1h-indazoles, 1,2-benzisoxazoles and 1,2-benzisothiazoles, synthesis thereof and use

FIELD: chemistry.

SUBSTANCE: present invention relates to new compounds of formulae and , in which radicals and symbols assume values defined in the formula of invention, e.g. to 1H-indazoles, 1,2-benzisoxazoles and 1,2-benzisothiazoles. Said compounds are receptor ligands of the α-7 nAChR subtype. The invention also relates to a pharmaceutical composition containing the said compounds.

EFFECT: possibility of using the said compounds to make medicinal agents for treating diseases associated with impaired functioning of nicotinic acetylcholine receptors and their abnormal functioning, primarily in brain cells.

46 cl, 85 ex

 

In the present application claims the priority in respect of application serial No. 60/530891, filed December 22, 2003, and application serial No. 60/606897, filed September 3, 2004, which is fully included in the present description as a reference.

The scope of the invention

The present invention mainly relates to ligands of nicotinic acetylcholine receptors (nAChR), nAChR activation and treatment of diseases associated with failure of function of nicotinic acetylcholine receptors or their abnormal function primarily in brain tissue. The present invention relates to new compounds, such as indoles, 1H-indazols, 1,2-benzisoxazoles and 1,2-benzisothiazoles, which are ligands of the receptor subtype nAChR, to methods of producing such compounds, compositions comprising these compounds, and to methods of using these compositions.

The background to the present invention

Know 2 types of receptors of neurotransmitters, such as acetylcholine: muscarinic receptors and nicotinic receptors, depending on the selectivity of action of muscarine and nicotine, respectively. Muscarinic receptors are receptors coupled with G-protein. Nicotinic receptors are members of a family of ligand-activated ion channels. When their activation increases the ionic conductor is a need nicotinic ion channels.

Nicotinic protein-receptor α-7 forms homopentameric channel in vitro, which is characterized by high permeability for a number of cations (such as CA++). Every nicotinic receptor α-7 contains 4 transmembrane domain, namely M1, M2, M3 and M4. Suppose that the domain of the M2 lines the walls of the channel. Comparison of the amino acid sequence shows a high degree of conservatism nicotinic receptor α-7 in the process of evolution. Amino acid sequence of the M2 domain, which lines the channel, identical to fabrics from a variety of sources from chicken to man. Description receptor α-7 are given in the articles, for example, Revah and others, Nature, 353, 846-849 (1991); Gaizi and others, Nature, 359, 500-505 (1992); Fucile, etc., PNAS 97 (7), 3643-3648 (2000); Briggs and others, Eur. J. Pharmacol., 366 (2-3). 301-308 (1999) and Gopalakrishnan and others, Eur. J. Pharmacol., 290 (3), 237-246 (1995).

Nicotinic receptor channels α-7 is expressed in various brain regions and included in the most important biological processes in the Central nervous system (CNS), including learning and memory. Nicotinic receptors α-7 is localized in presinapticheskih and postsynaptic endings and presumably included in the process of modulating synaptic transmission. In this regard, in the present time are actual new compounds acting as ligands for receptors nAChR subtype α-7, designed the for the treatment of diseases, associated with damaged nicotinic acetylcholine receptors or their abnormal function.

The present invention relates to new compounds which are ligands for receptors nAChR subtype α-7, methods of producing such compounds, compositions comprising such compounds, and to methods of their use.

Detailed description of the present invention

The present invention includes compounds of formulas I, II or III:

where

And means-CH2or

,

In means

;

Y represents O or S;

X1-X4every means independently CH, CR1or N, and at least one of X1-X4means N

X5-X8every means independently CH, CR2or N, and at least one of X5-X8means N

X9-X12every means independently CH, CR3or N, and at least one of X9-X12means N

R1, R2and R3each independently means

N

C1-C6alkyl (for example, CH3), which is unsubstituted or substituted by one or more groups F, Cl, Br, I, CN, IT, alkoxy containing from 1 to 4 carbon atoms (e.g., co3), NR4 R5, SH, SR4, SOR4With3-C8cycloalkyl, SO2R4, SO2NR4R5, Ar, Het, or combinations of these groups,

With2-C6alkenyl, which is unsubstituted or substituted by one or more groups F, Cl, Br, I, CN, IT, alkoxy containing from 1 to 4 carbon atoms (e.g., co3), NR4R5, SH, SR4, SOR4With3-C8cycloalkyl, SO2R4, SO2NR4R5, Ar, Het, or combinations of these groups,

With2-C6quinil, which is unsubstituted or substituted by one or more groups F, Cl, Br, I, CN, IT, alkoxy containing from 1 to 4 carbon atoms (e.g., co3), NR4R5, SH, SR4, SOR4With3-C8cycloalkyl, SO2R4, SO2NR4R5, Ar, Het, or combinations of these groups,

With3-C8cycloalkyl, which is unsubstituted or substituted by one or more groups F, Cl, Br, I, CN, IT, alkoxy containing from 1 to 4 carbon atoms (e.g., co3), NR4R5, SH, SR4, SOR4, unsubstituted With3-C8cycloalkyl, SO2R4, SO2NR4R5, Ar, Het, or combinations of these groups,

halogen (such as F, Cl, Br, I),

CN, NO2, NR4R5, SH, SR4, SOR4, SO2R4, SO2NR4R5, NR4SO2R5, CONR4R5, COOR4, NR COR5, NR4CO2R5, NR4CONR4R5,

Ar,

Het or

R6O-;

R4and R5each independently denotes H, or

Ar, Ar-C1-C4alkyl, Het,1-C4alkyl (for example, CH3)3-C8cycloalkyl (for example, cyclopropyl), or With4-C8cycloalkenyl (for example, cyclopropylmethyl), each of which is unsubstituted or substituted by one or more groups F, Cl, Br, I, CN, IT, alkoxy containing from 1 to 4 carbon atoms (e.g., co3), monoalkylamines, dialkylamino (for example, diethylamino)3-C8cycloalkyl or a combination of these groups,

R6means

N

C1-C6alkyl (for example, CH3), which is unsubstituted or substituted by one or more groups F, Cl, Br, I, CN, IT, alkoxy containing from 1 to 4 carbon atoms (e.g., co3), NR4R5, SH, SR4, SOR4With3-C8cycloalkyl, SO2R4, SO2NR4R5, Ar, Het, or combinations of these groups,

With3-C6alkenyl, which is unsubstituted or substituted by one or more groups F, Cl, Br, I, CN, IT, alkoxy containing from 1 to 4 carbon atoms (e.g., co3), NR4R5, SH, SR4, SOR4With3-C8cycloalkyl, SO2R4, SO2NR4R5, Ar, Het, or combinations of these groups,

With3-the 6quinil, which is unsubstituted or substituted by one or more groups F, Cl, Br, I, CN, IT, alkoxy containing from 1 to 4 carbon atoms (e.g., co3), NR4R5, SH, SR4, SOR4With3-C8cycloalkyl, SO2R4, SO2NR4R5, Ar, Het, or combinations of these groups,

With3-C8cycloalkyl, which is unsubstituted or substituted by one or more groups F, Cl, Br, I, CN, IT, alkoxy containing from 1 to 4 carbon atoms (e.g., co3), NR4R5, SH, SR4, SOR4, unsubstituted With3-C8cycloalkyl, SO2R4, SO2NR4R5, Ar, Het, or combinations of these groups,

With4-C8cycloalkenyl, which is unsubstituted or substituted by one or more groups F, Cl, Br, I, CN, IT, alkoxy containing from 1 to 4 carbon atoms (e.g., co3), NR4R5, SH, SR4, SOR4, unsubstituted With3-C8cycloalkyl, SO2R4, SO2NR4R5, Ar, Het, or combinations of these groups,

Ar or

Het;

R7means N or

With1-C4alkyl (for example, CH3), which is unsubstituted or substituted by one or more groups F, Cl, Br, I, CN, IT, alkoxy containing from 1 to 4 carbon atoms (e.g., co3), NR4R5or a combination of these groups,

m is 1, 2 or 3;

Ar signifies aryl group, terzidou from 6 to 10 carbon atoms, which is unsubstituted or substituted by one or more groups: alkyl containing from 1 to 8 carbon atoms, alkoxy containing from 1 to 8 carbon atoms, halogen (F, Cl, Br or I, preferably F or Cl), dialkylamino, in which each alkyl fragment contains from 1 to 8 carbon atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl containing from 1 to 8 carbon atoms, halogenated alkoxy containing from 1 to 8 carbon atoms, hydroxyalkyl containing from 2 to 8 carbon atoms, hydroxyalkoxy containing from 2 to 8 carbon atoms, alkenylacyl containing from 3 to 8 carbon atoms, alkylthio containing from 1 to 8 carbon atoms, alkylsulfonyl containing from 1 to 8 carbon atoms, alkylsulfonyl containing 1 to 8 carbon atoms, monoalkylamines containing from 1 to 8 carbon atoms, cycloalkenyl in which cycloalkyl group contains from 3 to 7 carbon atoms and optionally is substituted, aryloxy, in which the aryl fragment contains from 6 to 10 carbon atoms (for example, phenyl, naphthyl, biphenyl) and optionally is substituted, aaltio, in which the aryl fragment contains from 6 to 10 carbon atoms (for example, phenyl, naphthyl, biphenyl) and is optionally is substituted, cycloalkane in which cycloalkyl group contains from 3 to 7 carbon atoms and optionally is Samusenko is, sulfo, sulfonylamino, acylamino (e.g., acetamido), acyloxy (for example, acetoxy), carboxy, alkoxycarbonyl, alkylaminocarbonyl or a combination of these groups, and

Het means a heterocyclic group, a fully saturated, partially saturated or fully unsaturated, containing from 5 to 10 atoms in the cycle, in which at least 1 atom in the structure of the cycle atom is N, O or S, which is unsubstituted or substituted by one or more halogen atoms (F, Cl, Br or I, preferably F or Cl), groups: aryl containing from 6 to 10 carbon atoms (for example, phenyl, naphthyl, biphenyl) and is optionally substituted, arylalkyl containing from 6 to 10 carbon atoms in the aryl portion and 1 to 4 carbon atoms in the alkyl fragment, a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated and contains from 5 to 10 atoms in the cycle, in which at least 1 atom in the structure of the cycle atom is N, O or S, alkyl containing from 1 to 8 carbon atoms, alkoxy containing from 1 to 8 carbon atoms, cyano, trifluoromethyl, nitro, oxo, amino, monoalkylamines containing from 1 to 8 carbon atoms, dialkylamino in which each alkyl group contains from 1 to 8 carbon atoms, alkoxycarbonyl, alkylaminocarbonyl or a combination of these groups, and

pharmaceutical is acceptable salts of these compounds.

In another embodiment of the present invention in formulas I, II and III, R4and R5each independently denotes H, Ar, Het or1-C4alkyl (for example, CH3), which is unsubstituted or substituted by one or more groups: F, Cl, Br, I, CN, IT, alkoxy containing from 1 to 4 carbon atoms (e.g., co3), monoalkylamines, dialkylamino (for example, diethylamino)3-C8cycloalkyl or combinations thereof, and R1, R2and R3not mean NR4CO2R5or NR4CONR4R5.

The term alkyl used in this context, means a straight or branched aliphatic hydrocarbon radical, preferably containing from 1 to 4 carbon atoms. Suitable alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl.

The term "alkoxy" refers to the group alkyl-O-, in which alkyl fragment preferably contains from 1 to 4 carbon atoms. Suitable alkoxygroup include methoxy, ethoxy, propoxy, isopropoxy, isobutoxy and second-butoxy.

The term "cycloalkyl" means a cyclic, bicyclic or tricyclic saturated hydrocarbon radical containing from 3 to 8 carbon atoms. Suitable cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Other suitable qi is alkylene groups include spiropent, bicyclo[2.1.0]pentyl and bicyclo[3.1.0]hexyl.

Cycloalkyl group substituted by the groups:1-C4alkyl, C1-C4alkoxy, hydroxyl, amino, monoalkylamines containing from 1 to 4 carbon atoms, and/or dialkylamino in which each alkyl group contains from 1 to 4 carbon atoms.

The term "cycloalkenyl" means cycloalkenyl radicals, in which the fragments cycloalkyl and alkyl described above. Suitable examples include cyclopropylmethyl and cyclopentylmethyl.

The term "aryl"as a group or substituent in General, or as part of a group or substituent means an aromatic carbocyclic radical containing from 6 to 10 carbon atoms, unless otherwise indicated. Suitable aryl groups include phenyl, naphthyl and biphenyl. Substituted aryl groups include the above-described aryl groups which are substituted by one or more halogen atoms, alkyl groups, hydroxy, alkoxy, nitro, methylenedioxy, Ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylsulfonyl, phenoxy, acyloxy (for example, acetoxy).

The term "arylalkyl" means killkenny fragment, in which the values of the fragments of aryl and alkyl are defined above. Suitable examples include benzyl, 1-dryer is Il, 2-phenethyl, inproper, terbutyl, penpencil and naphthylmethyl. Ar-alkyl means also killkenny fragment, in which the aryl fragment meets the definition of a group Ar. Suitable examples include benzyl and tormentil.

The term "heterocyclic group" means a saturated, partially saturated or fully unsaturated heterocyclic group containing 1, 2 or 3 of the cycle and from 5 to 10 carbon atoms in all cycles in which at least one of the atoms in the structure of cycles atom is N, O or S. Preferably, the heterocyclic group contains from 1 to 3 heteroatoms as part of the cycle which are selected from N, O and S. Suitable saturated and partially saturated heterocyclic groups include, without limitation, tetrahydrofuranyl, tetrahydrothieno, pyrrolidinyl, piperidinyl, piperazinil, morpholinyl, isoxazolines etc. Suitable heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, chinoline, ethenolysis, naphthyridine etc. are Other examples of suitable heterocyclic groups include 2-chinoline, 1,3-benzodioxol, 2-thienyl, 2-benzofuranyl, 2-benzothiophene, 3-thienyl, 2,3-dihydro-5-benzofuranyl, 4-indolyl, 4-pyridyl, 3-chinoline, 4-chinoline, 1,4-benzodioxan-6-yl, 3-indolyl, 2-pyrrolyl, 3,4-1,2-what benzopyran-6-yl, 5-indolyl, 1,5-benzoxazepin-8-yl, 3-pyridyl, 6-coumarinyl, 5-benzofuranyl, 2-isoimidazole-4-yl, 3-pyrazolyl and 3-carbazolyl.

Substituted heterocyclic group means a heterocyclic group described above substituted by one or more of the provisions of the groups, for example, halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino.

Fragments, substituted by one or more substituents, preferably contain from 1 to 3 substituents, especially 1 or 2 substituent, which is selected from the above examples of substituents. Halogenated fragments, such as halogenated alkyl groups, preferably mean fluorinated fragments and include perhalogenated fragments, such as trifluoromethyl.

In the compounds of the formula I R1preferably denotes H, OR6, NR4R5, NR4COR5, NR4CONR4R5, CF3, Br, thienyl, which is unsubstituted or substituted (for example, 2-thienyl, 3-thienyl and methylthieno, such as 2-(4-methyl)thienyl and 2-(5-methyl)thienyl), furyl which is unsubstituted or substituted (for example, 2-furyl, 3-furyl and methylphenyl, such as 2-(5-methyl)furyl)phenyl, which is unsubstituted or substituted (for example, forfinal, such as 3-forfinal and 4-forfinal), methoxyphenyl, such as 4-methoxyphenyl, thiazolyl, such as 2-thiazolyl, 2-(4-methyl)thiazolyl and 2-(5-what ITIL)thiazolyl, oxazolyl, such as 2-oxazolyl, and pyranyl, such as 4-tetrahydropyranyl and 3.6-dihydropyran-4-yl.

In compounds of formula II, R2preferably denotes H, OR6, CF3, Br, thienyl, which is unsubstituted or substituted (for example, 2-thienyl, 3-thienyl and methylthieno, such as 2-(4-methyl)thienyl and 2-(5-methyl)thienyl), furyl which is unsubstituted or substituted (for example, 2-furyl, 3-furyl and methylphenyl, such as 2-(5-methyl-furyl, or phenyl, which is unsubstituted or substituted (for example, forfinal, such as 3-forfinal and 4-forfinal, methoxyphenyl, such as a 4-methoxyphenyl).

In compounds of formula III, R3preferably means N, cyclopropyl or or6.

R4preferably means H or methyl, a, R5preferably denotes H, methyl, cyclopropyl, cyclopentyl, cyclopropylmethyl, propyl or Ar-methyl.

R6preferably means methyl, ethyl, CF3, CHF2cyclopentyl or cyclopropylmethyl.

R7preferably denotes H, methyl or ethyl.

In the compounds of formulas I, II and III And means preferably-CO-. In the compounds of formulas I, II and III preferably m is 1 or 2.

Ar preferably denotes unsubstituted or substituted phenyl (for example, forfinal, such as 3-forfinal and 4-forfinal, methoxyphenyl, such as 4-methoxyphenyl).

Het preferably denotes unsubstituted or samisen the th thienyl (for example, 2-thienyl, 3-thienyl, and methylthieno, such as 2-(4-methyl)thienyl and 2-(5-methyl)thienyl), or unsubstituted or substituted furyl (e.g. 2-furyl, 3-furyl, and methylphenyl, such as 2-(5-methyl)furyl).

In formula I, each X1-X4preferably means SN or CR1. In formula II each X4-X8preferably means SN or CR2. In formula III, each X9-X12preferably means SN or CR3.

According to one object of the present invention compounds of formulas I, II and III are selected from the following compounds:

hydrochloride 3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-indazole,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazole,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazol,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(triptoreline)-1H-indazole,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(trifluoromethyl)-1H-indazole,

hydrochloride, 5-bromo-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-indazole,

formate 5-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,

the hydrochloride of 6-bromo-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-indazole,

formate 6 ethoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazole,

formate 6-methoxy-3-{[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazole,

6-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazol,

formate 7-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazole,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(2-thienyl)-1H-indazole,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(4-methyl-2-thienyl)-1H-indazole,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-2-thienyl)-1H-indazole,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-phenyl-1H-indazole,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(2-thienyl)-1H-indazole,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(3-thienyl)-1H-indazole,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(4-methyl-2-thienyl)-1H-indazole,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-2-furyl)-1H-indazole,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-2-thienyl)-1H-indazole,

formate 5-(2-furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,

formate 5-(3-forfinal)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,

formate 5-(4-forfinal)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,

formate 5-(4-methoxyphenyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1 ]Hep C is-2-yl]carbonyl}-1H-indazole,

formate 6-(2-furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1 ]hept-2-yl]carbonyl}-1H-indazole,

formate 6-(3-furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,

3-{[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(3-thienyl)-1H-indazole,

formate 5-(3-furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,

5-bromo-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol and their pharmaceutically acceptable salts.

According to one aspect of the present invention compounds of formulas I, II and III are selected from the following compounds:

hydrochloride 3-(2,5-diazabicyclo[2.2.2]Oct-2-ylcarbonyl)-6-(1,3-thiazol-2-yl)-1H-indazole,

3-(2,5-diazabicyclo[2.2.2]Oct-2-ylcarbonyl)-6-(1,3-thiazol-2-yl)-1H-indazol,

3-[(1S,4S)-(2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-indazol,

hydrochloride 3-(2,5-diazabicyclo[2.2.2]Oct-2-ylcarbonyl)-1H-indazole,

3-(2,5-diazabicyclo[2.2.2]Oct-2-ylcarbonyl)-1H-indazol,

formate 3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazole,

3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol,

formate 3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-6-(1,3-thiazol-2-yl)-1H-indazole,

3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-6-(1,3-enous the l-2-yl)-1H-indazol,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(1,3-thiazol-2-yl)-1H-indazole,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(1,3-thiazol-2-yl)-1H-indazol,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(2-thienyl)-1H-indazol,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(3-thienyl)-1H-indazol,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(4-methyl-2-thienyl)-1H-indazol,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-2-thienyl)-1H-indazol,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(triptoreline)-1H-indazol,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-phenyl-1H-indazol,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(1,3-oxazol-2-yl)-1H-indazole,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(1,3-oxazol-2-yl)-1H-indazol,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(1,3-thiazol-2-yl)-1H-indazole,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(1,3-thiazol-2-yl)-1H-indazol,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(2-thienyl)-1H-indazol,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(3-thienyl)-1H-indazol,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(4-methyl-1,3-thiazol-2-yl)-1H-and is desola,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazol,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(4-methyl-2-thienyl)-1H-indazol,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-1,3-thiazol-2-yl)-1H-indazol,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-2-furyl)-1H-indazol,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-2-thienyl)-1H-indazol,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(tetrahydro-2H-Piran-4-yl)-1H-indazole,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(tetrahydro-2H-Piran-4-yl)-1H-indazol,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(triptoreline)-1H-indazole,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(triptoreline)-1H-indazol,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(trifluoromethyl)-1H-indazol,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-7-(triptoreline)-1H-indazole,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-7-(triptoreline)-1H-indazol,

5-(2-furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol,

5-(3-forfinal)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-ind is angry,

5-(3-furyl)-3-{[(1S,4S)-5-metal-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol,

5-(4-forfinal)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol,

5-(4-methoxyphenyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol,

formate 5-(cyclopentyloxy)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,

5-(cyclopentyloxy)-3-{[(1S,4S)-5-metal-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl)-1H-indazol,

formate 5-(cyclopropylmethoxy)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo [2.2.1]hept-2-yl]carbonyl}-1H-indazole,

5-(cyclopropylmethoxy)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol,

5-amino-3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol,

5-amino-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(1,3-thiazol-2-yl)-1H-indazol,

5-bromo-3-{[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol,

5-hydroxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol,

formate 5-methoxy-3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazole,

hydrochloride 3-(2,5-diazabicyclo[2.2.2]Oct-2-ylcarbonyl)-5-methoxy-1H-indazole,

3-(2,5-diazabicyclo[2.2.2]Oct-2-ylcarbonyl)-5-methoxy-1H-indazol,

formate 5-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,

5-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol,

6-(2-furyl)-3-{[(1S,4S)-5-METI is -2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol,

formate 6-(3,6-dihydro-2H-Piran-4-yl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,

6-(3,6-dihydro-2H-Piran-4-yl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol,

6-(3-furyl)-3-{((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol,

formate 6-(cyclopentyloxy)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,

6-(cyclopentyloxy)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol,

formate 6-cyclopropyl-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazole,

6-cyclopropyl-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazol,

6 ethoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazol,

hydrochloride 3-(2,5-diazabicyclo[2.2.2]Oct-2-ylcarbonyl)-6-methoxy-1H-indazole,

3-(2,5-diazabicyclo[2.2.2]Oct-2-ylcarbonyl)-6-methoxy-1H-indazol,

formate 6-methoxy-3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazole,

6-methoxy-3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol,

the hydrochloride of 6-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,

formate 6-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1 ]hept-2-yl]carbonyl}-1H-indazole,

6-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol,

7-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]Carbo is Il}-1,2-benzisothiazol,

formate N-(3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-yl)-N'-propylbetaine,

N-(3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-yl)-N'-propylbetaine,

formate N-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-yl}cyclopropanecarboxamide,

N-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-yl}cyclopropanecarboxamide,

formate N-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-yl}-N'-propylbetaine,

N-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-yl}-N'-propylbetaine,

and their pharmaceutically acceptable salts.

According to one object of the present invention compounds of formulas I, II and III are selected from the following compounds:

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisoxazole,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisoxazol,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(4-methyl-1,3-thiazol-2-yl)-1H-indazole,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(4-methyl-1,3-thiazol-2-yl)-1H-indazol,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazol,

formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(those who rehydro-2H-Piran-4-yl)-1H-indazole,

3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(tetrahydro-2H-Piran-4-yl)-1H-indazol,

formate 5-(3,6-dihydro-2H-Piran-4-yl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,

5-(3,6-dihydro-2H-Piran-4-yl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol,

formate 5-(deformedarse)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,

5-(deformedarse)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol,

formate 6-(deformedarse)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo [2.2.1]hept-2-yl]carbonyl}-1H-indazole,

6-(deformedarse)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol,

formate 7-fluoro-6-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,

7-fluoro-6-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol,

formate N-(3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-yl)cyclopropanecarboxamide,

N-(3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-yl)cyclopropanecarboxamide,

formate N-(4-terbisil)-N'-(3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-yl)urea,

N-(4-terbisil)-N'-(3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-yl)urea,

formate N-(4-terbisil)-N'-{3-[5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-yl}urea

N-(4-terbisil)-N'-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-yl}urea,

N-(cyclopropylmethyl)-3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-amine,

N-(cyclopropylmethyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-amine,

formate, N,N-dimethyl-3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-amine,

N,N-dimethyl-3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-amine,

formate, N,N-dimethyl-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-amine,

N,N-dimethyl-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-amine,

formate, N,N-dimethyl-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-6-amine,

N,N-dimethyl-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-6-amine,

formate N-cyclopentyl-N'-(3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-yl)urea,

N-cyclopentyl-N'-(3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-yl)urea,

formate N-cyclopentyl-N'-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-yl}urea

N-cyclopentyl-N'-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-yl}urea,

and their pharmaceutically acceptable salts.

Preferred sites include pharmaceutical compositions containing the compound p is the present invention and a pharmaceutically acceptable carrier and, optionally, another active agent as discussed below; a method of stimulating or activating inhibiting alpha-7-nicotinic receptor, which, for example, define a standard method of analysis described in this context by the method of in vitro or in vivo (animal, for example, on the model of the animal, or part of a mammal or human), the method of treatment of a neurological syndrome, e.g., loss of memory, especially long-term memory loss, interruption or reduction of cognitive abilities, memory loss, etc., methods of treatment of pathological conditions that are modulated by the activity of alpha-7 nicotinic receptor, mammal, for example, in humans, for example, as specified in this context.

Compounds of the present invention receive by standard methods. Some of the known methods that can be used are described below. All source materials are described compounds or receive them by standard methods from known starting materials.

Synthesis of the starting compounds is described in pending application No. 10/669645, filed September 25, 2003, the full contents of which are incorporated in this description by reference.

The acid used in the preparation bizcloud are commercial products, get them on m is codicum, described in the literature, or methods for their production are described below. For example, indazol-3-carboxylic acid is a commercial product. Brindazolamide acid is also obtained from the corresponding satinov using hydrolysis in alkaline conditions, the diazotization and recovery (H.R. Snyder and others, SOC., 74, 2009 (1952)). Benzisoxazol-3-carboxylic acid is obtained from 2,5-dibromantratsena when interacting with diethylmalonate, saponification and decarboxylation, followed by transesterification, interaction with solidities in alkaline conditions, hydrogenation and saponification (Angell R., Baldwin I.R., Bamborough, P., Deboeck N.M., Longstaff, T., Swanson S, WO 04010995 A1). 3-Benzisothiazolinone kiloto get from thiophenol when interacting with oxalylamino and aluminum chloride followed by treatment with hydroxylamine, hydrogen peroxide and sodium hydroxide. Bicillin used when getting bicycloamine are commercial drugs, get them according to the methods described in the literature, or methods for their production are described below. For example, hydrochloride, (1S,4S)-2-tert-butyloxycarbonyl-2,5-diazabicyclo[2.2.1]heptane is a commercial product. (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1 ]heptane get when restoring tert-BUTYLCARBAMATE in the presence of lithium aluminium hydride or by the sequence of reactions restore the positive amination, followed by removal of protective groups. 2,5-Diazabicyclo[2.2.2]octane gain, as described in articles (H. Newman, J. Heterocyclic. Chem., 11, 449 (1974); Sturm P.A., Henry D.W., J.Med.Chem., 17, 481 (1974)). 2-Methyl-2,5-diazabicyclo[2.2.2]octane is obtained from diethyl ether 2,5-diaminohexanoic acid cyclization of the intermediate N-benzylbromide, restore, tertiary amides, hydrogenation, selective introduction of protective groups, rehabilitation aminating and removal of protective groups.

Bicycleand get the condensation reaction of acids with bicicletinha and HBTU or HOBt in the presence of EDCI in DMF, or by conversion of the acid into the corresponding acid chlorides, and then by reaction with bicicletinha (Masog J.E., D. Gurley, Lanthom So, Loch J., Mack, R. A., Mullen G., Tran A., Wright N., Macor J.E., Bioorg. Med. Chem. Lett., 9, 319 (2001). Condensation in most cases carried out at room temperature for 4-8 hours Analogues thioamides derived from amides when interacting with reagent Lawesson (Wipf P., Kim Y., D.M. Goldstein, J.Am. Chem. Soc., 117, 11106 (1995)). Analogues of bicyclopentadiene get from bicycloamine standard recovery techniques, as described, for example, below. The resulting adducts isolated and purified by standard methods such as chromatography or recrystallization, well-known specialists in this field of technology.

Specialists in the art it is known that compounds of formulas I-III exist in different tautomeric and GE the metric isomers. All such compounds, including CIS-and TRANS-isomers, TRANS isomers, diastereomers mixtures, racemates, nerezisca mixture of enantiomers, almost pure enantiomers are included in the scope of the present invention. Almost pure enantiomers contain not more than 5 wt.% the corresponding opposite enantiomer, preferably not more than 2%, and most preferably not more than 1%.

Optical isomers are obtained when the separation of racemic mixtures by standard methods, for example, in the formation of diastereomeric salts with an optically active acid or base or in the formation of covalent diastereomers. Examples of appropriate acids include tartaric, diatsetilvinny, dibenzoyltartaric, ditawarkan and camphorsulfonic acid. A mixture of diastereoisomers separated into individual diastereomers on the basis of their physical and/or chemical differences by methods known to experts in the art, for example, using chromatography or fractional crystallization. Optically active base or acid is then isolated from the separated diastereomeric salts. Another method of separation of optical isomers involves the use of chiral chromatography (for example using chiral columns IHVR), using the methods of modification or the ez them, moreover, methods of modification are choosing to improve the efficiency of the separation of enantiomers. Suitable columns for chiral GHUR are issued by the firm Diacel, such as Chiracel OD and Chiracel OJ, etc. which are characterized by the standard selectivity. Also use enzymatic separation, after the standard modification or without it. Optically active compounds of formulas I-III is obtained using optically active starting materials for chiral synthesis reaction conditions which exclude racemization.

Specialists in the art it is also known that compounds can be used in different enriched isotopic forms, e.g., enriched in the content of the2H,3H,11C,13With and/or14C. In one preferred embodiment, the connection deuterium. Such deuterated forms get the techniques described in U.S. patent No. 5846514 and 6334997. As described in the aforementioned U.S. patents, the use of deuterated compounds leads to improved efficiency and increased duration of action of drugs.

Replaced by deuterium compounds synthesized using various methods described in the book Dean Dennis C., Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development (Curr., Pharm. Des., 6 (10) (2000)), 110, CAN 133:68895'AN 2000:473538 CAPLUS; Kabalka, George W., Varma ajender S., The synthesis of radiolabeled compounds via organometaleic intermediates. Tetrahedron, 45 (21), 6601-21 (1989) CODEN: TETRAB ISSN:0040-4020. CAN 112:20527 AN 1990:20527 CAPLUS, and Evans Anthony E., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 64 (1-2), 9-32 (1981), CODEN: JRACBN ISSN:0022-4081, CAN 95:76229 AN 1981:476229 CAPLUS.

The present invention relates also to the applicable forms of the compounds, as described in this context, such as pharmaceutically acceptable salts or prodrugs of all the compounds of the present invention, for which you can get salt or prodrug. Pharmaceutically acceptable salts include the salts, which is obtained by the interaction of the compounds in the form of a base with an inorganic or organic acid with the formation of salts, for example salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, Hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, almond acid and carboxylic acid. Pharmaceutically acceptable salts also include salts in which the compound is in the form of acid interacts with a matching basis with the formation of salts, for example, salts of sodium, potassium, calcium, magnesium, ammonium and choline. Specialists in the art it is known that the acid additive salts with which dinani of the present invention obtained when the interaction of the compounds with the appropriate inorganic or organic acid by any known method. In another embodiment, salts of alkaline and alkaline-earth metals are in the interaction of the compounds according to the present invention in respective bases by any known method.

Below are examples of the acid additive salts, which is obtained by reaction with inorganic or organic acids: acetates, adipate, alginates, citrates, aspartate, benzoate, bansilalpet, bisulfate, butyrate, camphorate, digluconate, cyclopentanepropionate, dodecylsulfate, econsultancy, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic, lactates, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalates, palmoate, pectinate, persulfates, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartratami, the thiocyanates, tozilaty, mesylates and undecanoate.

The salts are preferably farmatsevticheskii acceptable to the introduction of mammals. However pharmaceutically unacceptable salts of the compounds are suitable for use as intermediates, for example, to highlight the connection in the form of salts, and then to turn it back to the free base by treatment with an alkaline reagent. The free base is then optionally converted into farmaci is almost acceptable acid additive salt.

Compounds of the present invention is administered alone or as an active ingredient in the composition. Thus, the present invention also includes pharmaceutical compositions of compounds of formulas I-III, containing, for example, one or more pharmaceutically acceptable carriers.

Methods to obtain various compositions suitable for administration of the compounds of the present invention, described in several well-known works. Examples of possible compositions and methods described, for example, in the book Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (latest edition)); Pharmaceutical Dosage Forms: (Tablets (edited by Lieberman, Lachman and Schwartz), the latest edition Marcel Dekker, Inc., Remington''s Pharmaceutical Sciences (Ed. by Arthur Osol), 1553-1593 (latest edition).

With regard to stimulating activity against receptor α-7 and, preferably, a high degree of selectivity of the compounds of the present invention is administered to patients in need of stimulation of receptors α-7. The introduction is carried out in accordance with the condition of the patient, for example, nazalnam, parenterally (subcutaneously, intravenously, intramuscularly, nutrigrain or by injection) by way of inhalation, rectal way, vaginal, local or introduction into the eye.

For the introduction of compounds according to the present invention using various solid dosage forms for pearling the introduction, including such solid forms as tablets, gel capsules, capsules, pills, capsules, granules, pellets and powders. Compounds of the present invention is administered alone or in combination with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and excipients known in the art, including, without limitation, suspendresume agents, solubilizing agents, buffering agents, binders, dezintegriruetsja agents, preservatives, dyes, perfumes, oil, etc. the introduction of the compounds of the present invention with the use of capsules, tablets and gels with a slow release also characterized by a certain advantage,

For the introduction of compounds of the present invention use various liquid dosage forms for oral administration, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs. Such dosage forms contain also suitable inert diluents known in the art, such as water, and suitable excipients known in the art, such as preservatives, wetting agents, sweeteners, fragrances, as well as agents for emulsification and/or suspension of the compounds of the present invention. Soy is inane of the present invention is administered, for example, intravenously, in the form of an isotonic sterile solution. Also use other types of liquid dosage forms.

Suppositories for rectal administration of the compounds of the present invention are obtained when mixing the compound with suitable excipients, such as cocoa butter, musk and glycols. Compositions for vaginal introduction are pessaries, tampons, creams, gels, pastes, foams or sprays containing the active ingredient and suitable carriers known in the art.

Pharmaceutical compositions for topical use in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration through the skin, eyes, ears or throat. Local injection are also percutaneous method using percutaneous patches.

Get the aerosol composition suitable for administration by inhalation. For example, for the treatment of respiratory diseases compounds of the present invention is administered by inhalation in the form of powder (for example, fine powder or in the form of sputtered solutions or suspensions. Aerosol compositions produced in cylinders containing a mixture of compounds with suitable propellants under pressure.

The compound is administered in the form of individual is property of the active agent or in combination with other pharmaceutical agents, such as other agents used in the treatment of impaired cognitive and/or memory loss, e.g., other agonists α-7, PDE4 inhibitors, calcium channel blockers, modulators of muscarinic m1 and m2, modulators of adenosine receptors, modulators of ampakines NMDA-R modulators, mGluR, modulators of dopamine, serotonin modulators, cannabinoid modulators, and cholinesterase inhibitors (such as donepezil, rivastigmine and glentanner). In such combinations, each active ingredient is administered in accordance with its standard dose or a lower dose compared to the standard dose.

Compounds of the present invention used in combination with "positive modulators which increase the efficacy of nicotinic receptor agonists. Positive modulators described, for example, in applications WO 99/56745, WO 01/32619 and WO 01/32622. Such combination therapy used in the treatment of conditions/diseases associated with reduced transmission of nicotinic receptors.

Compounds of the present invention is also used in combination with compounds that bind to peptides β and thus inhibit the binding of peptides to receptors subtype α7nAChr (see, for example, application WO 99/62505).

The present invention also includes methods of treatment, including activation nick is tenovyh receptor α-7. Thus, the present invention includes methods for selective activation/stimulation of nicotinic receptors α-7 in animals, for example, in mammals, especially in humans, and such activation/stimulation has a therapeutic effect, for example, such activation leads to a weakening of the symptoms of conditions including neurological syndromes, such as loss of memory, especially long-term memory. Such methods include the introduction of an animal in need of such treatment, especially a mammal, preferably a human, an effective amount of compounds of formulas I-III, individually or as a component in the composition, as described in this context.

One object of the method according to the present invention features a method of treating a patient (e.g. a mammal such as a human)suffering from a pathological condition (e.g., memory impairment), and the method comprises the administration to a patient compounds of formulas I, II or III. Preferably, the pathological condition involves reducing the activity of nicotinic acetylcholine receptor.

Another object of the method according to the present invention proposes a method of treatment or prevention of a disease or condition resulting from dysfunction of nicotinic transmission AC is Tihomirova receptors in mammals, for example, in humans, and the method comprises the administration to the patient an effective amount of compounds of formulas I, II or III.

One object of the method according to the present invention proposes a method of treatment or prevention of a disease or condition arising out of breach or failure of the function of nicotinic acetylcholine receptors, preferably of α7nACh receptors in mammals, for example humans, and the method comprises the administration to the patient an effective amount of compounds of formulas I, II or III.

Another object of the method according to the present invention proposes a method of treatment or prevention of a disease or condition resulting from the suppression of the transmission function of nicotinic acetylcholine receptors in mammals, for example humans, and the method includes the introduction of a number of compounds of formulas I, II or III, sufficient for activation of α7nACh receptors.

One object of the method according to the present invention proposes a method of treatment or prophylaxis of psychotic disorders, disorders of cognitive abilities (e.g., memory impairment) or neurodegenerative diseases in mammals, for example humans, and the method includes introducing an effective amount of compounds of formulas I, II or III.

Another object of the method according to the present izopet is the proposed method of treatment or prevention of a disease or condition resulting from loss of cholinergic synapses in mammals, for example humans, and the method includes introducing an effective amount of compounds of formulas I, II or III.

One object of the method according to the present invention proposes a method of treatment or prevention of neurodegenerative disorders in the activation of α7nACh receptors in mammals, for example humans, and the method includes introducing an effective amount of compounds of formulas I, II or III.

Another object of the method according to the present invention proposes a method of protecting neurons in mammals, for example, a man from the neurotoxic effects caused by activation of α7nACh receptors, and the method includes introducing an effective amount of compounds of formulas I, II or III.

One object of the method according to the present invention proposes a method of treatment or prevention of neurodegenerative disorders by inhibiting the binding of peptides β with α7nACh receptors in mammals, for example humans, and the method includes introducing an effective amount of compounds of formulas I, II or III.

Another object of the method according to the present invention proposes a method of protecting neurons in mammals, for example, a man from the neurotoxic effect of peptides β, and the method includes introducing an effective amount with the organisations of formula I, II or III.

One object of the method according to the present invention offers a method of reducing inhibition of cholinergic function, caused by the action of peptides β, in mammals, for example humans, and the method includes introducing an effective amount of compounds of formulas I, II or III.

Compounds of the present invention are nicotinic ligands of type α-7, preferably agonists, first of all partial agonists of nicotinic acetylcholine receptor α-7. The methods for determining the activity of nicotinanilide described in the art (see, for example, article A.R. Davies and others, "Characterization of the binding of [3H]methyllycaconitine: a new radioligand for labelling alpha 7-type neuronal nicotinic acetylcholine receptors," Neuropharmacology, 38(5), 679-90 (1999)). Compounds as agonists of receptors nAChR α-7 is used for the prevention and treatment of diseases and conditions associated with the Central nervous system. Nicotinic acetylcholine receptory are receptor type ligand-gastrol member of ion channels, and consist of 5 protein subunits that form a Central inprovided cavity. Currently, there are 11 neuronal subunits of nAChR receptor (α2-α9 and β2-β4). There are also 5 other subunits, which are expressed in the peripheral nervous system (α1, β1, γ, δ, ε).

Subtypes of nAChR receptors can image is to homopolymer or heteropolymer. Currently, the greatest interest is homopentameric receptor α7 subtype, consisting of 5 subunits α7. Receptors α7nAChR are characterized by high affinity for nicotine (agonist) and α-bungarotoxin (antagonist). It is established that the α7nAChR agonists can be used in the treatment of psychotic diseases, neurodegenerative diseases and disorders of memory, etc. Despite the fact that nicotine is a known agonist, there is a need to develop other agonists of receptors α7nAChR, primarily selective agonists, which have lower toxicity or reduced side effects compared with nicotine.

Anabaseine, i.e. the 2-(3-pyridyl)-3,4,5,6-tetrahydropyridine, a natural toxin isolated from some marine worms (nemerteans) and ants (see, for example, in the article Who and others, Toxicon, 9:23 (1971). Anabaseine is a highly effective activator of nicotinic receptors in mammals, see Kem, Amer. Zoologist, 25, 99 (1985)). Some analogues of anabaseine, such as anabasine and DMAB (3-[4-(dimethylamino)benzylidene]-3,4,5,6-tetrahydro-2',3'-bipyridine), also known as agonists of nicotinic receptor (see U.S. patent No. 5602257 and application WO 92/15306). One analogue of anabaseine, (E-3-[2,4-dimethoxybenzamide]anabaseine, also known as GTS-21 and DMXB (see, for example, U.S. patent No. 5741802), is a selective actionem receptor agonist of α7-nAChR, the properties of which are described in detail. For example, it was found that abnormal sensory inhibition observed in sensory processing failure in patients with schizophrenia, and GTS-21 leads to increased sensory inhibition in the interaction with the receptor α7-nAChRs (see, for example, article Stevens and others, Psychopharmacology, 136, 320-27 (1998)).

Other known selective agonist of the receptor α7-nAChR is tropisetron, i.e. 1αH, 5α-tropan-3α-Jindal-3-carboxylate (see J..Macor and others, "The 5-NT3-Antagonist Tropisetron (ICS 205-930) is a Potent and Selective A7 Nicotinic Receptor Partial Agonist", Bioorg. Med. Chem. Lett., Point of 319-321, 2001).

It is shown that agents that bind to nicotinic acetylcholine receptors, which are suitable for the treatment and/or prevention of various diseases and conditions, especially mental disorders, neurodegenerative diseases caused by dysfunction of the cholinergic system, and conditions associated with impaired memory and/or cognitive abilities, including, for example, schizophrenia, anxiety, mania, depression, manic depression (examples of mental disorders), a disease Tourette's, Parkinson's disease, Huntington's disease (examples of neurodegenerative disorders), disorders of cognitive abilities (such as Alzheimer's disease, dementia with calves Levi, side amyotrophic sclerosis, memory impairment, loss of memory and, failure cognitive abilities, lack of attention, hyperactive state nedostatocnosti attention), and in the treatment of nicotine addiction, the effects of Smoking cessation, treating pain (such as painkillers), ensuring neurotoxity, in the treatment of fear of flying by plane, in the treatment of inflammation or sepsis (see, for example, an application for the grant of U.S. patent # WO 97/30998, WO 99/03850, WO 00/42044, WO 01/36417; articles Holladay and others, J.Med. Chem., 40 (26), 4169-94 (1997), Schmitt and others, Annual Reports Med. Chem., ch.5, 41-51 (2000), Stevens and others, Psychopharmatology, 136: 320-27 (1998) and Shytle and other, Molecular Psychiatry, 7, 525-535 (2002)).

Thus, the present invention proposes a method of treatment of a patient, especially a human, suffering from psychotic diseases, neurodegenerative diseases caused by dysfunction of the cholinergic system, and conditions associated with impaired memory and/or cognitive abilities, including, for example, schizophrenia, anxiety, mania, depression, manic depression (examples of mental disorder), Tourette syndrome, Parkinson's disease, Huntington's disease (examples of neurodegenerative diseases and/or disorders cognitive abilities (such as Alzheimer's disease, dementia with calves Levi, amyotrophic lateral sclerosis, memory impairment, memory loss, failure on Navalny ability, the lack of attention, hyperactivity condition insufficient attention), and the method comprises the administration to the patient an effective amount of compounds of formulas I-III.

Neurodegenerative diseases described in the methods of the present invention, include, without limitation, treatment and/or prevention of Alzheimer's disease Peak, dementia with diffuse calves Levi, progressive supranuclear paralysis syndrome (Steele-Richardson), Multisystem degeneration (syndrome Shay-Drager), diseases of the motor neurons, including amyotrophic lateral sclerosis, degenerative ataxia, cortical basal degeneration, complex disease amyotrophic lateral sclerosis - Parkinson's - dementia (complex of GUAM), subacute sclerotic panencephalitis, disease Gettington, Parkinson's disease, synucleinopathies, primary progressive aphasia, striatonigral degeneration, a disease Machado-Joseph/spinal-cerebellar ataxia type 3, levomethamphetamine degeneration, disease, Gilles de La Tourette, bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, spinal bulbar muscular atrophy (Kennedy disease), primary lateral sclerosis, familial spastic paraplegia, disease werdnig-Hoffman disease Kugelberg the a-Velander, disease Tay-Sachs disease Sandhoff, familial spastic disease, illness Wohlfahrt-Kugelberg-Welander, the spasmodic prepares, progressive multifocal leucoencephalopathy, prion diseases (such as diseases of Creutzfeldt-Jakob, Gerstmann-Straussler-Sheinker, disease, Kuru and fatal hereditary insomnia), and neurodegenerative diseases that occur due to ischemia or infarction of the brain, including embolic occlusion and thrombotic occlusion, as well as intracranial hemorrhage of all kinds (including, but not limited to, epidural, subdural, subarachnoid and intracerebral), and intracranial and vnutriploschadochnye damages (including, without limitation, listed, contusion, penetration, shear, compression and gap).

Agonists of receptor α-7nAChR, such as compounds of the present invention, also used in the treatment of age-related dementia and other dementias and conditions characterized by memory loss, including age-related weakening of memory, dementia, multi-infarct dementia, diffuse edema of the white matter disease Binswanger), dementia of endocrine or metabolic nature, dementia caused by head trauma and diffuse brain damage, dementia syndrome boxers and dementia with frontal lobe syndrome (see, for example, an application for the grant of the patent WO 99/62505). Thus, the present invention proposes a method of treatment of a patient, especially a human, suffering from age-related dementia or other dementias and conditions characterized by the weakening of memory, including the introduction to the patient an effective amount of compounds of formulas I-III.

Thus, in one embodiment, the present invention features a method of treating patients suffering from memory impairment due to, for example, mild disorders cognitive abilities associated with age, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, diseases of the Peak of the disease of Creutzfeldt-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, multi-infarct dementia and other neurological conditions, as well as HIV and cardiovascular diseases, and the method comprises the administration to the patient an effective amount of compounds of formulas I-III.

It is established that amyloid protein precursor (APP) and separated from him peptides β, for example, peptides Aβ1-40, Aβ1-42and other fragments included in pathological processes in Alzheimer's disease. Peptides β1-42not only is included in the process of neurotoxicity, but also inhibit cholinergic neurotransmitter function. It was found t is the train, the peptides β contact with the receptor of α-7nAChR. Thus, agents that block the binding of peptides β with the receptor α-7nAChR, can be used in the treatment of neurodegenerative diseases (see, for example, application WO 99/62505). In addition, stimulation of the receptor α-7nAChR protects neurons from cytotoxicity-related peptides β (see, for example, article Kihara T., and others, Ann. Neurol., 42, 159 (1997).

Thus, in one embodiment, the present invention proposes a method of treatment and/or prophylaxis of dementia in a patient suffering from Alzheimer's disease, comprising administration to the subject a therapeutically effective amount of compounds of formulas I-III for the inhibition of the binding of amyloid beta peptide (preferably. β1-42with nAChR receptors, preferably the receptor α-7nAChR, more preferably receptors α-7nAChR person (and also a method of treating and/or preventing other clinical manifestations of Alzheimer's disease that include, without limitation, failure of the cognitive and speech impairments, apraxia, depression, hallucinations and other neuropsychiatrically symptoms and signs, as well as violations of the propulsion motor and gait.

In the present invention it is also proposed a method for the treatment of other amyloidogenic diseases, for example, hereditary cerebral and is Hypatia, non-neuropathic hereditary amyloidosis, down's syndrome, macroglobulinemia, secondary familial Mediterranean fever syndrome Make wells, multiple myeloma, pancreatic and cardiac amyloidosis, chronic hemodialysis of enteropatii and amyloidosis of Finnish and job.

Nicotinic receptors are also included in the process, the response of the body to alcohol consumption. Thus, agonists of receptor α-7nAChR can be used in the treatment of syndromes that occur during withdrawal from alcohol, and in the treatment of poisoning. Thus, in one embodiment, the present invention proposes a method of treatment of a patient with the syndrome of abstinence from alcohol, or from poisoning, and the method comprises the administration to the patient an effective amount of compounds of formulas I-III.

Agonists of receptor subtype α-7nAChR can also be used to neurotoxity from damage caused by strokes and ischemia and glutamate-induced excitotoxicity. Thus, in one embodiment, the present invention proposes a method of treatment of a patient, providing neurotoxity from damage caused by strokes and ischemia and glutamate-induced excitotoxicity, including the introduction to the patient an effective amount of compounds of formulas I-III.

As indicated above, the agonists of the receptor subtype α-7nAChR can also be used in the treatment of nicotine addiction, including Smoking cessation, pain and the treatment of fear of flying, obesity, diabetes, inflammation and sepsis. Thus, in one embodiment, the present invention proposes a method of treatment of a patient suffering from nicotine addiction, including Smoking cessation, pain and treatment of fear of flying, obesity and/or diabetes, or a way of facilitating Smoking cessation in a patient comprising the administration to a patient an effective amount of compounds of formulas I-III.

In addition, labeled derivatives of the compounds of formulas I-III (e.g., With11or r F18labeled derivatives) due to their affinity for receptor α-7nAChR used to produce images (tomography) receptor, for example, in the brain tissue. Thus, the use of such labeled agents when receiving image receptors in vivo may, for example, using the method of positron missinou tomography (PET).

Memory impairment is manifested by reduced ability to absorb new information and/or the inability to recall previously stored information. Memory loss is the primary symptom of dementia, and can also be a symptom of Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, the Peak of Creutzfeldt-Jakob disease, HIV, cardiovascular disease, head injuries, and deterioration of cognitive ability is, associated with age.

Thus, in one embodiment, the present invention features a method of treating a patient suffering from, for example, from reduced cognitive abilities moderate (MCI), vascular dementia (VaD), deterioration of cognitive abilities associated with age (AACD), amnesia, caused by open heart surgery, cardiac arrest, and/or after General anesthesia, failure of memory, caused by the action of the injected anesthetics, deterioration of cognitive abilities caused by lack of sleep, chronic fatigue syndrome, narcolepsy, dementia caused by AIDS, deterioration of cognitive abilities caused by epilepsy, down syndrome, dementia caused by alcoholism, memory loss, caused by taking drugs/reagents, dementia Legionnaires ' disease (syndrome boxers) and dementia in animals (e.g. dogs, cats, horses and the like), and the method comprises the administration to the patient an effective amount of compounds of formulas I-III.

Doses of the compounds of the present invention depend on a number of factors, including specific syndrome being treated, the severity of the symptom, route of administration, frequency, dose, specific connection, efficacy, toxicity profile, pharmacokinetic profile and the presence of side is otricatelniy impacts, and other factors.

Compounds of the present invention is administered to mammals, especially humans, and the level of standard doses is known for agonists of nicotinic receptors α-7, such as the above known agonists of nicotinic receptors α-7. Compounds administered, for example, in the form of single or multiple doses by oral method in an amount of, for example, of 0.0001-10 mg/kg/day, for example, 0.01 to 10 mg/kg/day. Dosage form contains, for example, 1-200 mg of the active component. The compound is injected in the form of single or multiple doses.

It should be understood that the description of the methods of the present invention to refer to specific buffers, media, reagents, cells, culture conditions, etc. do not limit the scope of the present invention and this includes all related materials that are obvious to a person skilled in the art. For example, in most cases, a buffer solution can be replaced with a buffer solution, one cultural environment to another, and get similar results. Specialists in the art can, without conducting additional experiments to determine the need for such replacement to optimize methods and techniques of the present invention.

The following examples illustrate the present from retina and do not limit its scope. It should be understood that in the application described in the examples of methods possible changes and modifications of the various embodiments of the invention.

Full details of all applications for patent, patents and publications, cited above and below, are included in the description of the present invention as references.

Examples

All NMR spectra were measured at 300 MHz NMR instrument (Bruker Instruments, unless otherwise indicated. Constant interaction (J) the Hertz (Hz), and the magnitude of the chemical shift is specified with respect to the signal of TMS (80,00 frequent./million). Reactions under microwave irradiation were performed in a microwave reactor of Personal Chemistry Optimizer™ in containers with a volume of 2.5 ml or 5 ml microwave reactor Personal Chemistry. All reactions were carried out at 200°C for 600 s at a fixed on-time, unless otherwise noted. For chromatography used ion-exchange resin based on sulfonic acids (SCX) firm Varian Technologies. Analytical GHUR was carried out on columns of 4.6 mm × 100 mm Xterra RP18, 3.5 µm (eluent: gradient of 0.1% formic acid)/acetonitrile (with 0.1% formic acid) from 20:80 to 80:20 water for 6 min, unless specified otherwise.

Receiving acids

The following techniques (1-10) is described getting indazol, benzisoxazol and benzisothiazolinone acids, which are not commercial products.

Method 1

Paul is an increase in the 6-nitroindazole-3-carboxylic acid and its condensation with bicyclopentadiene education nitrosamine derivatives

In the vessel for a microwave reactor with a volume of 5 ml were loaded 3-iodine-6-nitroindazole (1 mmol), copper cyanide (I) (2 mmole) and N,N-dimethylformamide (3 ml), the vessel was sealed and irradiated in a microwave reactor at 185°C for 600 C. the Reaction mixture was distributed between ethyl acetate (100 ml) and water (100 ml), the mixture was filtered through celite. The organic layer was collected, washed with saline, dried (magnesium sulfate) and concentrated, with received 122 mg of a mixture of 3-cyano-6-nitroindazole and 6-nitroindazole (10:1) in a solid yellow color. The mixture of 3-cyano-6-nitroindazole and 6-nitroindazole (10:1) was dissolved in 10h. the sodium hydroxide and the resulting solution was bright orange color was heated at 100°C for 1 h

Then the mixture was cooled to room temperature and was carefully acidified 3h. hydrochloric acid to pH 1. A solid substance was separated and triturated in EtOAc, was obtained 51 mg 6-nitroindazole-3-carboxylic acid in the form of a solid brown color. The resulting acid are condensed with bicycloalkanes by the method of A.

6-Nitro-1H-indazol-3-carboxylic acid was obtained as described above.

Method 2

Nitration indazolinone acid and its condensation with bicyclopentadiene education nitrosamine derivatives

Ethyl ether indazol-3-carboxylic acid (73.7 mmole) is astoral in 20 ml conc. sulfuric acid and the resulting reaction mixture was cooled to 0°C., then for 1 h was added dropwise a mixture of conc. sulfuric acid (12 ml) and 70% nitric acid (12 ml). The resulting mixture was stirred at 0°C for 1 h and was poured into crushed ice (200 g). A solid substance was separated by filtration under vacuum, washed with several portions of water and dried in vacuum. The dried solid is suspended in 250 ml of acetonitrile and the resulting mixture was boiled under reflux for 2 hours Then the mixture was cooled to room temperature, the solid was separated and dried in vacuum, to receive ethyl ester 5-nitroindazole-3-carboxylic acid (53%) as a colourless solid. Acid, obtained under the conditions of alkaline hydrolysis, are condensed with bicycloalkanes according to method A. (Org. Synthesis, Coll. vol. 1, str.)

5-Nitro-1H-indazol-3-carboxylic acid was obtained as described above.

Method 3

Interaction indissolubility with ketones and condensation with bicyclopentadiene with the formation of heterocyclic derivatives

Tert-butyl ester 6-brominated-3-carboxylic acid obtained from the acid in the interaction with 2-fold excess of di-tert-BUTYLCARBAMATE followed by treatment with sodium hydroxide. To a suspension of sodium hydride (60% dispersion in mineral oil, 4.8 mmole) and then it is carbonated is returne (40 ml) at 0°C was slowly added a solution of tert-butyl methyl ether 6-brominated-3-carboxylic acid (4.0 mmole) in tetrahydrofuran (4 ml). After stirring at 0°C for 0.5 h the mixture was cooled to -78°C was added a 1.7m solution of tert-utility in pentane (5.1 mmole). The resulting mixture was stirred at -78°C for 0.5 h, then was added dropwise a solution of tetrahydropyran-4-it (5 mmol) in tetrahydrofuran (1 ml). The mixture was stirred at -78°C for 1 h and warmed up to 0°C. the Reaction was stopped by adding a saturated aqueous solution of ammonium chloride and the mixture was distributed between ethyl acetate (100 ml) and water (100 ml). The organic layer was separated, washed with brine (50 ml), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (eluent: ethyl acetate/hexane, 70:30), it was obtained tert-butyl ester 6-(4-hydroxyethylamino-4-yl)-1H-indazol-3-carboxylic acid (68%) as a colourless solid.

Tert-butyl ester 6-(4-hydroxyethylamino-4-yl)-1H-indazol-3-carboxylic acid (0,86 mmole) was dissolved in triperoxonane acid (3 ml) and the mixture was stirred at room temperature for 16 hours the Solvent was evaporated in vacuo and the residue triturated in ethyl acetate, was thus obtained 6-(3,6-dihydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid (76%). Acid are condensed with bicycloalkanes by the method of A.

Tert-butyl ester 6-(4-hydroxyethylamino-4-yl)-1H-indazol-3-carboxylic acid (1.0 mmole) was dissolved in trivero ssnoi acid (5 ml), triethylsilane (2 ml) and dichloromethane (3 ml), the mixture was boiled under reflux for 16 hours the Solvent was evaporated in vacuo and the residue triturated in ethyl acetate, was thus obtained 6-(tetrahydropyran-4-yl)-1H-indazol-3-carboxylic acid (60%) as a solid yellow-brown color. Acid are condensed with bicycloalkanes by the method of A.

The following acids were obtained by the described method is:

6-(3,6-dihydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid,

6-(tetrahydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid.

Method 4

The transformation of substituted satinov in the appropriate indazol-3-carboxylic acid

The transformation of substituted satinov in the appropriate indazol-3-carboxylic acid was carried out similarly to that described for indazol-3-carboxylic acid, H.R. Snyder and others, J. Am. Chem. Soc. 74, 2009 (1952). Substituted isatin (22,1 mmole) was diluted 1H. sodium hydroxide (24 ml) and heated at 50°C for 30 minutes the resulting solution was dark red was heated to CT and kept for 1 h the Reaction mixture was cooled to 0°C and at the specified temperature was treated with a solution of sodium nitrite (22,0 mmole) in water (5.5 ml). The resulting solution at 0°C was added in intensively mixed solution of sulfuric acid (2.3 ml) in water (45 ml) using a pipette immersed below the level of the sulfuric acid is you. The addition was carried out for 15 min, then the reaction mixture was stirred for another 30 minutes In the reaction mixture for 10 min was added to a chilled (0°C.) solution of chloride dihydrate tin (II) (52,7 mmole) in conc. hydrochloric acid (20 ml) and the mixture was stirred for 60 minutes resulting solid precipitate was separated by filtration, washed with water and dried, when it received the product in quantitative yield. The resulting material had sufficient purity (according to1H NMR and MS-LC) and was used in the next stage without additional purification. In another embodiment, the acid is recrystallized from acetic acid, to receive the purified material.

The following acids were obtained by the described method is:

5-brominated-3-carboxylic acid,

6-brominated-3-carboxylic acid,

5-cryptomaterial-3-carboxylic acid,

6-cryptomaterial-3-carboxylic acid,

5-methoxyindol-3-carboxylic acid.

Method 5

Getting substituted benzisothiazole-3-carboxylic acids from the corresponding thiophenols

To a solution of 3-methoxythiophene (3.75 g, to 26.7 mmole) in ether (20 ml) was added dropwise oxalicacid (3,7 ml, 43 mmole). The mixture was boiled under reflux for 1.5 h, cooled to CT and concentrated in vacuum. The resulting yellow oil was dissolved in dichloro ethane (50 ml), was cooled to 0°C and the portions was added aluminium chloride (4,30 g, 32.0 mmole). The resulting mixture was boiled under reflux for 30 min, cooled to CT and with stirring, poured into ice. The organic layer was separated and sequentially washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified by chromatography (eluent: ethyl acetate/hexane, 4:1), was obtained 6-methoxy-1-benzothiophen-2,3-dione (2,46 g, 47%) as a solid orange color.

In the mixture of the dione (86 mg, of 0.44 mmole) in 30% aqueous ammonium hydroxide solution (2.0 ml) was added 35% aqueous hydrogen peroxide solution (0.2 ml) and the reaction mixture was stirred for 12 hours resulting solid precipitate pink color was separated by filtration, washed with water and dried in a high vacuum, to receive 6-methoxybenzothiazole-3-carboxamide (39 mg, 42%).

In the solution of amide (1,14 g, 5,46 mmole) in methanol (100 ml) was added 10h. sodium hydroxide (12 ml). The mixture was boiled under reflux for 12 h, cooled to CT and acidified by slow addition of conc. hydrochloric acid to pH<2. The organic layer was extracted with dichloromethane (2x) and dried over sodium sulfate. The crude product was purified by chromatography (eluent: dihormati the/methanol/formic acid, 300:50:1), was obtained 6-methoxybenzothiazole-3-carboxylic acid (1,02 g, 89%) as a solid pink color.

The following acids were obtained by the described method is:

benzo[d]isothiazol-3-carboxylic acid,

6 bromobenzo[d]isothiazol-3-carboxylic acid,

5-bromobenzo[d]isothiazol-3-carboxylic acid,

5-methoxybenzo[d]isothiazol-3-carboxylic acid,

6 methoxybenzo[d]isothiazol-3-carboxylic acid,

7 methoxybenzo[d]isothiazol-3-carboxylic acid,

6 ethoxybenzo[d]isothiazol-3-carboxylic acid,

Methodology 6

Condensation of brominated ethers benzothiazole-3-carboxylic acid and armored esters of indazole-3-carboxylic acid in the presence of Grignard reagent with the formation of alkyl - and substituted heterocyclic acids.

Bromide solution cyclopropylamine (25,0 mmole, 3.7 equiv., 0,5M) in tetrahydrofuran (THF) was diluted with tetrahydrofuran (60 ml) and treated at RT with a solution of zinc chloride (25,0 mmole, 3.7 equiv., 0,5M) in tetrahydrofuran. After 10 min, the resulting suspension was added ethyl ether octabromodiphenyl benzisothiazol-3-carboxylic acid (0.30 mmole) and chloride bis(triphenylphosphine)palladium (II) (0.95 mmole, 0.1 EQ.). The reaction mixture was stirred at ambient temperature for 1 h and then at 65°C for 1 h the Reaction was stopped by adding saturated ammonium chloride and enjoyment of the operating mixture was extracted with dichloromethane (3×). The extracts were dried over sodium sulfate and concentrated to dryness. The residue was purified by chromatography (eluent: gradient dichloromethane/methanol, 100:0 to 90:10), to receive cyclopropylmethyl amide. Amide was dissolved in methanol/tetrahydrofuran/water (90:10:20 ml) and treated with sodium hydroxide (5.8 g). The resulting mixture was boiled under reflux for 12 h, cooled to CT, filtered and acidified by slowly adding conc. hydrochloric acid, to pH<2. The aqueous layer was extracted with ethyl acetate (2×) and dried over sodium sulfate. The extracts were concentrated, was awarded acid (yield 38%). Acid are condensed with bicycloalkanes by the method of A.

The described method with minor modifications was used to obtain the brominated derivatives indazol-3-piperazinecarboxamide in the presence of various Grignard reagents. The Grignard reagent containing a thiazole, a commercial drug. In another embodiment, ability and the corresponding derived arylzinc was obtained according to the method described in the article Reeder M.R. and others, Org. Proc. Res. Devel. 7, 696, (2003). Derived zinc and oxazole, 4-methylthiazole and 5-methylthiazole received by the given method. The following acids were obtained by the described method is:

6 cyclopropylbenzene[d]isothiazol-3-carboxylic acid,

6-(1,3-thiazol-2-yl)-1H-indazol-3-carboxylic who Isleta,

5-(1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

5-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

5-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

6-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

6-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

6-(1,3-oxazol-2-yl)-1H-indazol-3-carboxylic acid.

Methodology 7

Getting 7-fluoro-6-methoxy-1H-indazol-3-carboxylic acid

In the solution of the ethyl ester of 6-methoxy-1H-indazol-3-carboxylic acid (500 mg, of 2.27 mmole) in acetonitrile (15.0 ml) was added bis(tetrafluoroborate) 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]austan (1,00 g, 2,82 mmole) and the reaction mixture was stirred at RT for 18 h Then the reaction mixture was distributed between water (50 ml) and ethyl acetate (50 ml), the organic layer was separated and washed with brine (25 ml), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (eluent: gradient of hexane/ethyl acetate, 95:5 to 80:20), when it received a fluorinated ether (541 mg, 23%). A solution of ester (124 mg, 0,520 mmole) in ethanol (5,00 ml) was diluted 5,0M with sodium hydroxide solution (2.00 ml) and the mixture was stirred at RT for 18 hours the mixture was acidified using 6N. hydrochloric acid and was distributed between water (50 ml) and ethyl acetate (50 ml). The layers were separated and the organic layer washed with brine (25 ml), dried (su is that magnesium) and concentrated in vacuum, when this was received acid (109 mg, 84%). Acid are condensed with bicycloalkanes by the method of A.

7-Fluoro-6-methoxy-1H-indazol-3-carboxylic acid was obtained by the described method.

Technique 8

Getting benzisoxazol-3-carboxylic acid from 2.5-dibromantratsena

To a suspension of sodium hydride (3,16 g, 132 mmole) in dimethyl sulfoxide (60 ml) for 30 min was added diethyl ester of malonic acid (12,6 g, 79 mmol). The temperature of the reaction mixture rises to 60°C and forms a clear solution, then added 1,4-dibromo-2-nitrobenzene (10 g, 36,0 mmole) and the resulting solution was kept at 100°C for 2 h Then the reaction mixture was cooled to CT and poured into ice (300-400 g). Resulting solid precipitate was separated by filtration and dried, to receive the product (11,0 g, 89%).

Ether (11,0 g, 32.0 mmole) was diluted 2n. a solution of sodium hydroxide (32 ml, 63 mmole) and the reaction mixture was stirred at room temperature for 16 hours the Aqueous layer was extracted with dichloromethane (20 ml) and acidified. Resulting solid precipitate was separated by filtration and dried, to receive acid (7,00 g, 89%).

In acid solution (7,00 g of 27.0 mmole) in ethanol (60 ml) was added sulfuric acid (1 ml). The reaction mixture is boiled under reflux and maintained for 2 h and then concentrated under reduced pressure. The remainder of the distribution is whether between ethyl acetate (250 ml) and saturated sodium carbonate (50 ml), the organic layer was washed with saturated sodium carbonate (50 ml) and brine (50 ml), the organic layer was dried (sodium sulfate) and concentrated, thus obtained ester (8.00 g, 98%) as a liquid.

The sodium ethylate received by interactions in the atmosphere N2with sodium (33,5 g of 1.46 mol) in ethanol.

In a solution of ether (420 g of 1.46 mol) in ethanol (3 l), placed in a three-neck round bottom flask with a volume of 10 l was added soliditet (225 ml) and the resulting mixture was heated to 60°C. To the mixture was added dropwise a solution of ethoxide sodium obtained from metallic sodium (33,5 g of 1.46 mmole) in ethanol (1 l)and the reaction mixture was stirred for 2 h, cooled to CT and neutralized 2n. hydrochloric acid. The reaction mixture was extracted with ethyl acetate (4×2 l) and the combined organic layers were washed with water (2×1 l), brine (2×1 l) and dried (sodium sulfate). The residue was purified by chromatography (eluent: gradient of hexane/ethyl acetate, from 1:1 to 0:1), to receive the product (110 g, 28%).

To a solution of 6-BROKBUSINESS-3-carboxylic acid (20 g, of 0.081 mol) in ethanol (300 ml) at 0°C under nitrogen atmosphere was added 10% palladium on coal (1.5 g) and triethylamine (7.5 g, 82,4 mmole). The nitrogen atmosphere was removed in vacuum and replaced with an atmosphere of hydrogen, the reaction mixture was stirred for 1 h, the hydrogen Gas was removed in vacuum and replacing the and nitrogen, while palladium was separated by filtration through celite. The filter cake was washed with ethanol (3×50 ml) and the filtrate was concentrated. The residue was dissolved in dichloromethane (200 ml) and the solution was washed with water (4×50 ml), dried (sodium sulfate) and was evaporated, the thus obtained product in the form of a solid yellow (13,0 g, 96%). Ether omilami in the presence of sodium hydroxide, to receive acid. Acid are condensed with bicycloalkanes according to method A. (Angell R., Baldwin I.R., Bamborough, P., Deboeck N.M., Longstaff, T., Swanson, S., WO 04010995 A1.)

1,2-Benzisoxazol-3-carboxylic acid was obtained by the described method.

Methodology 9

Getting 5-deformational-3-acid from 3-bromo-4-NITROPHENOL

To a suspension of sodium hydroxide (29,0 mmole) in N,N-dimethylformamide (15 ml) was added 3-bromo-4-NITROPHENOL (10.0 mmole) and the suspension was kept at RT for 15 min, the Reaction mixture was cooled to 0°C. and treated with ethyl ether Hortiflorexpo acid (20,0 mmole), then was heated at 70°C for 16 h and concentrated. The residue was diluted with ice water (200 ml) and was extracted with ethyl acetate (3×100 ml), the combined organic layers were dried (magnesium sulfate) and concentrated, to receive deformational ether (yield 75%) as a yellow oil.

To a suspension of sodium hydride (328 mmol) in dimethyl sulfoxide (40 ml) at 0°C was added dropwise diethyl the FYR of malonic acid (328 mmol). The reaction mixture was heated to 60°C. and maintained for 0.5 h Then the mixture was added dropwise a solution of deformational ether (149 mmol) in dimethyl sulfoxide (80 ml) and the reaction mixture was heated at 100°C for 5 hours, the Cooled solution was poured into ice water and the aqueous layer was extracted with dichloromethane (3×100 ml). The combined organic layers were dried (magnesium sulfate) and concentrated, to receive untreated fluids (exit 112%) as oil. Fluids (167 mmol), sodium hydroxide (500 mmol) and water (335 ml) were mixed and heated at 60°C for 1 h Then the reaction mixture was cooled to CT and the aqueous layer washed with dichloromethane (3×100 ml). The aqueous layer was carefully acidified using conc. hydrochloric acid to pH 1 and the reaction mixture was heated at 60°C for 1 h, the resulting suspension was cooled to 5°C., and the resulting solid precipitate was separated by filtration and dried, to receive acid (yield 61%).

In ethanol (300 ml) at 0°C was added dropwise acetylchloride (203 mmole). After 0.5 h was added the acid (101 mmol) and the reaction mixture is boiled under reflux for 15 hours and Then the reaction mixture was concentrated and the residue was distributed between dichloromethane (200 ml) and saturated sodium bicarbonate (100 ml). The aqueous layer was extracted with dichloromethane (2×200 ml), the combined organic layers were dried (sulfa is magnesium) and concentrated, it was given ether (yield 60%) as a brown oil.

Ether (60,4 mmole) was dissolved in ethanol (103 ml), diluted with water (71 ml), then treated with ammonium chloride (243 mmole) and powdered iron (301 mmol). The reaction mixture is boiled under reflux for 10 min and the resulting suspension was filtered through celite, the filter cake washed three times with ethanol. The filtrate was concentrated, the residue is suspended in 2n. hydrochloric acid and was intensively stirred for 0.5 hours the Aqueous layer was washed with ethyl acetate (3×50 ml) and 5M sodium hydroxide brought the pH to 9-10. The aqueous layer was extracted with chloroform (3×100 ml) and the combined organic layers were dried (magnesium sulfate). The organic layer was added acetic anhydride (392 mmole), isoamylase (291 mmol) and potassium acetate (51,0 mmole)obtained suspension was heated under reflux for 16 hours, the Solution was evaporated, the residue was distributed between saturated sodium bicarbonate (50 ml) and dichloromethane (100 ml). Then the aqueous layer was extracted with dichloromethane (2×100 ml), the combined organic layers were dried (magnesium sulfate) and concentrated, to receive the ether N-acetylimidazole (yield 79%) as a brown oil.

Ether (63,8 mmole), sodium hydroxide (193 mmole) and water (65 ml) was stirred and the reaction mixture videri the Ali at 60°C for 24 hours After cooling to CT the aqueous layer washed with dichloromethane (3×50 ml) and acidified using conc. hydrochloric acid to pH 1. Resulting solid precipitate was separated by filtration, washed with water and dichloromethane, dried and got acid (yield 27%).

5-(Deformedarse)-1H-indazol-3-carboxylic acid was obtained by the above method.

The method 10

Getting 6-deformational-3-carboxylic acid from 4-NITROPHENOL

To a suspension of sodium hydroxide (485 mmol) in N,N-dimethylformamide (150 ml) was added 4-NITROPHENOL (162 mmole) and the suspension was kept at RT for 15 min, the Reaction mixture was cooled to 0°C. and treated with ethyl ether Hortiflorexpo acid (329 mmol), then heated at 70°C for 16 h and concentrated. The residue was diluted with ice water (200 ml) and was extracted with ethyl acetate (3×100 ml), the combined organic layers were dried (magnesium sulfate) and concentrated, to receive deformational ether (yield 59%) as a yellow oil.

Nitrocefin (149 mmol) was dissolved in ethanol (37.5 ml), diluted with water (25 ml), then treated with ammonium chloride (84,7 mmole) and powdered iron (105 mmol). The reaction mixture is boiled under reflux for 30 min and the resulting suspension was filtered through celite, the filter cake washed three times with ethanol. United Phil is spending concentrated, the residue was dissolved in water and using 5M sodium hydroxide brought the pH to 9-10. The aqueous layer was extracted with ethyl acetate (3×100 ml), the combined organic layers were dried (magnesium sulfate) and concentrated, when it received a yellow oil. The oil was dissolved in acetic anhydride (23.5 mmole), the reaction mixture was stirred at RT for 16 h, the Reaction mixture was diluted with water (50 ml) and neutralized with solid sodium bicarbonate. Resulting solid precipitate was separated by filtration, washed with water, dried and got ndimethylacetamide (yield 62%) as a solid light yellow color.

In the solution ndimethylacetamide (13.2 mmole) in chloroform (20 ml) was added acetic anhydride (19.6 mmole) and the reaction mixture was heated up to the boiling point of the solvent. Then was added dropwise fuming nitric acid (16,0 mmole) and the reaction mixture is boiled under reflux for 30 minutes, the Cooled solution was diluted with water (20 ml) and the aqueous layer was extracted with dichloromethane (3×10 ml). The combined organic layers were dried (magnesium sulfate) and concentrated, to receive nitrone (yield 83%).

Amide (11.0 mmole), sodium hydroxide (43,8 mmole) and water (10 ml) was stirred and the reaction mixture was stirred at 60°C for 1.5 h, the Reaction mixture was cooled to CT, the resulting solid precipitate was separated by filtration, amywali water and dried, when this was received aniline (yield 98%) as a solid light yellow color.

Aniline (15.7 mmole) was stirred in a mixture of 40% Hydrobromic acid (14.3 g) and water (10 ml), the reaction mixture was heated to 80-90°C for complete dissolution of aniline. Then the mixture was cooled to 0°C and for 15 min, the solution was added sodium nitrite (to 23.2 mmole) in water (5.3 ml). The resulting solution was kept at 0-5°C for 40 min and filtered. The copper bromide (I) (18,8 mmole) was dissolved in 40% Hydrobromic acid (21 ml) and cooled to 0°C. a Solution of diazole was slowly added into a solution of copper and the mixture was stirred at 0-10°C for 30 minutes the Reaction mixture was heated at 60°C for 30 min and then at 100°C for 10 min until the reaction is completed. The reaction mixture was cooled to CT and was extracted with dichloromethane (3×40 ml). The combined organic layers washed with 1M sodium hydroxide, 1N. hydrochloric acid and water. The organic layer was dried (magnesium sulfate) and concentrated, this has been microbraid (yield 76%) as a solid light yellow color.

To a suspension of sodium hydride (from 25.8 mmole) in dimethyl sulfoxide (5 ml) at 0°C was added dropwise diethyl ester of malonic acid (25,7 mmole). The reaction mixture was heated to 60°C. and kept for 30 minutes and Then was added dropwise a solution of nitrosamide (11,7 m is Olya) in dimethyl sulfoxide (7 ml) and the reaction mixture was heated at 100°C for 5 hours The cooled solution was poured into ice water and the aqueous layer was extracted with dichloromethane (3×100 ml). The combined organic layers were dried (magnesium sulfate) and concentrated, to receive untreated fluids in the form of oil. Fluids (11,7 mmole), sodium hydroxide (35 mmol) and water (20 ml) were mixed and heated at 60°C for 1 h Then the reaction mixture was cooled to CT and the aqueous layer washed with dichloromethane (3×100 ml). The aqueous layer was carefully acidified using conc. hydrochloric acid to pH 1 and the reaction mixture was heated at 60°C for 1 h, the resulting suspension was cooled to 0°C., and the resulting solid precipitate was separated by filtration and dried, to receive acid (yield 64%).

In ethanol (50 ml) at 0°C was added dropwise acetylchloride (15.3 mmole). After 30 min was added the acid (7,69 mmole) and the reaction mixture is boiled under reflux for 15 hours and Then the reaction mixture was concentrated and the residue was distributed between dichloromethane (20 ml) and saturated sodium bicarbonate (10 ml). The aqueous layer was extracted with dichloromethane (2×20 ml), the combined organic layers were dried (magnesium sulfate) and concentrated, to receive ether (yield 94%) as a brown oil.

A suspension of ester (3.64 mmole) and acetic acid (7.0 ml) at 0°C was added acetic anhydride (6.0 ml), and then portions over 15 min we use and zinc dust (to 14.6 mmole) and the mixture was stirred at 0°C for 30 min and at RT for 1.5 h, added another portion of zinc dust (6,15 mmole) and the mixture was stirred for 3 hours, the Suspension was filtered through celite and the filtrate was concentrated. The residue was distributed between saturated sodium bicarbonate (10 ml) and ethyl acetate (20 ml). Then the aqueous layer was extracted with ethyl acetate (3×20 ml), the combined organic layers were dried (magnesium sulfate) and concentrated, this has been ndimethylacetamide (yield 92%) as a brown oil.

In the solution ndimethylacetamide (to 3.92 mmole) in chloroform (20 ml) was added acetic anhydride (13.7 mmole), isoamylase (13.7 mmole) and potassium acetate (2,04 mmole)obtained suspension was heated under reflux for 16 hours, the Solution was evaporated and the residue was distributed between saturated sodium bicarbonate (10 ml) and dichloromethane (20 ml). Then the aqueous layer was extracted with dichloromethane (2×20 ml) and the combined organic layers were dried (magnesium sulfate) and concentrated, to receive the ether N-acetylimidazole (yield 92%) as a brown oil.

Ether (3,36 mmole), sodium hydroxide (10 mmol) and water (5 ml) was stirred and the reaction mixture was stirred at 60°C for 24 hours After cooling to CT the aqueous layer washed with dichloromethane (3×30 ml) and acidified using conc. hydrochloric acid to pH 1. Resulting solid precipitate was separated by filtration, washed with water and dichloromethane, was dried, and the thus obtained acid (yield 26%).

6-(Deformedarse)-1H-indazol-3-carboxylic acid was obtained by the above method.

Preparation of amines: methodology 11

Obtaining 2-methyl-2,5-diazabicyclo[2.2.2]octane from diethyl ether 2,5-diaminohexanoic acid.

In a solution of dihydrochloride of diethyl ether 2,5-diaminohexanoic acid (10.0 mmole) in absolute ethanol (75 ml) and acetic acid (10 ml) at room temperature was added benzaldehyde (to 21.8 mmole). The resulting mixture was heated at 80°C for 2 h, the Reaction mixture was cooled to room temperature and in small portions was added triacetoxyborohydride sodium (54,2 mmole). The resulting white suspension was kept at RT for 16 h and concentrated. The residue was diluted with water, cooled to 0°C and using a 1H. sodium hydroxide brought the pH to 9. Then the aqueous layer was extracted with ethyl acetate (3×100 ml) and the combined organic layers were washed with saline, dried (magnesium sulfate) and concentrated, to receive solid white (3,05 g). In the solution dibenzylamine in ethanol (200 ml) was added sodium methoxide (25 wt.%, 23 mmole) and the reaction mixture is boiled under reflux for 16 hours Then the reaction mixture was cooled to CT and concentrated. The residue was diluted with ethyl acetate (200 ml), washed with 1N. hydrochloric acid, dried (magnesium sulfate) and Cohn who was entrirely, when this has been bicicletta (yield 47%) as a colourless solid.

In the suspension socialwise hydride (of 31.6 mmole) in tetrahydrofuran (50 ml) under stirring in nitrogen atmosphere was added dropwise sulfuric acid (15.8 mmole). The mixture was stirred for 30 min and at 0°C was added dropwise to the supernatant in a solution of bicyclic lactam (1.5 mmole) in tetrahydrofuran (50 ml). The reaction mixture was heated to CT and kept for 16 hours the Reaction was carefully stopped by the addition of portions of solid decahydrate sodium sulfate (2.5 g). The reaction mixture was diluted with 2M sodium hydroxide solution (10 ml), filtered through celite and the filtrate was concentrated. The residue was diluted with 2n. hydrochloric acid (100 ml) and was extracted with ethyl acetate. The aqueous layer was podslushivaet 2M sodium hydroxide to pH 9 and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with saline, dried (magnesium sulfate) and concentrated. The oil obtained light yellow color was treated with a solution of hydrogen chloride in methanol, which was obtained in situ by adding acetylchloride (0.5 ml) in methanol (10 ml) at room temperature for 10 min Volatile components were removed under reduced pressure, to receive the dihydrochloride of bicicletinha (yield 92%) as a foam off-white color.

Su is pensio diamine (3,00 mmole) and 10% palladium on coal (200 mg) in methanol (100 ml) and conc. hydrochloric acid (2 ml) were placed in an atmosphere of hydrogen and stood for 16 hours, the Catalyst was removed by filtration and the filter cake washed with water. The filtrate was concentrated, to receive the dihydrochloride of bicicletinha (yield 88%) as a colourless solid.

In a solution of diamine (7,06 mmole) in isopropanol (100 ml), water (35 ml) and 1M solution of sodium hydroxide (6.5 ml) at 0°C was added dropwise a solution of di-tert-BUTYLCARBAMATE (6.5 mmole) in isopropanol (15 ml). The reaction mixture was stirred at 0°C for 1.5 h and then concentrated to a volume of ~ 50 ml. of Water, the suspension was saturated with solid sodium chloride and using 2M sodium hydroxide brought the pH up to 10. The aqueous layer was extracted with ethyl acetate (3×35 ml) and the combined organic layers were washed with saline and dried (magnesium sulfate). Volatile components were removed under reduced pressure, it was obtained the crude mono-protected diamine (yield 42%) as oil is light yellow in color.

In the solution of the crude amine (2.97 mmole) in tetrahydrofuran (25 ml) was added an aqueous solution of formaldehyde (37%, 7,43 mmole) and acetic acid (4,46 mmole). After 10 min the reaction mixture in small portions was added solid triacetoxyborohydride sodium (5,94 mmole) and the reaction mixture was stirred for 16 hours Then the reaction mixture was diluted with 10% aqueous RA is tworoom sodium bicarbonate (100 ml) and was extracted with ethyl acetate (3×40 ml). The combined organic layers were washed with saline, dried (magnesium sulfate) and concentrated, to receive the balance of light yellow color. The residue was dissolved in dioxane (25 ml) and diluted conc. hydrochloric acid (12.5 ml). After 30 min the volatiles were removed and received monomethylethanolamine (yield 40%) as a colourless solid. The dihydrochloride of 2-methyl-2,5-diazabicyclo[2.2.1]heptane was obtained in terms of N-methylation and deletion carbamazapine group. (H. Newman, J.Heterocyclic Chem. 11, 449, (1974); Sturm P.A., Henry D.W., J.Med.Chem. 17, 481, (1974)).

The following reasons were given in this way:

the dihydrochloride of 2-methyl-2,5-diazabicyclo[2.2.2]octane

the dihydrochloride of (1S,4S)-2-methyl-2,5-diazabicyclo [2.2.1] heptane.

The synthesis methods

The following methods (A-G) described in detail the receipt substituted derivatives of balloonboy.

Method And

Condensation of balloonboy and carboxylic acids with the formation of carboxamide derivatives

To a solution of carboxylic acid (1 mmol) in tetrahydrofuran (10 ml) and N,N-dimethylformamide (1 ml) was added N,N-diisopropylethylamine (3 mmole) and the dihydrochloride bicillin (1 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 30 min, then was added HATU (1.00 mmole). After 18 h the reaction mixture was distributed between the feast upon the authorized aqueous solution of potassium carbonate and dichloromethane/methanol (95:5). The aqueous layer was twice extracted with dichloromethane/methanol (95:5), the combined organic layers were washed with saline, dried (sodium sulfate) and concentrated in vacuum. The residue was purified rapid chromatography on a column of silica gel (eluent: dichloromethane/methanol/ammonium hydroxide, 90:10:1), to receive carboxamid.

The following compounds were obtained according to the methods As:

Example 1

Hydrochloride 3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-indazole

The compound was obtained according to method A, yield 28%. MS-LC (EI), V.U. 3,55 min, m/z 243 (M++1).

1H NMR (CD3OD): δ by 8.22 (m, 1H), to 7.61 (m,1H), 7,45 (m, 1H), 7,27 (m, 1H), 3,82 (m, 1H), 3,51 (m, 2H), 2,30 (m, 1H), 2,07 (m, 1H).

Example 2

Hydrochloride 3-(2,5-diazabicyclo[2.2.2]Oct-2-ylcarbonyl)-6-(1,3-thiazol-2-yl)-1H-indazole

The compound was obtained according to method A, yield 30%. MS-LC (EI), V.U. 3.04 from min, m/z 340 (M++1).

Example 3

Hydrochloride 3-(2,5-diazabicyclo[2.2.2]Oct-2-ylcarbonyl)-1H-indazole

The compound was obtained according to method A, yield 30%. MS-LC (EI), V.U. 2,85 min, m/z 257 (M++1).

Example 4

Formate 3-[(5-methyl-2,5-diazabicyclo[CT-2-yl)carbonyl]-1H-indazole

The compound was obtained according to method a, yield 25%. MS-LC (EI), V.U. of 2.83 min, m/z 271 (M++1).

P is the iMER 5

Formate 3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-6-(1,3-thiazol-2-yl)-1H-indazole

The compound was obtained according to method a, yield of 20%. MS-LC (EI), V.U. 2,87 min, m/z 376 (M++1).

Example 6

Formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazole

The compound was obtained according to method A, yield 56%. MS-LC (EI), V.U. 2,53 min, m/z 274 (M++1).

Example 7

3-{[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazol

The compound was obtained according to method A, yield 77%. MS-LC (EI), V.U. 2,75 min, m/z 274 (M++1).

Example 8

Formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-icarbonell}-1,2-benzisoxazole

The compound was obtained according to method a, yield of 20%. MS-LC (EI), V.U. 3,48 min, m/z 258 (M++1).

Example 9

Formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-icarbonell}-5-(1,3-thiazol-2-yl)-1H-indazole

The compound was obtained according to method a, yield 25%. MS-LC (EI), V.U. 2,87 min, m/z 340 (M++1).

Example 10

Formate 3-{[(1S',4S')-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(4-methyl-1,3-thiazol-2-yl)-1H-indazole

The compound was obtained according to method A, yield 30%. MS-LC (EI), V.U. was 2.76 min, m/z 354 (M++1).

Example 11

Formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole

The compound was obtained according to method A, yield 30%. MS-LC (EI), V.U. 2,9 min, m/z 354 (M++1).

Example 12

Formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-icarbonell}-5-(tetrahydro-2H-Piran-4-yl)-1H-indazole

The compound was obtained according to method a, yield 25%. MS-LC (EI), V.U. 2,85 min, m/z 339 (M++1).

Example 13

Formate 3-{[(1S,4S)-5-methyl-2.5-diazabicyclo[2.2.1]hept-2-icarbonell}-5-(triptoreline)-1H-indazole

The compound was obtained according to method A, yield 45%. MS-LC (EI), V.U. 4,82 min, m/z 341 (M++1).

Example 14

Formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(1,3-oxazol-2-yl)-1H-indazole

The compound was obtained according to method A, yield 30%. MS-LC (EI), V.U. the 5.25 min, m/z 324 (M++1).

Example 15

Formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(1,3-thiazol-2-yl)-1H-indazole

The compound was obtained according to method a, yield 25%. MS-LC (EI, V.U. 2,69 min, m/z 362 (M++1).

Example 16

Formate 3-{[(1S,4S)-5-methyl-2.5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole

The compound was obtained according to method a, yield 25%. MS-LC (EI), V.U. 5,18 min, m/z 354 (M++1).

Example 17

Formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole

The compound was obtained according to method a, yield 25%. MS-LC (EI), V.U. 5,18 min, m/z 354 (M++1).

Example 18

Formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(tetrahydro-2H-Piran-4-yl)-1H-indazole

The compound was obtained according to method a, yield 25%. MS-LC (EI), V.U. 2,79 min, m/z 341 (M++1).

Example 19

Formate 3-{[(1S,4S)-5-methyl-2.5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(triptoreline)-1H-indazole

The compound was obtained according to method a, yield 25%. MS-LC (EI), V.U. 5,04 min, m/z 341 (M++1).

Example 20

Formate 3-{[(1S,4S)-5-methyl-2.5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(trifluoromethyl)-1H-indazole

The compound was obtained according to method A, yield 45%. MS-LC (EI), V.U. of 3.85 min, m/z 325 (M++1).

Example 21

Faure is IAT 3-{[(1S,4S)-5-methyl-2.5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-7-(triptoreline)-1H-indazole

The compound was obtained according to method a, yield 25%. MS-LC (EI), V.U. of 4.66 min, m/z 341 (M++1).

Example 22

Formate 5-(3,6-dihydro-2H-Piran-4-yl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole

The compound was obtained according to method A, yield 30%. MS-LC (EI), V.U. of 2.83 min, m/z 339 (M++1).

Example 23

Formate 5-(deformedarse)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole

The compound was obtained according to method A, yield 35%. MS-LC (EI), V.U. 2,52 min, m/z 323 (M++1).

Example 24

Hydrochloride, 5-bromo-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-indazole

The compound was obtained according to method A, yield 45%. MS-LC (EI), V.U. 4,76 min, m/z 321/323 (M++1).

Example 25

Formate 5-methoxy-3-[(5-methyl-2.5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazole

The compound was obtained according to method a, yield of 20%. MS-LC (EI), V.U. 2,85 min, m/z 301 (M++1).

Example 26

Hydrochloride 3-(2,5-diazabicyclo [2.2.2]Oct-2-ylcarbonyl)-5-methoxy-1H-indazole

The compound was obtained according to method A, yield 30%. MS-LC (EI), V.U. 2,87 min, m/z 287 (M++1).

Example 27

<> Hydrochloride 5-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole

The compound was obtained according to method A, yield 35%. MS-LC (EI), V.U. 2,85 min, m/z 287 (M++1).

Example 28

Formate 5-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole

The compound was obtained according to method A, yield 45%. MS-LC (EI), V.U. of 2.51 min, m/z 287 (M++1).

Example 29

Formate 6-(3,6-dihydro-2H-Piran-4-yl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole

The compound was obtained according to method a, yield 25%. MS-LC (EI), V.U. 2,8 min, m/z 339 (M++1).

Example 30

Formate 6-(deformedarse)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole

The compound was obtained according to method A, yield 35%. MS-LC (EI), V.U. 2,47 min, m/z 323 (M++1).

Example 31

The hydrochloride of 6-bromo-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-indazole

The compound was obtained according to method A, yield 45%. MS-LC (EI), V.U. 3,71 min, m/z 321/323 (M++1).

Example 32

Formate 6-cyclopropyl-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl)-1,2-benzisothiazole

The compound was obtained according to method A, yield 56%. MS-LC (EI), V.U. 4,48 min, m/z 314 (M++1).

Example 33

Formate 6 ethoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazole

The compound was obtained according to method A, yield 43%. MS-LC (EI), V.U. with 3.79 min; m/z318 (M++1).

Example 34

Hydrochloride 3-(2,5-diazabicyclo[2.2.2]Oct-2-ylcarbonyl)-6-methoxy-1H-indazole

The compound was obtained according to method A, yield 30%. MS-LC (EI), V.U. 2,89 min, m/z 287 (M++1).

Example 35

Formate 6-methoxy-3-[(5-methyl-2.5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazole

The compound was obtained according to method A, yield 28%. MS-LC (EI), V.U. of 2.83 min, m/z 301 (M++1).

Example 36

Formate 6-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazole

The compound was obtained according to method A, yield 64%. MS-LC (EI), V.U. 2,97 min, m/z 304 (M++1).

Example 37

6-Methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl)-1,2-benzisothiazol

The compound was obtained according to method A, yield 85%. MS-LC (EI), V.U. a 3.06 min, m/z 304 (M++1).

Example 38

The hydrochloride of 6-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo [2.2.1]hept-2-yl]rbony}-1H-indazole

The compound was obtained according to method A, yield 35%. MS-LC (EI), V.U. of 2.83 min, m/z 287 (M++1).

Example 39

Formate 6-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole

The compound was obtained according to method A, yield 35%. MS-LC (EI), V.U. of 2.83 min, m/z 287 (M++1).

Example 40

Formate 7-fluoro-6-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole

The compound was obtained according to method A, yield 31%. MS-LC (EI), V.U. of 2.54 min, m/z 305 (M++1).

Example 41

Formate 7-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazole

The compound was obtained according to method A, yield 50%. MS-LC (EI), V.U. of 2.6 min, m/z 304 (M++1).

Method In

Condensation of brominated and yugirovannykh bicyclogermacrene and Baranovich acids with the formation of aryl-substituted or heteroaromatic derivatives

In the vessel for a microwave reactor with a volume of 5 ml) was added commercially available brominated bicyclogermacrene (0.3 mmole), baronova acid (0.6 mmole), Tris(dibenzylideneacetone)diplegia (0) (0.03 mmole), tetrafluoroborate three-tert-butylphosphine (0,06 mmole) and potassium carbonate (0.8 mmole). Of the vessel was removed the air for anjali argon and the contents were diluted with N,N-dimethylformamide (5.0 ml). The vessel was sealed and irradiated in a microwave reactor at 200°C for 600 C. the Reaction mixture was filtered through celite (washed with methanol) and was applied on a column of 5 g SCX. The column was washed with methanol (50 ml) and the product was suirable 2M ammonia in methanol and concentrated. The residue was purified by chromatography (eluent: 1:1 to 0:1 ethyl acetate (ethyl acetate/methanol/ammonium hydroxide, 70:30:1)), then preparative GHUR (eluent: gradient over 8 min with 0.1% formic acid)/acetonitrile (with 0.1% formic acid) from 95:5 to 20:80 water), received heteroarylboronic product.

The following examples describe the formation of compounds by the method In:

Example 42

Formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(2-thienyl)-1H-indazole

The compound was obtained according to method b, yield 25%. MS-LC (EI), V.U. to 5.03 min, m/z 339 (M++1).

1H NMR (CD3OD): δ 8.48 (m, 2H), to 7.75 (m, 1H), 7,58 (m, 1H), 7,32 (m, 2H), was 7.08 (m, 1H), 4,25 (m, 1H), 3,70 (m, 2H), 3,32 (m, 1H), 2,85 (d, 3H), 2.22 (m, 2H).

Example 43

Formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]cabonyl}-5-(4-methyl-2-thienyl)-1H-indazole

The compound was obtained according to method b, yield 25%. MS-LC (EI), V.U. 5,33 min, m/z 353 (M++1).

Example 44

Formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-2-t the Nile)-1H-indazole

The compound was obtained according to method b, yield 25%. MS-LC (EI), V.U. 5,32 min, m/z 353 (M++1).

Example 45

Formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-phenyl-1H-indazole

The compound was obtained according to method b, yield 25%. MS-LC (EI), V.U. of 5.17 min, m/z 333 (M++1).

Example 46

Formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(2-thienyl)-1H-indazole

The compound was obtained according to method b, yield 25%. MS-LC (EI), V.U. 5,13 min, m/z 339 (M++1).

Example 47

Formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(3-thienyl)-1H-indazole

The compound was obtained according to method b, yield 25%. MS-LC (EI), V.U. the 4.3 min, m/z 339 (M++1).

Example 48

Formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(4-methyl-2-thienyl)-1H-indazole

The compound was obtained according to the method, a yield of 20%. MS-LC (EI), V.U. to 5.35 min, m/z 353 (M++1).

Example 49

Formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-2-furyl)-1H-indazole

The connection was received on the determination of the e, yield 25%. MS-LC (EI), V.U. to 5.35 min, m/z 337 (M++1).

Example 50

Formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-2-thienyl)-1H-indazole

The compound was obtained according to method b, yield 25%. MS-LC (EI), V.U. 4,67 min, m/z 353 (M++1).

Example 51

Formate 5-(2-furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole

The compound was obtained according to method b, yield 25%. MS-LC (EI), V.U. 41 min, m/z 323 (M++1).

Example 52

Formate 5-(3-forfinal)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole

The compound was obtained according to method b, yield 25%. MS-LC (EI), V.U. 5,28 min, m/z 351 (M++1).

Example 53

Formate 5-(4-forfinal)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole

The compound was obtained according to method b, yield 25%. MS-LC (EI), V.U. the 5.25 min, m/z 351 (M++1).

Example 54

Formate 5-(4-methoxyphenyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole

The compound was obtained according to the method, a yield of 20%. MS-LC (EI), V.U. 5,19 min, m/z 363 (M++1).

Example 55

Formate 6-(2-furyl)-3-{[(1S,4)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole

The compound was obtained according to method b, yield 25%. MS-LC (EI), V.U. 4,9 min, m/z 323 (M++1).

Example 56

Formate 6-(3-furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole

The compound was obtained according to method b, yield 25%. MS-LC (EI), V.U. 3,93 min, m/z 323 (M++1).

Methods With

Reductive condensation bicyclogermacrene and carboxaldehydes with the formation of derivatives of tertiary amines

To a suspension of the hydrochloride bicyclogermacrene (0.4 mmole), carboxaldehyde (1.0 mmole), N,N-diisopropylethylamine (1.2 mmole) and acetic acid (0.48 mmole) was added triacetoxyborohydride sodium (0.68 mmole). The reaction mixture was stirred at ambient temperature for 2 h and poured into ice water, extracted with a mixture of dichloromethane/methanol, 95:5 (2×30 ml) and the combined extracts were concentrated. The residue was purified preparative GHUR (eluent: gradient over 8 min water (with 0.1% formic acid)/acetonitrile (with 0.1% formic acid) from 95:5 to 20:80), received tertiary amine.

The following examples describe the formation of compounds by the method With:

Example 57

Formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole

The compound was obtained according to method C, 30%yield. MS-LC (EI), V.U. 2,5 min, m/z 257 (M++1).

1H NMR (CD3OD): δ 8,42 (s, 1H), 8,23 (m, 1H), a 7.85 (m, 1H), to 7.77 (m, 1H), to 7.64 (m, 1H), 4,15 (m, 2H), 4,01 (m, 2H), of 2.51 (d, 3H), 2,11 (m, 2H).

Example 58

3-{[(1S,4S)-5-Ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol

The compound was obtained according to method C, yield 45%. MS-LC (EI), V.U. 2,77 min, m/z 271 (M++1).

Example 59

N-(Cyclopropylmethyl)-3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-amine

The compound was obtained according to method C, yield 70%. MS-LC (EI), V.U. of 1.33 min, m/z 340 (M++1).

Example 60

N-(Cyclopropylmethyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-amine

The compound was obtained according to method C, yield 80%. MS-LC (EI), V.U. 1,36 min, m/z326 (M++1).

Example 61

Formate, N,N-dimethyl-3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-amine

The compound was obtained according to method C, yield 58%. MS-LC (EI), V.U. 1,49 min, m/z 314 (M++1).

Example 62

Formate, N,N-dimethyl-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-icarbonell}-1H-indazol-5-amine

The compound was obtained according to method C, 51%yield. MS-LC (EI), V.U. 1.5 min, m/z 300 (M++1).

Por the measures 63

Formate, N,N-dimethyl-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-6-amine

The compound was obtained according to method C, yield 59%. MS-LC (EI), V.U. 1.5 min, m/z 300 (M++1).

Example 64

5-Bromo-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol

The compound was obtained according to method C or a, yield 25%. MS-LC (EI), V.U. 3,57 min, m/z 335/337 (M++1).

Example 65

Formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(3-thienyl)-1H-indazole

The compound was obtained according to the method or, yield 25%. MS-LC (EI), V.U. 417 min, m/z 339 (M++1).

Example 66

Formate 5-(3-furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole

The compound was obtained according to the method or, exit 15%. MS-LC (EI), V.U. 4,1 min, m/z 323 (M++1).

Procedure D

Demethylation methoxsalen indazolinone with the formation of phenol derivatives and the subsequent reaction of phenol with various alkylating agents.

Methoxyazobenzene (6,98 mmole) was diluted with dichloromethane (60 ml) and dichloroethane (15 ml), the solution was cooled to -78°C. To the solution is added dropwise within 30 min was added a 1.0m solution of tribromide boron in chlormethine (35 mmol). The reaction mixture was heated to room temperature and kept for 20 hours To the mixture was added to another aliquot part of tribromide boron in dichloromethane (6 mmol) and the reaction mixture was stirred for a further 16 hours the Reaction was carefully stopped by adding Meon (30 ml) and concentrated to dryness. The residue was purified by chromatography (eluent: dichloromethane/methanol, 90:10, then a mixture of dichloromethane/methanol/ammonium hydroxide, 10:10:1), to receive phenol (54%) as a solid brown color. Phenol (0,734 mmole) was dissolved in N,N-dimethylformamide (10 ml) and treated with potassium carbonate (1,46 mmole) and methyl-alkyl (0.95 mmole). The reaction mixture was stirred for 16 h at ambient temperature, filtered and concentrated to dryness. The residue was purified preparative GHUR (eluent: gradient over 8 min water (with 0.1% formic acid)/acetonitrile (with 0.1% formic acid) from 95:5 to 20:80), it was given a simple ether.

The following examples describe the formation of compounds by the method D:

Example 67

5-Hydroxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol

The compound was obtained according to method D, yield 64%. MS-LC (EI), V.U. 0,75 min, m/z 273 (M++1).

1H NMR (Me2SO-d6): δ of 10.76 (s, 1H), of 8.90 (s, 1H), 8,25 (m, 2H), to 7.99 (s, 1H), a 7.85 (m, 1H), 4,46 (user., 1H), 3,62 (m, 1H), 3,38 (m, 1H), 3,20 (m, 3H), of 2.20 (m,2H), of 1.85 (m, 2H).

Example 68

Formate 5-(cyclopentyloxy)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonic}-1H-indazole

The compound was obtained according to method D, yield 25%. MS-LC (EI), V.U. the 5.25 min, m/z 341 (M++1).

1H NMR (CD3OD) δ 8,48 (m, 2H), to 7.75 (m, 1H), 7,58 (m, 1H), 7,32 (m, 2H), was 7.08 (m, 1H), 4.25 (m. 1H), 3,70 (m, 2H), 3,32 (m, 1H), 2,85 (d, 3H), 2,22 (m, 2H).

Example 69

Formate 5-(cyclopropylmethoxy)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo [2.2.1]hept-2-yl]carbonyl)-1H-indazole

The compound was obtained according to method D, yield 25%. MS-LC (EI), V.U. 2,85 min, m/z 327 (M++1).

Example 70

Formate 6-(cyclopentyloxy)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.11 hept-2-yl]carbonyl}-1H-indazole

The compound was obtained according to method D, yield 30%. MS-LC (EI), V.U. 6,1 min, m/z 341 (M++1).

Method E

Recovery nitrosamine bicycloamine with the formation of derivatives of aniline

In the solution nitrosamines balloonboy (3.8 mmole), obtained by the method And, in methanol (100 ml) was added 10% palladium on coal (200 mg). The reaction mixture was placed in an atmosphere of hydrogen (60 psi) and shaken overnight. The catalyst was removed by filtration through a layer of celite, which was washed with methanol (100 ml). United who's the filtrate was concentrated, it was obtained the desired product.

The following examples describe the formation of compounds according to method E:

Example 71

5-Amino-3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol

The compound was obtained according to method E, yield 92%. MS-LC (EI), V.U. 1,71 min, m/z 286 (M++1).

1H NMR (CD3OD): δ was 7.36 (d, J 12,0, 1H), 7,31 (s, 1H), 7,0 (d, J 12,0, 1H), a 4.03 (m, 1H), 3,62 (m, 1H), and 3.31 (s, 3H), 3,10 (m, 2H), 3,01 (m, 2H), 2,30-2,00 (m, 2H), 1,98 is 1.75 (m, 2H).

Example 72

5-Amino-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(1,3-thiazol-2-yl)-1H-indazol

The compound was obtained according to method E, yield 74%. MS-LC (EI), V.U. 1,76 min, m/z 272 (M++1).

Method F

The interaction of bicycloalkanes with acid chlorides and anhydrides with the formation of amide derivatives

In a solution of aniline (0,460 mmole) in pyridine (4 ml) was added carbonylchloride (0,59 mmole). The reaction mixture was stirred for 2 h and concentrated to dryness. The obtained residue was purified preparative GHUR (eluent: gradient over 8 min, water (with 0.1% formic acid)/acetonitrile (with 0.1% formic acid) from 95:5 to 20:80), received amide.

The following examples describe the formation of compounds by the method F:

Example 73

Formate N-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl-1H-indazol-5-yl}cyclopropanecarboxamide

The compound was obtained according to method F, yield 28%. MS-LC (EI), V.U. of 2.83 min, m/z 354 (M++1).

1H NMR (CD3OD): δ 8,53 (s, 1H), 8,40 (s, 1H), 7,86 (s, 1H), 4.70 (m, 1H), 4,33 (m, 1H), 4,20 (m, 1H), 3.90 (m, 1H), 3,60 is 3.40 (m, 2H), 3.0 a (s, 3H), 2,50 is 2.10 (m, 2H), 2.10-1,90 (m, 2H), 1,80 (m, 1H), 0,93 (m, 2H)to 0.85 (m, 2H).

Example 74

Formate N-{1-(cyclopropanecarbonyl)-3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-yl}cyclopropanecarboxamide

The compound was obtained according to method F, the output of 9.4%. MS-LC (EI), V.U. 5,13 min, m/z 422 (M++1).

Example 75

Formate N-(3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-yl)cyclopropanecarboxamide

The compound was obtained according to method F, yield 35%. MS-LC (EI), V.U. 2,78 min, m/z 340 (M++1).

Method G

Reaction bicycloalkanes with isocyanates with formation of urea derivatives

In a solution of aniline (0,550 mmole) in pyridine (4 ml) was added isocyanate (0.72 mmole). The reaction mixture was stirred for 16 h and concentrated to dryness. The residue was purified preparative GHUR (eluent: gradient over 8 min, water (with 0.1% formic acid)/acetonitrile (with 0.1% formic acid) from 95:5 to 20:80), received urea.

The following examples describe the formation of compounds by the method G:

Example 76

Formate N-(3-{[(1S,4S)-5-methyl-2,5-disabi is yclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-yl)-N'-propylacetic

The compound was obtained according to method G, yield 29%. MS-LC (EI), V.U. 2,84 min, m/z 357 (M++1).

1H NMR (CD3OD): δ 8,42 (user., 1H), 8,21-to 8.14 (m, 2H), 7,47 (m, 1H), 4,40-4,20 (m, 1H), 3,60 (m, 1H), 3,30 (s, 3H), 3,20 (m, 2H), 3,10 (t, J 6.0, 2H), 2,90 (m, 2H), 2.50-2,10 (m, 2H), 2,10-of 1.85 (m, 2H), 1,50 (q, J 6,0, 2H), and 0.98 (t, J 6,0, 3H).

Example 77

Formate 3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-N-propyl-5-{[(propylamino)carbonyl]amino}-1H-indazol-1-carboxamide

The compound was obtained according to method G, the yield of 7.8%. MS-LC (EI), V.U. 5,11 min, m/z 456 (M++1).

Example 78

Formate N-(4-terbisil)-N'-(3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-yl)urea

The compound was obtained according to method G, yield 27%. MS-LC (EI), V.U. 4,74 min, m/z 423 (M++1).

Example 79

Formate N-(4-terbisil)-5-({[(4-terbisil)amino]carbonyl}amino)-3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-1-carboxamide

The compound was obtained according to method G, the yield of 5.2%. MS-LC (EI), V.U. 5,9 min, m/z 5 88 (M++1).

Example 80

Formate N-cyclopentyl-N'-(3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-yl)urea

When the unity was obtained according to method G, yield 32%. MS-LC (EI), V.U. 2,85 min, m/z 383 (M++1).

Example 81

Formate N-cyclopentyl-5-{[(cyclopentylamine)carbonyl]amino}-3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-1-carboxamide

The compound was obtained according to method G, the yield of 6.6%. MS-LC (EI), V.U. 5,46 min, m/z 508 (M++1).

Example 82

Formate N-(4-terbisil)-N'-{3-[(5-methyl-2,5-diazabicyclo[CT-2-yl)carbonyl]-1H-indazol-5-yl}urea

The compound was obtained according to method G, yield 22%. MS-LC (EI), V.U. 4,78 min, m/z 437 (M++1).

Example 83

Formate N-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-yl}-N'-propylacetic

The compound was obtained according to method G, yield 33%. MS-LC (EI), V.U. 3,11 min, m/z 372 (M++1).

Example 84

Formate N-cyclopentyl-N'-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-yl}urea

The compound was obtained according to method G, yield 34%. MS-LC (EI), V.U. 2,9 min, m/z 397 (M++1).

Example 85

Binding of [3H] MLA

Materials

The rat brain: company Pel-Freez Biologicals, catalog No. 56004-2

Tablet mixture of protease inhibitors: firm Roche, catalog No. 1697498

Obtain the membrane fraction

MH the rats in 20 volumes (wt./about.) ice 0,32M sucrose solution, containing protease inhibitors (1 tablet per 50 ml), homogenized in the homogenizer Polytron for 10 s (speed 11), then centrifuged for 10 min at 1000 g at 4°C. the Supernatant was centrifuged for 20 min at 20000 g at 4°C. the Precipitate resuspendable in buffer solution for binding (200 mm TRIS-HCl, 20 mm HEPES, pH 7.5, 144 mm NaCl, 1.5 mm KCl, 1 mm MgSO4, 2 mm CaCl2, 0.1% (wt./about.) BSA) and stored at -80°C.

To determine the saturation 200 μl of the mixture in a buffer solution for binding, containing 200 μg of membrane protein, from 0.2 to 44 nm [3H] MLA. Nonspecific binding was determined using 1 μm MLA. Concurrency analysis was carried out in the presence of 2 nm [H] MLA and the studied compounds in the required concentration range. The analyzed mixture was stirred at 22°C for 2 h, then the precipitate was collected in a device for collecting cells Tomtec on the filter, GF/B, pre-soaked in 0.3% of the PAYS in the buffer solution for linking. The filter was washed 3 times with buffer solution to bind and radioactivity was determined using a Trilux.

The affinity for binding to the preferred compounds of the present invention ranges from 26 μm to 64 nm, especially from 2.5 μm to 64 nm.

The synthesis conditions described above in the examples, can be changed when replacing General or specific reagents and/or conditions of the reactions on this is the invention on the same reagents or conditions.

Although the present invention is illustrated in the examples of the preparation of specific compounds, it should be understood that changes and modifications of the invention without going beyond the scope or the invention.

1. The compound of formula I or III:


where And means
,
In means
;
Y represents O or S;
X1-X4every means independently CH or CR1,
X9-X12every means independently CH or CR3,
R1and R3each independently mean H,
C1-C6alkyl, which is unsubstituted or substituted by one or more groups of:
F, Cl, Br or I,
With3-C6cycloalkyl, halogen,
NR4R5, NR4CO2R5, NR4CONR4R5,
Ar,
Het or
R6O-;
R4and R5each independently denotes H or denotes phenyl, phenyl-C1-C4alkyl,
With1-C4alkyl, C3-C8cycloalkyl or4-C8cycloalkenyl, each of which is unsubstituted
or substituted by one or more groups: F, Cl, Br or I,
R6means
N
With1-C6alkyl, which is unsubstituted or substituted by one or more groups of:
F, Cl, Br or I,
With3-C8cycloalkyl, or
With4-sub> 8cycloalkenyl,
R7means N or
With1-C4alkyl,
m is 1 or 2;
Ar denotes a phenyl group which is unsubstituted or substituted by one or more groups selected from alkoxy containing from 1 to 8 carbon atoms, and halogen, or a combination of these groups, and
Het means a heterocyclic group, a fully saturated, partially saturated or fully unsaturated, containing 5 to 6 atoms in the cycle, in which 1 or 2 of the atom in the composition of the cycle each atom is N, O or S, which is unsubstituted or substituted by one or more alkyl groups containing from 1 to 8 carbon atoms, or a pharmaceutically acceptable salt of these compounds, and, if the compound exhibits chirality it can be in the form of mixtures of enantiomers or mixtures of diastereomers, or can be in the form of a single enantiomer or a single diastereoisomer.

2. The compound according to claim 1, in which R1and R3represent NR4R5, a R4and R5each independently mean H, phenyl or1-C4alkyl, which is unsubstituted or substituted by one or more groups F, Cl, Br or I.

3. The compound according to claim 1, characterized by formula I.

4. The compound according to claim 3 in which R1denotes H, OR, CF3, Br, unsubstituted or substituted C1-C8the alkyl is Anil, unsubstituted or substituted C1-C8the alkyl furyl or unsubstituted or substituted C1-C8alkoxygroup and/or halogen phenyl.

5. The compound according to claim 3 in which R1means N, OR6, NR4R5, NR4COR5, NR4CONR4R5, CF3, Br, 2-thienyl, 3-thienyl, matiltan, 2-furyl, 3-furyl, phenyl, forfinal, methoxyphenyl, thiazolyl, oxazolyl, tetrahydropyranyl or dihydropyran.

6. The compound according to claim 1, which is characterized by the formula III.

7. The compound according to claim 1, in which R3means N, cyclopropyl or or6.

8. The compound according to claim 1, in which R4means H or methyl.

9. The compound according to claim 1, in which R5denotes H, methyl, cyclopropyl, cyclopentyl, cyclopropylmethyl, propyl or benzyl.

10. The compound according to claim 1, in which R6means methyl, ethyl, CF3, CHF2cyclopentyl or cyclopropylmethyl.

11. The compound according to claim 1, in which R7denotes H, methyl or ethyl.

12. The compound according to claim 1, in which m is 1.

13. The compound according to claim 1, in which m is 2.

14. The connection according to claim 9, in which Y represents S.

15. The compound according to claim 1 in which Het denotes unsubstituted or substituted C1-C8the alkyl thienyl or unsubstituted or substituted C1-C8the alkyl furyl.

16. The compound according to claim 1, whereby the above-mentioned connection and choose the following connections:
3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(triptoreline)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(trifluoromethyl)-1H-indazole,
5-bromo-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-indazole,
5-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
6-bromo-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-indazole,
6 ethoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazole,
6-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazole,
7-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(2-thienyl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(4-methyl-2-thienyl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-2-thienyl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-phenyl-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(2-thienyl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(3-thienyl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(4-methyl-2-thienyl)-1H-indazole,
3-{[(1S,4S)-5-methyl-,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-2-furyl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-2-thienyl)-1H-indazole,
5-(2-furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
5-(3-forfinal)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
5-(4-forfinal)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
5-(4-methoxyphenyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
6-(2-furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
6-(3-furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
3-{[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(3-thienyl)-1H-indazole,
5-(3-furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
5-bromo-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole and their pharmaceutically acceptable salts, and the connection can be in the form of mixtures of enantiomers or mixtures of diastereomers, or can be in the form of a single enantiomer or a single diastereoisomer.

17. The connection clause 16, which represents cleaners containing hydrochloride or formiate salt.

18. Connection item 16 or 17, and the above-mentioned compound selected from the following compounds:
hydrochloride 3-[(1S,4S)-2,-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-indazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(triptoreline)-1H-indazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(trifluoromethyl)-1H-indazole,
hydrochloride 5-bromo-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-indazole,
formate 5-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
hydrochloride of 6-bromo-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-indazole,
formate 6 ethoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazole,
formate 6-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazole,
formate 7-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(2-thienyl)-1H-indazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2,2 .1]hept-2-yl]carbonyl}-5-(4-methyl-2-thienyl)-1H-indazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-2-thienyl)-1H-indazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-phenyl-1H-indazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(2-thienyl)-1H-indazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(3-thienyl)-1H-indazole,
form is the 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(4-methyl-2-thienyl)-1H-indazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-2-furyl)-1H-indazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-2-thienyl)-1H-indazole,
formate 5-(2-furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
formate 5-(3-forfinal)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
formate 5-(4-forfinal)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo [2.2.1]hept-2-yl]carbonyl}-1H-indazole,
formate 5-(4-methoxyphenyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
formate 6-(2-furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
formate 6-(3-furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
formate 3-{[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(3-thienyl)-1H-indazole,
formate 5-(3-furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
5-bromo-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
moreover, the connection can be in the form of mixtures of enantiomers or mixtures of diastereomers, or can be in the form of a single enantiomer or a single diastereoisomer.

19. The compound according to claim 1, whereby said connection is of choose from the following connections:
3-(2,5-diazabicyclo[2.2.2]Oct-2-ylcarbonyl)-6-(1,3-thiazol-2-yl)-1H-indazole,
3-[(1S,4S)-(2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-indazole,
3-(2,5-diazabicyclo [2.2.2]Oct-2-ylcarbonyl)-1H-indazole,
3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazole,
3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-6-(1,3-thiazol-2-yl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(1,3-thiazol-2-yl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(2-thienyl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(3-thienyl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(4-methyl-2-thienyl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-2-thienyl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(triptoreline)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-phenyl-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(1,3-oxazol-2-yl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(1,3-thiazol-2-yl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(2-thienyl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(3-thienyl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(-methyl-1,3-thiazol-2-yl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(4-methyl-2-thienyl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-2-furyl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-2-thienyl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(tetrahydro-2H-Piran-4-yl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(triptoreline)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(trifluoromethyl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-7-(triptoreline)-1H-indazole,
5-(2-furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
5-(3-forfinal)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
5-(3-furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
5-(4-forfinal)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
5-(4-methoxyphenyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
5-(cyclopentyloxy)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
5-(cyclopropylmethoxy)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
5-amino-3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol is,
5-amino-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(1,3-thiazol-2-yl)-1H-indazole,
5-bromo-3-{[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
5-hydroxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
5-methoxy-3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazole,
3-(2,5-diazabicyclo[2.2.2]Oct-2-ylcarbonyl)-5-methoxy-1H-indazole,
5-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
6-(2-furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
6-(3,6-dihydro-2H-Piran-4-yl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo [2.2.1]hept-2-yl]carbonyl}-1H-indazole,
6-(3-furyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
6-(cyclopentyloxy)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
6-cyclopropyl-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazole,
6 ethoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazole,
3-(2,5-diazabicyclo[2.2.2]Oct-2-ylcarbonyl)-6-methoxy-1H-indazole,
6-methoxy-3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazole,
6-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
7-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazole,
N-(3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-yl)-N'-propylbetaine,
N-{-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-yl}cyclopropanecarboxamide,
N-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-yl}-N'-propylbetaine,
and their pharmaceutically acceptable salts,
moreover, the connection can be in the form of mixtures of enantiomers or mixtures of diastereomers, or can be in the form of a single enantiomer or a single diastereoisomer.

20. The connection according to claim 19, which represents cleaners containing hydrochloride or formiate salt.

21. Connection claim 20, whereby the above-mentioned compound selected from the following compounds:
hydrochloride 3-(2,5-diazabicyclo[2.2.2]Oct-2-ylcarbonyl)-6-(1,3-thiazol-2-yl)-1H-indazole,
hydrochloride 3-(2,5-diazabicyclo[2.2.2]Oct-2-ylcarbonyl)-1H-indazole,
formate 3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazole,
formate 3-(2,5-diazabicyclo[2.2.2]Oct-2-ylcarbonyl)-6-(1,3-thiazol-2-yl)-1H-indazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(1,3-thiazol-2-yl)-1H-indazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl)-6-(1,3-oxazol-2-yl)-1H-indazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(1,3-thiazol-2-yl)-1H-indazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(tetrahydro-2H-PYRAN-yl)-1H-indazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-6-(triptoreline)-1H-indazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-7-(triptoreline)-1H-indazole,
formate 5-(cyclopentyloxy)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
formate 5-(cyclopropylmethoxy)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
formate 5-methoxy-3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazole,
hydrochloride 3-(2,5-diazabicyclo[2.2.2]Oct-2-ylcarbonyl)-5-methoxy-1H-indazole,
formate 5-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
formate 6-(3,6-dihydro-2H-Piran-4-yl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo [2.2.1]hept-2-yl]carbonyl}-1H-indazole,
formate 6-(cyclopentyloxy)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo [2.2.1]hept-2-yl]carbonyl}-1H-indazole,
formate 6-cyclopropyl-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo [2.2.1]hept-2-yl]carbonyl}-1,2-benzisothiazole,
hydrochloride 3-(2,5-diazabicyclo[2.2.2]Oct-2-ylcarbonyl)-6-methoxy-1H-indazole,
formate 6-methoxy-3-[(5-methyl-2,5-diazabicyclo [2.2.2]Oct-2-yl)carbonyl]-1H-indazole,
hydrochloride of 6-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
formate 6-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
formate N-(3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-yl)-N'-propylbetaine,
formate N-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-yl}cyclopropanecarboxamide,
moreover, the connection can be in the form of mixtures of enantiomers or mixtures of diastereomers, or can be in the form of a single enantiomer or a single diastereoisomer.

22. The compound according to claim 1, whereby the above-mentioned compound selected from the following compounds:
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisoxazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(4-methyl-1,3-thiazol-2-yl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole,
3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(tetrahydro-2H-Piran-4-yl)-1H-indazole,
5-(3,6-dihydro-2H-Piran-4-yl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
5-(deformedarse)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
6-(deformedarse)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
7-fluoro-6-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
N-(3-([(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-yl)cyclopropanecarboxamide,
N-(4-terbisil)-N'-(3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-yl)urea,
N-(4-terbisil)-N'-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-yl}urea,
N-(cyclopropylmethyl)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-amine,
N,N-dimethyl-3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-amine,
N,N-dimethyl-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2,2 .1]hept-2-yl]carbonyl}-1H-indazol-5-amine,
N,N-dimethyl-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-6-amine,
N-cyclopentyl-N'-(3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-yl)urea,
N-cyclopentyl-N'-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-yl}urea
and their pharmaceutically acceptable salts,
moreover, the connection can be in the form of mixtures of enantiomers or mixtures of diastereomers, or can be in the form of a single enantiomer or a single diastereoisomer.

23. Connection p.22, which represents the cleaners containing hydrochloride or formiate salt.

24. Connection item 23, and the above-mentioned compound selected from the following compounds:
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1,2-benzisoxazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(4-methyl-1,3-thiazol-2-yl)-1H-indazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole,
formate 3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-5-(tetrahydro-2H-Piran-4-yl)-1H-indazole,
formate 5-(3,6-dihydro-2H-Piran-4-yl-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazole,
formate 5-(deformedarse)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo [2.2.1]hept-2-yl]carbonyl}-1H-indazole,
formate 6-(deformedarse)-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo [2.2.1]hept-2-yl]carbonyl}-1H-indazole,
formate 7-fluoro-6-methoxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo [2.2.1]hept-2-yl]carbonyl}-1H-indazole,
formate N-(3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-yl)cyclopropanecarboxamide,
formate N-(4-terbisil)-N'-(3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-yl)urea,
formate N-(4-terbisil)-N'-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-yl}urea
formate N,N-dimethyl-3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-amine,
formate N,N-dimethyl-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-amine,
formate N,N-dimethyl-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-6-amine,
formate N-cyclopentyl-N'-(3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-1H-indazol-5-yl)urea,
formate N-cyclopentyl-N'-{3-[(5-methyl-2,5-diazabicyclo[2.2.2]Oct-2-yl)carbonyl]-1H-indazol-5-yl}urea
moreover, the connection can be in the form of mixtures of enantiomers or mixtures of diastereomers, or can be in the form of a single enantiomer or a single diastereoisomer.

25. Pharmaceutical composition for activating/stimulating nicotinic α-7 the patient, comprising the compound according to any one of claims 1 to 24 and a pharmaceutically acceptable carrier.

26. The use of compounds according to any one of claims 1 to 24 for the preparation of drugs for the selective activation/stimulation of nicotinic receptors α-7 mammal, and such activation/stimulation exerts a therapeutic effect.

27. The use of compounds according to any one of claims 1 to 24 for the preparation of drugs for the treatment of a patient suffering from psychotic diseases, neurodegenerative diseases, including dysfunction of the cholinergic system, and/or condition associated with impaired memory and/or cognitive abilities.

28. The application of item 27, in which said patient is suffering from the following diseases: schizophrenia, anxiety, mania, depression, manic depression, disease, Tourette's, Parkinson's disease, Huntington's disease, Alzheimer's disease, dementia with calves Levi, amyotrophic lateral sclerosis, memory impairment, memory loss, lack of cognitive abilities, lack of attention, hyperactive state of deficiency of attention.

29. The use of compounds according to any one of claims 1 to 24 for the preparation of drugs for the treatment of a patient suffering from dementia and/or other condition associated with loss of memory.

30. Note the persistence of the compounds according to any one of claims 1 to 24 for the preparation of drugs for the treatment of the patient, suffering from memory impairment due to age-related impaired cognitive abilities of an average degree, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, diseases of the Peak of the disease of Creutzfeldt-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, multi-infarct dementia, HIV and cardiovascular diseases.

31. The use of compounds according to any one of claims 1 to 24 for the preparation of drugs for the treatment and/or prophylaxis of dementia in patients with Alzheimer's disease by inhibiting the binding of an amyloid beta-peptide with the receptor nAChR.

32. The use of compounds according to any one of claims 1 to 24 for the preparation of drugs for the treatment of a patient with the syndrome of abstinence from alcohol or from poisoning.

33. The use of compounds according to any one of claims 1 to 24 for the preparation of drugs for the treatment of the patient to ensure neurotoxity from damage caused by strokes and ischemia and glutamate-induced excitotoxicity.

34. The use of compounds according to any one of claims 1 to 24 for the preparation of drugs for the treatment of a patient suffering from nicotine addiction, pain, for the treatment of disorders of biorhythms in connection with the flight through several time zones, obesity and/or diabetes.

35. the label compound according to any one of claims 1 to 24 for the preparation of drugs to facilitate Smoking cessation in a patient.

36. The use of compounds according to any one of claims 1 to 24 for the preparation of drugs for the treatment of a patient suffering from disorders cognitive abilities moderate (MCI), vascular dementia (VaD), deterioration of cognitive abilities associated with age (AACD), amnesia, caused by open heart surgery, cardiac arrest, and/or after General anesthesia, failure of memory, caused by the action of the injected anesthetics, deterioration of cognitive abilities caused by lack of sleep, chronic fatigue syndrome, narcolepsy, dementia caused by AIDS, deterioration of cognitive abilities caused by epilepsy, down syndrome, dementia caused by alcoholism, memory loss, caused by taking drugs/reagents, dementia Legionnaires ' disease (syndrome boxers) and dementia in animals.

37. The use of compounds according to any one of claims 1 to 24 for the preparation of drugs for the treatment of memory loss.

38. The use of compounds according to any one of claims 1 to 24 for the preparation of drugs for the treatment of a patient suffering from memory impairment.

39. The application of § 38, in which the said memory impairment is associated with reduced activity of the nicotinic acetylcholine receptor.

40. The use of compounds according to any one of claims 1 to 24 for the preparation of medicines is the means for the treatment or prevention of a disease or condition resulting from dysfunction of the transmission of nicotinic acetylcholine receptors in mammals.

41. The use of compounds according to any one of claims 1 to 24 for the preparation of drugs for treatment or prevention of a disease or condition arising out of breach or failure of the function of nicotinic acetylcholine receptors in mammals.

42. The use of compounds according to any one of claims 1 to 24 for the preparation of drugs for treatment or prevention of a disease or condition resulting from the suppression of the transmission function of nicotinic acetylcholine receptors in mammals.

43. The use of compounds according to any one of claims 1 to 24 for the preparation of drugs for treatment or prevention of a disease or condition resulting from loss of cholinergic synapses in mammals.

44. The use of compounds according to any one of claims 1 to 24 for the preparation of drugs for the treatment of protection of neurons in mammals from the neurotoxic effects caused by activation of α7nACh receptors.

45. The use of compounds according to any one of claims 1 to 24 for the preparation of drugs for treatment or prevention of neurodegenerative disorders in the inhibition of the binding of peptides β with α7nACh receptors in mammals.

46. Application with the organisations according to any one of claims 1 to 24 for the preparation of drugs for the treatment of the patient, suffering from inflammatory diseases.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula I and their pharmaceutically acceptable salts. In structural formula I , X is oxygen; Y is oxygen; Y1 Y2, R7 and R4 represent H; X1 and X2 are independently selected from a group consisting of hydrogen, an alkyl group containing 1 to 5 carbon atoms, in which one or more hydrogen atoms of the alkyl group can be substituted with a halogen, aryl group containing 6 to 10 carbon atoms or a cycloalkyl group containing 3 to 9 carbon atoms, or a 5-9-member heterocyclic group with 2 heteroatoms selected from N and O, or a cycloalkyl group containing 5 to 9 carbon atoms; values of the rest of the radicals are given in the formula of invention. The invention also pertains to a pharmaceutical composition having properties of selective inhibitors of type IV phosphodiesterase, containing a therapeutically effective amount of the invented compound.

EFFECT: increased effectiveness of the compounds.

6 cl, 23 ex

FIELD: chemistry.

SUBSTANCE: described is a compound selected from formulae , , , , and , where X1 denotes CH; X2-X5 each independently denotes CH or C-, where -C represents the point where group B is bonded and where one of X2-X5 denotes -C; X7-X10 each independently denotes CH or CR2; X18-X21 each independently denotes CH or CR5; X22 and X23 each independently denotes CH or CR12, where at least one of X22 and X23 denotes CR12; X24 denotes CH; B denotes CH2 or C=O; B1 denotes CH; Y denotes oxygen or sulphur; Z denotes O; m equals 2; R denotes hydrogen or R denotes each indendently (C1-C6)alkyl, (C3-C8)cycloalkyl, halogen, imidazolyl substituted with (C1-C6)alkyl and/or an oxo group or OR9; R9 denotes hydrogen, (C1-C6)alkyl which is unsubstituted or substituted with once or several times with fluorine, or (C4-C8)cycloalkylalkyl; R12 denotes a (C1-C6)alkoxy group which is substituted once or several times with fluorine, unsubstituted thiazolyl, thiazolyl which is substituted with (C1-C6)alkyl, unsubstituted oxazolyl, dihydropyranyl, tetrahydropyranyl or tetrahydropyranyloxy, and pharmaceutically acceptable salts of the said compounds. Described also are pharmaceutical compositions containing the said compounds.

EFFECT: invention relates to ligands of nicotinic acetylcholine receptors (nAChR), activation of nAChRs and treatment of diseases associated with defective or with functional disorders of nicotinic acetylcholine receptors, especially in the brain.

69 cl, 55 ex

FIELD: chemistry.

SUBSTANCE: described is a compound selected from a group consisting of formula II formula III and formula IV , or its salt or ester, where G1 is selected from a group which includes - (CR1R2)n-, n equals 0 or 1; R1 and R2 are independently selected from a group which includes hydrogen; X1, X2 and X3 are independently selected from a group consisting of hydrogen, optionally substituted lower alkyl, halogen, optionally substituted lower alkoxy, G2 is a heterocycloalkyl linker optionally substituted with X4 and X5, where the heterocycloalkyl linker is selected from a group consisting of piperazinyl, 3,6-dihydro-2N-pyridinyl, [1,4]diazepanyl, 3,9-diazabicyclo[3,3,1]nonyl; X4 and X5 are independently selected from a group consisting of hydrogen and optionally substituted lower alkyl; CO2R; R is selected from a group consisting of optionally substituted lower alkyl and hydrogen; G3 is a bond; G4 is selected from a group consisting of hydrogen, aryl, selected from phenyl which is optionally substituted with a lower alkyl, halogen, lower haloalkyl or lower haloalkoxy; heteroaryl selected from pyridinyl which is optionally substituted with a halogen or lower haloalkyl; and optionally substituted cycloheteroalkyl selected from 1,3-benzodioxolyl. Described also are specific compounds and a pharmaceutical composition.

EFFECT: disclosed compounds are used as modulators of receptors activated by a peroxisomal proliferator.

5 cl, 2 tbl, 117 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula (I) or their pharmaceutically acceptable salts, where symbols assume values given in the description, where the said compounds are chemokine receptor (CCR-1) antagonists. Also described is a method of inhibiting the chemokine receptor to reduce inflammation in mammals.

EFFECT: possibility of use in treating inflammatory diseases.

8 cl, 160 ex

FIELD: medicine.

SUBSTANCE: there are described new diazabicyclic aryl derivatives of general formula (I), where A', A", L and B, n possess the values as specified in the description which are cholinergic ligands to nicotinic acetylcholine receptors, as well as a based pharmaceutical composition. Owing to their pharmacological profile, the compound according to the invention, can be effective in treating such various diseases or disorders, as those associated with the cholinergic system of central nervous system (CNS), peripheral nervous system (PNS), as those associated with plain muscle contraction, endocrine diseases or disorders, neurodegenerative diseases or disorders, diseases or disorders involving inflammation, pain and abstinence symptoms caused by termination of abusing the chemical substances.

EFFECT: effective with regard to various diseases.

16 cl, 3 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,4-diazabicyclo[3,2,1]octanecarboxamide with general formula (1) , in which X is a nitrogen atom, P and W each independently represent a nitrogen atom or a group with general formula C-R3, Q and R each independently represent a group with general formula C-R3, R1 is a hydrogen atom, R3 is a hydrogen atom or halogen or C1-C6-alkyl, C1-C6-alkoxy, O-Ms. The invention also relates to a medicinal preparation and pharmaceutical composition based on these compounds for treating or preventing disorders, related to malfunction of nicotinic receptors.

EFFECT: obtaining new compounds and a pharmaceutical composition based on the said compounds, which can be used for treating cognition failure and attention failure, or for treating motor, neurological or alerting symptoms related to dependency on different addictive substances.

5 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to quinobenzoxazin analogues with general formula (1) where V represents H, halo-, or NR1R2; NH2, or NR1-(CR12)n-NR3R4; A represents H, fluoro-, or NR12; Z represents O, S, NR1 or CH2; U represents NR1R2; X represents NR1R2 or halo-; n=1-6; where in NR1R2, R1 and R2 can form 5-7-member heterocyclic ring which is optionally substituted and has 1-2 heteroatoms, selected from group consisting of N, O and S; R1 represents H or C1-6alkyl; R2 represents C1-10alkyl optionally including one or more non-adjacent heteroatoms N or O and is optionally substituted with if necessary substituted 3-6-member carbocyclic or 5-14-member heterocyclic ring; or R2 is 5-14-member heterocyclic ring, which has 1-2 heteroatoms, selected from group consisting of N, O or S, 6-member aryl or 5-7member heteroaryl ring, which contains 1-3 heteroatoms, selected from group consisting of N, O and S, each of which can be, if necessary, substituted; R3 represents H or C1-6alkyl; R4 represents H, C1-6alkyl, optionally substituted with 3-6 carbocyclic or 5-14-member heterocyclic ring, or 6-member aryl, R4 and R3, if necessary, can form optionally 5-7-member substituted heterocyclic ring, which contains 1-2 heteroatoms selected from N and O; W represents substituent, such as described in i.1 of invention formula, where Q, Q1, Q2, and Q3 represents independently CH or N; Y represents independently O or CH; R5 represents substituent in any position of closed ring in form of H or OR2; on condition that U is not morpholinyl or 2,4-difluoroaniline, when X represents F or pyrrolidinyl, A is F, Z represents O, and W represents phenylene; each obligatorily substituted fragment being substituted with one or more halogen, C1-6-alkoxy, amino, carbamate, C1-10alkyl, C2-10alkenyl, each of which is optionally substituted with halogen, =O, 6-member aryl or one or more heteroatom, selected from N and O; 6-member aryl, 3-6-member carbocyclic ring or 5-7-member heterocyclic ring containing 1-2 heteroatoms, selected from group, consisting of N and O; or its pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition based on formula (1) compound and to method of treatment of proliferative cell diseases using formula (1) compounds.

EFFECT: obtaining novel quinobenzoxazin analogues possessing useful biological properties.

48 cl, 3 tbl, 50 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new macrocyclic compounds with formula (I): (where R3, R6, R7 and R21 can be identical or different from each other, and each of them assume values given in the description), their salts used in pharmacology and their hydrate. Compounds with formula (I) are capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, and can be used as therapeutic means of treating solid malignant tumours. The invention also relates to medicinal agents based on these compounds, prevention and treatment method and use of these compounds in making preparations for preventing and treating cancerous diseases.

EFFECT: obtaining compounds, capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, which can be used as therapeutic means of treating solid malignant tumours.

35 cl, 3 tbl, 147 ex

FIELD: chemistry.

SUBSTANCE: invention concerns malonamide derivatives of the formulae (IA) or (IB) , and pharmaceutically acceptable acid additive salts of them, where R1, R1',(R2)1,2,3, R3, R4, R14, L, and are such as described in this invention. Also the invention concerns a medicine with inhibition effect on γ-secretase, which can be applied in treatment of Alzheimer's disease.

EFFECT: obtaining new malonamide derivatives with beneficial biological properties.

17 cl, 188 ex

FIELD: medicine; veterinary science.

SUBSTANCE: invention refers to application of compounds with common structural formula

R1=-H, -NH2, -Br, -Cl, -ОН, -СООН,

B=-N=, -CH=, Z=-CH=, -N=,

A=-CH- at B=-N=, Z=-CH-,

A=-CH- at В=-СН=, Z=-CH=,

A=-N= at B=-N=, Z=-CH-,

A=-CH- at B=-N=, Z=-N=,

A=-CH= at В=-СН=, Z=-N=.

Structures of specified formula are active for nitrergic and dopaminergic systems of mammal body including human body. These compounds can be applied as neuroprotectors, to improve cognitive function and to normalise psychophysiologic state, to treat consequences of substance abuse, as well as to treat wide range of diseases including neuropsychic, cardiovascular, immune, inflammatory and gastro-intestinal disorders.

EFFECT: application of new and well-known compound to effect nitrergic and dopaminergic systems for treatment purposes.

4 ex, 3 tbl, 8 dwg

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of imidazolyl derivative of the general formula (I) wherein each Ra and Rb represents independently (C1-C6)-alkyl, (C1-C6)-alkoxyalkyl, optionally substituted aryl or heteroaryl, or wherein Ra and Rb form in common additional homocyclic or heterocyclic system comprising one or some rings; each Ra' and Rb' represents hydrogen atom, or they in common form a carbon-carbon double bond wherein indicated carbon-carbon double bond is optionally part of aromatic system; Rc represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkoxyalkyl or halogen atom; Rd represents hydrogen atom or (C1-C4)-alkyl; Re represents hydrogen atom or (C1-C4)-alkyl; m = 1 or 2; R1 represents hydrogen atom or (C1-C4)-alkyl, and its salts after addition of acid and wherein compound of the general formula (II) wherein values Ra, Ra', Rb, and Rb' are given above is subjected for interaction with compound of the formula (III) wherein R represents hydrogen atom, (C1-C4)-alkyl group optionally substituted with hydroxy-group, or optionally substituted aryl group; each R', R'', R''' and R'''' represents independently hydrogen atom or (C1-C4)-alkyl group followed by interaction with compound of the formula (IV) wherein R, Rd and Re have values given above and the following optional interaction with the corresponding acid. Proposed method shows high effectiveness for synthesis of ondansetron and cilansetron.

EFFECT: improved method of synthesis.

10 cl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of [1,4]diazepino[6,7,1-IJ]-quinoline of the general formula (I): wherein R1 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkanoyl or (C7-C11)-carboarylalkoxy-group; each R2 and R3 represents independently hydrogen atom, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, halogen atom, (C2-C6)-carboalkyloxy-group, (C1-C6)-perfluoroalkyl, (C2-C6)-alkanoyloxy-group, (C2-C6)-alkanoyl, (C6-C8)-aroyl, (C5-C7)-aryl, (C6-C13)-alkylaryl having 5-7 carbon atoms in aryl moiety; R4 and R5 represents independently hydrogen atom or (C1-C6)-alkyl, or R4 and R5 taken in common with carbon atoms with which they are bound form cyclic group chosen from (C4-C8)-cycloalkane, (C4-C8)-cycloalkene; each R6 and R7 represents independently hydrogen atom or (C1-C6)-alkyl; n = 1 or 2; a dotted line means a double bond optionally. Also, invention describes using compounds of the formula (I) in preparing a drug used in treatment of different psychotic disorders. Also, invention relates to a pharmaceutical composition possessing activity as 5-HT2C antagonist based on proposed compounds, and a method for synthesis of compounds of the formula (I). Invention provides synthesis of novel compounds, preparing a pharmaceutical composition and a drug based on thereof.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

53 cl, 1 tbl, 34 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula (I): wherein Y represents lower alkylene; R1 represents phenyl substituted with one or two similar or different substitutes taken among a group including lower alkoxy-group, mono- (or di-, or tri-)-halogen-lower)-alkyl, nitro-, amino-, lower alkylamino-, di-(lower)-alkylamino-, lower alkylthio-group,alkylsulfonyl, lower alkylaminosulfonyl, di-(lower)-alkylaminosulfonyl, and pyrrolyl; R2 means phenyl substituted with hydroxy-group at position 3 and with lower alkyl and halogen atom additionally; R3 means hydrogen atom; R4 represents (2,6-dimethylmorpholino)-(lower)-alkyl, (2-methoxymethylmorpholino)-(lower)-alkyl, (3-methoxymethylmorpholino)-(lower)-alkyl. Also, invention relates to their pharmaceutically acceptable salts, to method for their preparing, pharmaceutical composition and a method for vomiting inhibition. Proposed compounds are antagonists of tachykinin and can be used for vomiting inhibition.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

9 cl, 47 ex

The invention relates to medicine, specifically to 2-(2'-hydroxy-2'-substituted)ethyl-1,2,3,4-tetrahydropyrrolo[1,2-a] pyrazines or their fumarate with antiarrhythmic and antiischemic activity

The invention relates to novel condensed polycyclic heterocyclic compounds of the formula I and the way they are received

The invention relates to new, containing in the 3-position of the indole ring is substituted piperazinylcarbonyl the rest of 1.7-bellrowan derivatives of indole and their salts, to the way they are received, as well as containing these compounds, pharmaceutical compositions and the intermediate product to obtain these compounds

FIELD: medicine, pharmaceutics.

SUBSTANCE: according to the invention, a pharmaceutical composition contains aripiprazole metabolite combined with serotonin reuptake inhibitor. Aripiprazole metabolite is chosen from dehyoaripiprazole DM-1458, DM-1451, DM-1452, DM-1454 or DCPP. Aripiprazole metabolite is a stabiliser of dopamine-serotonin system. Serotonin reuptake inhibitor can be fluoxetine, duloxetine, venlafaxine, milnaciprane, citalopram, fluvoxamine, paroxetin, sertraline or escitalopram and their salts. The pharmaceutical composition contains one weight part of said aripiprazole metabolite and 0.01 to 50 weight parts of said serotonin reuptake inhibitor. The pharmaceutical composition under the invention can be used for treating the patients with phrenopathies, particularly with depression or major depressive disorder.

EFFECT: pharmaceutical composition is effective and does not cause by-effects.

22 cl, 8 dwg, 3 tbl, 9 ex

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