New aryl - and heteroarylpiperazines

FIELD: chemistry.

SUBSTANCE: invention relates to aryl or heteroarylpiperazines with general formula II , where R2 is hydrogen or C1-4-alkyl (i) R1 is branched C4-6-alkyl, branched C4-6-alkenyl or branched C4-6-alkynyl, under the condition that R1 is not isobutyl, - C3-5-cycloalkyl, C3-7-cycloalkenyl, C3-6-cycloalkyl-C1-3-alkyl or C3-6-cycloalkenyl-C1-3-alkyl, -R1 and R2 together form a C3-6-alkylene bridge, and A is or or (ii) R1 - is ethyl, n-propyl or isopropyl, - R1 and R2 together form a C3-6-alkylene bridge, and A is or . Described also is a pharmaceutical composition based on formula II compounds, use of formula II compounds and method of treatment.

EFFECT: compounds exhibit high and selective bonding affinity to histamine H3 receptor and can be used for treating diseases and disorders, related to histamine H3 receptor.

49 cl, 149 ex

 

The technical field

This invention relates to new aryl - and heteroarylboronic, to the use of these compounds in pharmaceutical compositions, to pharmaceutical compositions containing these compounds, and to a method of treatment using such compounds and compositions. Compounds in accordance with this invention show high and selective affinity binding to the histamine receptor H3, indicating antagonist, inverse agonist or agonistic activity to the receptor of histamine H3. In the compounds used for the treatment of diseases and disorders related to the histamine receptor H3.

The level of technology

The existence of receptor for histamine H3-known for several years, and this receptor is of great interest for the development of new medicines. Was recently cloned receptor histamine H3 person. The histamine receptor H3 is a presynaptic autoreceptor located in both Central and peripheral nervous system, skin and organs, such as lungs, intestines, probably, spleen and gastrointestinal tract. Recent evidence suggests that the H3 receptor shows the internal, unregulated activity in vitro and in vivo (i.e. it is active in the absence of agonist). The connection is operating as inverse agonists, can inhibit the specified action. It was demonstrated that the histamine receptor H3 regulates the release of histamine and other neurotransmitters, such as serotonin and acetylcholine. Therefore, it is expected that the antagonist or inverse agonist of the histamine receptor H3 will increase the allocation of these neurotransmitters in the brain. Agonist of the histamine receptor H3, on the contrary, inhibits biosynthesis of histamine and inhibits the release of histamine and other neurotransmitters, such as serotonin and acetylcholine. These findings suggest that agonists, inverse agonists and antagonists of the histamine receptor H3 may be important mediators of neuronal activity. Therefore, the histamine receptor H3 is an important factor for the creation of new medicines.

Compounds similar to the compounds in accordance with this invention, is described in J. Med. Chem.1999, 42, 336, J. Med. Chem.,1992, 35, 2369, DE 2804096, J. Org. Chem.1996, 61, 3849, Bull. Soc. Chim. Fr.1969, 319 WO 00/66578, WO 99/21845 and J. Med. Chem.1968, 11(6), 1144-1150. However, in these references, there is neither description nor the assumption that these compounds may have antagonistic or agonistic action against the histamine receptor H3.

Several publications describe the preparation and use of agonists and antagonists of the histamine H3. Most of them is proizvodnymi imidazole. However, recently there have been described some not containing imidazole ligands of the histamine receptor H3 (see, for example, Linney et al., J. Med. Chem. 2000, 43, 2362-2370; US 6316475, WO 01/66534 and WO 01/74810). However, these compounds differ structurally from the compounds in accordance with this invention.

Given existing in the prior art interest agonists, inverse agonists and antagonists of the histamine receptor H3, new compounds that interact with the histamine receptor H3, are highly desirable contribution in this area. The present invention presents such a contribution in this area, which is based on the discovery that a new class of aryl - and heteroarylboronic has a high and specific affinity to the histamine receptor H3.

Due to their interaction with the histamine receptor H3 compounds in accordance with this invention can be used in the treatment of a wide range of conditions and disorders in which preference is given to the interaction with the histamine receptor H3. Thus, the compounds can be used, for example, in the treatment of diseases of the Central nervous system, peripheral nervous system, cardiovascular system, pulmonary system, gastrointestinal system and the endocrine system.

Definitions

In the structural formulas shown below, and in the following description of the terms is s have a specified value:

The term "halogen" means F, Cl, Br or I.

The term "alkyl" herein represents a saturated, branched or straight hydrocarbon group having the specified number of carbon atoms. Thus, "C1-3-alkyl", "C1-8-alkyl" and "C1-10-alkyl" herein means saturated, branched or straight hydrocarbon group having from 1 to 3 carbon atoms, from 1 to 8 carbon atoms and from 1 to 10 carbon atoms, respectively. Typical alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.

The term "alkenyl" in this description is a branched or straight hydrocarbon group having the specified number of carbon atoms and at least one double bond. Thus, "C2-8alkenyl" and "C2-10alkenyl" in this description means saturated, branched or straight hydrocarbon group having from 2 to 8 carbon atoms and from 2 to 10 carbon atoms, respectively, and at least one double bond. Examples of such groups include, but are not limited to, ethynyl, 1-propenyl, 2-propenyl, allyl, Isopropenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, 1-heptenyl, 2-heptenyl, 1-octenyl, 2-octenyl, 2-nonenal, 2-decenal and such is.

The term "quinil" in this description is a branched or straight hydrocarbon group having the specified number of carbon atoms and at least one triple bond. Thus, "C2-8-quinil" in this description means a branched or straight hydrocarbon group having from 2 to 8 carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, 2-heptenyl, 1-octenyl, 2-octenyl and the like.

The term "branched C4-6-alkyl" in the present description means a branched hydrocarbon group having from 4 to 6 carbon atoms. Typical branched C4-6-alkali include, but are not limited to, 1-methylpropyl, tert-butyl, 1-ethylpropyl, 1,1-(dimethyl)propyl, isopentyl 1-ethylbutyl, 1,1-(dimethyl)butyl, 1,1-(dimethyl)pentyl, 1-ethylphenyl, 1,1-(dimethyl)hexyl, 1-ethylhexyl and the like.

The term "branched C4-6alkenyl" in this description means a branched hydrocarbon group having from 4 to 6 carbon atoms and at least one double bond. Typical branched C4-6alkenyl include, but are not limited to, 1-aterproof-2-enyl, 1,1-(dimethyl)prop-2-enyl, 1-Etherboot-3-enyl, 1,1-(dimethyl)but-2-enyl, 1,1-(dimethyl)Penta-3-enyl, 1-ethylpent-2-Yeni is, 1,1-(dimethyl)Penta-3-enyl, 1,1-(dimethyl)Gex-3-enyl, 1-ethylhex-4-enyl and the like.

The term "branched C4-6-quinil" in this description means a saturated branched hydrocarbon group having from 4 to 6 carbon atoms and at least one triple bond. Typical branched C4-6-alkinyl include, but are not limited to, 1-aterproof-2-inyl, 1,1-(dimethyl)prop-2-inyl, 1-Etherboot-3-inyl, 1,1-(dimethyl)but-2-inyl, 1,1-(dimethyl)Penta-3-inyl, 1-ethylpent-2-inyl, 1,1-(dimethyl)Penta-3-inyl, 1,1-(dimethyl)Gex-3-inyl, 1-ethylhex-4-inyl and the like.

The term "C1-6-alkoxy" herein refers to the radical-O-C1-6-alkyl, where C1-6-alkyl such as defined above. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentox, isopentane, hexose, isohexane and the like.

The term "C2-10-alkanoyl" in this description refers to the radical-C(=O)1-9-alkyl, where C1-9-alkyl represents a saturated, branched or straight hydrocarbon group containing 1 to 9 carbon atoms. Examples include acetyl, propionyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl and the like.

The term "C1-6-alkylamino" in this description refers to the radical-NH-C1-6-alkyl, where C1-6-alkyl such as defined above. Note the market include methylamino, ethylamino, isopropylamino, n-propylamino, butylamino, pentylamine, hexylamine and the like.

The term "CI-C1-6-alkylamino" in this description refers to the radical-N(C1-6-alkyl)2where1-6-alkyl such as defined above. It should be clear that With1-6-alkyl groups may be the same or different. Examples include dimethylamino, methylethylamine, diethylamine, Diisopropylamine, di-n-propylamino, dibutylamino, diphenhydamine, digoxigenin and the like.

The term "C3-5-cycloalkyl" in this description refers to a monocyclic, carbocyclic group containing from 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl and the like.

Similarly, the terms "C3-6-cycloalkyl" and "C3-8-cycloalkyl" in this description refers to monocyclic, carbocyclic group containing from 3 to 6 carbon atoms and from 3 to 8 carbon atoms, respectively.

The term "C3-7-cycloalkenyl" in this description refers to a monocyclic, carbocyclic, not aromatic group containing from 3 to 7 carbon atoms and at least one double bond. Examples include cyclopropyl, cyclobutyl, cyclopentenyl and the like.

Similarly, the term "C3-6-cycloalkenyl" in this description refers to monocyclic, carb is cyclic, not aromatic group containing from 3 to 6 carbon atoms and at least one double bond.

The term "C3-6-cycloalkyl-C1-3-alkyl" herein refers to the radical-C1-3-alkyl-C3-6-cycloalkyl, where C3-6-cycloalkyl and C1-3-alkyl such as defined above.

The term "C3-6-cycloalkenyl-C1-3-alkyl" herein refers to the radical-C1-3-alkyl-C3-6-cycloalkenyl, where C3-6-cycloalkenyl and C1-3-alkyl such as defined above.

The term "C3-8-cycloalkane" in this description refers to the radical-O-C3-8-cycloalkyl, where C3-8-cycloalkyl such as defined above. Examples include cyclopropane, CYCLOBUTANE, cyclopentyloxy, cyclohexyloxy, cycloheptylamine, cyclooctylamine and the like.

The term "C4-9-cycloalkenyl" in this description refers to the radical-C(=O)3-8-cycloalkyl, where C3-8-cycloalkyl such as defined above. Examples include cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexylcarbonyl, cyclohexylcarbonyl, cyclooctylmethyl and the like.

The term "C1-6-alkylsulfonyl" in this description refers to the radical

-S(=O)2-C1-6-alkyl, where C1-6-alkyl such as defined above. Examples include methylsulphonyl, utils Lionel, isopropylphenyl, n-propylsulfonyl, butylsulfonyl, peterculter and the like.

The term "C1-6-alkylsulfanyl" in this description refers to the radical-S-C1-6-alkyl, where C1-6-alkyl such as defined above. Examples include methylsulfonyl, ethylsulfonyl, isopropylphenyl, n-propylsulfonyl, butylsulfonyl, intercultural and the like.

The term "C3-8-heterocyclyl" in this description refers to maidenname 3-8-membered monocyclic ring, containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. Examples include aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, tetrahydrofuranyl and the like.

The term "C4-9-heterocyclochain" in this description refers to the radical-C(=O)3-8-heterocyclyl, where C3-8-heterocyclyl such as defined above. Examples include aziridination, pyrrolidinylcarbonyl, piperidinylcarbonyl, morpholinylcarbonyl, piperazinylcarbonyl, tetrahydrofuranyl and the like.

The term "aryl" herein includes carbocyclic aromatic ring system such as phenyl, biphenyl, naphthyl, anthracene, phenanthrene, feranil, indenyl, pentalene, azulene and the like. Aryl also includes partially hydrogenated derivatives of carbocyclic systems listed above. the e limiting examples of such partially hydrogenated derivatives include 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphtho and the like.

The term "aryloxy" in this description refers to the radical

-O-aryl, where aryl as defined above. Non-limiting examples include phenoxy, naphthoxy, anthranilate, phenanthridinone, fertilome, ingenerate and the like.

The term "aroyl" in this description refers to the radical

-C(=O)-aryl, where aryl as defined above. Non-limiting examples include benzoyl, Naftoli, intracerebral, phenanthrenequinones, fertiliser, interkabel and the like.

The term "arylamino" in this description refers to the radical

-NH-aryl, where aryl as defined above. Non-limiting examples include phenylamino, naphtylamine, anthranilamide, phenanthroline, tortillini, Ingenierie and the like.

The term "heteroaryl" includes 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 and the like. Heteroaryl also includes partially hydrogenated derivatives of heterocyclic systems listed above. Non-limiting examples of such partially hydrogenated derivatives include 2,3-dihydrobenzofuranyl, pyrrolyl, pyrazolyl, indanyl, indolinyl, oxazolidinyl, oxazolyl, oxazepines and the like.

The term "heteroaromatic" in this description refers to the radical-O-heteroaryl where heteroaryl such as described above.

The term "heteroaryl" in this description refers to the radical-C(=O)-heteroaryl where heteroaryl such as defined above.

The term "heteroarenes" in this description refers to the radical-NH-heteroaryl where heteroaryl such as defined above.

Some of the above terms can occur in the structural formula more than once, and in such cases each term shall be defined independently of the other.

"Aryl-C1-6-alkyl", "aryl-C1-6-alkoxy" and the like mean With1-6-alkyl or C1-6-alkoxy, such as defined above, substituted aryl, therefore, the AK defined above, for example:

The term "optionally substituted" in this description means that these groups are either unsubstituted or substituted with one or more of these substituents. If these groups substituted by more than one Deputy, the substituents may be the same or different.

The term "treatment" in this description means the management and care of the patient with the aim of combating the disease, disorder or condition. The term includes a delay development of a disease, disorder or condition, alleviating or relieving symptoms and complications and/or the cure or elimination of the disease, disorder or condition. Treat the patient is preferably a mammal, in particular people.

Description of the invention

This invention relates to the compound of General formula (I):

where

(i) R1is

- extensive With4-8-alkyl, branched C4-8-alkenyl or branched C4-8-quinil, which may be optionally substituted by one or more Halogens,

- C3-5-cycloalkyl,3-7-cycloalkenyl,3-6-cycloalkyl-C1-3-alkyl or C3-6-cycloalkenyl-C1-3-alkyl which may be optionally substituted in any position by one and the or more Halogens and

And is

(ii) R1is ethyl, n-propylene or isopropyl and

And is

Z and X are independently-N=, -CH=, -CF= or-C(CF3)=,

W is-N= or-CR3=,

Y is-N= or-CR4=,

R2a, R2b, R3and R4independently are

is hydrogen, halogen, hydroxy, trifluoromethyl, triptoreline,1-10-alkyl, C2-10-alkenyl,3-8-cycloalkyl,1-6-alkoxy, aryl-C1-6-alkyl, amino, C1-6-alkylamino, di-C1-6-alkylamino,3-8-cycloalkane, cyano, nitro, C1-6-alkylsulfanyl,1-6-alkylsulfonyl or-C(=O)NR4aR4bwhere R4aand R4bindependently are hydrogen, C1-6the alkyl or aryl-C1-6-alkyl,

- C2-10-alkanoyl,4-9-cycloalkenyl,3-8-heterocyclyl or4-9-geteroseksualbnogo, which may be optionally substituted in any position by one or more substituents selected from aryl, heteroaryl,3-8-cycloalkyl, halogen, trifloromethyl, triptoreline and C1-6-alkoxy,

- aryl, aryl-C1-6-alkyl, aryl-C1-6-alkoxy or heteroaryl, which may be optionally substituted by one or more substituents selected from halogen, hydroc and, trifloromethyl, triptoreline,1-6-alkoxy, C1-6-alkyl, amino, C1-6-alkylamino, di-C1-6-alkylamino, cyano, aryl, heteroaryl and C3-8-cycloalkyl,

- Arola, heteroaryl, aryloxy, heteroaromatic, arylamino or heteroarenes, which may be optionally substituted by one or more substituents selected from aryl, heteroaryl,1-10-alkyl, C3-8-cycloalkyl, halogen, trifloromethyl, triptoreline,1-6-alkoxy, cyano, amino, C1-6-alkylamino, di-C1-6-alkylamino and hydroxy,

or two of R2a, R2b, R3and R4in adjacent positions together form1-6-Allenby bridge,

provided that the connection should not be

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

In one embodiment, R1is branched C4-8-alkyl, C3-5-cycloalkyl or3-6-cycloalkyl-C1-3-alkyl which may be optionally substituted by one or more Halogens.

In another embodiment, R1is branched C4-8-alkyl, C3-5-cycloalkyl or3-6-cycloalkyl-C1-3-alkyl.

In d the natives embodiment, R 1is 1,1-(dimethyl)propylene, 1-ethylpropyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl or 1-cyclopropyl-1-mutilation.

In another embodiment, R1is 1-ethylpropyl, cyclopropylmethyl, cyclopropyl or cyclopentyl.

In another embodiment, R1is branched C4-8-alkyl or C3-5-cycloalkyl, which may be optionally substituted by one or more Halogens.

In another embodiment, R1is branched C4-8-alkyl or C3-5-cycloalkyl.

In another embodiment, R1is 1-ethylpropyl, cyclopropyl or cyclopentyl.

In another embodiment, R1is isopropyl.

In another embodiment, And is

where R2a, R2b, R3and R4such as defined in formula (I).

In another embodiment, And is

where R2a, R3and R4such as defined in formula (I).

In another embodiment, And is

where R2a, R3and R4such as defined in formula (I).

In another embodiment, And is

where R2a, R2b, R3and R4such as defined in formula (I).

In another embodiment, R2a, R2b, R3and R4independently researched the Simo choose from

is hydrogen, hydroxy, halogen, trifloromethyl, triptoreline,2-10alkanoyl,4-9cycloalkenyl or4-9geterotsiklicheskikh or

- aryl-C1-6-alkyl, aryl-C1-6-alkoxy or Arola, which may be optionally substituted as defined in formula (I).

In another embodiment, R2a, R2b, R3and R4independently selected from

is hydrogen, hydroxy, halogen, trifloromethyl, triptoreline,2-10alkanoyl,4-9cycloalkenyl or4-9geterotsiklicheskikh,

- phenyl-C1-6-alkyl, phenyl-C1-6-alkoxy or benzoyl, which is optionally substituted by one or two substituents selected from halogen and C1-6-alkoxy.

In another embodiment, R2a, R2band R4are hydrogen and R3different from hydrogen.

In another embodiment, R3is halogen, trifluoromethyl or triptoreline.

In another embodiment, the invention relates to a compound of General formula (I1):

where As the same as defined in formula (I) or in any of the above option.

In another embodiment, the invention relates to a compound of General formula (I2):

where As the same as defined in formula (I) or in any of the above option.

In another variant of the invention relates to a compound of General formula (I 3):

where R1is

- extensive With4-8-alkyl, branched C4-8-alkenyl or branched C4-8-quinil, which may be optionally substituted by one or more Halogens,

- C3-5-cycloalkyl,3-7-cycloalkenyl,3-6-cycloalkyl-C1-3-alkyl or C3-6-cycloalkenyl-C1-3-alkyl which may be optionally substituted in any position by one or more Halogens,

- ethyl, n-propylene or isopropyl,

R2a, R2b, R3and R4such as defined in formula (I).

In another embodiment of this invention, the compound is chosen from

4-(4-cyclopentylpropionyl-1-yl)phenol,

1-cyclopentyl-4-[4-(4-forbindelse)phenyl]piperazine,

1-(3-chlorophenyl)-4-cyclopentenopyridine,

1-[4-(4-cyclopentylpropionyl-1-yl)phenyl]ethanone,

1-(3,4-dichlorophenyl)-4-(1-ethylpropyl)piperazine,

{4-[4-(1-ethylpropyl)piperazine-1-yl]phenyl}of phenylmethanone,

1-(4-benzoylphenyl)-4-(1-ethylpropyl)piperazine,

cyclopropyl-{4-[4-(1-ethylpropyl)piperazine-1-yl]phenyl}methanone,

(2-chlorophenyl)-{4-[4-(1-ethylpropyl)piperazine-1-yl]phenyl}methanone,

{4-[4-(1-ethylpropyl)piperazine-1-yl]phenyl}-(4-forfinal)methanone,

1-cyclopentyl-4-(6-triptorelin-2-yl)piperazine,

1-cyclopentyl-4-(5-triptorelin-2-yl)piperaz is on,

1-cyclopentyl-4-(3-triptorelin-2-yl)piperazine,

2-[4-(1-ethylpropyl)piperazine-1-yl]quinoline,

7-chloro-4-[4-(1-ethylpropyl)piperazine-1-yl]quinoline,

[4-(4-cyclopentylpropionyl-1-yl)phenyl]-(3,4-acid)methanone,

[4-(4-cyclopentylpropionyl-1-yl) - for 3,5-differenl]phenylmethanone,

2-(4-cyclopentylpropionyl-1-yl)finokalia,

2-(4-cyclopropylamines-1-yl)finokalia,

[6-(4-cyclopentylpropionyl-1-yl)pyridine-3-yl]piperidine-1-ylmethanone,

2-(4-cyclopentylpropionyl-1-yl)quinoline,

2-(4-cyclopentylpropionyl-1-yl)-7-methoxy-3-(4-methoxyphenyl)quinoline,

{6-[4-(1-cyclopropyl-1-methylethyl)piperazine-1-yl]pyridine-3-yl}phenylmethanone,

{4-[4-(1-cyclopropyl-1-methylethyl)piperazine-1-yl] - for 3,5-differenl}of phenylmethanone,

{4-[4-(1-cyclopropyl-1-methylethyl)piperazine-1-yl] - for 3,5-differenl}phenylmethanol,

[4-(4-cyclopropylamines-1-yl) - for 3,5-differenl]-(4-forfinal)methanone,

{4-[4-(1-ethylpropyl)piperazine-1-yl] - for 3,5-differenl}-(4-forfinal)methanone,

2-[4-(1-ethylpropyl)piperazine-1-yl]-6,7-dimethoxyaniline,

2-[4-(1-ethylpropyl)piperazine-1-yl]-4-triptoreline,

2-(4-cyclopropylamines-1-yl)-6-methoxy-4-triptoreline,

[4-(4-cyclopropylamines-1-yl) - for 3,5-differenl]phenylmethanone,

[4-(4-cyclopropylamines-1-yl) - for 3,5-differenl]-(3-fluoro-4-methoxyphenyl)methanone,

{6-[4-(1-ethylpropyl)is piperazin-1-yl]pyridine-3-yl}phenylmethanone,

{2-[4-(1-ethylpropyl)piperazine-1-yl]pyridine-4-yl}phenylmethanone,

{4-[4-(1-ethylpropyl)piperazine-1-yl]phenyl}-(4-hydroxyphenyl)methanone,

{6-[4-(1-ethylpropyl)piperazine-1-yl]pyridine-3-yl}piperidine-1-yl-methanone,

N-benzyl-6-[4-(1-ethylpropyl)piperazine-1-yl]-N-nicotine amide,

2-[4-(1-ethylpropyl)piperazine-1-yl]-6-methoxyquinoline,

6-[4-(1-ethylpropyl)piperazine-1-yl]-N-methyl-N-fenilcetonuria,

{6-[4-(1-ethylpropyl)piperazine-1-yl]pyridine-3-yl}-(4-forfinal)methanone,

2-[4-(1-ethylpropyl)piperazine-1-yl]-4-methylinosine,

2-[4-(1-ethylpropyl)piperazine-1-yl]-5,6,7,8-tetrahydroquinoline,

2-(4-cyclopropylamines-1-yl)-6-methoxyquinoline,

2-(4-isopropylpiperazine-1-yl)-6-methoxyquinoline,

2-[4-(1-ethylpropyl)piperazine-1-yl]-6-fluoro-4-methylinosine,

2-(4-cyclopropylmethyl-1-yl)-6-triptoreline,

2-(4-cyclopropylmethyl-1-yl)-6-propylenimine,

2-(4-ethylpiperazin-1-yl)quinoline,

or any of diastereomers or enantiomers, or a tautomeric forms, including mixtures thereof, or their pharmaceutically acceptable salts.

In another embodiment, the invention relates to a compound of General formula (I):

where

R1is

- extensive With4-8-alkyl, branched C4-8-alkenyl or branched C4-8-quinil, which may be optionally substituted by one the or more Halogens,

- C3-5-cycloalkyl,3-7-cycloalkenyl,3-6-cycloalkyl-C1-3-alkyl or C3-6-cycloalkenyl-C1-3-alkyl which may be optionally substituted by one or more Halogens,

And is

Z and X are independently-N=, -CH=, -CF= or-C(CF3)=,

W is-N= or-CR3=,

Y is-N= or-CR4=,

R2, R3and R4independently are

is hydrogen, halogen, hydroxy, trifluoromethyl, triptoreline,1-10-alkyl, C2-10-alkenyl,3-8-cycloalkyl,1-6-alkoxy, aryl-C1-6-alkyl, amino, C1-6-alkylamino, di-C1-6-alkylamino,3-8-cycloalkane or cyano, or

- C2-10-alkanoyl or4-9-cycloalkenyl, which may be optionally substituted by one or more substituents selected from aryl, heteroaryl,3-8-cycloalkyl, halogen, trifloromethyl, triptoreline and C1-6-alkoxy,

- aryl, aryl-C1-6-alkyl, aryl-C1-6-alkoxy or heteroaryl, which may be optionally substituted by one or more substituents selected from halogen, hydroxy, trifloromethyl, triptoreline,1-6-alkoxy, C1-6-alkyl, amino, C1-6-alkylamino, di-C1-6-alkylamino, cyano, aryl, heteroaryl and C3-8-the cycle is the alkyl or

- Arola, heteroaryl, aryloxy, heteroaromatic, arylamino or heteroarenes, which may be optionally substituted by one or more substituents selected from aryl, heteroaryl,1-10-alkyl, C3-8-cycloalkyl, halogen, trifloromethyl, triptoreline,1-6-alkoxy, cyano, amino, C1-6-alkylamino, di-C1-6-alkylamino and hydroxy,

provided that the connection should not be

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

In one embodiment, R1is branched C4-8-alkyl, C3-5-cycloalkyl or3-6-cycloalkyl-C1-3-alkyl which may be optionally substituted by one or more Halogens.

In another embodiment, R1is branched C4-8-alkyl, C3-5-cycloalkyl or3-6-cycloalkyl-C1-3-alkyl, such as 1,1-(dimethyl)propyl, 1-ethylpropyl, cyclopropylmethyl, cyclopropyl, cyclobutyl or cyclopentyl, for example, 1-ethylpropyl, cyclopropylmethyl or cyclopentyl.

In another embodiment, R1is branched C4-8-alkyl or C3-5-cycloalkyl, which may be optionally substituted od is them or more halogen, such as branched C4-8-alkyl or C3-5-cycloalkyl, for example 1-ethylpropyl or cyclopentyl.

In another embodiment, And is

where R2, R3and R4such as defined in formula (I”).

In another embodiment, And is

where R2, R3and R4such as defined in formula (I”).

In another embodiment, And is

where R2, R3and R4such as defined in formula (I”).

In another embodiment, R2, R3and R4independently selected from

is hydrogen, hydroxy, halogen, trifloromethyl,2-10alkanoyl or4-9cycloalkenyl or

- aryl-C1-6-alkyl, aryl-C1-6-alkoxy or Arola, which may be optionally substituted as defined in formula (I”).

In another embodiment, R2, R3and R4independently selected from

is hydrogen, hydroxy, halogen, trifloromethyl,2-10alkanoyl or4-9cycloalkenyl,

- phenyl-C1-6-alkyl, phenyl-C1-6-alkoxy or benzoyl, which is optionally substituted by one or two substituents selected from halogen and C1-6-alkoxy.

In another embodiment, R2and R4are both hydrogen and R3different from hydrogen.

In another embodiment, after retina relates to compounds of General formula (I 1):

where As the same as defined in formula (I”) or in any of the above option.

In another embodiment, the invention relates to compounds of General formula (I2):

where As the same as defined in formula (I”) or in any of the above option.

Therefore, in another embodiment, this invention relates to the compound of General formula (I)and any of its diastereoisomers or enantiomers, or a tautomeric forms, including mixtures thereof, or pharmaceutically acceptable salts for use in pharmaceutical compositions.

The 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 pharmaceutically acceptable salt, together with one or more pharmaceutically acceptable carriers or diluents.

Further, this invention relates to the compound of General formula (I')

where R1is

- C1-8-alkyl, C2-8-alkenyl or2-8-quinil, which may be optionally substituted by one or more Halogens,

- C3-5-cycloalkyl,3-7-cycloalkenyl,3-6the cycle is alkyl-C 1-3-alkyl or C3-6-cycloalkenyl-C1-3-alkyl which may be optionally substituted by one or more Halogens,

And is

Z and X are independently-N=, -CH=, -CF= or-C(CF3)=,

W is-N= or-CR3=,

Y is-N= or-CR4=,

R2a, R2b, R3and R4independently are

is hydrogen, halogen, hydroxy, trifluoromethyl, triptoreline,1-10-alkyl, C2-10-alkenyl,3-8-cycloalkyl,1-6-alkoxy, aryl-C1-6-alkyl, amino, C1-6-alkylamino, di-C1-6-alkylamino,3-8-cycloalkane, cyano, nitro, C1-6-alkylsulfanyl,1-6-alkylsulfonyl or-C(=O)NR4aR4bwhere R4aand R4bindependently are hydrogen, C1-6the alkyl or aryl-C1-6-alkyl, or

- C2-10-alkanoyl,4-9-cycloalkenyl,3-8-heterocyclyl or4-9-geteroseksualbnogo, which may be optionally substituted in any position by one or more substituents selected from aryl, heteroaryl,3-8-cycloalkyl, halogen, trifloromethyl, triptoreline and C1-6-alkoxy,

- aryl, aryl-C1-6-alkyl, aryl-C1-6-alkoxy or heteroaryl, which may be optionally substituted by one or more substituents, in the swear from halogen, hydroxy, trifloromethyl, triptoreline,1-6-alkoxy, C1-6-alkyl, amino, C1-6-alkylamino, di-C1-6-alkylamino, cyano, aryl, heteroaryl and C3-8-cycloalkyl, or

- Arola, heteroaryl, aryloxy, heteroaromatic, arylamino or heteroarenes, which may be optionally substituted by one or more substituents selected from aryl, heteroaryl,1-10-alkyl, C3-8-cycloalkyl, halogen, trifloromethyl, triptoreline,1-6-alkoxy, cyano, amino, C1-6-alkylamino, di-C1-6-alkylamino and hydroxy,

or two of R2a, R2b, R3and R4in adjacent positions together form1-6-Allenby bridge,

and also any diastereomers or enantiomers, or a tautomeric form, including mixtures thereof, or pharmaceutically acceptable salts to obtain a pharmaceutical composition for the treatment of disorders and diseases associated with histamine receptor H3.

In another aspect this invention relates to the compound of General formula (II)

where

R2is hydrogen or C1-4-alkyl,

(i) R1is

- extensive With4-6-alkyl, branched C4-6-alkenyl or branched C4-6-quinil, provided that R1is not isobutyl,

- C-5 -cycloalkyl,3-7-cycloalkenyl,3-6-cycloalkyl-C1-3-alkyl or C3-6-cycloalkenyl-C1-3-alkyl,

- R1and R2together form3-6-Allenby bridge and

And is

or

(ii) R1is

- ethyl, n-propylene or isopropyl,

- R1and R2together form3-6-Allenby bridge and

And is

R3is hydrogen, halogen, hydroxy, trifluoromethyl, triptoreline,

With1-10-alkyl, C2-10-alkenyl,3-8-cycloalkyl,1-6-alkoxy, aryl, aryl-C1-6-alkyl, amino, C1-6-alkylamino, di-C1-6-alkylamino,3-8-cycloalkyl,3-8-cycloalkane, cyano, nitro, C1-6-alkylsulfanyl or1-6-alkylsulfonyl,

Z and X are independently-N=, -C(H)=, -C(F)=, -C(Cl)=,

-C(SP)= or-C(CF3)=,

W is-N= or-C(R10)=,

Y is-N= or - C(R11)=,

R4, R5, R6, R7, R8, R9, R10, R11, R12and R13independently are

is hydrogen, halogen, hydroxy, trifluoromethyl, triptoreline, -SCF3, amino, cyano, nitro or-C(=O)NR14R15,

- C1-10-alkyl, C2-10-alkenyl,3-8-cycloalkyl,1-6-alkoxy, sub> 3-8-cycloalkyl-C1-6-alkoxy, C1-6-alkylamino, di-C1-6-alkylamino,3-8-cycloalkane,1-6-alkylsulfanyl,1-6-alkylsulfonyl,2-10-alkanoyl,4-9-cycloalkenyl,3-8-heterocyclyl or4-9-geteroseksualbnogo,4-9-heterocyclics, which may be optionally substituted by one or more substituents selected from R16,

- aryl, aryl-C1-6-alkyl, aryl-C1-6-alkoxy or heteroaryl, which may be optionally substituted by one or more substituents selected from R17,

- Arola, heteroaryl, aryloxy, heteroaromatic, arylamino or heteroarenes, which may be optionally substituted by one or more substituents selected from R18,

or two of R5, R6, R7, R8, R9, R10, R11, R12and R13in adjacent positions together form1-6-Allenby bridge or-O-C1-6-alkylen-O-bridge,

R14and R15independently are hydrogen, C1-6-alkyl, aryl-C1-6-alkyl, or R14and R15may together form a3-6-Allenby bridge,

R16independently selected from aryl, heteroaryl,3-8-cycloalkyl, halogen, trifloromethyl, triptoreline, NR19R20and C1-6 -alkoxy,

R17independently selected from halogen, hydroxy, trifloromethyl, triptoreline,

With1-6-alkoxy, C1-6-alkyl, amino, C1-6-alkylsulfonyl,1-6-alkylamino, di-C1-6-alkylamino, cyano, aryl, heteroaryl and C3-8-cycloalkyl,

R18independently selected from aryl, heteroaryl,1-10-alkyl, C3-8-cycloalkyl, halogen, trifloromethyl, triptoreline,1-6-alkoxy, cyano, amino, C1-6-alkylamino, di-C1-6-alkylamino and hydroxy,

R19and R20independently are hydrogen or C1-6-alkyl, R19and R20together can form With3-6-Allenby bridge,

provided that the connection should not be

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

In one embodiment, R1is branched C4-6-alkyl, C3-5-cycloalkyl or3-6-cycloalkyl-C1-3-alkyl, provided that R1is not isobutyl.

In another embodiment, R1is 1,1-(dimethyl)propylene, 1-ethylpropyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl or 1-cyclo is ropyl-1-mutilation.

In another embodiment, R1is 1-ethylpropyl, cyclopropylmethyl, cyclopropyl or cyclopentyl.

In another embodiment, R1is branched C4-6-alkyl or C3-5-cycloalkyl, provided that R1is not isobutyl.

In another embodiment, R1is 1-ethylpropyl, cyclopropyl or cyclopentyl.

In another embodiment of this invention, Z is-C(H)=,

-N= or-C(F)=.

In another embodiment of this invention, Z is-C(H)= or-N=.

In another embodiment of this invention, Z is-C(H)=.

In another embodiment of this invention, Z is-N=.

In another embodiment of this invention X is-C(H)=,

-N= or-C(F)=.

In another embodiment of this invention, Z is-C(H)= or-N=.

In another embodiment of this invention, Z is-C(H)=.

In another embodiment of this invention, Z is-N=.

In another embodiment of this invention W is-N=.

In another embodiment of this invention W is-C(R10)=.

In another embodiment of this invention Y is-N=.

In another embodiment of this invention Y is-C(R11)=.

In another embodiment, R2is hydrogen.

In another embodiment, R2is1-4-alkyl.

In another embodiment, R2is stands or ethyl.

In another aspect of this invention from OSISA to compounds of General formula (III)

where a and R3such as defined in the General formula (II).

In another embodiment of the invention R3is hydrogen, halogen, hydroxy, trifluoromethyl, triptoreline,1-10-alkyl, C1-6-alkoxy, aryl, aryl-C1-6-alkyl, amino, C3-8-cycloalkyl,3-8-cycloalkane, cyano or nitro.

In another embodiment of the invention R3is hydrogen, halogen, hydroxy, trifluoromethyl, C1-10-alkyl, C1-6-alkoxy, cyano or nitro.

In another embodiment of the invention R3is hydrogen, halogen, hydroxy, trifluoromethyl, C1-6-alkyl or cyano.

In another embodiment of the invention R3is hydrogen, halogen or1-6-alkyl.

In another embodiment of the invention R3is hydrogen or stands.

In another embodiment of the invention R4, R5, R6, R7, R8and R9independently are

is hydrogen, halogen, hydroxy, trifluoromethyl, triptoreline, -SCF3, amino or cyano,

- C1-10-alkyl, C3-8-cycloalkyl,1-6-alkoxy, C3-8-cycloalkane,2-10-alkanoyl,4-9-cycloalkenyl,3-8-heterocyclyl or4-9-geteroseksualbnogo, which may be optionally substituted by one or more substituents, select the tion of R 16,

- aryl, aryl-C1-6-alkyl, aryl-C1-6-alkoxy or heteroaryl, which may be optionally substituted by one or more substituents selected from R17,

- Arola, heteroaryl, aryloxy, heteroaromatic, which may be optionally substituted by one or more substituents selected from R18,

or two of R5, R6, R7, R8, R9in adjacent positions together form1-6-Allenby bridge or-O-C1-6-alkylen-O-bridge.

In another embodiment of the invention R4, R5, R6, R7, R8and R9independently are

is hydrogen, halogen, hydroxy, trifluoromethyl, triptoreline, -SCF3or cyano,

- C1-10-alkyl, C1-6-alkoxy, C3-8-cycloalkane, which may be optionally substituted by one or more substituents selected from R16,

- aryl or aryl-C1-6-alkyl which may be optionally substituted by one or more substituents selected from R17,

- Arola or aryloxy, which may be optionally substituted by one or more substituents selected from R18,

or two of R5, R6, R7, R8, R9in adjacent positions together form1-6-Allenby bridge or-O-C1-6-alkylen-O-bridge.

In each the m variant of the invention R 4, R5, R6, R7, R8and R9independently are

is hydrogen, halogen or cyano,

- C1-10-alkyl or C1-6-alkoxy that may be optionally substituted by one or more substituents selected from R16,

- aryl, optionally substituted by one or more substituents selected from R17,

- Arola or aryloxy, which may be optionally substituted by one or more substituents selected from R18,

or two of R5, R6, R7, R8, R9in adjacent positions together form1-6-Allenby bridge or-O-C1-6-alkylen-O-bridge.

In another embodiment of the invention R4, R5, R6, R7, R8and R9independently are

is hydrogen, halogen or cyano,

- stands, ethyl, propylene, isopropyl or1-6-alkoxy that may be optionally substituted by one or more substituents selected from R16,

- aryl, optionally substituted by one or more substituents selected from R17,

- Arola or aryloxy, which may be optionally substituted by one or more substituents selected from R18,

or two of R5, R6, R7, R8, R9in adjacent positions together form1-6-Allenby bridge or-O-sub> 1-6-alkylen-O-bridge.

In another embodiment of the invention R4, R5, R6, R7, R8and R9independently are

is hydrogen, halogen or cyano,

- C1-10-alkyl, methoxy, ethoxy or propoxy, which may be optionally substituted by one or more substituents selected from R16,

- aryl, optionally substituted by one or more substituents selected from R17,

- Arola or aryloxy, which may be optionally substituted by one or more substituents selected from R18,

or two of R5, R6, R7, R8, R9in adjacent positions together form1-6-Allenby bridge or-O-C1-6-alkylen-O-bridge.

In another embodiment of the invention R4, R5, R6, R7, R8and R9independently are

is hydrogen, halogen or cyano,

- C1-10-alkyl or methoxy, which may be optionally substituted by one or more substituents selected from R16,

- aryl, optionally substituted by one or more substituents selected from R17,

- Arola or aryloxy, which may be optionally substituted by one or more substituents selected from R18,

or two of R5, R6, R7, R8, R9in neighboring positions along the image of the t 1-6-Allenby bridge or-O-C1-6-alkylen-O-bridge.

In another embodiment of the invention R4, R5, R6, R7, R8and R9independently are

is hydrogen, halogen, or cyano,

- C1-10-alkyl or C1-6-alkoxy that may be optionally substituted by one or more substituents selected from R16,

- phenyl, optionally substituted by one or more substituents selected from R17,

- Arola or aryloxy, which may be optionally substituted by one or more substituents selected from R18,

or two of R5, R6, R7, R8, R9in adjacent positions together form1-6-Allenby bridge or-O-C1-6-alkylen-O-bridge.

In another embodiment of the invention R4, R5, R6, R7, R8and R9independently are

is hydrogen, halogen or cyano,

- C1-10-alkyl or C1-6-alkoxy that may be optionally substituted by one or more substituents selected from R16,

- aryl, optionally substituted by one or more substituents selected from R17,

- -C(=O)-phenyl or aryloxy, which may be optionally substituted by one or more substituents selected from R18,

or two of R5, R6, R7, R8,R 9in adjacent positions together form1-6-Allenby bridge or-O-C1-6-alkylen-O-bridge.

In another embodiment of the invention R4, R5, R6, R7, R8and R9independently are

is hydrogen, halogen or cyano,

- C1-10-alkyl or C1-6-alkoxy that may be optionally substituted by one or more substituents selected from R16,

- aryl, optionally substituted by one or more substituents selected from R17,

- Arola or-O-phenyl, which may be optionally substituted by one or more substituents selected from R18,

or two of R5, R6, R7, R8, R9in adjacent positions together form1-6-Allenby bridge or-O-C1-6-alkylen-O-bridge.

In another embodiment of the invention R1is ethyl or isopropyl.

In another embodiment of the invention R1is isopropyl.

In another embodiment of the invention R1is ethyl.

In another embodiment of the invention R1and R2together form3-4-alkilinity the bridge.

In another embodiment of the invention R10, R11, R12and R13independently are

is hydrogen, halogen, hydroxy, trifluoromethyl, triptoreline, cyano or-C(=O)NR14R15,

- C1-10-Alki the Ohm, With3-8-cycloalkyl,1-6-alkoxy, C2-10-alkanoyl,4-9-cycloalkenyl,3-8-heterocyclyl or4-9-geteroseksualbnogo,4-9-heterocyclics, which may be optionally substituted by one or more substituents selected from R16,

- aryl, aryl-C1-6-alkyl, aryl-C1-6-alkoxy or heteroaryl, which may be optionally substituted by one or more substituents selected from R17,

- Arola, optionally substituted by one or more substituents selected from R18,

or two of R10, R11, R12and R13in adjacent positions together form1-6-alkilinity the bridge.

In another embodiment of the invention R10, R11, R12and R13independently are

is hydrogen, halogen, hydroxy, trifluoromethyl, triptoreline, cyano or-C(=O)NR14R15,

- C1-10-alkyl, C3-8-cycloalkyl,1-6-alkoxy, C2-10-alkanoyl,4-9-cycloalkenyl,3-8-heterocyclyl or4-9-geteroseksualbnogo,4-9-heterocyclics, which may be optionally substituted by one or more substituents selected from R16,

- aryl, aryl-C1-6-alkyl, aryl-C1-6-alkoxy or heteroaryl, which can be optional for the emeny one or more substituents, selected from R17,

- Arola, optionally substituted by one or more substituents selected from R18,

or two of R10, R11, R12and R13in adjacent positions together form1-6-alkilinity the bridge.

In another embodiment of the invention R10, R11, R12and R13independently are

is hydrogen, halogen, trifluoromethyl or-C(=O)NR14R15,

- C1-10-alkyl, C1-6-alkoxy, C2-10-alkanoyl,4-9-cycloalkenyl,4-9-geteroseksualbnogo or4-9-heterocyclics, which may be optionally substituted by one or more substituents selected from R16,

- aryl, aryl-C1-6the alkyl or aryl-C1-6-alkoxy that may be optionally substituted by one or more substituents selected from R17,

- Arola, optionally substituted by one or more substituents selected from R18,

or two of R10, R11, R12and R13in adjacent positions together form1-6-alkilinity the bridge.

In another embodiment of the invention R10, R11, R12and R13independently are

is hydrogen, halogen, trifluoromethyl or-C(=O)NR14R15,

- C1-10-alkyl or C4-9-geteroseksualbnogo that can be NeoMaster is but substituted by one or more substituents, selected from R16,

- aryl, optionally substituted by one or more substituents selected from R17,

- Arola, optionally substituted by one or more substituents selected from R18,

or two of R10, R11, R12and R13in adjacent positions together form1-6-alkilinity the bridge.

In another embodiment of the invention R10, R11, R12and R13independently are

is hydrogen, halogen, trifluoromethyl or-C(=O)NR14R15,

- stands, ethyl, propylene or4-9-geteroseksualbnogo, which may be optionally substituted by one or more substituents selected from R16,

- aryl, optionally substituted by one or more substituents selected from R17,

- Arola, optionally substituted by one or more substituents selected from R18,

or two of R10, R11, R12and R13in adjacent positions together form1-6-alkilinity the bridge.

In another embodiment of the invention R10, R11, R12and R13independently are

is hydrogen, halogen, trifluoromethyl or-C(=O)NR14R15,

- C1-10-alkyl, piperidine-alkanoyl or pyrrolidin-alkanoyl, which may be optionally substituted by one or more substituents selected and the R 16,

- aryl, optionally substituted by one or more substituents selected from R17,

- Arola, optionally substituted by one or more substituents selected from R18,

or two of R10, R11, R12and R13in adjacent positions together form1-6-alkilinity the bridge.

In another embodiment of the invention R10, R11, R12and R13independently are

is hydrogen, halogen, trifluoromethyl or-C(=O)NR14R15,

- C1-10-alkyl or C4-9-geteroseksualbnogo, which may be optionally substituted by one or more substituents selected from R16,

- phenyl, optionally substituted by one or more substituents selected from R17,

- Arola, optionally substituted by one or more substituents selected from R18,

or two of R10, R11, R12and R13in adjacent positions together form1-6-alkilinity the bridge.

In another embodiment of the invention R14and R15independently are stands, ethyl or benzyl.

In another embodiment of the invention R16is halogen, trifluoromethyl, triptoreline and C1-6-alkoxy.

In another embodiment of the invention R17is halogen, hydroxy, trifluoromethyl, C1-6-alkoxy, C1-6-alkyla is, With1-6-alkylsulfonyl or cyano.

In another embodiment of the invention R17is halogen, trifluoromethyl, C1-6-alkoxy or C1-6-alkylsulfonyl.

In another embodiment of the invention R18is1-10the alkyl halogen, trifluoromethyl, C1-6-alkoxy, cyano, amino and hydroxy.

In another embodiment of the invention R18is halogen, C1-6-alkoxy and hydroxy.

In another aspect of this invention is the use of compounds of formula (II) or (III) in the pharmaceutical composition. The pharmaceutical composition may, in another embodiment, the invention contain, as active ingredient, at least one compound of the formula (II) or (III) together with one or more pharmaceutically acceptable carriers or excipients. In another embodiment, this invention is of such a pharmaceutical composition in a standard dosage form containing from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg, particularly preferably from about 0.5 mg to about 200 mg of the compounds of formula (II) or (III).

In another embodiment, the present invention is the use of compounds of General formula (II')

where

R2is hydrogen or C1-4-alkyl;

R1is

- C1-8-alkyl With 2-8-alkenyl or2-8-quinil, which may be optionally substituted by one or more Halogens,

- C3-5-cycloalkyl,3-7-cycloalkenyl,3-6-cycloalkyl-C1-3-alkyl or C3-6-cycloalkenyl-C1-3-alkyl which may be optionally substituted by one or more Halogens,

- R1and R2together form3-6-Allenby bridge,

And is

R3is hydrogen, halogen, hydroxy, trifluoromethyl, triptoreline,

With1-10-alkyl, C2-10-alkenyl,3-8-cycloalkyl,1-6-alkoxy, aryl, aryl-C1-6-alkyl, amino, C1-6-alkylamino, di-C1-6-alkylamino,3-8-cycloalkyl,3-8-cycloalkane, cyano, nitro, C1-6-alkylsulfanyl or1-6-alkylsulfonyl,

Z and X are independently-N=, -C(H)=, -C(F)=, -C(Cl)=,

-C(SP)= or-C(CF3)=,

W is-N= or-C(R10)=,

Y is-N= or - C(R11)=,

R4, R5, R6, R7, R8, R9, R10, R11, R12and R13independently are

is hydrogen, halogen, hydroxy, trifluoromethyl, triptoreline, -SCF3, amino, cyano, nitro or-C(=O)NR14R15,

- C1-10-alkyl, C2-10-alkenyl,3-8-cycloalkyl,1-6-alcox is, With3-8-cycloalkyl-C1-6-alkoxy, C1-6-alkylamino, di-C1-6-alkylamino,3-8-cycloalkane,1-6-alkylsulfanyl or1-6-alkylsulfonyl,2-10-alkanoyl,4-9-cycloalkenyl,3-8-heterocyclyl or4-9-geteroseksualbnogo,4-9-heterocyclics, which may be optionally substituted by one or more substituents selected from R16,

- aryl, aryl-C1-6-alkyl, aryl-C1-6-alkoxy or heteroaryl, which may be optionally substituted by one or more substituents selected from R17,

- Arola, heteroaryl, aryloxy, heteroaromatic, arylamino or heteroarenes, which may be optionally substituted by one or more substituents selected from R18,

or two of R5, R6, R7, R8, R9, R10, R11, R12and R13in adjacent positions together form1-6-Allenby bridge or-O-C1-6-alkylen-O-bridge,

R14and R15independently are hydrogen, C1-6-alkyl, aryl-C1-6-alkyl, or R14and R15may together form a3-6-Allenby bridge,

R16independently selected from aryl, heteroaryl,3-8-cycloalkyl, halogen, trifloromethyl, triptoreline, NR19R20and sub> 1-6-alkoxy,

R17independently selected from halogen, hydroxy, trifloromethyl, triptoreline,

With1-6-alkoxy, C1-6-alkyl, amino, C1-6-alkylsulfonyl,1-6-alkylamino, di-C1-6-alkylamino, cyano, aryl, heteroaryl and C3-8-cycloalkyl,

R18independently selected from aryl, heteroaryl,1-10-alkyl, C3-8-cycloalkyl, halogen, trifloromethyl, triptoreline,1-6-alkoxy, cyano, amino, C1-6-alkylamino, di-C1-6-alkylamino and hydroxy,

R19and R20independently are hydrogen or C1-6-alkyl, R19and R20together can form With3-6-Allenby bridge,

and also any diastereomers or enantiomers, or a tautomeric form, including mixtures thereof, or pharmaceutically acceptable salts to obtain a pharmaceutical composition for the treatment of disorders and diseases associated with histamine receptor H3.

In another embodiment, the present invention is the use of compounds of General formula (II'), such as defined above, to obtain a pharmaceutical composition for the treatment of diseases and disorders in which inhibition of the histamine receptor H3 plays a significant role.

In another embodiment, the present invention is the use of compounds of General formula (II'), such as is designated above, to obtain a pharmaceutical composition having an antagonistic activity against histamine receptor H3 or inverse agonistic activity against receptor histamine H3.

In another embodiment, the present invention is the use of compounds of General formula (II'), such as defined above, to obtain a pharmaceutical composition for weight reduction.

In another embodiment, the present invention is the use of compounds of General formula (II'), such as defined above, to obtain a pharmaceutical composition for the treatment of overweight or obesity.

In another embodiment, the present invention is the use of compounds of General formula (II'), such as defined above, to obtain a pharmaceutical composition for suppressing appetite or to activate the reflex of saturation.

In another embodiment, the present invention is the use of compounds of General formula (II'), such as defined above, to obtain a pharmaceutical composition for prevention and/or treatment of disorders and diseases related to overweight or obesity.

In another embodiment, the present invention is the use of compounds of General formula (II'), such as defined above, to obtain a pharmaceutical composition for prevention and/or treatment of disorders of Appeti is a, such as bulimia and excessive appetite.

In another embodiment, the present invention is the use of compounds of General formula (II'), such as defined above, to obtain a pharmaceutical composition for the treatment of IGT.

In another embodiment, the present invention is the use of compounds of General formula (II'), such as defined above, to obtain a pharmaceutical composition for the treatment of type 2 diabetes.

In another embodiment, the present invention is the use of compounds of General formula (II'), such as defined above, to obtain a pharmaceutical composition for the delaying or prevention of the development from IGT to type 2 diabetes.

In another embodiment, the present invention is the use of compounds of General formula (II'), such as defined above, to obtain a pharmaceutical composition for the delaying or prevention of the development from ainsliezubaida type 2 diabetes to insulin-dependent type 2 diabetes.

In another embodiment, the present invention is the use of compounds of General formula (II'), such as defined above, to obtain a pharmaceutical composition for the treatment of diseases and disorders in which stimulation of the histamine receptor H3 plays a significant role.

In another embodiment, the present invention is the use of compounds of General formula (I'), such as defined above, to obtain a pharmaceutical composition having agonistic activity against receptor histamine H3.

In another embodiment, the present invention is the use of compounds of General formula (II'), such as defined above, to obtain a pharmaceutical composition for the treatment of allergic rhinitis, ulcers or anorexia.

In another embodiment, the present invention is the use of compounds of General formula (II'), such as defined above, to obtain a pharmaceutical composition for the treatment of Alzheimer's disease, narcolepsy or disorders attention deficit.

In another embodiment, the invention provides a method of treatment of disorders or diseases associated with histamine receptor H3, where the method comprises the administration to a patient in need thereof, an effective amount of compounds of General formula (II'), such as defined above, or a pharmaceutical composition containing such a compound.

In another embodiment, the invention provides a method of treatment of disorders or diseases associated with histamine receptor H3, in which an effective amount of the compounds of General formula (II'), such as defined above, is from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to about 1000 mg, especially preferably from the Colo 0.5 mg to about 500 mg per day.

In another embodiment, the invention provides a method of treatment of disorders or diseases associated with histamine receptor H3, where the method comprises the administration to a patient in need thereof, an effective amount of compounds of General formula (I), any diastereoisomer or enantiomer or tautomeric forms, including mixtures thereof, or pharmaceutically acceptable salt, or containing pharmaceutical compositions.

In another embodiment, this invention relates to compounds having antagonistic or inverse agonistic action on the receptor histamine H3, which can be used to treat a wide range of conditions and disorders in which the desired receptor blockade of the histamine H3.

In another embodiment, this invention relates to compounds with agonistic action on the receptor histamine H3, which can be used to treat a wide range of conditions and disorders in which the desired activation of the histamine receptor H3.

In a preferred embodiment of the invention compounds in accordance with this invention is used to obtain pharmaceutical compositions for weight loss.

In a preferred embodiment of the invention compounds in accordance with this invention is used to obtain the pharmacist is ical compositions for the treatment of overweight or obesity.

In a preferred embodiment of the invention compounds in accordance with this invention is used to obtain pharmaceutical compositions for the suppression of appetite or reflex activation of saturation.

In a more preferred embodiment, compounds according to this invention is used to obtain pharmaceutical compositions for the prevention and/or treatment of disorders and diseases related to overweight or obesity such as atherosclerosis, hypertension, IGT (worsened glucose tolerance, diabetes, especially type 2 diabetes (NIDDM (ainsliezubaida diabetes), dyslipidemia, coronary heart disease, gall bladder disease, osteoarthritis and various types of cancer such as cancer of the uterus, breast, prostate and colon.

In a more preferred embodiment, compounds according to this invention is used to obtain pharmaceutical compositions for the prevention and/or treatment of disorders of appetite, such as bulimia and excessive appetite.

In a more preferred embodiment, compounds according to this invention is used to obtain pharmaceutical compositions for the treatment of IGT.

In a more preferred embodiment, compounds according to this invention is used to obtain pharmaceutical compositions for the prevention and/and the and treatment of type 2 diabetes. Such treatment includes, among other things, delay or prevent development from IGT to type 2 diabetes, and delay or prevent the development from ainsliezubaida type 2 diabetes to insulin-dependent type 2 diabetes.

Compounds in accordance with this invention can also be used to treat disorders of the respiratory tract, such as asthma, as antidiarrheic means, and for modulating the secretion of gastric acid.

Moreover, the compounds in accordance with this invention can be used for the treatment of diseases associated with the regulation of sleep and insomnia, and for the treatment of narcolepsy and disorders attention deficit.

Moreover, the compounds in accordance with this invention can be used as CNS stimulants or painkillers.

Compounds in accordance with this invention can also be used to treat conditions associated with epilepsy. In addition, the compounds in accordance with this invention can be used for the treatment of nausea and dizziness. Moreover, they can be used as regulators of secretion of the hypothalamic-pituitary, antidepressants, modulators of cerebral circulation and to treat irritable bowel syndrome.

Further, the compounds in accordance with this invention can note the change for the treatment of dementia and Alzheimer's disease.

Compounds in accordance with this invention can also be used for the treatment of allergic rhinitis, ulcers or anorexia.

Compounds in accordance with this invention can also be used to treat migraine, see McLeod et al.,The Journal of Pharmacology and Experimental Therapeutics287(1998), 43-50, and for the treatment of myocardial infarction, see Mackins et al.,Expert Opinion on Investigational Drugs9(2000), 2537-2542.

In another embodiment of the invention the treatment of the patient a compound in accordance with this invention is combined with diet and/or exercise.

In another embodiment, compounds of the invention in accordance with this invention is administered in combination with one or more additional active substances in any suitable ratios. Such active agents may be selected from funds from obesity, antidiabetic agents, protivoepilepticheskih funds, antihypertensive agents, agents for the treatment of complications arising from or associated with diabetes and agents for the treatment of complications and disorders arising from or associated with obesity.

Thus, in another embodiment, compounds of the invention in accordance with this invention is administered in combination with one or more tools from obesity or agents that regulate appetite.

Such agents can be selected from the group including agonists CART (cocaine-and the methamphetamine-regulated transcript), antagonists of NPY (neuropeptide Y)antagonists MS (melanocortin 4), agonists MS (melanocortin 3), antagonists of orexin, agonists of TNF (tumor necrosis factor)agonists, CRF (releasing factor corticotropin), antagonists of CRF BP (binding protein releasing factor corticotropin), agonists of urocortin, b3 adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, agonists, MSH (melanocyte-stimulating hormone)antagonists sit (melanocyte-concentrating hormone), agonists SCQ (cholecystokinin), reuptake inhibitors SSRIs, such as fluoxetine, seroxat or citalopram, inhibitors of reuptake of serotonin and norepinephrine, mixed serotonin and noradrenergic compounds, agonists NT (serotonin)agonists bombezin antagonists Galanina, growth hormone, growth factors such as prolactin or placental lactogenic, compounds that produce growth hormone, TRH agonists (hormone secreting tireotropina), modulators of the UCP 2 or 3 (uncoupling protein 2 or 3), leptin agonists, DA agonists (parlodel, depressin), inhibitors of lipase/amylase, PPAR modulators (proliferator-activated receptor peroxisome), RXR modulators (receptor retinoid X), agonists TR b inhibitors AGRP (agouti related protein), opioid antagonists (such as naltrexone), the basis-4, GLP-1 and the ciliary neurotrophic the ski factor.

In one embodiment of the present invention remedy for obesity is leptin.

In another embodiment, the cure for obesity is dexamfetamine or amphetamine.

In another embodiment, the cure for obesity is fenfluramine or dexfenfluramin.

In another embodiment, the cure for obesity is sibutramine.

In another embodiment, the cure for obesity is orlistat.

In another embodiment, the cure for obesity is mazindol or phentermine.

In another embodiment, the cure for obesity is phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate, or ecopipam.

In yet another embodiment, the compounds in accordance with this invention is administered 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), for example, NeB29the deletion of des (B30) human insulin, EP 0214826 and EP 0705275, (Novo Nordisk A/S), for example, AspB28human insulin, US 5504188 (Eli Lilly), for example, LysB28ProB29human insulin, EP 0368187 (Aventis), for example, Lantus®, which is included here as a reference, a derivative of GLP-1, such as described in WO 98/08871 (Novo Nordisk A/S), which is included here as a reference, as well as orally active hypoglycemic agents.

Oral is active hypoglycemic agents preferably include imidazoline, sulfonylureas, biguanides, meglitinide, oxadiazolidine preparations, thiazolidinediones, activators of insulin, inhibitors of a-glucosidase, agents acting on the ATP-dependent potassium channel b-cells, for example, potassium channels openers such as those described in WO 97/26265, WO 99/0381 and WO 00/37474 (Novo Nordisk A/S), which are included here as a reference, or mitiglinide, or blockers of potassium channels, such as BTS-67582, nateglinide, glucagon antagonists such as those described in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), included here as a reference, agonists of GLP-1, such as described in WO 00/42026 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), included here as a reference, inhibitors of DPP-IV (dipeptidylpeptidase-IV)inhibitors Rtrsy (protein tyrosine phosphatase)inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, modulators of absorption of glucose, inhibitors of GSK-3 (glikogensintetazy kinase-3), compounds modifying the lipid metabolism such as antilipidemic agents, compounds that decrease the absorption of food, PPAR (proliferator-activated receptor peroxisome) and RXR agonists (receptor retinoid X), such as ALRT-268, LG-1268 or LG-1069.

In one embodiment, the compounds of the invention in accordance with this invention is administered in combination with insulin or an analogue or derivative of insulin, such as the N the deletion of des (B30) human insulin, AspB28human insulin, LysB28ProB29human insulin, Lantus®, or a mixed form, containing one or more of the above.

In another embodiment, compounds of the invention in accordance with this invention is administered in combination with a sulfonylurea, for example, tolbutamide, chlorpropamide, tolazamide, glibenclamide, glipizide, glimepiride, glicazide or glyburide.

In another embodiment, compounds of the invention in accordance with this invention is administered in combination with biguanides, for example, Metformin.

In another embodiment, compounds of the invention in accordance with this invention is administered in combination with meglitinides, for example, Repaglinide or nateglinide.

In another embodiment, compounds of the invention in accordance with this invention is administered in combination with thiazolidinediones stimulator of insulin, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone, eaglecasino, darglitazone, englitazone, CS0011/Cl-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 are incorporated here by reference.

In another embodiment, compounds of the invention in accordance with this invention is administered in combination with stimulants of insulin, such as GI 262570, YM-440, MCC-555, JT-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 are incorporated here by reference.

In another embodiment, compounds of the invention in accordance with this invention is administered in combination with inhibitors of a-glucosidase, for example, voglibose, emiglitate, miglitol or acarbose.

In another embodiment, compounds of the invention in accordance with this invention is administered in combination with an agent acting as an ATP-dependent potassium channel b-cells, for example, tolbutamide, glibenclamide, glipizide, glicazide, BTS-37582 or Repaglinide.

In another embodiment, compounds of the invention in accordance with this invention is administered in combination with nateglinide.

In another embodiment, compounds of the invention in accordance with this invention is administered in combination with an antihyperlipidemic agent or antilipidemic agent, for example, cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.

In another embodiment, compounds of the invention in accordance with this invention is administered in combination with more than one of the above compounds, in the example, in combination with Metformin and sulfonylurea, such as glyburide; a sulfonylurea and acarbose; nateglinide and Metformin; acarbose and Metformin; a sulfonylurea, Metformin and troglitazone; insulin and a sulfonylurea; insulin and Metformin; insulin, Metformin and a sulfonylurea; insulin and troglitazone; insulin and lovastatin; etc

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

It should be clear that any suitable combination of the compounds in accordance with this invention with diet and/or exercise one or more of the above mentioned compounds and optionally one or more active washes the PTO is included in the scope of this invention.

Compounds in accordance with this invention can be chiral, that is, any enantiomers, such as separated, pure or partially purified enantiomers or racemic mixtures are also included in the scope of this invention.

Further, if the molecule has a cash bond or a partially or fully saturated ring system, or more than one center of asymmetry, or Association with a limited capacity for rotation, can be formed diastereomers. It is assumed that any diastereoisomers separated, pure or partially purified diastereomers or mixtures thereof is included in the scope of this invention.

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

The invention also encompasses pharmaceutically acceptable salts of the compounds in accordance with this invention. Such salts include pharmaceutically acceptable acid additive salts, pharmaceutically acceptable metal salts, ammonium and alkyl ammonium salts. Acid additive salts include salts with inorganic acids, and with organic acids. Pokazatel the examples of suitable inorganic acids include hydrochloric, Hydrobromic, yodiewonderdog, phosphoric, sulphuric, nitric acid and the like. Illustrative 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, citraconate, spartanbug, stearic, palmitic, etc, glycolic, p-aminobenzoic, glutamic, benzosulfimide, p-toluensulfonate acid and the like. Other examples of pharmaceutically acceptable inorganic and organic acid additive salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is included here as a reference. Examples of salts with metals include salts of lithium, sodium, potassium, magnesium and the like. Examples of ammonium and alkyl ammonium salts include ammonium salts, methylamine, dimethylamine, trimethylammonium, ethylamine, hydroxyethylamine, diethylamine, butylamine, Tetramethylammonium and the like.

As well as pharmaceutically acceptable acid additive salts can be taken hydrates that SP is able to form compounds in accordance with this invention.

Acid additive salts can be obtained as direct product of the synthesis of compounds. Alternatively, the free base can be dissolved in a suitable solvent containing the appropriate acid and salt selected by evaporating the solvent or other method of separation of salt and solvent.

Compounds in accordance with this invention may form a solvate with standard solvents with low molecular weight, using methods well-known to specialists in this field of technology. Such a solvate is also included in the scope of this invention.

The invention also encompasses prodrugs of the compounds in accordance with this invention that when introducing undergo chemical conversion by metabolic and become active pharmacological compounds. In General, such prodrugs are functional derivatives of the compounds in accordance with this invention, which are easily converted in vivo into the required compound of formula (I). Conventional methods for selecting and obtaining the appropriate derivative prodrugs described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

The invention also includes active metabolites of compounds in accordance with this invention.

Compounds according to izaberete the receiving interact with the histamine receptor H3 and therefore, can be used to treat a wide range of conditions and disorders in which the predominant role played by the interaction of histamine receptor H3.

The pharmaceutical composition

Compounds in accordance with this invention can be administered alone or in combination with pharmaceutically acceptable carriers or excipients, one or more doses. Pharmaceutical compositions in accordance with this invention can be formulated with pharmaceutically acceptable carriers or diluents, as well as other known adjuvants and diluents according to conventional methods, such as described in Remington: The Science and Practice of Pharmacy, 19thEdition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. The pharmaceutical compositions can be formed in a certain way for the introduction of any suitable way, such as oral, rectal, nasal, pulmonary, local (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, where it is preferable to oral path. It is clear that the preferred path depends on the General condition and age treat the patient, nature cure status and selected asset from the second ingredient.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, coated tablets, pills, lozenges, powders and granules. If acceptable, they can be obtained in environments, such as intersolubility shell, or they can be obtained in such a way as to provide controlled release of active ingredient, such as delayed or prolonged isolation in accordance with methods known in the art.

Liquid dosage 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 emulsions, and sterile powders that are playable in a sterile injectable solutions or dispersions just prior to use. The injected composition depot also included in the scope of this invention.

Other suitable administration forms include suppositories, sprays, ointments, creams, gels, inhalants, skin patches, implants, etc.

The typical dose for oral administration is 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, more preferably from about 0.05 to OK is around 10 mg/kg of body weight per day, with the introduction of one or more doses, for example from 1 to 3 doses. The exact dose depends on the frequency and route of administration, sex, age, weight and General state of cure of the patient, nature and severity treat the condition and treat any co-morbidities and other factors evident to a person skilled in the technical field.

The composition can be in standard dosage forms and obtained by the methods known to experts in this field of technology. Standard dosage form for oral administration one or more 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 to about 200 mg For parenteral routes of administration, such as intravenous, intrathecal, intramuscular and the like route of administration, typical doses are of the order of half the dose used for oral administration. Compounds in accordance with this invention is generally used in the form of free substance or in the form of its pharmaceutically acceptable salts. One example is the acid additive salt compounds having the application in the form of free base. If the compound of formula (I) contains a free base such salts have an ordinary method, the processing solution or WM is enzie free base of formula (I) chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic or organic acids. The examples presented above. 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 may apply the solutions of the new compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol, or hemp oil, or peanut oil. Such aqueous solutions should include an appropriate buffer, if necessary, and an aqueous diluent, which is the first isotonic, and the appropriate amount of saline or glucose. Aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. Apply a sterile aqueous medium is easily obtained by standard methods known to experts in this field of technology.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers include lactose, kaolin, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkylamine cellulose. Examples of liquid carriers include syrup, peanut oil, olivkovaya, phospholipids, fatty acids, amines, fatty acids, polyoxyethylene or water. The carrier or diluent may include any material for delayed allocation, known in the art, such as glycerylmonostearate or glycerylmonostearate, the Pharmaceutical compositions formed by combining the new compounds of the formula (I) and pharmaceutically acceptable carriers, it is easy to introduce different doses suitable for the described routes of administration. The composition can be obtained in standard dosage forms by methods known in the pharmaceutical field.

Compositions in accordance with this invention suitable for oral administration may be in separate dosage forms, such as capsules or tablets each containing a predetermined amount of the active ingredient and which may include a suitable filler. Such compositions can be in the form of a powder or granules; as solution or suspension in aqueous or non-aqueous liquid or in the form of emulsions of oil-in-water or water-in-oil.

If oral administration is used, the solid carrier, the composition may be tableted, placed in a hard gelatin capsule in powder or pellet, or it can be in the form of pellets or pastilles. The amount of solid filler can widely various is, but usually ranges from about 25 mg to about 1, If applied liquid carrier, the composition may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

A typical tablet, which may be obtained by conventional tabletting, may contain:

Filling:
The active compound (as free compound or its salts)5.0 mg
Lactose Ph. Eurand 67.8 mg
Cellulose, microcrystalline (Avicel)of 31.4 mg
Amberlite® IRP88*1.0 mg
Magnesium stearate Ph. Eur.q.s.
Shell:
The hypromelloseabout 9 mg
Mywacett 9-40 T**about 0.9 mg
* Polacrilin potassium NF, baking powder for tablets, Rohm and Haas.
** Atilirovanie the monoglyceride, p is isenemy as a plasticizer to obtain a film of the shells.

If desired, the pharmaceutical compositions in accordance with this invention may contain the compound of formula (I) in combination with other pharmacologically active substances, such as described above.

EXAMPLES

In the following examples, the following terms are presented below total value:

DIPEA: diisopropylethylamine

DMSO: dimethyl sulfoxide

THF: tetrahydrofuran

HPLC (method A)

The NMR spectrum of the recorded instruments Bruker 300 MHz and 400 MHz. HPLC-MS carried out on the instrument Perkin Elmer API (100). Used column X-Terra C18, 5 μm, 50×3 mm, elution is carried out at 1.5 ml/min at room temperature with a gradient from 5 to 90% acetonitrile in water containing 0.01% of triperoxonane acid for a period of 7.5 minutes

HPLC (method B)

Analysis with the reversible phase is carried out with the use of UV definitions at 214 and 254 nm on a column of silica gel TO 4.6 mm x 150 mm C-18, which elute at 1 ml/min at a temperature of 42°C. the Column balance 5% acetonitrile, 85% water and 10% of a solution of 0.5% triperoxonane acid in water and elute with a linear gradient from 5% acetonitrile, 85% water and 10% of a solution of 0.5% triperoxonane acid to 90% acetonitrile and 10% of a solution of 0.5% triperoxonane acid within 15 minutes

HPLC (method C)

OF the analysis is performed with the use of system Waters Alliance 2695 equipped define who eat double stripes Waters 2487. The UV data are collected using column Symmetry C18, 3.5 µm, 3.0 mm x 100 mm, Elution is carried out with a linear gradient of 5-90% acetonitrile, 90-0% water and 5% triperoxonane acid (1,0%) in water over 8 minutes at a flow rate of 1.0 ml/min

General method (A)

General method (A) is used for obtaining the compounds of General formula (Ia):

where is CH(R20R21is ethyl, isopropyl, branched C4-6the alkyl, branched C4-6-alkenyl branched C4-6-quinil,3-5-cycloalkyl,

With3-7-cycloalkenyl,3-6-cycloalkyl-C1-3-alkyl or C3-6-cycloalkenyl-C1-3-alkyl, which optionally can be substituted by one or more Halogens.

To a mixture of monosubstituted piperazine (15,2 mmol) in a suitable solvent, such as THF, add the ketone or aldehyde (22,6 mmol), water, acetic acid (45,0 mmol) and then NaCNBH3(18 mmol). The mixture is stirred at a temperature of 55°C for 5.5 hours (ketones) or at room temperature over night (aldehydes) and then concentrated under reduced pressure. Add saturated aqueous solution of NaHCO3(100 ml) and the mixture is extracted with a solvent such as ethyl acetate (3×40 ml). The combined extracts washed with saturated salt solution, dried over magnesium sulfate is concentrated under reduced pressure. The remainder may be converted into a suitable salt, such as hydrochloride, joint evaporation of acid, such as a 1-molar aqueous hydrochloric acid, ethanol and toluene, and the residue is then purified by recrystallization.

General method (B)

Compounds of General formula (I) can be obtained by the General method (B):

A mixture of monosubstituted piperazine (2.00 mmol), DMSO (1.0 ml) and the appropriate aryl - or heteroaryl of halide (2.00 mmol) and bases, such as DIPEA (0,20 ml), stirred for one hour at a temperature of 100°C. and then 18 hours at a temperature of 120°C., water is Added and the potassium carbonate and the mixture is extracted with a solvent such as ethyl acetate (3×20 ml). Isolation and purification were carried out as described in the General method (A).

Not commercially available substituted 2-chlorhydrin receive, as described in the literature: F. Effenberger, W. Hartmann, Chemische Berichte1969,102, 3260-3267.

General method (C)

Compounds of General formula (I) can be obtained by the General method (S):

The compound of formula (I) can be obtained from the appropriate monosubstituted piperazine and appropriate arilbred in the presence of a suitable catalyst, such as, for example, Tris(dibenzylideneacetone)dipalladium in a suitable solvent, such as toluene, when the approach is overall a temperature of from 0°C. to 150°C.

Example 1

4-(4-Cyclopentylpropionyl-1-yl)phenol

To a suspension of 1-(4-hydroxyphenyl)piperazine (2.70 g, of 15.2 mmol) in THF (28 ml) was added Cyclopentanone (1.90 ml, and 22.6 mmol), water (0.15 ml), acetic acid (2,70 ml of 45.0 mmol) and then NaCNBH3(18 ml, 1 mol in THF, 18 mmol). The mixture is stirred at a temperature of 55°C for 5.5 hours and then concentrated under reduced pressure. Add saturated aqueous solution of NaHCO3(100 ml) and ethyl acetate (40 ml) and the mixture filtered. The obtained solid is re-suspended in methanol (30 ml), heated to the boiling temperature under reflux and stand at room temperature overnight. Filtration and drying under reduced pressure to give specified in the header connection (1,82 g, 49%) as a solid.

1H NMR (DMSO-d6) δ of 1.34 (m, 2H), 1,49 (m, 2H), 1,60 (m, 2H), 1,79 (m, 2H), 2,43 (m, 1H), of 2.51 (m, 4H), of 2.92 (m, 4H), 6,62 (d, J=8 Hz, 2H), 6,77 (d, J=8 Hz, 2H), 8,78 (s, 1H); HPLC-MS: m/z 247 (MH+); Rf: 2,70 minutes

Example 2

1-Cyclopentyl-4-[4-(4-forbindelse)phenyl]piperazine

To a suspension of potassium hydroxide (0,165 g, 2,95 mmol) in ethanol (4 ml) is added 4-(4-cyclopentylpropionyl-1-yl)phenol (0.25 g, of 1.02 mmol). After 10 minutes add 4-tormentilla (0,18 ml and 0.22 g and 1.51 mmol) and the mixture is stirred at 70°C for 5 hours. Add Aut saturated aqueous solution of NaHCO 3(20 ml) and the mixture extracted with ethyl acetate (3×20 ml). The combined extracts washed with saturated salt solution, dried over magnesium sulfate and concentrated. Recrystallization from methanol (4 ml) to give 0.125 g (35%) specified in the connection header.

1H NMR (DMSO-d6) δ of 1.34 (m, 2H), 1,50 (m, 2H), 1,62 (m, 2H), is 1.81 (m, 2H), 2,45 (m, 1H), of 2.51 (m, 4H), 2,99 (m, 4H), to 5.00 (s, 2H), 6.87 in (m, 4H), 7,19 (t, J=8 Hz, 2H), 7,46 (m, 2H); HPLC-MS: m/z 355 (MH+); Rf: 4,73 minutes

Example 3

1-(3-Chlorophenyl)-4-cyclopentylpropionyl

Connection receive according to the method of example 1, starting from 1-(3-chlorophenyl)piperazine.

1H NMR (DMSO-d6) δ of 1.34 (m, 2H), 1,50 (m, 2H), 1,60 (m, 2H), 1,80 (m, 2H), 2,45 (m, 1H), of 2.51 (m, 4H), 3,14 (m, 4H), 6,78 (d, J=8 Hz, 1H), to 6.88 (m, 2H), 7,19 (t, J=8 Hz, 1H); HPLC-MS: m/z 265 (MH+); Rf: 3,88 minutes

Example 4

1-[4-(4-Cyclopentylpropionyl-1-yl)phenyl]alanon

Connection receive according to the method of example 1, starting from 1-(4-acetylphenyl)piperazine.

1H NMR (DMSO-d6) δ 1.30 and a 1.88 (m, 8H), of 2.45 (s, 3H), of 2.45 (m, 1H), of 2.51 (m, 4H), and 3.31 (m, 4H), to 6.95 (d, J=8 Hz, 2H), 7,79 (d, J=8 Hz, 2H); HPLC-MS: m/z 273 (MH+); Rf: 3,25 minutes

Example 5

1-(3,4-Dichlorophenyl)-4-(1-ethylpropyl)piperazine

Connection receive according to the method of example 1, starting from 1-(3,4-dichlorophenyl)piperazine and 3-pentanone.

1H NMR (DMSO-d6) δ of 0.68 (t, J=7 Hz, 6H), 1.28 (in m,2H), of 1.45 (m, 2H), 2,19 (m, 1H), 2,56 (sh. s, 4H), 3,12 (sh. s, 4H), 6,91 (m, 1H), 7,09 (sh. s, 1H), was 7.36 (d, J=8 Hz, 1H); HPLC-MS: m/z 301 (MH+); Rf: 4,25 minutes

Example 6

{4-[4-(1-Ethylpropyl)piperazine-1-yl]phenyl}of phenylethanone hydrochloride

A mixture of 1-(3-pentyl)piperazine (0.31 g, 2.00 mmol), DMSO (1.0 ml), 4-terbinafine (0.40 g, 2.00 mmol) and DIPEA (0,20 ml) is stirred for one hour at a temperature of 100°C. and then for 18 hours at a temperature of 120°C. Add water (50 ml) and potassium carbonate (2 g) and the mixture extracted with ethyl acetate (3×20 ml). The combined extracts washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The crude product is re-dissolved in ethanol (10 ml) and 1 molar aqueous HCl (4 ml) and the solution concentrated under reduced pressure. After co-evaporation with ethanol and toluene the residue utverjdayut and recrystallized from acetonitrile (100 ml). Obtain 0.20 g (27%) specified in the connection header.

1H NMR (DMSO-d6) δ of 0.95 (m, 6H), of 1.62 (m, 2H), 1,89 (m, 2H), 3.04 from-with 3.27 (m, 3H), of 3.48 (m, 4H), of 4.05 (m, 2H), was 7.08 (m, 2H), 7,51 (m, 2H), 7,65 (m, 5H), 10,75 (sh. s, 1H); HPLC-MS: m/z 337 (MH+); Rf: 4,27 minutes

Example 7

1-(4-Benzoylphenyl)-4-(1-ethylpropyl)piperazine hydrochloride

A mixture of {4-[4-(1-ethylpropyl)piperazine-1-yl]phenyl}of phenylethanone hydrochloride (77 mg, 0.21 mmol), trifter kusnoy acid (2.0 ml) and triethylsilane (0.5 ml) is stirred at 60°C for 20 hours. The mixture is concentrated under reduced pressure and mixed with water and potassium carbonate. The mixture is extracted with ethyl acetate (3×20 ml). The combined extracts washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The crude product is re-dissolved in ethanol and 1-molar aqueous HCl and the solution concentrated under reduced pressure. After co-evaporation with ethanol and toluene the residue utverjdayut. Receive 45 mg (61%) specified in the connection header.

1H NMR (DMSO-d6) δ and 0.98 (t, J=7 Hz, 6H), of 1.64 (m, 2H), 1,89 (m, 2H), 3.04 from is 3.23 (m, 5H), of 3.48 (m, 2H), and 3.72 (m, 2H), 3,85 (s, 2H), 6,93 (d, J=8 Hz, 2H), 7,10-7,30 (m, 7H), of 10.05 (sh. s, 1H); HPLC-MS: m/z 323 (MH+); Rf: 4,93 minutes

Example 8

Cyclopropyl-{4-[4-(1-ethylpropyl)piperazine-1-yl]phenyl}methanone hydrochloride

Connection receive according to the method of example 6, starting from 4-forfinal(cyclopropyl)ketone.

1H NMR (DMSO-d6) δ 0,98 (m, 10H), of 1.64 (m, 2H), 1,89 (m, 2H), 2,82 (sh. s, 1H), 3.04 from is 3.23 (m, 3H), 3,49 (m, 4H), Android 4.04 (m, 2H), 7,07 (d, J=8 Hz, 2H), of 7.96 (d, J=8 Hz, 2H), 10,95 (sh. s, 1H); HPLC-MS: m/z 301 (MH+); Rf: 4,03 minutes

Example 9

(2-Chlorophenyl)-{4-[4-(1-ethylpropyl)piperazine-1-yl]phenyl}methanone hydrochloride

Connection receive according to the method of example 6, starting from 4-forfinal(2-chlorophenyl)ketone.

1H NMR (DMSO-d6) δ 0,98 (who, J=7 Hz, 6H), of 1.64 (m, 2H), of 1.88 (m, 2H), is 3.08 is 3.23 (m, 3H), 3,50 (m, 4H), 4,06 (m, 2H), was 7.08 (d, J=8 Hz, 2H), 7,31 (m, 1H), of 7.48 (m, 1H), 7,50-to 7.61 (m, 4H), 10,85 (sh. s, 1H); HPLC-MS: m/z 371 (MH+); Rf: 4,43 minutes

Example 10

{4-[4-(1-Ethylpropyl)piperazine-1-yl]phenyl}-(4-forfinal)methanone hydrochloride

Connection receive according to the method of example 6, starting from 4,4'-diftorbenzofenon.

1H NMR (DMSO-d6) δ and 0.98 (t, J=7 Hz, 6H), of 1.66 (m, 2H), 1,89 (m, 2H), is 3.08-of 3.25 (m, 3H), 3,41-of 3.53 (m, 4H), of 4.05 (m, 2H), to 7.09 (d, J=8 Hz, 2H), 7,38 (m, 2H), 7,69 (d, J=8 Hz, 2H), 7,76 (m, 2H), 10,80 (sh. s, 1H); HPLC-MS: m/z 355 (MH+); Rf: 4,37 minutes

Example 11

1-Cyclopentyl-4-(6-triptorelin-2-yl)piperazine

Connection receive according to the method of example 1, starting from 1-(6-triptorelin-2-yl)piperazine.

1H NMR (DMSO-d6) δ of 1.34 (m, 2H), 1,50 (m, 2H), 1,60 (m, 2H), 1,80 (m, 2H), 2,45 is 2.51 (m, 5H), 3,52 (m, 4H), 7,02 (d, J=8 Hz, 1H), 7,11 (d, J=8 Hz, 1H), 7,71 (t, J=8 Hz, 1H); HPLC-MS: m/z 300 (MH+); Rf: 4,10 minutes

Example 12

1-Cyclopentyl-4-(5-triptorelin-2-yl)piperazine

Connection receive according to the method of example 1, starting from 1-(5-triptorelin-2-yl)piperazine.

1H NMR (DMSO-d6) δ of 1.36 (m, 2H), 1,50 (m, 2H), 1,60 (m, 2H), 1,80 (m, 2H), 2,45-2,52 (m, 5H), to 3.58 (m, 4H), 6,92 (d, J=8 Hz, 1H), 7,78 (sh. d, J=8 Hz, 1H), 8,39 (s, 1H); HPLC-MS: m/z 300 (MN+); Rf: a 3.87 min

Example 13

1-Cyclopentyl-4-(3-triform terpyridine-2-yl)piperazine

Connection receive according to the method of example 1, starting from 1-(3-triptorelin-2-yl)piperazine.

1H NMR (DMSO-d6) δ 1,29-of 1.65 (m, 6H), of 1.80 (m, 2H), 2,45 (m, 1H), 2,52 (m, 4H), 3,18 (m, 4H), 7,16 (m, 1H), 8,02 (m, 1H), 8,49 (m, 1H); HPLC-MS: m/z 300 (MN+); Rf: 3,70 minutes

Example 14

2-[4-(1-Ethylpropyl)piperazine-1-yl]quinoline hydrochloride

Connection receive according to the method of example 6, starting from 2-chlorhydrin.

1H NMR (DMSO-d6) δ 0,99 (t, J=7 Hz, 6H), of 1.65 (m, 2H), was 1.94 (m, 2H), 3,12 (sh. s, 1H), 3.33 and (m, 2H), only 3.57 (m, 2H), 3,93 (m, 2H), a 4.83 (m, 2H), 7,44-7,58 (m, 2H), 7,76 (m, 1H), 7,92 (m, 1H), 8,25 (sh. s, 1H), 8,42 (m, 1H), 11,20 (sh. C, H); HPLC-MS: m/z 284 (MN+); Rf: 3,03 minutes

Example 15

7-Chloro-4-[4-(1-ethylpropyl)piperazine-1-yl]quinoline hydrochloride

Connection receive according to the method of example 6, starting with a 4.7-dichlorohydrin.

1H NMR (DMSO-d6) δ 1.00 each (t, J=7 Hz, 6H), to 1.67 (m, 2H), 1,95 (m, 2H), 3.15 in (sh. s, 1H), 3,30-3,70 (m, 4H), of 4.05 (m, 2H), 4,20 (m, 2H), 7,32 (m, 1H), 7,73 (m, 1H), 8,28 (m, 2H), 8,83 (m, 1H), 11,35 (sh. C, H); HPLC-MS: m/z 318 (MN+); Rf: 3,13 minutes

Example 16

[4-(4-Cyclopentylpropionyl-1-yl)phenyl]-(3,4-acid)methanone hydrochloride

Connection receive according to the method of example 6, starting from 4'-fluoro-3,4-dimethoxybenzophenone.

1H NMR (DMSO-d6) δ of 1.55 (m, 2H), 1,65-1,90 (m, 4H), 2,02 (m, 2H), 3,05 is 3.40 (m, 4H), 355 (m, 3H), 3,81 (s, 3H), 3,88 (s, 3H), 4,08 (m, 2H), 7,10 (m, 3H), 7,29 (m, 2H), 7,69 (d, J=8 Hz, 2H), 10,78 (sh. s, 1H); HPLC-MS: m/z 395 (MN+); Rf: 3,03 minutes

Example 17

[4-(4-Cyclopentylpropionyl-1-yl) - for 3,5-differenl]phenylethanone hydrochloride

Connection receive according to the method of example 6, starting from 3,4,5-triptoreline.

1H NMR (DMSO-d6) δ of 1.55 (m, 2H), 1,65-1,90 (m, 4H), 2,02 (m, 2H), 3.15 in (m, 2H), 3,50-3,71 (m, 7H), 7,42 (m, 2H), 7,58 (m, 2H), 7.68 per for 7.78 (m, 3H), 10,90 (sh. s, 1H); HPLC-MS: m/z 371 (MN+) Rf: 2,77 minutes

Example 18

2-(4-Cyclopentylpropionyl-1-yl)finokalia hydrochloride

Connection receive according to the method of example 6, starting from 2-chlorphenoxamine and applying propionitrile as a solvent.

1H NMR (DMSO-d6) δ of 1.55 (m, 2H), 1,64-1,90 (m, 4H), 2,02 (m, 2H), 3.15 in (m, 2H), 3,42-the 3.65 (m, 5H), 4,71 (m, 2H), 7,49 (m, 1H), to 7.67 (m, 2H), 7,88 (SD, J=8 Hz, 1H), 8,91 (s, 1H), 10,92 (sh. s, 1H); HPLC-MS; m/z 283 (MN+); Rf: 1,70 minutes

Example 19

2-(4-Cyclopropylamines-1-yl)finokalia hydrochloride

1H NMR (DMSO-d6) δ 0,41 (m, 2H), 0,66 (m, 2H), 1,18 (m, 1H), to 3.02 (m, 2H), 3,13 (m, 2H), 3,52 at 3.69 (m, 4H), 4,71 (m, 2H), of 7.48 (m, 1H), 7,66 (m, 2H), 7,88 (d, J=8 Hz, 1H), of 8.90 (s, 1H), 11,17 (sh. s, 1H); HPLC-MS: m/z 269 (MN+); Rf: 1,73 minutes

Example 20

[6-(4-Cyclopentylpropionyl-1-yl)pyridine-3-yl]piperidine-1-ylmethanone hydrochloride

1H NMR (DMSO-d6) δ 1,45-of 2.08 (m, 14H), 3,06 (m, 2H), 3,38-3,61 (m, 9H), of 4.44 (m, 2H), 7,02 (d, J=8 Hz, 1H), of 7.70 (DD, J=8 Hz, 1 Hz, 1H), 8,19 (d, J=1 Hz, 1H); HPLC-MS: m/z (MN+).

Connection receive according to the method of example 6 (General procedure (C)), using 1-(6-chloronicotinoyl)piperidine (Thunus,Ann. Pharm. Fr.1977,35, 197).

Example 21

2-(4-Cyclopentylpropionyl-1-yl)quinoline hydrochloride

1H NMR (DMSO-d6) δ of 1.62 (m, 2H), equal to 1.82 (m, 2H), 1,96 (m, 2H), 2,09 (m, 2H), 3,25 (m, 2H), 3,55-3,70 (m, 5H), of 4.83 (m, 2H), 7,46-of 7.60 (m, 2H), 7,80 (m, 1H), 7,94 (m, 1H), 8,13 (m, 1H), 8,42 (m, 1H), to 11.52 (sh. s, 1H); HPLC-MS: m/z 282 (MN+); Rf: 0,34 minutes

Connection receive according to the method of example 6, starting from 2-chlorhydrin.

Example 22

2-(4-Cyclopentylpropionyl-1-yl)-7-methoxy-3-(4-methoxyphenyl)quinoline hydrochloride

1H NMR (DMSO-d6) δ of 1.53 (m, 2H), 1,63 is 1.86 (m, 4H), to 1.98 (m, 2H), 3,05 (m, 2H), 3.33 and-to 3.52 (m, 5H), of 3.75 (m, 2H), 3,82 (s, 3H), 3,91 (s, 3H), was 7.08 (d, J=8 Hz, 2H), 7,13 (DD, J=8 Hz, 1 Hz, 1H), 7,49 (sh. s, 1H), to 7.61 (d, J=8 Hz, 2H), 7,83 (d, J=8 Hz, 1H), 8,15 (s, 1H), 11,29 (sh. s, 1H); HPLC-MS: m/z 418 (MN+); Rf: 3,40 minutes

Example 23

{6-[4-(1-Cyclopropyl-1-methylethyl)piperazine-1-yl]pyridine-3-yl}phenylmethanone hydrochloride

1H NMR (DMSO-d6) δ 0,48-of 0.62 (m, 4H), 1,22-of 1.39 (m, 7H), 3,14 (m, 2H), 3,69 (m, 4H), with 4.64 (m, 2H), was 7.08 (d, J=8 Hz, 1H), 7,55 (m, 2H), to 7.61-7,72 (m, 3H), of 8.00 (DD, J=8 Hz, 1 Hz, 1H), charged 8.52 (d, J=1 Hz, 1H), 11,27 (sh. s, 1H); HPLC-MS: m/z 35 (MN +); Rf: 3,03 minutes

Connection receive according to the method of example 6, starting from 2-chloro-5-benzoylpyridine (T.D. Penning et al.,J. Med. Chem.2000,43, 721-735).

Example 24

{4-[4-(1-Cyclopropyl-1-methylethyl)piperazine-1-yl] - for 3,5-differenl}of phenylethanone hydrochloride

1H NMR (DMSO-d6) δ of 0.48 to 0.63 (m, 4H), 1,23-of 1.40 (m, 7H), 3,18 (m, 2H), of 3.56 (m, 2H), 3,69 (m, 2H), 3,84 (m, 2H), 7,42 (m, 2H), 7,58 (m, 2H), 7,66-7,76 (m, 3H), 10,90 (sh. s, 1H); HPLC-MS: m/z 385 (MN+); Rf: to 3.73 min

Example 25

{4-[4-(1-Cyclopropyl-1-methylethyl)piperazine-1-yl] - for 3,5-differenl}phenylethanol hydrochloride

1H NMR (DMSO-d6) δ 0,47-0,61 (m, 4H), of 1.23 to 1.34 (m, 7H), of 3.12 (m, 2H), 3,29 (m, 2H), the 3.65 (m, 4H), to 5.66 (m, 1H), between 6.08 (m, 1H), 7,06 (m, 2H), 7,19-7,40 (m, 5H), the 10.40 (sh. s, 1H); HPLC-MS: m/z 387 (MN+); Rf: 3,40 minutes

The connection is produced by restoration with sodium borohydride from example 24.

Example 26

[4-(4-Cyclopropylamines-1-yl) - for 3,5-differenl]-(4-forfinal)methanone hydrochloride

1H NMR (DMSO-d6) δ x 0.40 (m, 2H), 0,66 (m, 2H), 1,13 (m, 1H), 3,02 is 3.23 (m, 5H), 3,52-3,68 (m, 5H), 7,40 (m, 4H), 7,82 (m, 2H), 10,55 (sh. s, 1H); HPLC-MS: m/z 375 (MH+); Rf: 2,78 minutes

Connection receive according to the method of example 6, starting with 3,4,5,4'-tetrafluorobenzene. The latter is obtained by acylation of fervently with 3,4,5-triterpenoids by Friedel-Crafts.

Example 27

{4-[4-(1-Ethylpropyl)piperazine-1-yl] - for 3,5-differenl}-(4-forfinal)methanone hydrochloride

1H NMR (DMSO-d6) δ of 0.97 (t, J=7 Hz, 6H), by 1.68 (m, 2H), of 1.88 (m, 2H), 3,06-3,26 (m, 3H), 3,52 (m, 4H), of 3.75 (m, 2H), 7,41 (m, 4H), 7,82 (m, 2H), 10,31 (sh. s, 1H); HPLC-MS: m/z 391 (MN+); Rf: 3,00 minutes

Example 28

2-[4-(1-Ethylpropyl)piperazine-1-yl]-6,7-dimethoxyaniline hydrochloride

1H NMR (DMSO-d6) δ 0,99 (t, J=7 Hz, 6H), of 1.66 (m, 2H), 1.91 a (m, 2H), 3,11 (m, 1H), 3,29 (m, 2H), of 3.56 (m, 4H), 3,88 (s, 3H), 3,92 (s, 3H), 4.72 in (m, 2H), 7,31-the 7.43 (m, 2H), 7,82 (sh. s, 1H), 8,30 (sh. s, 1H), 10,95 (sh. s, 1H); HPLC-MS: m/z 344 (MN+); Rf: 2,00 minutes

Connection receive according to the method of example 6 from 2-chloro-6,7-dimethoxyaniline (Pettit.,Can. J. Chem.1964,42, 1764).

Example 29

2-[4-(1-Ethylpropyl)piperazine-1-yl]-4-triptoreline hydrochloride

1H NMR (DMSO-d6) δ 0,99 (t, J=7 Hz, 6H), of 1.65 (m, 2H), 1.91 a (m, 2H), is 3.08 (m, 1H), 3,19 (m, 2H), 3,52 (m, 2H, in), 3.75 (m, 2H), 4,77 (m, 2H), of 7.48 (t, J=7 Hz, 1H), 7,72 (m, 2H), 7,88 (m, 2H), 11,19 (sh. s, 1H); HPLC-MS: m/z 352 (MN+); Rf: 3,70 minutes

The compound is obtained from 2-chloro-4-triptoreline. The latter is obtained as described in the literature: R.D. Westland et al.,J. Med. Chem.1973,16, 319-327.

Example 30

2-(4-Cyclopropylamines-1-yl)-6-methoxy-4-triptoreline hydrochloride

1H NMR (DMSO-d6 ) δ x 0.40 (m, 2H), 0.67 and (m, 2H), 1.14 in (m, 1H), 3,01-and 3.16 (m, 4H), 3.46 in (m, 2H), to 3.64 (m, 2H), a 3.87 (s, 3H), of 4.66 (m, 2H), 7,16 (sh. s, 1H), 7,43 (DD, J=7 Hz, 1 Hz, 1H), 7,68 (s, 1H), 7,73 (d, J=7 Hz, 1H), 10,70 (sh. s, 1H); HPLC-MS: m/z 366 (MN+); Rf: 3,63 minutes

Example 31

[4-(4-Cyclopropylamines-1-yl) - for 3,5-differenl]phenylethanone hydrochloride

1H NMR (DMSO-d6) δ x 0.40 (m, 2H), 0.67 and (m, 2H), 1.14 in (m, 1H), 3,03-3,20 (m, 4H), of 3.60 (m, 6H), 7,40 (m, 2H), 7,58 (m, 2H), of 7.70 (m, 3H), or 10.60 (sh. s, 1H); HPLC-MS: m/z 357 (MN+); Rf: 3,53 minutes

Example 32

[4-(4-Cyclopropylamines-1-yl) - for 3,5-differenl]-(3-fluoro-4-methoxyphenyl)methanone hydrochloride

1H NMR (DMSO-d6) δ 0,41 (m, 2H), 0,65 (m, 2H)and 1.15 (m, 1H), 3,06 (m, 2H), 3,18 (m, 2H), 3,50-3,70 (m, 6H), of 3.95 (s, 3H), 7,33 (t, J=8 Hz, 1H), 7,41 (m, 2H), 7,60 (m, 2H), 10,79 (sh. s, 1H); HPLC-MS: m/z 405 (MH+); Rf: 3,67 minutes

Example 33

{6-[4-(1-Ethylpropyl)piperazine-1-yl]pyridine-3-yl}phenylmethanone hydrochloride

1H NMR (DMSO-d6) δ of 0.97 (t, J=7 Hz, 6H), of 1.65 (m, 2H), 1,90 (m, 2H), 3,02-up 3.22 (m, 3H), 3.49 points at 3.69 (m, 4H), 4,60 (m, 2H), was 7.08 (d, J=8 Hz, 1H), 7,56 (m, 2H), 7,68 (m, 3H), to 7.99 (DD, J=8 Hz, 1 Hz, 1H), and 8.50 (d, J=1 Hz, 1H), 10,90 (sh. s, 1H); HPLC-MS: m/z 338 (MH+); Rf: 3,00 minutes

Example 34

{2-[4-(1-Ethylpropyl)piperazine-1-yl]pyridine-4-yl}phenylmethanone hydrochloride

1H NMR (DMSO-d6) δ of 0.97 (t, J=7 Hz, 6H), and 1.63 (m, 2H), of 1.85 (m, 2H), 3,12 (m, 3H), 3,47 (m, 4H), 4,43 (m, 2H), ,91 (d, J=6 Hz, 1H), 7,14 (s, 1H), 7,58 (t, J=8 Hz, 2H), 7,70-to 7.84 (m, 3H), of 8.33 (d, J=6 Hz, 1H), 10,43 (sh. s, 1H); HPLC-MS: m/z 338 (MH+); Rf: 2,97 minutes

The compound is obtained from 2-chloro-4-benzoylpyridine. The latter is obtained by acylation of benzene with 2-chloro-4-chlororespiration by Friedel-Crafts.

Example 35

{4-[4-(1-Ethylpropyl)piperazine-1-yl]phenyl}-(4-hydroxyphenyl)methanone hydrochloride

1H NMR (DMSO-d6) δ of 0.97 (t, J=7 Hz, 6H), of 1.65 (m, 2H), 1,92 (m, 2H), 3,05-of 3.25 (m, 3H), 3,35-3,55 (m, 4H), was 4.02 (m, 2H), 6.89 in (d, J=8 Hz, 2H), was 7.08 (d, J=8 Hz, 2H), to 7.59 (d, J=8 Hz, 2H), 7,63 (d, J=8 Hz, 2H), 10,36 (s, 1H), or 10.60 (sh. s, 1H); HPLC-MS: m/z 353 (MH+); Rf: 2,13 minutes

Example 36

{6-[4-(1-Ethylpropyl)piperazine-1-yl]pyridine-3-yl}piperidine-1-yl-methanone hydrochloride

1H NMR (DMSO-d6) δ of 0.97 (t, J=7 Hz, 6H), 1,50 (m, 4H), and 1.63 (m, 4H), 1,89 (m, 2H), 3,05-3,20 (m, 3H), 3,50 (m, 8H), to 4.46 (m, 2H),? 7.04 baby mortality (m, 1H), of 7.70 (m, 1H), 8,18 (sh. s, 1H), 10,90 (sh. s, 1H); HPLC-MS: m/z 345 (MN+); Rf: 2,27 minutes

Example 37

N-Benzyl-6-[4-(1-ethylpropyl)piperazine-1-yl]-N-nicotine amide hydrochloride

1H NMR (DMSO-d6) δ of 0.97 (t, J=7 Hz, 6H), and 1.63 (m, 2H), of 1.88 (m, 2H), 2,89 (s, 3H), to 3.09 (m, 3H), 3,50 (m, 4H), of 4.45 (m, 2H), 4,62 (sh. s, 2H), 7,02 (d, J=8 Hz, 1H), 7,25-7,41 (m, 5H), 7,78 (m, 1H), 8,28 (sh. s, 1H), 10,78 (sh. s, 1H); HPLC-MS: m/z 381 (MH+); Rf: 3,10 minutes

Example 38

2-[4-(1-Ethylpropyl)piperazine-1-yl]-6-methoxyquinoline hydrochloride

1H NMR (DMSO-d6) δ and 0.98 (t, J=7 Hz, 6H), of 1.66 (m, 2H), 1,92 (m, 2H), 3,11 (m, 1H), and 3.31 (m, 2H), only 3.57 (m, 2H), 3,82 (m, 2H), 3,88 (s, 3H), 4,74 (m, 2H), 7,41 (sh. s, 2H), 7,53 (m, 1H), 8,12 (sh. s, 1H),8.34 per (W. s, 1H), 10,95 (sh. s, 1H); HPLC-MS: m/z 314 (MN+); Rf: 2,17 minutes

Example 39

6-[4-(1-Ethylpropyl)piperazine-1-yl]-N-methyl-N-fenilcetonuria hydrochloride

1H NMR (DMSO-d6) δ of 0.95 (t, J=7 Hz, 6H), of 1.62 (m, 2H)and 1.83 (m, 2H), 3,05 (m, 3H), 3,34 (s, 3H), 3.43 points (m, 4H), 4,35 (m, 2H), 6,76 (d, J=8 Hz, 1H), 7,21 (m, 3H), 7,31 (m, 2H), 7,42 (DD, J=8 Hz, 1 Hz, 1H), 8,01 (d, J=1 Hz, 1H), 10,54 (sh. s, 1H); HPLC-MS: m/z 367 (MN+); Rf: 2,90 minutes

Example 40

{6-[4-(1-Ethylpropyl)piperazine-1-yl]pyridine-3-yl}-(4-forfinal)methanone hydrochloride

1H NMR (DMSO-d6) δ of 0.95 (t, J=7 Hz, 6H), of 1.62 (m, 2H)and 1.83 (m, 2H), 3,10 (m, 3H), 3.45 points-of 3.65 (m, 4H), 4,55 (m, 2H), 7,05 (d, J=8 Hz, 1H), 7,38 (d, J=8 Hz, 2H), 7,78 (DD, J=8 Hz, 4 Hz, 2H), of 7.96 (DD, J=8 Hz, 1 Hz, 1H), 8,48 (d, J=1 Hz, 1H), 10,85 (sh. s, 1H); HPLC-MS: m/z 356 (MH+); Rf: 2,40 minutes

Example 41

2-[4-(1-Ethylpropyl)piperazine-1-yl]-4-methylinosine hydrochloride

1H NMR (DMSO-d6) δ and 0.98 (t, J=7 Hz, 6H), of 1.64 (m, 2H), 1,92 (m, 2H), 2,69 (s, 3H), of 3.12 (m, 1H), 3,32 (m, 2H), only 3.57 (m, 2H), 3,94 (m, 2H), a 4.86 (m, 2H), 7,53 (sh. s, 2H), 7,80 (m, 1H), 8,01 (m, 1H), 8,32 (sh. s, 1H), 11,20 (sh. s, 1H); HPLC-MS: m/z 298 (MN+); Rf: 1,26 minutes

Example 42

2-[4-(1-Ethylpropyl)piperazine-1-yl]-5,6,7,8-tetrahydroquinoline hydrochloride

1H NMR (DMSO-d6) δ and 0.98 (t, J=7 Hz, 6H), 1,50-2,03 (m, 8H), 2.63 in (m, 2H), 2,90 (m, 2H), 3.00 and-of 3.33 (m, 3H), 3,50 (m, 2H, in), 3.75 (m, 2H), 4,48 (m, 2H), 7,13 (sh. s, 1H), 7,75 (sh. s, 1H), 11,10 (sh. s, 1H); HPLC-MS: m/z 288 (MN+); Rf: 1,83 minutes

The compound is obtained from 2-chloro-5,6,7,8-tetrahydroquinoline (S.C. Zimmerman, Z. Zeng,J. Org. Chem.1990,55, 4789-5791).

Example 43

2-(4-Cyclopropylamines-1-yl)-6-methoxyquinoline hydrochloride

1H NMR (DMSO-d6) δ 0,41 (m, 2H), 0,66 (m, 2H), 1,18 (m, 1H), to 3.02 (m, 2H), 3,13 (m, 2H), 3,52 at 3.69 (m, 4H), 3,85 (s, 3H), 4,71 (m, 2H), 7,41 (sh. s, 2H), 7,53 (m, 1H), 8,12 (sh. s, 1H), 8.34 per (W. s, 1H), 11,38 (sh. s, 1H); HPLC-MS: m/z 298 (MN+); Rf: 1,87 minutes

Example 44

2-(4-Isopropylpiperazine-1-yl)-6-methoxyquinoline hydrochloride

1H NMR (DMSO-d6) δ of 1.32 (d, J=7 Hz, 6H), of 3.28 (m, 2H), 3,53 (m, 3H), 3,80 (m, 1H), 3,85 (s, 3H), 4,85 (m, 2H), 7,43 (sh. s, 2H), to 7.59 (d, J=8 Hz, 1H), 8,27 (sh. s, 1H), 8.34 per (W. s, 1H), 8,40 (d, J=8 Hz, 1H), 11,60 (sh. s, 1H); HPLC-MS: m/z 286 (MN+); Rf: 1.77 in minutes

Example 45

2-[4-(1-Ethylpropyl)piperazine-1-yl]-6-fluoro-4-methylinosine hydrochloride

1H NMR (DMSO-d6) δ and 0.98 (t, J=7 Hz, 6H), of 1.64 (m, 2H), 1,92 (m, 2H), to 2.67 (s, 3H), of 3.12 (m, 1H), 3,32 (m, 2H), 3,57-4,00 (m, 4H), 4,85 (m, 2H), EUR 7.57 (sh. s, 2H), 7,68 (m, 1H), 7,82 (m, 1H), 8,33 (sh. s, 1H), 11,10 (sh. s, 1H); HPLC-MS: m/z 316 (MH+); Rf: 1,92 minutes

The compound is obtained from 2-chloro-6-fluoro-4-methylinosine, which is obtained by acetoacetanilide 4-f is ornelia followed Mediolanum acid shorting rings and transformation obtained barbastella in chlorhydrin treatment with phosphorus oxychloride.

Example 46

2-(4-Isopropylpiperazine-1-yl)quinoline hydrochloride

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H), 3,19 (m, 2H), 3,52 (m, 3H), and 3.72 (m, 2H), 4,79 (m, 2H), 7,45 (m, 2H), 7,68 (m, 1H), 7,86 (m, 1H), 8,03 (m, 1H), 8,31 (m, 1H), of 11.45 (sh. s, 1H); HPLC-MS: m/z 256 (MN+); Rf: 1,47 minutes

Example 47

2-(4-Cyclopropylmethyl-1-yl)-6-methoxyquinoline hydrochloride

1H NMR (DMSO-d6) δ 0,81 (m, 2H), 1,20 (sh. s, 2H), 2,86 (sh. s, 1H), 3,25-3,75 (m, 4H), 3,85 (s, 3H), 4.09 to (m, 2H), 4,73 (m, 2H), 7,41 (m, 2H), 7,55 (m, 1H), 8,14 (m, 1H), of 8.37 (m, 1H), 11,51 (sh. s, 1H); HPLC-MS: m/z 284 (MN+); Rf: 1,80 minutes

Example 48

2-(4-Isopropylpiperazine-1-yl)-6-cryptomaterial hydrochloride

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H), 3,17 (m, 2H), 3,52 (m, 3H), 3,68 (m, 2H), 4,79 (m, 2H), 7,56 (d, J=8 Hz, 1H), 7,68 (sh. d, J=7 Hz, 1H), to $ 7.91 (sh. s, 1H), 8,04 (sh. s, 1H), 8,35 (sh. d, J=7 Hz, 1H), 11,28 (sh. s, 1H); HPLC-MS: m/z 340 (MN+); Rf: 3.04 from minutes

Example 49

6-Chloro-2-(4-cyclopropylmethyl-1-yl)-quinoline hydrochloride

1H NMR (DMSO-d6) δ 0,81 (m, 2H), 1.14 in (sh. s, 2H), 2,88 (sh. s, 1H), 3.25 to 3,70 (m, 6H), of 4.67 (m, 2H), 7,44 (d, J=8 Hz, 1H), to 7.61 (d, J=8 Hz, 1H), 7,72 (m, 1H),to $ 7.91 (sh. s, 1H), 8,18 (sh. d, J=8 Hz, 1H), 10,75 (sh. s, 1H); HPLC-MS: m/z 288 (MN+); Rf: 1.77 in minutes

Example 50

2-(4-Cyclopropylmethyl-1-yl)-6-cryptomaterial hydrochloride

1H NMR (DMSO-d6) δ 0,81 (m, 2H), 1,15 (sh. s, 2H), 2,88 (sh. s, 11-1), 3,20-3,70 (m, 6H), and 4.68 (m, 2H), 7,49 (d, J=8 Hz, 1H), to 7.59 (sh. d, J=8 Hz, 1H), 7,82 (m, 2H), of 8.27 (d, J=8 Hz, 1H), 10,89 (sh. s, 1H); HPLC-MS: m/z 338 (MH+); Rf: 2,24 minutes

Example 51

2-(4-Isopropylpiperazine-1-yl)-8-triptoreline hydrochloride

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H), 3,10 (m, 2H), 3,51 (m, 5H), 4.72 in (m, 2H), 7,38 (t, J=8 Hz, 1H), 7,46 (d, J=8 Hz, 1H), 7,95 (sh. d, J=7 Hz, 1H), 8,05 (sh. d, J=7 Hz, 1H), compared to 8.26 (d, J=8 Hz, 1H), 10,66 (sh. s, 1H); HPLC-MS; m/z 324 (MN+); Rf: is 3.08 min

Example 52

2-(4-Isopropylpiperazine-1-yl)-6-triptoreline hydrochloride

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H), of 3.12 (m, 2H), 3,50-3,68 (m, 5H), 4,78 (m, 2H), 7,52(d, J=7 Hz, 1H), 7,88 (m, 2H), compared to 8.26 (sh. s, 1H), at 8.36 (d, J=7 Hz, 1H), 10,95 (sh. s, 1H); HPLC-MS; m/z 324 (MN+); Rf: 2,11 minutes

Example 53

2-(4-Isopropylpiperazine-1-yl)-6-propylhexedrine hydrochloride

1H NMR (DMSO-d6) δ of 0.91 (t, J=7 Hz, 3H), of 1.31 (d, J=7 Hz, 6H), 1,66 (Sextus, J=7 Hz, 2H), 2,70 (t, J=7 Hz, 2H), 3,23 (m, 2H), 3,48-3,90 (m, 5H), to 4.81 (m, 2H), 7,52 (m, 1H), 7,63 (m, 1H), 7,70 (sh. s, 1H), 8,09 (sh. s, 1H), 8.34 per (W. s, 1H), 11,35 (sh. s, 1H); HPLC-MS: m/z 298 (MN+) Rf: 1,97 minutes

Example 54

6,8-Debtor-2-(4-isopropylpiperazine-1-yl)quinoline hydrochloride

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H), to 3.09 (m, 2H), 3,51 (m, 5H), of 4.66 (m, 2H), 7,45-7,58 (m, 3H), 8,18 (d, J=7 G is, 1H), 10,92 (sh. s, 1H).

Example 55

8-fluoro-2-(4-isopropylpiperazine-1-yl)quinoline hydrochloride

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H), to 3.09 (m, 2H), 3,52 (m, 5H), 4,70 (m, 2H), 7,24 (m, 1H), 7,40 (m, 2H), to 7.59 (d, J=7 Hz, 1H), to 8.20 (d, J=7 Hz, 1H), 10,84 (sh. s, 1H).

Example 56

2-(4-Cyclopropylmethyl-1-yl)-6-triptoreline hydrochloride

1H NMR (DMSO-d6) δ 0,81 (m, 2H), 1,19 (sh. s, 2H), 2,88 (sh. s, 1H), 3,20-3,70 (m, 6H), to 4.73 (m, 2H), 7,52 (d, J=8 Hz, 1H), 7,86 (m, 2H), compared to 8.26 (sh. s, 1H), with 8.33 (d, J=8 Hz, 1H), 11,12 (sh. s, 1H); HPLC-MS: m/z 322 (MH+); Rf: 2,41 minutes

Example 57

2-(4-Cyclopropylmethyl-1-yl)-6-propylhexedrine hydrochloride

1H NMR (DMSO-d6) δ of 0.82 (m, 2H), of 0.91 (t, J=7 Hz, 3H), 1,18 (sh. s, 2H), 1,66 (Sextus, J=7 Hz, 2H), 2,69 (t, J=7 Hz, 2H), 2,85 (sh. s, 1H), 3,30 of 3.75 (m, 6H), 4.72 in (m, 2H), 7,51 (m, 1H), 7.62mm (m, 1H), 7,69 (sh. s, 1H), 7,97 (sh. s, 1H), 8,33 (sh. s, 1H), 11,20 (sh. s, 1H); HPLC-MS: m/z 296 (MN+); Rf: 1,97 minutes

Example 58

2-(4-Ethylpiperazin-1-yl)quinoline hydrochloride

Reference S. Cacchi et al., SynLett 1997, 1400-1402.

1H NMR (DMSO-d6) δ of 1.30 (t, J=7 Hz, 3H), 3.15 in (m, 4H), 3,55-of 3.85 (m, 4H), to 4.81 (m, 2H), 7,47 (m, 1H), 7,53 (m, 1H), 7,74 (m, 1H), 7,89 (d, J=8 Hz, 1H), 8,13 (sh. s, 1H), 8,40 (sh. s, 1H), 11,34 (sh. s, 1H); HPLC-MS: m/z 242 (MN+); Rf: 1,04 minutes

Example 59 (General procedure (C))

3-(4-isopropylpiperazine-1-yl)-6-phenylpyridazin, hydrochloride

Connection get the General method (B), starting from 1-isopropylpiperazine and 3-chloro-6-phenylpyridazin, obtained as described in J. Heterocycl. Chem.,15, 881 (1978).

1H NMR (D2O): δ of 1.46 (d, 6H); or 3.28 (m, 2H); of 3.48 (m, 2H); 3,64-a-3.84 (m, 3H); of 4.57 (m, 2H); 7,63-7,72 (m, 4H); of 7.90 (m, 2H); to 8.12 (d, 1H); HPLC-MS: m/z=283,2 (M+1); Rt=1,52 minutes

Example 60 (General procedure (C))

3-(4-Cyclopentylpropionyl-1-yl)-6-(4-methanesulfonyl)-pyridazin

Connection get the General method (B), starting from 1-cyclopentenopyridine and 3-chloro-6-(4-methanesulfonyl)-pyridazine, obtained as described in J. Heterocycl. Chem.,15, 881 (1978).

1H NMR (CDCl3): δ 1,38 and 1.80 (m, 6H), of 1.92 (m, 2H); 2,56 (quint, 1H); to 2.66 (DD, 4H); 3,10 (s, 3H); of 3.97 (DD, 4H); 6,99 (d, 1H); of 7.69 (d, 1H); 8,03 (d, 2H); to 8.20 (d, 2H); HPLC-MS: m/z=387,0 (M+1);Rt=2,20 minutes

Example 61 (General procedure (C))

3-(4-Cyclopropylamines-1-yl)-6-(4-methanesulfonyl)-pyridazin

Connection get the General method (B), starting from 1-cyclopentenopyridine and 3-chloro-6-(4-methanesulfonyl)-pyridazine, obtained as described in J. Heterocycl. Chem.,15, 881 (1978).

1H NMR (CDCl3): δ 0,15 (q, 2H); or 0.57 (m, 2H); 0,92 (m, 1H); 2,34 (d, 2H); 2,69 (DD, 4H); 3,10 (s, 3H); of 3.80 (DD, 4H); 7,01 (d, 1H); of 7.70 (d, 1H); 8,03 (d, 2H); 8,21 (d, 2H); HPLC-MS: m/z=373,4 (M+1);Rt=2,04 minutes

Example 62 (General procedure (C))

3-(4-Isopropylpiperazine-1-yl)-6-(4-methanesulfonyl)-pyridazin

Connection get the General method (B), starting from 1-isopropylpiperazine and 3-chloro-6-(4-methanesulfonyl)-pyridazine, obtained as described in J. Heterocycl. Chem.,15, 881 (1978).

1H NMR (DMSO-d6): δ of 1.01 (d, 6H); 2.57 m (m, 4H); a 2.71 (m, 1H); 3,26 (s, 3H); to 3.67 (m, 4H); 7,39 (d, 1H); 8,02 (d, 2H); of 8.06 (d, 1H); 8.30 to (d, 2H); HPLC-MS: m/z=360,8 (M+1); Rt=1,43 minutes

Example 63 (General procedure (C))

3-(4-Chlorophenyl)-6-(4-isopropylpiperazine-1-yl)-4-methylpyridazin, dihydrochloride

Connection get the General method (B), starting from 1-isopropylpiperazine and 6-chloro-3-(4-chlorophenyl)-4-methylpyridazine, obtained as described in J. Heterocycl. Chem.,15, 881 (1978).

1H NMR (D2O): δ 1,08 (d, 6H); 2,10 (s, 1H); 3,01 (m, 2H); 3,23 (m, 2H); 3,28-3,44 (m, 3H); or 4.31 (sh. d, 2H); 7,27 (d, 2H); 7,34 (d, 2H); 7,58 (s, 1H); HPLC-MS: m/z=331,1 (M+1); Rt=3,1 minutes

C18 H23 Cl N4, 2 HCl

Calculated: C 53,54 H 6,24 N 13,88

Found: C 53,34 Of 6.31 H N 13,70.

Example 64 (General procedure (C))

3-(4-Chlorophenyl)-6-(4-cyclopentylpropionyl-1-yl)-4-methylpyridazin, hydrochloride

Connection get the General method (B), starting from 1-cyclopentenopyridine and 6-chloro-3-(4-chlorophenyl)-4-methylpyridazine, obtained as described in J. Heterocycl. Chem.,15, 881 (1978).

1H NMR (D2O): δ 1,29-1,0 (m, 6H); at 1.91 (m, 2H); 2,12 (s, 3H); 3,00 (m, 2H); 3.24 in (m, 2H); to 3.36 (m, 1H); 3,51 (sh. d, 2H); 4,29 (sh. d, 2H); 7,29 (d, 2H); of 7.36 (d, 2H); of 7.60 (s, 1H); HPLC-MS: m/z=357,1 (M+1); Rt=3,25 minutes

C20 H25 N4 Cl, 2 HCl

Calculated: 55,89 N 6,33 N 13,04

Found: C 55,83 N 6,47 N 12,93.

Example 65 (General procedure (C))

3-(4-Chlorophenyl)-6-(4-cyclopentylpropionyl-1-yl)-pyridazin

Connection receive according to the method of example 6, starting from 1-cyclopentenopyridine and 3-chloro-6-(4-chlorophenyl)-pyridazine, obtained as described in J. Heterocycl. Chem.,15, 881 (1978). Specified in the title compound obtained as free base.

1H NMR (CDCl3): δ 1,39-of 1.81 (m, 6H), 1.91 a (m, 2H), 2,56 (kV, 1H), 2,66 (DD, 4H), 3,74 (DD, 4H), of 6.96 (d, J=9.5 Hz, 1H), 7,43 (d, J=8.7 Hz, 2H), to 7.61 (d, J=9.5 Hz, 1H), to 7.93 (d, J=8.7 Hz, 2H); HPLC-MS (method #): m/z=343 (M+1); Rt=2,93 minutes

Example 66 (General procedure (C))

3-(4-Cyclopentylpropionyl-1-yl)-6-(3-fluoro-4-methoxyphenyl)-pyridazine, dihydrochloride

Connection receive according to the method of example 6, starting from 1-cyclopentenopyridine and 3-chloro-6-(3-fluoro-4-methoxyphenyl)-pyridazine, obtained as described in J. Heterocycl. Chem.,15, 881 (1978).

1H NMR (DMSO-d6): δ 1,45-of 2.15 (m, 8H), 3,17 (m, 2H), 3,40-of 3.77 (m, 5H), to 3.92 (s, 3H), 7,34 (t, J=8.7 Hz, 1H), 7,80 (d, J=9.8 Hz, 1H), 7,85-with 8.05 (m, 2H), 8,29 (d, J=9.8 Hz, 1H), 11,75 (sh. s, 1H); HPLC-MS: m/z=357 (M+1); Rt=2,47 minutes

Example 67 (General procedure (C))

3-(4-Cyclopentolate Azin-1-yl)-6-(3,4-acid)-pyridazin

Connection receive according to the method of example 6, starting from 1-cyclopentenopyridine and 3-chloro-6-(3,4-acid)-pyridazine, obtained as described in J. Heterocycl. Chem.,15, 881 (1978). Specified in the title compound obtained as free base.

1H NMR (CDCl3): δ 1,40-of 1.65 (m, 4H), at 1.73 (m, 2H), 1.91 a (m, 2H), 2,55 (kV, 1H), 2,66 (t, 4H), and 3.72 (t, 4H), 3,93 (s, 3H), 3,98 (s, 3H), 6,93 (d, 1H), 6,97 (d, 1H), was 7.36 (DD, 1H), to 7.64 (d, 1H), 7,86 (d, 1H); HPLC-MS: m/z=370 (M+1); Rt=1,90 minutes

Example 68 (General procedure (C))

3-(4-Chlorophenyl)-6-(4-cyclopropylamines-1-yl)-pyridazin

Connection receive according to the method of example 6, starting from 1-cyclopropylalanine and 3-chloro-6-(4-chlorophenyl)-pyridazine, obtained as described in J. Heterocycl. Chem.,15, 881 (1978). Specified in the title compound obtained as free base.

1H NMR (CDCl3): δ 0,46 (m, 2H), 0.88 to (m, 2H), 1,33 (m, 1H), 2,90 (d, 2H), 3,1-3,5 (m, 4H), 4,1 is 4.35 (m, 4H), 7,05 (d, 1H), 7,46 (d, 2H), 7,72 (d, 1H), 7,95 (d, 2H); HPLC-MS; m/z=329 (M+1); Rt=2,11 minutes

Example 69 (General procedure (C))

Connection receive according to the method of example 6, starting from 1-cyclopentenopyridine and 3-chloro-6-(4-triptoreline)-pyridazine, obtained as described in J. Heterocycl. Chem.,15, 881 (1978). Specified in the title compound obtained as free base.

1 H NMR (CDCl3): δ 1,40-of 1.65 (m, 4H), of 1.65 and 1.80 (m, 2H), 1,92 (m, 2H), 2,55 (kV, 1H), 2,65 (t, 4H), 3,76 (t, 4H), of 6.99 (d, 1H), to 7.67 (d, 1H), 7,72 (d, 2H), 8,12 (d, 2H); HPLC-MS: m/z=377 (M+1); Rt=2,68 minutes

Example 70 (General procedure (C))

3-(4-Isopropylpiperazine-1-yl)-6-(4-triptoreline)-pyridazin

Connection receive according to the method of example 6, starting from 1-isopropylpiperazine and 3-chloro-6-(4-triptoreline)-pyridazine, obtained as described in J. Heterocycl. Chem.,15, 881 (1978). Specified in the title compound obtained as free base.

1H NMR (DMSO-d6): δ of 1.20 (d, 6H), 2,8-4,2 (m, 9H), 7,47 (d, 1H), a 7.85 (d, 2H), 8,12 (d, 1H), 8,28 (d, 2H); HPLC-MS: m/z=351 (M+1); Rt=of 2.51 minutes

Example 71 (General procedure (C))

3-(4-Cyclopropylamines-1-yl)-6-(4-triptoreline)-pyridazin

Connection receive according to the method of example 6, starting from 1-cyclopropylalanine and 3-chloro-6-(4-triptoreline)-pyridazine, obtained as described in J. Heterocycl. Chem.,15, 881 (1978). Specified in the title compound obtained as free base.

1H NMR (CDCl3): δ of 0.15 (m, 2H), or 0.57 (m, 2H), 0,92 (m, 1H), 2,33 (d, 2H), 2,69 (t, 4H), with 3.79 (t, 4H), of 7.00 (d, 1H), to 7.67 (d, 1H), 7,72 (d, 2H), 8,12 (d, 2H); HPLC-MS: m/z=363 (M+1); Rt=2,65 minutes

Example 72 (General procedure (C))

3-(4-Chlorophenyl)-6-(4-isopropylpiperazine-1-yl)-pyridazin

Connection receive according to the method of example 6, starting from 1-isopropylpiperazine and 3-chloro-6-(4-chlorophenyl)-pyridazine, obtained as described in J. Heterocycl. Chem.,15, 881 (1978). Specified in the title compound obtained as free base.

1H NMR (CDCl3): δ of 1.10 (d, 6H), 2,68 (t, 4H), 2,75 (kV, 1H), of 3.73 (t, 4H), 6,97 (d, 1H), 7,43 (d, 2H), to 7.61 (d, 1H), 7,94 (d, 2H); HPLC-MS: m/z=317 (M+1); Rt=2,03 minutes

Example 73 (General procedure (C))

3-(4-Cyclopropylamines-1-yl)-6-(3-fluoro-4-methoxyphenyl)-pyridazin

Connection receive according to the method of example 6, starting from 1-cyclopropylalanine and 3-chloro-6-(3-fluoro-4-methoxyphenyl)-pyridazine, obtained as described in J. Heterocycl. Chem.,15, 881 (1978). Specified in the title compound obtained as free base.

1H NMR (DMSO-d6): δ 0,40 (m, 2H), 0,65 (m, 2H)and 1.15 (m, 1H), 2,8-3,7 (m, 10H), 3,90 (s, 3H), 7,29 (t, 1H), 7,47 (d, 1H), 7,88 (d, 1H), to 7.93 (d, 1H), of 8.06 (d, 1H); HPLC-MS; m/z=343 (M+1); Rt=1,90 minutes

Example 74 (General procedure (C))

3-(3-Fluoro-4-methoxyphenyl)-6-(4-isopropylpiperazine-1-yl)-pyridazin

Connection receive according to the method of example 6, starting from 1-isopropylpiperazine and 3-chloro-6-(3-fluoro-4-methoxyphenyl)-pyridazine, obtained as described in J. Heterocycl. Chem.,15, 881 (1978). Specified in the title compound obtained as free base.

1H NMR (Cl3): δ is 1.11 (d, 6H), 2,70 (m, 4H), 2,80 (kV, 1H), 3,74 (m, 4H), of 3.94 (s, 3H), of 6.96 (d, 1H),? 7.04 baby mortality (t, 1H), EUR 7.57 (d, 1H), 7,72 (d, 1H), 7,78 (m, 1H); HPLC-MS: m/z=331 (M+1); Rt=1,57 minutes

Example 75 (General procedure (C))

3-(3,4-Acid)-6-(4-isopropylpiperazine-1-yl)-pyridazin, dihydrochloride

Connection receive according to the method of example 6, starting from 1-isopropylpiperazine and 3-chloro-6-(3,4-acid)-pyridazine, obtained as described in J. Heterocycl. Chem.,15, 881 (1978).

1H NMR (DMSO-d6): δ of 1.32 (d, 6H), 3,17 (kV, 1H), 3,3-4,1 (m, 6H), of 3.84 (s, 3H), a 3.87 (s, 3H), 4,56 (d, 2H), to 7.09 (d, 1H), 7.62mm (d, 1H), 7.68 per-7,73 (m, 2H), 8,23 (d, 1H), 11,35 (s, 1H); HPLC-MS: m/z=343 (M+1); Rt=1,50 minutes

Example 76 (General procedure (C))

(9a-R)-2-(6-Cryptomaterial-2-yl)octahedrite[1,2-a]pyrazine hydrochloride

Connection receive General method (C) from (9a-R)-octahedrite[1,2-a]pyrazine and 2-chloro-6-cryptomaterial.

1H NMR (DMSO-d6) δ 1,40-of 1.55 (m, 1H), 1,65-of 2.08 (m, 5H), of 2.93 (m, 1H), 3,18 (m, 1H), 3.25 to 3,55 (m, 4H), 3,71 (m, 1H), 4,85 (m, 2H), to 7.61 (d, J=8 Hz, 1H), of 7.70 (d, J=8 Hz, 1H), to 7.93 (s, 1H), 8,19 (sh. s, 1H), 8,39 (d, J=8 Hz, 1H), 11,60 (sh. s, 1H); HPLC-MS: m/z 352 (MN+); Rt=2,67 minutes

Example 77 (General procedure (C))

7-fluoro-2-(4-isopropylpiperazine-1-yl)-6-methylinosine hydrochloride

Connection get the General method (B) from 1-isopropylpiperazine is 2-chloro-7-fluoro-6-methylinosine.

1H NMR (DMSO-d6) δ of 1.32 (d, J=7 Hz, 6H), a 2.36 (s, 3H), 3,26 (m, 2H), 3,54 (m, 3H), 3,83 (m, 2H), 4,88 (sh. s, 2H), 7,49 (d, J=8 Hz, 1H), a 7.85 (d, J=8 Hz, 1H), 8,09 (sh. s, 1H), 8,35 (d, J=8 Hz, 1H), 11,57 (sh. s, 1H); HPLC-MS; m/z 287 (MN+); Rt=1,47 minutes

Example 78 (General procedure (C))

7-Chloro-2-(4-isopropylpiperazine-1-yl)quinoline hydrochloride

Connection get the General method (B) from 1-isopropylpiperazine and 2.7-dichlorohydrin.

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H), 3,23 (m, 2H), 3,53 (m, 3H), 3,79 (m, 2H), 4,87 (sh. s, 2H), of 7.48 (d, J=8 Hz, 1H), 7,54 (d, J=8 Hz, 1H), 7,92 (d, J=8 Hz, 1H), compared to 8.26 (sh. s, 1H), scored 8.38 (d, J=8 Hz, 1H), 11,50 (sh. s, 1H); HPLC-MS: m/z 289 (MN+); Rt=1,61 minutes

Example 79 (General procedure (C))

6-fluoro-2-(4-isopropylpiperazine-1-yl)quinoline hydrochloride

Connection get the General method (B) from 1-isopropylpiperazine and 2-chloro-6-ftorhinolona.

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H), up 3.22 (m, 2H), 3,53 (m, 3H), 3,79 (m, 2H), 4,85 (sh. s, 2H), 7,55-of 7.70 (m, 2H), 7,45 (d, J=8 Hz, 1H), compared to 8.26 (sh. s, 1H), at 8.36 (d, J=8 Hz, 1H), to 11.52 (sh. s, 1H); HPLC-MS: m/z 274 (MN+); Rt=1,21 minutes

Example 80 (General procedure (C))

2-(4-Cyclopropylmethyl-1-yl)-7-fluoro-6-methylinosine hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 2-chloro-7-fluoro-6-methylinosine.

1H NMR (DMSO-d6) δ of 0.82 (m, 2H), 1,20 (m, 2H), a 2.36 (s, 3H), 2,87 (m, 1H) 3.25 to to 4.15 (m, 6H), 4,74 (sh. s, 2H), 7,43 (d, J=8 Hz, 1H), 7,80 (m, 2H), 8,28 (d, J=8 Hz, 1H), 11,36 (sh. s, 1H); HPLC-MS: m/z 287 (MN+); Rt=1,47 minutes

Example 81 (General procedure (C))

2-(4-Cyclopropylmethyl-1-yl)-7-fluoro-6-methoxyquinoline hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 2-chloro-7-fluoro-6-methoxyquinoline.

1H NMR (DMSO-d6) δ of 0.82 (m, 2H), 1,18 (m, 2H), 2,88 (m, 1H), 3,25-4,10 (m, 6H), 3,93 (s, 3H), with 4.64 (sh. s, 2H), 7,40 (d, J=8 Hz, 1H), 7,55 (d, J=8 Hz, 1H), 7,73 (sh. s, 1H), 8,24 (d, J=8 Hz, 1H), 11.11 is (sh. s, 1H); HPLC-MS: m/z 301 (MN+); Rt=1,37 minutes

Example 82 (General procedure (C))

7-fluoro-2-(4-isopropylpiperazine-1-yl)-6-methoxyquinoline hydrochloride

Connection get the General method (B) from 1-isopropylpiperazine and 2-chloro-7-fluoro-6-methoxyquinoline.

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H), and 3.16 (m, 2H), 3.45 points-of 4.05 (m, 5H), 3,93 (s, 3H), 4.72 in (m, 2H), 7,42 (d, J=8 Hz, 1H), 7,56 (d, J=8 Hz, 1H), 7,83 (sh. s, 1H), 8,25 (d, J=8 Hz, 1H), 11,13 (sh. s, 1H); HPLC-MS: m/z 303 (MN+); Rt=1,41 minutes

Example 83 (General procedure (C))

(9a-R)-2-(7-Fluoro-6-methoxyquinoline-2-yl)octahedrite[1,2-a]pyrazine hydrochloride

Connection receive General method (C) from (9a-R)-octahedrite[1,2-a]pyrazine and 2-chloro-7-fluoro-6-methoxyquinoline.

1H NMR (DMSO-d6) δ 1,40-of 1.55 (m, 1H), 1,65-of 2.08 (m, 5H), of 2.93 (m, 1H), 3,20 (m, 1H), 3.25 to 3,55 (m, 4H), to 3.73 (m, 1H), 4,81 (who, 2H), 7,50 (d, J=8 Hz, 1H), 7.62mm (d, J=8 Hz, 1H), 8,13 (sh. s, 1H), 8.34 per (d, J=8gts, 1H), 11,59 (sh. s, 1H); HPLC-MS: m/z 315 (MN+); Rt=1,41 minutes

Example 84 (General procedure (C))

(9a-R)-2-(6-Trifloromethyl-2-yl)octahedrite[1,2-a]pyrazine hydrochloride

Connection receive General method (C) from (9a-R)-octahedrite[1,2-a]pyrazine and 2-chloro-6-triptoreline.

1H NMR (DMSO-d6) δ 1,40-of 1.55 (m, 1H), 1,65-2,05 (m, 5H), of 2.92 (m, 1H), 3,20 (m, 1H), 3,30-3,55 (m, 4H), 3,70 (m, 1H), 4,88 (m, 2H), to 7.61 (d, J=8 Hz, 1H), to 7.93 (d, J=8 Hz, 1H), 8,15 (sh. s, 1H), 8,31 (s, 1H), 8,43 (d, J=8 Hz, 1H), 11,60 (sh. s, 1H); HPLC-MS: m/z 335 (MN+); Rt=2,27 minutes

Example 85 (General procedure (C))

7-fluoro-2-(4-isopropylpiperazine-1-yl)quinoline hydrochloride

Connection get the General method (B) from 1-isopropylpiperazine and 2-chloro-7-ftorhinolona.

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H), 3,19 (m, 2H), 3,45-4,20 (m, 5H), 4,84 (m, 2H), 7,32 (m, 1H), 7,45 (d, J=8 Hz, 1H), 7,83 (sh. s, 1H), 7,95 (m, 1H), 8,35 (m, 1H), 11,35 (sh. s, 1H); HPLC-MS: m/z 274 (MN+); Rt=1,31 minutes

Example 86 (General procedure (C))

6-Chloro-2-(4-isopropylpiperazine-1-yl)quinoline hydrochloride

Connection get the General method (B) from 1-isopropylpiperazine and 2,6-dichlorohydrin.

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H), 3,19 (m, 2H), 3.45 points-of 3.80 (m, 5H), 4,82 (m, 2H), 7,55 (d, J=8 Hz, 1H), 7,72 (d, J=8 Hz, 1H), to 7.99 (s, 1H), 8,07 (sh. s, 1H), 8,29 (d, J=8gts, 1H), 11,38 (sh. s, 1H); HPLC-MS: m/z 290 (MN+); Rt=1,64 minutes

Example 87 (General procedure (C))

6-Isopropyl-2-(4-isopropylpiperazine-1-yl)quinoline hydrochloride

Connection get the General method (B) from 1-isopropylpiperazine and 2-chloro-6-isopropylaniline.

1H NMR (DMSO-d6) δ of 1.27 (d, J=7 Hz, 6H), 1,32 (d, J=7 Hz, 6H), was 3.05 (sept, J=7 Hz, 1H), 3,26 (m, 2H), 3,40-3,95 (m, 5H), a 4.86 (m, 2H), 7,55 (d, J=8 Hz, 1H), 7,72 (d, J=8 Hz, 1H), to 7.77 (s, 1H), 8,21 (sh. s, 1H), 8,42 (d, J=8 Hz, 1H), 11,55 (sh. s, 1H); HPLC-MS: m/z 298 (MN+); Rt=1,87 minutes

Example 88 (General procedure (C))

2-(4-Cyclopropylmethyl-1-yl)-6-isopropylpyridine hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 2-chloro-6-isopropylaniline.

1H NMR (DMSO-d6) δ 0,83 (m, 2H), 1,20 (m, 2H), 1.27mm (d, J=7 Hz, 6H), 2,86 (sh. s, 1H), 3.04 from (sept, J=7 Hz, 1H), 3.25 to of 3.85 (m, 5H), 4,15 (sh. s, 1H), 4,74 (m, 2H), 7,53 (m, 1H), of 7.70 (d, J=8 Hz, 1H), of 7.75 (s, 1H), 8,06 (sh. s, 1H), scored 8.38 (m, 1H), 11,41 (sh. s, 1H); HPLC-MS: m/z (MN+); Rt=minutes

Example 89 (General procedure (C))

2-(4-Cyclopropylmethyl-1-yl)quinoline hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 2-chlorhydrin.

1H NMR (DMSO-d6) δ 0,83 (m, 2H), 1,19 (m, 2H), 2,87 (sh. s, 1H), 3,30-of 3.80 (m, 6H), 4,74 (m, 2H),7,45 (m,1H), 7,52 (d, J=8 Hz, 1H), 7,73 (m, 1H), 7,89 (d, J=8 Hz, 1H), 8,02 (sh. s, 1H), scored 8.38 (m, 1H), 11,22 (sh. s, 1H); In the LC-MS: m/z (MN +); Rt=minutes

Example 90 (General procedure (C))

2-(4-Cyclopropylmethyl-1-yl)-6,7-dimethoxyaniline hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 2-chloro-6,7-dimethoxyaniline.

1H NMR (DMSO-d6) δ of 0.82 (m, 2H), 1,20 (m, 2H), 2,87 (sh. s, 1H), 3,25-3,75 (m, 6H), 3,86 (s, 3H), 3,90 (s, 3H), of 4.66 (m, 2H), 7,25 is 7.50 (m, 3H), 8,24 (sh. s, 1H), 11,38 (sh. s, 1H); HPLC-MS: m/z 314 (MH+)); Rt=1,27 minutes

Example 91 (General procedure (C))

2-(4-Isopropylpiperazine-1-yl)-6,7-dimethoxyaniline hydrochloride

Connection get the General method (B) from 1-isopropylpiperazine and 2-chloro-6,7-dimethoxyaniline.

1H NMR (DMSO-d6) δ of 1.32 (d, J=7 Hz, 6H), of 3.25 (m, 2H), 3.45 points-of 4.00 (m, 5H), a 3.87 (s, 3H), 3,91 (s, 3H), 4,80 (m, 2H), 7,39 (m, 2H), of 7.96 (sh. s, 1H), 8.34 per (W. s, 1H), 11,50 (sh. s, 1H); HPLC-MS: m/z 316 (MH+); Rt=1,27 minutes

Example 92 (General procedure (C))

2-(4-Cyclopropylmethyl-1-yl)-7-ftorhinolona hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 2-chloro-7-ftorhinolona.

1H NMR (DMSO-d6) δ of 0.82 (m, 2H), 1,22 (m, 2H), 2,87 (sh. s, 1H), 3,30-of 3.80 (m, 6H), 4,79 (m, 2H), 7,34 (m, 1H), 7,47 (d, J=8 Hz, 1H), 7,85 (sh. s, 1H), of 7.96 (m, 1H), of 8.37 (m, 1H), 11,55 (sh. s, 1H); HPLC-MS: m/z 271 (MN+); Rt=1,24 minutes

Example 93 (General procedure (C))

2-(4-Cyclopropylmethyl-1-yl)-6,8-debtorin the ina hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 2-chloro-6,8-divergingly.

1H NMR (DMSO-d6) δ of 0.82 (m, 2H), 1,19 (m, 2H), 2,87 (sh. s, 1H), 3,20-3,70 (m, 6H), 4,63 (m, 2H), of 7.48 (m, 3H), 8,19 (d, J=8 Hz, 1H), 11.11 is (sh. s, 1H); HPLC-MS: m/z 290 (MN+); Rt=2,27 minutes

Example 94 (General procedure (C))

2-(4-Cyclopropylmethyl-1-yl)-6-ftorhinolona hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 2-chloro-6-ftorhinolona.

1H NMR (DMSO-d6) δ of 0.82 (m, 2H), 1,21 (m, 2H), 2,87 (sh. s, 1H), 3,30-of 3.80 (m, 6H), to 4.73 (m, 2H), 7,56 (d, J=8 Hz, 1H), 7.62mm (m, 1H), 7,71 (d, J=8 Hz, 1H), 8,09 (sh. s, 1H), with 8.33 (d, J=8 Hz, 1H), 11,42 (sh. s, 1H); HPLC-MS: m/z 272 (MN+); Rt=1,27 minutes

Example 95 (General procedure (C))

7-Chloro-2-(4-cyclopropylmethyl-1-yl)quinoline hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 2.7-dichlorohydrin.

1H NMR (DMSO-d6) δ of 0.82 (m, 2H), 1,20 (m, 2H), 2,87 (sh. s, 1H), 3,25-3,75 (m, 6H), 4.72 in (m, 2H), 7,40 (d, J=8 Hz, 1H), 7,46 (d, J=8 Hz, 1H), 7,87 (d, J=8 Hz, 1H), 7,94 (sh. s, 1H), 8,29 (d, J=8 Hz, 1H), 11,29 (sh. s, 1H); HPLC-MS: m/z 288 (MN+); Rt=1,71 minutes

Example 96 (General procedure (C))

(9a-R)-2-Quinoline-2-yl-octahedrite[1,2-a]pyrazine hydrochloride

Connection receive General method (C) from (9a-R)-octahydro is up[1,2-a]pyrazine and 2-chlorhydrin.

1H NMR (DMSO-d6) δ 1,40-of 1.55 (m, 1H), 1,65-2,10 (m, 5H), of 2.92 (m, 1H), 3,25 (m, 1H), 3,35-3,90 (m, 5H), of 4.90 (m, 2H), 7,49 (m, 1H), to 7.59 (d, J=8 Hz, 1H), to 7.77 (m, 1H), 7,92 (d, J=8 Hz, 1H), 8,32 (sh. s, 1H), 8,46 (m, 1H), of 11.69 (sh. s, 1H); HPLC-MS: m/z 268 (MN+); Rt=1,07 minutes

Example 97 (General procedure (C))

(9a-R)-2-(6-Chlorhydrin-2-yl)octahedrite[1,2-a]pyrazine hydrochloride

Connection receive General method (C) from (9a-R)-octahedrite[1,2-a]pyrazine and 2,6-dichlorohydrin.

1H NMR (DMSO-d6) δ 1,40-of 1.55 (m, 1H), 1,65-2,05 (m, 5H), of 2.93 (m, 1H), 3,18 (m, 1H), 3.25 to 3,55 (m, 4H), 3,68 (m, 1H), 4,90 (m, 2H), 7,56 (d, J=8 Hz, 1H), 7,71 (d, J=8 Hz, 1H), 7,98 (s, 1H), 8,07 (sh. s, 1H), 8,29 (d, J=8 Hz, 1H), 11,47 (sh. s, 1H); HPLC-MS: m/z 302 (MN+); Rt=1,81 minutes

Example 98 (General procedure (C))

(9a-R)-2-(7-Fluoro-6-methylinosine-2-yl)octahedrite[1,2-a]pyrazine hydrochloride

Connection receive General method (C) from (9a-R)-octahedrite[1,2-a]pyrazine and 2-chloro-7-fluoro-6-methylinosine.

1H NMR (DMSO-d6) δ 1,40-of 1.55 (m, 1H), 1,65-2,10 (m, 5H), a 2.36 (s, 3H), of 2.92 (m, 1H), 3,23 (m, 1H), 3,30-of 3.60 (m, 4H), 3,80 (m, 1H), 4,87 (m, 2H), 7,51 (d, J=8 Hz, 1H), to 7.84 (d, J=8 Hz, 1H), 8,13 (sh. s, 1H), at 8.36 (d, J=8 Hz, 1H), 11,77 (sh. s, 1H); HPLC-MS: m/z 300 (MN+); Rt=1,54 minutes

Example 99 (General procedure (C))

(9a-R)-2-(6-Propilinian-2-yl)octahedrite[1,2-a]pyrazine hydrochloride

Connection receive General method (C) from (9a-R)-Oct is droperidol[1,2-a]pyrazine and 2-chloro-6-propylenimine.

1H NMR (DMSO-d6) δ of 0.91 (t, J=7 Hz, 3H), 1,40-of 1.55 (m, 1H), 1,60 is 2.10 (m, 7H), 2,70 (t, J=7 Hz, 2H), 2,92 (m, 1H), 3,24 (m, 1H), 3,30-of 3.85 (m, 5H), 4,88 (m, 2H), EUR 7.57 (d, J=8 Hz, 1H), 7,65 (d, J=8 Hz, 1H), 7,72 (s, 1H), 8,28 (sh. s, 1H), to 8.41 (m, 1H), of 11.69 (sh. s, 1H); HPLC-MS: m/z 309 (MN+); Rt=2,27 minutes

Example 100 (General procedure (C))

2-(4-Isopropylpiperazine-1-yl)finokalia hydrochloride

Connection get the General method (B) from 1-isopropylpiperazine and 2-chlorphenoxamine.

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H), of 3.13 (m, 2H), 3.45 points-of 3.65 (m, 5H), and 4.75 (m, 2H), of 7.48 (m, 1H), 7,66 (m, 2H), 7,88 (d, J=8 Hz, 1H), 8,91 (s, 1H), of 11.15 (sh. s, 1H); HPLC-MS; m/z 257 (MN+Rt=1,25 minutes

Example 101 (General procedure (C))

[4-(4-Cyclopropylmethyl-1-yl)phenyl]phenylmethanone hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 4-fermentation.

1H NMR (DMSO-d6) δ of 0.82 (m, 2H), 1,16 (m, 2H), 2,92 (sh. s, 1H), 3,30 is 3.40 (t, 4H), 3,56 (sh. s, 2H), 4.09 to (m, 2H), 7,12 (d, J=8 Hz, 2H), 7,54 (m, 2H), 7,60 to 7.75 (m, 5H), 10,82 (sh. s, 1H); HPLC-MS: m/z 307 (MN+); Rt=2,00 minutes

Example 102 (General procedure (C))

[4-(4-Cyclopropylmethyl-1-yl) - for 3,5-differenl]phenylethanone hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 3,4,5-triptoreline.

1H NMR (DMSO-d6) δ of 0.82 (m, 2H), 1,16 (m, 2H), 2,96 (sh. s, 1H), 3,30-3,75 (who, 8H), the 7.43 (d, J=8 Hz, 2H), 7,58 (t, J=8 Hz, 2H), 7,65 for 7.78 (t, 3H), 10,90 (sh. s, 1H); HPLC-MS: m/z 343 (MN+); Rt=2,29 minutes

Example 103 (General procedure (C))

2-(4-Isopropylpiperazine-1-yl)-5,6,7-trimethoxyaniline hydrochloride

Connection get the General method (B) from 1-isopropylpiperazine and 2-chloro-5,6,7-trimethoxyaniline.

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H), 3,21 (m, 2H), 3.45 points-of 3.85 (m, 5H), 3,82 (s, 3H), 3,93 (s, 3H), 3,99 (s, 3H), 4,78 (m, 2H), 7,31 (m, 1H), 7,56 (m, 1H), 8,31 (m, 1H), 11,36 (sh. s, 1H); HPLC-MS: m/z 346 (MN+); Rt=1,22 minutes

Example 104 (General procedure (C))

2-(4-Cyclopropylmethyl-1-yl)-5,6,7-trimethoxyaniline hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 2-chloro-5,6,7-trimethoxyaniline.

1H NMR (DMSO-d6) δ of 0.82 (m, 2H), 1,22 (m, 2H), 2,87 (sh. s, 1H), 3,30-4,10 (m, 6H), 3,83 (s, 3H), 3,93 (s, 3H), of 4.00 (s, 3H), amounts to 4.76 (m, 2H), 7,33 (m, 1H), 7,65 (sh. s, 1H), 8.34 per (m, 1H), are 11.62 (sh. s, 1H); HPLC-MS: m/z 344 (MN+); Rt=1,46 minutes

Example 105 (General procedure (C))

2-(4-Cyclopropylmethyl-1-yl)-6-triftormetilfullerenov hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 2-chloro-6-triftormetilfullerenov.

1H NMR (DMSO-d6) δ of 0.82 (m, 2H), 1,20 (m, 2H), 2,86 (sh. s, 1H), 3,20-3,70 (m, 6H), and 4.75 (m, 2H), 7,53 (m, 1H), 7,86 (m, 2H), 8,20-to 8.40 (m, 2H), 11,28 (sh. s, 1H); VE is X-MS: m/z 354 (MN +); Rt=2,61 minutes

Example 106 (General procedure (C))

7-Chloro-2-(4-cyclopropylmethyl-1-yl)-6-methoxyquinoline hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 2,7-dichloro-6-methoxyquinoline.

1H NMR (DMSO-d6) δ of 0.82 (m, 2H), 1,16 (m, 2H), 2,88 (m, 1H), 3.25 to 3,70 (m, 6H), of 3.94 (s, 3H), to 4.62 (m, 2H), 7,45 (d, J=8 Hz, 1H), 7,51 (s, 1H), of 7.96 (sh. s, 1H), 8,23 (d, J=8 Hz, 1H), 10,98 (sh. s, 1H); HPLC-MS: m/z 318 (MN+); Rt=1,80 minutes

Example 107 (General procedure (C))

5,7-Dichloro-2-(4-cyclopropylmethyl-1-yl)quinoline hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 2,5,7-trichlorohydrin.

1H NMR (DMSO-d6) δ of 0.82 (m, 2H), 1,19 (m, 2H), 2,86 (m, 1H), 3,20-the 3.65 (m, 6H), 4,69 (m, 2H), 7,51 (d, J=8 Hz, 1H), 7,56 (s, 1H), 7,68 (s, 1H), 8,30 (d, J=8 Hz, 1H), 11,24 (sh. s, 1H); HPLC-MS: m/z 322 (MH+; Rt=2,78 minutes

Example 108 (General procedure (C))

1-Cyclopropyl-4-[5-(triptoreline)pyridine-2-yl]piperazine hydrochloride

The desired 2-chloro-5-(4-tryptophanyl)pyridine receive, as described in R. Church, R. Trust, J.D. Albright and D. Powell,J. Org. Chem.1995,60, 3750-3758, as follows.

The reagent solution of Vilsmeier obtained from dimethylformamide (5,98 g, 0,082 mol) and phosphorus oxychloride (22,5 g, 0,146 mol) at a temperature of 10°C add 4-(trifluoromethyl)phenyl UKS who scurry acid (6,64 g, 0,033 mol). The mixture is stirred at 70°C for 8 hours After cooling to ambient temperature the mixture is added slowly to a mixture of ice and water (temperature <10°C) and then slowly add a solution of Na2CO3up until the pH becomes 11. To the alkaline mixture is added toluene (125 ml) and the resulting mixture is refluxed for 1.5 hours After cooling to ambient temperature the separated aqueous layer extracted with toluene (100 ml). The combined organic layers washed with water, dried (Na2SO4) and concentrate under reduced pressure. The obtained solid is recrystallized from a mixture of dichloromethane and heptane to obtain 6,98 g (87%) of 3-dimethylamino-2-(4-triptoreline)propanal in the form of yellow crystals, TPL 97°C.

1H NMR (CDCl3) δ 9,10 (s, 1H), EUR 7.57 (m, 2H), 7,32 (m, 2H), 6,95 (s, 1H), 2,85 (s, 6H); RF(SiO2, chloroform/methanol 95:5) 0,34.

To a solution of sodium methoxide (of 3.64 g, 0,068 mol) in methanol (68 ml) add cyanoacetamide (6,95 g, 0,082 mol) and the product obtained above (6,98 g 0,029 mol). The mixture was stirred at ambient temperature for 1.5 hours and then refluxed for 8 hours At this time, the precipitated yellow solid. The reaction mixture was diluted with water (75 ml) and acidified with 10% aqueous hydrochloric acid. Yellow t ardoe substance is filtered off, washed with water, ethanol, diethyl ether and then hexane. This gives 2-hydroxy-5-(4-triptoreline)nicotinamide (6,66 g, 87%) as a yellow solid, so pl. 235-242°C.

1H NMR (DMSO-d6) δ 8,42 (m, 1H), to $ 7.91 (m, 1H), 7,66 (m, 4H); RF(SiO2, chloroform/methanol 95:5) to 0.18.

The above product (6,66 g of 0.025 mol) is added to a mixture of acetic acid (100 ml) and concentrated hydrochloric acid (70 ml). The reaction mixture was refluxed for 18 h, diluted with water (200 ml) and cooled down to room temperature under stirring. The solid is filtered off, washed with water and then 50% aqueous ethanol to obtain 5,42 g (77%) of 2-hydroxy-5-(4-triptoreline)nicotinic acid as a light grey solid, so pl. 305-315°C.

1H NMR (DMSO-d6) δ 8,71 (d, 1H), 8,43 (d, 1H), of 7.96 (m, 2H), 7,81 (m, 2H); RF(SiO2, chloroform/methanol 95:5) to 0.13.

The mixture obtained above product (5,42 g, 0.019 mol) and freshly distilled quinoline (50 ml) is stirred at a temperature of 215°C for 12 h, the Reaction mixture was cooled to ambient temperature and add heptane (250 ml). The solid is filtered off, washed with heptane and recrystallized from a mixture of dichloromethane and heptane with getting to 3.92 g (86%) of 2-hydroxy-5-(4-triptoreline)pyridine, T. pl. 178-182°C.

1H NMR (CCl 3) δ 7,79 (DD, 2H), 7,68 (d, 3H), 7,52 (d, 2H), 6.73 x (d, 1H); RF(SiO2, chloroform/methanol 95:5) to 0.23.

A mixture of phosphorus oxychloride (27,6 g, 0.18 mol) and the product obtained above (to 3.92 g, to 0.016 mol) was stirred at 105°C for 10 hours the Excess phosphorus oxychloride is evaporated under reduced pressure and the residue is distilled one off with toluene (75 ml). To the residue is added water (75 ml) and dichloromethane (75 ml), the dichloromethane layer is separated and the aqueous phase extracted with dichloromethane (75 ml). The combined extracts washed with water, then with sodium hydrogen carbonate solution, dried (MgSO4) and concentrate under reduced pressure to get 2,95 g (72%) of 2-chloro-5-(4-triptoreline)pyridine in the form of light brown crystals, so pl. 98-101°C.

1H NMR (CDCl3) δ to 8.62 (DD, 1H), 7,86 (DD, 1H), 7,44 (DD, 1H), 7,66 (m, 2H), to 7.75 (m, 2H); RF(SiO2, chloroform/methanol 95:5) to 0.94.

This product is treated with 1-cyclopropylethanol, as described in the General method (B), obtaining specified in the connection header.

1H NMR (DMSO-d6) δ 0,83 (m, 2H), 1,13 (m, 2H), 2,85 (m, 1H), 3,25-3,75 (m, 6H), 4,51 (m, 2H), 7,12 (d, J=8 Hz, 1H), 7,79 (d, J=8 Hz, 2H), 7,89 (d, J=8 Hz, 2H), with 8.05 (m, 1H), 8,59 (m, 1H), 10,56 (sh. s, 1H); HPLC-MS: m/z 348 (MN+); Rt=2,77 minutes

Example 109 (General procedure (C))

3-(4-Cyclopropylmethyl-1-yl)-6-(4-triptoreline)pyridazine hydrochloride

Connect the s get the General method (B) from 1-cyclopropylbenzene and 3-chloro-6-(4-triptoreline)pyridazine.

1H NMR (DMSO-d6) δ 0,83 (m, 2H), 1,19 (m, 2H), 2,89 (m, 1H), 3,30-3,70 (m, 6H), br4.61 (m, 2H), to 7.61 (d, J=8 Hz, 1H), 7,88 (d, J=8 Hz, 2H), by 8.22 (d, J=8 Hz, 1H), 8,29 (d, J=8 Hz, 2H), 11.11 is (sh. s, 1H); HPLC-MS: m/z 349 (MH+); Rt=2,40 minutes

Example 110 (General procedure (C))

6-(4-Cyclopropylmethyl-1-yl)-[1,3]dioxolo[4,5-g]quinoline hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 6-chloro-[1,3]dioxolo[4,5-g]quinoline.

1H NMR (DMSO-d6) δ 0,83 (m, 2H)and 1.15 (m, 2H), 2,88 (m, 1H), 3,20-3,70 (m, 6H), 4,59 (m, 2H), 6,17 (s, 2H), 7,29 (m, 3H), 8,13 (m, 1H), 10,80 (sh. s, 1H); HPLC-MS: m/z 298 (MN+); Rt=0,68 minutes

Example 111 (General procedure (C))

6-Cyclohexyl-2-(4-cyclopropylmethyl-1-yl)quinoline hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 2-chloro-6-cyclohexylaniline.

1H NMR (DMSO-d5) δ 0,83 (m, 2H), 1,10-of 1.55 (m, 8H), 1.70 to of 1.93 (m, 4H), to 2.65 (m, 1H), 2,86 (m, 1H), 3,30-3,70 (m, 6H), 4.72 in (m, 2H), 7,50 (m, 1H), 7,66 (m, 1H), 7,72 (m, 1H), 7,99 (sh. s, 1H), 8,35 (sh. s, 1H), 11,29 (sh. s, 1H); HPLC-MS: m/z 336 (MH+); Rt=2,55 minutes

Example 112 (General procedure (C))

6-Cyclohexyl-2-(4-isopropylpiperazine-1-yl)quinoline hydrochloride

Connection get the General method (B) from 1-isopropylpiperazine and 2-chloro-6-cyclohexylaniline.

1H NMR (DMSO-d6) δ 1,10-of 1.55 (m, 8H), is 1.31 (d, J=7 Hz, 6H), 1.70 to-1,3 (m, 4H), to 2.65 (m, 1H), 3,23 (m, 2H), 3,50-of 3.85 (m, 3H), 4,80 (m, 2H), 7,51 (m, 1H), to 7.67 (m, 1H), 7,73 (m, 1H), 8,08 (sh. s, 1H), at 8.36 (sh. s, 1H), 11,31 (sh. s, 1H); HPLC-MS: m/z 338 (MH+); Rt=2,50 minutes

Example 113 (General procedure (C))

2-(4-Cyclopropylmethyl-1-yl)-6,7-dimethoxy-3-methylinosine hydrochloride

The desired 2-chloro-6,7-dimethoxy-3-methylinosine receive according to the method described in etrahedron Letters1979, 4885, as follows.

To a solution of 3,4-dimethoxyaniline (4,70 g, 30.7 mmol) in dichloromethane (50 ml) is added pyridine (8.0 ml, 3 equivalents) and then added dropwise to propionate (3.5 ml, of 40.5 mmol). After stirring at room temperature for 1 hour and 50 min the mixture was poured into a mixture of water (200 ml) and concentrated hydrochloric acid (8 ml). The phases are separated and the aqueous phase is a one off is extracted with dichloromethane. Wash the combined organic phases with saturated salt solution, dried over magnesium sulfate and concentration gives 6,89 g of oil which crystallized after a few minutes. Recrystallization from a mixture of ethyl acetate and heptane gives of 3.60 g (49%) of N-(3,4-acid)propionamide in the form of dark crystals.

This anilide (2.1 g, 10.0 mmol) is mixed with DMF (1.1 ml, 15 mmol) and to this mixture are added dropwise POCl3(6.5 ml, 70 mmol) at room temperature. After complete addition, the mixture is stirred at a temperature of 75°is within 2 hours The mixture was poured into ice-water (100 ml), stirred for 30 min and filtered. The solid is distilled off with toluene and acetonitrile to obtain 1.60 g (67%) 2-chlor-6,7-dimethoxy-3-methylinosine in the form of solids. This product is treated with 1-cyclopropylethanol, as described in the General method (B), obtaining specified in the connection header.

1H NMR (DMSO-d6) δ 0,83 (m, 2H), 1,23 (m, 2H), 2,42 (s, 3H), equal to 2.94 (m, 1H), 3,40-4,50 (m, 8H), 3,88 (s, 3H), 3,91 (s, 3H), 7,29 (s, 1H), of 7.48 (sh. s, 1H), 8,12 (sh. s, 1H), 11,24 (sh. s, 1H); HPLC-MS; m/z 328 (MN+); Rt=1,63 minutes

Example 114 (General procedure (C))

6-(4-Isopropylpiperazine-1-yl)-[1,3]dioxolo[4,5-g]quinoline hydrochloride

Connection get the General method (B) from 1-isopropylpiperazine and 6-chloro-[1,3]dioxolo[4,5-g]quinoline.

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H), 3,40 (m, 2H), 3.45 points-of 4.00 (m, 5H), 4.72 in (m, 2H), 6,21 (s, 2H), 7,34 (m, 2H), 7.62mm (sh. s, 1H),8,21 (m, 1H), 11,12 (sh. s, 1H); HPLC-MS: m/z 300 (MN+); Rt=0,65 minutes

Example 115 (General procedure (C))

[3,5-Debtor-4-(4-isopropylpiperazine-1-yl)-phenyl]-piperidine-1-yl-methanone hydrochloride

Connection get a shared approach to the interaction of 1-isopropylpiperazine and 3,4,5-triterpenoids acid of piperidine. The reaction gives two products, namely this example and example 121.

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H, 1,40-of 1.62 (m, 6H), to 3.09 (m, 2H), 3,20-the 3.65 (m, 11H), 7,12 (m, 2H), 10,42 (sh. s, 1H); HPLC-MS: m/z 352 (MN+); Rt=3,75 minutes

Example 116 (General procedure (C))

(9a-R)-2-(6,7-Dimethoxyquinazolin-2-yl)octahedrite[1,2-a]pyrazine hydrochloride

Connection receive General method (C) from (9a-R)-octahedrite[1,2-a]pyrazine and 2-chloro-6,7-dimethoxyaniline.

1H NMR (DMSO-d6) δ 1,40-of 1.55 (m, 1H), 1,65-2,05 (m, 5H), of 2.93 (m, 1H), up 3.22 (m, 1H), 3.25 to of 3.60 (m, 4H), 3,65-4,20 (m, 1H), a 3.87 (s, 3H), 3,90 (s, 3H), 4,79 (m, 2H), 7,40 (m, 2H), 8,00 W. s, 1H), 8,33 (sh. s, 1H), 11,55 (sh. s, 1H); HPLC-MS: m/z 328 (MN+); Rt=0,97 minutes

Example 117 (General procedure (C))

2-(4-Cyclopropylmethyl-1-yl)-5,6,7,8-tetrahydroquinoline hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 2-chloro-5,6,7,8-tetrahydroquinoline.

1H NMR (DMSO-d6) δ 0,81 (m, 2H), 1,17 (m, 2H), 1,67-to 1.82 (m, 4H), 2,62 (m, 2H), of 2,75 2,95 (m, 3H), 3,20-the 3.65 (m, 6H), 4,37 (m, 2H), 7,02 (sh. s, 1H), 7,63 (sh. s, 1H), 11,10 (sh. s, 1H); HPLC-MS: m/z 258 (MN+); Rt=0,62 minutes

Example 118 (General procedure (C))

[5-Chloro-6-(4-cyclopropylmethyl-1-yl)pyridine-3-yl]-piperidine-1-ylmethanone hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 5,6-dichloronicotinic acid of piperidine.

1H NMR (DMSO-d6) δ of 0.82 (m, 2H), 1,12 (m, 2H), 1,45-of 1.65 (m, 6H), 2,96 (m, 1H), 3,30-of 3.60 (m, 10H, of 3.96 (m, 2H), 7,89 (s, 1H), of 8.27 (s, 1H), is 10.68 (sh. s, 1H); HPLC-MS: m/z 349 (MH+); Rt=1,50 minutes

Example 119 (General procedure (C))

(9a-R)-[6-(Octahedrite[1,2-a]pyrazin-2-yl)pyridine-3-yl]piperidine-1-ylmethanone hydrochloride

Connection receive General method (C) from (9a-R)-octahedrite[1,2-a]pyrazine and 6-chloronicotinic acid of piperidine.

1H NMR (DMSO-d6) δ is 1.51 (m, 3H), 1,60 (m, 2H), 1,78-to 1.98 (m, 3H), 2,90-of 3.25 (m, 4H), 3,30-to 3.50 (m, 5H), 3,74 (m, 6H), 4,50 (m, 2H), 7,02 (d, J=7 Hz, 1H), 7,66 (d, J=7 Hz, 1H), 8,19 (s, 1H), 10,86 (sh. s, 1H); HPLC-MS: m/z 329 (MN+); Rt=1,31 minutes

Example 120 (General procedure (C))

[6-(4-cyclopropylmethyl-1-yl)pyridine-3-yl]-piperidine-1-ylmethanone hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 6-chloronicotinic acid of piperidine.

1H NMR (DMSO-d6) δ 0,81 (m, 2H), 1,17 (m, 2H)and 1.51 (m, 4H), to 1.60 (m, 2H), 2,87 (m, 1H), 3,20-of 3.60 (m, 10H), 4,47 (m, 2H), 7,01 (d, J=7 Hz, 1H), to 7.67 (d, J=7 Hz, 1H), 8,21 (s, 1H), 11,04 (sh. s, 1H); HPLC-MS: m/z 315 (MN+); Rt=1,22 minutes

Example 121 (General procedure (C))

[3,4-Debtor-5-(4-isopropylpiperazine-1-yl)-phenyl]-piperidine-1-yl-methanone hydrochloride

Connection get a shared approach to the interaction of 1-isopropylpiperazine and 3,4,5-triterpenoids acid of piperidine. The reaction gives two products, and it is this prospect which measures and example 115.

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H), 1,40-of 1.65 (m, 6H), 3,12-3,62 (m, 13H), 6,89 (d, J=8 Hz, 1H), to 7.09 (m, 1H), 11,09 (sh. s, 1H); HPLC-MS: m/z 352 (MN+); Rt=3,95 minutes

Example 122 (General procedure (C))

[4-(4-Isopropylpiperazine-1-yl)-3-triptoreline]-piperidine-1-yl-methanone hydrochloride

Connection get a shared approach to the interaction of 1-isopropylpiperazine and 4-fluoro-3-triftorperasin acid of piperidine.

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H), 1,40-of 1.65 (m, 6H), was 3.05 (m, 1H), 3.15 in (m, 1H), or 3.28 (m, 8H), 3,52 (m, 3H), EUR 7.57 (sh. d, J=8 Hz, 1H), 7,68 (sh. s, 1H), 7,71 (sh. d, J=8 Hz, 1H), accounted for 10.39 (sh. s, 1H); HPLC-MS: m/z 384 (MN+); Rt=4,21 minutes

Example 123 (General procedure (C))

2-(4-Cyclopropyl-3-methylpiperazin-1-yl)-6,7-dimethoxyaniline hydrochloride

Connection receive rehabilitation cyclopropylamine 6,7-dimethoxy-2-(3-methylpiperazin-1-yl)quinoline as described Gillaspy, M.L.; Lefker, B.A.; Hada, W.A.; and Hoover, D.J. inTetrahedron Lett.1995,36(41), 7399-7402.

1H NMR (DMSO-d6) δ 0,82 (m, 1H), 0,99 (m, 2H), 1,40 (m, 1H), 1.55V (d, J=7 Hz, 3H), was 2.76 (m, 1H), 3,30-of 3.80 (m, 5H), a 3.87 (s, 3H), 3,90 (s, 3H), 4,65 of 4.83 (m, 2H), 7,38 (sh. s, 2H), 7,82 (sh. s, 1H), 8,31 (sh. s, 1H), 11,30 (sh. s, 1H); HPLC-MS: m/z 328 (MN+); Rt=3,09 minutes

Example 124 (General procedure (C))

[6-(4-Cyclopropylmethyl-1-yl)pyridine-3-yl]-pyrrolidin-1-yl-methanone hydrochloride

Obedinenie get the General method (B) from 1-cyclopropylbenzene and 6-chloronicotinic acid of pyrrolidide.

1H NMR (DMSO-d6) δ 0,81 (m, 2H)and 1.15 (m, 2H), of 1.84 (m, 4H), 2,88 (m, 1H), 3,15-of 3.60 (m, 10H), of 4.49 (m, 2H), 7,00 (d, J=7 Hz, 1H), 7,83 (d, J=7 Hz, 1H), scored 8.38 (s, 1H), 10,91 (sh. s, 1H); HPLC-MS: m/z 301 (MN+); Rt=1,22 minutes

Example 125 (General procedure (C))

2-(4-Isopropylpiperazine-1-yl)quinoline-6-carbonitrile hydrochloride

To a mixture of ethyl ester of 3,3-diethoxypropionate (62 g, 326 mmol) and water (100 ml) is added NaOH (16.0 g) with stirring. Stirred at a temperature of 110°C (open flask). After 40 min the mixture becomes homogeneous, the heating is interrupted and the mixture is cooled to room temperature. The mixture is acidified (about 35 ml conc. HCl, pH 3-2) and extracted (4 dichloromethane). The combined extracts washed with saturated salt solution (1×50 ml), dried (magnesium sulfate) and concentrated. Obtain 48 g of oil.

To the oil is added dropwise thionyl chloride (80 ml). The mixture is stirred at the boiling point under reflux (80°C) for 1 h 30 min After careful concentration, the residue is weighed to obtain 48 g (theoretical weight should be 43 g). The acid chloride stored over night at -20°C.

The product is mixed with dichloromethane (70 ml) and 5/7 of this solution (230 mmol), are added to a solution of 4-bromoaniline (34,5 g, 201 mmol) and pyridine (50 ml) in dichloromethane (150 ml) and the mixture shaken at room temperature the night.

The mixture is filtered and the obtained solid is washed with dichloromethane and dried to obtain 21 g of N-(4-bromophenyl)-3-ethoxyacrylate in the form of a colorless solid. To the filtrate add a mixture of water (700 ml) and concentrated hydrochloric acid (50 ml). Solid precipitates when shaken, it is filtered off, washed with dichloromethane and AcOEt and dried. Get more of 14.4 g of the product.

The filtrate is extracted with (3 dichloromethane), one off washed with saturated salt solution, dried and concentrated. Get another 18 g of the product. Total yield: 53,4,

This product (58,8 g, 218 mmol) is mixed with ice-cold concentrated sulfuric acid (390 ml) and the mixture is stirred first at 0°C for 15 min (until then, until you dissolve almost all of acrylamide) and then at room temperature for 4 h Then the mixture is poured into ice water (3 l) and stand over night. The mixture is filtered and the solid washed with water. The solid is transferred into a flask with addition of acetonitrile, ethanol and dichloromethane and the suspension is concentrated under reduced pressure. The residue re-suspended in acetonitrile (300 ml), heated to the boiling temperature under reflux and stand at room temperature overnight. Filtering and drying the solids under reduced pressure the network of 31.3 g (64%) of 6-bromo-2-quinolone in the form of a yellow solid.

This hinolan (6,28 g of 28.0 mmol) is mixed with copper cyanide(I) (5,02 g, or 56.1 mmol) and NMP (15 ml) and the mixture is stirred at the boiling point under reflux (202°C) for 6 h, then at room temperature overnight. Add water (150 ml), the mixture is filtered and the solid washed with water. The solid is re-suspended in 1N hydrochloric acid (200 ml) and add the uranyl chloride iron(III) (17.8 g). The resulting mixture was stirred at room temperature for 3 days, filtered and the solid is a one off washed with water, distilled with ethanol and dried under reduced pressure to get to 4.33 g (91%) of 6-cyano-2-quinolone as a gray solid. Treatment of the product POCl3and then 1-isopropylpiperazine according to the General method (B) gives specified in the header of the connection.

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H), 3,10 (m, 2H), 3,52 (m, 5H), 4,79 (m, 2H), 7,49 (d, J=8 Hz, 1H), 7,71 (d, J=8 Hz, 1H), 7,86 (d, J=8 Hz, 1H), 8,23 (d, J=8 Hz, 1H), 8,35 (s, 1H), of 10.73 (sh. s, 1H); HPLC-MS: m/z 281 (MN+); Rt=1,62 minutes

Example 126 (General procedure (C))

3-(4-Cyclopropylmethyl-1-yl)-6-phenylpyridine hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 3-chloro-6-phenylpyridazin.

1H NMR (DMSO-d6) δ of 0.82 (m, 2H), 1,22 (m, 2H), 2,88 (sh. s, 1H), 3,37 (m, 2H)and 3.59 (m, 4H), of 4.57 (m, 2H), 7,53 (m, 3H), 7,80 (d,J=8 Hz, 1H), of 8.06 (m, 2H), 8,29 (d, J=8 Hz, 1H), 11,47 (sh. s, 1H); HPLC-MS: m/z 281 (MN+); Rt=1,43 minutes

Example 127 (General procedure (C))

3-(4-Cyclopropylmethyl-1-yl)-6-(3,4-acid)pyridazine hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 3-chloro-6-(3,4-acid)pyridazine.

1H NMR (DMSO-d6) δ 0,83 (m, 2H), 1,22 (m, 2H), 2,88 (sh. s, 1H), 3,36 (m, 2H), 3,60 (m, 4H), of 3.84 (s, 3H), a 3.87 (s, 3H), 4.53-in (m, 2H), 7,14 (d, J=8 Hz, 1H), 7,66 (m, 2H), 7,86 (d, J=8 Hz, 1H), of 8.37 (d, J=8 Hz, 1H), 11,43 (sh. s, 1H); HPLC-MS: m/z 341 (MN+); Rt=1,45 minutes

Example 128 (General procedure (C))

7-(4-Isopropylpiperazine-1-yl)-2,3-dihydro[1,4]like[2,3-g]quinoline

Connection get the General method (B) from 1-isopropylpiperazine and 7-chloro-2,3-dihydro[1,4]like[2,3-g]quinoline.

1H NMR (DMSO-d6) δ 1,00 (d, J=7 Hz, 6H), 2,67 (hept, J=7 Hz, 1H), 3.33 and (s, 4H), of 3.56 (m, 4H), 4,29 (m, 4H), to 6.95 (s, 1H), 7,02 (d, J=8 Hz, 1H), 7,13 (s, 1H), to 7.84 (d, J=8 Hz, 1H); HPLC-MS: m/z 314 (MN+); Rt=1,14 minutes

Example 129

2-(4-Cyclopropyl-3-methylpiperazin-1-yl)quinoline hydrochloride

Connection receive rehabilitation cyclopropylamine 2-(3-methylpiperazin-1-yl)quinoline as described Gillaspy, M.L.; Lefker, B.A.; Hada, W.A.; and Hoover, D.J. inTetrahedron Lett.1995,36(41), 7399-7402.

1H NMR (DMSO-d6) δ 0,82 (m, 1H), and 1.00 (m, 2H), 1,41 (m, 1H), and 1.56 (d, J=7 Hz,3H), was 2.76 (m, 1H), 3.25 to of 3.80 (m, 5H), to 4.81 (m, 2H), 7,44 (sh. s, 1H), 7,55 (m, 1H), 7,72 (m, 1H), 7,88 (m, 1H), 8,11 (sh. s, 1H), of 8.37 (sh. s, 1H), 11,40 W. s, 1H); HPLC-MS: m/z 268 (MN+); Rt=1,18 minutes

Example 130 (General procedure (C))

6 Cyclopropylmethoxy-2-(4-cyclopropylmethyl-1-yl)quinoline hydrochloride

Connection get the General method (B) from 1-isopropylpiperazine and 2-chloro-6-(cyclopropylmethoxy)quinoline. The desired 2-chloro-6-(cyclopropylmethoxy)quinoline obtained by treatment of 6-(cyclopropylmethoxy)-2-quinolone POCl3. 6-(Cyclopropylmethoxy)-2-chinolone obtained from the corresponding 6-hydroxyquinoline processing (methyl bromide)cyclopropane and potassium carbonate in dimethylformamide in the presence of catalytic amounts of sodium iodide.

1H NMR (DMSO-d6) δ 0,35 (m, 2H), 0,60 (m, 2H), 0,82 (m, 2H), 1,20 (m, 2H), 1.28 (in m, 1H), 2,87 (sh. s, 1H), 3,25-4,20 (m, 6H), to 3.92 (d, J=7 Hz, 2H), 4,70 (m, 2H), 7,30-of 7.60 (m, 3H), 8,08 (sh. s, 1H), 8,32 (sh. s, 1H), 11,37 (sh. s, 1H); HPLC-MS: m/z 324 (MN+); Rt=1,94 minutes

Example 131 (General procedure (C))

2-(4-Isopropylpiperazine-1-yl)-6-pyrazole-1-rhinolin hydrochloride

Connection get the General method (B) from 1-isopropylpiperazine and 2-chloro-6-(1-pyrazolyl)quinoline. The desired 2-chloro-6-(1-pyrazolyl)quinoline obtained by treatment of 6-(1-pyrazolyl)-2-quinolone POCl3. 6-(1-Pyrazolyl)-2-chinolone obtained as follows.

Mix-bromo-2-quinolone (3.58 g, 16.0 mmol), DMF (15 ml), pyrazole (1.66 g, 24.4 mmol), potassium carbonate (3.33 g, 24,1 mmol) and copper iodide(I) (0,76 g, 3,99 mmol) is stirred at a temperature of 160°C for 22 hours Add water (300 ml) and after careful grinding the mixture is filtered and the solid washed with water. The solid is evaporated with EtOH, re-suspended in a mixture of acetonitrile and ethanol (100 ml, 1:1), heated to the boiling temperature under reflux and kept at room temperature during the night. Filtration, washing with a small amount of acetonitrile and dried under reduced pressure to give 1.7 g (50%) of 6-(1-pyrazolyl)-2-quinolone in the form of metallic green solid.

1H NMR (DMSO-d6) δ of 1.32 (d, J=7 Hz, 6H), 3,10-3,70 (m, 7H), to 4.81 (m, 2H), 6,60 (m, 1H), 7,56 (d, J=8 Hz, 1H), 7,81 (s, 1H), 8,09 (m, 1H), they were 8.22 (d, J=8 Hz, 1H), 8,32 (s, 1H), scored 8.38 (d, J=8 Hz, 1H), 8,58 (m, 1H)that is 11.11 (sh. s, 1H); HPLC-MS: m/z 322 (MH+); Rt=1,67 minutes

Example 132 (General procedure (C))

2-(4-Isopropylpiperazine-1-yl)-quinoline-6-ol hydrochloride

Connection get the General method (B) from 1-isopropylpiperazine and 2-chloro-6-hydroxyquinoline solution.

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H), 3,15-3,90 (m, 7H), 4,79 (m, 2H), 7,22 (m, 1H), 7,33 (d, J=8 Hz, 1H), 7,53 (d, J=8 Hz, 1H), 8,13 (sh. s, 1H),8,35 (d, J=8 Hz, 1H), 10,17 (sh. s, 1H), 11,41 (sh. s, 1H); HPLC-MS: m/z 272 (MN+); Rt=0,40 minutes

Example 133 (General procedure (C))

2-(4-Cyclopropylamino the-1-yl)-quinoline-6-carbonitrile hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 2-chloro-6-cyanohydrin.

1H NMR (DMSO-d6) δ 0,83 (m, 2H)and 1.15 (m, 2H), 2,87 (sh. s, 1H), 3,20-the 3.65 (m, 6H), 4,74 (m, 2H), 7,49 (d, J=8 Hz, 1H), 7,72 (d, J=8 Hz, 1H), 7,86 (d, J=8 Hz, 1H), 8,24 (d, J=8 Hz, 1H), 8,35 (s, 1H), 10,88 (sh. s, 1H); HPLC-MS; m/z 279 (MN+); Rt=1,43 minutes

Example 134 (General procedure (C))

(9a-R)-2-(Octahedrite[1,2-a]pyrazin-2-yl)quinoline-6-carbonitrile hydrochloride

Connection receive General method (C) from (9a-R)-octahedrite[1,2-a]pyrazine and 2-chloro-6-cyanohydrin.

1H NMR (DMSO-d6) δ 1,40-1,60 (m, 1H), 1,65-2,00 (m, 5H), 2,85-the 3.65 (m, 7H), 4,80 (m, 2H), 7,53 (d, J=8 Hz, 1H), 7,79 (d, J=8 Hz, 1H), 7,89 (d, J=8 Hz, 1H), compared to 8.26 (d, J=8 Hz, 1H), of 8.37 (s, 1H), 11,31 (sh. s, 1H); HPLC-MS: m/z 293 (MN+); Rt=1,72 minutes

Example 135 (General procedure (C))

4-Chloro-6-(4-isopropylpiperazine-1-yl)-3-phenylpyridazin hydrochloride

Connection get the General method (B) from 1-isopropylpiperazine and 4,6-dichloro-3-phenylpyridazin.

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H), of 3.13 (m, 2H), 3.40 in-the 3.65 (m, 5H), 4,63 (m, 2H), 7,50 (m, 3H), 7,63 (m, 2H), 7,78 (s, 1H), br11.01 (sh. s, 1H); HPLC-MS; m/z 317 (MN+); Rt=2,11 minutes

Example 136 (General procedure (C))

3-(4-Cyclopropylmethyl-1-yl)-6-(3-triptoreline)pyridazine hydrochloride

Soedineniya according to the General method (B) from 1-cyclopropylbenzene and 3-chloro-6-(3-triptoreline)pyridazine.

1H NMR (DMSO-d6) δ 0,83 (m, 2H), 1,22 (m, 2H), 2,89 (sh. s, 1H), 3,35 (m, 2H)and 3.59 (m, 4H), 4,63 (m, 2H), 7,68 (d, J=8 Hz, 1H), to 7.77 (m, 1H), to 7.84 (m, 1H), 8,32 (d, J=8 Hz, 1H), 8,40 (m, 2H), 11,40 W. s, 1H); HPLC-MS: m/z 349 (MH+); Rt=2,43 minutes

Example 137 (General procedure (C))

1-[2-(4-Isopropylpiperazine-1-yl)quinoline-6-yl]ethanone hydrochloride

The compound is obtained by treatment of 2-(4-isopropylpiperazine-1-yl)quinoline-6-carbonitrile excess bromide Metalmania in tetrahydrofuran.

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H), to 2.65 (s, 3H), 3,18 (m, 2H), 3,40-of 3.80 (m, 5H), 4,82 (m, 2H),7,52 (d, J=8 Hz, 1H), to $ 7.91 (sh. s, 1H), 8,15 (d, J=8 Hz, 1H), 8,40 (d, J=8 Hz, 1H), 8,54 (s, 1H), 11,16 (sh. s, 1H); HPLC-MS: m/z 298 (MN+); Rt=1,47 minutes

Example 138 (General procedure (C))

3-(4-Isopropylpiperazine-1-yl)-6-phenylpyridazin-4-carbonitrile hydrochloride

Connection get the General method (B) from 1-isopropylpiperazine and 3-chloro-6-phenylpyridazin-4-carbonitrile.

1H NMR (DMSO-d6) δ of 1.32 (d, J=7 Hz, 6H), 3,23 (m, 2H), 3,50-3,75 (m, 5H), to 4.46 (m, 2H), 7,55 (m, 3H), 8,13 (d, J=7 Hz, 2H), 8,72 (s, 1H), 10,67 (sh. s, 1H); HPLC-MS: m/z 308 (MH+); Rt=2,16 minutes

Example 139 (General procedure (C))

6-Bromo-2-(4-isopropylpiperazine-1-yl)quinoline

Connection get the General method (B) from 1-isopropylpiperazine and 6-bromo-2-chlorhydrin.

1H NMR (DMSO-d6) δ 1,00 (d, J=7 Hz, 6H),2,52 (m, 4H), 2,69 (sept, J=7 Hz, 1H), 3,68 (m, 4H), 7,28 (d, J=8 Hz, 1H), of 7.48 (d, J=8 Hz, 1H), 7,60 (DD, J=1 Hz, 8 Hz, 1H), to 7.93 (d, J=1 Hz, 1H), 8,00 (d, J=8 Hz, 1H).

Example 140 (General procedure (C))

2-(4-Cyclopropylmethyl-1-yl)-6-pyrazole-1-rhinolin hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 2-chloro-6-pyrazole-1-rhinolin.

1H NMR (DMSO-d6) δ 0,83 (m, 2H), 1,22 (m, 2H), 2,88 (m, 1H), 3,30-of 3.80 (m, 6H), 4,79 (m, 2H), is 6.61 (m, 1H),to 7.59 (d, J=6 Hz, 1H), 7,81 (s, 1H), 8,10-8,30 (m, 2H), 8.34 per (s, 1H), to 8.41 (d, J=6 Hz, 1H), 8,59 (s, 1H), 11,47 (sh. s, 1H); HPLC-MS: m/z 320 (MN+); Rt=1,64 minutes

Example 141 (General procedure (C))

7-Chloro-2-(4-cyclopropylmethyl-1-yl)quinoline-6-ol hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 2,7-dichloro-6-hydroxyquinoline solution. The desired 2,7-dichloro-6-hydroxyquinolin obtained by demethylation by tribromide boron in dichloromethane 2,7-dichloro-6-methoxyquinoline, which is obtained from 3-chloro-4-methoxyaniline as described F. Effenberger and W. Hartmann inChemische Berichte1969,102, 3260-3267.

1H NMR (DMSO-d6) δ 0,83 (m, 2H), 1.14 in (m, 2H), 2,88 (m, 1H), 3,20-of 3.80 (m, 6H), br4.61 (m, 2H), 7,32 (s, 1H), 7,42 (m, 1H), of 7.96 (m, 1H), 8,21 (m, 1H), 10,65 (sh. s, 1H), 10,84 (sh. s, 1H); HPLC-MS: m/z 304 (MN+); Rt=1,06 minutes

Example 142 (General procedure (C))

[2-(4-Cyclopropylmethyl-1-yl)quinoline-6-yl]-(4-forfinal)methanone hydrochloride

The compound is obtained by treatment of 2-(4-cyclopropylmethyl-1-yl)quinoline-6-carbonitrile excess bromide (4-forfinal)magnesium in tetrahydrofuran.

1H NMR (DMSO-d6) δ 0,84 (m, 2H), 1.14 in (m, 2H), 2,89 (m, 1H), 3.25 to 3,90 (m, 6H), of 4.77 (m, 2H), 7,44 (m, 3H), 7,76 (m, 1H), 7,86 (m, 2H), 7,98 (m, 1H), 8,21 (s, 1H), 8.34 per (d, J=8 Hz, 1H), 10,65 (sh. s, 1H); HPLC-MS: m/z 376 (MH+); Rt=2,61 minutes

Example 143 (General procedure (C))

Cyclopropyl-[2-(4-cyclopropylmethyl-1-yl)quinoline-6-yl]methanone hydrochloride

The compound is obtained by treatment of 2-(4-cyclopropylmethyl-1-yl)quinoline-6-carbonitrile excess bromide cyclopropylamine in tetrahydrofuran.

1H NMR (DMSO-d6) δ 0,83 (m, 2H), 1,07 (m, 4H), of 1.18 (m, 2H), 2,88 (m, 1H), 3.00 and (quint., J=7 Hz, 1H), 3,30-3,70 (m, 6H), was 4.76 (m, 2H), 7,50 (d, J=8 Hz, 1H), 7,82 (sh. s, 1H), 8,18 (d, J=8 Hz, 1H), of 8.37 (d, J=8 Hz, 1H), 8,66 (s, 1H), 11,05 (sh. s, 1H); HPLC-MS: m/z 322 (MH+); Rt=1,98 minutes

Example 144 (General procedure (C))

2-(4-Cyclopropylmethyl-1-yl)-6-(4-forbindelse)quinoline hydrochloride

Connection get the General method (B) from 1-cyclopropylbenzene and 2-chloro-6-(4-forbindelse)quinoline.

1H NMR (DMSO-d6) δ 0,83 (m, 2H), 1,20 (m, 2H), 2,87 (m, 1H), 3,30-of 3.80 (m, 6H), 4,70 (m, 2H), by 5.18 (s, 2H), 7,25 (t, J=8 Hz, 2H), 7,54 (m, 5H), 8,08 (sh. s, 1H), 8,33 (m, 1H), 11,34 (sh. s, 1H); HPLC-MS: m/z 378 (MH+)); Rt=2,53 minutes

Example 145 (General procedure (C))

6-Cyclohex-1-the Nile-2-(4-isopropylpiperazine-1-yl)quinoline hydrochloride

The compound is obtained by treatment of 6-bromo-2-(4-isopropylpiperazine-1-yl)quinoline-butyllithium and then cyclohexanone. When acid treatment of the tertiary alcohol is subjected to removal of obtaining specified in the connection header.

1H NMR (DMSO-d6) δ is 1.31 (d, J=7 Hz, 6H), 1,60-1,80 (m, 4H), 2,22 (m, 2H), 2,45 (m, 2H), 3,23 (m, 2H), 3.45 points-of 4.00 (m, 5H), 4,78 (m, 2H), 6,34 (m, 1H), 7,50 (m, 1H), 7,86 (m, 2H), 7,98 (sh. s, 1H), 8.34 per (m, 1H), 11,06 (sh. s, 1H); HPLC-MS; m/z 336 (MH+); Rt=2,50 minutes

Example 146 (General procedure (C))

1-(Biphenyl-3-yl)-4-(cyclopentyl)piperazine

A mixture of 3-bromobiphenyl (300 mg, 1.28 mmol), 1-cyclopentenopyridine (238 mg, 1.54 mmol), tert-butoxide sodium (173 mg, 1.8 mmol), Tris(dibenzylideneacetone)diplegia (12 mg, 0.01 mmol) and racemic 2,2'-bis(diphenylphosphino)-1,1 binaphthyl (24 mg, 0.04 mmol) in toluene (11 ml) are mixed in a nitrogen atmosphere in a closed reaction vessel. The reaction mixture is stirred at a temperature of 80°C for 3 days in a closed reaction vessel. It is cooled to room temperature and washed with water (2×10 ml). The combined organic layers extracted with 1N hydrochloric acid (2×20 ml). The combined aqueous extracts alkalinized 1N aqueous sodium hydroxide solution and extracted with tert-butylmethylamine ether (3×20 ml). Layers of tert-butyl methyl ether, dried over self the volume of magnesium. The solvent is removed in vacuum to obtain 220 mg specified in the connection header.

1H NMR (CDCCl3), two sets of signals, broad signals) δ 1,35-of 1.85 (m, 6H); 1,95 (m, 2H); to 2.55 (m, 1H); 2,70 (m, 4H); 3,30 (m, 4 H); to 6.95 (d, 1H); 7,05 (d, 1H); to 7.15 (s, 1H); to 7.35 (t, 2H); 7,45 (t, 2H); of 7.60 (d, 2H); HPLC method B: elution at 10,45 minutes

Specified in the title compound converted into the hydrochloride by dissolving in ethyl acetate (5 ml). 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 147 (General procedure (C))

1-Cyclopentyl-4-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl]piperazine

86 mg specified in the title compounds are synthesized as described for 1-(biphenyl-3-yl)-4-(cyclopentyl)piperazine, using 1-(2-(4-bromophenoxy)ethyl)pyrrolidine instead of 3 bromobiphenyl.

1H-NMR (DMSO-d6) δ of 1.55 (m, 2H); to 1.75 (m, 2H); of 1.85 (m, 4H); 2,00 (m, 4H); 3,10 (m, 6H); 3.40 in-3,70 (m, 9H); 4,30 (t, 2H); 7,00 (AB, 4H); 10,80 (W., 1H); 11,10 (W., 1H), HPLC method C: elution at 2,24 min-MS: calculated for [M+H]+: 344; found: 344.

Specified in the title compound converted into the hydrochloride by dissolving in ethyl acetate (5 ml). 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.

p> Example 148 (General procedure (C))

1-(Biphenyl-4-yl)-4-(cyclopentyl)piperazine

180 mg specified in the title compounds are synthesized as described for 1-(biphenyl-3-yl)-4-(cyclopentyl)piperazine using 4-bromobiphenyl instead of 3 bromobiphenyl.

1H-NMR (CDCl3) δ 1,80-2,00 (m, 8H); to 2.55 (m, 1H); 2,70 (m, 4H); 3,20 (m, 4H); 7,00 (d, 2H); 7,30 (m, 1H); 7,40 (t, 2H); and at 7.55 (m, together 4H), HPLC method C: elution when to 4.52 min

Specified in the title compound converted into the hydrochloride by dissolving in ethyl acetate (5 ml). 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 149 (General procedure (C))

[3-(4-(Cyclopentyl)piperazine-1-yl)phenyl]-(4-forfinal)metano

300 mg specified in the title compounds are synthesized as described for 1-(biphenyl-3-yl)-4-(cyclopentyl)piperazine, using 3-bromo-4'-terbinafine instead of 3 bromobiphenyl.

1H-NMR (CDCl3) δ of 1.45 (m, 2H)and 1.60 (m, 2H); to 1.75 (m, 2H); 1,90 (m, 2H); 2,55 (quintet, 1H); 2,70 (m, 4H); 3,30 (m, 4H); to 7.15 (m, 4H); 7,35 (m, 2H); a 7.85 (m, 2H), HPLC method C; elution with 4,22 min-MS: calculated for [M+H]+: 353; found: 353.

Specified in the title compound converted into the hydrochloride by dissolving in ethyl acetate (5 ml). Add a 3.2 M solution of hydrogen chloride in e is racette (5 ml). The solvent is removed in vacuum. The residue is dissolved in ethanol (50 ml). The solvent is removed in vacuum.

The following compounds are also included in the scope of this invention:

Pharmacological methods

The ability of compounds to interact with the histamine receptor H3 can be determined in the following studies on the binding in vitro.

The analysis of binding I

The cerebral cortex of rats homogenized in ice-cold buffer K-Hepes, 5 mm MgCl2pH of 7.1. After two differential zentrifugenbau last residue re-suspended in fresh Hepes buffer containing 1 mg/ml bacitracin. Aliquots of the suspension membrane (400 µg/ml) incubated for 60 min at 25°C 30 PM [125I]-iodoprotein known antagonist of the histamine receptor H3, and test compound in various concentrations. The incubation is stopped by dilution with ice-cold medium followed by filtration through filters Whatman GF/B, pre-treated for 1 hour with 0.5% polyethylenimine. The radioactivity remaining on the filters counted using an automatic gamma counter Cobra II. The radioactivity of the filter is inversely proportional to the affinity of binding of the test compound. The results analyzed by analysis nainan the th regression.

The analysis of binding II

The H3 agonist-receptor ligand R-a-methyl[3H]histamine (RAMHA) incubated with the selected cell membranes of the cerebral cortex of the rat at 25°C for 1 hour followed by filtration of incubate through filters Whatman GF/b Radioactivity remaining on the filters, and counted using a beta counter. Male Wistar rats (150-200 g) and decapitate the cortex quickly cut and immediately frozen in dry ice. Tissue stored at a temperature of -80°C to obtain membranes. While obtaining membranes fabric store on ice all the time. The cerebral cortex of rats homogenized in 10 volumes (about./about.) ice-cold Hepes buffer (20 mm Hepes, 5 mm MgCl2pH of 7.1 (CON) + 1 mg/ml bacitracin) using homogenizer Ultra-Turrax for 30 seconds. The homogenate was centrifuged at 140 g for 10 min. the Supernatant transferred into a new tube and centrifuged for 30 min at 23000 g. The last residue is suspended in 5-10 ml of Hepes buffer, homogenized and centrifuged for 10 min at 23000 g. This short stage centrifugation was repeated twice. After the last centrifugation the precipitate is re-suspended in 2-4 ml of Hepes buffer and determine the protein concentration. Membranes were diluted to a protein concentration of 5 mg/ml Hepes buffer, aliquoting and stored at a temperature of -80°C until use.

50 μl of esteruelas connection 100 μl of membranes (200 ál/ml)300 ál of Hepes buffer and 50 μl of R-a-methyl[3H]histamine (1 nm) are mixed in a test tube. Test compounds dissolved in DMSO and then diluted in N2On to the desired concentrations. Radioligand and membranes diluted in 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-cold 0.9% NaCl, followed by rapid filtration through filters Whatman GF/B, pre-treated for 1 hour with 0.5% polyethylenimine. The filters are washed with 2×5 ml ice-cold NaCl. In each filter add 3 ml of scintillation cocktail and the remaining radioactivity was measured by a beta counter Packard Tri-Carb. The values of the IC50estimated using analysis of nonlinear regression curves binding (6 points minimum), using the program for Windows, GraphPad Prism, GraphPad software, USA.

The analysis of binding III

The human H3 receptor clone using PCR and subcloning in the pcDNA3 expression vector. Cells stably expressing the H3 receptor, generated by transfection of vectors H3-expression in SOME of 293 cells using G418 for selection of clones H3. Clones of human H3 NECK 293 were cultured in DMEM (GIBCO-BRL) with glutamax, 10% fetal calf serum, 1% penicillin/streptavidin and 1 mg/ml G 418 at a temperature of 37°C and 5% CO2. Before collecting confluently cells washed RFB and in ubermut Versen (proteinase, GIBCO-BRL) for about 5 minutes, the Cells are washed RFB and DMEM and the cell suspension is collected in a test tube and centrifuged for 5-10 min at 1500 rpm in a Heraeus Sepatech Megafuge 1.0. The precipitate is re-suspended in 10-20 volumes of Hepes buffer (20 mm Hepes, 5 mm MgCl2pH of 7.1 (CON)) and homogenized for 10 to 20 seconds with the use of a homogenizer Ultra-Turrax. The homogenate was centrifuged for 30 min at 23000 g, the precipitate is re-suspended in 5-10 ml of Hepes buffer, homogenized for 5-10 seconds with Ultra-Turrax and centrifuged for 10 min at 23000 g. After this stage centrifugation the precipitate, containing membranes, re-suspended in 2-4 ml of Hepes buffer, homogenized with a syringe or a Teflon homogenizer and determine the protein concentration. Membranes were diluted to a protein concentration of 1-5 mg/ml in Hepes buffer, aliquoting and stored at a temperature of -80°C until use.

Aliquots of a suspension of membranes incubated for 60 min at 25°C 30 PM [125I]-iodoprotein known compounds with a high affinity for the H3 receptor, and the test compound in various concentrations. The incubation is stopped by dilution with ice-cold medium, followed by rapid filtration through filters Whatman GF/B, pre-treated for 1 hour with 0.5% polyethylenimine. The radioactivity remaining on the filters, calculate, using the automatic the cue gamma counter Cobra II. The radioactivity of the filter is inversely proportional to the affinity of binding of the test compound. The results analyzed by analysis of nonlinear regression.

When testing the compounds of formula (I) in accordance with this invention typically show high affinity binding to the histamine receptor H3.

Preferably, the compounds in accordance with this invention have the IC50the values defined in one or more research, less than 10 microns, more preferably less than 1 μm, even more preferably less than 500 nm, more specifically, less than 100 nm.

Functional studies I

The ability of compounds to interact with the histamine receptor H3 as agonists, inverse agonists and/or antagonists determine the functional in vitro studies using membranes from SOME of 293 cells expressing human H3 receptors.

H3 receptor clone using PCR and subcloning in the expression vector pcDNA3. Cells stably expressing the H3 receptor, generated by transfection of vectors H3-expression in SOME of 293 cells using G418 for selection of clones H3. Clones of human H3 NECK 293 were cultured in DMEM with glutamax, 10% fetal calf serum, 1% penicillin/streptavidin and 1 mg/ml G 418 at a temperature of 37°C and 5% CO2.

Cells expressing the H3 receptor, Odie is ODI washed with saline phosphate buffer (RFB) and collected using versen (GIBCO-BRL). Add RFB and cells centrifuged for 5 min at 188 g. The rest of the cells re-suspended in a stimulating buffer to a concentration of 1×106cells/ml Accumulation of camp was measured using a research camp Flash Plate® (NEN™ Life Science Products). Research is usually carried out as described by the manufacturer.

Briefly, 50 µl of cell suspension added to each cell 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 or agonists and antagonists together). Research can be carried out by the method of agonist, which means that the test compound added in increasing concentrations, in itself, to cells, to measure camp. If the camp is growing, the compound is an inverse agonist; if camp is not changed, the connection is a neutral antagonist, and if the camp is reduced, the compound is an agonist. The study can also be conducted using a antagonist, which means that the test compound added in increasing concentrations, together with the increasing concentration of a known agonist H3 (for example, RAMHA). If the compound is an antagonist, the increase of its concentration gives the right offset curves dose-effect of the H3 agonist. End of jam in each cell is 100 ál. Test compounds dissolved in DMSO and diluted with N2O. the Mixture is shaken for 5 min and stand for 25 min at room temperature. The reaction is stopped with 100 μl of a mixture of to determine on the cell. Then tablets, sealed with plastic lids, shaken for 30 min, stand over night and finally count the radioactivity in an automatic gamma counter Cobra II. The values of EC50expect the analysis of nonlinear regression curves dose-effect (6 points minimum), using GraphPad Prism. The Kb values are estimated using analysis curve Schild.

Functional study II

The ability of compounds to communicate and interact with human H3 receptor as agonists, inverse agonists and/or antagonists is determined by the functional study, namely, the study of [35S]GTPgS. The study determined the activation of G proteins catalysis exchange guanosine 5'-diphosphate (GDP) on guanosine 5'-triphosphate (GTP) in the a-polyadenine. GTP-bound G proteins fall into two pojedynczy, GaGTPand Gbg, which, in turn, regulate intracellular enzymes and ion channels. GTP is rapidly hydrolyzed Ga-pojedinacni (GTP), and protein G is deactivated and ready for a new exchange of GTP cycle. To study the function of activation-induced do what andom receptor combinations of protein G (GPCR) increase the exchange of guanine nucleotide proteins G, binding of [35S]-guanosin-5'-O-(3-thio)triphosphate [35S]GTPgS, determined not hydrolyzed analogue of GTP. This process can be monitored in vitro by incubation of the membranes of cells containing conjugated with protein G H3 receptor with GDP and [35S]GTPgS. Cell membranes derived from Cho cells stably expressing human H3 receptor. Cells are washed twice in RFB, collect from FHB + 1 mm add, pH 7.4 and centrifuged at 1000 rpm for 5 minutes the rest of the cells homogenized in 10 ml of ice-cold Hepes buffer (20 mm Hepes, 10 mm add pH 7.4 (NaOH))using a homogenizer (Ultra-Turrax for 30 seconds, and centrifuged for 15 min at 20000 rpm After this centrifugation, the residue membranes re-suspended in 10 ml ice-cold Hepes buffer (20 mm Hepes, 0.1 mm add pH 7.4 (NaOH)) and homogenized as described above. The procedure was repeated twice except that the last stage of homogenization determine the concentration of the protein and the membrane is diluted to a protein concentration of 2 mg/ml, aliquoting and stored at a temperature of -80°C until use.

To examine the presence and power of the inverse agonists/antagonists add agonist receptor H3 R-a-methyl histamine (RAMHA). Measure the ability of test compounds to counteract the action RAMHA. When studying the effect of agonist RAMHA not add to the environment for research. Test the generated compound is diluted with a buffer for research (20 mm Hepes, 120 mm NaCl, 10 mm MgCl2pH 7.4 (NaOH)) at various concentrations with subsequent addition of 10-8nm RAMHA (only for testing inverse agonist/antagonist), 3 μm GDP, 2.5 ág of membranes, 0.5 mg SPA beads and 0.1 nm [35S]GTPgS and incubated for 2 hours with mild shaking at room temperature. Tablets centrifuged at 1500 rpm for 10 min and the radioactivity was measured using top count. The results analyzed by nonlinear regression and determine the values of the IC50. RAMHA and other H3 agonists stimulate the binding of [35S]GTPgS with membranes expressing the H3 receptor. When testing antagonist/inverse agonist, the ability of the test compound in increased quantities to inhibit the increased binding of [35S]GTPgS caused 10-8M RAMHA, measured as reduction of the radioactive signal. The value of the IC50defined for the antagonist, represents the ability of the compounds to inhibit the action of 10-8M RAMHA 50%. When testing agonist ability high amounts of test compounds is measured as the increase of the radioactive signal. Is EU50defined for agonist, represents the ability of this compound to increase the signal to 50% of the maximum signal, which is obtained for the 10-5M RAMHA.

Predpochtitel is about, antagonists and agonists in accordance with this invention have the value of the IC50/EC50defined in one or more research, less than 10 microns, more preferably less than 1 μm, even more preferably less than 500 nm, more specifically, less than 100 nm.

The model rats in an open cage with feeding schedule

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

Male rats Sprague-Dawley (SD) aged from about 1½ to 2 months and weighing about 200-250 g buy Møllegård Breeding and Research Centre A/S (Denmark). When enrolling allow them to acclimate for several days before being placed in separate open plastic cells. They get used to the presence of food (chewing food for rats Altromin) in cells within only 7 hours in the morning from 07.30 to 14.30 every day of the week. Water give in unlimited quantity. As soon as the meal is stabilized after 7-9 days, the animals are ready for use.

Each animal is used only once to avoid the influence of the conditions of the previous experiment between cycles of treatment. During the sessions of the test, the test compound is administered intraperitoneally or orally 30 min prior to the session. One group of animals administered the test compound at various doses and control the Noah group of animals give media. Absorption of food and water control after 1, 2 and 3 hours after injection.

Any side effects are detected very quickly (skating, thickening wool etc), because animals are kept in transparent plastic cages, allowing continuous observation.

1. The compound of General formula (II)

where R2is hydrogen or C1-4-alkyl
(i) R1is
branched C4-6-alkyl, branched C4-6-alkenyl or branched
With4-6-quinil, provided that R1is not isobutyl,
With3-5-cycloalkyl,3-7-cycloalkenyl,3-6-cycloalkyl-C1-3-alkyl or C3-6-cycloalkenyl-C1-3-alkyl,
R1and R2together form3-6-Allenby bridge, and
A is
,or
or
(ii) R1is
the ethyl, n-propylene or isopropyl,
R1and R2together form3-6-Allenby bridge, and
And is
or
R3is hydrogen, halogen, hydroxy, trifluoromethyl, triptoreline, C1-10-alkyl, C2-10-alkenyl,3-8-cycloalkyl, C1-6-alkoxy, aryl, aryl-C1-6-alkyl, amino, C1-6-and what calamine, di-C1-6-alkylamino,3-8-cycloalkyl,3-8-cycloalkane, cyano, nitro, C1-6-alkylsulfonyl or C1-6-alkylsulfonyl,
Z and X are independently-N=, -C(H)=, -C(F)=, -C(Cl)=, -C(CN)= or-C(CF3)=,
W is-C(R10)=,
Y is-N= or - C(R11)=,
where at least one of X, Y and Z represents-N=,
R4, R5, R6, R7, R8, R9, R10, R11, R12and R13independently are
hydrogen, halogen, hydroxy, trifluoromethyl, triptoreline, -SCF3, amino, cyano, nitro or-C(=O)NR14R15,
With1-10-alkyl, C2-10-alkenyl,3-8-cycloalkyl, C1-6-alkoxy, C3-8-cycloalkyl-C1-6-alkoxy, C1-6-alkylamino, di-C1-6-alkylamino,3-8-cycloalkane,1-6-alkylsulfonyl, C1-6-alkylsulfonyl,2-10-alkanoyl,4-9-cycloalkenyl,3-8-heterocyclyl or C4-9-geteroseksualbnogo,4-9-heterocyclics, which may be optionally substituted by one or more substituents selected from R16,
the aryl, aryl-C1-6-alkyl, aryl-C1-6-alkoxy or heteroaryl, which may be optionally substituted by one or more substituents selected from R17,
Arola, heteroaryl, aryloxy, heteroaromatic, aryl is Ino or heteroarenes, which may be optionally substituted by one or more substituents selected from R18where R11is not arylamino,
or two of R5, R6, R7, R8, R9, R10, R11, R12and R13in adjacent positions together form1-6-Allenby bridge or-O-C1-6-alkylen-O-bridge,
R14and R15independently are hydrogen, C1-6-alkyl, aryl-C1-6-alkyl, or R14and R15may together form a3-6-Allenby bridge,
R16independently selected from aryl, heteroaryl,3-8-cycloalkyl, halogen, trifloromethyl, triptoreline, NR19R20and C1-6-alkoxy,
R17independently selected from halogen, hydroxy, trifloromethyl, triptoreline,1-6-alkoxy, C1-6-alkyl, amino, C1-6-alkylsulfonyl, C1-6-alkylamino, di-C1-6-alkylamino, cyano, aryl, heteroaryl and C3-8-cycloalkyl,
R18independently selected from halogen, C1-6-alkoxy and hydroxy,
R19and R20independently are hydrogen or C1-6-alkyl, R19and R20together can form With3-6-Allenby bridge,
provided that the connection should not be
,,
, ,
,,
,,
,,
,,
,,
,,
,
,,
,,
,,
,,
,,
,,
,or

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

2. The compound according to claim 1, in which R1is branched C4-6-alkyl, C3-5-cycloalkyl or3-6-cycloalkyl-C1-3-alkyl, provided that R1is not isobutyl.

3. The compound according to claim 2, in which R1is 1,1-(dimethyl)propylene, 1-ethylpropyl, cyclopropylmethyl, cyclopropyl the Ohm, cyclobutyl, cyclopentyl or 1-cyclopropyl-1-mutilation.

4. The compound according to claim 1, in which Z is-C(H)=, -N= or-C(F)=.

5. The compound according to claim 1, in which X is-C(H)=, -N= or-C(F)=.

6. The compound according to claim 1, in which W is-C(R10)=.

7. The compound according to claim 1, in which Y is-N=.

8. The compound according to claim 1, in which Y is-C(R11)=.

9. The compound according to claim 1, in which R2is hydrogen.

10. The compound according to claim 1, in which R2is1-4-alkyl.

11. The connection of claim 10, in which R2is stands or ethyl.

12. The compound according to claim 1 of General formula (III)

where a and R3such as defined in claim 1.

13. The compound according to claim 1, in which R3is hydrogen, halogen, hydroxy, trifluoromethyl, triptoreline,1-10-alkyl, C1-6-alkoxy, aryl, aryl-C1-6-alkyl, amino, C3-8-cycloalkyl,3-8-cycloalkane, cyano or nitro.

14. The connection 13, in which R3is hydrogen or stands.

15. The compound according to claim 1, in which R4, R5, R6, R7, R8and R9independently are
hydrogen, halogen, hydroxy, trifluoromethyl, triptoreline, -SCF3, amino or cyano,
With1-10-alkyl, C3-8-cycloalkyl,1-6-alkoxy, C3-8-cycloalkane,2-10-Alcano the scrap, With4-9-cycloalkenyl,3-8-heterocyclyl or C4-9-geteroseksualbnogo, which may be optionally substituted by one or more substituents selected from R16,
the aryl, aryl-C1-6-alkyl, aryl-C1-6-alkoxy or heteroaryl, which may be optionally substituted by one or more substituents selected from R17,
Arola, heteroaryl, aryloxy, heteroaromatic, which may be optionally substituted by one or more substituents selected from R18,
or two of R5, R6, R7, R8, R9in adjacent positions together form a C1-6-Allenby bridge or-O-C1-6-alkyl-O-bridge.

16. The connection indicated in paragraph 15, in which1-10-alkyl is stands, ethyl, propylene or isopropyl.

17. The connection indicated in paragraph 15, in which C1-6-alkoxy is methoxy, ethoxy or propoxy.

18. The connection indicated in paragraph 15, in which aryl is phenyl.

19. The connection indicated in paragraph 15, in which aroyl is-C(=O)-phenyl.

20. The connection indicated in paragraph 15, in which aryloxy is-O-phenyl.

21. The compound according to claim 1, in which R1is ethyl or isopropyl.

22. Connection item 21, in which R1and R2together form3-4-alkilinity the bridge.

23. The connection to item 21 or 22, in which R10, R11, R12and R13not avisio are - hydrogen, halogen, hydroxy, trifluoromethyl, triptoreline, cyano or-C(=O)NR14R15,
With1-10-alkyl, C3-8-cycloalkyl,1-6-alkoxy, C2-10-alkanoyl, C4-9-cycloalkenyl,3-8-heterocyclyl or4-9-geteroseksualbnogo, C4-9-heterocyclics, which may be optionally substituted by one or more substituents selected from R16,
the aryl, aryl-C1-6-alkyl, aryl-C1-6-alkoxy or heteroaryl, which may be optionally substituted by one or more substituents selected from R17,
Arola, optionally substituted by one or more substituents selected from R18,
or two of R10, R11, R12and R13in adjacent positions together form1-6-alkilinity the bridge.

24. Connection item 23, in which1-10-alkyl is stands, ethyl or propylene.

25. Connection item 23, in which4-9-heterocyclochain is piperidinylcarbonyl or pyrrolidineethanol.

26. Connection item 23, in which aryl is phenyl.

27. The compound according to claim 1, in which R14and R15independently are stands, ethyl or benzyl.

28. The compound according to claim 1, in which R16is halogen, trifluoromethyl, triptoreline and C1-6-alkoxy.

29. The compound according to claim 1 in which R 17is halogen, hydroxy, trifluoromethyl, C1-6-alkoxy, C1-6-alkyl, C1-6-alkylsulfonyl or cyano.

30. The compound according to claim 1, in which R18is C1-10-alkyl, halogen, trifluoromethyl, C1-4-alkoxy, cyano, amino and hydroxy.

31. The use of compounds according to any one of claims 1 to 30 as a component of the pharmaceutical composition.

32. Pharmaceutical composition having antagonist, inverse agonist or agonist action against the histamine receptor H3 containing as active ingredient at least one compound according to any one of claims 1 to 30, together with one or more pharmaceutically acceptable carriers or excipients.

33. The pharmaceutical composition according p in a standard dosage form containing from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg, particularly preferably from about 0.5 mg to about 200 mg of the compound according to any one of claims 1 to 30.

34. The use of compounds of General formula (II')

where R2is hydrogen or C1-4-alkyl,
R1is
C1-8-alkyl, C2-8-alkenyl or2-8-quinil, which may be optionally substituted by one or more halogen,
With3-5-cycloalkyl,3-7-cycloalkenyl,36 -cycloalkyl-C1-3-alkyl or C3-6-cycloalkenyl-C1-3-alkyl which may be optionally substituted by one or more halogen,
R1and R2together form3-6-Allenby bridge,
And is
,or
R3is hydrogen, halogen, hydroxy, trifluoromethyl, triptoreline,1-10-alkyl, C2-10-alkenyl,3-8-cycloalkyl, C1-6-alkoxy, aryl, aryl-C1-6-alkyl, amino, C1-6-alkylamino, di-C1-6-alkylamino,3-8-cycloalkyl,3-8-cycloalkane, cyano, nitro, C1-6-alkylsulfanyl or1-6-alkylsulfonyl,
Z and X are independently-N=, -C(H)=, -C(F)=, -C(Cl)=, -C(CN)= or-C(CF3)=,
W is-C(R10)=,
Y is-N= or-C(R11)=,
where at least one of X, Y and Z represents-N=,
R4, R5, R6, R7, R8, R9, R10, R11, R12and R13independently are
hydrogen, halogen, hydroxy, trifluoromethyl, triptoreline, -SCF3, amino, cyano, nitro or-C(=O)NR14R15,
C1-10-alkyl, C2-10-alkenyl,3-8-cycloalkyl, C1-6-alkoxy, C3-8-cycloalkyl-C1-6-alkoxy, C1-6-alkylamino, di-C1-6-alkylamino,3-8cycloalkane, With1-6-alkylsulfanyl,1-6-alkylsulfonyl,2-10-alkanoyl,4-9-cycloalkenyl,3-8-heterocyclyl or4-9-geteroseksualbnogo,4-9-heterocyclics, which may be optionally substituted by one or more substituents selected from R16,
the aryl, aryl-C1-6-alkyl, aryl-C1-6-alkoxy or heteroaryl, which may be optionally substituted by one or more substituents selected from R17,
Arola, heteroaryl, aryloxy, heteroaromatic, arylamino or heteroarenes, which may be optionally substituted by one or more substituents selected from R18where R11is not arylamino,
or two of R5, R6, R7, R8, R9, R10, R11, R12and R13in adjacent positions together form1-6-Allenby bridge or-O-C1-6-alkylen-O-bridge,
R14and R15independently are hydrogen, C1-6-alkyl, aryl-C1-6-alkyl, or R14and R15may together form a3-6-Allenby bridge,
R16independently selected from aryl, heteroaryl,3-8-cycloalkyl, halogen, trifloromethyl, triptoreline, NR19R20and C1-6-alkoxy,
R17independently selected from halogen, hydroxy, trifloromethyl, crypto is methoxy, C1-6-alkoxy, C1-6-alkyl, amino, C1-6-alkylsulfonyl, C1-6-alkylamino, di-C1-6-alkylamino, cyano, aryl, heteroaryl and C3-8-cycloalkyl,
R18independently selected from halogen, C1-6-alkoxy and hydroxy,
R19and R20independently are hydrogen or C1-6-alkyl, R19and R20together can form With3-6-Allenby bridge,
as well as its any diastereoisomer or enantiomer or tautomeric forms, including mixtures thereof, or pharmaceutically acceptable salts, pharmaceutical compositions for treating disorders and diseases associated with histamine receptor H3.

35. The application 34 to obtain a pharmaceutical composition for the treatment of diseases and disorders in which inhibition of the histamine receptor H3 has a beneficial effect.

36. The application 34 to obtain a pharmaceutical composition having an antagonistic activity against histamine receptor H3 or inverse agonistic activity against receptor histamine H3.

37. The application 34 to obtain a pharmaceutical composition for weight reduction.

38. The application 34 to obtain a pharmaceutical composition for the treatment of overweight or obesity.

39. The application 34 to receive pharmaceutical companies who stand to suppress appetite or to activate the reflex of saturation.

40. The application 34 to obtain a pharmaceutical composition for prevention and/or treatment of disorders and diseases related to overweight or obesity.

41. The application 34 to obtain a pharmaceutical composition for prevention and/or treatment of disorders of appetite, such as bulimia and excessive appetite.

42. The application 34 to obtain a pharmaceutical composition for the treatment of IGT.

43. The application 34 to obtain a pharmaceutical composition for the treatment of type 2 diabetes.

44. The application 34 to obtain a pharmaceutical composition for the delaying or prevention of the development from IGT to type 2 diabetes.

45. The application 34 to obtain a pharmaceutical composition for the delaying or prevention of the development from non-insulin dependent type 2 diabetes to insulin-dependent type 2 diabetes.

46. The application 34 to obtain a pharmaceutical composition for the treatment of diseases and disorders that stimulation of the histamine receptor H3 has a beneficial effect.

47. The application 34 to obtain a pharmaceutical composition having agonistic activity against receptor histamine H3.

48. A method of treating disorders or diseases using the compounds according to clause 34, which has antagonist, inverse agonist or agonist on the op perate in relation to the histamine receptor H3, where the method comprises the administration to a patient in need thereof, an effective amount of the compound according to clause 34 or the pharmaceutical composition according p or 33.

49. The method according to p, in which an effective amount of the compound is from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to about 1000 mg, especially preferably from about 0.5 mg to about 500 mg per day.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine derivatives with general formula (I), their tautomeric or stereoisomeric form, in free form, in form of pharmaceutically acceptable salt or C1-6alkyl ester which are effective antagonists of CRTH2 (G-protein-associated chemoattractant receptor, ex prone on Th2 cells) and can be used for preventing and treating diseases related to CRTH2 activity, particularly in treatment of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, diseases related to eosinophil. In formula (I) R1 is hydrogen, or in which n is an integer from 0 to 6; -Q1- is -NH-, -N(C1-6alkyl)- or -O; Y is hydrogen, C1-6alkyl, C3-6cycloalkyl, optionally substituted with C1-6alkyl, C3-6cycloalkyl, condensed with a benzene ring, phenyl, naphthyl or 5-6-member heteroaryl, possibly condensed with a benzene ring, and containing at least one heteroatom, chosen from a group consisting of oxygen and nitrogen, where the said phenyl, naphthyl or heteroaryl are optionally substituted on the displaceable position with one or several substitutes, chosen from a group consisting of cyano, halogen, nitro, guanidine, pyrroyl, sulfamoyl, phenyloxy, phenyl, di(C1-6)alkylamino, C1-6alkanoylamino, C1-6alkyl, optionally mono-, di- or tri-substituted with halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen and C1-6alkylthio, optionally mono-, di- or tri-substituted with halogen; or phenyl, condensed with 1,3-dioxolane; R2 is hydrogen or C1-6alkyl; R3 is a halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen, or , R3a and R3b are independently C3-8cycloalkyl or C1-6alkyl, this C1-6alkyl is optionally substituted with hydroxyl, carboxy, C3-6cycloalkylcarbamoyl, C5-6heterocyclocarbonyl containing a heteroatom in form of nitrogen, or C1-6alkoxy, q is an integer from 1 to 3; R3c is hydrogen, hydroxyl or carboxy; Xa is -O-; R4 is hydrogen, halogen, di(C1-6alkyl) amino or C1-6alkyl, optionally substituted C1-6alkoxy or mono- , di- or tri-substituted with halogen; R5 is hydrogen or C1-6alkyl; and R6 is carboxy, carboxamide, nitrile or tetrazolyl.

EFFECT: wider field of use of compounds.

32 cl, 9 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: in new compounds with general formula (I): , R1 stands for a naphthyl group, which can be substituted with a halogen atom, W represents a bond, a equals 0, 1 or 2, X1 represents C1-4alkylene, which can be substituted with a hydroxy group, Y1 represents -C(O)-,A represents a piperazine ring or piperidine ring, X2 represents a bond, Y2 represents -C(O)-, -S(O)2- or -C(=NR7)- (where R7 represents a hydrogen atom), X3 represents C1-4alkylene, which can be substituted with a hydroxyl group, oxo group or C1-6alkyl group; or C2-4alkylene, which can be substituted with a C1-6alkyl group, where two alkyl groups can be bonded to each other forming, together with carbon atoms to which they are bonded, an aryl ring when X3 represents C2-4alkylene, substituted with two alkyl groups, Z3 represents -N(R4)- or a bond (where R4 represents a hydrogen atom, C1-6alkyl group, which can be substituted with a hydroxy group or methoxy group, or acyl group), represents a single or double bond, where if represents a single bond, then Z1 represents -C(R2)(R2')-, -N(R2)- or -O- and Z2 represents C(R3)(R3')-, -N(R3)-, -O- or a bond (under the condition that, when Z2 represents -O-, then Z is different from -O-), and when represents a double bond, then Z1 represents -C(R3)= or a nitrogen atom and Z2 represents =C(R3)- or a nitrogen atom, each of R2, R2', R3 and R3' represents a hydrogen atom or C1-6alkylene. The invention also relates to salts of the given new compounds. The invention also relates to compounds, chosen from the group, to pharmaceutical compositions, to use of compounds in sub-paragraph 1 or 2, to prevention or treatment methods, as well as to the method of obtaining compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds, which inhibit activated factor X of blood clotting and have anticoagulation activity and antithrombotic activity.

33 cl, 46 ex, 1 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; medicine.

SUBSTANCE: in novel triazole derivatives of general formula I or their pharmaceutically acceptable salts R4 is hydrogen; X is selected from group, consisting of single bond, NH- and groups: , values of R1-R3 radicals are given in description, pharmaceutical composition containing them, and application of novel compounds for obtaining medication for treating hyperglycemia, insulin-resistance, type 2 diabetes, fat exchange derangements, obesity, atheroslerosis and metabolic syndrome.

EFFECT: medications possess higher efficiency.

26 cl, 8 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the group including hydronopol-substituted benzimidazolone- and quinazolinone-derivatives as agonists of human ORL1 receptors (nociceptors). In addition, the invention refers to making specified compounds, to pharmaceutical compositions containing pharmacologically active amount of at least one specified new benzimidazolone- and quinazolinone-derivatives as an active component, and to application of said pharmaceutical compositions in treatment of disorders involving ORL1 receptors. The invention concerns compounds of general formula where symbols take on values specified in the description.

EFFECT: higher effectiveness of the composition and therapy.

7 cl, 17 ex, tbl

FIELD: chemistry.

SUBSTANCE: invention can be applied in medicine and concerns inhibitors of MaR-kinase p38 of formula where W represents N or O, when Y represents C, and W represents C, when Y represents N; U represents CH or N; V represents C-E or N; X represents O, S, SO, SO2, NH, C=O,-C=NOR1 or CHOR1; B represents H or NH2; R1, E and A stands for H or various alkyl, heteroalkyl, aromatic and heteroaromatic substitutes.

EFFECT: production of new biologically active compounds.

48 cl, 138 ex, 54 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns novel bicyclic imidazol derivatives of the general formula I , where: W is CH or N; R is selected out of group including hydrogen, (C1-C10)alkyl, substituted (C1-C10)alkyl, (C3-C10)cycloalkyl and substituted (C3-C10)cycloalkyl; Z is selected out of group including a) -C(=O)OR7, where R7 is selected out of group including hydrogen and alkyl; b) -C(=O)NR8R9, where R8 and R9 are independently selected out of group including hydrogen, alkyl, aryl, substituted aryl, heterocyclic group, or alternatively R8 and R9 form heterocyclic group or substituted heterocyclic group, together with nitrogen atom linked to them; c) tetrazolyl; HET is condensed 6,6-bicycle maintained by condensed link of any two 6-member cycles selected out of aryl, cycloalkyl, cycloalkenyl, heterocyclic or heteroaryl cycles optionally substituted by (Y)q; on the condition that at least one 6-member cycle in bicycle is heterocyclic or heteroaryl; each Y is independently selected out of group including halogen, (C1-C10)alkyl, substituted (C1-C10)alkyl, (C3-C10)cycloalkyl, substituted (C3-C10)cycloalkyl, heterocyclic group, substituted heterocyclic group, aryl, substituted aryl, heteroaryl, substituted heteroaryl, -CO2R7, -NR14R15, -NHNR14R15, -C(=O)NR14R15, -OR14, -SR14; where R7 is as defined above, and each of R14 and R15 is independently selected out of group including hydrogen, (C1-C10)alkyl, substituted (C1-C10)alkyl, aryl, substituted aryl; n is integer equal to 0, 1 or 2; q is integer equal to 1, 2 or 3; where heterocyclic group relates to substituted or non-substituted group with 1 ring or several condensed rings including 1 to 10 carbon atoms and 1 to 2 heteroatoms selected out of group including nitrogen, sulfur and oxygen, inside the ring including optionally 1 to 2 exocarbonyl groups; and pharmaceutically accepted salts or tautomers. Additionally, invention concerns compounds of general formulae II-VIII

and pharmaceutical composition based on compounds of the general formulae I- VIII, XI and XII, and treatment method for mammal virus infection partially mediated by a virus of Flaviviridae virus family, using claimed pharmaceutical composition.

EFFECT: obtaining new compounds, with useful biological effect.

82 cl, 9 tbl, 261 ex

FIELD: chemistry.

SUBSTANCE: invention claims compounds of the formula (I) with radicals as described in the claim, and medicine with inhibition effect on glycine absorption, based on compound of the formula (I) .

EFFECT: medicine for diseases treatment where glycine absorption inhibition can be effective.

21 cl, 1 tbl, 173 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 relates to new compounds with general formula (I) or pharmaceutically acceptable salts thereof, where R1 is chosen from a group containing optionally substituted C1-C6alkyl, lower alkoxy group, (lower)alkoxy(lower)alkyl, cycloalkyoxy(lower)alkyl, lower thioalkyl, (lower)alkylthio(lower)alkyl, cycloalkyl, cycloalkyl(lower)alkyl; R2 is chosen from a group containing optionally substituted (lower)alkyl, cycloalkyl, cycloalkyl(lower)alkyl; R3 is chosen from a group containing halogen, cyano group, optionally substituted (lower alkyl, lower thioalkyl, aryl, aryl(lower)alkyl, lower alkenyl, lower alkynyl); R4 is chosen from a group containing hydrogen, halogen, cyano group, hydroxyl group, optionally substituted (lower alkyl, lower alkoxy group, aryl, pyridyl, aryl(lower)alkyl, heteroaryl, which is an aromatic mono- or bicyclic hydrocarbon, containing from 5 to 9 ring atoms, from which one or more is a heteroatom, chosen from O, N or S, and an amino group) and a group, with formula R8-Z-(CH2)n-; where Z is a single bond or chosen from a group consisting of O, NH, CH2, CO, SO, SO2 or S; where R8 is chosen from a group containing optionally substituted (aryl, pyridyl); and where n=0, 1 or 2; R5 represents hydrogen; R6 is chosen from a group containing halogen, optionally substituted lower alkoxy group; R7 is one or more substitutes, independently chosen from a group containing hydrogen, optionally substituted lower alkoxy group; where the optional substitute or substitutes when R1-R8 are independently chosen from a group containing halogen, hydroxyl group, lower alkyl, mono- or di(lower)alkylamino group, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono- or di(lower)alkylaminocarbonyl, amino group, carboxyl group, lower alkoxy group, C3-C12cycloalkyl, (lower)alkylcarbonyl, (lower)alkoxycarbonyl, nitrile, aryl; all of which, except halogen, are independently optionally substituted with one or more substitutes, chosen from a group containing halogen, hydroxyl group, lower alkyl, sulfinyl, sulfonyl, sulfanyl, amino group, carboxyl group, lower alkoxy group, carbamoyl. Invention also relates to formula (I'), to a pharmaceutical composition, as well as use of formula (I) compounds given in paragraph 1.

EFFECT: obtaining new biologically active compounds, for preventing or treating bone diseases, associated with very low or resorption of calcium.

6 cl, 151 ex

FIELD: chemistry.

SUBSTANCE: in new compounds with general formula (I): , R1 stands for a naphthyl group, which can be substituted with a halogen atom, W represents a bond, a equals 0, 1 or 2, X1 represents C1-4alkylene, which can be substituted with a hydroxy group, Y1 represents -C(O)-,A represents a piperazine ring or piperidine ring, X2 represents a bond, Y2 represents -C(O)-, -S(O)2- or -C(=NR7)- (where R7 represents a hydrogen atom), X3 represents C1-4alkylene, which can be substituted with a hydroxyl group, oxo group or C1-6alkyl group; or C2-4alkylene, which can be substituted with a C1-6alkyl group, where two alkyl groups can be bonded to each other forming, together with carbon atoms to which they are bonded, an aryl ring when X3 represents C2-4alkylene, substituted with two alkyl groups, Z3 represents -N(R4)- or a bond (where R4 represents a hydrogen atom, C1-6alkyl group, which can be substituted with a hydroxy group or methoxy group, or acyl group), represents a single or double bond, where if represents a single bond, then Z1 represents -C(R2)(R2')-, -N(R2)- or -O- and Z2 represents C(R3)(R3')-, -N(R3)-, -O- or a bond (under the condition that, when Z2 represents -O-, then Z is different from -O-), and when represents a double bond, then Z1 represents -C(R3)= or a nitrogen atom and Z2 represents =C(R3)- or a nitrogen atom, each of R2, R2', R3 and R3' represents a hydrogen atom or C1-6alkylene. The invention also relates to salts of the given new compounds. The invention also relates to compounds, chosen from the group, to pharmaceutical compositions, to use of compounds in sub-paragraph 1 or 2, to prevention or treatment methods, as well as to the method of obtaining compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds, which inhibit activated factor X of blood clotting and have anticoagulation activity and antithrombotic activity.

33 cl, 46 ex, 1 tbl

FIELD: chemistry; medicine.

SUBSTANCE: in novel triazole derivatives of general formula I or their pharmaceutically acceptable salts R4 is hydrogen; X is selected from group, consisting of single bond, NH- and groups: , values of R1-R3 radicals are given in description, pharmaceutical composition containing them, and application of novel compounds for obtaining medication for treating hyperglycemia, insulin-resistance, type 2 diabetes, fat exchange derangements, obesity, atheroslerosis and metabolic syndrome.

EFFECT: medications possess higher efficiency.

26 cl, 8 ex, 2 tbl

FIELD: chemistry; medicine.

SUBSTANCE: compounds of claimed invention possess properties of positive allosteric modulator mGluR5. In general formula I , W represents 6-member heterocycloalkyl ring with 1-2 heteroatoms, selected from N, O; R1 and R2 independently represent hydrogen, C1-C6-alkyl; P and Q each independently is selected from: , R3, R4, R5, R6 and R7 independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-member heteroaryl with 1-2 atoms N as heteroatoms; 6-member heterocycle with 2 heteroatoms representing N, O; phenyl, optionally substituted with halogen; naphtyl; -OR8; where optionally two substituents together with located between them atoms form 9-10-member bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S; R8 represents hydrogen, C1-C6-alkyl; D, E, F, G and H independently represent -C(R3)=, -O-, -N=, -N(R3)- or -S-; A represents ethinyl, -C(=O)NR8- or group of formula . B represents -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6-alkenyl-. Invention also relates to pharmaceutical composition based on invention compounds.

EFFECT: novel compounds possess useful biological proprties.

20 cl, 3 dwg, 75 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the group including hydronopol-substituted benzimidazolone- and quinazolinone-derivatives as agonists of human ORL1 receptors (nociceptors). In addition, the invention refers to making specified compounds, to pharmaceutical compositions containing pharmacologically active amount of at least one specified new benzimidazolone- and quinazolinone-derivatives as an active component, and to application of said pharmaceutical compositions in treatment of disorders involving ORL1 receptors. The invention concerns compounds of general formula where symbols take on values specified in the description.

EFFECT: higher effectiveness of the composition and therapy.

7 cl, 17 ex, tbl

FIELD: chemistry.

SUBSTANCE: invention concerns novel bicyclic imidazol derivatives of the general formula I , where: W is CH or N; R is selected out of group including hydrogen, (C1-C10)alkyl, substituted (C1-C10)alkyl, (C3-C10)cycloalkyl and substituted (C3-C10)cycloalkyl; Z is selected out of group including a) -C(=O)OR7, where R7 is selected out of group including hydrogen and alkyl; b) -C(=O)NR8R9, where R8 and R9 are independently selected out of group including hydrogen, alkyl, aryl, substituted aryl, heterocyclic group, or alternatively R8 and R9 form heterocyclic group or substituted heterocyclic group, together with nitrogen atom linked to them; c) tetrazolyl; HET is condensed 6,6-bicycle maintained by condensed link of any two 6-member cycles selected out of aryl, cycloalkyl, cycloalkenyl, heterocyclic or heteroaryl cycles optionally substituted by (Y)q; on the condition that at least one 6-member cycle in bicycle is heterocyclic or heteroaryl; each Y is independently selected out of group including halogen, (C1-C10)alkyl, substituted (C1-C10)alkyl, (C3-C10)cycloalkyl, substituted (C3-C10)cycloalkyl, heterocyclic group, substituted heterocyclic group, aryl, substituted aryl, heteroaryl, substituted heteroaryl, -CO2R7, -NR14R15, -NHNR14R15, -C(=O)NR14R15, -OR14, -SR14; where R7 is as defined above, and each of R14 and R15 is independently selected out of group including hydrogen, (C1-C10)alkyl, substituted (C1-C10)alkyl, aryl, substituted aryl; n is integer equal to 0, 1 or 2; q is integer equal to 1, 2 or 3; where heterocyclic group relates to substituted or non-substituted group with 1 ring or several condensed rings including 1 to 10 carbon atoms and 1 to 2 heteroatoms selected out of group including nitrogen, sulfur and oxygen, inside the ring including optionally 1 to 2 exocarbonyl groups; and pharmaceutically accepted salts or tautomers. Additionally, invention concerns compounds of general formulae II-VIII

and pharmaceutical composition based on compounds of the general formulae I- VIII, XI and XII, and treatment method for mammal virus infection partially mediated by a virus of Flaviviridae virus family, using claimed pharmaceutical composition.

EFFECT: obtaining new compounds, with useful biological effect.

82 cl, 9 tbl, 261 ex

FIELD: chemistry.

SUBSTANCE: invention concerns novel compounds of the formula (I): , where R1 is -COOH or -(CH2)n-R14; R2 is or , where X is -CH or -N; each of R3, R4, R5 and R6 is selected out of group including -H, -(lower) alkyl, -N(CH3)2, -O-(lower) alkene, -(lower) alcoxy, or where R5 and R6 are substitutes in adjoining carbon atoms in ring, R5 and R6 optionally form 5- or 6-member saturated carbocyclic ring together with adjoining carbon atoms, R14 is unsaturated 5-member substituted or non-substituted heterocyclic ring including 1 to 4 heteroatoms selected out of N, O and S, n is 0 or 1, or their pharmaceutically acceptable salts or complex ethers. Invention also concerns pharmaceutical composition.

EFFECT: obtaining new bioactive compounds and pharmaceutical composition based on them, with inhibition effect on glutamine fructose-6-phosphate amidotransferase (GFAT).

16 cl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention claims compounds of the formula (I) with radicals as described in the claim, and medicine with inhibition effect on glycine absorption, based on compound of the formula (I) .

EFFECT: medicine for diseases treatment where glycine absorption inhibition can be effective.

21 cl, 1 tbl, 173 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula (I), their obtaining and application as elastase inhibitors, and can be applied in medicine, where Y = CH; R№ represents H or alkyl; RІ represents phenyl or 5-6-memner heteroaryl, G1 represents phenyl; R5 represents H, halogen, alkyl, CN or fluorinated alkyl; n=1-3; R4 = H; L represents bond, O, NR29 or alkyl; or R4 and L are bound together in such way that group -NR4L- represents 5-7-member asacyclic ring; G2 represents phenyl, 5-6-member heteroaryl, cycloalkyl, C4-7-heterocycle, bicycle from two condensed, bound with direct bond or separated with O atom rings, selected from phenyl, 5-6-member heteroaryl, cycloalkyl or C4-7-heterocycle; or when L does not represent bond, G2 represents H; s = 0-2; R25 represents H, alkyl or cycloalkyl; R29 represents H or alkyl.

EFFECT: obtaining novel biologically active compounds.

10 cl, 95 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining mirtazapine enantiomer, containing less than 10% of other enantiomer, which includes reaction of closing cycle of compound of formula , where X represents leaving group, said stage includes processing with acid, by means of which mirtazapine with enantiomer excess is obtained by closing cycle R- or S-enantiomer of formula (II) compound by processing with polyphosporic acid in absence of solvent or combination of polyphosphoric acid and N-methylpyrrolidinol or DMF.

EFFECT: stereochemical purity of target product.

10 ex

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to compounds represented by the formula: wherein values of substitutes are given in the invention description. Also, invention relates to pharmaceutically acceptable salts of the compound that can be used in treatment and/or prophylaxis of cathepsin-dependent states or diseases of mammals. Proposed compound are useful in treatment of diseases wherein bone resorption inhibition is desired, such as osteoporosis, increased mineral density of bone and reducing risk of fractures. Proposed claimed compounds are designated for preparing a drug possessing the inhibitory activity with respect to cathepsin.

EFFECT: valuable medicinal and biochemical properties of compounds.

24 cl, 13 sch, 4 tbl, 15 ex

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