Amides of aminoalkyl-substituted azetidines, pirrolidines, piperidines and azepanes

FIELD: chemistry.

SUBSTANCE: invention refers to the new compounds of general formula (II) , whereat values R1, R2, X, R11, R12, R18, R19, m, n are displayed in claim 1 of the formula.

EFFECT: compounds display agonistic and antagonistic activity which allows to propose their usage in pharmaceutical compositions for treatment of diseases and distresses connected with histamine H3 receptor.

38 cl, 80 ex

 

The present invention relates to new Amida aminoalkylsilane of azetidinol, pyrrolidino, piperidino and Azarov, the use of these compounds as pharmaceutical compositions, to pharmaceutical compositions containing these compounds, and to a method of treatment using such compounds and compositions. Compounds of the present invention have a high and selective affinity binding to H3-receptor histamine, which indicates that the manifestation of their antagonist, inverse agonist or agonist activity toward H3-receptor histamine. Thus, the compounds according to the present invention is applicable for treating diseases and disorders associated with H3-receptor histamine.

The existence of H3-receptor histamine is known for a number of years, and the specified receptor attracted continuous interest from the point of view of development of new medicines. Recently H3-receptor histamine man was cloned. The H3-receptor histamine is a presynaptic autoreceptor located in both Central and peripheral nervous system, skin and organs, such as lung, intestine, probably, spleen and gastrointestinal tract. Recent reports suggest that H3-receptor inherent constitutive activity in vitro, in vivo (i.e. he is active in the absence of agonist). Compounds that act as inverse agonists can inhibit this activity. It was shown that the H3-receptor histamine regulates the release of histamine and other neurotransmitters, such as serotonin and acetylcholine. It should therefore be expected that the antagonist or inverse agonist H3-receptor histamine will increase the release of these neurotransmitters in the brain. In contrast, the H3 agonist-receptor histamine causes the inhibition of the biosynthesis of histamine and inhibition of release of histamine and other neurotransmitters, such as serotonin and acetylcholine. These data suggest that agonists, inverse agonists and antagonists of the H3-receptor histamine, may be important mediators of neuronal activity. Thus, the H3-receptor histamine is an important target in the development of new therapeutic methods.

Compounds similar to the compounds of the present invention, were obtained previously, and studied their biological activity, see, for example, patent application WO 00/59880, WO 00/39081. However, in these documents is not disclosed and it is not expected that these compounds may have antagonistic or agonistic activity toward H3-receptor histamine.

In several publications opisyvaet the receipt and use of agonists and antagonists of the H3-receptor histamine. Most of them are derivatives of imidazole. However, recently been described, some not containing imidazole ligands H3-receptor for histamine (see, for example, Linney et al., J. Med. Chem. 2000, 43, 2362-2370; U.S. Patent No. 6316475, patent application WO 01/66534 and WO 01/74810). However, these compounds differ structurally from the compounds of the present invention.

Because this field of technology there is interest in agonists, inverse agonists and antagonists of the H3-receptor histamine, new compounds that interact with the H3-receptor histamine, could be very useful for the art. The present invention is from this point of view, useful in the art, since it is based on the authors found a high and specific affinity for the new class of amides aminoalkylsilane of azetidinol, pyrrolidino, piperidino and asianow relative to H3-receptor histamine.

Through their interaction with H3-receptor histamine, the compounds according to the present invention is applicable in the treatment of a wide range of conditions and disorders for which it is useful interaction with H3-receptor histamine. Thus, the compounds may find application in particular in the treatment of diseases of the Central nervous system, peripheral nervous system, cardiovascular the system, pulmonary system, gastrointestinal system and the endocrine system.

In the above structural formula and forth throughout the text of this description, the following terms have the following meaning:

The term “halogen” means F, Cl, Br or I.

The term “C1-6-alkyl” in the present description denotes a saturated, branched or unbranched hydrocarbon group containing from 1 to 6 carbon atoms. Typical C1-6-alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl etc.

The term “C2-6alkenyl” in the text of the present description denotes branched or unbranched hydrocarbon group containing from 2 to 6 carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, ethynyl, 1-propenyl, 2-propenyl, Isopropenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl etc.

The term “C2-6-quinil” in the text of the present description denotes branched or unbranched hydrocarbon group containing from 2 to 6 carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-is utiny, 2-butynyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl etc.

The term “C3-6-alkylen” in the text of the present description denotes a saturated divalent, branched or unbranched hydrocarbon group containing from 3 to 6 carbon atoms. Typical C3-6-alkylene groups include, but are not limited to, 1,2-propylene, 1,3-propylene, butylene, isobutylene, pentile, hexylen etc.

The term “C3-6-albaniles” in the text of the present description denotes a divalent branched or unbranched hydrocarbon group containing from 3 to 6 carbon atoms and at least one double bond. Typical C3-6-alkenylamine groups include, but not limited to, n-propanole, butylen, penttinen, hexarelin etc.

The term “C1-6-alkoxy” in the present description refers to a radical-O-C1-6-alkyl, where the value of C1-6-alkyl stated previously. Some examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentox, isopentane, hexose, isohexane etc.

The term “C1-6-alkylthio” in this description refers to the radical-S-C1-6-alkyl, where the value of C1-6-alkyl stated previously. Some examples are methylthio, ethylthio, isopropylthio, n-propylthio, butylthio, pentylthio etc

The term “C1-6-alkylsulfonyl” in this description refers to the radical-S(=O)-C1-6-alkyl, where the value of C1-6-alkyl stated previously. Individual examples are methylsulfonyl, ethylsulfonyl, isopropylphenyl, n-propylsulfonyl, butylsulfonyl, pentasulfide etc.

The term “C1-6-alkylsulfonyl” in the text of the present description refers to a radical-S(=O)2-C1-6-alkyl, where the value of C1-6-alkyl stated previously. Some examples are methylsulphonyl, ethylsulfonyl, isopropylphenyl, n-propylsulfonyl, butylsulfonyl, intercultural etc.

The term “C1-7-alkanoyl” in this description refers to the radical-C(=O)H or-C(=O)-C1-6-alkyl, where the value of C1-6-alkyl stated previously. Some examples are formyl, acetyl, propionyl, butanoyl, pentanoyl, hexanoyl, heptanoyl etc.

The term “C1-6-allylcarbamate” in this description refers to the radical-C(=O)NH-C1-6-alkyl, where the value of C1-6-alkyl stated previously. Some examples are methylcarbamoyl, ethylcarbitol, isopropylcarbamate, n-propellerblades, butylcarbamoyl, intercalator, exaltabitur etc.

The term “CI-C1-6-allylcarbamate” in this description refers to the radical-C(=O)N(C1-6-alkyl)2where the value of C 1-6-alkyl stated previously. It should be understood that C1-6-alkyl groups may be the same or different. Some examples are dimethylcarbamoyl, methylethylketon, diethylcarbamoyl, diisopropylamino, di-n-propellerblades, dibutylbarbituric, dimetilkarbamida, digoxigenin etc.

The term “C3-8-cycloalkyl” in the text of the present description denotes a monocyclic carbocyclic group containing from 3 to 8 carbon atoms. Individual examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc.

The term “C5-8-cycloalkenyl” in the text of the present description denotes a monocyclic carbocyclic, non-aromatic group containing from 5 to 8 carbon atoms and at least one double bond. Some examples are cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctyl etc.

The term “C3-8-cycloalkenyl” in this description refers to the radical-C(=O)-C3-8-cycloalkyl, where the value of C3-8-cycloalkyl stated previously. Individual examples are cyclopropanol, cyclobutanol, Cyclopentanol, cyclohexanol, cycloheptanol, cyclooctanol etc.

The term “C3-8-cycloalkylcarbonyl” in this description refers to the radical-C(=O)NH-C3-8-cycloalkyl, DG is the value of C 3-8-cycloalkyl stated previously. Some examples are cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexylcarbonyl, cyclohexylcarbonyl, cyclooctylamino etc.

The term “C3-8-cycloalkylcarbonyl” in this description refers to the radical-C(=O)-O-C3-8-cycloalkyl, where the value of C3-8-cycloalkyl stated previously. Individual examples are cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexyloxycarbonyl, cyclohexyloxycarbonyl, cyclooctylmethyl etc.

The term “aryl” in the present description includes carbocyclic aromatic ring system such as phenyl, biphenylyl, naphthyl, anthracene, phenanthrene, fluorene, indenyl, pentalene, azulene etc. Aryl also includes partially hydrogenated derivatives of the above carbocyclic systems. Not limiting the present invention, examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphtho etc.

The term “aryloxy” in this description refers to the radical-O-aryl, where aryl stated previously. Not limiting the present invention examples are phenoxy, naphthoxy, anthranilate, phenanthridinone, fluorenone, inderalici etc.

T is pmin “aroyl” in this description refers to the radical-C(=O)-aryl, where is aryl stated previously. Not limiting the present invention examples are benzoyl, Naftoli, intracerebral, phenanthrenequinones, fluorenylmethyl, interkabel etc.

The term “aristeo” in this description refers to the radical-S-aryl, where aryl stated previously. Not limiting the present invention examples are phenylthio, naphthylthio, intracavity, financemalta, fluorination, indenity etc.

The term “arylsulfonyl” in this description refers to the radical-S(=O)-aryl, where aryl stated previously. Not limiting the present invention examples are phenylsulfinyl, naphthylmethyl, anthracenesulfonic, phenanthrolines, fluorenylmethyl, intersurgical etc.

The term “arylsulfonyl” in this description refers to the radical-S(=O)2-aryl, where aryl stated previously. Not limiting the present invention examples are phenylsulfonyl, naphthylmethyl, anthracenesulfonic, phenanthridinone, fluorenylmethyl, intersoliton etc.

The term “heteroaryl” in the text of the present description denotes a heterocyclic aromatic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulphur, such as furyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazole, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazolyl, indolyl, isoindolyl, benzofuran, benzothiazyl, indazoles, benzimidazoles, benzothiazoles, benzothiazolyl, benzoxazolyl, benzisoxazole, purinol, hintline, hemolysins, chinoline, ethenolysis, honokalani, naphthyridine, pteridine, carbazole, azepine, diazepine, acridine etc. Heteroaryl also includes partially hydrogenated derivatives of the above heterocyclic systems. Not limiting the present invention, examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolyl, pyrazolyl, indanyl, indolinyl, oxazolidinyl, oxazolyl, oxazepines etc.

The term “heteroaryl” in this description refers to the radical-C(=O)-heteroaryl, where the value of heteroaryl stated previously.

The term “heteroaromatic” in this description refers to the radical-O-heteroaryl, where the value of heteroaryl stated previously.

Some of the above terms can occur in structural formulas over h is m once and in this case, each term shall be defined independently of the other.

The term “optionally substituted” in this description means that the appropriate groups are either unsubstituted or may contain one or more of these substituents. In the case where the groups contain more than one Deputy, such substituents may be the same or different from each other.

The term “treatment” in this description means care and patient care with the purpose of combating a disease, disorder or condition. This term also includes the suspension of the disease, disorder or condition, alleviating or relieving symptoms or complications and/or treatment to eliminate the disease, disorder or condition. The patient whose treatment is carried out, is mostly a mammal, in particular people.

The present invention relates to a compound of General formula (I):

where

m denotes 1, 2 or 3,

n denotes 1, 2 or 3,

R1and R2independently represent

hydrogen

With1-6-alkyl, C2-6alkenyl or2-6-quinil, which optionally may be substituted by one or more substituents selected from C3-8-cycloalkyl,5-8-cycloalkenyl, ha is Ohana and hydroxyl, or

With3-8-cycloalkyl or5-8-cycloalkenyl, which optionally may be substituted by one or more substituents selected from halogen, hydroxyl, C1-6-alkyl, C2-6-alkenyl and C2-6-quinil,

or R1and R2together form3-6-Allenby bridge or3-6-alkenylamine bridge, which may be optionally substituted by one or more substituents selected from halogen and hydroxyl,

R11and R12independently represent

hydrogen

With1-6-alkyl, which optionally may be substituted by one or more substituents selected from C3-8-cycloalkyl,5-8-cycloalkenyl, halogen and hydroxyl, or

With3-8-cycloalkyl or5-8-cycloalkenyl, which optionally may be substituted by one or more substituents selected from halogen and hydroxyl,

X denotes

R3, R4, R5, R6, R7, R8, R9and R10independently represent

is hydrogen, halogen, cyano, -NR15R16, hydroxyl, carbarnoyl, -CF3, -OCF3carboxyl, amidinopropane, guanidinium or nitrogroup, or

- C1-6-alkoxy, C1-6-alkyl, C1-7-alkanoyl,1-6-allylcarbamate, di-C1-6-alquiler email, With1-6-allyloxycarbonyl,1-6-alkylthio,1-6-alkylsulfonyl,1-6-alkylsulfonyl, aryl, aroyl, aryloxy, aryloxyalkyl, aaltio, arylsulfonyl or arylsulfonyl, which optionally may be substituted by one or more substituents selected from halogen, hydroxyl, ceanography and-NR15R16,

R15and R16independently represent

hydrogen or carbarnoyl,

With1-6-alkyl, which optionally may be substituted by one or more substituents selected from C3-8-cycloalkyl,

With5-8-cycloalkenyl, halogen, hydroxyl, ceanography and amino or

With3-8-cycloalkyl,5-8-cycloalkenyl,1-6-allylcarbamate,

di-C1-6-allylcarbamate or1-6-allyloxycarbonyl, which optionally may be substituted by one or more substituents selected from halogen, hydroxyl, ceanography, amino, C1-6-alkyl, C2-6-alkenyl or2-6-quinil,

or R15and R16together form3-6-Allenby bridge or

With3-6-alkenylamine bridge, which may be optionally substituted by one or more substituents selected from halogen and hydroxyl,

or two or more of R3and R4, R4and R5, R5and R6, R6R 7, R7and R8, R8and R9, R9and R6, R8and R10together form a bridge selected from-co2O-, -och2CH2O-, -och2CH2CH2O - and3-5-alkylene,

or R11and R3, R11and R7or R11and R10together form a bridge selected from-O-, -S-, -CH2-, -C(=O)-, -CH(OH)-, -NR13-, -OCH2- and-CH2Oh,

R13means

hydrogen

With1-6-alkyl, which optionally may be substituted by one or more substituents selected from C3-8-cycloalkyl,

With5-8-cycloalkenyl, halogen, hydroxyl, ceanography and amino groups,

With3-8-cycloalkyl or5-8-cycloalkenyl, which optionally may be substituted by one or more substituents selected from halogen, hydroxyl, ceanography, amino group,

With1-6-alkyl, C2-6-alkenyl and C2-6-quinil,

-Y - represents-CH2-, -C(=O)-, -NR14-, -O-, -S-, -CH2O-, -OCH2- or-CH(OH)-,

R14means

hydrogen

With1-6-alkyl, which optionally may be substituted by one or more substituents selected from C3-8-cycloalkyl,

With5-8-cycloalkenyl, halogen, hydroxyl of ceanography and amino groups,

With3-8-cycloalkyl or5-8-cycloalkenyl that neo is Astelin may be substituted by one or more substituents, selected from halogen, hydroxyl, ceanography and amino groups,

R17denotes hydrogen, C1-6-alkyl, C2-6alkenyl or2-6-quinil,

R18and R19independently represent hydrogen, halogen, hydroxyl, amino, C1-6-alkyl, C2-6alkenyl or2-6-quinil,

as well as any of its diastereoisomer or enantiomer or tautomeric form, including mixtures thereof, or its pharmaceutically acceptable salt.

In one of the embodiments of the present invention R17, R18and R19all represent hydrogen.

In another embodiment, the present invention m is 1.

In yet another embodiment, the present invention n is 1.

Finally, in yet another embodiment, the present invention R1and R2together form a C3-6-Allenby bridge, which optionally may be substituted by one or more substituents selected from halogen or hydroxyl.

In another embodiment, the present invention R1and R2together form a C4-Allenby bridge, which optionally may be substituted by one or more substituents selected from halogen or hydroxyl.

In another embodiment, the present invention R1and R2together about what will formed C 4-alkilinity the bridge.

In yet another embodiment, the present invention R11denotes hydrogen.

In yet another embodiment, the present invention R12denotes hydrogen.

In another embodiment, the present invention X represents

where the values of R3, R4, R5, R6and R7stated previously for formula (I).

In one of the embodiments of the present invention R3, R4, R5, R6and R7independently selected from hydrogen, halogen, -CF3and C1-6-alkoxy.

In another embodiment of the present invention, four of the substituents R3, R4, R5, R6and R7denote hydrogen, and the remaining Deputy chosen from halogen, -CF3and C1-6-alkoxy.

It should be understood that when n is 2 or 3, the groups R19may be the same or different.

As another aspect of the present invention provides compounds of General formula (II):

where

m denotes 1, 2 or 3,

n denotes 1, 2 or 3,

R1and R2independently represent

hydrogen

With1-6-alkyl, C2-6alkenyl or2-6-quinil, which optionally may be substituted by one or more replacement is a Fort worth, selected from C3-8-cycloalkyl,5-8-cycloalkenyl, halogen and hydroxyl, or

With3-8-cycloalkyl or5-8-cycloalkenyl, which optionally may be substituted by one or more substituents selected from halogen, hydroxyl, C1-6-alkyl, C2-6-alkenyl and C2-6-quinil,

or R1and R2together form3-6-Allenby bridge or3-6-alkenylamine bridge, which may be optionally substituted by one or more substituents selected from halogen and hydroxyl,

R11and R12independently represent

hydrogen

With1-6-alkyl, which optionally may be substituted by one or more substituents selected from C3-8-cycloalkyl,

With5-8-cycloalkenyl, halogen and hydroxyl, or

With3-8-cycloalkyl or5-8-cycloalkenyl, which optionally may be substituted by one or more substituents selected from halogen and hydroxyl,

X denotes

R3, R4, R5, R6, R7, R8, R9and R10independently represent

is hydrogen, halogen, cyano, -NR15R16, hydroxyl, carbarnoyl, -CF3, -OCF3carboxyl, amidinopropane, guanidinium or nitrogroup, or

- C1-6-ALCO is si, With1-6-alkyl, C1-7-alkanoyl,1-6-allylcarbamate, di-C1-6-allylcarbamate,1-6-allyloxycarbonyl,3-8-cycloalkyl,3-8-cycloalkenyl,3-8-cycloalkylcarbonyl,3-8-cycloalkylcarbonyl,1-6-alkylthio,1-6-alkylsulfonyl,1-6-alkylsulfonyl, C1-6-alkylsulfonyl, aryl, aroyl, aryloxy, aryloxyalkyl, aaltio, arylsulfonyl, arylsulfonyl, heteroaryl, heteroaryl or heteroaromatic, which may not necessarily be substituted by one or more substituents selected from halogen, hydroxyl, ceanography and-NR15R16,

R15and R16independently represent

hydrogen or carbarnoyl,

With1-6-alkyl, which optionally may be substituted by one or more substituents selected from C3-8-cycloalkyl,

With5-8-cycloalkenyl, halogen, hydroxyl, ceanography and amino groups, or

With3-8-cycloalkyl,5-8-cycloalkenyl,1-6-allylcarbamate,

di-C1-6-allylcarbamate or1-6-allyloxycarbonyl, which optionally may be substituted by one or more substituents selected from halogen, hydroxyl, ceanography, amino, C1-6-alkyl, C2-6-alkenyl or2-6-quinil,

or R15and R16together form3-6 -Allenby bridge or

With3-6-alkenylamine bridge, which may be optionally substituted by one or more substituents selected from halogen and hydroxyl,

or two or more of R3and R4, R4and R5, R5and R6, R6and R7, R7and R8, R8and R9, R9and R6, R8and R10together form a bridge selected from-co2O-, -och2CH2O-, -och2CH2CH2O - and3-5-alkylene,

or R11and R3, R11and R7or R11and R10together form a bridge selected from-O-, -S-, -CH2-, -C(=O)-, -CH(OH)-, -NR13-, -OCH2- and-CH2Oh,

R13means

hydrogen

With1-6-alkyl, which optionally may be substituted by one or more substituents selected from C3-8-cycloalkyl,

With5-8-cycloalkenyl, halogen, hydroxyl, ceanography and amino groups,

With3-8-cycloalkyl or5-8-cycloalkenyl, which optionally may be substituted by one or more substituents selected from halogen, hydroxyl, ceanography, amino group,

With1-6-alkyl, C2-6-alkenyl and C2-6-quinil,

-Y - represents-CH2-, -C(=O)-, -NR14-, -O-, -S-, -CH2O-, -OCH2- or-CH(OH)-,

R14means

hydrogen

1-6-alkyl, which optionally may be substituted by one or more substituents selected from C3-8-cycloalkyl,

With5-8-cycloalkenyl, halogen, hydroxyl, ceanography and amino groups,

With3-8-cycloalkyl or5-8-cycloalkenyl, which optionally may be substituted by one or more substituents selected from halogen, hydroxyl, ceanography and amino groups,

R17denotes hydrogen, C1-6-alkyl, C2-6alkenyl or2-6-quinil,

R18and R19independently represent hydrogen, halogen, hydroxyl, amino, C1-6-alkyl, C2-6alkenyl or2-6-quinil,

and any diastereoisomer or enantiomer, or any tautomeric form, including mixtures thereof, or their pharmaceutically acceptable salt.

In one of the embodiments of the present invention R1means

hydrogen

With1-6-alkyl, optionally substituted by one or more substituents selected from C3-8-cycloalkyl,5-8-cycloalkenyl, halogen or hydroxyl, or

R1and R2together form a C3-6-Allenby bridge or C3-6-alkenylamine bridge, which optionally may be substituted by one or more substituents selected from halogen and hydroxyl.

In another embodiment, implementation is tvline of the present invention R 1means

With1-6-alkyl or

R1and R2together form a C3-6-Allenby bridge or C3-6-alkenylamine bridge, which optionally may be substituted by one or more substituents selected from halogen and hydroxyl.

In another embodiment, the present invention R1means

With1-8-alkyl or

R1and R2together form a C3-6-Allenby bridge, which optionally may be substituted by one or more substituents selected from halogen and hydroxyl.

In another embodiment, the present invention R1means

With1-8-alkyl or

R1and R2together form a C4-5-Allenby bridge, which optionally may be substituted by one or more substituents selected from halogen and hydroxyl.

In another embodiment, the present invention R1means

With1-6-alkyl or

R1and R2together form a C4-5-alkilinity the bridge.

In another embodiment, the present invention R1and R2together form a C4-5-alkilinity the bridge.

In another embodiment, the present invention R1and R2together form a C4-alkilinity the bridge.

In another embodiment, the implementation of the ia of the present invention R 1and R2together form a C5-alkilinity the bridge.

In another embodiment, the present invention m is 1.

In another embodiment, the present invention n is 1 or 2.

In yet another embodiment, the present invention n is 1.

In another embodiment, the present invention X represents

where the values of R3, R4, R5, R6and R7stated previously for formula (I).

In another embodiment, the present invention-Y - represents-O - or-S-.

In yet another embodiment, the present invention-Y - represents-O-.

In another embodiment, the present invention X represents

where the values of R3, R4, R5, R6and R7stated previously for formula (I).

In another embodiment, the present invention R3, R4, R5, R6and R7independently selected from

is hydrogen, halogen, ceanography, -NR15R16, -CF3, -OCF3or nitro, where the values of R15and R16indicated for formula (I),

- C1-6-alkoxy, C3-8-cycloalkylcarbonyl, aryl, heteroaryl,3-8-cycloalkenyl,1-6-alkylsulfonyl or C1-6-alkylsulfonyl-O-, which optionally can is to be substituted by one or more halogen atoms,

or R4and R5together form a bridge-och2Oh,

or R11and R3together form a bridge selected from-O - or

S.

In another embodiment, the present invention R3, R4, R5, R6and R7independently selected from

is hydrogen, halogen, ceanography, -CF3or-OCF3,

- C1-6-alkoxy, 1,2,4-triazolyl, cyclopropanol or1-6-alkylsulfonyl-O-, which may be optionally substituted by one or more halogen atoms,

or R4and R5together form a bridge-och2Oh,

or R11and R3together form a bridge selected from-O - or

S.

In another embodiment, the present invention R3, R4, R5, R6and R7independently selected from

is hydrogen, halogen, ceanography, -CF3or-OCF3,

- -O-CH3, 1,2,4-triazolyl, -O-CH2CH3or CH3-sulfonyl, which may be optionally substituted by one or more halogen atoms,

or R11and R3together form a bridge selected from-O - or

S.

In another embodiment, the present invention R3, R4, R5, R6and R7independently selected from

is hydrogen, halogen, ceanography, -CF3or-OCF3,

- -O-CH3, -O-C is 2CH3or CH3-sulfonyl-O-, or

CF3-sulfonyl-O-,

or R11and R3together form a bridge selected from-O - or

S.

In another embodiment, the present invention R11denotes hydrogen.

In another embodiment, the present invention R12denotes hydrogen or C1-6-alkyl.

In another embodiment, the present invention R12denotes hydrogen or methyl.

In another embodiment, the present invention R15denotes hydrogen.

In another embodiment, the present invention R16denotes hydrogen.

In another embodiment, the present invention all R17, R18and R19denote hydrogen.

Compounds of the present invention can be chiral, and it is assumed that any enantiomers, such as separated, pure or partially pure enantiomers or racemic mixtures are included in the scope of claims of the present invention.

Moreover, if the molecule has a double bond, or fully or partially saturated cyclic system, or more than one center of asymmetry, or connection, rotation around which the molecule is limited, can be obtained diastereomers. It is assumed that any diastereomers, such as by the, pure or partially pure diastereomers or mixtures thereof, are included in the scope of claims of the present invention.

Further, some of the compounds of the present invention may exist in different tautomeric forms, and it is assumed that any tautomeric forms of the compounds are able to form, included in the scope of claims of the present invention.

The present invention also includes pharmaceutically acceptable salts of the compounds of the present invention. Such salts include pharmaceutically acceptable acid additive salts, pharmaceutically acceptable metal salts, ammonium or salt of alkylamine. Acid additive salts include salts of inorganic acids, and organic acid salts. Some examples of suitable inorganic acids include hydrochloric, Hydrobromic, idiscovered, phosphoric, sulphuric, nitric acid, etc. some examples of suitable organic acids include formic, acetic, trichloroacetic, triperoxonane, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, almond, oxalic acid, picric acid, pyruvic acid, salicylic, succinic, methansulfonate, econsultancy, tartaric, ascorbic, pambou, biotranslation, etanislao, gluconic, citric the new, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic acid, benzosulfimide, p-toluensulfonate etc. are Other examples of pharmaceutically acceptable inorganic or organic acid additive salts include the pharmaceutically acceptable salts listed in the publication J. Pharm. Sci. 1977, 66, 2, which is reproduced here for reference. Examples of salts with metals include salts of lithium, sodium, potassium, magnesium, etc. are Examples of ammonium and alkylammonium salts include ammonium salts, methylamine, dimethylamine, trimethylammonium, ethylamine, hydroxyethylamine, diethylamine, butylamine, Tetramethylammonium etc.

As the pharmaceutically acceptable acid additive salts in the present invention also includes hydrates, which can form compounds of the present invention.

Acid additive salts can be obtained as the products directly in the synthesis of compounds. Alternatively, the free base can be dissolved in a suitable solvent containing the appropriate acid and salt to allocate by evaporation of the solvent or by using another method of separation of salt and solvent.

Of the compounds of the present invention can form a solvate with standard low the molecular solvents, using methods well-known to specialists in this field of technology. Such a solvate is also included in the scope of claims of the present invention.

The invention also encompasses prodrugs of the compounds of the present invention, which after administration to the patient, before becoming active pharmacological substances undergo chemical transformation in the metabolic processes. In General, such prodrugs are functional derivatives of the compounds of the present invention, which are easily converted in vivo into the required compound of formula (I). Conventional procedures for the selection and obtaining of suitable prodrug derivatives are, for example, in “Design of Prodrugs”, ed. H.Bundgaard, Elsevier, 1985. The invention also encompasses active metabolites of compounds of the present invention.

Compounds of the present invention interact with the H3-receptor histamine and therefore applicable for the treatment of a wide range of conditions and disorders for which beneficial effects have interaction with H3-receptor histamine.

Thus, another aspect of the present invention relates to compounds of General formula (I), as well as any of its diastereoisomer or enantiomer or tautomeric forms, including mixtures thereof, or its pharmaceutically acceptable salt for IP is of use as pharmaceutical compositions.

The present invention also relates to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) or any of its diastereoisomer or enantiomer or tautomeric form, including mixtures thereof, or its pharmaceutically acceptable salt together with one or more pharmaceutically acceptable carriers or excipients.

Further, the present invention also relates to the use of compounds of General formula (I), as well as any of its diastereoisomer or enantiomer or tautomeric forms, including mixtures thereof, or its pharmaceutically acceptable salt to obtain a pharmaceutical composition for the treatment of disorders and diseases that are associated with H3-receptor histamine.

Another aspect of the present invention relates to a method of treating diseases and disorders associated with H3-receptor histamine, thus this method is to assign requiring treatment to a subject an effective amount of the compounds of formula (I) or any of its diastereoisomer or enantiomer or tautomeric forms, including mixtures thereof, or its pharmaceutically acceptable salt, or containing pharmaceutical compositions.

One aspect of the present invention relates to compounds that possess antagonistic activity or inverse agonist eskay activity toward H3-receptor histamine and which for this reason can be used to treat a wide range of conditions and disorders which is beneficial blockade H3-receptor histamine.

Another aspect of the present invention relates to compounds that possess agonistic activity toward H3-receptor histamine and which for this reason can be used to treat a wide range of conditions and disorders for which is beneficial activation of H3-receptor histamine.

In a preferred embodiment of the invention the compounds of the present invention is used with the purpose of obtaining a pharmaceutical composition for weight reduction.

In a preferred embodiment of the invention the compounds of the present invention is used with the purpose of obtaining a pharmaceutical composition for the treatment of overweight or obesity.

In another preferred variant of the invention, the compounds of the present invention is used with the purpose of obtaining a pharmaceutical composition for suppressing appetite or to cause a feeling of fullness.

In another preferred variant of the invention, the compounds of the present invention is used with the purpose of obtaining a pharmaceutical composition for prevention and/or treatment of disorders and diseases related to overweight or obesity such as atherosclerosis, hypertension, weakened the military glucose tolerance, diabetes, especially type 2 diabetes (insulin-independent diabetes), dyslipidemia, coronary heart disease, gallbladder disease, osteoarthritis and various types of cancer such as cancer of the uterus, breast, prostate and colon.

In another preferred variant of the invention, the compounds of the present invention is used with the purpose of obtaining a pharmaceutical composition for prevention and/or treatment of eating disorders such as bulimia syndrome and binge eating.

In another preferred variant of the invention, the compounds of the present invention is used with the purpose of obtaining a pharmaceutical composition for the treatment of weakened glucose tolerance.

In another preferred variant of the invention, the compounds of the present invention is used with the purpose of obtaining a pharmaceutical composition for the treatment of type 2 diabetes. Such treatment includes, among other treatment in order to delay or prevent the progression weakened glucose tolerance to type 2 diabetes, as well as to delay or prevent the progression of non-insulin dependent type 2 diabetes to insulin-dependent type 2 diabetes.

Compounds of the present invention can also be used for treatment of respiratory diseases, such as asthma, as anti-diarrhea and to modulate the secretion of gastric acid.

Further, the compounds of the present invention can also be used for treatment of diseases associated with the regulation of sleep and wakefulness, and for the treatment of narcolepsy and disorders related to syndrome of impaired attention.

Moreover, the compounds of the present invention can be used as Central nervous system stimulants or sedatives.

Compounds of the present invention can also be applied in the treatment of conditions associated with epilepsy. Further, the compounds of the present invention can be used in the treatment of motion sickness and vertigo. Moreover, they can be used as regulators of the hypothalamic-hypofyse secretion, antidepressants, modulators of cerebral circulation and in the treatment of mucous colitis.

Further, the compounds of the present invention can be used in the treatment of dementia and Alzheimer's disease.

Compounds of the present invention can be used in the treatment of allergic rhinitis, ulcers or anorexia.

Compounds of the present invention can also be applied in the treatment of migraine, see McLeod et al., The Journal of Pharmacology and Experimental Therapeutics287(1998), 43-50 in the treatment of myocardial infarction, see Mackins et al., Expert Opinion on Investiational Drugs 9(2000), 2537-2542.

In accordance with another aspect of the present invention the treatment of the patient with the use of the compounds of the present invention combine with diet and/or physical stress.

In accordance with another aspect of the invention the compounds of the present invention is administered in combination with one or more additional active substances in any suitable ratios. These additional active agents may be selected from anti-obesity, anti-diabetic funds antidyslipidemic agents, antihypertensive agents, agents for the treatment of complications caused by or associated with diabetes and agents for the treatment of complications or diseases caused by or associated with obesity.

Thus, in accordance with another aspect of the present invention compounds of the present invention is administered in combination with one or more anti-obesity or through regulation of appetite.

These agents can be selected from the group including CART (transcript, adjustable amphetamine and cocaine) agonists, NPY (neuropeptide Y) antagonists, MS (melanocortin 4) agonists, MSH (melanocortin 3) agonists, antagonists orexin, TNF (tumor necrosis factor) agonists, CRF (a factor that stimulates corticotropin) agonists, CRF BP (protein is Azania factor, stimulates corticotropin) antagonists, agonists of urocortin, β3 adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH (melanocyte-stimulating hormone) agonists, sit (hormone concentrating melanocytes) antagonists, CCK (cholecystokinin) agonists, serotonin reuptake inhibitors SSRIs, such as fluoxetine, seroxat or citalopram, serotonin reuptake inhibitors of serotonin and norepinephrine, mixed serotonin and noradrenergic compounds, NT (serotonin) agonists, agonists of bombezin antagonists Galanina; growth hormones, factors growth, such as prolactin or the placenta lactogenic, connection, releasing growth hormone, TRH (the hormone that stimulates tireotropina) agonists, UCP 2 or 3 (uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists (parlodel, depressin), inhibitors of lipase/amylase, PPAR (receptor activated peroxisomal proliferation) modulators, RXR (receptor retinoid X) modulators, TR β agonists, AGRP (protein-related gene agouti) inhibitors, opioid antagonists (such as naltrexone), the basis-4, GLP 1 and neurotrophic factor ciliary.

In one preferred implementation method of the present invention remedy against obesity is leptin.

In another preferred implementation method of the present invention means the om against obesity is dexamfetamine or amphetamine.

In another preferred implementation method of the present invention remedy against obesity is fenfluramine or dexfenfluramin.

In yet another preferred implementation method of the present invention remedy against obesity is sibutramine.

In the following preferred method of implementation of the present invention remedy against obesity is orlistat.

In yet another preferred implementation method of the present invention remedy against obesity is mazindol or phentermine.

In another preferred implementation method of the present invention remedy against obesity is phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate, or ecopipam.

In accordance with another aspect of the present invention compounds of the present invention are introduced in combination with one or more antidiabetic agents.

Appropriate antidiabetic agents include insulin, analogs and derivatives of insulin, such as described in EP 0792290 (Novo Nordisk A/S), in particular the human insulin NB29the deletion of des (B30), EP 0214826 and EP 0705275 (Novo Nordisk A/S), in particular the human insulin AspB28in U.S. Patent No. 5504188 (Eli Lilly), in particular the human insulin LysB28ProB29in EP 0368187 (Aventis), including Lantus®, which are all VK is uceni in the present description is for reference, derivatives of GLP-1, such as described in WO 98/08871 (Novo Nordisk A/S), which are included in the present description is for reference, as well as orally active hypoglycemic agents.

Orally active hypoglycemic agents preferably include imidazolines, sulfonylureas, biguanides, meglitinide, oxadiazolidine preparations, thiazolidinediones, insulin sensitizers, inhibitors of α-glucosidase, agents acting on the ATP-dependent potassium channel of the β-cells, in particular substances that open potassium channels, such as described in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S), which are included in the present description is for reference, or mitiglinide, or blockers of potassium channels, such as BTS-67582, nateglinide, glucagon antagonists, such as described in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), included in the present description is for reference, GLP-1 agonists, such as described in WO 00/42026 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), included in the present description is for reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors, PTPase (protein tyrosine phosphatase) inhibitors, inhibitors of liver enzymes involved in stimulating gluconeogenesis and/or glycogenolysis, modulators of glucose uptake, GSK-3 (glycogen-synthase-kinase-3) inhibitors, compounds modifying the lipid metabolism such as antilipidemic agents, compounds panyhose the digestion, PPAR (receptor activated peroxisomal proliferation) and RXR (receptor retinoid X) agonists such as ALRT-268, LG-1268 or LG-1069.

In one of the methods of the invention, the compounds of the present invention are introduced in combination with insulin or an analogue or derivative of insulin, such as human insulin NB29the deletion of des (B30)human insulin AspB28the human insulin LysB28ProB29, Lantus®, or a combination preparation containing one or more of these compounds.

In another way of carrying out the invention the compounds of the present invention are introduced in combination with sulfonylurea, particularly tolbutamide, chlorpropamide, tolazamide, glibenclamide, glipizide, glimepiride, glicazide or gliburid.

In another way of carrying out the invention the compounds of the present invention are introduced in combination with biguanides, in particular Metformin.

In another way of carrying out the invention the compounds of the present invention are introduced in combination with meglitinides, in particular repaglinida or nateglinide.

Finally, in another way of carrying out the invention the compounds of the present invention are introduced in combination with thiazolidinediones the insulin sensitizer, in particular troglitazone, ciglitazone, pioglita the one, rosiglitazone, eaglecasino, darglitazone, englitazone, CS-011/CI-1037 or T 174 or the compounds described in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation), which is incorporated into this description by reference.

In another way of carrying out the invention the compounds of the present invention can be administered in combination with an insulin sensitizer, in particular, such as GI 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds described in WO 99/19313, WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193 (Dr. Reddy's Research Foundation) and WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196, WO 00/63209, WO 00/63190 and WO 00/63189 (Novo Nordisk A/S), which is incorporated into this description by reference.

In another way of carrying out the invention the compounds of the present invention can be administered in combination with inhibitors of α-glucosidase, in particular with voglibose, emiglitate, miglitol or acarbose.

In another method of carrying out the invention the compounds of the present invention can be administered in combination with an agent acting on the ATP-dependent potassium channel of the β-cells, in particular with tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or Repaglinide.

In another way of carrying out the invention the compounds of the present invention can be administered in combination with nateglinide./p>

Finally, in another way of carrying out the invention the compounds of the present invention can be administered in combination with antilipidemic agent, in particular with cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.

In accordance with another aspect of the invention the compounds of the present invention are introduced in combination with one or more of the above compounds, in particular with Metformin and a sulfonylurea, such as gliburid; with some sulfonylurea and acarbose; nateglinide and Metformin; acarbose and Metformin; a sulfonylurea, Metformin and troglitazone; insulin and a sulfonylurea; insulin and metforminum; insulin, Metformin and a sulfonylurea; insulin and troglitazone; insulin and lovastatin, etc.

Further, the compounds of the present invention can be administered in combination with one or more antihypertensive agents. Examples of antihypertensive drugs are β-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors, such as benazepril, captopril, enalapril, fosinopril, lisinopril, ginepri and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and α-blockers such as doxazosin, Oedipal, prazosin and terazosin. Further references can be found in Remington: The Science and Practice of Pharmacy, 19thEdition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

It should be understood that the scope of the claims of the present invention includes any suitable combination of the compounds of the present invention with diet and/or exercise or with one or more of the above-mentioned compounds and optionally with one or more other active ingredients.

The pharmaceutical composition

Compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in the form of both single and multiple doses. The pharmaceutical compositions of the present invention can be formulated together with pharmaceutically acceptable carriers or diluents, as well as any other known AIDS and fillers in accordance with known methods, such as contained in document Remington: The Science and Practice of Pharmacy, 19thEdition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. The pharmaceutical compositions may be specially prepared for the introduction of l is the favorite color in a suitable manner, such as oral, rectal, intranasal, intra-lungs, local (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal), while the oral route is preferred. It should be understood that the preferred path will depend on the General condition and age of the subject, the treatment is carried out, the type of condition and treatment is carried out, and the selected active ingredient.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, coated tablets, pills, pellets, powders and granules. If you want, they can have a coating, such as intersolubility shell, or they may be prepared in such a way as to provide controlled release of active ingredients, such as delayed or prolonged release of the active ingredients, in accordance with methods well known in this technical field.

Liquid forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injection solutions, dispersions, suspensions or EMU is sii, as well as sterile powders which before use restore in suitable for injection, sterile solutions or suspensions. Formulations for injection in the form of depot also included in the scope of claims of the present invention.

Other suitable forms for administration include suppositories, sprays, ointments, creams, gels, formulations for inhalation, patches on the skin, implants, etc.

Typical oral dosages are in the range of from about 0.001 to about 100 mg/kg of body weight per day, preferably from about 0.01 to about 50 mg/kg of body weight per day and more preferably from about 0.05 to about 10 mg/kg of body weight per day administered as a single dose or as multiple doses, such as from 1 to 3 doses per day. The exact dosage will depend on the frequency and mode of appointment, gender, age, weight and General condition of the subject, the treatment is carried out, the type and severity of the condition, the treatment is carried out, any concomitant diseases whose treatment is conducted, and other factors evident to experts in the field of technology.

The compositions are conveniently prepared in the form of a unit dosage forms, using methods well-known to specialists in this field of technology. Typical unit dosage form for oral administration one or more of the LCO times a day, for example, from 1 to 3 times a day, can contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferably from about 0.5 mg to about 200 mg For parenteral administration, such as intravenous, intrathecal, intramuscular and similar introduction, the typical dose is about half the dose used for oral administration. Compounds of the present invention in General used in the form of free substance or in the form of its pharmaceutically acceptable salts. An example is an acid additive salt of the compound, which has the form of a free base. If the compound of formula (I) contains a free base such salts get in the usual way by treatment of a solution or suspension of the free base of formula (I) chemical equivalent of a pharmaceutically acceptable acids, for example inorganic and organic acids. Some examples listed previously. Physiologically acceptable salts of the compounds with a hydroxyl group include the anion of the compounds in combination with a suitable cation such as sodium ion or ammonium.

For parenteral administration can be used solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous solution of propylene glycol or to NewTom or peanut butter. Such solutions, if necessary, should be buffered, and the liquid diluent first make isotonic by adding a sufficient amount of salt or glucose. Aqueous solutions are most suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. Apply a sterile aqueous medium can be easily obtained using standard methods known to experts in this field of technology.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, white clay, sucrose, cyclodextrin, talc, gelatin, agar, pectin, gum, magnesium stearate, stearic acid or lower alkalemia cellulose ethers. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, amines, fatty acids, polyoxyethylene or water. Similarly, the carrier or diluent may include any well-known from the field of engineering material, capable of slow release of the active substances, such as glycerol monostearate or distearate glycerin, alone or in mixture with wax. The pharmaceutical compositions obtained by the incorporation of the new compounds of the formula (I) and pharmaceutically acceptable carriers then bestrode injected in the form of various dosage forms, which are appropriate for the indicated route of administration. The compositions are conveniently prepared in the form of a unit dosage forms, using methods well known in pharmacy.

The compositions of the present invention suitable for oral administration may be in the form of discrete units such as capsules or tablets each containing a predetermined amount of the active ingredient and may include a suitable filler. These compounds may be in the form of a powder or granules; as solution or suspension in aqueous or non-aqueous liquid, or as an emulsion oil in water or water in oil.

If for oral administration use solid media, the drug can be tabletsarava, placed in a hard gelatin capsule in powder form or granules or in the form of tablets or cakes. The amount of solid carrier may vary, but typically ranges from about 25 mg to about 1, If used carrier liquid, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile water for injection such as aqueous or non-aqueous liquid suspension or solution.

A typical tablet, which you can obtain by conventional tabletting methods may include:

Cores is:
The active compound (as free compound or its salts)5.0 mg
Lactose (European pharmacy)and 67.8 mg
Microcrystalline cellulose (Avicel)of 31.4 mg
Amberlite® IRP88*1.0 mg
Magnesium stearate (European pharmacy)in sufficient quantity
Shell:
The hypromelloseapproximately 9 mg
Mywacett 9-40 T**approximately 0.9 mg

* Potassium salt of polacrilin NF, baking powder for tablets (Rohm and Haas).

** The acylated monoglyceride used as plasticizer in the manufacture of coatings for tablets.

If necessary, the pharmaceutical composition of the present invention may contain the compound of formula (I) in combination with other pharmacologically active substances, such as the ones listed above.

EXAMPLES

The NMR spectra are taken spectrometers (Bruker working with what astotal 300 MHz and 400 MHz. HPLC-mass spectrometry was carried out on the appliance company Perkin Elmer (API 100).

HPLC (method A)

Analysis using reverse phase were performed using a UV detector at a wavelength of 214 and 254 nm column TR 4.6 mm x 150 mm C-18 silica gel, which was suirable with a flow rate of 1 ml/min at a temperature of 42°C. the Column was called composition containing 5% acetonitrile, 85% water and 10% with a 0.5%aqueous solution triperoxonane acid in water, and suirable for 15 min in a linear gradient from 5% acetonitrile, 85% water and 10% with a 0.5%aqueous solution triperoxonane acid to 90% acetonitrile and 10% of a 0.5%aqueous solution triperoxonane acid.

HPLC (method C)

Analysis using reverse phase were performed using Waters Alliance 2695 equipped with two-way detector Waters 2487. The UV active fractions were collected on a column of Symmetry C-18, 3.5 µm, 3.0 mm x 100 mm was Suirable in a linear gradient of 5-90% acetonitrile, 90-0% water and 5% triperoxonane acid (1,0%) in water for 8 min with a flow rate of 1.0 ml/min

General method (A)

The compounds of formula (I) according to the present invention can be obtained according to the General method (A):

Stage A:

Compounds of General formula (I) is obtained from N-protected amerosport General formula (II). The protective group can be selected from protective groups known from the technical field and are given in the literature (cast the STI, T.W.Greene, P.G.Wuts, Protective groups in organic synthesis, 2ndedition, John Wiley & Sons Inc., New York, 1991). The aminoalcohols of General formula (II) are oxidized using a suitable method known from the technical field, in particular through chloride of oxalyl and dimethyl sulfoxide or using dicyclohexylcarbodiimide and dimethyl sulfoxide, and receive the aldehyde of General formula (III).

Stage:

The aldehyde of General formula (III) reacts with the amine of General formula (IV) in acidic or neutral medium with a reducing agent, such as, for example, acetoxyvalerenic sodium or cyanoborohydride sodium, with the formation of the amine of General formula (V).

Stage C:

The protective group is removed using methods known from the technical field and are documented in the literature (for example, T.W.Greene, P.G.Wuts, Protective groups in organic synthesis, 2ndedition, John Wiley & Sons Inc., New York, 1991), and get an amine of General formula (VI) or in the form of a free base or as a salt.

Stage D:

The amine of General formula (VI) or in the form of a free base or as a salt is subjected to interaction with the acid of formula (VII) and a reagent reaction combinations, such as, for example, the combination of 1-hydroxy-7-isobenzofuranone and hydrochloric salt of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or a combination of 3-hydroxy-1,2,3-benzotriazin-4(3H)-she and hydrochloric salt of 1-(3-dimethylaminopropyl)-3-this is carbodiimide, optionally in the presence of an amine base, such as, for example, triethylamine or ethyldiethanolamine, or with an activated derivative of the acid of formula (VII), such as the acid chloride acid, imidazole acid or ester with phenol, and get a connection General formula (I).

General method ()

The compounds of formula (I) according to the present invention can be also obtained according to the General method (B):

Stage A:

Compounds of General formula (I) are synthesized from N-protected amino acids of General formula (VIII). The protective group can be selected from protective groups known from the technical field and are documented in the literature (in particular, T.W.Greene, P.G.Wuts, Protective groups in organic synthesis, 2ndedition, John Wiley & Sons Inc., New York, 1991). The amine of General formula (IV) or in the form of a free base or as a salt interacts with the N-protected amino acid of General formula (VIII) and a reagent reaction combinations, such as, for example, the combination of 1-hydroxy-7-isobenzofuranone and hydrochloric salt of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or a combination of 3-hydroxy-1,2,3-benzotriazin-4(3H)-she and hydrochloric salt of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, optionally in the presence of an amine base, such as, for example, triethylamine or ethyldiethanolamine, or activated derivative to the slots of the formula (VIII), such as the acid chloride acid, imidazole acid and ester with phenol, with the formation of the amide of General formula (IX).

Stage:

Amide (IX) restore using a suitable reductant such as, for example, borane, a combination of sodium borohydride and iodine, or a combination of sodium borohydride and sulfuric acid to obtain an amine of General formula (V).

Stage C and stage D:

These stages are identical to stages C and D General methods (A).

General method (C)

Stage A:

This stage is identical to stage And General methods ().

Stage:

The protective group of the amine is removed using methods known from the art (for example, T.W.Greene, P.G.Wuts, Protective groups in organic synthesis, 2ndedition, John Wiley & Sons Inc., New York, 1991), and get amide of General formula (X) or in the form of a free base or as a salt.

Stage C:

Amide (X) restore using the appropriate reductant such as, for example, alumoweld lithium and receive amine of General formula (VI).

Stage D:

This stage is identical to stage D General methods (A).

General procedure (D)

Stage A:

By metallation join this group (for example, 2-tetrahydropyranyloxy group) to the phenol type (XI) using methods known what's specialists in the art and described in the literature (in particular, T.W.Greene, P.G.Wuts, Protective groups in organic synthesis, 2ndedition, John Wiley & Sons Inc., New York, 1991), and get the connection type (XII).

Stage:

Connection type (XII) is treated metalsalkaline agent such as n-utility, second-utility or tert-utility with or without chelat forming agent, such as N,N,N',N'-tetramethylethylenediamine at suitable temperatures, such as temperatures between minus 78°C and room temperature, within a reasonable time (from 5 minutes to 16 hours). Add a suitable electrophile such as N,N-dimethylformamide. The specified group or removed in the process of moving the product, or on a separate stage, using a method known in the art or described in the literature (for example, T.W.Greene, P.G.Wuts, Protective groups in organic synthesis, 2ndedition, John Wiley & Sons Inc., New York, 1991), and obtain the aldehyde of type (XIII).

Stage C:

The aldehyde of type (XIII) is subjected to interaction with a suitable 2-halogenation, such as, for example, diethyl ether of bromomalonate acid in the presence of a suitable base such as potassium carbonate, in a suitable solvent, such as ethylmethylketone, at a suitable temperature (e.g. between 0°C and 200°C) and receive an ester of type (XIV).

Stage D:

Ester type (XIV) omelet, using a method known in the art or described in the literature (for example, T.WGreene, P.G.Wuts, Protective groups in organic synthesis, 2ndedition, John Wiley & Sons Inc., New York, 1991), for example, potassium hydroxide in methanol or lithium hydroxide in a mixture of dioxane and water, and get acid type (XV).

Stage E:

This stage is identical to stage D General methods (A).

The General procedure (E)

where Hal means halogen.

Stage A:

Suitable halogenated, such as bromo - or imprisonme compounds of General structure (XVI)is subjected to interaction reactions with alkylacrylate General structure (XVII) in the presence of a suitable catalyst, such as, for example, palladium catalyst, such as, for example, palladium (II)acetate, in the presence of a suitable ligand, such as triphenylphosphine, and a suitable base, such as, for example, amine base, such as, for example, triethylamine or ethyldiethanolamine, and get alkylacrylate General structure (XVIII).

Stage:

Ester type (XVIII) omelet, using a method known in the art or described in the literature (for example, T.W.Greene, P.G.Wuts, Protective groups in organic synthesis, 2ndedition, John Wiley & Sons Inc., New York, 1991), for example, potassium hydroxide in methanol or lithium hydroxide in a mixture of dioxane and water, and get acid type (XIX).

Stage C:

This stage is identical to stage D General methods (a) and leads to the connection common to the touch (Ib).

Example 1(General procedure (A))

(E)-3-(4-Bromophenyl)-1-((2S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

Stage A: tert-Butyl ether (S)-2-formylpyridine-1-carboxylic acid

A solution of dimethyl sulfoxide (7,06 ml, 0,099 mol) in dichloromethane (10 ml), at a temperature of minus 78°C is added dropwise to a solution of chloride of oxalyl (6,40 ml of 0.075 mol) in dichloromethane (15 ml). The reaction mixture is stirred at minus 78°C for 20 minutes, Add a solution of (S)-1-(tert-butoxycarbonyl)-2-pyrrolidineethanol (10 g, 0,050 mol) in dichloromethane (50 ml). The reaction mixture is stirred at minus 78°C for 20 minutes Add triethylamine (27.7 ml, 0,199 mol). The reaction mixture is stirred at minus 78°C for 10 min and allowed to warm to room temperature. Washed with 10%aqueous solution of sodium bisulfate (60 ml). The aqueous phase is extracted with dichloromethane (30 ml). The organic extracts are combined and washed with saturated aqueous sodium bicarbonate (100 ml) and dried over magnesium sulfate. The solvent is removed in vacuum and obtain 11.2 g of crude tert-butyl ether (S)-2-formylpyridine-1-carboxylic acid, which is used in the next stage without further purification.

Range1H-NMR (CDCl32 set signal is): δ 1,50 (m, N); 1,75-of 2.20 (m, 4H); 3,20-4,00 (m, 3H); 4,05 and 4,20 (both t, together 1H); 9,50 and 9,60 (both s, together 1H).

Stage b: tert-Butyl ether (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-carboxylic acid

Triacetoxyborohydride sodium (35,7 g has 0.168 mol) are added to a mixture of crude tert-butyl ether (S)-2-formylpyridine-1-carboxylic acid (11.2 g, 0,056 mol), pyrrolidine (5,16 ml, holding 0.062 mol) and molecular sieves (10 g) in dichloromethane (100 ml). Add acetic acid (6.42 per g, 0,112 mol). The reaction mixture was stirred at room temperature for 16 hours. The precipitate was separated by filtration. The filtrate is diluted with 1 n aqueous sodium hydroxide solution (100 ml) and tert-butylmethylamine ether (100 ml). The phases are separated. The aqueous phase is extracted with tert-butylmethylamine ether (3 x 80 ml). The organic layers are combined and dried over magnesium sulfate. The solvent is removed in vacuum. The crude product was purified flash chromatography on silica gel (90 g)using a mixture of ethyl acetate/heptane/triethylamine (1:1, 5%) as eluent, and get 9,23 g tert-butyl ether (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-carboxylic acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ 1,45 (s, N); 1,80-2,10 (m, 8H); 2,50-3,70 (m, 8H); 3.90 and 4.00 points (both m, together 1H); HPLC (method A): elution at 10,70 min; mass spectrum: calculated for [M+H]+: 255; found: 255.

Stage C: (S)-2-((Pyrrolidin-yl)methyl)pyrrolidin

3.2 M solution of hydrogen chloride in ethyl acetate (470 ml, 1.5 mol) are added to a solution of tert-butyl methyl ether (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-carboxylic acid (9,23 g, being 0.036 mol) in ethyl acetate (100 ml). The reaction mixture was stirred at room temperature for 45 minutes the Solvent is removed in vacuum. The residue is dissolved in ethyl acetate (200 ml). The solvent is removed in vacuum and get 10.30 g of dihydrochloride of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.

Range1H-NMR (DMSO-d6): δ 1.60-to 2,30 (m, 8H); 3,10 (m, 2H); of 3.25 (m, 2H); 3,55 (m, 1H); 3,70 (m, 3H); 3,90 (m, 1H); 9,80 (user., 2H); 11,20 (user., 1H).

Stage D:

Hydrochloric salt of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide added at a temperature of 0°C. to a solution of (E)-4-bromcresol acid (0.50 g, of 2.20 mmol) and 3-hydroxy-1,2,3-benzotriazin-4(3H)-she (0.36 g, of 2.20 mmol) in a mixture of dichloromethane (6 ml) and N,N-dimethylformamide (6 ml). The reaction mixture was stirred at 0°C for 20 minutes Add the hydrochloric salt of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine (0.50 g, of 2.20 mmol) in N,N-dimethylformamide (8 ml). The reaction mixture is stirred for 16 hours and during this time, allow it to warm to room temperature. Dilute the mixture with ethyl acetate (100 ml), washed with saturated salt solution (100 ml) and dried over magnesium sulfate. The solvent is removed in vacuum. With the swarm product purified flash chromatography on silica gel (40 g), using as eluent a mixture of dichloromethane/methanol/25% aqueous ammonia, and obtain 340 mg specified in the connection name.

Range1H-NMR (CDCl3, 2 sets of signals): δ 1.70 to of 2.20 (m, 8H); 2,45 is 2.80 (m, 6N); of 3.60 and 3.70 (both m, together 2H); 4,20 and and 4.40 (both m, together 1H); 7,70 and of 7.90 (both d, together 1H); 7,40 (m, 2H); to 7.50 (m, 2H); the 7.65 (d, 1H); HPLC (method A): elution at 9,19 min; mass spectrum: calculated for [M+H]+: 363; found: 363.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

C18H23BrN2O•HCl•3H2O(363,30•36,46•3·18,02)

Calculated: 47,64; N 6,66; N 6,17.

Found: 47,41; N. Of 6.68; N 7,39.

Example 2(General procedure (A))

(E)-3-(5-Bromo-2-ethoxyphenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

300 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((2S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-5-bromo-2-toxicology acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.45 (t, 3H); 1,80-2,20 (m, 8H); 2,45 is 2.80 (m, 6N)and 1.60 and 1.70 (both m, together 2H); 4,05 (square, 2H; 4,15 and and 4.40 (both m, together 1H); 6.75 in (d, 1H); 6,85 and 6,95 (both d, together 1H); to 7.35 (d, 1H); of 7.60 (DD, 1H); 7,85 and 7,95 (both d, together 1H); HPLC (method A): elution at 9,89 min; mass spectrum: calculated for [M+H]+: 407; found: 407.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

C20H27BrN2O2•HCl•H2O (407,35•36,46•18,02)

Calculated: 52,02; N 6,55; N 6,07.

Found: 51,55; N, 6.42 Per; N 6,60.

Example 3(General procedure (A))

(E)-3-(4-Chlorophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

310 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((2S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-harkrisnowo acid instead of (E)-4-bromcresol acid.

HPLC (method A): elution at 9,04 min; mass spectrum: calculated for [M+H]+: 319; found: 319.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in et is zero (50 ml). The solvent is removed in vacuum.

Range1H-NMR (DMSO-d6, 2 sets of signals): δ 1,80-of 2.15 (m, 8H); 3,10, 3,20, 3,30, 3,45, and 3,55-3,85 (all m, together 8H); 4,40 and 4,75 (both m, together 1H); 7,05 and 7.15m (both d, together 1H); to 7.50 (m, 3H); 7,80 and of 7.90 (both d, together 2H); 10,2 (user., 1H).

Example 4(General procedure (A))

(E)-1-((S)-2-((Pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)-3-(4-(trifluoromethyl)phenyl)propane

160 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((2S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-(trifluoromethyl)cinnamic acid instead of (E)-4-bromcresol acid.

HPLC (method A): elution at 9,58 min; mass spectrum: calculated for [M+H]+: 353; found: 353.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Range1H-NMR (DMSO-d6, 2 sets of signals): δ 1,80-of 2.15 (m, 8H); 3,10, 3,25, 3,30, 3,45, and 3,55-3,80 (all m, together 8H); and 4,40 4,80 (both m, together 1H); 7.20 and 7,30 (both d, together 1H); 7,70 and 7.75 (both d, together 1H); 7.75, and 7,80 (both d, together 2H); 7.95 and 8,10 (both d, together 2H); of 10.25 (user., 1H).

Example 5(General procedure (A))

(E)-3-(3-Bromophenyl)-1-((S) - 2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

290 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((2S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-bromcresol acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ 1.70 to of 1.85 (m, 4H); 1,90-of 2.20 (m, 5H); 2,40-of 2.75 (m, 6N); of 3.60 (t, 1H); 4,15 and and 4.40 (both m, together 1H); 6,70 and 6,95 (both d, together 1H); was 7.45 (m, 2H); of 7.60 (d, 1H); 7,80 (t, 1H); HPLC (method A): elution at 9,10 min; mass spectrum: calculated for [M+H]+: 363; found: 363.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 6(General procedure (A))

(E)-3-(2-Bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

250 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((2S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-2-bromcresol acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ 1,50-1,90 (m, 4H); 1,90-of 2.20 (m, 4H); 2,50-to 2.85 (m, 6N); 3,55-of 3.80 (m, 2H); 4,15 and and 4.40 (both m, VM is the extent 1H); 6,65 and 6,85 (both d, together 1H); 7,10-7,40 (m, 2H); 7,50-of 7.70 (m, 2H); with 8.05 (d, 1H); HPLC (method A): elution at 8,89 min; mass spectrum: calculated for [M+H]+: 363; found: 363.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 7(General procedure (A))

(E)-3-(4-Methoxyphenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

340 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((2S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-methoxycatechol acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.80 (m, 4H); 1,90-2,10 (m, 3H); of 2.20 (m, 2H); 2,45 is 2.80 (m, 5H); of 3.60 and 3.70 (both m, together 2H); 3,85 (s, 3H); 4,15 and and 4.40 (both m, together 1H); 6,60 and 6.75 (both d, together 1H); 6.90 to (m, 2H); of 7.48 (d, 2H); to 7.64 and the 7.65 (both d, together 1H); HPLC (method A): elution at to $ 7.91 min; mass spectrum: calculated for [M+H]+: 315; found: 315.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). Races shall foretell removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 8(General procedure (A))

(E)-3-(3-Methoxyphenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

420 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((2S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-methoxycatechol acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.80 (m, 4H); 1,90-of 2.20 (m, 5H); 2,45 is 2.80 (m, 5H); of 3.60 and 3.70 (both m, together 2H); 3,85 (s, 3H); 4,15 and and 4.40 (both m, together 1H); 6,70 and 6,85 (both d, together 1H); 6.90 to (DD, 1H); 7,05 (s, 1H); to 7.15 (d, 1H); 7,30 (m, 1H); of 7.70 (d, 1H); HPLC (method A): elution at 7,99 min; mass spectrum: calculated for [M+H]+: 315; found: 315.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 9(General procedure (A))

(E)-3-(4-Bromophenyl)-1-((R)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

520 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((2S)-2-((pyrrolidin the-1-yl)methyl)pyrrolidin-1-yl)propenone, using (R)-1-(tert-butoxycarbonyl)-2-pyrrolidineethanol instead of (S)-1-(tert-butoxycarbonyl)-2-pyrrolidineethanol.

Range1H-NMR (CDCl3, 2 sets of signals): δ 1.70 to of 2.20 (m, 8H); 2,45 is 2.80 (m, 6N); of 3.60 and 3.70 (both m, together 2H); 4,15 and and 4.40 (both m, together 1H); 7,70 and of 7.90 (both d, together 1H); 7,40 (m, 2H); to 7.50 (m, 2H); the 7.65 (d, 1H); HPLC (method A): elution at 9,05 min; mass spectrum: calculated for [M+H]+: 363; found: 363.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 10(General procedure (A))

(E)-1-((R)-2-((Pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)-3-(4-triptoreline)propane

352 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((2S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (R)-1-(tert-butoxycarbonyl)-2-pyrrolidineethanol instead of (S)-1-(tert-butoxycarbonyl)-2-pyrrolidineethanol and (E)-4-(trifluoromethyl)cinnamic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.80 (m, 4H); 1,90-of 2.20 (m, 4H); 2,45-of 1.85 (m, 6N); of 3.60 and 3.70 (both m, together 2H); 4,15 and and 4.40 (both m, together 1H); 6,80 and 7,00 (both d, together 1H); the 7.65 (AB, 4H); of 7.70 (d, 1H); HPLC (method A): elution at was 9.33 min; mass spectrum: calculated for [M+H]+: 353; found: 353.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 11(General procedure (A))

(E)-3-(3-Chlorophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

340 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((2S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-harkrisnowo acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.75 (m, 4H); 1.85 to to 2.15 (m, 4H); 2.40 a is 2.75 (m, 6N); 3,50-3,75 (m, 2H); 4,15 and and 4.40 (both m, together 1H); 6.75 in and 6,90 (both d, together 1H); 7,20-7,40 (m, 3H); to 7.50 (s, 1H); the 7.65 (d, 1H).

HPLC (method A): elution at 8,82 minutes

Mass spectrum: calculated for [M+H]+: 319; found: 319.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is dilaut in vacuum.

Example 12(General procedure (A))

(E)-3-(3-Forfinal)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

210 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((2S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-folkorico acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.75 (m, 4H); 1,90-2,10 (m, 4H); 2,45 is 2.75 (m, 7H); 3,60 and 3.67 (t and d, together 2H); 4,15 and and 4.40 (both m, together 1H); 6,70 6,90 and (both d, together 1H); 7,05 (dt, 1H); then 7.20 (d, 1H); 7,25-7,40 (m, 2H); the 7.65 (d, 1H).

HPLC (method A): elution at 8,07 minutes

Mass spectrum: calculated for [M+H]+: 303; found: 303.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 13(General procedure (A))

(E)-3-(4-Forfinal)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

280 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((2S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-folkorico acid instead of (the)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.80 (m, 4H); 1.85 to of 2.20 (m, 4H); 2.40 a is 2.75 (m, 6N); 3,55 of 3.75 (m, 2H); 4,15 and and 4.40 (both m, together 1H); 6,65 and 6.80 (both d, together 1H); 7,05 (m, 2H); to 7.50 (m, 2H); the 7.65 (d, 1H).

HPLC (method A): elution at 8,05 minutes

Mass spectrum: calculated for [M+H]+: 303; found: 303.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 14(General procedure (A))

(E)-3-(Benzo[1,3]dioxol-5-yl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

340 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((2S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(benzo[1,3]dioxol-5-yl)acrylic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.80 (m, 4H); 1,90-of 2.30 (m, 4H); 2,45 is 2.80 (m, 6N); 3,55 of 3.75 (m, 2H); 4,15-and 4.40 (both m, together 1H); 6,00 (s, 2H); 6,55 and 6,70 (both d, together 1H); to 6.80 (DD, 1H); 7,00 (d, 1H), 7,02 (s, 1H); of 7.60 (d, 1H).

HPLC (method A): elution at 7,86 minutes

Mass spectrum: calculated for [M+H]+: 329; found: 329.

Specified in the title compound turn in his chloritoid the native salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 15(General procedure (A))

(E)-3-(3,4-Acid)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

240 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((2S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3,4-dimethoxyphenyl acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.75 (m, 4H); 1.85 to of 2.20 (m, 4H); 2,45 is 2.75 (m, 6N); 3,55 of 3.75 (m, 2H); 3,90 (C, 6N); 4,15 and and 4.40 (both m, together 1H); 6,55 and 6,70 (both d, together 1H); 6,85 (DD, 1H); 7,05 (d, 1H); 7,10 (DD, 1H); at 7.55 (d, 1H).

HPLC (method A): elution at 7,60 minutes

Mass spectrum: calculated for [M+H]+: 345; found: 345.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 16(General procedure (A))

(E)-3-(2,4-Acid)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

320 mg specified in the title compounds are synthesized by the method similar to that shown on the I (E)-3-(4-bromophenyl)-1-((2S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-2,4-dimethoxyphenyl acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.75 (m, 4H); 1.85 to of 2.20 (m, 4H); 2,45 is 2.75 (m, 6N); 3,50-3,75 (m, 2H); is 3.82 (s, 3H); 3,85 (s, 3H); 4,15 and and 4.40 (both m, together 1H); 6,45 (m, 2H); 6.75 in and 6,90 (both d, together 1H); was 7.45 (DD, 1H); 7,85 and of 7.90 (both d, together 1H).

HPLC (method A): elution at of 8.47 minutes

Mass spectrum: calculated for [M+H]+: 345; found: 345.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 17(General procedure (A))

(E)-3-(4-Bromo-2-forfinal)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

390 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((2S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-bromo-2-folkorico acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.75 (m, 4H); 1.85 to of 2.20 (m, 4H); 2,35 is 2.75 (m, 6N); 3,50-3,75 (m, 2H); 4,15 and and 4.40 (both m, together 1H); 6,85 and 7,05 (both d, together 1H); 7,25 was 7.45 (m, 3H); 7,65 and 7,70 (both d, together 1H).

HPLC (method A): elution at 9,27 minutes

Mass spectrum: calculated for [M+H]sup> +: 381; found: 381.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 18(General procedure (A))

(E)-1-((S)-2-((Pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)-3-(4-(triptoreline)phenyl)propane

98 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((2S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-(triptoreline)cinnamic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.80 (m, 4H); 1.85 to of 2.20 (m, 4H); 2.40 a is 2.80 (m, 6N); 3,55 of 3.75 (m, 2H); 4,15 and and 4.40 (both m, together 1H); 6,70 and 6,85 (both d, together 1H); then 7.20 (d, 2H); at 7.55 (d, 2H); the 7.65 (d, 1H).

HPLC (method A): elution at 9,75 minutes

Mass spectrum: calculated for [M+H]+: 369; found: 369.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 19(General procedure (A))

(E)-3-(-(Dimethylamino)phenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

74 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-(dimethylamino)cinnamic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ 1,50-of 2.15 (m, 8H); 2,45 is 2.80 (m, 6N); 3,00 (C, 6N); 3,60 & 3.65 (both m, together 2H); to 4.15 and 4.45 (both m, together 1H); 6.50 and 6,65 (both d, together 1H); to 6.67 (m, 2H); 7,40 (d, 2H); the 7.65 (d, 1H).

HPLC (method A): elution at 7.23 percent minutes

Mass spectrum: calculated for [M+H]+: 328; found: 328.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 20(General procedure (A))

(E)-3-(4-Bromophenyl)-1-((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)propenone

Stage 1:

1-(((S)-Pyrrolidin-2-yl)methyl)piperidine

of 8.3 g of 1-(((S)-pyrrolidin-2-yl)methyl)piperidine synthesized as described for (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine using piperidine instead of pyrrolidine.

Range1H-NMR (CDCl3, free base): δ 1.30 on (m, 1H); of 1.40 (m, 2H); of 1.55 (m,4H); of 1.75 (m, 2H); 1,90 (m, 1H); 2,30 (m, 2H); 2,35 (m, 2H); 2.50 each (m, 2H); 2,65 (user., 1H); 2,90 (m, 1H); 3,00 (m, 1H); of 3.25 (m, 1H).

Stage 2:

520 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.45 (m, 2H); of 1.55 (m, 4H); 2,85 is 2.10 (m, 4H); 2,15-2,70 (m, 6N); 3,55 of 3.75 (m, 2H); 4,15 and and 4.40 (both m, together 1H); 6,70 and 6,95 (both d, together 1H); 7,40 (d, 2H); 7,50 (d, 2H); of 7.60 (d, 1H).

HPLC (method A): elution at 9,48 minutes

Mass spectrum: calculated for [M+H]+: 377; found: 377.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 21(General procedure (A))

(E)-3-(4-Chlorophenyl)-1-((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)propenone

220 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methylpyrrolidine and (E)-4-harkrisnowo acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.45 (m, 2H); of 1.55 (m, 4H); 1,80-2,10 (m, 4H); 2,15-2,70 (m, 6N); 3,50-3,75 (m, 2H); 4,15 and and 4.40 (both m, together 1H); 6,70 6,90 and (both d, together 1H); to 7.35 (d, 2H); was 7.45 (d, 2H); the 7.65 (d, 1H).

HPLC (method A): elution at 9,37 minutes

Mass spectrum: calculated for [M+H]+: 333; found: 333.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 22(General procedure (A))

(E)-1-((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)-3-(4-(trifluoromethyl)phenyl)propane

130 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine and (E)-4-(trifluoromethyl)cinnamic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.40 (m, 2H); of 1.55 (m, 4H); 1,80-2,10 (m, 4H); 2,15-2,70 (m, 6N); 3,55 of 3.75 (m, 2H); 4,15 and and 4.40 (both m, together 1H); 6,80 and 7,05 (both d, together 1H); of 7.60 (m, 4H); of 7.70 (d, 1H).

HPLC (method A): elution at 9,87 minutes

Mass spectrum: calculated for [M+H]+: 367; found: 367.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 23(General procedure (A))

(E)-3-(3-Bromophenyl)-1-((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)propenone

140 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine and (E)-3-bromcresol acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.45 (m, 2H)and 1.60 (m, 4H); 1,80-2,10 (m, 4H); 2,15-2,70 (m, 6N); 3,50-3,75 (m, 2H); 4,15 and and 4.40 (both m, together 1H); 6,70 and 6,95 (both d, together 1H); 7,25 (m, 1H); 7,45 (m, 1H); 7,60 and to 7.61 (both d, together 1H); of 7.70 (m, 1H).

HPLC (method A): elution at 9,60 minutes

Mass spectrum: calculated for [M+H]+: 377; found: 377.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). Dissolve the al is removed in vacuum.

Example 24(General procedure (A))

(E)-3-(4-Methoxyphenyl)-1-((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)propenone

160 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine and (E)-4-methoxycatechol acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.45 (m, 2H); of 1.55 (m, 4H); 1.85 to 2,10 (m, 4H); 2,15-2,70 (m, 6N); 3,55 of 3.75 (m, 2H); 3,85 (s, 3H); 4,15 and and 4.40 (both m, together 1H); 6,60 and 6.75 (both d, together 1H); 6.90 to (m, 2H); 7,50 (d, 2H); the 7.65 (d, 1H).

HPLC (method A): elution at 8,61 minutes

Mass spectrum: calculated for [M+H]+: 329; found: 329.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 25(General procedure (A))

(E)-3-(3,4-Acid)-1-((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)propenone

190 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((Pirro is one-1-yl)methyl)pyrrolidin-1-yl)propenone, using 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine and (E)-3,4-dimethoxyphenyl acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.40 (m, 2H); of 1.55 (m, 4H); 1,80-2,10 (m, 4H); 2,15-2,70 (m, 6N); 3,50-3,75 (m, 2H); 3,90 (C, 6N); 4,15 and and 4.40 (both m, together 1H); 6,55 and 6.75 (both d, together 1H); 6,85 (m, 1H); 7,10 (AB, 2H); the 7.65 (d, 1H).

HPLC (method A): elution at 8,00 minutes

Mass spectrum: calculated for [M+H]+: 359; found: 359.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 26(General procedure (A))

(E)-3-(4-Chloro-3-nitrophenyl)-1-((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)propenone

200 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine and (E)-4-chloro-3-nitrocatechol acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.45 (m, 2H); of 1.55 (m, 4H); 1.85 to 2,10 (m, 4H); 2,15-2,70 (m, 6N); 3,55 of 3.75 (m, N); 4,15 and and 4.40 (both m, together 1H); 6.75 in and 7,05 (both d, together 1H); 7,50-of 7.70 (m, 2H); 8,00 and 8,05 (both s, together 1H).

HPLC (method A): elution at 9,19 minutes

Mass spectrum: calculated for [M+H]+: 377; found: 377.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 27(General procedure (A))

(E)-1-((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)-3-(4-(triptoreline)phenyl)propane

370 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine and (E)-4-(triptoreline)cinnamic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.45 (m, 2H); of 1.55 (m, 4H); 1.85 to 2,10 (m, 4H); 2,15-2,70 (m, 6N); 3,50-3,75 (m, 2H); 4,15 and and 4.40 (both m, together 1H); 6,70 6,90 and (both d, together 1H); then 7.20 (d, 2H); at 7.55 (d, 2H); the 7.65 (d, 1H).

HPLC (method A): elution at 10,11 minutes

Mass spectrum: calculated for [M+H]+: 383; found: 383.

Specified in the title compound is transformed into its hydrochloric salt put the m dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 28(General procedure (A))

(E)-3-(Biphenyl-4-yl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

180 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(biphenyl-4-yl)acrylic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ 1.70 to of 2.20 (m, 8H); 2,45 is 2.80 (m, 6N); of 3.60 and 3.70 (t and m, together 2H); 4,20 and and 4.40 (both m, together 1H); 6.75 in and 6,90 (both d, together 1H); 7,30-to 7.50 (m, 3H); 7,60 (m, 6N); of 7.75 (d, 1H).

HPLC (method A): elution at 10,26 minutes

Mass spectrum: calculated for [M+H]+: 361; found: 361.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 29(General procedure (A))

4-[(E)-3-Oxo-3-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenyl]benzonitrile

180 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-pompini is)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-ciancarini acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.75 (m, 4H); 1.85 to of 2.20 (m, 4H); 2.40 a is 2.75 (m, 6N); 3,55 of 3.75 (m, 2H); 4,15 and and 4.40 (both m, together 1H); 6,80 and 7,00 (both d, together 1H); 7,55-of 7.70 (m, 5H).

HPLC (method A): elution at 7,46 minutes

Mass spectrum: calculated for [M+H]+: 310; found: 310.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 30 (General procedure (A))

(5-Chlorobenzophenone-2-yl)-((S)-2-((pyrrolidin-1-yl) methyl)pyrrolidin-1-yl)methanon

400 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone using 5-chlorobenzo[b]furan-2-carboxylic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ to 1.70 (m, 4H); 1.85 to 2,90 (m, 10H); 3,65-4,10 (m, 2H); 4,50 and 4,85 (both m, together 1H); 7,30-to 7.50 (m, 3H); the 7.65 (s, 1H).

HPLC (method A): elution at 8,62 minutes

Mass spectrum: calculated for [M+H]+: 333; found: 333.

Specified in the title compound is transformed into its hydrochloric salt n is the dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 31 (General procedure (A))

(7-(Ethoxy)benzofuran-2-yl)-((S)-2-((pyrrolidin-1-yl) methyl)pyrrolidin-1-yl)methanon

340 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using 7-(ethoxy)benzo[b]furan-2-carboxylic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ 1.50 in (t, 3H); 1.60-to of 1.85 (m, 4H); 1.85 to to 2.15 (m, 4H); 2,15-2,90 (m, 6N); 3,70 (m, 1H); 3.90 and of 4.05 (both m, together 1H); 4,20 (m, 2H); and 5,00 4,50 (both m, together 1H); 6,85 (d, 1H); 7,10-7,30 (m, 2H); 7,30-of 7.55 (m, 1H).

HPLC (method A): elution at 8,67 minutes

Mass spectrum: calculated for [M+H]+: 343; found: 343.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 32 (General procedure (A))

(E)-3-(4-(Methylsulphonyl)phenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

Stage 1:

Ethyl ester of (E)-3-(4-(methylsulphonyl)phenyl) acrylic acid

Tert-piperonyl potassium (10,96 g, 98 mmol) in tetrahydrofuran (60 ml) is added by portions to a solution of triethylphosphate (to 21.91 g, 98 mmol) in tetrahydrofuran (150 ml). The reaction mixture was stirred 40 min at room temperature. Added dropwise a solution of 4-(methylsulphonyl)benzaldehyde (Acros No. 42490-0025, 10.0 g, 54 mmol) in tetrahydrofuran (60 ml). The reaction mixture was stirred at room temperature for 1 hour, diluted with ethyl acetate (500 ml) and washed with 1 n hydrochloric acid (300 ml). The aqueous phase is extracted with ethyl acetate (2×100 ml), organic layers combined and dried over magnesium sulfate. The solvent is removed in vacuum. The crude product is purified by recrystallization from a mixture of ethyl acetate/heptane and obtain 4.3 g of ethyl ester of (E)-3-(4-(methylsulphonyl)phenyl)acrylic acid.

Range1H-NMR (CDCl3): δ of 1.35 (t, 3H), 3,10 (s, 3H), 4,30 (kV, 2H), 6,55 (d, 1H), of 7.70 (m, 3H), 7,95 (d, 2H).

Stage 2:

(E)-4-Methylsulfonylamino acid

A solution of ethyl ester of (E)-3-(4-(methylsulphonyl)phenyl)acrylic acid and lithium hydroxide in a mixture of dioxane/water (100 ml/100 ml) was stirred at room temperature for 16 hours. Washed with tert-butylmethylamine ether (200 ml). The aqueous phase is acidified with 10%aqueous solution of sodium bisulfate to pH 2. The precipitation is filtered off and dried in vacuum. Mod is it suspended in ethanol (100 ml). The solvent is evaporated. The last procedure is repeated again and get to 2.74 g of crude (E)-4-methylsulfonylamino acid, which is used in the next stage without further purification.

Range1H-NMR (DMSO-d6): δ of 3.25 (s, 3H), 6,70 (d, 1H), 7,65 (d, 1H), 7,95 (AB, 4H), 12,60 (user., 1H).

Stage 3:

340 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-methylsulfonylamino acid instead of (E)-4-bromcresol acid.

Range1H-H-NMR (CDCl3, 2 sets of signals): δ of 1.75 (m, 4H); 1.85 to of 2.20 (m, 4H); 2,45 is 2.80 (m, 6N); 3,05 (s, 3H); 3,55-of 3.80 (m, 2H); 4,10 and and 4.40 (both m, together 1H); 6,85 and 7,05 (both d, together 1H); the 7.65 (m, 3H); to 7.95 (d, 1H).

HPLC (method A): elution at 6,58 minutes

Mass spectrum: calculated for [M+H]+: 363; found: 363.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 33 (General procedure (A))

(E)-3-(4-Chlorophenyl)-1-(2-((pyrrolidin-1-yl)methyl)piperidine-1-yl)propenone

140 mg specified in the title compounds are synthesized according to the method similar to the Eden for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-harkrisnowo acid instead of (E)-4-bromcresol acid tert-butyl ester 2-formylpiperidine-1-carboxylic acid instead of tert-butyl methyl ether (S)-2-formylpyridine-1-carboxylic acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ 1,35-of 1.95 (m, 10H); 2,40-2,90 and 3,20 (all m, together 7H); 3.90 and of 4.25 (both m, together 1H); 4,60 and of 5.05 (both m, together 1H); 6.90 to (d, 1H); to 7.35 (d, 2H); was 7.45 (d, 2H); at 7.55 (d, 1H).

HPLC (method A): elution at KZT 12.39 minutes

Mass spectrum: calculated for [M+H]+: 333; found: 333.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 34 (General procedure (A))

(E)-3-(4-Bromophenyl)-1-(2-((pyrrolidin-1-yl)methyl)piperidine-1-yl)propenone

90 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone using tert-butyl ester 2-formylpiperidine-1-carboxylic acid instead of tert-butyl methyl ether (S)-2-formylpyridine-1-carboxylic acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ 1,35-1,90 (m, 10H); 2,40-2,90 (m, 7H); 3.90 and of 4.25 (both m, together 1H); 4,60 è5,05 (both m, together 1H); to 6.95 (d, 1H); to 7.35 (d, 2H); 7,45-the 7.65 (m, 3H).

HPLC (method C): elution at 4,28 minutes

Mass spectrum: calculated for [M+H]+: 377; found: 377.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 35 (General procedure (A))

(E)-1-(2-((Pyrrolidin-1-yl)methyl)piperidine-1-yl)-3-(4-(trifluoromethyl)phenyl)propane

130 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-(trifluoromethyl)cinnamic acid instead of (E)-4-bromcresol acid and tert-butyl methyl ether formylpiperidine-1-carboxylic acid instead of tert-butyl methyl ether (S)-2-formylpyridine-1-carboxylic the acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ 1,40-of 1.95 (m, 10H); 2,45-to 2.85 (m, 7H); 3,90-of 4.25 (both m, together 1H); and 5,00 4,60 (both m, together 1H); 7,00 (d, 1H); 7,55-the 7.65 (m, 5H).

HPLC (method C): elution at of 4.44 minutes

Mass spectrum: calculated for [M+H]+: 367; found: 367.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add the effect to 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 36 (General procedure (A))

(E)-3-(4-Methoxyphenyl)-1-(2-((pyrrolidin-1-yl)methyl)piperidine-1-yl)propenone

100 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-methoxycatechol acid instead of (E)-4-bromcresol acid tert-butyl ester 2-formylpiperidine-1-carboxylic acid instead of tert-butyl methyl ether (S)-2-formylpyridine-1-carboxylic acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ 1.30 and of 1.95 (m, 10H); 2,40-3,20 (m, 7H); 3,85 (s, 3H); 4.00 and of 4.25 (both m, together 1H); and 5,00 4,60 (both m, together 1H); to 6.80 (d, 1H); 6.90 to (d, 2H); was 7.45 (d, 2H); of 7.60 (d, 1H).

HPLC (method C): elution at 3,79 minutes

Mass spectrum: calculated for [M+H]+: 329; found: 329.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 37 (General procedure (A))

(E)-1-((S)-((2-Pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)-3-(Tien-2-yl)propane

160 mg of the decree is tion in the title compounds are synthesized according to the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(Tien-2-yl)acrylic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.80 (m, 4H); 1.85 to to 2.15 (m, 4H); 2,35 is 2.75 (m, 6N); 3,50-3,70 (m, 2H); 4,10 and 4.35 (both m, together 1H); 6,52 and 6,65 (both d, together 1H); 7,05 (m, 1H); 7,20 (m, 1H); 7,30 (m, 1H); 7,80 (d, 1H).

HPLC (method A): elution at 7,34 minutes

Mass spectrum: calculated for [M+H]+: 291; found: 291.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 38 (General procedure (A))

(E)-1-((S)-((2-Pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)-3-(Tien-3-yl)propenone

100 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(Tien-3-yl)acrylic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.75 (m, 4H); 1.85 to of 2.20 (m, 4H); 2.40 a is 2.80 (m, 6N); 3,50-3,75 (m, 2H); 4,15 and and 4.40 (both m, together 1H); 6,55 and 6,70 (both d, together 1H); 7,20-7,35 (m, 2H); 7,45 (m, 1H); of 7.70 (DD, 1H).

HPLC (method A): the Lucia when 7,32 minutes

Mass spectrum: calculated for [M+H]+: 291; found: 291.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 39 (General procedure (A))

(E)-3-(Furan-2-yl)-1-((S)-2-((pyrrolidin-1-yl) methyl)pyrrolidin-1-yl)propenone

78 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(furan-2-yl)acrylic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ to 1.70 (m, 4H); 1.85 to of 2.20 (m, 4H); 2.40 a is 2.80 (m, 6N); 3,50-3,75 (m, 2H); 4,15 and and 4.40 (both m, together 1H); 6,45 (m, 1H); 6,55 (m, 1H); of 6.65 and 6.75 (both d, together 1H); was 7.45 (m, 2H).

HPLC (method A): elution at 6,78 minutes

Mass spectrum: calculated for [M+H]+: 275; found: 275.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 40 (General procedure (A))

(E)-3-(Furan-3-yl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

190 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(furan-3-yl)acrylic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.75 (m, 4H); 1.85 to of 2.20 (m, 4H); 2.40 a is 2.75 (m, 6N); 3,45-3,70 (m, 2H); 4,10 and 4.35 (both m, together 1H); 6,45 and 6,55 (l and m, together 2H); 7,40 (s, 1H); 7,55-the 7.65 (m, together 2H).

HPLC (method A): elution at 6,66 minutes

Mass spectrum: calculated for [M+H]+: 275; found: 275.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 41 (General procedure (A))

4-[(E)-3-Oxo-3-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenyl]phenyl ester methanesulfonate

Stage 1:

4-Formylphenoxy broadcast methansulfonate

Methansulfonate (9,51 ml, 0,123 mol) is added dropwise at 0°C. to a solution of 4-hydroxybenzaldehyde (15 g, 0,123 mol) in pyridine (12,91 ml, 0,160 mol). Rea is operating, the mixture is stirred at 0°C for 3 h, and then leave at room temperature for 16 hours. Add in a mixture of concentrated hydrochloric acid and ice (200 ml/200 ml). Extracted the mixture with ethyl acetate (4×300 ml). The organic layers are combined, washed with 5%aqueous sodium bicarbonate solution (3×200 ml) and saturated salt solution (100 ml) and dried over magnesium sulfate. The solvent is removed in vacuum and get 22,87 g of crude 4-formylphenyl ether methanesulfonate, which is used in the next stage without further purification.

Range1H-NMR (CDCl3): δ 13,22 (s, 3H); was 7.45 (d, 2H); 8,00 (d, 2H); 10,02 (s, 1H).

Stage 2:

(E)-3-(4-(Methanesulfonamide)phenyl)acrylic acid

Malonic acid (7,80 g, 74,92 mmol) are added to a solution of crude 4-formylphenyl ether methanesulfonate (10 g, 49,95 mmol), synthesized in the previous phase, and piperidine (0.7 ml, to 7.09 mmol) in pyridine (50 ml). The reaction mixture for 2.5 hours, heated to 90°C. Cool to room temperature. Add a mixture of concentrated hydrochloric acid and ice (400 ml/100 ml). The precipitate is filtered off and washed with 10%aqueous solution of acetic acid (200 ml). Dried in the vacuum and get of 6.95 g (E)-3-(4-(methanesulfonamide)phenyl)acrylic acid.

Range1H-NMR (DMSO-d6): δ 3.40 in (s, 3H); 6,55 (d, 1H); 7,40 (d, 2H); of 7.60 (d, 1H); 7,80 (d, 2H).

Stage 3:

150 m is specified in the title compounds are synthesized according to the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(4-(methanesulfonamide)phenyl)acrylic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.75 (m, 4H); 1.85 to of 2.20 (m, 4H); 2.40 a is 2.80 (m, 5H); 3.15 in (s, 3H); 3,50-3,75 (m, 2H); 4,15 and and 4.40 (m, 1H); 6,70 and 6,85 (both d, together 1H); 7,30 (m, 2H); at 7.55 (d, 2H); the 7.65 (d, 1H).

HPLC (method A): elution at 7,50 minutes

Mass spectrum: calculated for [M+H]+: 379; found: 379.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 42 (General procedure (A))

4-[(E)-3-Oxo-3-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenyl]phenyl ester triftoratsetata

Stage 1:

(E)-3-(4-(Tripterocalyx)phenyl)acrylic acid

of 13.4 g of (E)-3-(4-(tripterocalyx)phenyl)acrylic acid synthesized by the method described for (E)-3-(4-(methanesulfonamide)phenyl)acrylic acid using the anhydride of triftoratsetata instead of methanesulfonamide.

Range1H-NMR (DMSO-d6): δ 6,60 (d, 1H); at 7.55 (d, 2H); the 7.65 (d, 1H); of 7.90 (who, 2H).

Stage 2:

130 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(4-(tripterocalyx)phenyl)acrylic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.75 (m, 4H); 1.85 to to 2.15 (m, 4H); 2.40 a is 2.80 (m, 5H); 3,55 of 3.75 (m, 2H); 4,15 and and 4.40 (both m, together 1H); 6,70 6,90 and (both d, together 1H); 7,30 (d, 2H); of 7.60 (d, 2H); the 7.65 (d, 1H).

HPLC (method A): elution at becomes 9.97 minutes

Mass spectrum: calculated for [M+H]+433; found: 433.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 43 (General procedure (A))

3-[(E)-3-Oxo-3-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl) propenyl]benzonitrile

Stage 1:

(E)-3-(3-Cyanophenyl)acrylic acid

11.3 g (E)-3-(3-cyanophenyl)acrylic acid synthesized by the method described for (E)-3-(4-(methanesulfonamide)phenyl)acrylic acid using 3-cyanobenzaldehyde (marketed by the company Aldrich) instead of 4-formylphenyl ether methanesulfonate.

the range of 1H-NMR (DMSO-d6): δ 6,70 (d, 1H); of 7.60 (m, 2H); a 7.85 (d, 1H); with 8.05 (d, 2H), of 8.25 (s, 1H); 12,50 (user., 1H).

Stage 2:

220 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(3-cyanophenyl)acrylic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (in the form of a salt triperoxonane acid, CDCl3): 5 1,90 (m, 1H); 2,00-2,30 (m, 7H); 3,05-3,20 (m, 2H); of 3.25 (m, 1H); the 3.65 (m, 1H); 3,70-3,90 (m, 3H); 4,15 (m, 1H); 4,50 (m, 1H); 6.75 in (d, 1H); at 7.55 (t, 1H); the 7.65 (d, 1H); of 7.70 (d, 1H); of 7.75 (d, 1H); the 7.85 (s, 1H).

HPLC (method A): elution at 7,37 minutes

Mass spectrum: calculated for [M+H]+310; found: 310.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 45 (General procedure (A))

(E)-1-((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)-3-(3-triptoreline)propane

310 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrol the DIN-1-yl)methyl)pyrrolidine and (E)-3-(trifluoromethyl)cinnamic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.40 (m, 2H); of 1.55 (m, 4H); 1,80-of 2.15 (m, 4H); 2,15-2,70 (m, 6N); of 3.60 and 3.70 (both m, together 2H); 4,15 and and 4.40 (both m, together 1H); 6,80 and 7,05 (both d, together 1H); 7,45-a 7.85 (m, along 5H).

HPLC (method A): elution at 9,73 minutes

Mass spectrum: calculated for [M+H]+: 367; found: 367.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 46 (General procedure (A))

3-[(E)-3-Oxo-3-((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)propenyl]benzonitrile

370 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(3-cyanophenyl)acrylic acid instead of (E)-4-bromcresol acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.40 (m, 2H); of 1.55 (m, 4H); 1.85 to to 2.15 (m, 4H); 2,15-to 2.55 (m, 5H); to 2.65 (m, 1H); of 3.60 and 3.75 (both m, together 2H); 4,15 and and 4.40 (both m, together 1H); 6.75 in and 7,05 (both d, together 1H); to 7.50 (t, 1H); 7,60 to 7.75 (m, 4H); a 7.85 (d, 1H).

HPLC (method C): elution at 3,10 minutes

Mass spectrum: calculated on the I [M+H] +: 324; found: 324.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 47 (General procedure (A))

4-[(E)-3-Oxo-3-((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl) propenyl]benzonitrile

150 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-ciancarini acid instead of (E)-4-bromcresol acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.

Range1H-NMR (CDCl3, 2 sets of signals): δ 1.30 and of 1.65 (m, 6N); 1,95-2,15 (m, 4H); 2,15-2,70 (m, 6N); of 3.60 and 3.70 (both m, together 2H); 4,15 and and 4.40 (both m, together 1H); 6,80 and 7,05 (both d, together 1H); 7,50-of 7.70 (m, 5H).

HPLC (method C): elution at 3,05 minutes

Mass spectrum: calculated for [M+H]+: 324; found: 324.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent UD is collected in a vacuum.

Example 48 (General procedure (A))

(E)-3-(4-(Methylsulphonyl)phenyl)-1-((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)propenone

190 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-methylsulfonylamino acid instead of (E)-4-bromcresol acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.45 (m, 2H); 1,50-1,70 (m, 4H); 1.85 to to 2.15 (m, 4H); 2,15-2,70 (m, 6N); 3,10 (s, 3H); of 3.65 and 3.75 (both m, together 2H); 4,20 and and 4.40 (both m, together 1H); 6,85 and 7.10 (both d, together 1H); of 7.70 (m, 3H); TO 7.95 (D, 2H).

HPLC (method C): elution at 2,60 minutes

Mass spectrum: calculated for [M+H]+: 377; found: 377.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 49 (General procedure (A))

4-[(E)-3-Oxo-3-((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)propenyl]phenyl ester methanesulfonate

230 mg specified in the title compounds are synthesized by the method similar to bring the Noi for (E)-3- (4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(4-(methanesulfonamide)phenyl)acrylic acid instead of (E)-4-bromcresol acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.45 (m, 2H); of 1.55 (m, 4H); 1.70 to to 2.15 (m, 4H); 2,15-2,70 (m, 6N); 3.15 in (s, 3H); of 3.60 and 3.70 (both m, together 2H); to 4.15 and 4.35 (both m, together 1H); 6,70 6,90 and (both d, together 1H); 7,30 (d, 2H); at 7.55 (d, 2H); the 7.65 (d, 1H).

HPLC (method C): elution at 3,17 minutes

Mass spectrum: calculated for [M+H]+: 393; found: 393.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 50 (General procedure (A))

4-[(E)-3-Oxo-3-((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)propenyl]phenyl ester triftoratsetata

190 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(4-(tripterocalyx)phenyl)acrylic acid instead of (E)-4-bromcresol acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.

Range1N-I Is R (CDCl 3, 2 sets of signals): δ 1.30 and 2,70 (m, N); of 3.60 and 3.70 (both m, together 2H); 4,15 and and 4.40 (both m, together 1H); 6,70 and 6,95 (both d, together 1H); 7,30 (d, 2H); of 7.60 (d, 2H); the 7.65 (d, 1H).

HPLC (method C): elution at 4,45 minutes

Mass spectrum: calculated for [M+H]+: 447; found: 447.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 51 (General procedure (A))

2-Fluoro-5-[(E)-3-oxo-3-((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)propenyl]benzonitrile

Stage 1:

(E)-3-(3-Cyano-4-forfinal)acrylic acid

5,52 g (E)-3-(3-cyano-4-forfinal)acrylic acid synthesized by the method described for (E)-3-(4-(methanesulfonamide)phenyl)acrylic acid, using 4-fluoro-3-cyanobenzaldehyde (marketed by the company Aldrich) instead of 4-formylphenyl ether methanesulfonate.

Range1H-NMR (DMSO-d6): δ 6,60 (d, 1H); at 7.55 (m, 2H); 8,15 (m, 1H); 8,35 (DD, 1H), 12,50 (user., 1H).

Stage 2:

300 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, and the but using (E)-3-(3-cyano-4-forfinal)acrylic acid instead of (E)-4-bromcresol acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.

Range1H-NMR (CDCl3, 2 sets of signals): 5 to 1.45 (m, 2H); of 1.55 (m, 4H); 2,85 is 2.10 (m, 4H); 2,15-to 2.55 (m, 5H); to 2.65 (m, 1H); of 3.60 and 3.70 (both m, together 2H); 4,15 and and 4.40 (both m, together 1H); 6,70 and 7,00 (both d, together 1H); 7,20 (m, 1H); of 7.60 (DD, 1H); of 7.70 (m, 1H); 7,80 (m, 1H).

HPLC (method C).

Mass spectrum: calculated for [M+H]+: 342; found: 342.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 52 (General procedure (A))

(E)-3-(2-Fluoro-4-triptoreline)-1-((S)-2-(piperidine-l-yl)methyl)pyrrolidin-1-yl)propenone

Stage 1:

(E)-2-Fluoro-4-(trifluoromethyl)cinnamic acid

5,12 g (E)-2-Fluoro-4-(trifluoromethyl)cinnamic acid synthesized by the method described for (E)-3-(4-(methanesulfonamide)phenyl)acrylic acid using 2-fluoro-4-triftormetilfosfinov (marketed by the company Aldrich) instead of 4-formylphenyl ether methanesulfonate.

Range1H-NMR (DMSO-d6): δ 6,70 (d, 1H); the 7.65 (m, 2H); 7,80 (d, 1H); 8,10 (t, 1H), 12,00 (user., 1H).

Stage 2:

220 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-br is fenil)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-2-fluoro-4-(trifluoromethyl)cinnamic acid instead of (E)-4-bromcresol acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl) methyl)pyrrolidine.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.40 (m, 2H); of 1.55 (m, 4H); 1,75-of 2.15 (m, 4H); 2,15-2,70 (m, 6N); of 3.60 and 3.70 (both m, together 2H); 4,15 and and 4.40 (both m, together 1H); 6,95 and 7.15m (both d, together 1H); 7,30 was 7.45 (m, 2H); 7,60 (m, 1H); 7,65-7,80 (m, 2H).

HPLC (method C): elution at 4,54 minutes

Mass spectrum: calculated for [M+H]+: 385; found: 385.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 53 (General procedure (A))

(General procedure (C)): (E)-3-(2-Fluoro-4-triptoreline)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

Stage 1:

Tert-butyl ether (S)-2-(pyrrolidin-1-ylcarbonyl)pyrrolidin-1-carboxylic acid

Hydrochloric salt of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (17,81 g, 93 mmol) is added at 0°C. to a solution of (S)-1-(tert-butoxycarbonyl)pyrrolidin-1-carboxylic acid (20,0 g, 93 mmol) and 3-hydroxy-1,2,3-benzotriazin-4(3H)she (15.2 g, 93 mmol) in a mixture of dihormati is a (150 ml) and N,N-dimethylformamide (150 ml). The reaction mixture was stirred at 0°C for 20 minutes Consistently add pyrrolidine (7,76 ml, 93 mmol) and triethylamine (91 ml, 650 mmol). The reaction mixture is stirred for 16 hours and during this time, allow it to warm to room temperature. Dilute with ethyl acetate (500 ml), washed with a mixture of water and saturated aqueous sodium bicarbonate solution (250 ml/250 ml) and dried over magnesium sulfate. The solvent is removed in vacuum. The crude product is purified by the method of flash chromatography on silica gel (90 g)using a mixture of dichloromethane/methanol/25%aqueous ammonia (100:10:1) as eluent, and obtain 5.9 g of tert-butyl methyl ether (S)-2-(pyrrolidin-1-ylcarbonyl)pyrrolidin-1-carboxylic acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ 1.40 and 1,45 (both s, together N); 1,75-2,25 (m, 8H); 3,35-of 3.80 (m, 6N); of 4.35 and 4.50 (both DD, together 1H).

HPLC (method A): elution at 9,35 minutes

Mass spectrum: calculated for [M+H]+: 269; found: 269.

Stage 2:

(Pyrrolidin-1-yl)-((S)-pyrrolidin-2-yl)methanon

Tert-butyl ether (S)-2-(pyrrolidin-1-ylcarbonyl)pyrrolidin-1-carboxylic acid (5,90 g, 22 mmol) dissolved in dichloromethane (50 ml). Add triperoxonane acid (30 ml). The reaction mixture was stirred at room temperature for 50 minutes the Solvent is removed in vacuum. The residue is dissolved in saturated water is aStore potassium carbonate (200 ml). Extracted with dichloromethane (3×100 ml). The aqueous phase is saturated with sodium chloride and re-extracted with dichloromethane (3×200 ml). The organic extracts are combined and dried over magnesium sulfate. The solvent is removed in vacuum and get 4,89 g crude (pyrrolidin-1-yl)-((S)-pyrrolidin-2-yl)methanone, which is used in the next stage without further purification.

Range1H-NMR (CDCl3): δ 1,90 (m, 7H); to 2.25 (m, 1H); 3,10-3,70 (m, 6N); 4,10 (m, 1H); 4,60 (user., 1H).

Stage 3:

(S)-2-((Pyrrolidin-1-yl)methyl)pyrrolidin

1.0 M solution of lithium aluminum hydride in tetrahydrofuran (87 ml, 87 mmol) is added dropwise to a solution of crude (pyrrolidin-1-yl)- ((S)-pyrrolidin-2-yl)methanone (4,89 g, 29 mmol) in tetrahydrofuran (90 ml). The reaction mixture is boiled for 6 hours. Cooled to room temperature and carefully add water (3.6 ml). Then carefully add 1 n sodium hydroxide solution (3.6 ml, 3.6 mmol). Add water (to 10.7 ml). The mixture is stirred at room temperature for one hour. The precipitation is filtered off. The solvent is removed in vacuum and obtain 2.67 g (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.

Range1H-NMR (CDCl3): δ 1,25-2,00 (m, 8H); 2,30-2,70 (m, 6N); to 2.85 (m, 1H); 3,00 (m, 1H); 3,20 (m, 1H).

Stage 4:

220 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bramp the Nile)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-2-fluoro-4-(permitil)cinnamic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ 1,45-of 1.85 (m, 4H); 1.85 to of 2.20 (m, 4H); 2.40 a is 2.75 (m, 6N); of 3.60 and 3.70 (both m, together 2H); 4,15 and and 4.40 (both m, together 1H); 6,95 and 7.15m (both d, together 1H); 7,40 (m, 2H); 7,60 (m, 1H); to 7.75 (m, 1H).

HPLC (method C): elution at or 4.31 minutes

Mass spectrum: calculated for [M+H]+: 371; found: 371.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 54 (General procedure (A))

2-Fluoro-5-[(E)-3-oxo-3-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenyl]benzonitrile

250 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(3-cyano-4-forfinal)acrylic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ 1,55-of 2.15 (m, 8H); 2,40-of 2.75 (m, 6N); the 3.65 and 3.70 (both m, together 2H); 4,15 and and 4.40 (both m, together 1H); 6,70 and 6,95 (both d, together 1H); to 7.25 (t, 1H); of 7.60 (d, 1H); of 7.70 (m, 1H); 7,80 (m, 1H).

HPLC (method C): elution 3,59 minutes

Mass spectrum: calculated for [M+H] +: 328; found: 328.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 55 (General procedure (A))

(E)-1-((S)-2-((Pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)-3-(3-(trifluoromethyl)phenyl)propane

320 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(trifluoromethyl)cinnamic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.75 (m, 4H); 1.85 to to 2.25 (m, 4H); 2,45 is 2.80 (m, 6N); of 3.60 and 3.75 (both m, together 2H); 4,15 and and 4.40 (both m, together 1H); 6,80 and 7,00 (both d, together 1H); 7,45-7,80 (m, 5H).

HPLC (method C): elution at 4,16 minutes

Mass spectrum: calculated for [M+H]+: 353; found: 353.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 56 (General procedure (A))

(E)-3-(4-tert-Butylphenyl is)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

340 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-tert-butylcatechol acid (marketed, for example, a company Emkachem) instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.40 (s, N); to 1.75 (m, 4H); 1.85 to of 2.20 (m, 4H); 2.40 a is 2.75 (m, 6N); of 3.60 and 3.70 (both m, together 2H); 4,15 and and 4.40 (both m, together 1H); 6,70 and 6,85 (both d, together 1H); 7,40 (m, 2H); 7,50 (d, 2H); of 7.70 (d, 1H).

HPLC (method C): elution at 4,76 minutes

Mass spectrum: calculated for [M+H]+: 341; found: 341.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 57 (General procedure (A))

(E)-1-((S)-2-((Pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)-3-(3-(triptoreline)phenyl)propane

340 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(triptoreline)cinnamic acid (marketed in particular by the company Lacaster) instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.80 (m, 4H); 1.85 to of 2.20 (m, 4H); 2.40 a is 2.80 (m, 6N); the 3.65 and 3.70 (both m, together 2H); 4,15 and and 4.40 (both m, together 1H); 6.75 in and 6,90 (both d, together 1H); 7,20 (m, 1H); 7,40 (m, 2H); the 7.65 (d, 1H).

HPLC (method C): elution at 4,30 minutes

Mass spectrum: calculated for [M+H]+: 369; found: 369.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 58 (General procedure (A))

(E)-3-(4-Chloro-3-triptoreline)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone

210 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-chloro-3-(trifluoromethyl)cinnamic acid (marketed in particular by the company Interchim, France) instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.75 (m, 4H); 1.85 to of 2.20 (m, 4H); 2.40 a is 2.75 (m, 6N); of 3.60 and 3.70 (both m, together 2H); 4,15 and and 4.40 (both m, together 1H); 6.75 in and 6,95 (both d, together 1H); 7,45-of 7.60 (m, 2H); the 7.65 (d, 1H); a 7.85 (m, 1H).

HPLC (method C): elution at 4,50 minutes

Mass spectrum: calculated for [M+H]+: 387; found is: 387.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 59 (General procedure (A))

(E)-3-(3-Fluoro-5-(trifluoromethyl)phenyl)-1-((S)-2-((pyrrolidin-1-yl) methyl)pyrrolidin-1-yl)propenone

290 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-fluoro-5-(trifluoromethyl)cinnamic acid (marketed in particular by the company Interchim, France) instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.75 (m, 4H); 1.85 to to 2.15 (m, 4H); 2,45 is 2.75 (m, 6N); of 3.60 and 3.70 (both m, together 2H); 4,15 and and 4.40 (both m, together 1H); 7,80 and 7,00 (both d, together 1H); 7,30 (d, 1H); 7,40 (d, 1H); at 7.55 (m, 1H); the 7.65 (DD, 1H).

HPLC (method C): elution at 4,29 minutes

Mass spectrum: calculated for [M+H]+: 371; found: 371.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is dilaut in vacuum.

Example 60 (General procedure (C))

(E)-1-((S)-2-(Diethylaminomethyl)pyrrolidin-1-yl)-3-(4-(triptoreline)phenyl)propane

Stage 1:

N,N-Diethyl-N-(((S) -pyrrolidin-2-yl)methyl)Amin

N,N-Diethyl-N-(((S)-pyrrolidin-2-yl)methyl)amine synthesized according to the method described for (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine, using as source of N,N-diethylamine instead of pyrrolidine.

Range1H-NMR (CDCl3): δ 1.00 each (t, 6N); of 1.35 (m, 1H); to 1.75 (m, 2H); of 1.85 (m, 1H); 2,35 (m, 2H); to 2.55 (m, 4H); to 2.85 (m, 1H), 3,00 (m, 1H); 3,20 (m, 1H).

Stage 2:

170 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-(triptoreline)cinnamic acid instead of (E)-4-bromcresol acid and N,N-diethyl-N-(((S)-pyrrolidin-2-yl)methyl)amine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.05 (m, 6N); 1.85 to to 2.15 (m, 4H); 2,15 is 2.80 (m, 6N); 3,50-3,75 (m, 2H); 4,10 and 4,30 (both m, together 1H); 6,70 6,90 and (both d, together 1H); then 7.20 (d, 2H); at 7.55 (d, 2H); 7,65 and 7,66 (both d, together 1H).

HPLC (method C): elution at 4,54 minutes

Mass spectrum: calculated for [M+H]+: 371; found: 371.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and adding the s 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 61 (General procedure (C))

(E)-1-((S)-2-(Diethylaminomethyl)pyrrolidin-1-yl)-3-(4-(trifluoromethyl)phenyl)propane

310 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-triptorelin acid instead of (E)-4-bromcresol acid and N,N-diethyl-N-(((S)-pyrrolidin-2-yl)methyl)amine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.

Range1H-NMR (CDCl3, 2 sets of signals): δ 1.00 each (m, 6N); 1.85 to to 2.15 (m, 4H); 2,20-2,80 (m, 6N); of 3.60 and 3.70 (both m, together 2H); 4,10 and 4,30 (both m, together 1H); 6,80 and 7,00 (both d, together 1H); 7,60 (AB, 2H); 7,70 and 7,71 (both d, together 1H).

HPLC (method C): elution at 4,39 minutes

Mass spectrum: calculated for [M+H]+: 355; found: 355.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 62 (General procedure (C))

(E)-1-((S)-2-(Diethylaminomethyl)pyrrolidin-1-yl)-3-(3,4-acid)propane

190 mg of the title compound is synthesized according to the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3,4-dimethoxyphenyl acid instead of (E)-4-bromcresol acid and N,N-diethyl-N-(((S)-pyrrolidin-2-yl)methyl)amine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.05 (m, 6N); 1.85 to to 2.15 (m, 4H); 2,15 is 2.80 (m, 6N); of 3.60 and 3.75 (both m, together 2H); 3,90 (C, 6N); 4,10 and 4.35 (both m, together 1H); 6,60 and 6.75 (both d, together 1H); 6,85 (d, 1H); 7.03, and 7,05 (both s, together 1H); 7,10 (d, 1H); 7,65 and 7,66 (both d, together 1H).

HPLC (method C): elution at 3,47 minutes

Mass spectrum: calculated for [M+H]+: 347; found: 347.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 63 (General procedure (C))

(E)-1-((R)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)-3-(4-(triptoreline)phenyl)propane

Stage 1:

1-(((R)-Pyrrolidin-2-yl)methyl)piperidine

1-(((R)-Pyrrolidin-2-yl)methyl)piperidine synthesized by the method similar to that shown for (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine, using as source (R)-1-(tert-butoxycarbonyl peer who ridin-1-carboxylic acid instead of (S)-1-(tert-butoxycarbonyl)pyrrolidin-1-carboxylic acid.

Range1H-NMR (CDCl3): δ 1.30 on (m, 1H); of 1.40 (m, 2H); of 1.55 (m, 4H); to 1.70 (m, 3H); of 1.85 (m, 1H); 2,25-2,60 (m, 6N); 2,80 (m, 1H); 3,00 (m, 1H); of 3.25 (m, 1H).

Stage 2:

185 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-trevormarsicano acid instead of (E)-4-bromcresol acid and 1-(((R)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.45 (m, 2H)and 1.60 (m, 4H); 1,80-2,10 (m, 4H); 2,15-2,70 (m, 6N); 3,50-3,75 (m, 2H); 4,15 and and 4.40 (both m, together 1H); 6,70 6,90 and (both d, together 1H); then 7.20 (d, 2H); at 7.55 (d, 2H); the 7.65 (d, 1H).

HPLC (method C): elution at br4.61 minutes

Mass spectrum: calculated for [M+H]+: 383; found: 383.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 64 (General procedure (C))

(E)-1-((R)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)-3-(4-(trifluoromethyl)phenyl)propane

479 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)shall ethyl)pyrrolidin-1-yl)propenone, using (E)-4-triptorelin acid instead of (E)-4-bromcresol acid and 1-(((R)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.45 (m, 2H); of 1.55 (m, 4H); 1.85 to 2,10 (m, 4H); 2,15-2,70 (m, 6N); 3,50-3,75 (m, 2H); 4,15 and and 4.40 (both m, together 1H); 6,80 and 7,05 (both d, together 1H); 7,65 (AB, 4H); of 7.70 (d, 1H).

HPLC (method C): elution at of 4.44 minutes

Mass spectrum: calculated for [M+H]+: 367; found: 367.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 65 (General procedure (D))

((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)-(5-(trifluoromethyl)benzofuran-2-yl)methanon

Stage 1:

2-(4-(Trifluoromethyl)phenoxy)tetrahydropyran

A solution of 4-(trifluoromethyl)phenol (2,44 g, 15 mmol) in dichloromethane (5 ml) are added to a solution of 3,4-dihydro-2H-Piran (4,10 ml, 45 mmol) and 3.6 M solution of hydrogen chloride in ethyl acetate (0,015 ml, 0.05 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 16 hours. Dilute with ethyl acetate (100 ml) and washed with saturated podnimetsia sodium bicarbonate (100 ml). The aqueous phase is extracted with ethyl acetate (2×30 ml). The organic extracts are combined and dried over magnesium sulfate. The solvent is removed in vacuum. The crude product was purified flash chromatography on silica gel (90 g), using as eluent a mixture of ethyl acetate/heptane 1:10, and get to 3.09 g of 2-(4-(trifluoromethyl)phenoxy)tetrahydropyran.

Range1H-NMR (CDCl3): δ of 1.65 (m, 3H); of 1.85 (m, 2H); 2,00 (m, 1H); of 3.60 (m, 1H); of 3.85 (m, 1H); of 5.45 (t, 1H); to 7.15 (d, 2H); at 7.55 (d, 2H).

Stage 2:

2-Hydroxy-5-(trifluoromethyl)benzaldehyde

a 1.6 n solution of n-utility in hexane (7,20 ml, 11.5 mmol) is added at a temperature of minus 15°C to N,N,N',N'-tetramethylethylenediamine (1,72 ml of 11.4 mmol). The reaction mixture is stirred at minus 10°C for 10 minutes Add 2-(4-(trifluoromethyl)phenoxy)tetrahydropyran (2.0 g, 8,12 mmol) and the reaction mixture is stirred at minus 10°C for 2 hours. Add N,N-dimethylformamide (0,88 ml of 11.4 mmol). The reaction mixture is stirred at minus 10°C for 15 minutes then Poured into 6 M hydrochloric acid solution and the resulting mixture was stirred at room temperature for 16 hours. The organic layer is separated and dried. The solvent is removed in vacuum. From the crude product by method of a flash chromatography on silica gel (90 g), using as eluent a mixture of ethyl acetate/heptane 1:10, allocate 659 mg of 2-hydroxy-5-(cryptomite is)benzaldehyde.

Range1H-NMR (CDCl3): δ 7,10 (d, 1H); 7,80 (d, 1H), of 7.90 (s, 1H); for 9.90 (s, 1H); RS 11.30 (s, 1H).

Stage 3:

Ethyl ester 5-(trifluoromethyl)benzofuran-2-carboxylic acid

A mixture of potassium carbonate (4,00 g, 8.6 mmol), diethyl ether of bromomalonate acid (1,43 ml, 8.4 mmol), 2-hydroxy-5-(trifluoromethyl)benzaldehyde (638 mg, 3,40 mmol) and methyl ethyl ketone (15 ml) is heated to boiling for 16 hours. Cool to room temperature. The precipitate is filtered and washed with acetone. The filtrate is evaporated. The crude product was purified flash chromatography on silica gel (40 g), using as eluent a mixture of ethyl acetate/heptane 1:5, and receive 747 mg ethyl ester 5-(trifluoromethyl)benzofuran-2-carboxylic acid.

Range1H-NMR (CDCl3): δ of 1.45 (t, 3H); 4,50 (q, 2H); of 7.60 (s, 1H); of 7.70 (s, 2H), 8,00 (s, 1H).

Stage 4:

5-(Trifluoromethyl)benzofuran-2-carboxylic acid

To a solution of ethyl ester 5-(trifluoromethyl)benzofuran-2-carboxylic acid (705 mg, 2,73 mmol) in 1,4-dioxane (6 ml) add a solution of lithium hydroxide (78 mg, 3.7 mmol) in water (6 ml). Add additional amounts of 1,4-dioxane to form a clear solution. The reaction mixture was stirred at room temperature for 16 hours. Dilute 1 N. aqueous sodium hydroxide solution and washed with tert-butyl the tilov ether (2×30 ml). The aqueous phase is acidified with 10%aqueous solution of sodium bisulfate to pH 3. Extracted with ethyl acetate (3×40 ml). An ethyl acetate extracts are combined and dried over magnesium sulfate. The solvent is removed in vacuum and receive crude 5-(trifluoromethyl)benzofuran-2-carboxylic acid, which is used in the next stage without further purification.

Range1H-NMR (DMSO-d6): δ 7,80 (s, 1H); a 7.85 (d, 1H), 7,95 (d, 1H); of 8.25 (s, 1H); 13,80 (user., 1H).

180 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using 5-(trifluoromethyl)benzofuran-2-carboxylic acid instead of (E)-4-bromcresol acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.

Range1H-NMR (CDCl3): δ of 1.40 and 1.80 (user., 6N); 2,00 (user., 2H); 2,30 (user., 2H); 2,55 (user., 2H); 3,60-4,10 (user., 2H); 4,50 and 4,85 (both user., together 1H); 7,35-7,70 (user., 3H); 8,00 (s, 1H).

HPLC (method A): elution at of 9.55 minutes

Mass spectrum: calculated for [M+H]+: 381; found: 381.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

When the EP 66 (General procedure (E))

(E)-3-(4-(Cyclopropanecarbonyl)phenyl)-1-((S)-2-((pyrrolidin-1-yl) methyl)pyrrolidin-1-yl)propenone

Stage 1:

Methyl ester (E)-3-(4-(cyclopropanecarbonyl)phenyl)acrylic acid

A mixture of (4-bromophenyl)-(cyclopropyl)methanone (0,450 t, 2.00 mmol), palladium acetate (49 mg, 0,220 mmol), triphenylphosphine (55 mg, 0.21 mmol), methyl acrylate (0,43 g of 2.50 mmol) and triethylamine (10 ml, 72 mmol) is heated in a sealed ampoule to a temperature of 100°C for 48 hours. Cool the mixture to room temperature. The solid is separated by filtration. To the liquid add a mixture of ice and 1 N. hydrochloric acid and the mixture is stirred for one hour at room temperature. Extracted with ethyl acetate (2×150 ml), the organic extracts are combined, washed with saturated aqueous sodium bicarbonate solution (100 ml) and dried over magnesium sulfate. The solvent is removed in vacuum. The crude product was purified flash chromatography on silica gel (40 g), using as eluent a mixture of dichloromethane/ethyl acetate/heptane (1:1:1), and obtain 217 mg of methyl ester of (E)-3-(4-(cyclopropanecarbonyl)phenyl)acrylic acid.

Range1H-NMR (CDCl3): δ of 1.05 (m, 2H); 1,25 (m, 2H); to 2.65 (m, 1H); 3,85 (s, 3H); 6,55 (d, 1H); a 7.62 (d, 2H); of 7.75 (d, 1H); with 8.05 (d, 2H).

Stage 2:

(E)-3-(4-(Cyclopropanecarbonyl)phenyl)acrylic acid

To the solution met the business ester (E)-3-(4-(cyclopropanecarbonyl)phenyl)acrylic acid (217 mg, to 0.94 mmol) in 1,4-dioxane (2.00 ml) add a solution of lithium hydroxide (27 mg, 1.1 mmol) in water (2.00 ml). Add additional amounts of 1,4-dioxane to form a clear solution. The reaction mixture was stirred at room temperature for 16 hours. Dilute 1 N. aqueous sodium hydroxide solution (50 ml) and washed with tert-butylmethylamine ether (2×40 ml). The aqueous phase is acidified with 10%aqueous solution of sodium bisulfate to pH 3. Extracted with ethyl acetate (3×100 ml). The organic layers are combined and dried over magnesium sulfate. The solvent is removed in vacuum and obtain 170 mg of crude (E)-3-(4-(cyclopropanecarbonyl)phenyl)acrylic acid, which is used in the next stage without further purification.

Range1H-NMR (DMSO-d6): δ of 1.05 (m, 4H); 2.95 and (m, 1H); 6,70 (d, 1H); the 7.65 (d, 1H); a 7.85 (d, 2H); with 8.05 (d, 2H); 12,60 (user., 1H).

Stage 3:

130 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(4-(cyclopropanecarbonyl)phenyl)acrylic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.05 (m, 2H); 1,25 (m, 2H); of 1.80 (m, 4H); 1,90-of 2.15 (m, 4H); 2.40 a is 2.80 (m, 6N); of 3.60 and 3.70 (both m, together 2H); 4,15 and and 4.40 (both m, together 1H); 6,85 and 7,00 (both d, together 1H); 7,40 (d, 2H); of 7.75 (d, 1H); 8,00 (m, 2H).

HPLC (method A): als what I 8,48 minutes

Mass spectrum: calculated for [M+H]+: 353; found: 353.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 67 (General procedure (D))

((S)-2-((Pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)-(5-(triptoreline)benzofuran-2-yl)methanon

Stage 1:

5-(Triptoreline)benzofuran-2-carboxylic acid

93 mg of 5-(triptoreline)benzofuran-2-carboxylic acid get by the method described for 5-(trifluoromethyl)benzofuran-2-carboxylic acid using 4-(triptoreline)phenol instead of 4-(trifluoromethyl)phenol.

Range1H-NMR (DMSO-d6): δ 7,50 (d, 1H); of 7.70 (s, 1H); a 7.85 (m, 2H), 13,80 (user., 1H).

69 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using 5-(triptoreline)benzofuran-2-carboxylic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals, broadened signals): δ of 1.75 (m, 5H); 1,90-of 2.30 (m, 5H); 2,30-2,90 (m, 6N); 3,60-4,10 (m, 2H); 4,50 and 4,85 (both m, together 1H); 7,30 (m, 1H); 7,35-of 7.60 (m, 2H).

HPLC (method A): elution at 9,51 minutes

Mass spectrum: calculated for [M+H]+: 383; found: 383.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 68 (General procedure (D))

((S)-2-((Diethylamino)methyl)pyrrolidin-1-yl)-(6-(trifluoromethyl)benzofuran-2-yl)methanon

Stage 1:

6-(Trifluoromethyl)benzofuran-2-carboxylic acid

93 mg of 6-(trifluoromethyl)benzofuran-2-carboxylic acid get by the method described for 5-(trifluoromethyl)benzofuran-2-carboxylic acid using 3-(trifluoromethyl)phenol instead of 4-(trifluoromethyl)phenol.

Range1H-NMR (DMSO-d6): δ of 7.70 (d, 1H); 7,80 (s, 1H); with 8.05 (d, 1H), to 8.20 (s, 1H); 13,90 (user., 1H).

220 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using 6-(trifluoromethyl)benzofuran-2-carboxylic acid instead of (E)-4-bromcresol acid and N,N-diethyl-N-(((S)-pyrrolidin-2-yl)methyl)amine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.

Range1H-NMR (CDCl32 set the ignatow): δ of 0.90 and 1.05 (both m, together 6N); 1,90-of 2.15 (m, 4H); 2,20-2,90 (m, 6N); 3,75, 3,90, and of 4.05 (all m, together 2H); 4,50 and 4,85 (both m, together 1H); 7,40-of 7.60 (m, 2H); 7,70-a 7.85 (m, 2H).

HPLC (method A): elution at 10,18 minutes

Mass spectrum: calculated for [M+H]+: 369; found: 369.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 69 (General procedure (D))

((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)-(6-(trifluoromethyl)benzofuran-2-yl)methanon

71 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using 6-(trifluoromethyl)benzofuran-2-carboxylic acid instead of (E)-4-bromcresol acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.

Range1H-NMR (CDCl3, 2 sets of signals): δ 1,20-1,70 (m, 6N); 1,90-of 2.20 (m, 4H); 2,20-to 2.85 (m, 6N); 3,60-3,95, and 3.95-4,15 (both m, together 2H); 4,55 and 4,85 (and both, together 1H); 7,40-of 7.60 (m, 2H); 7,65-of 7.90 (m, 2H).

HPLC (method A): elution at 9,74 minutes

Mass spectrum: calculated for [M+H]+: 381; found: 381.

Specified in the title compound turn in his chloritoid the same salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 70 (General procedure (D))

((S)-2-((Pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)-(6-(trifluoromethyl)benzofuran-2-yl)methanon

150 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using 6-(trifluoromethyl)benzofuran-2-carboxylic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ to 1.70 (m, 4H); 1,90-of 2.20 (m, 4H); 2,20-2,90 (m, 6N); 3,60-4,10 (m, 2H); 4,55 and 4,85 (both m, together 1H); 7,40-of 7.60 (m, 2H); 7,70-of 7.90 (m, 2H).

HPLC (method A): elution at 9,39 minutes

Mass spectrum: calculated for [M+H]+: 367; found: 367.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 71 (General procedure (C))

(E)-3-(4-Chloro-3-triptoreline)-1-((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)propenone

220 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((IRTP who ridin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-chloro-3-(trifluoromethyl)cinnamic acid instead of (E)-4-bromcresol acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl) methyl)pyrrolidine.

Range1H-NMR (CDCl3, 2 sets of signals): δ 1,30-1,70 (m, 6N); 1,80-of 2.15 (m, 4H); 2,15-of 2.75 (m, 6N); of 3.60 and 3.70 (both m, together 2H); 4,15 and and 4.40 (both m, together 1H); 6.75 in and 7,00 (both d, together 1H); 7,45-of 7.70 (m, 3H); 7,80 and a 7.85 (both s, together 1H).

HPLC (method A): elution at 10,41 minutes

Mass spectrum: calculated for [M+H]+: 401; found: 401.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 72 (General procedure (C))

(E)-3-(3-Fluoro-5-(trifluoromethyl)phenyl)-1-((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)propenone

210 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-fluoro-5-(trifluoromethyl)cinnamic acid instead of (E)-4-bromcresol acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl) methyl)pyrrolidine.

Range1H-NMR (CDCl3, 2 sets of signals): δ 1.25 and to 1.70 (m, 6N); 1,80-of 2.15 (m, 4H); 2,15-2,70 (m, 6N); of 3.60 and 3.70 (both m, together 2H); 4,15 and and 4.40 (both m, together 1H); 6.75 in and 7,05 (both d, together 1H); 7,20 was 7.45 (m, 2H); 7,45-of 7.70 (m, 2H).

HPLC (method A): elution at 9,74 minutes

Mass spectrum: calculated for [M+H]+: 385; found: 385.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 73 (General procedure (D))

((S)-2-((Pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)-(5-(trifluoromethyl)benzofuran-2-yl)methanon

210 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using 5-(trifluoromethyl)benzofuran-2-carboxylic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ 1.

HPLC (method A).

Mass spectrum: calculated for [M+H]+.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Por the measures 74 (General procedure (D))

((S)-2-((Diethylamino)methyl)pyrrolidin-1-yl)-(5-(trifluoromethyl)benzofuran-2-yl)methanon

110 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using 5-(trifluoromethyl)benzofuran-2-carboxylic acid instead of (E)-4-bromcresol acid and N,N-diethyl-N-(((S)-pyrrolidin-2-yl)methyl)amine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.

Range1H-NMR (CDCl3, 2 sets of signals): δ 0,80-1,20 (m, 6N); of 1.65 and 2.00 (both m, together 4H); 2,20-2,90 (m, 6N); 3,75, 3,90, and of 4.05 (all m, together 2H); 4,45 and 4,80 (both m, together 1H); 7,40-of 7.70 (m, 3H); 8,00 (s, 1H).

HPLC (method A): elution at 9,31 minutes

Mass spectrum: calculated for [M+H]+: 369; found: 369.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 75 (General procedure (A))

(E)-1-((S)-2-((Pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)-3-(4-(trifluoromethyl)phenyl)but-2-EN-1-he

Stage 1:

(E)-3-(4-(Trifluoromethyl)phenyl)but-2-ANOVA acid

2.85 g (E)-3-(4-(trifluoromethyl)phenyl)but-2-ANOVA the acid get method similar to that shown for (E)-4-methylsulfonylamino acid using 1-(4-(trifluoromethyl)phenyl)Etalon instead of 4-(methylsulphonyl)benzaldehyde.

Range1H-NMR (DMSO-d6): δ 2.50 each (s, 3H); of 6.20 (s, 1H); 7,80 (s, 4H).

Stage 2:

240 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(4-(trifluoromethyl)phenyl)but-2-envoy acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals, broadened signals): δ 1,65-of 1.85 (m, 4H); 1.85 to to 2.15 (m, 4H); 2,35 is 2.80 (m, 6N); of 2.50 (s, 3H); 3.40 in-3,70 (m, 2H); 4,05 and and 4.40 (both m, together 1H); of 6.25 and 6.50 (both s, together 1H); at 7.55 (m, 2H); the 7.65 (d, 2H).

HPLC (method A): elution at 10,43 minutes

Mass spectrum: calculated for [M+H]+: 367; found: 367.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 76 (General procedure (A))

(E)-1-((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)-3-(4-(trifluoromethyl)phenyl)but-2-EN-1-he

110 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(4-(trifluoromethyl)phenyl)but-2-envoy acid instead of (E)-4-bromcresol acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.

Range1H-NMR (CDCl3, 2 sets of signals, broadened signals): δ 1.30 and of 1.65 (m, 6N); 2,80 is 2.10 (m, 4H); 2,15-2,70 (m, 6N); of 2.45 (s, 3H); 3.40 in-3,70 (m, 2H); 4.00 and 4,35 (both m, together 1H); of 6.25 and 6.50 (both s, together 1H); 7,50-the 7.65 (m, 4H).

HPLC (method A): elution at 10,69 minutes

Mass spectrum: calculated for [M+H]+: 381; found: 381.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 77 (General procedure (A))

(E)-3-(4-(Isobutyl)phenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)but-2-EN-1-he

Stage 1:

(E)-3-(4-(Isobutyl)phenyl)but-2-ANOVA acid

of 0.91 g (E)-3-(4-(isobutyl)phenyl)but-2-ene acid get by the method similar to that shown for (E)-4-methylsulfonylamino acid using 1-(4-(isopropyl)phenyl)Etalon instead of 4-(methylsulphonyl)benzaldehyde.

Range1H-NMR (DMSO-d6): δ of 0.90 (d, 6N); of 1.85 (m, 1H); 2.50 each (m, 5H); 6,10 (s, 1H); then 7.20 (d, 2H); was 7.45 (d, 2H); 12,15 (user., 1H).

u> Stage 2:

250 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(4-(isobutyl)phenyl)but-2-envoy acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals, broadened signals): δ of 0.95 (d, 6N); of 1.65 and 1.80 (m, 4H); 1,80-of 2.15 (m, 5H); 2,40 is 2.80 (m, 6N); 2,45 (C, ZN); 2,50 (d, 2H), 3.45 points-of 3.60 (m, 2H); 4,05 and and 4.40 (both m, together 1H); 6.25 and 6,45 (both s, together 1H); to 7.15 (d, 2H); 7,40 (m, 2H).

HPLC (method A): elution at 11,19 minutes

Mass spectrum: calculated for [M+H]+: 355; found: 355.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 78 (General procedure (A))

(E)-3-(4-(Isobutyl)phenyl)-1-((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)but-2-EN-1-he

130 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(4-(isobutyl)phenyl)but-2-envoy acid instead of (E)-4-bromcresol acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrol the DIN-1-yl) methyl)pyrrolidine.

Range1H-NMR (CDCl3, 2 sets of signals, broadened signals): δ of 0.90 (d, 6N); 1,30-of 1.65 (m, 6N); 1,70 is 2.10 (m, 5H); 2,10-2,70 (m, 6N); 2,45 (C, ZN); 2,50 (d, 2H); 3,35-the 3.65 (m, 2H); 4,05 and and 4.40 (both m, together 1H); 6.25 and 6,45 (both s, together 1H); to 7.15 (d, 2H); 7,35 and 7,45 (both d, together 2H).

HPLC (method A): elution at 11,63 minutes

Mass spectrum: calculated for [M+H]+: 369; found: 369.

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 79 (General procedure (A))

(E)-1-((S)-2-((Pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)-3-(4-(1,2,4-triazole-1-yl)phenyl)propene

Stage 1:

(E)-3-(4-(1,2,4-Triazole-1-yl)phenyl)acrylic acid

to 1.9 g of (E)-3-(4-(1,2,4-triazole-1-yl)phenyl)acrylic acid get by the method similar to that shown for (E)-3-(4-(methanesulfonamide)phenyl)acrylic acid using 4-(1,2,4-triazole-1-yl)benzaldehyde instead of 4-formylphenyl ether methanesulfonate.

Range1H-NMR (DMSO-d6): δ 6,60 (d, 1H); the 7.65 (d, 1H); of 7.90 (AB, 4H); 8,30 (s, 1H); 9,40 (s, 1H); 12,50 (user., 1H).

Stage 2:

74 mg specified in the title compounds are synthesized by the method similar to the cm is authorized to (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(4-(1,2,4-triazole-1-yl)phenyl)acrylic acid instead of (E)-4-bromcresol acid.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.80 (m, 4H); 1.85 to of 2.20 (m, 4H); 2,45 is 2.80 (m, 6N); of 3.60 and 3.70 (both m, together 2H); 4,20 and and 4.40 (both m, together 1H); 6,80 and 6,95 (both m, together 1H); of 7.70 (m, 5H); 8,10 (s, 1H); at 8.60 (s, 1H).

HPLC (method A): elution at 2,96 minutes

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

Example 80 (General procedure (A))

(E)-1-((S)-2-(piperidine-1-yl)methyl)pyrrolidin-1-yl)-3-(4-(1,2,4-triazole-1-yl)phenyl)propene

165 mg specified in the title compounds are synthesized by the method similar to that shown for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(4-(1,2,4-triazole-1-yl)phenyl)acrylic acid instead of (E)-4-bromcresol acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl) methyl)pyrrolidine.

Range1H-NMR (CDCl3, 2 sets of signals): δ of 1.40 (m, 2H); of 1.55 (m, 4H); 1,80-of 2.15 (m, 4H); 2,15-2,70 (m, 6N); of 3.60 and 3.70 (both m, together 2H); 4,20 and and 4.40 (both m, together 1H); 6.75 in and 7,00 (both d, together 1H); of 7.70 (m, 5H); 8,10 (s, 1H); at 8.60 (s, 1H).

HPLC (method A): elution of CR is 3,15 minutes

Specified in the title compound is transformed into its monohydrochloride salt by dissolving it in ethyl acetate (5 ml) and add a 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

The ability of the compounds of the present invention to interact with the H3-receptor histamine can be set using the following in vitro tests on the binding.

The test link I

The cerebral cortex of rats homogenized in ice buffer K-Hepes with pH of 7.1, containing 5 mm MgCl2. After two differential zentrifugenbau final tablet again suspended in fresh Hepes buffer containing 1 mg/ml bacitracin. Aliquots of a suspension of membranes (400 µg/ml) incubated for 60 min at 25°C 30 PM [125I]-iodoprotein known antagonist H3-receptor histamine, and various concentrations of the test compounds. Incubation is interrupted, diluting chilled with ice, and then quickly filtered through filters Whatman GF/B, pre-treated for 1 hour with 0.5%by polyethylenimine. The radioactivity remaining on the filters counted using an automatic counter gamma radiation Cobra II. The radioactivity on the filter is inversely proportional to the affinity of binding and pitamaha connection. The results of the process using nonlinear regression analysis.

Test associate II

The ligand R-α-methyl[3H]histamine (RAMHA) agonist H3-receptor incubated with the selected cell membranes of the cerebral cortex of rats for one hour at a temperature of 25°C and then filtered incubat through filters Whatman GF/b Radioactivity remaining on the filters are counted by a counter beta particles.

Male Wistar rats (150-200 g) decapitate, quickly remove the cortex and placed on dry ice. Tissue stored at minus 80°C until preparation of membranes. During the preparation of membranes fabric all the time kept on ice. The cerebral cortex of rats homogenized for 30 s in 10 volumes (about./about.) ice Hepes buffer (20 mm Hepes, 5 mm MgCl2pH 1,1 (CON)+1 mg/ml bacitracin) using a homogenizer (Ultra-Turrax. The homogenate was centrifuged with acceleration 140g within 10 minutes the Liquid above the precipitate is transferred into another tube and centrifuged for 30 min with acceleration 23000g. Received the tablet again suspended in 5-10 ml of Hepes buffer, homogenized and again centrifuged with acceleration 23000g for 10 minutes This short operation centrifugation was repeated twice. After the last centrifugation tablet resuspended in 2-4 ml of Hepes buffer and determine the protein concentration. Membranes RA is billaut with Hepes buffer to a protein concentration of 5 mg/ml, take an aliquot and store them until use at a temperature of minus 80°C.

In vitro mixing 50 μl of the test compound, 100 μl of membranes (200 μg/ml)300 ál of Hepes buffer and 50 μl of R-α-methyl[3H]histamine (1 nm). Studied in the test compounds dissolved in DMSO and then diluted with water to the desired concentration. Radioligand and membranes diluted with Hepes buffer+1 mg/ml bacitracin. The mixture was incubated for 60 min at 25°C. the Incubation is interrupted by adding 5 ml ice with 0.9%NaCl, and then quickly filtered through filters Whatman GF/B, pre-treated for 1 hour with 0.5%by polyethylenimine. The filters are washed with 2×5 ml of cold NaCl. To each filter add 3 ml of scintillation cocktail and the remaining radioactivity is counted using a counter beta particles Packard Tri-Carb. The values of the IC50determined using nonlinear regression analysis of the binding curves (minimum 6 points)using the program GraphPad Prism company GraphPad Software, USA.

Test associate III

H3-receptor human clone polymerase chain reaction and subcloning on the expression vector pcDNA3. Cells stably expressing the H3-receptor, generated by transfection of vectors expressing the H3 in cells of SOME 293 using G418 for selection of clones H3. Clones H3 NECK 293 people cultivate the mod is fitiavana by way of Dulbecco environment Needle (DMEM, from the company GIBCO-BRL) with glutamax, 10%serum, fetal cow, 1%penicillin/streptavidin and 1 mg/ml G 418 at 37°C and 5% CO2. Before collecting merged cells washed with phosphate buffered saline (PBS) and incubated with Versene (proteinase, from GIBCO-BRL) for approximately 5 minutes, the Cells washed with PBS and DMEM, cell suspension is collected in a test tube and centrifuged for 5-10 min with a speed of 1500 rpm in a centrifuge Heraeus Sepatech Megafuge 1.0. Received the tablet again suspended in 10-20 volumes of Hepes buffer (20 mm Hepes, 5 mm MgCl2pH of 7.1 (CON)) and homogenized within 10 to 20 seconds using a homogenizer Ultra-Turrax. The homogenate was centrifuged for 30 min with acceleration 23000g. Received the tablet again suspended in 5-10 ml of Hepes buffer, homogenized within 5-10 using the Ultra-Turrax and centrifuged for 10 min with acceleration 23000g. After centrifugation tablet membranes resuspended in 2-4 ml of Hepes buffer, homogenized syringe or Teflon homogenizer and determine the protein concentration. Membranes diluted with Hepes buffer to a protein concentration of 1-5 mg/ml, take an aliquot and store them until use at a temperature of minus 80°C.

Aliquots of a suspension of membranes incubated for 60 min at 25°C 30 PM [125I]-iodoprotein, compounds with known high affinity for the H3 receptor is, and with the test compound in various concentrations. Incubation is interrupted, diluting chilled with ice, and then quickly filtered through filters Whatman GF/B, pre-treated for 1 hour with 0.5%by polyethylenimine. The radioactivity remaining on the filters counted using an automatic counter gamma radiation Cobra II. The radioactivity on the filter is inversely proportional to the affinity of binding of the test compound. The results of the process using nonlinear regression analysis.

When testing these compounds of formula (I) exhibit high affinity binding to H3-receptor histamine.

Compounds of the present invention preferably have a value IC50defined using one or more tests, less than 10 microns, more preferably smaller than 1 μm and even more preferably less than 500 nm, such as less than 100 nm.

Functional test I

The ability of the compounds of the present invention to interact with the H3-receptor histamine as agonists, inverse agonists and/or antagonists is determined using an in vitro functional test, using the cell membranes of SOME 293 expressing the H3-receptors of the man.

H3-receptor clone polymerase chain reaction and subcloning on the expression vector pcDNA3. the yrs, stably expressing the H3-receptor, generated by transfection of vectors expressing the H3 in cells of SOME 293 using G-418 for selection of clones H3. Clones H3 NECK 293 human cultured in DMEM with glutamax, 10%serum, fetal cow, 1%penicillin/streptavidin and 1 mg/ml G 418 at 37°C and 5% CO2.

Cells expressing the H3-receptor, washed once with PBS and harvested using Versene (from GIBCO-BRL). Add PBS and the cells centrifuged for 5 min with acceleration 188g. Received the tablet again suspended in a stimulating buffer to a concentration of 1×106cells/ml For the accumulation of cyclic amp (camp) see using the test Flash Plate® cAMP (NEN™ Life Science Products). The test is usually carried out in accordance with the manufacturer's recommendations. In brief, 50 µl of cell suspension added to each well of the tablet Flashplate, which also contains 25 μl of 40 μm izoprenalin, to stimulate the formation of camp, and 25 μl of test compound (either agonists or inverse agonists individually, or combinations of agonist and antagonist). The test can be performed in mode agonist, which means that the cells add individual test connection with increasing concentration and measure the content of camp. If the value for camp increases, then the test compound is an inverse agonist is; if the value for the camp does not change, then the test compound is a neutral antagonist, and if the value for camp decreases, then the test compound is an agonist. The test can be performed in mode antagonist", which means that the cell type tested connection with the increasing concentration with increasing known concentrations of H3 agonist (e.g., RAMHA). If the connection of the present invention is an antagonist, his increasing concentrations cause a right shift of the curves of the response of the H3 agonist dose-dependent. The final volume in each well is 100 μl. Compound dissolved in DMSO and diluted with water. The mixture is shaken for 5 minutes and leave for 25 min at room temperature. The reaction is interrupted by adding to each well 100 μl of a mixture of to detect". Tablets sealed polymeric film, shaken for 30 min, left overnight and, finally, the radioactivity counted using an automatic counter gamma radiation Cobra II. Size EU50estimated using a nonlinear regression analysis response curves dose-response (minimum 6 points)using GraphPad Prism. Size Kb define graphical analysis on the Shield.

Functional test II

The ability of compounds according to the present izobreteny who to contact and interact with the H3-receptor of man as agonists, inverse agonists and/or antagonists determined using functional test, called test [35S] GTPγS. In this test determines the activation of G-proteins catalyzed by replacement guanosin-5'-diphosphate (GDP) guanosin-5'-triphosphate (GTP) in the α-subunit. Related GTP G-protein dissociates into two subunits, GαGTPand Gβγthat, in turn, regulate intracellular enzymes and ion channels. GTP is rapidly hydrolyzed Gα-subunit (guanozintrifosfata), and G-protein is deactivated and ready for a new cycle of exchange of GTP. To study the function induced by ligand activation of the receptor coupled to a G-protein (GPCR), to accelerate the exchange of gurinovka nucleotide G-proteins determine the binding of [35S]-guanosin-5'-O-(3-thio)triphosphate[35S] GTPγS, neytralinogo analogue of GTP. This process can be monitored in vitro by incubation of cell membranes containing the H3-receptor associated G-protein, together with GDP and [35S] GTPγS. Cell membranes derived from cells of Cho, stably expressing the H3-receptor of human rights. Cells are washed twice with PBS, grown in PBS + 1 mm add at pH 7.4 and centrifuged for 5 min at a speed of 1000 Rev/min Received the tablet from the cells within 30 homogenized in 10 ml ice buffer Nerez (20 mm Nerez, 10 mm add at pH 7.4 (NaOH)) using the homogenizer Ultra-Turrax and centrifuged for 15 min with a speed of 20000 rpm After centrifugation, the resulting tablet again suspended in 10 ml ice Hepes buffer (20 mm Hepes, 0.1 mm add at a pH of 7.4 (NaOH)) and homogenized, as described above. The procedure was repeated twice and after the last stage of homogenization determine the concentration of protein, membranes were diluted to a protein concentration of 2 mg/ml, take an aliquot and store them until use at a temperature of minus 80°C.

To study the presence and effectiveness of the inverse agonist/antagonist type H3 agonist-receptor ligand R-α-methylhistamine (RAMHA). Measure the ability of test compounds to counteract the influence of RAMHA. When studying the effect of the agonist in the test environment does not add RAMHA. The test compound is diluted in a buffer for testing (20 mm HEPES, 120 mm NaCl, 10 mm MgCl2with pH 7.4 (NaOH)) to obtain different concentrations, and then add 10-8nm RAMHA (only in the case when investigating inverse agonist/antagonist), 3 μm GDP, 2.5 ág of membranes, 0.5 mg of beads for scintillation proximal analysis and 0.1 nm [35S] GTPγS and incubated at room temperature for 2 hours with gentle shaking. Tablets centrifuged for 10 min with a speed of 1500 Rev/min and the radioactivity is measured using a counter. The results analyzed by the method of nonlinear regression and determine the values ICsub> 50. RAMHA and other H3 agonists stimulate the binding of [35S] GTPγS to membranes, repressiruyuschy the H3 receptor. In the test for antagonist/inverse agonist to reduce signal radioactivity determine the ability of increasing amounts of the test compounds to inhibit the increased binding of [35S] GTPγS to 10-8M RAMHA. The value of the IC50defined for the antagonist, is the ability of this compound to inhibit by 50% the effects of 10-8M RAMHA. In the test for agonistic ability of increasing amounts of the compounds measured as the increase in signal of radioactivity. The EC50defined for agonist, is the ability of this compound to increase by 50% the signal relative to the maximum signal obtained for the 10-5M RAMHA.

Antagonists and agonists of the present invention preferably have a value IC50/EC50defined using one or more tests, less than 10 microns, more preferably smaller than 1 μm and even more preferably less than 500 nm, such as less than 100 nm.

The model on the rat in an open cage with feeding schedule

The ability of the compounds of the present invention to reduce the weight determined in vivo using the model in the rat in an open cage with feeding on schedule.

Male rats Sprague-Dawle (SD) aged approximately 14 to 2 months and weighing approximately 200-250 g acquire the company Breeding and Research Centre A/S (Denmark). Upon arrival they are given a few days to acclimate, and then placed in individual open plastic cells. They are accustomed to the presence of food (pellets for rats from Altromin) in their house for only 7 hours 07.30-14.30 every day of the week. Water is in abundance. After food consumption stabilizes after 7-9 days, the animals are ready for use.

Each animal, in order to avoid transfer effects between treatments, only used once. During the sessions of the test, the test compound is administered intraperitoneally or orally 30 min before testing sessions. One group of animals administered the test compound with different doses and the control group of animals given media. Consumption of food and water watch through 1, 2 and 3 hours after injection.

Any side effects can be easily detected (bookowania, coating on the tongue and so on), as animals, to facilitate constant monitoring, kept in transparent plastic cages.

1. The compound of General formula (II)

where m denotes 1, 2 or 3,
n denotes 1, 2 or 3,
R1and R2independently represent C1-6-alkyl,
or R1and R2together form3-6-Allenby bridge,
R11and R12independently represent in the location, With1-6-alkyl,
X means:
,,,
,,,
,,
or,
R3, R4, R5, R6, R7, R8, R9and R10independently represent
hydrogen, halogen, cyano, -NR15R16, -CF3, -OCF3the nitrogroup,1-6-alkoxy, C1-6-alkyl, C3-8-cycloalkyl,3-8-cycloalkenyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkylsulfonyl, C1-6-alkylsulfonyl-O-, the latter can be substituted by one or more halogen, aryl, triazolyl;
R15and R16independently denote With1-6-alkyl;
or two of R3and R4, R4and R5, R5and R6, R6and R7, R7and R8, R8and R9, R9and R6and R8and R10together form a bridge selected from-OCH2O-, -OCH2CH2O-, -OCH2CH2CH2O-,
or R11and R3, R11and R7or R11and R10together form a bridge selected from-O;
Y represents-O - or-S-;
and any Diaz is reamer or enantiomer or tautomeric form, including mixtures thereof, or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R1does
C1-6-alkyl, or R1and R2together form3-6-alkilinity the bridge.

3. The compound according to claim 2, where R1does
C1-6-alkyl, or R1and R2together form4-5-alkilinity the bridge.

4. The compound according to claim 3, where R1and R2together form4-5-alkilinity the bridge.

5. The compound according to claim 4, where R1and R2together form4-alkilinity the bridge.

6. The compound according to claim 4, where R1and R2together form5-alkilinity the bridge.

7. The compound according to any one of claims 1 to 6, where m is equal to 1.

8. The compound according to claim 1, where n is 1 or 2.

9. The connection of claim 8, where n is equal to 1.

10. The compound according to claim 1, where X denotes
,,,
where the values of R3, R4, R5, R6and R7defined in claim 1.

11. The compound according to claim 1, where Y denotes-O - or-S-.

12. Connection to item 11, where Y represents-O-.

13. The connection of claim 10, where X denotes

where the values of R3, R4, R5, R6and R7defined in claim 1.

14. The compound according to claim 1, where R3, R4, R5, R6and R7independently selected from hydrogen, halogen, ziang uppy, -NR15R16, -CF3, -OCF3or nitro, where the values of R15and R16defined in claim 1, C1-6-alkoxy, aryl, triazolyl,3-8-cycloalkenyl, C1-6-alkylsulfonyl or C1-6-alkylsulfonyl-O-, which optionally may be substituted by one or more halogen atoms;
or R4and R5together form a bridge-OCH2O-,
or R11and R3together form a bridge selected from-O-.

15. The connection 14, where R3, R4, R5, R6and R7independently selected from hydrogen, halogen, ceanography, -CF3or-OCF3C1-6-alkoxy, 1,2,4-triazolyl or1-6-alkylsulfonyl-O-, where the latter may be optionally substituted by one or more atoms of halogen,
or R4and R5together form a bridge-och2Oh,
or R11and R3together form a bridge selected from-O-.

16. The connection indicated in paragraph 15, where R3, R4, R5, R6and R7independently selected from hydrogen, halogen, ceanography, -CF3or-OCF3, -O - CH3, 1,2,4-triazolyl, -O-CH2CH3or CH3-sulfonyl-O-, where the latter may be optionally substituted by one or more atoms of halogen,
or R11and R3together form a bridge selected from-O-.

17. Connection P16, where R3, R4, Rsup> 5, R6and R7independently selected from hydrogen, halogen, ceanography, -CF3or-OCF3, -O-CH3, -O-CH2CH3or CH3-sulfonyl-O-, or-CF3-sulfonyl-O-,
or R11and R3together form a bridge selected from-O-.

18. The compound according to claim 1, where R11denotes hydrogen.

19. The compound according to claim 1, where R12denotes hydrogen or C1-6-alkyl.

20. The connection according to claim 19, where R12denotes hydrogen or methyl.

21. The compound according to claim 1, where all R17, R18and R19denote hydrogen.

22. Pharmaceutical composition having antagonistic and agonistic activity toward H3-histamine receptor, comprising as active ingredient at least one compound according to any one of claims 1 to 21, together with one or more pharmaceutically acceptable carriers or excipients.

23. The pharmaceutical composition according to item 22 in the form of a unit dose containing from about 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and most preferably from about 0.5 mg to about 200 mg of the compound according to any one of claims 1 to 20.

24. The use of compounds according to any one of claims 1 to 21 for receiving the pharmaceutical composition according to item 22 for the treatment of disorders or diseases associated with H3-prescriptions the op to histamine.

25. The application of paragraph 24, where the pharmaceutical composition is intended for treating diseases or disorders in which the beneficial effect of inhibition of H3-receptor histamine.

26. The application of paragraph 24, where the pharmaceutical composition has an antagonistic activity toward H3-receptor histamine or inverse agonistic activity toward H3-receptor histamine.

27. The application of paragraph 24, where the pharmaceutical composition is intended for weight reduction.

28. The application of paragraph 24, where the pharmaceutical composition is intended for treating excessive weight or obesity.

29. The application of paragraph 24, where the pharmaceutical composition is intended to suppress appetite or to cause a feeling of fullness.

30. The application of paragraph 24, where the pharmaceutical composition intended for the prevention and/or treatment of disorders and diseases related to overweight or obesity.

31. The application of paragraph 24, where the pharmaceutical composition intended for the prevention and/or treatment of eating disorders such as bulimia syndrome and binge eating.

32. The application of paragraph 24, where the pharmaceutical composition is intended for the treatment of weakened glucose tolerance.

33. The application of paragraph 24, where the pharmaceutical composition is intended for the treatment d is the Abete 2 type.

34. The application of paragraph 24, where the pharmaceutical composition is intended to delay or prevent the progression weakened glucose tolerance in type 2 diabetes.

35. The application of paragraph 24, where the pharmaceutical composition is intended to delay or prevent the progression of non-insulin-dependent type 2 diabetes in insulin-dependent type 2 diabetes.

36. The application of paragraph 24, where the pharmaceutical composition is intended for diseases and disorders, for which a beneficial effect of stimulation of the H3-receptor histamine.

37. The application of paragraph 24, where the pharmaceutical composition is intended for the treatment of allergic rhinitis, ulcers or anorexia.

38. The application of paragraph 24, where the pharmaceutical composition is intended for the treatment of Alzheimer's disease, narcolepsy or disorders associated with syndrome of impaired attention.
The priority according to claim 1 and connection examples 1-76 07.10.2002.
The priority for the compounds of examples 77-82 from 27.01.2003.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention refers to the aminopyridin compound of general formula (I) or its salt wherein X1, X2, X3, Z, Y1, Y2 are carbon or nitrogen atom, R, R1, R5, R6 are hydrogen atom, alkyl group, further see formula of the invention, and R7 is hydrogen or halogen atom, nitro or cyano group, -CpH2(p-1)(Ra1)(Ra2)-O-Ra3, -C(=O)-Rd1, 5-or 6-membered saturated heterocycle group, aromatic heterocycle group, -N(Rh1)(Rh2), further see formula of the invention. The invention refers also to the pharmaceutic composition thereof intended for treatment or prevention of allergic diseases, autoimmune diseases caused by malignant tumour, to the Syk inhibitor containing the compound of formula I and to the therapeutic and/or preventive agent.

EFFECT: compounds which not only possess high Syk inhibition activity but are selective Syk inhibitors are obtained and described.

24 cl, 24 ex, 2 tbl

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula I , where R0 is 1) monocyclic 6-14-member aryl, where aryl is independently mono-, di- or trisubstituted by R8, 2) heterocyclyl out of group of benzothiazolyl, indazolyl, pyridyl, where the said heterocyclyl is independently non-substituted or mono-, di- or trisubstituted by R8, and other radicals referred to in point 1 of the claim; R8 is halogen; on condition that R8 is at least one halogen atom if R0 is monocyclic 6-14-member aryl; substructure in the formula I is 4-8-member saturated, partly non-saturated or aromatic cyclic group including 0, 1 heteroatom selected out of nitrogen or sulfur, and is non-substituted or substituted 1, 2, 3 times by R3; Q is -(C0-C2)alkylene-C(O)NR10-, methylene; R1 is hydrogen atom, -(C1-C4)alkyl, where alkyl is non-substituted or substituted one to three times by R13; R2 is a direct link; R1-N-R2-V can form 4-8-member cyclic group selected out of piperazine or piperidine group; R14 is halogen, =O, -(C1-C8)alkyl, -CN; V is 1) 6-14-member aryl, where aryl is independently non-substituted or mono-, di- or trisubstituted by R14, and other radicals referred to in point 1 of the claim; G is direct link, -(CH2)m-NR10, where m is 0 and R10 is hydrogen, -(CH2)m-C(O)-(CH2)n-, where m is 0 or 1, and n is 0, -(CH2)m-C(O)-NR10-(CH2)n-, where m is 0 or 1, and n is 0, 1 or 2, -(CH2)m-, where m is 1; M is 1) hydrogen atom, 2) 6-14-member aryl, and other radicals referred to in point 1 of the claim; R3 is 1) hydrogen atom, 2) halogen atom, 3) -(C1-C4)alkyl, where alkyl is non-substituted, and other radicals referred to in point 1 of the claim; R11 and R12 are independently the same or different and are 1) hyfrogen atom, 2) -(C1-C6)alkyl, where alkyl is non-substituted or monosubstituted by R13, and other radicals referred to in point 1 of the claim; or R11 and R12 can form 4-8-member monocyclic heterocyclic ring together with nitrogen atoms to which they are linked, and beside the nitrogen atom the ring can include one or two similar or different ring heteroatoms selected out of oxygen, sulfur and nitrogen; where the said heterocyclic ring is independently non-substituted or mono-, disubstituted by R13; R13 is halogen, =O, -OH, -CF3, -(C3-C8)cycloalkyl, -(C0-C3)alkylene-O-R10; R10 is hydrogen, -(C1-C6)alkyl; R15 and R16 are independently hydrogen, -(C1-C6)alkyl; R17 is -(C1-C6)alkyl, -(C3-C8)cycloalkyl; in all stereoisomer forms and their mixes at any ratio, and physiologically tolerable salts. Compounds of the formula I are reversible inhibitors of enzyme factor Xa (FXa) and/or factor VIIa (FVIIa) of blood clotting, and can be generally applied in states accompanied by undesirable factor Xa and/or factor VIla activity, or supposing factor Xa and/or factor VIla inhibition for treatment or prevention. In addition, invention concerns methods of obtaining compounds of the formula I, their application as agents in pharmaceutical compositions.

EFFECT: obtaining compounds applicable as agents in pharmaceutical compositions.

19 cl, 1 tbl, 169 ex

FIELD: medicine; pharmacology.

SUBSTANCE: in formula (I) V represents -N (R1) (R2) or OR4; R4 represents H, C1-6alkyl, C1-6halogenalkyl or (C1-6alkylen)0-1R4' R4' represents C3-7cycloalkyl, phenyl, pyridyl, piperidinyl; and R4' is optionally substituted with 1 or 2 identical or different substitutes chosen from group consisting of C1-4alkyl, amino, C1-3alkylamino, C1-3dialkylamino, phenyl and benzyl; and each R1 and R2 independently represents L1, where L1 is chosen from group consisting from H, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, - adamantyl, pyrrolidinyl, pyridyl, or R1 and R2 together with nitrogen atom to which attached, form X, where X represents pyrrolidinyl, piperazinyl, piperidinyl, morpholino; where X is optionally substituted with Y, where Y represents dioxolanyl, C1-9alkyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrrolidinyl; and where X and Y are optionally split with Z, where Z represents -C1-3alkylen-, C1-3alkylen-. Other radical values are specified in formula of invention.

EFFECT: effective application for treatment of migraine and other headache mediated by action of CGRP-receptors.

34 cl, 11 dwg, 6 tbl, 201 ex

FIELD: medicine; pharmacology.

SUBSTANCE: compounds of this invention possess properties of protein kinase inhibitors. In the general formula p means integer within 0 to 2; R and R1 mean O; A1 and A2 mean single bond, (C1-C6)alkyl; B2 means monocyclic or bicyclic, saturated or unsaturated heterocyclic radical including 1 to several identical or different heteroatoms, chosen among O, S, N and NR7, probably substituted with one or several identical or different substitutes.

EFFECT: inhibiting effect on protein kinase, effective application of compounds of formula for medical products.

49 cl, 1 tbl, 6 dwg, 334 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

Crystal form // 2339634

FIELD: chemistry.

SUBSTANCE: (E)-2-(5-Chlorothiene-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl} ethensulfonamide in essentially crystal form has powder radiograph, expressed in angle values 20, and obtained by means of difractometer, including peaks, located in the following positions expressed in angles 2θ: 9.1-9.2 (±0.1), 16.0-16.1(±0.1), 18.0-18.2 (±0.1) and 18.3-18.4 (±0.1) degrees, and term "essentially crystal form" means that said form is mainly free from amorphous form of (E)-2-(5-Chlorothiene-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl} ethensulfonamide, and by term "mainly free from" content of amorphous form less than 50% is meant.

EFFECT: increased activity.

15 cl, 2 dwg, 5 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: new compounds with formula Ia are proposed, where: P represents pyridine or pyrimidine; R1 represents hydrogen; R2 is chosen from halogen, nitro, C0-6alkylheteroaryl, (CO)OR4, trifluoromethyl, C0-6alkylcyano, C0-6alkylNR4R5, OC1-6alkylNR4R5, C0-6alkylCONR4R5, C0-6alkyl(SO2)NR4R5 and X1R6 group, where X1 represents a direct link; R6 represents a 5- or 6-member heterocyclic group, containing one or two heteroatoms, independently chosen from N, O, and S, for which the given heterocyclic group can be unsaturated and can be substituted with by one substitute, chosen from W; m equals 0, 1, or 2; R3 is chosen from CO(OR4), C0-6alkylNR4R5, C0.6alkylCONR4R5, OC1-6alkylNR4R5 C1-6alkyl(SO2)NR4R5; n equals 1 or 2; R4 is chosen from hydrogen, C1-6alkyl; R5 is chosen from hydrogen, C1-6 alkyl, C0-6 alkyl C3-6 cycloalkyl, C0-6 alkylaryl, C0-6alkylheteroaryl and C1-6alkylNR14R15 or R4 and R5 together can form a 4-, 5-, 6- or 7-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O, where the given heterocyclic group can be substituted by group Y; and where any C1-6alkyl, indicated in defining R2-R5, can be substituted with one or more one Z group; R14 and R15 together can form a 5-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O; W and Z are independently chosen from halogen, CN, OR16, C1-6alkyl, trifluoromethyl, trifluoromethoxy, 5-member heterocyclic group, containing one heteroatom, independently chosen from N, for which the given heterocyclic group can be substituted with group Y; Y is chosen from oxo, halogen, C1-6alkyl, C0-6alkylaryl, NR16R17, phenyl, C0-6alkylaryl, where the phenyl and C0-6alkylaryl groups can be substituted with nitro, trifluoromethyl; R16 and R17 are independently chosen from hydrogen and C1-6alkyl, or where R16 and R17 together can form a 5-member heterocyclic group, containing one heteroatom, chosen from N; in form of a free base or pharmaceutical salt. Formula Ia compounds have inhibiting effect to glycogen-synthase-kinase-3 (GSK3). The invention also relates to the method of obtaining the proposed compounds and to new intermediate compounds, used in them, pharmaceutical compositions, containing the given therapeutically active compounds, and use of the given active compounds in therapy for treating conditions, related to GSK3.

EFFECT: new method of obtaining indole derivatives.

33 cl, 1 tbl, 112 ex

FIELD: medicine; pharmacology.

SUBSTANCE: derivatives possess antiproliferative activity and stimulate an apoptosis in cells where absence of normal regulation of development of a cell and its destruction is observed. The derivatives are applied as a part of pharmaceutical compositions in combination with pharmaceutically acceptable mediums. The pharmaceutical compositions can be applied for treatment of diseases caused by hyperproliferation, including tumour growth, lymphoproliterative diseases and angiogenesis. Invention compounds pertain to the group of replaced pyrazoles and Pyrazolinums characterised by the formula of the invention.

EFFECT: derivatives possess useful biological properties.

56 cl, 115 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry, medicine.

SUBSTANCE: invention refers to the triheterocylic compounds of formula (Ia) and their pharmaceutically acceptable salts used as growth inhibitors of the cancer or tumor cells, to the preparation method and pharmaceutical compositions thereof, to the treatment method used aforesaid compounds as well as to the intermediates of formula (II) the to the method of its preparation. In general formulas (Ia) and

, Q1 is -N(R1)-; Q2 is -C(R3)-; Q3 is -C(R5)-; Q4 is -C(R9)-; R1 is -Ym(Ra), where -Ra is -H, -OH, -C(O)R14, -O-C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OS(O)2ONa-; R2 is -H; R3, R4 and R5 independently are -Ym(Rb), where Rb is -H, halogen, -C1-C8 alkyl, -O-(C1-C8 alkyl) or -OR14, -at condition that if value m of radical Ym(Rb) is equal 0, then R5 is not H; R6 is -H; R7 is -Ym-(RC), where -RC is -O-(C1-C8 alkyl) or -NH(phenyl), R8 is -Ym(Rd), where - Rd is -H, -OH, R9, R10, R11, R12 and R13 independently are -Ym(Re), where Re is -H, halogen, 5-6-membered heterocycle containing 2 heteroatoms selected from N or O, -OR14, or -O-C(O)OR14; every R14 independently is -H, -C1-C8 alkyl, -phenyl, 5-6-membered heterocycle containing one heteroatom being S; every Y independently is -C1-C8 alkylene-; every m independently is equal 0 or 1.

EFFECT: claimed compounds can find application for treatment of different cancer species.

41 cl, 4 tbl, 4 dwg, 8 ex

FIELD: chemistry, medicine.

SUBSTANCE: invention refers to the new substituted dihydroquinazolines of formula (I) and to their pharmaceutically acceptable salts having antiviral properties. In general formula (I) , Ar is phenyl group which can be mono-, di- or trisubstituted. The substituting group are independently selected from the group including C1-6 alkyl-, C1-6 alkoxy-, trifluoromethyl groups and halogen atoms or two substituting groups together with linked carbon atoms form 1,3-dioxolane; R1 is hydrogen atom, amine group, C1-6 alkyl group, C1-6 alkoxy group, C1-6 alkylthiol group, cyanic group, halogen atoms, nitro group or trifluoromethyl group; R2 is hydrogen atom, C1-6 alkyl group, C1-6 alkoxy group, C1-6 alkylthiol group, cyanic group, halogen atoms, nitro group or trifluoromethyl group; R3 is C1-6 alkyl group, C1-6 alkoxy group, C1-6 alkylthiol group, cyanic group, halogen atoms, nitro group or trifluoromethyl group; or one of the radicals R1, R2 and R3 is hydrogen atom and two others together with linked carbon atoms form cyclopentane or cyclohexane ring, R4 is hydrogen atom or C1-6 alkyl group, R5 is hydrogen atom or alkyl group, R6 is carboxyl, aminocarbonyl, alkoxycarbonyl groups, halogen atoms, cyanic or hydroxyl groups, R7 is hydrogen atom or halogen atoms and R8 is hydrogen atom or halogen atoms, its pharmaceutically acceptable salts.

EFFECT: claimed compounds can find application for treatment and prevention of diseases and as antiviral agents.

21 cl, 3 tbl, 201 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new nitroxide compounds with formula I: where one of A, B and D represents N-O and others represent CR6; R1 represents alkyl, containing 1 to 4 carbon atoms, which is branched or straight and which is unsubstituted or substituted once or several times with a halogen; R2 represents alkyl, containing 1 to 12 carbon atoms, which is branched or straight and which is unsubstituted or substituted once or several times with a halogen; cycloalkylalkylk, containing 3 to 10 carbon atoms, which is unsubstituted or substituted once or several times with oxo, aryl, containing 6 to 14 carbon atoms, which is unsubstituted or substituted once or several times with OCF3; or a heterocyclic group, which is saturated, partially saturated or unsaturated, with 5 to 10 atoms in the ring, where at least 1 atom in the ring is an atom of N, O, or S; R3 represents cycloalkyl, containing 3 to 10 carbon atoms, which is unsubstituted once or several times with oxo, aryl, containing from 6 to 14 carbon atoms or which is unsubstituted or substituted once or several times with OCF3; or heteroaryl, with 5 to 10 atoms in the ring, in which at least 1 atom in the ring is a heteroatom; R represents H or alkyl, containing 1 to 4 carbon atoms. The invention also relates to pharmaceutically used salts of these compounds, pharmaceutical compositions containing these compounds, method of inhibiting PDE4 enzyme and to methods treatment using these compounds.

EFFECT: new compounds with useful biological properties.

62 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of formula 1: where R1 stands for cycloalkyl containing 3 to 10 carbon atoms, R2 stands for alkyl containing 1 to 4 carbon atoms, R3 stands for pyridylmethyl, R4 stands for phenyl unsubstituted or substituted with carboxy-, cyanogroup or alkoxycarbonyl; or to its pharmaceutically acceptable salts provided the specified compounds is not 4-(2-chlor-4-methoxyphenyl)-5-methyl-2-[N-(1-propylindazole-6-yl)-N-propylamino]thiazole where optically active compound can be in the form of one of its separated enantiomers or their mixtures, including racemic mixtures, or to compounds of formula II: where R3 stands for hydrogen or pyridylmethyl, R4 stands for hydrogen or phenyl unsubstituted or substituted with carboxy-, cyanogroup, alkoxycarbonyl, tetrazole-5-yl or phenylsulphonyl aminocarbonyl; R7 stands for alkoxygroup containing 1 to 4 carbon atoms being branched or nonbranched; R8 stands for -CO-C1-4- alkyl or dioxanyl, and at least one of R3 and R4 is different from hydrogen, or to its pharmaceutically acceptable salts where optically active compound can be in the form of one of its separated enantiomers or their mixtures, including racemic mixtures. Additionally, the invention refers to pharmaceutical enzyme PDE4, based on compounds of formula I and II and to their application for producing medical products for enzyme PDE4 inhibition in treatment of various diseases.

EFFECT: compound improvement.

35 cl, 11 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of formula I or its pharmaceutically acceptable salts: , where R1 is phenyl group optionally substituted by substitutes selected out of halogen atom, -O-C1-6-alkyl; or R1 is phenyl condensed with aromatic or non-aromatic 5-7-member ring where the ring can optionally include up to three heteroatoms selected independently out of N, O and S; R2 is hydrogen, -O-C1-6-alkyl, -C1-6-alkyl or halogen atom; R3 is C1-6-alkyl, -(CH2)P-NO2, -(CH2)p-NR4R5, -(CH2)P-CONHOH, -(CH2)p-CN, -(CH2)P-CO2H, -(CH2)p-CO2R4, -(CH2)P-CONR4R5, -(CH2)p-OR4, -(CH2)p-NHCOR4 or -(CH2)p-NHSO2R4; R4 and R5 are independently hydrogen or C1-6-alkyl; p is 0, 1, 2, 3 or 4; X is C1-10-alkylene group; one of A1 and A2 is nitrogen atom, while the other is NR7; and R7 is hydrogen atom or OH-group. Also invention concerns pharmaceutical composition, method of TGF-β and/or activine signal transit route inhibition, method of reduction of excessive exocellular matrix accumulation for mammals, method of tumour cell metastasis inhibition for mammals, method of treatment of cancer neoplasm caused by TGF-β superexpression by TGF-β signal transit route inhibition for mammals, method of disease treatment, and method of thrombosis inhibition for mammals.

EFFECT: new compounds with useful biological properties.

16 cl, 19 ex, 2 tbl, 8 dwg

FIELD: chemistry.

SUBSTANCE: present invention pertains to new macrocyclic compounds with formula (I): (where R3, R6, R7 and R21 can be identical or different from each other, and each of them assume values given in the description), their salts used in pharmacology and their hydrate. Compounds with formula (I) are capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, and can be used as therapeutic means of treating solid malignant tumours. The invention also relates to medicinal agents based on these compounds, prevention and treatment method and use of these compounds in making preparations for preventing and treating cancerous diseases.

EFFECT: obtaining compounds, capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, which can be used as therapeutic means of treating solid malignant tumours.

35 cl, 3 tbl, 147 ex

FIELD: chemistry.

SUBSTANCE: description is given of a piperidine derivative with general formula (I) , where L represents CH or N; M represents CH or N; under the condition that, L and M both do not represent CH; R1 represents phenyl (possibly substituted with a halogen or C1-4alkyl), S(O)2(C1-4alkyl), S(O)2(C1-4fluroalkyl), S(O)2phenyl (possibly substituted with CF3 or OCF3), benzyl, benzoyl (possibly substituted with a halogen) or C(O)NHphenyl (possibly substituted with a halogen); R2 represents phenyl, possibly substituted with a halogen; R3 represents hydrogen or C1-4alkyl; R4 represents methyl or ethyl; R5 represents phenyl-NH, phenyl (C1-2alkyl), phenyl(C1-C2)alkyl-NH or pyridyl(C1-2alkyl). The phenyl can be substituted with a halogen, cyano, C1-4alkyl, C1-4alkoxy, S(O)k(C1-4alkyl) or S(O)2NR8R9; k is equal to 2; R8 and R9 represent hydrogen or its pharmaceutical salts. The compound is a modulator of the activity of the CCR5 receptor. Description is given of the method of obtaining the compound, where L represents N, and the pharmaceutical composition based on a compound with formula (I).

EFFECT: design of a method of obtaining a compound, where L represents N, and a pharmaceutical composition based a compound with formula (I).

7 cl, 7 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns to new diamides of pyrimidine-4,6-dicarboxylic acid of I formula, selective inhibitors of collagenases possessing properties which concern to the metalloproteinase superfamily and the matrix metalloproteinases. The bonds render influence on hyperactivity of the matrix metalloproteinase-13 (MMP-13) and thus do not render influence on MMP-3 and MMP-8. In the formula I R1 means an atom of hydrogen, R2 means - (C1-C6)-alkyl where alkyl is unitary replaced by phenyl where phenyl is replaced 1) -(C0-C6)-alkyl-C(O)-N(R9)-(R10), where R9 and R10 identical or different and independently from each other mean i) atom of hydrogen or ii) - (C1-C6)-alkyl or R9 and R10 together with atom of nitrogen to which they are bound, form 5, 6-links the sated cycle, and instead of one or two other atoms of carbon there can be also a heteroatom from an oxygen row, sulphur and nitrogen, and in case of nitrogen atoms of nitrogen independently from each other can be unsubstituted or substituted with (C1-C6)-alkyl, 2) -(C0-C6)-alkyl-C(O)-NH-SN, 3) -O-(C0-C6)-alkyl-C(O)-N(R9)-(R10) where R9 and R10 have the specified above value, 4) -(C0-C6)-alkyl-C(O)-N (R8)-(C0-C6)-alkyl-N(R9)-(R10) where R8 means hydrogen, R9 and R10 have the specified above value, 5) -(C0-C6)-alkyl-C(O)-N(R8)-(C0-C6)-alkyl-Het, and R8 has the specified above value, and Het means the sated or nonsaturated monocyclic heterocyclic system with number of links from 3 to 6 which contains in a cycle of 1 or 2 identical or different heteroatoms from a number nitrogen, oxygen and sulphur and unsubstituted or one-, two- or triple independently from each other is replaced by halogen, b) hydroxy,) -(C1-C6)-alkyl, and alkyl is unsubstituted or one-, two- or triple is substituted by halogen, d)=0,e)-Het, R4 and R5 or R5 and R6 together with atom of Carboneum to which they are bound, independently from each other form 5 or 6-unit cycle which is sated and contains one or two heteroatoms from an oxygen row.

EFFECT: obtaining of bonds which can find application for treatment of degenerate diseases of joints, such as osteoarthritis, rheumatic disease.

7 cl, 3 tbl, 117 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

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