SO-, -SO2-, -NR8SO2- (where R8means a hydrogen atom or a C1-6alkyl group which may be substituted), >C=N-OR9(where R9means a hydrogen atom or a C1-6alkyl group which may be substituted), -NH-CO-NH-, -NH-CS-NH-, -C(=NR15)NR16- (where R15and R16have identical or different meanings and represent a hydrogen atom, nitrile group, With1-6alkyl group, a C2-6alkenylphenol group3-8cycloalkyl group or3-8cycloalkenyl group), -NHC(=NH)-, -O-CO-S-, -S-CO-O-, LLC-, -NHCOO-, -OCONH-, -CO(CH2)mO- (where m is 0 or an integer from 1 to 6), -SNON or SNAN(CH2)nO- (where n is 0 or an integer from 1 to 6);

R1Aussie multiple groups, selected from hydroxyl group, halogen atom and nitrile group2-6alkenylphenol group which may be substituted by one or more groups selected from hydroxyl group, halogen atom and nitrile group2-6alkylamino group which may be substituted by one or more groups selected from hydroxyl group, halogen atom and nitrile group3-8cycloalkyl group which may be substituted by one or more groups selected from hydroxyl group, halogen atom and nitrile group1-6alkoxy-C1-6alkyl group; and

D1D2, W1and W2have identical or different meanings and represent a simple bond or a C1-6alkylenes chain which may be substituted,

provided that the above definition excluded 1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine; 1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(3-pertenece)ethyl]piperazine and 1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-pertenece)ethyl] piperazine.

2. Connection on p. 1, its salt or hydrate, where Ar means6-14aromatic hydrocarbon ring or an 5-14 membered aromatica means thiophene ring or benzene ring, which may be substituted.

4. Connection on p. 1, its salt or hydrate, where Ar means6-14aromatic hydrocarbon ring or a 5 to 14-membered aromatic hydrocarbon ring which may be substituted by one or more groups selected from nitrile group and halogen atom.

5. Connection on p. 1, its salt or hydrate, where Ar means thiophene ring or benzene ring which may be substituted by one or more groups selected from nitrile group and halogen atom.

6. Connection on p. 1, its salt or hydrate, where the ring And represents pieperazinove ring, homopiperazine ring or piperidine ring.

7. Connection on p. 1, its salt or hydrate, where the ring a represents pieperazinove ring.

8. Connection on p. 1, its salt or hydrate, where the ring a represents pieperazinove ring, homopiperazine ring or piperidine ring which may be substituted by one or more groups selected from hydroxyl group, halogen atom, ceanography,1-6alkyl group which may be substituted With2-6alkenylphenol group which may be substituted With2-6alkenylphenol group, which m the which may be substituted With1-6alkylcarboxylic group which may be substituted With2-6alkenylamine group which may be substituted With1-6alkoxycarbonyl group which may be substituted, and2-6alkenylcarbazoles group which may be substituted.

9. Connection on p. 1, its salt or hydrate, where the ring is In6-14aromatic hydrocarbon ring or a 5 to 14-membered aromatic heterocyclic ring, which respectively may be substituted.

10. Connection on p. 1, its salt or hydrate, where ring b is a benzene, thiophene, pyridine, 1,4-benzodioxan, indole, benzothiazole, benzoxazole, benzimidazole, 2-keto-1-benzimidazole, thiazole, oxazole, isoxazol, 1,2,4-oxadiazole, indanan, benzofuran, quinoline, 1,2,3,4-tetrahydroquinolin, naphthalene or 1,2,3,4-tetrahydronaphthalen, which, respectively, can be substituted.

11. Connection on p. 1, its salt or hydrate, where the ring is In6-14aromatic hydrocarbon ring or a 5 to 14-membered aromatic heterocyclic ring, which respectively may be substituted by one or more groups selected from a halogen atom, nitrile group,1-6alkyne under item 1, its salt or hydrate, where D1and D2have identical or different meanings and represent a simple bond or a C1-6alkylenes chain which may be substituted by one or more groups selected from hydroxyl group, halogen atom, nitrile group, With1-6alkyl group, a C2-6alkenylphenol group and1-6CNS group.

13. Connection on p. 1, its salt or hydrate, where E means of simple communication.

14. Connection on p. 1, its salt or hydrate, where D1and D2mean1-6alkylenes chain and E means of simple communication.

15. Connection on p. 1, its salt or hydrate, where the partial structure of-D1-E-D2- is1-4alkylenes group.

16. Connection on p. 1, its salt or hydrate, where W1and W2have identical or different meanings and represent each simple communication or1-6alkylenes chain which may be substituted by one or more groups selected from hydroxyl group, halogen atom, nitrile group, With1-6alkyloxy and C2-6alkenylacyl.

17. Connection on p. 1, its salt or hydrate, where W1means of simple communication or1-6alkylenes chain, which can Batora may be substituted by one or more groups, choose from C1-6CNS group and2-6alkenylacyl, and C2-6alkenylphenol group, and W2means of simple communication.

18. Connection on p. 1, its salt or hydrate, where W1and W2have identical or different meanings and represent each1-6alkylenes chain, substituted by one or more groups selected from C1-6alkyl groups and C2-6alkenylphenol group, and the above With1-6an alkyl group and/or C2-6Alchemilla group can be connected to each other to form rings or above With a1-6an alkyl group or2-6Alchemilla group can be connected with the ring or X with the formation of rings.

19. Connection on p. 1, its salt or hydrate, where X is a simple bond, an oxygen atom or-NH-SO2-.

20. Connection on p. 1, its salt or hydrate, where X means an oxygen atom or-NH-SO2-.

21. Connection on p. 1, its salt or hydrate, where the partial structure-W1-X-W2- is1-6alkylenes group which may be substituted.

22. Connection on p. 1, its salt or hydrate, where W1means1-6alkylenes chain which may be substituted; W2means about the Sabbath.

23. Connection on p. 22, its salt or hydrate where the Deputy W1represents one or more groups selected from nitrile groups, With1-6alkyl group which may be substituted With1-6alkyloxyaryl or2-6alkenylacyl, and C2-6alkenylphenol group, and R2means1-6alkyl group which may be substituted.

24. Connection on p. 1, its salt or hydrate, where R1means1-6alkyl group.

25. Connection on p. 1, its salt or hydrate, where R1means methyl, ethyl, n-sawn or ISO-propyl group.

26. The compound of formula (II), its salt or hydrate:

where R1has the above meanings;

R13and R14have identical or different meanings and represent a hydrogen atom, halogen atom, hydroxyl group, mercaptopropyl,1-6alkyl group which may be substituted by one or more groups selected from hydroxyl groups and halogen atom, a C1-6CNS group which may be substituted by one or more groups selected from hydroxyl group, halogen atom and C1-6alkoxycarbonyl group, nor is manilow group, With1-6tolkatelnye group1-6alkylsulfonyl group, a lower acyl group, a C6-14aromatic hydrocarbon cyclic group which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be optionally substituted, alloctype or aralkylated, or all together elements of R13or all together elements of R14connected to each other to form an aliphatic ring which may be substituted, heterocyclic ring which may be substituted, or alkylenedioxy; n indicates 0 or an integer from 1 to 3; R denotes an integer from 1 to 6; q indicates an integer from 1 to 6; and r is 0 or an integer from 1 to 5,

provided that the above definition excluded 1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine; 1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(3-pertenece)ethyl]piperazine and 1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-pertenece)ethyl]piperazine.

27. The compound of formula (III), its salt or hydrate:

where in this formula, R1and R2have the above meanings;

R13and R14have the same or different znaczeniu, which may be substituted by one or more groups selected from hydroxyl groups and halogen atom, a C1-6CNS group which may be substituted by one or more groups selected from hydroxyl group, halogen atom and C1-6alkoxycarbonyl group, a nitrogroup, an amino group which may be substituted, cyano, carboxyl group, With1-6alkoxycarbonyl group1-6tolkatelnye group1-6alkylsulfonyl group, a lower acyl group, a C6-14aromatic hydrocarbon cyclic group which may be substituted, a 5 to 14-membered aromatic heterocyclic group which may be substituted, alloctype, aralkylated, or all together13or all together elements of R14can be connected to each other to form an aliphatic ring which may be substituted, heterocyclic ring which may be substituted, or alkylenedioxy; n indicates 0 or an integer from 1 to 3; R denotes an integer from 1 to 6; q indicates an integer from 1 to 6; r is 0 or an integer from 1 to 5.

28. Connection on p. 1 of formula (I), its salt or hydrate:

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-unopenable)ethyl]piperazine;

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

and

1-[4-cyano-4-(3-cyano-5-thienyl)-5-methylhexan]-4-[2-(3-cianfrocca)ethyl]piperazine.

30. Connection on p. 1 of formula (I), its salt or hydrate, where the compound is selected from the group consisting of

1-[4-cyano-5-methyl-4-(5-cyano-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

and

1-[4-cyano-4-(3-cyano-5-thienyl)-5-methylhexan]-4-[2-(3-cianfrocca)ethyl]piperazine.

31. Connection on p. 1, its salt or hydrate, where the compound is 1-[ 4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-(3-cianfrocca)ethyl]piperazine

.

32. Connection on p. 1, its salt or hydrate, where the compound is 1-[ 4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-cianfrocca)ethyl]piperazine

.

33. Connection on p. 1, its salt or hydrate, where the compound is 1-[4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexyl]-4-[2-(3-cianfrocca) ethyl]piperazine

.

35. Connection on p. 1, its salt or hydrate, where the ring And is pyrrolidinium ring and a specified compound selected from the

36. Connection on p. 1, its salt or hydrate, which is chosen from the group comprising

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-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-diazepan-1-yl]-1-isopropyl-1-phenylbutazone;

4-[4-(1-ethyl-1H-benzo[d]imidazol-2-yl)-1,4-diazepan-1-yl]-1-isopropyl-1-phenylbutazone;

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-phenylbutyramide and

4-[4-(4-benzylpiperidine)piperidinyl]-1-isopropyl-1-phenylbutyramide.

37. Pharmaceutical composition, which is a calcium antagonist containing a compound of the formula (I), its salt or hydrate:

where Ar means6-14aromatic hydrocarbon cyclic group which may be zames the em respectively pieperazinove ring, homopiperazine ring, piperidine ring, pyrolidine ring or diazabicyclo[2,2,1]heptane ring, which respectively may be substituted;

the ring is In3-14hydrocarbon ring which may be substituted, or a 5-14-membered heterocyclic ring which may be substituted;

E. means a simple bond or a group of the formula-CO-;

X is a simple bond, oxygen atom, With1-6alkylenes chain which may be substituted, a group of the formula-CO-, -SO-, -SO2-, -NR8SO2- (where R8means a hydrogen atom or a C1-6alkyl group which may be substituted), >C=N-OR9(where R9means a hydrogen atom or a C1-6alkyl group which may be substituted), -NH-CO-NH-, -NH-CS-NH-, -C(=NR15)NR16- (where R15and R16have identical or different meanings and represent a hydrogen atom, nitrile group, With1-6alkyl group, a C2-6alkenylphenol group3-8cycloalkyl group or3-8cycloalkenyl group), -NHC(=NH)-, -O-CO-S-, -S-CO-O -, -? -,- NHCOO-, -OCONH-, -CO(CH2)mO- (where m is 0 or an integer from 1 to 6), -SNON or SNAN(CH2)nO- (where n is 0 or an integer from 1 to 6);

R1Aussie multiple groups, selected from hydroxyl group, halogen atom and nitrile group2-6alkenylphenol group which may be substituted by one or more groups selected from hydroxyl group, halogen atom and nitrile group2-6alkylamino group which may be substituted by one or more groups selected from hydroxyl group, halogen atom and nitrile group3-8cycloalkyl group which may be substituted by one or more groups selected from hydroxyl group, halogen atom and nitrile group1-6alkoxy-C1-6alkyl group; and

D1D2, W1and W2have identical or different meanings and represent a simple bond or a C1-6alkylenes chain which may be substituted,

provided that the above definition excluded 1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(4-pertenece)ethyl]piperazine; 1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(3-pertenece)ethyl]piperazine and 1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-pertenece)ethyl] piperazine.

38. The composition according to p. 37, which is an inhibitor of at least one calcium channel P/Q-type and N-type.

39. Composition or effective inhibitory activity against at least one calcium channel P/Q-type and one calcium channel N-type.

40. The composition according to p. 37, which is a means of preventing neuronal cell death or protecting the nerve cells of the brain.

41. The composition according to p. 37, which is a tool for the treatment, prevention or improvement of symptoms in the case of nervous diseases.

42. The composition according to p. 41, affecting any nervous disease selected from the group comprising acute ischemic stroke, brain hemorrhage, heart attack, brain, head injury, loss of nerve cells in the brain, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, a metabolic disorder of brain blood flow, impaired brain function, pain, spasm, schizophrenia, migraine, epilepsy, manic-depressive syndrome, degenerative nerve diseases, cerebral ischemia, dementia caused by AIDS, brain swelling, state of fear, diabetic neuropathy, dementia due to vascular lesions of the brain and multiple sclerosis.

43. The composition according to p. 37, which is analgetikom.

44. Connection on p. 1, its salt or hydrate to obtain a calcium antagonist, neurovisualising a calcium antagonist, ingebi the AE diseases, susceptible to inhibition of calcium channel P/Q-type and/or N-type, means of preventing neuronal cell death or protecting the nerve cells of the brain, the funds for the treatment, prevention or improvement of symptoms in the case of nervous diseases or analgetika.

45. Connection on p. 44, in which the nerve disease is any disease selected from the group comprising acute ischemic stroke, brain hemorrhage, heart attack, brain, head injury, loss of nerve cells in the brain, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, a metabolic disorder of brain blood flow, impaired brain function, pain, spasm, schizophrenia, migraine, epilepsy, manic-depressive syndrome, degenerative nerve diseases, cerebral ischemia, dementia caused by AIDS, brain swelling, state of fear, diabetic neuropathy, dementia due to vascular lesions of the brain and multiple sclerosis.

46. Method of prevention, treatment or improvement in disease susceptible to antagonism in relation to calcium, neionizirovannuu the antagonism Vya needy subject a pharmacologically effective amount of the compounds on p. 1, its salt or hydrate.

47. The way to prevent the death of nerve cells or protect nerve cells in the brain by introducing the needy to the subject a pharmacologically effective amount of the compounds on p. 1, its salt or hydrate.

48. Method of prevention, treatment or improvement in the case of nervous disorders or pain syndrome by introducing the needy to the subject a pharmacologically effective amount of the compounds on p. 1, its salt or hydrate.

49. The method according to p. 48, in which the nerve disease is any disease selected from the group comprising acute ischemic stroke, brain hemorrhage, heart attack, brain, head injury, loss of nerve cells in the brain, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, a metabolic disorder of brain blood flow, impaired brain function, pain, spasm, schizophrenia, migraine, epilepsy, manic-depressive syndrome, degenerative nerve diseases, cerebral ischemia, dementia caused by AIDS, brain swelling, state of fear, diabetic neuropathy, dementia due to vascular lesions of the brain is known from group including acute ischemic stroke, brain hemorrhage, head injury, pain, migraine, epilepsy, diabetic neuropathy and multiple sclerosis.

 

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< / BR>
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< / BR>
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