Derivatives of heteroarylalkylpiperazine and pharmaceutical composition based on thereof

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of heteroarylalkylpiperazine of the general formula (I):

wherein m = 1, 2 or 3; q means NH or oxygen atom (O); R1, R2, R3, R4 and R5 are taken independently among the group including hydrogen atom, (C1-C15)-alkyl, OR20 wherein R20 represents hydrogen atom; R6, R7 and R8 represent hydrogen atom; R9, R10, R11, R12, R13, R14, R15 and R16 are taken independently among the group including hydrogen atom, (C1-C4)-alkyl; or R9 and R10 in common with carbon atom to which they are joined form carbonyl group; R17 means heteroaryl that is taken among the group including indolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, pyridyl, benzopyrazinyl substituted optionally with 1-2 substitutes taken among the group including hydrogen atom, CF3 group, (C1-C8)-alkyl, phenyl, CON(R20)2. Compounds elicit property as a partial inhibitor of oxidation of fatty acids and can be used in therapy for protection of skeletal muscles against results of muscular or systemic diseases. Also, invention describes a pharmaceutical composition based on the claimed compounds.

EFFECT: valuable medicinal properties of compounds.

39 cl, 3 tbl, 25 ex

 

Description

Background of the invention

1. The technical field

The present invention relates to piperazine derivatives, dosage forms containing one or more of these derivatives, and methods of treatment of mammals, in particular humans, including protection of skeletal muscles against damage resulting from trauma, protection of skeletal muscle from the effects of muscle or systemic diseases such as intermittent claudication, treatment of shock, protection of donor tissue and organs used in transplants, and treatment of cardiovascular diseases including atrial and ventricular premature beats, angina Prinzmetala (changeable), persistent angina and angina exercise, congestive heart failure, and myocardial infarction.

2. The level of technology

In U.S. patent No. 4567264, which are included in this description by reference, describes a class of compounds substituted piperazine, which includes a compound known as ranolazine, (±)-N-(2,6-dimetilfenil)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazineethanol, and its pharmaceutically acceptable salts, and the use of these substances for the treatment of cardiovascular disease, including arrhythmias, unstable angina, angina physical activity is myocardial infarction.

In U.S. patent No. 5506229, which are included in this description by reference, describes the use of ranolazine, its pharmaceutically acceptable salts and esters for the treatment of tissue subjected to physical or chemical lesion, including cardioplegia, hypoxia or reperfusion of cardiac or skeletal muscle or brain tissue, and for use in transplants. In particular, ranolazine especially useful for treatment of arrhythmia, volatile angina, angina exercise and myocardial infarction due to partial inhibition of fatty acid oxidation in the tissues of the heart. In the mentioned patent are considered the drugs of ranolazine for oral and parenteral administration, including acting drugs. For example, in example 7D U.S. patent No. 5506229 described the prolonged action drug capsules containing microspheres of ranolazine and microcrystalline cellulose coated with polymers, which regulates the release of the active substance.

Despite the important discovery that ranolazine is a very useful tool for the treatment of heart disease, there is still a need for compounds which are partial inhibitor of fatty acid oxidation, which are characterized by a longer half-life compared to what amolatina and have at least the same activity, as ranolazine.

A brief statement of the substance of the invention

The present invention relates to new derivatives heterooligomerization, which is a partial inhibitor of fatty acid oxidation with a long half-life.

This invention relates to new compounds substituted piperazine, which can be introduced mammal protection of skeletal muscles against damage resulting from trauma, to protect skeletal muscle from the effects of muscle or systemic diseases such as intermittent claudication, for the treatment of shock States, for protection of donor tissue and organs used in transplants, and for the treatment of cardiovascular diseases including atrial and ventricular premature beats, angina Prinzmetala (changeable), persistent angina and angina exercise, congestive heart failure, and myocardial infarction.

This invention relates to a class of compounds substituted piperazine of the formula

where m is 1, 2 or 3;

q indicates NH, O or S;

R1, R2, R3, R4and R5independently selected from the group comprising hydrogen, halogen, NO2, CF3CN, OR20, SR20N(R20)2, S(O)R22, SO2R22, SO2N(R20/sup> )2, NR20CO2R22, NR20CON(R20)2, COR20, CO2R20, CON(R20)2, NR20SO2R22C1-15alkyl, C2-15alkenyl,2-15quinil, heterocyclyl, aryl and heteroaryl, where the alkyl and aryl substituents optionally substituted by 1 Deputy chosen from the group comprising halogen, NO2, CF3CN, OR20, SR20N(R20)2, S(O)R22and SO2R22or R1and R2or R2and R3or R3and R4or R4and R5together with the carbon atoms to which they are attached, may form a 6-membered aromatic ring, which is optionally substituted by alkyl, triptorelin, alkoxy or halogen;

R6, R7and R8independently selected from the group comprising hydrogen or C1-3alkyl;

R9, R10, R11, R12, R13, R14, R15and R16independently selected from the group comprising hydrogen, CO2R20, CON(R20)2C1-4alkyl or aryl, where alkyl and aryl substituents optionally substituted by 1 Deputy chosen from the group comprising halogen, CF3CN, OR20N(R20)2, CO2R20, CON(R20)2or aryl, or R9and R10may together form a carbonyl, R11/sup> and R12may together form a carbonyl, R13and R14may together form a carbonyl, or R15and R16may together form a carbonyl, R11and R13or R9and R15or R9and R11or R11and R15or R9and R13may together form a ring having from 1 to 3 carbon atoms;

R17means heteroaryl, optionally substituted by 1-3 substituents selected from the group comprising hydrogen, halogen, NO2, CF3CN, OR20, SR20N(R20)2, S(O)R22, SO2R22, SO2N(R20)2, NR20CO2R22, NR20CON(R20)2, COR20, CO2R20, CON(R20)2, NR20SO2R22C1-15alkyl, C2-15alkenyl,2-15quinil, heterocyclyl, aryl or heteroaryl, where the alkyl and aryl substituents optionally substituted by 1 Deputy chosen from the group comprising halogen, NO2, CF3CN, OR20, SR20N(R20)2, S(O)R22or SO2R22;

R20selected from the group including H, C1-15alkyl, aryl or heteroaryl, where the alkyl and aryl substituents optionally substituted by 1 Deputy chosen from the group comprising halogen, alkyl, mono - or dialkylamino, alkyl-CN,-O-C 1-6alkyl or CF3; and

R22selected from the group including1-15alkyl, aryl or heteroaryl, where the alkyl and aryl substituents optionally substituted by 1 Deputy chosen from the group comprising halogen, alkyl, monoalkylamines, dialkylamines, alkylamide, arylamide, heteroaryl, CN, O-C1-6alkyl, CF3or heteroaryl.

Another variant of implementation of the present invention relates to substituted connection piperazine selected from the group including

N-(2,6-dimetilfenil)-2-(4-{2-hydroxy-3-[2-(3-triptoreline)-benzoxazol-5-yloxy]propyl}piperazine-1-yl)acetamide", she

2-{4-[3-(benzothiazol-2-yloxy)-2-hydroxypropyl]piperazine-1-yl}-N-(2,6-dimetilfenil)-ndimethylacetamide,

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazine-1-yl}acetamide", she amide

4-(3-{4-[(2,6-dimethylphenylcarbamate)methyl]piperazine-1-yl}-2-hydroxypropoxy)-1H-indole-2-carboxylic acid,

2-{4-[3-(benzothiazol-6-yloxy)-2-hydroxypropyl]piperazine-1-yl}-N-(2,6-dimetilfenil)ndimethylacetamide,

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-6-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl] - for 3,5-dimethylpiperazine-1-yl}ndimethylacetamide, 2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazine-1-yl}-N-(4-hydroxyphenyl)ndimethylacetamide,

N-(2,6-dimetilfenil)-2-{4-[2-g is droxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-phenylbenzoxazole-5-yloxy)propyl)piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-7-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-methyl-benzothiazol-5-yloxy)propyl]-2-oxopiperidin-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-(4-{2-hydroxy-3-[2-(4-triptoreline)benzoxazol-5-yloxy]propyl}piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-(hydroxy-3-(cinoxacin-2-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(pyridine-3-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(quinoline-4-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(isoquinoline-5-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(quinoline-6-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylinosine-7-yl-oxy)propyl]piperazine-1-yl}acetamide", she

2-{4-[3-(benzothiazol-2-ylamino)-2-hydroxypropyl]piperazinil}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[3-(benzoxazol-2-ylamino)-2-hydroxypropyl]piperazinil}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,5-dimethylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide

2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,6-dimethylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3,3-dimethylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{(3S)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{(2R)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,6-dimethylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](1,4-disabilitating)}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-(4-hydroxyphenyl)ndimethylacetamide,

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,6-dimethylpiperazine}-N-(4-carboxamidine)ndimethylacetamide,

2-{(3S)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2R)-2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazinil}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)is ropyl]piperazinil}-N-(2,6-dimethyl-4-hydroxyphenyl)ndimethylacetamide,

2-{5-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-(4-sulfamoylbenzoyl)ndimethylacetamide,

2-{(3S)-4-[(2S)-2-hydroxy-3-(2-phenyl-benzoxazol-5-yloxy)propyl]-3-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-naphthylacetamide,

N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}ndimethylacetamide,

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-phenylacetamide,

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-(3,4,5-trichlorophenyl)ndimethylacetamide,

2-{4-[2-hydroxy-3-(4-methoxyphenyl)-propyl]piperazinil}-N-(3,4,5-trichlorophenyl)ndimethylacetamide,

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-(2-chloro-4-were)ndimethylacetamide,

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-(3,4,5-trichlorophenyl)ndimethylacetamide,

2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazinil}-N-(3,5-dichlorophenyl)acetamide", she

2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazinil}-N-(3,4-dichlorophenyl)acetamide", she

2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazinil}-N-[3-methoxy-5-(trifluoromethyl)phenyl]acetamide", she

2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)about the Il]piperazinil}-N-[3,5-dichlorophenyl]-ndimethylacetamide and

2-{4-[2-hydroxy-3-(2-((1E)buta-1,3-dienyl)-benzothiazole-5-yloxy)propyl]piperazinil}-N-[4-chloro-2-methoxy-5-were]ndimethylacetamide.

Another variant implementation of the present invention relates to a method for introducing to a mammal one or more compositions according to this invention for protection of skeletal muscles against damage resulting from trauma, to protect skeletal muscle from the effects of muscle or systemic diseases such as intermittent claudication, for the treatment of shock States, for protection of donor tissue and organs used in transplants, and for the treatment of cardiovascular diseases including atrial and ventricular premature beats, angina Prinzmetala (changeable), persistent angina and angina exercise, congestive heart failure or myocardial infarction.

Detailed description of the invention

The class of compounds substituted piperazine of the formula

where m is 1, 2 or 3;

q indicates NH, O or S;

R1, R2, R3, R4and R5independently selected from the group comprising hydrogen, halogen, NO2, CF3CN, OR20, SR20N(R20)2, S(O)R22, SO2R22, SO2N(R20)2, NR20CO2R22, NR20CON(R20)2, COR20, CO2Rsup> 20, CON(R20)2, NR20SO2R22C1-15alkyl, C2-15alkenyl,2-15quinil, heterocyclyl, aryl and heteroaryl, where the alkyl and aryl substituents optionally substituted by 1 Deputy chosen from the group comprising halogen, NO2, CF3CN, OR20, SR20N(R20)2, S(O)R22and SO2R22or R2and R3or R3and R4or R4and R5together with the carbon atoms to which they are attached, may form a 6-membered aromatic ring, which is optionally substituted by alkyl, triptorelin, alkoxy or halogen;

R6, R7and R8independently selected from the group comprising hydrogen or C1-3alkyl;

R9, R10, R11, R12, R13, R14, R15and R16independently selected from the group comprising hydrogen, CO2R20, CON(R20)2C1-4alkyl or aryl, where alkyl and aryl substituents optionally substituted by 1 Deputy chosen from the group comprising halogen, CF3CN, OR20N(R20)2, CO2R20, CON(R20)2or aryl, or R9and R10may together form a carbonyl, R11and R12may together form a carbonyl, R13and R14can put together to form arbonyl or R 15and R16may together form a carbonyl, R11and R13or R9and R15or R9and R11or R11and R15or R9and R13may together form a ring having from 1 to 3 carbon atoms;

R17means heteroaryl, optionally substituted by 1-3 substituents selected from the group comprising hydrogen, halogen, NO2, CF3CN, OR20, SR20N(R20)2, S(O)R22, SO2R22, SO2N(R20)2, NR20CO2R22, NR20CON(R20)2, COR20, CO2R20, CON(R20)2, NR20SO2R22C1-15alkyl, C2-15alkenyl,2-15quinil, heterocyclyl, aryl or heteroaryl, where the alkyl and aryl substituents optionally substituted by 1 Deputy chosen from the group comprising halogen, NO2, CF3CN, OR20, SR20N(R20)2, S(O)R22or SO2R22;

R20selected from the group including H, C1-15alkyl, aryl or heteroaryl, where the alkyl and aryl substituents optionally substituted by 1 Deputy chosen from the group comprising halogen, alkyl, mono - or dialkylamino, alkyl-CN, -O-C1-6alkyl or CF3; and

R22selected from the group including1-15alkyl, aryl or heteroaryl where Alki the performance communications and aryl substituents optionally substituted by 1 Deputy selected from the group including halogen, alkyl, monoalkylamines, dialkylamines, alkylamide, arylamide, heteroaryl, CN, O-C1-6alkyl, CF3or heteroaryl.

In a preferred embodiment of the invention q indicates NH or O.

In a preferred embodiment of the invention R1, R2, R3, R4and R5independently selected from the group comprising hydrogen, halogen, CF3CN, OR20, SR20N(R20)2, SO2N(R20)2, CO2R20, CON(R20)2C1-8alkyl, C2-8alkenyl,2-8quinil, heterocyclyl, aryl or heteroaryl, where the alkyl and aryl substituents optionally substituted by 1 Deputy chosen from the group comprising halogen, NO2, CF3CN, OR20, SR20N(R20)2, S(O)R22or SO2R22. In another preferred embodiment of the invention R1, R2, R3, R4and R5independently selected from the group comprising hydrogen, halogen, CF3, OR20C1-5alkyl, C2-5alkenyl or2-5quinil, where the alkyl substituent optionally substituted CF3. In another preferred embodiment of the invention R1, R2, R3, R4and R5independently selected from the group comprising hydrogen, halogen, CFsub> 3, OR20or1-3alkyl, where the alkyl substituent optionally substituted CF3. More preferably R1, R2, R3, R4and R5independently selected from the group including hydrogen, CF3, OR20or1-2alkyl, and more preferred are hydrogen, OR20or methyl, and most preferred are hydrogen or methyl.

In an alternative preferred embodiment of the invention, any element of R1and R2or R2and R3or R3and R4or R4and R5together with the carbon atoms to which they are attached, may form a 6-membered aromatic ring, which is optionally substituted by alkyl, triptorelin, alkoxy or halogen and where the remaining substituents have the values listed in the above paragraph. In this embodiment of the invention most preferably, if R2and R3together with the carbon atoms to which they are attached, form a 6-membered aromatic ring.

In a preferred embodiment of the invention R6, R7and R8independently selected from the group comprising hydrogen or C1-3alkyl and most preferably hydrogen or methyl.

In a preferred embodiment of the invention R9, R10 , R11, R12, R13, R14, R15and R16independently selected from the group including hydrogen, CON(R20)2With1-4alkyl, or R9and R10may together form a carbonyl, R11and R12may together form a carbonyl, R13and R14may together form a carbonyl, or R15and R16may together form a carbonyl. In another embodiment of the invention R9, R10, R11, R12, R13, R14, R15and R16independently selected from the group comprising hydrogen or C1-2alkyl, or R9and R10may together form a carbonyl, R11and R12may together form a carbonyl, R13and R14may together form a carbonyl, or R15and R16may together form a carbonyl. In a more preferred embodiment of the invention R9, R10, R11, R12, R13, R14, R15and R16independently selected from the group comprising hydrogen or methyl, or R9and R10may together form a carbonyl, R11and R12may together form a carbonyl, R13and R14may together form a carbonyl, or R15and R16can put together the e to form a carbonyl. In another embodiment of the invention R9, R10, R11, R12, R13, R14, R15and R16independently selected from the group comprising hydrogen or C1-2alkyl, where the alkyl substituent optionally substituted by 1 Deputy selected from the group including N(R20)2or aryl, or R9and R10may together form a carbonyl. In another preferred embodiment of the invention R9, R10, R11, R12, R13, R14, R15and R16independently selected from the group comprising hydrogen or C1-2alkyl, or R9and R10may together form a carbonyl. In another preferred embodiment of the invention R11and R15selected from the group comprising hydrogen or methyl, R9, R10, R12, R13, R14and R16mean hydrogen and R9and R10may together form a carbonyl. In another preferred embodiment of the invention, all elements of R9, R10, R11, R12, R13, R14, R15and R16mean hydrogen.

In one preferred embodiment of the invention R17means heteroaryl, optionally substituted with 1-2 substituents selected from the group comprising hydrogen, halogen, CF 3, OR20N(R20)2, CON(R20)2C1-3alkyl, aryl or heteroaryl, where the alkyl and aryl substituents optionally substituted by 1 Deputy independently selected from the group including halogen, CF3, OR20or N(R20)2. In another embodiment of the invention R17means heteroaryl representing condensed 6,5-membered ring system, having from 1 to 5 heteroatoms selected from the group comprising N, O or S that is optionally substituted by 1-3 substituents selected from the group comprising hydrogen, halogen, NO2, CF3CN, OR20, SR20N(R20)2, S(O)R22, SO2R22, SO2N(R20)2, NR20CO2R22, NR20CON(R20)2, COR20, CO2R20, CON(R20)2, NR20SO2R22C1-15alkyl, C2-15alkenyl,2-15quinil, heterocyclyl, aryl or heteroaryl, where the alkyl and aryl substituents optionally substituted by 1 Deputy independently selected from the group including halogen, NO2, CF3CN, OR20, SR20N(R20)2, S(O)R22or SO2R22. In this embodiment of the invention R17preferably means heteroaryl representing condensed 6,5-membered ring system, have th from 1 to 3 heteroatoms, selected from the group comprising N, O or S that is optionally substituted with 1-2 substituents selected from the group comprising hydrogen, halogen, CF3, OR20N(R20)2, CON(R20)2C1-8alkyl, C2-8alkenyl,2-8quinil, aryl or heteroaryl, where the alkyl and aryl substituents optionally substituted by 1 Deputy independently selected from the group including halogen, CF3, OR20or N(R20)2. More preferably R17means heteroaryl representing condensed 6,5-membered ring system, having 1 to 2 heteroatoms selected from the group comprising N, O or S that is optionally substituted with 1-2 substituents selected from the group comprising hydrogen, halogen, CF3, OR20N(R20)2, CON(R20)2C1-3alkyl, aryl or heteroaryl, where the alkyl and aryl substituents neonatale substituted 1 Deputy chosen from the group comprising halogen, CF3or or20. More preferably in this embodiment of the invention R17means heteroaryl representing condensed 6,5-membered ring system selected from the group including indole, benzothiazole and benzoxazole, which optionally is substituted by 1-2 substituents selected from the group comprising hydrogen, halogen, CF 3, OR20N(R20)2, CON(R20)2With1-3alkyl, aryl or heteroaryl, where the alkyl and aryl substituents optionally substituted by 1 Deputy chosen from the group comprising halogen, CF3or or20. In this preferred embodiment of the invention R17preferably means benzothiazole, optionally substituted 1 Deputy chosen from the group comprising hydrogen, halogen, CF3, OR20N(R20)2, CON(R20)2C1-3alkyl or aryl, where alkyl and aryl substituents optionally substituted by 1 Deputy chosen from the group comprising halogen or CF3. More preferably R17means benzothiazole, optionally substituted in position 2 by a single Deputy, selected from the group comprising hydrogen, methyl or phenyl. In an alternative preferred embodiment of the invention R17means of 5-substituted benzothiazole which is optionally substituted by 1 Deputy chosen from the group comprising hydrogen, halogen, CF3, OR20N(R20)2, CON(R20)2C1-3alkyl or aryl, where alkyl and aryl substituents optionally substituted by 1 Deputy chosen from the group comprising halogen or CF3. 5-Substituted benzothiazole preferably substituted, position 2 one Deputy, selected from the group comprising hydrogen, methyl or phenyl.

In another preferred embodiment of the invention R17means heteroaryl representing condensed 6,6-membered ring system, having from 1 to 4 nitrogen atoms, which optionally is substituted by 1-3 substituents selected from the group comprising hydrogen, halogen, NO2, CF3CN, OR20, SR20N(R20)2, S(O)R22, SO2R22, SO2N(R20)2, NR20CO2R22, NR20CON(R20)2, COR20, CO2R20, CON(R20)2, NR20SO2R22C1-15alkyl, C2-15alkenyl,2-15quinil, heterocyclyl, aryl or heteroaryl, where the alkyl and aryl substituents optionally substituted by 1 Deputy independently selected from the group including halogen, NO2, CF3CN, OR20, SR20N(R20)2, S(O)R22or SO2R22. More preferably R17means heteroaryl representing condensed 6,6-membered ring system, having from 1 to 3 nitrogen atoms, which optionally is substituted by 1-2 substituents selected from the group comprising hydrogen, halogen, CF3, OR20N(R20)2, CON(R20)2With1-8alkyl, C2-8alkenyl,2-8quinil, aryl or heteroaryl, where skylinee and aryl substituents optionally substituted by 1 Deputy independently selected from the group including halogen, CF3, OR20or N(R20)2. Most preferably, R17means heteroaryl representing condensed 6,6-membered ring system, having 1 to 2 nitrogen atoms, which is optionally substituted by stands.

In another preferred embodiment of the invention R17means 5 - or 6-membered ring having from 1 to 3 heteroatoms selected from the group comprising N, S or O, which is optionally substituted by 1-3 substituents selected from the group comprising hydrogen, halogen, NO2, CF3CN, OR20, SR20N(R20)2, S(O)R22, SO2R22, SO2N(R20)2, NR20CO2R22, NR20CON(R20)2, COR20, CO2R20, CON(R20)2, NR20SO2R22C1-15alkyl, C2-15alkenyl,2-15quinil, heterocyclyl, aryl or heteroaryl, where the alkyl and aryl substituents optionally substituted by 1 Deputy, optionally selected from the group including halogen, NO2, CF3CN, OR20, SR20N(R20)2, S(O)R22or SO2R22. More preferably R17means 5 - or 6-membered ring having from 1 to 3 heteroatoms selected from N, S or O, which optionally is substituted by 1-2 substituents selected from the group comprising hydrogen, halogen, CF3, OR20N(R20)2, CON(R20)2C1-8alkyl, C2-8alkenyl,2-8quinil, aryl or heteroaryl, where the alkyl and aryl substituents optionally substituted by 1 Deputy independently selected from the group including halogen, CF3, OR20or N(R20)2. More preferably R17mean 6-membered ring having 1 to 2 nitrogen atoms, which optionally is substituted by 1-2 substituents selected from the group comprising hydrogen, halogen, CF3, OR20N(R20)2, CON(R20)2C1-8alkyl, C2-8alkenyl,2-8quinil, aryl or heteroaryl, where the alkyl and aryl substituents optionally substituted by 1 Deputy independently selected from the group including halogen, CF3, Or SIG20or N(R20)2. Most preferably in this embodiment of the invention R17mean 6-membered ring having 1 to 2 nitrogen atoms, which is optionally substituted by stands.

In another preferred embodiment of the invention R17means heteroaryl representing condensed 6,5-membered ring system selected from the group including benzothiazole and benzoxazole, which is optionally substituted by 1 Deputy chosen from the group including the cabbage soup hydrogen, CF2, OR20With1-3alkyl or aryl, where alkyl and aryl substituents optionally substituted by 1 Deputy chosen from the group comprising halogen or CF3and preferably optionally substituted stands.

In a preferred embodiment of the invention R20selected from the group including H, C1-15alkyl, aryl or heteroaryl, where the alkyl and aryl substituents optionally substituted by 1 Deputy chosen from the group comprising halogen, alkyl, monoalkylamines, dialkylamines, alkylene, -O-C1-6alkyl or CF3. R20selected from the group including H, C1-5alkyl, aryl or heteroaryl, where the alkyl and aryl substituents optionally substituted by 1 Deputy chosen from the group comprising halogen, -OMe or CF3. In a more preferred embodiment of the invention R20selected from the group including H, C1-3alkyl or aryl, where alkyl and aryl substituents optionally substituted by 1 Deputy chosen from the group comprising halogen, -OMe and CF3. Most preferably, R20selected from the group comprising H or C1-3alkyl and particularly preferably H or methyl.

In a preferred embodiment of the invention R22selected from the group including1-15alkyl, aryl or g is tetraaryl, where the alkyl and aryl substituents optionally substituted by 1 Deputy chosen from the group comprising halogen, alkyl, monoalkylamines, dialkylamines, alkylamide, arylamide, heteroaryl, CN, O-C1-6alkyl, CF3or heteroaryl.

The most preferable implementation of the present invention relates to the connection of substituted piperazine selected from the group including

N-(2,6-dimetilfenil)-2-(4-{2-hydroxy-3-[2-(3-triptoreline)benzoxazol-5-yloxy]propyl}piperazine-1-yl)acetamide", she

2-{4-[3-(benzothiazol-2-yloxy)-2-hydroxypropyl]piperazine-1-yl}-N-(2,6-dimetilfenil)ndimethylacetamide,

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazine-1-yl}acetamide", she

amide 4-(3-{4-[(2,6-dimethylphenylcarbamate)methyl]piperazine-1-yl}-2-hydroxypropoxy)-1H-indole-2-carboxylic acid,

2-{4-[3-(benzothiazol-6-yloxy)-2-hydroxypropyl]piperazine-1-yl}-N-(2,6-dimetilfenil)ndimethylacetamide,

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-6-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl] - for 3,5-dimethylpiperazine-1-yl}acetamide", she

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazine-1-yl}-N-(4-hydroxyphenyl)ndimethylacetamide,

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2{4-[2-hydroxy-3-(2-phenylbenzoxazole-5-yloxy)propyl)piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-7-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2-oxopiperidin-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-(4-{2-hydroxy-3-[2-(4-triptoreline)benzoxazol-5-yloxy]propyl}piperazine-1-yl)acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-(hydroxy-3-(cinoxacin-2-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(pyridine-3-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(quinoline-4-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(isoquinoline-5-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(quinoline-6-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylinosine-7-yloxy)propyl]piperazine-1-yl}acetamide", she

2-{4-[3-(benzothiazol-2-ylamino)-2-hydroxypropyl]piperazinil}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[3-(benzoxazol-2-ylamino)-2-hydroxypropyl]piperazinil}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,5-dimethylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,6-dimethylpiperazine}-N-(2,6-dimethylphenyl is)ndimethylacetamide,

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3,3-dimethylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{(3S)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{(2R)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,6-dimethylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](1,4-disabilitating)}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-(4-hydroxyphenyl)ndimethylacetamide,

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,6-dimethylpiperazine}-N-(4-carboxamidine)ndimethylacetamide,

2-{(3S)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2R)-2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazinil}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-(2,6-dimethyl-4-hydroxyphenyl)ndimethylacetamide,

2-{5-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)is ropyl]-2,5-diazabicyclo-[2.2.1]hept-2-yl}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-(4-sulfamoylbenzoyl)ndimethylacetamide,

2-{(3S)-4-[(2S)-2-hydroxy-3-(2-phenylbenzoxazole-5-yloxy)propyl]-3-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-naphthylacetamide,

N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}ndimethylacetamide,

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-phenylacetamide,

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-(3,4,5-trichlorophenyl)ndimethylacetamide,

2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinil}-N-(3,4,5-trichlorophenyl)ndimethylacetamide,

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-(2-chloro-4-were)ndimethylacetamide,

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-piperazinil}-N-(3,4,5-trichlorophenyl)ndimethylacetamide,

2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazinil}-N-(3,5-dichlorophenyl)acetamide", she

2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazinil}-N-(3,4-dichlorophenyl)acetamide", she

2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazinil}-N-[3-methoxy-5-(trifluoromethyl)phenyl]acetamide", she

2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazinil}-N-[3,5-dichlorophenyl]ndimethylacetamide and

2-{4-[2-hydroxy-3-(2-((1E)buta-1,3-dienyl)benzothiazol-5-yloxy)propyl]PIP is retinyl}-N-[4-chloro-2-methoxy-5-were]ndimethylacetamide.

Below are definitions of terms used in this description.

“Halogen”used separately or in combination, denotes all the Halogens, i.e. chlorine (Cl), fluorine (F), bromine (Br), iodine (I).

“Hydroxyl” means the group-HE.

“Thiol” or “mercapto” refers to the group-SH.

“Alkyl”, used alone or in combination, means derived from alkane radical having 1-20, preferably 1-15 carbon atoms (except where otherwise stated). The term represents an alkyl straight chain alkyl and branched-chain or cycloalkyl. Alkyl groups are straight or branched chain, preferably having 1-15 carbon atoms, more preferably 1 to 8 carbon atoms, more preferably 1-6 carbon atoms, particularly preferably 1-4 carbon atoms and most preferably 1-2 carbon atoms, are groups such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like. The term “lower alkyl” used to describe the above-mentioned alkyl group with a straight chain. Cycloalkyl groups are preferably monocyclic, bicyclic or tricyclic ring system having 3-8, more preferably 3-6 members in a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted and the like. Alkyl also represent alkyl group with straight or branched chain, which contains cycloalkyl part or divided specified part. An alkyl group with straight or branched-chain can be attached to any active site with the formation of stable compounds. Examples of such groups include, but are not limited to, 4-(isopropyl)cyclohexylmethyl or 2-methylcyclopropene. Substituted alkyl represents the above-mentioned alkyl group with a straight chain alkyl group, branched chain or cycloalkyl group, which is independently substituted by 1 to 3 groups or substituents including halogen, hydroxy, alkoxy, alkylthio, alkylsulfonyl, alkylsulfonyl, acyloxy, aryloxy, heteroaromatic, amino group, optionally mono - or disubstituted by alkyl, aryl or heteroaryl groups, amidino, urea, optionally substituted alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl, optionally N-mono - or N,N-disubstituted by alkyl, aryl or heteroaryl groups, alkylsulfonyl, arylsulfonyl, heteroarylboronic alkylcarboxylic, arylcarboxamide, heteroarylboronic or the like.

“Alkenyl used separately or in combination, means a hydrocarbon group with a straight or branched chain or cyclic hydrocarbon group having 2-20 the volume of carbon preferably 2-17 carbon atoms, more preferably 2-10 carbon atoms, more preferably 2-8 carbon atoms, most preferably 2-4 carbon atoms, having at least one, preferably 1-3, more preferably 1-2, and most preferably one carbon-carbon double bond. If cycloalkyl group pairing more carbon-carbon double bonds makes the aromatic ring. The carbon-carbon double bond can be in cycloalkenes parts except cyclopropyl or in part with a straight or branched chain. Examples alkenyl groups include ethynyl, propenyl, Isopropenyl, butenyl, cyclohexenyl, cyclohexadienyl and the like. Replaced alkenyl is above alkenylphenol group with a straight chain, alkenylphenol group branched chain or cycloalkenyl group independently substituted by 1 to 3 groups or substituents including halogen, hydroxy, alkoxy, alkylthio, alkylsulfonyl, alkylsulfonyl, acyloxy, aryloxy, heteroaromatic, amino group, optionally mono - or disubstituted by alkyl, aryl or heteroaryl groups, amidino, urea, optionally substituted alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl, optionally N-mono - or N,N-disubstituted and kilenyi, aryl or heteroaryl groups, alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkylcarboxylic, arylcarboxamide, heteroarylboronic, carboxy, alkoxycarbonyl, aryloxyalkyl, heteroarylboronic or the like attached to any active site with the formation of stable compounds.

“Quinil”, used separately and in combination, means a hydrocarbon group with a straight or branched chain containing 2 to 20 carbon atoms, preferably 2-17 carbon atoms, more preferably 2-10 carbon atoms, more preferably 2-8 carbon atoms, most preferably 2-4 carbon atoms, having at least one, preferably one carbon-carbon triple bond. Examples etkinlik groups include ethinyl, PROPYNYL, butynyl and the like. Substituted quinil is above quinil straight chain or quinil branched chain, independently substituted by 1 to 3 groups or substituents including halogen, hydroxy, alkoxy, alkylthio, alkylsulfonyl, alkylsulfonyl, acyloxy, aryloxy, heteroaromatic, amino group, optionally mono - or disubstituted by alkyl, aryl or heteroaryl groups, amidino, urea, optionally substituted alkyl, aryl, heteroaryl or heterocyclyl the different groups, aminosulfonyl, optionally N-mono - or N,N-disubstituted by alkyl, aryl or heteroaryl groups, alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkylcarboxylic, arylcarboxamide, heteroarylboronic or the like attached to any active site with the formation of stable compounds.

“Alkylaryl” means a group-R-CR’=CR’’R’’, where R represents lower alkyl or substituted lower alkyl, R’, R’’, R’’ independently represent hydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as specified below.

“Alkylamine” means the group-RC≡CR’, where R represents lower alkyl or substituted lower alkyl, R’ represents hydrogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as specified below.

“Alkoxy” means the group-OR, where R is lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroalkyl, heteroallyl, cycloalkyl, substituted cycloalkyl, cyclogeranyl or substituted cyclogeranyl specified below.

“Alkylthio” means the group-SR, -S(O)n=1-2-R, where R is lower alkyl, substituted lower alkyl, aryl, substituted aryl, aralkyl is whether substituted aralkyl, below).

“Acyl” means a group-C(O)R, where R is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, and similar groups specified below.

“Aryloxy” means the group-OAr, where Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl specified below.

“Amino” means a group NRR’, where R and R’ can independently represent hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, and hetaryl substituted hetaryl, specified below, or acyl.

“Amido” denotes the group-C(O)NRR’, where R and R’ can independently represent hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, and hetaryl substituted hetaryl, specified below.

“Carboxyl” means the group-C(O)or SIG, where R represents hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, and hetaryl substituted hetaryl, specified below.

“Aryl”used alone or in combination, means a phenyl or naphthyl, optionally carbocyclic condensed with cycloalkyl, which preferably has 5-7, more preferably 5-6 members in the ring and/or optionally substituted by 1 to 3 groups or substituents including halogen, hydroxy, alkoxy, alkylthio, alkylsulfonyl, alkylsulfonyl, acyloxy, aryloxy, heteroaromatic, amino group, optionally mono - or di is amestoy alkyl, aryl or heteroaryl groups, amidino, urea, optionally substituted alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl, optionally N-mono - or N,N-disubstituted by alkyl, aryl or heteroaryl groups, alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkylcarboxylic, arylcarboxamide, heteroarylboronic or the like.

“Substituted aryl” means aryl, optionally substituted by one or more functional groups such as halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

“Heterocycle” means a saturated, unsaturated or aromatic carbocyclic group having a single ring (e.g., morpholino, pyridyl or furyl) or multiple condensed rings (e.g., Natterer, Minoxidil, chinoline, indolizinyl or benzo[b]thienyl) and at least one heteroatom, such as N, O or S, within the ring, which may be not substituted or substituted by such groups as halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, ti is l, sulfamido and the like.

“Heteroaryl used separately or in combination, means a monocyclic aromatic ring having 5 or 6 atoms in the ring, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more heteroatoms, preferably 1 to 4 heteroatoms, more preferably 1-3 heteroatoms, more preferably 1-2 heteroatoms independently selected from O, S and N, which is optionally substituted by 1 to 3 groups or substituents including halogen, hydroxy, alkoxy, alkylthio, alkylsulfonyl, alkylsulfonyl, acyloxy, aryloxy, heteroaromatic, amino group, optionally mono - or disubstituted by alkyl, aryl or heteroaryl groups, amidino, urea, optionally substituted alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl, optionally N-mono - or N,N-disubstituted by alkyl, aryl or heteroaryl groups, alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkylcarboxylic, arylcarboxamide, heteroarylboronic or the like. Heteroaryl also includes oxides S or N, such as sulfinil, sulfonyl and N-oxides of tertiary nitrogen atom in the ring. Carbon atom or nitrogen is the place of attachment of the heteroaryl ring with maintaining sustainable aromatice the one ring. Examples of heteroaryl groups are pyridinyl, pyridazinyl, pyrazinyl, hintline, purinol, chinoline, ethenolysis, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxadiazolyl, isothiazolin, tetrazolyl, imidazolyl, triazinyl, furanyl, benzofuran, indolyl, benzothiazolyl, benzoxazolyl and the like. Substituted heteroaryl has a Deputy, joined the active carbon atom or nitrogen with the formation of stable compounds.

“Heterocyclyl used separately or in combination, means a non-aromatic cycloalkyl group having 5 to 10 atoms, of which 1-3 carbon atoms in the ring are replaced by heteroatoms O, S or N and which are optional benzoannelirovannykh or condensed heteroaryl with 5-6 members in the ring and/or optionally substituted, as, for example, in the case of cycloalkyl. Heterocyclyl also includes oxides S or N, such as sulfinil, sulfonyl and N-oxides of tertiary nitrogen atom in the ring. The place of attachment of the carbon atom or nitrogen. Examples heterocyclyl groups are tetrahydrofuranyl, dihydropyridines, piperidinyl, pyrrolidinyl, piperazinil, dihydrobenzofuran, dihydroindole and the like. Substituted heterocyclyl contains substitutional nitrogen attached to the active carbon atom or nitrogen by the research of sustainable connections.

“Substituted heteroaryl” means a heterocycle, optionally mono - or politeley one or more functional groups, such as halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

“Aralkyl” means a group-R-Ar, in which Ar represents an aryl group and R represents lower alkyl or substituted lower alkyl group. Aryl groups can be substituted or substituted by such groups as halogen, lower alkyl, alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

“Heteroalkyl” means a group-R-Het, in which Het represents a heterocyclic group and R represents a lower alkyl group. Heteroalkyl group may not be substituted or substituted by such groups as halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

“Heteroaromatic” means a group-R-HetAr where HetAr the submitted the heteroaryl group and R represents lower alkyl or substituted lower alkyl. Heteroallyl group may not be substituted or substituted, for example, such groups as halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

“Cycloalkyl” means a divalent cyclic or polycyclic alkyl group having 3-15 carbon atoms.

“Substituted cycloalkyl” means cycloalkyl group having one or more substituents, such as halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

“Cyclogeranyl” means cycloalkyl group in which one or more carbon atoms in the ring are replaced by heteroatoms (e.g. N, O, S, or P).

“Substituted cyclogeranyl” means specified cyclogeranyl group which has one or more substituents, such as halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

“Alkylsilanes” means a group-R-is cloaker, in which cycloalkyl is cycloalkyl group and R represents lower alkyl or substituted lower alkyl. Cycloalkyl group may not be substituted or substituted, for example, such groups as halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

“Alkylcyclopentanes” means a group-R-cyclogeranyl, in which R represents lower alkyl or substituted lower alkyl. Cyclogeranyl group may not be substituted or substituted, for example, such groups as halogen, lower alkyl, lower alkoxy, alkylthio, amino, amido, carboxyl, acetylene, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

“Optional”, and “optional” means that the described event or phenomenon can occur or not occur and that the description includes all cases when the specified event or phenomenon occurs, and all cases when the specified event occurs. For example, the term “optional pharmaceutical excipients” means that the described product may contain or not contain any pharmaceutical fill is whether in addition to those specifically indicated and that the described drug is valid for all cases, when optional fillers, and in all cases where they are missing.

The term “treatment” means any therapeutic effect in a mammal, in particular humans, which includes:

(i) prevention of disease in a subject prone to the disease that is not diagnosed;

(ii) suppression of the disease, i.e. the cessation of its development; or

(iii) the weakening of the disease, i.e. achieving regression of the disease.

All of the above embodiments of the invention relates to pharmaceutically acceptable acid additive salts, in particular mono - or dihydrochloride and their mixtures.

Compounds of General formula Ia (q = O) or Ic (q = S) can be obtained in accordance with schemes 1-5. General synthesis of compounds according to this invention is shown in scheme 1. Compound IV can be obtained N-acylation of substituted aniline II 2-substituted chloroacetanilides III. Compound II can be purchased commercially or easily obtained, restoring the corresponding nitrobenzene derivative (acid/SnCl2or catalytic hydrogenation, see Advanced Organic Chemistry, Ed. J. March (1992) A. Wiley-Interscience). Some examples of commercially manufactured substituted anilines corresponding to General formula II, include 2,6-dimethylaniline, 2,3-dimethylaniline, 2-Metylan the Lin, 4-methylaniline, 4-methylaniline, 2,4-dichloroaniline, 3,4-dichloroaniline, 2,5-dichloroaniline, 2,4-dichloroaniline, 2-Chloroaniline, 3-Chloroaniline, 2,6-diptiranjan, 2,5-diptiranjan, 3,4-diptiranjan, 2-ftoranila, 4-ftoranila, 3-ftoranila, 2-fluoro-6-Chloroaniline, 4-fluoro-3-Chloroaniline, 4-acetoacetanilide.

Scheme 1

Compound VI can be obtained by the interaction of the compound IV with N-protected substituted piperazine V when heated in an acceptable solvent (such as DMF, EtOH). It is necessary to protect the nitrogen atom in compound V, only if you want to control the regioselectivity of the joining compound V to compound IV. In some cases, the compound V can be purchased commercially. Examples of commercially produced compounds corresponding to General formula V include 2-methylpiperazine, 2,5-dimethylpiperazine, 2,6-dimethylpiperazine, 2,3,5,6-tetramethylpyrazine, piperazine-2-carboxylic acid, perhydrophenanthrene, 2-aminomethyl-6-methylpiperazine, 2-AMINOETHYLPIPERAZINE, 2-(o-chlorophenyl)piperazine and 2-(m-chlorophenyl)piperazine. Removing protection from compounds VI can be performed under standard conditions (for example, the BOC group can be removed by using TFU, CBZ and benzyl removed by hydrogenation). Compound Ia or Ic can be obtained by the interaction of the compounds with the epoxide VII VIII by heating in an appropriate solvent (ethanol, DMF, CHl 2, THF) or under stirring at room temperature in the presence of lanthanide (III), which is a Lewis acid (Chini, M et al., Tetrahedron Lett., 35:433-36 (1994).

Scheme 2

Epoxide VIII (where m = 1, 2, or 3) can be obtained according to scheme 2. Heating the substituted phenol or thiophenol IX with epichlorohydrin or epibromohydrin, 4-bromo-1,2-epoxybutane and potassium carbonate in acetone or sodium hydride in DMF, you can get epoxide VIII. Compound IX can be purchased commercially by. Examples of commercially produced compounds of formula XI include 2-methyl-5-hydroxybenzothiazole, 2-hydroxybenzothiazole, 8-hydroxyjulolidine, 6-hydroxyquinoline, 4-hydroxyquinoline, 5-hydroxyisoquinoline, 3 hydroxypyridine, 2-finokalia and 4-(imidazol-1-yl)phenol. In some cases, the compound VIII can be purchased commercially. Examples of commercially produced compounds of General formula VIII include 4-glycidyloxy-2-indolocarbazole.

Compound IX can in turn be obtained, removing the protection of the corresponding methyl or benzyl ester (X) with Lewis acids, shown in figure 3 (BBr3BF3and so on, see Advanced Organic Chemistry, Ed. J. March (1992) A. Wiley Intersciences, p. 434). The benzyl esters can also unprotect heating these esters under reflux together with g is droxicam palladium in ethanol/cyclohexene (see Catalytic hydrogenation over platinum metals., P.N. Rylander, Academic Press, New York, NY, (1976), p. 464). Commercially produced methyl esters include 6-methoxy-2-methylbenzothiazole.

Scheme 3

Compound IX can also be obtained by diazotization of the corresponding amino compounds (XI) in accordance with scheme 4 (Boggust, W.A. and Cocker, W. J., Chem. Soc. 1949, 355). Commercially produced amines include 6-aminobenzothiazole.

Scheme 4

6,5-Condensed ring system of compound X can be obtained by cyclization of commercially produced ethers of 2-aminophenol, 2-aminothiophenol or 2-aminoaniline (XII) with a complex areafile (XIII) (Musser, J. H. et al., J. Med. Chem. 1985, 28, 1255-1259) or imitate (XIV) (Gregory, G. I. Et al., J. Chem. Soc. Perkin Trans.1, 1973, 47-51) in accordance with schemes 5 and 6. Commercially produced ethers of aminophenols include 4-methoxy-2-aminophenol, complex areavery include triethylorthoformate and triethylorthoformate, imidate include the hydrochloride of ethylacetamide and hydrochloride of ethylbenzamide.

Scheme 5

Scheme 6

Similar thiophenol compound XII can be obtained from commercially produced compounds XV, interaction with hydrate of sodium disulfide and subsequent reduction with tin and hydrochloric sour the Oh (Dannley, R;l and Zazaris, D. A.; Can. J. Chem. 1965, 43, 2610-2612) in accordance with scheme 7. Commercially produced nitro compounds include 3-nitro-4-chloroanisole.

Scheme 7

Hal=Cl, Br, I; Y=Me, benzil

Imidate XIV can be obtained barbotine gaseous HCl through alcohol solution of commercially produced NITRILES XVI in accordance with scheme 8. Commercially produced NITRILES include benzonitrile, 4-cryptomathematical and 3-cryptomathematical.

Scheme 8

Structureas 6,5-condensed ring system of compound X can also be obtained from commercially produced ethers anilines XVII (Stevens, M.F.G. et al., J. Med. Chem. 1994, 37, 1689-1695) in accordance with scheme 9. Tioned XX can be obtained by the interaction of the reagent Lawesson with Amida XIX, which in turn can be obtained by the interaction of compound XVII with a compound XVIII. Compound XXI is obtained by cyclization of compound XX with ferrocyanide of potassium in basic conditions. Commercially produced ethers anilines include benzyloxyaniline and anisidine.

Scheme 9

General synthesis of compound XXV according to this invention is shown in scheme 10. Compound XXIV can be obtained by removing the protection of the compound XXIII in standard conditions (for example, the BOC-group is removed p and assistance TFU, CBZ and benzyl removed by hydrogenation). Compound XXIII in turn can be obtained by the interaction of the commercially produced similar protected monochlorobenzene formula XXII with a compound IV and sodium hydride in an appropriate solvent (DMF), THF). An example of commercially produced monochlorobenzene includes 4-benzyloxycarbonylamino-2-it.

Scheme 10

General synthesis of compounds Ib (q=NH) this invention are shown in schemes 11 and 12. Compound XXVII can be obtained by heating under reflux compound VII with epoxide XXVI in an acceptable solvent (ethanol, THF). Removing protection from compound XXVII can be performed under standard conditions (for example, the BOC group can be removed by using TFU; CBZ removed by hydrogenation or Pd(OH)2). Compound Ib can be obtained by heating under reflux connection XXVIII with a compound XXIX in an acceptable solvent (ethanol, THF). Commercially produced compound XXIX includes 2-chlorobenzothiazole, 2-chlorobenzoxazole, 2-chloropyridine, 2-chloropyrimidine, 2-chloro-4-(trifluoromethyl)pyrimidine and chlorphenesin.

Scheme 11

Epoxide XXVI, in turn, can be obtained according to scheme 12. Commercially produced compound XXX can be protected under standard conditions (protection of BOC-group implemented Aut using BOC-anhydride; the CBZ protection group perform using CBZ-Cl). Compound XXV can be obtained by the interaction of the compounds XXXI with m-chloroperbenzoic acid in an appropriate solvent (e.g. dichloromethane). An example of commercially produced compounds XXX includes, but is not limited to, allylamine.

Scheme 12

Compound V can be obtained according to scheme 13. Compound XXXIII get method Polman and others (Pohlman et al., J. Org. Chem., 1997, 62, 1016-1022), alkylating compound XXXII alkylhalogenide using tert-BuLi as the base. Restoring the connection XXXIV with DIBORANE, you can get N-benzylamine connection V after removal of N-BOC-protective group using triperoxonane acid (TFU) (recovery method by DIBORANE described in article Jacobson et al., J. Med. Chem. 1999, 42, 1123-1144).

Scheme 13

Compound V can also be obtained by performing a normal reaction mix (for example, EDC or PyBroP) D - or L-amino acids and normal reaction unprotect shown in figure 14 (Cledera, P. et al., Tetrahdron, 1998, p. 12349-12360; Smith, R.A. et al. Bioorg. Med. Chem. Lett. 1998, p. 2369-2374). Restoring diketopiperazine XXXVII by DIBORANE, you can get N-benzylamine connection V.

Scheme 14

Compound V can also be obtained according to scheme 15. They the n XLI can be obtained by bromirovanii aldehydes XXXVIII with subsequent interaction with Ethylenediamine. Compound V can be obtained by subjecting compound XLI catalytic hydrogenation (Bogeso, K. P., et al., J. Med. Chem., 1995, 38, p. 4380-4392). Commercially produced aldehydes include somelady aldehyde.

Scheme 15

Connection V also includes bicyclic homologues piperazine: (1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane 83, 3,8-diazabicyclo[3.2.1]octane 84 and 2,5-diazabicyclo[2.2.2]octane 85.

Commercially produced bicyclic analogues include (1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane 83. Connections 84, 85 and (1R,4R)-isomer of compound 83 can be obtained by methods described in the scientific literature (obtaining compounds 84 and 85 described in the article Sturm, P.A. et al., J. Med. Chem., 1974, 17, 481-487; receiving connection 83 is described in the article Barnish, T. F. and Fox, D.E, J. Org. Chem., 1990, 55, 1684-1687).

Typical examples of the preparation of the compounds shown in the above General schemes shown in schemes 16 to 29, which further illustrate alternative methods of producing compounds of the present invention. In particular, 2,6-methylaniline acelerou 2-chloroacetanilide 2, using saturated bicarbonate and diethyl ether (1:1) as a base and a co-solvent, and receive the derived chloracetamide 3. Connection 5 get, the interaction of compound 3 with piperazine under heating in ethanol. A derivative of piperazine 7 floor which indicate the interaction of compound 5 with the epoxide 6 when both components boiling in ethanol under reflux, as shown in scheme 16. Connection 6 receive heating epichlorohydrin with phenol 8 in acetone in the presence of K2CO3as shown in scheme 17.

Scheme 16

Scheme 17

Derived benzoxazole 8 receive, removing protection from the connection 13 in accordance with the scheme 18. Compound 10 is obtained by condensation of 2-amino-4-methoxyphenol 12. Connection 12 produced by the catalytic hydrogenation of commercially produced 4-methoxy-2-NITROPHENOL 11 and derived benzimidate 13 in accordance with the scheme 19. Compound 13 is obtained from 3-triftormetilfosfinov 14, performing the Pinner reaction (ethanol/anhydrous HCl).

Scheme 18

Scheme 19

Scheme 20

Synthesis of key intermediates used in the preparation of the compounds of the present invention, shown in the diagrams 21-25. Compound 16 is obtained by diazotization of commercially produced 6-aminobenzothiazole in accordance with the scheme 21.

Scheme 21

Compound 19 is obtained by condensation of compound 12 with triethylorthoformate 18, as shown in figure 22.

Scheme 22

Compound 22 can be obtained, vosstanavlivaetsya 21 tin and hydrochloric acid according to scheme 23. Connection 21 are synthesized by the interaction of the connection 20 with the hydrate of sodium disulfide.

Scheme 23

The connection 26 is produced by interaction of compound 25 with reagent Lawesson according to scheme 24. Compound 25 is obtained by interaction of aniline 23 with benzoyl chloride 24. Performing the cyclization thioamide 26 with potassium ferrocyanide in aqueous sodium hydroxide solution, get a mixture of compounds 27 and 28. Compounds 27 and 28 divide column chromatography.

Scheme 24

Connection 27 dibenzyline in accordance with the scheme 25, through the exchange hydrogenolysis using a catalyst Perlmann in ethanol/cyclohexene.

Scheme 25

Synthesis of compound 34 according to this invention is shown in scheme 26. Amide 3 receive in accordance with the scheme 16. The connection 31 receive, exposing the connection 3 to the interaction with the anion monochlorobenzene 30, obtained by treatment with sodium hydride in DMF. The connection 34 receive heating connection 32 with the epoxide 33 in ethanol. The connection 32 receive, removing protection from connection 31 by catalytic dehydrogenation. Epoxide 33 get similar production method of compound 6 shown in scheme 17.

Scheme 26

Synthesis tipi is its connection 39 according to this invention is shown in scheme 27. Synthesis of compound 5 shown above (scheme 16). The connection 36 receive heating under reflux connection 5 with the epoxide 35. The connection 36 is removed protection, making the processing of palladium hydroxide in ethanol/cyclohexene in the conditions of heating under reflux, and receive amine 37. The target compound 39 is produced by interaction of compound 37 with 2 chlorobenzothiazole in ethanol and triethylamine.

Scheme 27

Epoxide 35 synthesized according to scheme 28. Allylamine 40 is subjected to interaction with benzylchloride in dichloromethane, while receiving the connection 42. Epoxide 35 receive as a result of the interaction of m-chloroperbenzoic acid with compound 42.

Scheme 28

Acid additive salts of the compounds of the present invention can be converted into the corresponding free base by treatment acceptable base, such as potassium carbonate or sodium hydroxide, typically in the presence of an aqueous solvent and at a temperature of from about 0 to 100°C. the Free base of the produce by conventional means such as extraction with an organic solvent.

Salts of the compounds according to this invention can vzaimozamenjat, taking advantage of different degrees of solubility and volatility or producing ion processing the exchange resin in an appropriate form. The specified transformation is carried out at a temperature of from about 0°C to the boiling point of the solvent used as protection when performing this reaction. Described active compounds and salts can be entered by any acceptable means of administering drugs. Such methods include oral, parenteral, transcutaneous, subcutaneous, and other means of systemic administration. The preferred method of administration is oral, except in those cases where the subject is not able to swallow any medicine. In such cases, the composition must enter parenteral.

Depending on the proposed method of administration of the composition can be in the form of solid, semi-solid or liquid unit dosage forms such as tablets, suppositories, pills, capsules, powders, liquids, suspensions and the like, and a unit dosage forms preferably should be designed for a single administration of precise dosages. The composition can contain one or more commonly used pharmaceutically acceptable excipients and at least one active compound according to this invention or its pharmaceutically acceptable salt, as well as other drugs, pharmaceutical agents, carriers, adjuvants, razbaby the spruce etc.

The amount of the active compound depends on the mass of the body in need of treatment of a subject, the severity of the disease, the route of administration and prescription of the attending physician. However, the effective dose is usually 0.1 to 30 mg/kg/day, preferably 0.5 to 20 mg/kg/day. For the average person weighing 70 kg effective dose 7-2100 mg/day or preferably 35-1400 mg/day. As described compounds are characterized by the same mechanism of action (partial inhibition of fatty acid oxidation), dose (or shape), used to treat these diseases (protection of skeletal muscles against damage resulting from trauma; protection of skeletal muscle from the effects of muscle or systemic diseases such as intermittent claudication; treatment of shock; protection of donor tissue and organs used in transplants; and the treatment of cardiovascular diseases including atrial and ventricular premature beats, angina Prinzmetala (changeable), persistent angina and angina exercise, congestive heart failure or myocardial infarction)usually are in the same General and preferred ranges.

In solid compositions typically use non-toxic solids, which include, for example, Pharma is iticheskie grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and similar substances. The above active compound may be part of suppositories containing as a carrier polyalkylene glycols, such as propylene glycol. Liquid pharmaceutical compositions can be obtained by dissolving, dispersive, etc. an active compound and optional pharmaceutical adjuvants in the filler, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, with the formation of a solution or suspension. Enter the pharmaceutical composition may optionally also contain minor amounts of nontoxic auxiliary substances such as wetting agents or emulsifying agents, pH-regulating buffering agents and the like, for example sodium acetate, monolaurate sorbitol, sodium acetate, triethanolamine, triethanolamine oleate, etc. Methods for such dosage forms are well known or should be apparent to experts in this area; see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 15thEdition, 1975. Intended for insertion compositions or preparations in any case must contain a therapeutically effective amount of one or more active connection of the clusters that is the number that allows you to effectively reduce the symptoms of the disease in need of treatment of a subject. Intended for oral administration of pharmaceutically acceptable non-toxic composition was prepared using any commonly used excipients, such as, for example, pharmaceutically grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and similar substances. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained-release preparations and the like. These compositions may contain 10%-95% of active ingredient, preferably 1-70%.

Parenteral administration is usually carried out by subcutaneous, intramuscular or intravenous injection. Injectable preparations can be obtained in the form of liquid solutions or suspensions, in the form of solid substances intended for dissolution or suspension in a liquid immediately prior to injection, or as emulsions. Acceptable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like. In addition, intended for insertion pharmaceutical compositions, if desired, can also contain minor amounts of nontoxic auxiliary substances, such as smace the surrounding substances or emulsifiers, pH-regulating buffering agents and the like, for example sodium acetate, monolaurate sorbitol, triethanolamine oleate, etc.

The recently proposed method of parenteral administration is implantation system with a slow or extended release of the active substance, so that the body remains constant level of the input dose. See, for example, U.S. patent No. 3710795, which are included in this description by reference. Another new method involves the oral administration of compositions according to this invention in a unit dosage pharmaceutical form prolonged action using the compositions and/or methods, described in application for U.S. patent No. 09/321522, filed may 27, 1999, which is incorporated in this description by reference.

In the scope of the present invention also includes other methods of administration to a mammal, preferably a human, one or more compounds according to this invention, which include, but are not limited to, bolus, intravenous, percutaneous and subcutaneous administration, inhalation and other routes of administration of drugs known to specialists in this field.

The following examples merely serve to illustrate the invention without limiting the scope of the claims.

Example 1

N-(2,6-Dimetilfenil)-2-(4-{2-g is droxy-3-[2-(3-triptoreline)benzoxazol-5-yloxy]propyl}piperazine-1-yl)ndimethylacetamide (7)

Part a

Synthesis of N-(2,6-dimetilfenil)-2-chloroacetamide (3)

2,6-Dimethylaniline (9,8 g, 81.2 mmol) was dissolved in diethyl ether (100 ml) and a saturated aqueous solution of NaHCO3(100 ml) and the reaction mixture is cooled in a bath with a mixture of water with ice. To the cold solution is added dropwise chlorocatechol 2 (9,17 g, 81.2 mmol) for 2 hours. The mixture is left to warm to room temperature over 14 hours. The mixture is then extracted with ethyl acetate (3×50). The combined organic layers dried over MgSO4filter and concentrate. The residue is triturated in diethyl ether and filtered, obtaining compound 3 as a white solid.

Part b

Synthesis of N-(2,6-dimetilfenil)piperazine-1-ylacetamide (5)

To a solution of compound 3 (5 g, of 25.2 mmol) in ethanol (100 ml) was added piperazine 4 (2.1 g, 25,0 mmol) and N,N-diisopropylethylamine (3.2 g, to 25.2 mmol). The reaction mixture is refluxed for 24 hours. The mixture is then concentrated in vacuo and the residue purified column chromatography (DCM:MeOH, 10:1)to give compound 5.

The part With

Synthesis of 5-(oxiran-2-ylethoxy)-2-[(3-trifluoromethyl)phenyl]benzoxazole (6)

1. Synthesis of 2-amino-4-methoxyphenol (12)

A solution of 4-methoxy-2-NITROPHENOL 11 (10 g, to 59.1 mmol) and Pd/C (1.0 g) in methanol (100 ml) was placed in a Parr apparatus in an atmosphere of H2(3.5 ATM (50 is the boots psi)for 60 minutes. The reaction mixture was filtered through celite 521 and the filter cake washed with Meon. The filtrate is evaporated (in vacuo)to give compound 12 as a yellowish brown solid.

2. Synthesis of the hydrochloride of the ethyl ester of 3-triftormetilfosfinov (13)

In the solution α,α,α-trifluoromethyl-m-tolunitrile 14 (1 g, of 5.84 mmol) in EtOH (10 ml, anhydrous) bubbled HCl (gaseous, anhydrous) for 10 minutes and stir the solution overnight. The solvent is evaporated, obtaining compound 13 as a white solid. The obtained solid substance use in the next stage without purification.

3. Synthesis of 5-methoxy-2-(3-triptoreline)benzoxazole (10)

A solution of compound 13 and compound 12 (850 mg, 6,13 mmol) in THF (10 ml) is heated to the boiling temperature under reflux and stirred overnight. The reaction mixture is allowed to cool and the THF is evaporated (in vacuo). The residue is dissolved in ethyl acetate and washed with water. The organic layer is dried over MgSO4and treated with activated carbon Norit A. the Mixture is filtered through celite 521, evaporated (in vacuo) and the residue is purified column chromatography (20% ethyl acetate/ hexane)to give compound 10 as a pale yellow solid.

4. Synthesis of 2-[(3-trifluoromethyl)phenyl]benzoxazol-5-ol (8)

To a solution of compound 10 (200 mg, of 0.68 mmol who) in CH 2Cl2(5 ml) added dropwise BBr3(1 M solution in CH2Cl2, 1 ml, 1 mmol). The resulting solution is stirred for 48 hours. The solvent is removed by evaporation in vacuum, the residue is dissolved in ethyl acetate and washed with saturated solution of NaHCO3. The organic layer is dried over MgSO4and evaporated (in vacuo). The residue is purified column chromatography (30% ethyl acetate/hexane)to give compound 8 as a white solid.

5. Synthesis of 5-(oxiran-2-ylethoxy)-2-[(3-trifluoromethyl)phenyl]benzoxazole (6)

To a suspension of NaH (7 mg, 60% dispersion in oil, 0.18 mmol) in DMF (2 ml, anhydrous) is added dropwise a solution of compound 8 (54 mg, 0,19 mmol) in DMF (2 ml, anhydrous). The solution is stirred for 15 minutes. To the above solution add epichlorohydrin (50 μl, was 0.63 mmol) and the resulting solution stirred overnight. The solvent is evaporated in vacuum, the residue is dissolved in water and extracted with ethyl acetate. The organic layers are combined, dried over MgSO4and evaporated, receiving the connection 6 in the form of a clear oil.

Part D

Synthesis of N-(2,6-dimetilfenil)-2-(4-{2-hydroxy-3-[2-(3-triptoreline)benzoxazol-5-yloxy]propyl}piperazine-1-yl)ndimethylacetamide (7)

A solution of compound 5 (183 mg, 0.73 mmol) and compound 6 in EtOH (2 ml) and triethylamine (0.2 ml) is heated to 90°C and stirred overnight. actionnow the mixture is allowed to cool and the solvent is evaporated (in vacuo) with the formation oil. The oil is purified preparative TLC (Meon/NH4OH/CH2Cl2, 5:0,5:94,5)to give compound 7 as a white solid. Mass spectrum (MN+) = 583,4.

Example 2

2-{4-[3-(Benzothiazol-2-yloxy)-2-hydroxypropyl]piperazine-1-yl}-N-(2,6-dimetilfenil)ndimethylacetamide (43)

Synthesis of 2-(oxiran-2-ylethoxy)benzothiazole (44)

The connection 44 get similar production method of compound 6, substituting compound 8 2-hydroxybenzothiazole part C-5 of example 1.

The connection 43 get similar production method of compound 7, substituting the compound 6 compound 44 in part D of the synthesis of compound 7. Mass spectrum (MN+)=455,3.

Example 3

N-(2,6-Dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazine-1-yl}ndimethylacetamide (45)

Synthesis of 2-methyl-5-(oxiran-2-ylethoxy)benzothiazole (33)

The connection 33 get similar production method of compound 6, substituting compound 8 2-methylbenzothiazol-5-I in part-5 of example 1.

The connection 45 get similar production method of compound 7, substituting the compound 6 compound 33 in part D of the synthesis of compound 7. Mass spectrum (MN+)=469,3.

Example 4

Amide 4-(3-{4-[(2,6-dimethylphenylcarbamate)methyl]piperazine-1-yl}-2-hydroxypropoxy)-1H-shall ndol-2-carboxylic acid (46)

Connection 19 get similar production method of compound 7, substituting the compound 6 commercially produced 4 glycidyloxy-2-indocarbocyanine in part D of the synthesis of compound 7. Mass spectrum (MN+)=480,4.

Example 5

2-{4-[3-(Benzothiazol-6-yloxy)-2-hydroxypropyl]piperazine-1-yl}-N-(2,6-dimetilfenil)ndimethylacetamide (47)

Synthesis of benzothiazole-6-ol (16)

To a solution of 6-aminobenzothiazole (1.0 g, of 6.66 mmol) in water (22 ml) and H2SO4(16 ml) at 5°add a solution of sodium nitrite (460 mg, 6,72 mmol) in water (13 ml), keeping the temperature below 5°C. the resulting solution was stirred for 15 minutes. The reaction mixture is heated to 160°and slowly add a solution of H2SO4(50 ml) and water (38 ml). The resulting mixture was stirred for 1 hour. The mixture is allowed to cool and add an aqueous solution of 50% sodium hydroxide to achieve a pH of 7. The mixture is extracted with ethyl acetate and washed with a saturated solution of salt. The combined organic portion is dried over MgSO4and evaporated with the formation of semi-solid substances. Semi-solid substance is purified column chromatography (40% ethyl acetate/hexane), receiving benzothiazol-6-ol 16 in the form of not-quite-white solid.

Synthesis of 6-(oxiran-2-ylethoxy)Ben is thiazole (48)

The connection 48 get similar production method of compound 6, substituting compound 8 compound 16 part C-5 of example 1.

Connection 47 get similar production method of compound 7, substituting the compound 6 compound 48 in part D of the synthesis of compound 7. Mass spectrum (MN+)=455,3.

Example 6

N-(2,6-Dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-6-yloxy)propyl]piperazine-1-yl}ndimethylacetamide (49)

Synthesis of 2-methylbenzothiazol-6-ol (50)

The connection 50 is obtained from commercially produced 6-methoxy-2-methylbenzothiazole similar to the production method, described in part-4 of example 1.

Synthesis of 2-methyl-6-(oxiran-2-ylethoxy)benzothiazole (51)

The connection 51 get similar production method of compound 6, substituting compound 8 compound 50 part C-5 of example 1.

The connection 49 get similar production method of compound 7, substituting the compound 6 compound 51 in part D of the synthesis of compound 7. Mass spectrum (MN+)=469,3.

Example 7

N-(2,6-Dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl] - for 3,5-dimethylpiperazine-1-yl}ndimethylacetamide (52)

Synthesis of N-(2,6-dimetilfenil)-2-(3,5-dimethylpiperazine-1-yl)ndimethylacetamide (53)

The connection 53 get similar production method of compound 3, replacing piperazine 2,6-dimethylpiperazine in part a of example 1.

The connection 52 get similar production method of compound 7, substituting the compound 6 compound 33 and compound 5 compound 53 in part D of the synthesis of compound 7. Mass spectrum (MN+)=497.4 m.

Example 8

2-{4-[2-Hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazine-1-yl}-N-(4-hydroxyphenyl)ndimethylacetamide (54)

Synthesis of 4-aminophenylacetate (55)

The connection 55 get similar production method of compound 12, replacing the connection 11 4-nitrophenylacetate part C-1 of example 1.

Synthesis of 4-(2-chloroacetamido)phenylacetate (56)

The connection 56 get similar production method of compound 3, replacing the connection 1 connection 55 in part a of example 1.

Synthesis of 4-(2-piperazinylcarbonyl)phenylacetate (57)

Connection 57 receive is similar to the production method, described in part b of example 1, substituting compound 3 compound 56.

The connection 54 get similar production method of compound 7, substituting the compound 6 compound 33 and compound 5 compound 57 in part D of the synthesis of compound 7. Mass spectrum (MN+)=the rate of 457.5.

Example 9

N-(2,6-Dim is terphenyl)-2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazine-1-yl}ndimethylacetamide (58)

Synthesis of phenyl-N-[3-(phenylmethoxy)phenyl]carboxamide (25)

To a solution of 3-benzyloxyaniline 23 (1.0 g, 5.0 mmol) and TEA (of 0.74 ml, 5.3 mmol) in CH2Cl2dropwise added benzoyl chloride (0,61 ml of 5.26 mmol) and the mixture is stirred over night. The reaction mixture was diluted with water and the resulting solid is filtered off under vacuum. The solid is air-dried, obtaining compound 25 as a white solid.

Synthesis of phenyl{[(3-phenylmethoxy)phenyl]amino}methane-1-thione (26)

A solution of compound 25 (455 mg, 1.5 mmol) and reagent Lawesson (0.6 mol. EQ.) in chlorobenzene (15 ml) is heated to 120°C and stirred for 1.5 hours. The reaction mixture is allowed to cool and the solvent is evaporated (in vacuo). The residue is purified column chromatography (ethyl acetate/hexane, 1:9)to give compound 26 as a yellow solid.

Synthesis of 2-phenyl-5-(phenylmethoxy)benzothiazole (27)

To a solution of compound 26 (960 mg, 3 mmol) in ethanol (5 ml) is added aqueous sodium hydroxide solution (30%, 8 mol. EQ.). The mixture was diluted with water (6 ml) and receive the final 10% aqueous sodium hydroxide solution. The resulting solution was added an aliquot (1 ml) to a stirred solution of ferricyanide feces is I (4 mol. EQ.) in water at 90°and the resulting mixture heated for 30 minutes. The reaction mixture is allowed to cool and extracted the product with ethyl acetate. The organic layer is dried and evaporated. The residue, a mixture of compounds 27 and 28, purified on column (ethyl acetate/hexane, 1:99)to give compound 27 as a white solid.

Synthesis of 2-phenylbenzothiazole-5-ol (29)

The palladium hydroxide (100 mg) are added to a solution of compound 27 (260 mg, 0.8 mmol) in ethanol/cyclohexene (5 ml/2 ml) and refluxed for 16 hours. The reaction mixture is cooled and the catalyst removed by filtration through celite). The solvent is evaporated, obtaining compound 29 as a white solid.

Synthesis of 5-(oxiran-2-ylethoxy)-2-phenylbenzothiazole (59)

Connection 59 get similar production method of compound 6, substituting compound 8 compound 29 part C-5 of example 1.

The connection 58 get similar production method of compound 7, substituting the compound 6 compound 59 in part D of the synthesis of compound 7. Mass spectrum (MN+) = 531,6.

Example 10

N-(2,6-Dimetilfenil)-2-{4-[2-hydroxy-3-(2-phenylbenzoxazole-5-yloxy)propyl]piperazine-1-yl}ndimethylacetamide (60)

Synthesis of 5-(oxiran-2-ylethoxy)-2-phenylbenzoxazole (61)

The connection 61 get similar production method of compound 6, replacing the connection 13 of the hydrochloride of ethylbenzamide in part of the S1-5 of example 1.

The connection 60 get similar production method of compound 7, substituting the compound 6 compound 61 in part D of the synthesis of compound 7. Mass spectrum (MN+)=515,3.

Example 11

N-(2,6-Dimetilfenil)-2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-7-yloxy)propyl]piperazine-1-yl}ndimethylacetamide (62)

Synthesis of 7-(oxiran-2-ylethoxy)-2-phenylbenzothiazole (63)

Connection 63 receives the same way as the receive connection 59, substituting compound 29 compound 28 is removed from protection in example 9.

The connection 62 get similar production method of compound 7, substituting the compound 6 compound 63 in part D of the synthesis of compound 7. Mass spectrum (MN+)=531,3.

Example 12

N-(2,6-Dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2-oxopiperidin-1-yl}ndimethylacetamide (64)

Synthesis of phenylmethyl-4-{[N-(2,6-dimetilfenil)carbarnoyl]methyl}-3-oxopiperidine (31)

To a solution of compound 30 (252 mg, 1.3 mmol) in THF (13 ml) and NaH (62 mg, 1.6 mmol) is added compound 3 (300 mg, 1.3 mmol). The solution is stirred under nitrogen atmosphere overnight. The reaction mixture is ASAT water (0.1 ml) and dried over Na 2SO4. The solution is concentrated and purified column chromatography, obtaining the connection 31 in the form of solids.

Synthesis of N-(2,6-dimetilfenil)-2-(2-oxopiperidin)ndimethylacetamide (32)

To a solution of compound 31 in methanol (10 ml) is added 10% palladium on coal. In the reactor, introducing hydrogen (2,8 bar (40 psi)and the reaction mixture is stirred for 4 hours. The catalyst was removed by filtration, the filtrate concentrated and purified column chromatography (Meon:DCM, 1:15)to give compound 32 in the form of semi-solid connection.

The connection 64 get similar production method of compound 7, substituting the compound 6 compound 33 and compound 5 compound 32 in part D of the synthesis of compound 7. Mass spectrum (MN+)=483,3.

Example 13

N-(2,6-Dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazine-1-yl}ndimethylacetamide (65)

Synthesis of 5-methoxy-2-methylbenzothiazole (19)

A solution of 2-amino-4-methoxyphenol 17 (8 g, 57,4 mmol) in triethylorthoformate 18 (50 ml) is heated to the boiling temperature under reflux and stirred for 24 hours. The reaction mixture is allowed to cool and the excess solvent 18 is evaporated (in vacuo). The residue is dissolved in ethyl acetate and washed with water. The organic layer su is at over MgSO 4and treated with activated charcoal Norit A. the resulting solution was filtered through celite 521 and evaporated to an oil formation. Oil chromatographic on silica gel (20% ethyl acetate/hexane)to give compound 19 as a pale yellow solid.

Synthesis of 2-methyl-5-oxiran-2-ylmethoxycarbonyl (67)

Connection 67 get similar production method of compound 6, substituting compound 8 6-hydroxy-2-methylbenzoxazolium 66 part C-5 of example 1.

The connection 66, in turn, receive, removing protection from compound 19, as described in part-4 of example 1.

The connection 65 get similar production method of compound 7, substituting the compound 6 compound 67 in part D of the synthesis of compound 7. Mass spectrum (MN+)=543,4.

Example 14

N-(2,6-Dimetilfenil)-2-(4-{2-hydroxy-3-[2-(4-triptoreline)-benzoxazol-5-yloxy]propyl}piperazine-1-yl)ndimethylacetamide (68)

Synthesis of 5-(oxiran-2-ylethoxy)-2-(4-triptoreline)benzoxazole (69)

Connection 69 get similar production method of compound 6, replacing the connection 13 hydrochloride ethyl ester 4-trifluoromethyl-benzimidazole in part of the S1-5 of example 1.

The connection 68 get similar production method of compound 7, substituting the compound 6 compound 69 in part D of the Intesa connection 7. Mass spectrum (MN+)=583,4.

Example 15

N-(2,6-Dimetilfenil)-2-{4-[2-hydroxy-3-(cinoxacin-2-yloxy)propyl]piperazine-1-yl}ndimethylacetamide (70)

Synthesis of 2-(oxiran-2-ylethoxy)finokalia (71)

Connection 71 get similar production method of compound 6, substituting compound 8 cinoxacin-2-I in part-5 of example 1.

The connection 70 get similar production method of compound 7, substituting the compound 6 compound 71 in part D of the synthesis of compound 7. Mass spectrum (MN+)=450,9.

Example 16

N-(2,6-Dimetilfenil)-2-{4-[2-hydroxy-3-(pyridine-3-yloxy)propyl]piperazine-1-yl}ndimethylacetamide (72)

Synthesis of 3-(oxiran-2-ylethoxy)pyridine (73)

Connection 73 get similar production method of compound 6, substituting compound 8 3-hydroxypyridine part C-5 of example 1.

The connection 72 get similar production method of compound 7, substituting the compound 6 compound 73 in part D of the synthesis of compound 7. Mass spectrum (MN+)=RUB 399.4.

Example 17

N-(2,6-Dimetilfenil)-2-{4-[2-hydroxy-3-(quinoline-4-yloxy)propyl]piperazine-1-yl}ndimethylacetamide (74)

Synthesis of 4-(oxiran-2-ylethoxy)quinoline (75)

Connection 75 receive similar ways the receiving connection 6, substituting compound 8 4-hydroxyquinoline part C-5 of example 1.

The connection 74 get similar production method of compound 7, substituting the compound 6 compound 75 in part D of the synthesis of compound 7. Mass spectrum (MN+)=449,4.

Example 18

N-(2,6-Dimetilfenil)-2-{4-[2-hydroxy-3-(isoquinoline-5-yloxy)propyl]piperazine-1-yl}ndimethylacetamide (76)

Synthesis of 5-(oxiran-2-ylethoxy)isoquinoline (77)

Connection 77 get similar production method of compound 6, substituting compound 8 5-hydroxyisoquinoline part C-5 of example 1.

The connection 76 get similar production method of compound 7, substituting the compound 6 compound 77 in part D of the synthesis of compound 7. Mass spectrum (MN+)=449,4.

Example 19

N-(2,6-Dimetilfenil)-2-{4-[2-hydroxy-3-(quinoline-6-yloxy)propyl]piperazine-1-yl}ndimethylacetamide (78)

Synthesis of 6-(oxiran-2-ylethoxy)quinoline (79)

Connection 79 get similar production method of compound 6, substituting compound 8 6-hydroxyquinoline part C-5 of example 1.

The connection 78 get similar production method of compound 7, substituting the compound 6 compound 79 in part D of the synthesis of compound 7. Mass spectrum (MN+)=449,4.

Example 20

N-(2,6-Dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylinosine-7-yloxy)propyl]piperazine-1-and the}ndimethylacetamide (80)

Synthesis of 2-methyl-7-(oxiran-2-ylethoxy)quinoline (81)

Connection 81 get similar production method of compound 6, substituting compound 8 7-hydroxy-2-methylinosine part C-5 of example 1.

The connection 80 get similar production method of compound 7, substituting the compound 6 compound 81 in part D of the synthesis of compound 7. Mass spectrum (MN+)=463,5.

Example 21

2-{4-[3-(Benzothiazol-2-ylamino)-2-hydroxypropyl]piperazinil}-N-(2,6-dimetilfenil)ndimethylacetamide (39)

Synthesis of (phenylmethoxy)-N-prop-2-talkability (42)

To a solution of allylamine (3,34 g of 5.85 mmol) in dichloromethane (100 ml) and triethylamine (16 ml) add benzylchloride (of 8.25 ml, 5,78 mmol) at 0°C. the Mixture was stirred at 0°C for 2 hours and another 90 minutes at room temperature. The solvent is removed by evaporation and the residue purified flash column chromatography (30% EtOAc/hexane)to give compound 42 as a clear oil.

Synthesis of N-(oxiran-2-ylethoxy)(phenylmethoxy)carboxamide (35)

Compound 42 (5.0 g, 2,61 mmol) is treated with m-chloroperbenzoic acid (11,71 g, 9.1 mmol) in dichloromethane (110 ml) at room temperature for 18 hours. Dichloromethane is evaporated OBR is using viscous oil, which cleanse column flash chromatography (30% EtOAc/ hexane)to give compound 35 as a clear oil.

Synthesis of N-(2,6-dimetilfenil)-2-(4-{2-hydroxy-3-[phenylmethoxy]carbylamine]propyl}piperazinil)ndimethylacetamide (36)

A solution of compound 42 (2.5 g, 1.2 mmol) and compound 5 (5,94 g, 2.4 mmol) in ethanol (100 ml) and triethylamine (3,34 ml) is heated under reflux for 18 hours. The solvents were removed and the residue purified flash column-chromatography (ethyl acetate)to give compound 36 as a white solid.

Synthesis of 2-[4-(3-amino-2-hydroxypropyl)piperazinil]-N-(2,6-dimetilfenil)ndimethylacetamide (37)

A solution of compound 36 (3.0 g, 0.66 mmol) in methanol (70 ml) in the presence of 10% palladium on coal (of 0.337 g) is stirred in hydrogen atmosphere for 16 hours. The catalyst is filtered off and the reaction mixture is concentrated, receiving the connection 37 in the form of a sticky solid.

To a solution of compound 37 (75 mg) in ethanol (2 ml), add triethylamine (0,13 ml) and 2-chlorobenzothiazole (87 mg) and heated at boiling temperature under reflux for 16 hours. The reaction mixture was concentrated and purified preparative TLC (5% Meon/dichloromethane)to give compound 39 as a white solid. Mass spectrum (MN+)=454,4.

Example 22

2-{4-[3-(Ben is oxazol-2-ylamino)-2-hydroxypropyl]piperazinil}-N-(2,6-dimetilfenil)ndimethylacetamide (82)

The connection 82 receives the same way as the receive connection 39, substituting 2-chlorobenzothiazole used in example 21, 2-chlorobenzoxazole. Mass spectrum (MN+)=438,4.

The following compounds produced by the methods described in examples 1-21. All these compounds are characterized by satisfactory mass spectroscopic data (MN+).

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,5-dimethylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide

2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,6-dimethylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3,3-dimethylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide

2-{(3S)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide

2-{(2R)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide

2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,6-dimethylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](1,4-disapere rapini)}-N-(2,6-dimetilfenil)ndimethylacetamide

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-(4-hydroxyphenyl)ndimethylacetamide

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,6-dimethylpiperazine}-N-(4-carboxamidine)ndimethylacetamide

2-{(3S)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide

2-{4-[(2R)-2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazinil}-N-(2,6-dimetilfenil)ndimethylacetamide

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-(2,6-dimethyl-4-hydroxyphenyl)ndimethylacetamide

2-{5-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-(2,6-dimetilfenil)ndimethylacetamide

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-(4-sulfamoylbenzoyl)ndimethylacetamide

2-{(3S)-4-[(2S)-2-hydroxy-3-(2-phenylbenzoxazole-5-yloxy)propyl]-3-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-naphthylacetamide

N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}ndimethylacetamide

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-phenylacetamide

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-(3,4,5-trichlorophenyl)ndimethylacetamide

2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinil}-N-(3,4,5-trichlorophenyl)ndimethylacetamide

2-{4-[2-hydroxy-3-(2-methylbenzo eazol-5-yloxy)propyl]piperazinil}-N-(2-chloro-4-were)ndimethylacetamide

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-(3,4,5-trichlorophenyl)ndimethylacetamide

2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazinil}-N-(3,5-dichlorophenyl)ndimethylacetamide

2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazinil}-N-(3,4-dichlorophenyl)ndimethylacetamide

2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazinil}-N-[3-methoxy-5-(trifluoromethyl)phenyl]ndimethylacetamide

2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazinil}-N-[3,5-dichlorophenyl]ndimethylacetamide

2-{4-[2-hydroxy-3-(2-((1E)buta-1,3-dienyl)benzothiazol-5-yloxy)propyl]piperazinil}-N-[4-chloro-2-methoxy-5-were]ndimethylacetamide

Example 23

Mitochondrial analyses

Mitochondria from rat heart allocate method of Nedergaard and cannon (Methods in Enzymol., 55, 3, 1979).

The oxidation of Palmitoyl-COA. The oxidation of Palmitoyl-COA is carried out at a total volume of 100 µl, containing the following substances: 110 mm KCl, 33 mm Tris buffer pH 8, 2 mm KPi, 2 mm MgCl2, 0.1 mm EDTA, 14,7 μm fat-free bovine serum albumin (BSA), 0.5 mm malic acid, 13 mm carnitine, 1 mm ADP, 52 µg of mitochondrial protein and 16 μm Palmitoyl-COA, labeled position 1 radioactive isotope14(specific activity 60 MCI/mmol; 20 MX/ml (using 5 ál in a single analysis). Compounds according to this invention is added to the DMSO solution in the following concentrations: 100 μm and 50 μm. is each assay using control sample, containing only DMSO. The mixture is incubated at 30°C for 15 minutes, after which the product of the enzymatic reaction centrifuged (at acceleration 20000 g for 1 minute) and 70 μl of the supernatant is injected into the activated column of silicic acid chromatography with reversed phase (approximately 0.5 ml of silicic acid). Column elute 2 ml water and 0.5 ml of eluent used for scintillation counting to determine the number of14captured in the form of bicarbonate ion With14.

Table 1 shows the inhibition of oxidation of fatty acids to the mitochondria using Palmitoyl-COA as substrate -% the content of the test substance in 2 concentrations and IC50

Table 1

Connection # 100 μm (%)50 µm (%)IC50(µm)
7-77-
3927--
4321--
4587-~20
4661-~125
4770-~125
493- -
5295-~1
5481-~8
60-61-
62-62-
6441--
68-68-
7012--
728--
7412--
7626--
7842--
8022--
8222--

Example 25

Metabolic stability. To measure the metabolic stability of the compounds in this invention are incubated with microsome fractions S-9 human liver. The reaction mixture was incubated at 37°C for 30 minutes using LC - mass spectroscopy to determine the remaining amount of the parent drug. Response parameters for each connection is determined by constructing a standard curve and is the sing of the internal standard in the analysis of samples. The percentage of ranolazine after 30 minutes, which represents the average value for the five experiments, is 57%. Compounds according to this invention analyzed in accordance with the following method and the percentage remaining of the original medicinal substance divided by the average %content remaining ranolazine (57%), thereby determining the ratio of metabolic stability. Connection with the stability factor above 1,2, characterized by a better stability than ranolazine when performing analysis of S-9 liver. Connection with the stability coefficient of from 1.2 to 0.8, characterized by the equivalent resistance when performing analysis of S-9 liver. Connection with the stability factor less than 0.8, characterized by a lower resistance than ranolazine when performing analysis of S-9 liver.

The purpose of this experiment is to compare the percentage of the remaining compounds of the present invention with the percentage remaining ranolazine after incubation of S9 fractions of the liver of a person within 30 minutes.

Reagents

When performing analysis using the following reagents: potassium phosphate, 0.5 M solution, pH 7.4 (buffer for incubation)at room temperature; 0.05 M solution of MgCl2at 4°; TETRANITRATE the ol restored β -adenine dinucleotide phosphate (NADPH), 0.02 M solution in water (~16.6 mg/ml) of the company Sigma, batch No. N received to-day use. 1 mm ranolazine or compounds 43, 45, 47, 52, 70, 74, 76, 78 and 80 in the TSA was diluted to 100 μm in 10% TSA; the original solution S9 person: 20 mg/ml of the company Gentest.

The method of analysis

Inkubirovanie mixture was prepared as follows.

Table 2
ComponentVolume of 0.25 ml

inkubiruemykh mixture
End

concentration
10 μm of the compounds CVT25 ál10 µm
MgCl225 ál0.005 M
NADPH25 ál0,002 M
S925 ál2 mg/ml
Buffer for incubation25 ál0.05 M
Water125 ál-
* Inkubiruemykh mixture using 1% of organic solvent (acetonitrile). Usually at the same time get 30 inkubiruemykh mixtures, which are pre-mixed with 0.75 ml MgCl2, 0.75 ml of buffer for incubation, 0.75 ml NADPN, 3,75 ml of water. Then 200 ál inkubiruemykh mix by pipette, add 25 ál of the test compound, mix the initiate the reaction, adding S-9.

All components (table 2) combined with the buffer for incubation and the pipette is introduced into the tube 200 μl mixture + 25 μl of the test compound together with 25 μl of S-9.

The mixture is pre-incubated at 37°C for 5 minutes, then after 0 and 30 minutes after start of the reaction, remove 50 ál aliquot of inkubiruemykh mixture and added to 100 μl of a mixture of acetonitrile : methanol (9:1)containing internal standard.

The mixture is centrifuged and 100 µl aliquot of supernatant was diluted in 1 ml of solvent (0.1% of formic acid in water). Samples analyzed using LC/MS (introduction 10 ál) to determine changes in the ratio between the test compound and the internal standard in the periods of time corresponding to the 0 and 30 minutes.

Analysis and calculation of data

Samples analyzed to identify the source of connections and possible metabolites using LC/MS using an internal standard and column ODS-C18 with a volumetric flow rate of 0.25 ml/min. In accordance with the above described method will receive are shown in table 3, the coefficients of relative stability of the compounds of this invention in comparison with ranolazine.

Table 3
Connection # The stability factor for liver S9
43 0,6
450,8
461,1
471,5
520,5
700,1
741,0
760,8
780,6
800,5

1. Derivatives heterooligomerization General formula (I)

(I)

where m is 1, 2 or 3;

q indicates NH or O;

R1, R2, R3, R4and R5independently selected from the group including hydrogen, C1-15alkyl, OR20, R20represents hydrogen;

R6, R7and R8represent hydrogen;

R9, R10, R11, R12, R13, R14, R15and R16independently selected from the group including hydrogen, C1-4alkyl, or R9and R10together with the atom ogorod to which they are attached, form a carbonyl;

R17means heteroaryl chosen from the group comprising indolyl, benzoxazolyl, benzothiazolyl, chinoline, ethenolysis, pyridyl, benzopyranyl, optionally substituted with 1-2 substituents selected from the group including hydrogen, CF3C1-8alkyl, phenyl, SOPS(R20)2.

p> 2. The compound according to claim 1, in which q denotes NH or O; R1, R2, R3, R4and R5independently selected from the group including hydrogen, C1-8alkyl, OR20, R20is hydrogen; R6, R7and R8represent hydrogen; R9, R10, R11, R12, R13, R14, R15and R16independently selected from the group including hydrogen, C1-4alkyl, or R9and R10together with the atom ogorod to which they are attached, form a carbonyl;

R17means heteroaryl chosen from the group comprising indolyl, benzoxazolyl, benzothiazolyl, chinoline, ethenolysis, pyridyl, benzopyranyl, optionally substituted with 1-2 substituents selected from the group including hydrogen, CF3C1-8alkyl, phenyl, SOPS(R20)2.

3. The compound according to claim 1, in which R1, R2, R3, R4and R5independently selected from the group including hydrogen, OR20C1-5alkyl, R20is hydrogen; R6, R7and R8represent hydrogen; R9, R10, R11, R12, R13, R14, R15and R16independently selected from the group comprising hydrogen or C1-4alkyl, or R9and R10together with the carbon atom to which they are attached, form a carbonyl; R17OZNA is anything heteroaryl, chosen from the group comprising indolyl, benzoxazolyl, benzothiazolyl, chinoline, ethenolysis, pyridyl, benzopyranyl, optionally substituted with 1-2 substituents selected from the group including hydrogen, CF3C1-8alkyl, phenyl, SOPS(R20)2.

4. The compound according to claim 1, in which R1, R2, R3, R4and R5independently selected from the group including hydrogen, OR20C1-3alkyl, R20is hydrogen; R6, R7and R8represent hydrogen; R9, R10, R11, R12, R13, R14, R15and R16independently selected from the group comprising hydrogen or C1-2alkyl, or R9and R10together with the atom ogorod to which they are attached, form a carbonyl; R17means heteroaryl chosen from the group comprising indolyl, benzoxazolyl, benzothiazolyl, chinoline, ethenolysis, pyridyl, benzopyranyl, optionally substituted with 1-2 substituents selected from the group including hydrogen, CF3C1-8alkyl, phenyl, SOPS(R20)2.

5. The compound according to claim 1, in which m is 1; R1, R2, R3, R4and R5independently selected from the group including hydrogen, OR20or C1-3alkyl, R20is hydrogen; R6, R7and R8represent hydrogen;R 9, R10, R11, R12, R13, R14, R15and R16independently selected from the group comprising hydrogen or methyl, or R9and R10together with the atom ogorod to which they are attached, form a carbonyl; R17means heteroaryl chosen from the group comprising indolyl, benzoxazolyl, benzothiazolyl, chinoline, ethenolysis, pyridyl, benzopyranyl, optionally substituted with 1-2 substituents selected from the group including hydrogen, CF3C1-8alkyl, phenyl, SOPS(R20)2.

6. The compound according to claim 1, in which R17means heteroaryl chosen from the group comprising indolyl, benzoxazolyl, benzothiazolyl, optionally substituted with 1-2 substituents selected from the group including hydrogen, CF3C1-8alkyl, phenyl, SOPS(R20)2.

7. The connection according to claim 6, in which q indicates NH, O; R1, R2, R3, R4and R5independently selected from the group including hydrogen, OR20, R20is hydrogen; R6, R7and R8represent hydrogen; R9, R10, R11, R12, R13, R14, R15and R16independently selected from the group including hydrogen, C1-4alkyl, or R9and R10together with the carbon atom to which they are attached, form a carbonyl; R17oz ACHAT heteroaryl, chosen from the group comprising indolyl, benzoxazolyl, benzothiazolyl, optionally substituted with 1-2 substituents selected from the group including hydrogen, CF3C1-8alkyl, phenyl, SOPS(R20)2.

8. The connection according to claim 6, in which q denotes NH or O; R1, R2, R3, R4and R5independently selected from the group including hydrogen, OR20C1-5alkyl, R20is hydrogen; R6, R7and R8represent hydrogen; R9, R10, R11, R12, R13, R14, R15and R16independently selected from the group including hydrogen, C1-3alkyl, or R9and R10together with the carbon atom to which they are attached, form a carbonyl; R17means heteroaryl chosen from the group comprising indolyl, benzoxazolyl, benzothiazolyl, optionally substituted with 1-2 substituents selected from the group including hydrogen, CF3C1-8alkyl, phenyl, SOPS(R20)2.

9. The connection according to claim 6, in which q denotes NH or O; R1, R2, R3, R4and R5independently selected from the group including hydrogen, OR20or C1-3alkyl, R20is hydrogen; R6, R7and R8represent hydrogen; R9, R10, R11, R12, R13, R14, R15and R16 independently selected from the group including hydrogen, C1-3alkyl, or R9and R10together with the carbon atom to which they are attached, form a carbonyl; R17means heteroaryl chosen from the group comprising indolyl, benzoxazolyl, benzothiazolyl, optionally substituted with 1-2 substituents selected from the group including hydrogen, CF3C1-8alkyl, phenyl, SOPS(R20)2.

10. The connection according to claim 6, in which q denotes NH or O; R1, R2, R3, R4and R5independently selected from the group including hydrogen, OR20or C1-3alkyl, R20is hydrogen; R6, R7and R8is hydrogen; R9, R10, R11, R12, R13, R14, R15and R16independently selected from the group comprising hydrogen or C1-2alkyl, or R9and R10together with the carbon atom to which they are attached, form a carbonyl; R17means heteroaryl chosen from the group comprising indolyl, benzoxazolyl, benzothiazolyl, optionally substituted with 1-2 substituents selected from the group including hydrogen, CF3C1-8alkyl, phenyl, SOPS(R20)2.

11. The connection of claim 10, in which q denotes O and R17means heteroaryl chosen from the group comprising indolyl, benzoxa is alil, benzothiazolyl, optionally substituted with 1-2 substituents selected from the group including hydrogen, CF3C1-8alkyl, phenyl, SOPS(R20)2.

12. The connection of claim 10, in which q denotes O; R1, R2, R3, R4and R5independently selected from the group including hydrogen, OR20or C1-2alkyl, R20is hydrogen; R6, R7and R8represent hydrogen; R9, R10, R11, R12, R13, R14, R15and R16independently selected from the group comprising hydrogen or C1-2alkyl, or R9and R10together with the carbon atom to which they are attached, form a carbonyl; R17means heteroaryl chosen from the group comprising indolyl, benzoxazolyl, benzothiazolyl, optionally substituted with 1-2 substituents selected from the group including hydrogen, CF3C1-8alkyl, phenyl, SOPS(R20)2.

13. The connection section 12, in which R17means benzothiazolyl, optionally substituted 1 Deputy chosen from the group comprising hydrogen, CF3C1-3alkyl, phenyl, SOPS(R20)2.

14. The connection section 12, in which R17means benzothiazolyl, optionally substituted in position 2 by a single Deputy, selected from the group comprising hydrogen, methyl or phenyl.

15. With the Association indicated in paragraph 12, in which R17means of 5-substituted benzothiazolyl, optionally substituted 1 Deputy chosen from the group comprising hydrogen, CF3, CON(R20)2With1-3alkyl or phenyl, R20represents hydrogen.

16. The connection section 12, in which R17means of 5-substituted benzothiazolyl, optionally substituted in position 2 by a single Deputy, selected from the group comprising hydrogen, methyl or phenyl.

17. The connection section 12, in which q denotes O; R1, R2, R3, R4and R5independently selected from the group including hydrogen, OR20or methyl; R6, R7and R8represent hydrogen; R11and R15selected from the group comprising hydrogen or methyl, R9, R10, R12, R13, R14and R16mean hydrogen, R9and R10together with the carbon atom to which they are attached, form a carbonyl; R17means of 5-substituted benzothiazolyl, substituted in position 2 of the stands.

18. The connection section 12, in which q denotes O; R1, R2, R3, R4and R5independently selected from the group including hydrogen, OR20or methyl, R20is hydrogen; R6, R7and R8mean hydrogen; R11and R15selected from the group comprising hydrogen or methyl, R9, R10, R12, R 13, R14and R16mean hydrogen, R9and R10together with the carbon atom to which they are attached, form a carbonyl; R17means of 5-substituted benzothiazolyl, substituted in position 2 of the phenyl.

19. The connection section 12, in which q denotes O; R1, R4and R5independently selected from the group including hydrogen, OR20or methyl; R6, R7and R8mean hydrogen; R11and R15selected from the group comprising hydrogen or methyl, R9, R10, R12, R13, R14and R16mean hydrogen, R9and R10together with the carbon atom to which they are attached, form a carbonyl; R17means of 5-substituted benzothiazolyl, substituted in position 2 of the stands.

20. The compound according to any one of p-16, in which R17means of 5-substituted benzothiazolyl, substituted in position 2 of the stands.

21. The compound according to any one of p-16, in which R17means of 5-substituted benzothiazolyl, substituted in position 2 of the phenyl.

22. The compound according to claim 1, in which R17means heteroaryl, which are selected from the group including chinoline, ethenolysis, benzopyranyl, optionally substituted with 1-2 substituents selected from the group including hydrogen, CF3C1-8alkyl, phenyl, SOPS(R20)2.

23. Connection p.22, in which q oznacza is t O; R1, R2, R3, R4and R5independently selected from the group including hydrogen, OR20C1-8alkyl, R20is hydrogen; R6, R7and R8is hydrogen; R9, R10, R11, R12, R13, R14, R15and R16independently selected from the group including hydrogen, C1-4alkyl.

24. Connection p.22, in which q denotes O; R1, R2, R3, R4and R5independently selected from the group including hydrogen, OR20C1-5alkyl, R20is hydrogen; R6, R7and R8represent hydrogen; R9, R10, R11, R12, R13, R14, R15and R16independently selected from the group including hydrogen, C1-3alkyl, or R9and R10together with the carbon atom to which they are linked, represent carbonyl; R17means heteroaryl, which are selected from the group including chinoline, ethenolysis, benzopyranyl, optionally substituted with 1-2 substituents selected from the group including hydrogen, CF3C1-8alkyl, phenyl, SOPS(R20)2.

25. Connection p.22, in which q denotes O; R1, R2, R3, R4and R5independently selected from the group including hydrogen, OR20or methyl, R20is hydrogen; R6, R and R8mean hydrogen; R9, R10, R11, R12, R13, R14, R15and R16independently selected from the group comprising hydrogen or C1-2alkyl, or R9and R10together with the carbon atom to which they are attached, form a carbonyl; R17means heteroaryl, which are selected from the group including chinoline, ethenolysis, benzopyranyl, optionally substituted stands.

26. Connection p.22, in which q denotes O; R1, R2, R3, R4and R5independently selected from the group comprising hydrogen or methyl; R6, R7and R8represent hydrogen; R9, R10, R11, R12, R13, R14, R15and R16represent hydrogen; R17means heteroaryl, which are selected from the group including chinoline, ethenolysis, benzopyranyl, optionally substituted stands.

27. The compound according to claim 1, in which R17means pyridyl, optionally substituted with 1-2 substituents selected from the group including hydrogen, CF3C1-8alkyl, phenyl, SOPS(R20)2.

28. Connection item 27, in which q denotes O; R1, R2, R3, R4and R5independently selected from the group including hydrogen, OR20C1-8alkyl, R20is hydrogen; R6, R7and R8PR is astavliaut hydrogen; R9, R10, R11, R12, R13, R14, R15and R16independently selected from the group including hydrogen, C1-4alkyl, or R9and R10together with the carbon atom to which they are attached, form a carbonyl; R17means pyridyl, optionally substituted with 1-2 substituents selected from the group including hydrogen, CF3C1-8alkyl, phenyl, SOPS(R20)2.

29. Connection item 27, in which q denotes O; R1, R2, R3, R4and R5independently selected from the group including hydrogen, OR20C1-5alkyl, R20is hydrogen; R6, R7and R8represent hydrogen; R9, R10, R11, R12, R13, R14, R15and R16independently selected from the group including hydrogen, C1-3alkyl, or R9and R10together with the carbon atom to which they are attached, form a carbonyl; R17means means pyridyl, optionally substituted with 1-2 substituents selected from the group including hydrogen, CF3C1-8alkyl, phenyl, SOPS(R20)2.

30. The connection clause 29, in which R17means pyridyl, optionally substituted with 1-2 substituents selected from the group including hydrogen, CF3C1-8alkyl, phenyl, SOPS(R20)2.

31. The connection is .30, in which q denotes O; R1, R2, R3, R4and R5independently selected from the group including hydrogen, OR20or methyl, R20is hydrogen; R6, R7and R8represent hydrogen; R9, R10, R11, R12, R13, R14, R15and R16independently selected from the group comprising hydrogen or C1-2alkyl, or R9and R10together with the carbon atom to which they are bound, form a carbonyl; R17means pyridyl, optionally zalesny the stands.

32. Connection item 30, in which q denotes O; R1, R2, R3, R4and R5independently selected from the group comprising hydrogen or methyl; R6, R7and R8represent hydrogen; R9, R10, R11, R12, R13, R14, R15and R16mean hydrogen; R17means pyridyl, optionally substituted stands.

33. The connection of claim 10, where q indicates NH; R17means heteroaryl chosen from the group comprising indolyl, benzoxazolyl, benzothiazolyl, optionally substituted with 1-2 substituents selected from the group including hydrogen, CF3C1-8alkyl, phenyl, SOPS(R20)2.

34. The connection of claim 10, where q indicates NH; R1, R2, R3, R4and R5independently selected from the group, Lucaya hydrogen, OR20or C1-2alkyl, R20is hydrogen; R6, R7and R8mean hydrogen; R9, R10, R11, R12, R13, R14, R15and R16independently selected from the group comprising hydrogen or C1-2alkyl, or R9and R10together with the carbon atom to which they are bound, form a carbonyl; R17means heteroaryl chosen from the group comprising indolyl, benzoxazolyl, benzothiazolyl, optionally substituted with 1-2 substituents selected from the group including hydrogen, CF3C1-8alkyl, phenyl, SOPS(R20)2.

35. The connection of claim 10, where q indicates NH; R1, R2, R3, R4and R5independently selected from the group comprising hydrogen or methyl; R6, R7and R8mean hydrogen; R9, R10, R11, R12, R13, R14, R15and R16mean hydrogen; R17means heteroaryl selected from the group including benzothiazole and benzoxazole, which is optionally substituted by stands.

36. Compound selected from the group including

N-(2,6-dimetilfenil)-2-(4-{2-hydroxy-3-[2-(3-triptoreline)benzoxazol-5-yloxy]-propyl}piperazine-1-yl)acetamide", she

2-{4-[3-(benzothiazol-2-yloxy)-2-hydroxypropyl]piperazine-1-yl}-N-(2,6-dimetilfenil)ndimethylacetamide,

N-(2,6-dime ylphenyl)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazine-1-yl}acetamide", she

amide 4-(3-{4-[(2,6-dimethylphenylcarbamate)methyl]piperazine-1-yl}-2-hydroxypropoxy)-1H-indole-2-carboxylic acid,

2-{4-[3-(benzothiazol-6-yloxy)-2-hydroxypropyl]piperazine-1-yl}-N-(2,6-dimetilfenil)ndimethylacetamide,

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-6-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl] - for 3,5-dimethylpiperazine-1-yl}acetamide", she

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazine-1-yl}-N-(4-hydroxyphenyl)ndimethylacetamide,

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-phenylbenzoxazole-5-yloxy)propyl)piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-7-yloxy)propyl]piperazine-1-ylacetamide,

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2-oxopiperidin-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-(4-{2-hydroxy-3-[2-(4-triptoreline)benzoxazol-5-yloxy]propyl}piperazine-1-yl)acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(cinoxacin-2-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(pyridine-3-yloxy)PR who drank]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(quinoline-4-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(isoquinoline-5-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(quinoline-6-yloxy)propyl]piperazine-1-yl}acetamide", she

N-(2,6-dimetilfenil)-2-{4-[2-hydroxy-3-(2-methylinosine-7-yloxy)propyl]piperazine-1-yl}acetamide", she

2-{4-[3-(benzothiazol-2-ylamino)-2-hydroxypropyl]piperazinil}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[3-(benzoxazol-2-ylamino)-2-hydroxypropyl]piperazinil}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,5-dimethylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,6-dimethylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3,3-dimethylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{(3S)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{(2R)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,6-demetrii azinil}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yl-oxy)propyl]-2-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](1,4-disabilitating)}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-(4-hydroxyphenyl)ndimethylacetamide,

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,6-dimethylpiperazine}-N-(4-carboxamidine)ndimethylacetamide,

2-{(3S)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2R)-2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazinil}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-(2,6-dimethyl-4-hydroxyphenyl)ndimethylacetamide,

2-{5-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-2,5-diazabicyclo[2.2.1]-hept-2-yl}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-(4-sulfamoylbenzoyl)ndimethylacetamide,

2-{(3S)-4-[(2S)-2-hydroxy-3-(2-phenylbenzoxazole-5-yloxy)propyl]-3-methylpiperazine}-N-(2,6-dimetilfenil)ndimethylacetamide,

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-naphthylacetamide,

N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}ndimethylacetamide,

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-phenylacetamide,

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-(3,4,5-trichlorophenyl)ndimethylacetamide,

2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinil}-N-(3,4,5-trichlorophenyl)ndimethylacetamide,

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-(2-chloro-4-were)ndimethylacetamide,

2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinil}-N-(3,4,5-trichlorophenyl)ndimethylacetamide,

2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazinil}-N-(3,5-dichlorophenyl)acetamide", she

2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazinil}-N-(3,4-dichlorophenyl)acetamide", she

2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazinil}-N-[3-methoxy-5-(trifluoromethyl)-phenyl]acetamide", she

2-{4-[2-hydroxy-3-(2-phenylbenzothiazole-5-yloxy)propyl]piperazinil}-N-[3,5-dichlorophenyl]ndimethylacetamide and

2-{4-[2-hydroxy-3-(2-((1E)-buta-1,3-dienyl)benzothiazol-5-yloxy)propyl]piperazinil}-N-[4-chloro-2-methoxy-5-were]ndimethylacetamide.

37. The pharmaceutical composition showing the properties of a partial inhibitor of fatty acid oxidation, containing a compound according to claim 1 and one or more pharmaceutical excipients.

38. The pharmaceutical composition according to clause 37, having the form of a solution.

39. The pharmaceutical composition according to clause 37, having the General form of tablets or capsules.



 

Same patents:

The invention relates to new heterocycles compounds, more particularly to a new heterocycles compounds which are inhibitors of the enzyme 5-lipoxygenase (5-LO)

The invention relates to organic chemistry and can find application in medicine

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to sulfhemoglobinemia heterocyclic compound represented by formula (I), its pharmaceutically acceptable salts and their hydrates

where the values of A, B, K, T, W, X, Y, U, V, Z, R1specified in paragraph 1 of the claims

The invention relates to new and nitrate salts of compounds of formulas (I) to(VI), which can be used in medicine for the treatment of bone disorders such as abnormalities in bone and joints
The invention relates to a method for producing 5-chloro-4-/(2-imidazolin-2-yl)amino/-2,1,3-benzothiadiazole the hydrochloride by hydrochlorination 5-chloro-4-/(2-imidazolin-2-yl)amino/-2,1,3-benzothiadiazole of concentrated hydrochloric acid in the environment of ethyl alcohol at 20-35With target product is separated from the reaction mixture by dilution with water, heating to 75-80With that clarification of the resulting solution activated carbon, cooling the clarified solution to 0-2With, then the selected product is filtered, washed with alcohol and dried at 70C in vacuum (120 mm RT.CT.) get 5-chloro-4-/(2-imidazolin-2-yl)amino/-2,1,3-benzothiadiazole hydrochloride with a melting point 292-294C (with decomposition) and mass fractions of the main substance of at least 99.8%, the product yield is 80% on the original basis

The invention relates to compounds of formula (I)

in which f represents phenylenebis radical, a represents the radical

in which Rl, R2, R3, R4, R5represent independently a hydrogen atom, IT is a group or an unbranched or branched alkyl or alkoxyalkyl having from 1 to 6 carbon atoms; R11represents a hydrogen atom, an unbranched or branched alkyl radical having from 1 to 6 carbon atoms, or the radical

in which Rl, R2, R3, R4, R5represent independently a hydrogen atom, IT is a group or an unbranched or branched alkyl or alkoxyalkyl having from 1 to 6 carbon atoms; b is a thiophene; W is absent or represents an Association or S; X represents a bond or a radical -(CH2)k-NR16-, -O-, -CO-, -NR16-CO-, and so forth, and k is 0 or 1; Y represents a bond or a radical selected from the radicals -(CH2)m-, -(CH2)m-O-(CH2)n, -(CH-Q-(CH2)n; and Q represents pieperazinove radical, m and n are equal to integers from 0 to 6; R16, R17, R18represent independently a hydrogen atom, or a salt of the compounds

The invention relates to new effectors dipeptidylpeptidase IV - the dipeptide mimetics (I) formed from amino acids and thiazolidinone or pyrrolidino groups, namely: L-ALLO-isoleucyl-thiazolidine, L-ALLO-isoleucyl-pyrrolidino and their salts, salts of L-threo-isoleucyl-thiazolidine and L - threo-isoleucyl-pyrrolidine; a pharmaceutical composition having the ability to lower blood sugar, containing at least one of the above-mentioned compounds (1)

The invention relates to new compounds of the formula (I) and their pharmaceutically acceptable salts and esters possessing inhibitory ability against endothelioma receptors, the Compounds can be used to treat diseases associated with abnormal vascular tone and endothelial dysfunction

The invention relates to new derivatives of 1,3-diaryl-2-pyridin-2-yl-3-(pyridine-2-ylamino)propanol of the formula (I)

where Z denotes-NH-(C1-C16-alkyl)-(C=O)-; -(C=O)-(C1-C16-alkyl)-(C=O)-;

-(C=O)-phenyl-(C=O)-; AND1AND2AND3AND4denote independently of each amino-acid residue, E represents-SO2-R4and-CO-R4; R1- phenyl, thiazolyl, oxazolyl, thienyl, thiophenyl and others, R2- N., HE, CH2HE, OMe; R3Is h, F, methyl, OMe; R4denotes -(C5-C16-alkyl), -(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylene)-NH-R5and others, R5denotes-COO-R6, -(C=O)-R6-(C1-C6-alkylen)-R7, phenyl, naphthyl and others, R6denotes H, -(C1-C6) alkyl; R7denotes H, -(C1-C7-cycloalkyl, phenyl, naphthyl and others, l, q, m, n, o, p denote 0 or 1, and l+q+m+n+o+p is greater than or equal to 1, and their pharmaceutically acceptable salts

The invention relates to a method for producing 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] methoxy] benzyl] thiazolidin-2,4-dione of formula (1), including the restoration of the compounds of formula (2'), where R is a (C1-C4)alkyl group, with the use of Raney Nickel or magnesium and, optionally, re-esterification using sulfuric acid in the temperature range from 0 to 60oWith obtaining the compounds of formula (3'), which is subjected to hydrolysis to obtain the acid of formula (4), the condensation of the acid of formula (4) with N-methyl-anthranilamide formula (7) without any pre-activation of the acid to obtain the compounds of formula (1), which is optionally transformed into a pharmaceutically acceptable salt

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

The invention relates to organic chemistry and can find application in medicine

The invention relates to the field of pharmacy and medicine and relates to solid dosage forms such as tablets "Apolar" anabolic and act-protective action based on the nature of the pharmacologically active component of the drone brood

The invention relates to pharmacy and medicine and relates to the development of new medicines

The invention relates to substituted cyclic aminoven compounds of formula (I)

< / BR>
where Ar represents thienyl, substituted pyridine, phenyl unsubstituted or substituted with halogen, hydroxy, alkoxy, C1-C4the alkyl, phenyloxy, NO2or phenyl; R1is NHOR2where R2is hydrogen; W is one or more hydrogen atoms; Y is independently one or more members of the group consisting of hydroxy, SR3, alkoxy, NR6R7where R6and R7independently selected from hydrogen, alkyl, pyridylethyl, SO2R8, COR9or R6and R7can be combined with the formation of the ring containing the nitrogen to which they relate, formulas

< / BR>
where Y' is CH2OH , SO2; R3represents hydrogen, alkyl, aryl, benzothiazolyl, pyrazinyl, N-methylimidazole; R8represents C1-C4alkyl, phenyl; R9represents hydrogen, alkyl, phenyl; Z is hydrogen; n = 1, and its optical isomer, diastereoisomer, or enantiomer, or its pharmaceutically acceptable salt

The invention relates to the pharmaceutical industry and relates to improved pharmaceutical preparations containing dehydroepiandrosterone (DHEA), enriched to polymorphic forms I or II, for therapeutic purposes
The invention relates to pharmaceutical industry

The invention relates to the field of medicine and relates to pharmaceutical compositions for the treatment of complex and coronary heart disease, myocardial infarction, myocardiodystrophy, rhythm disturbances associated with the use of cardiac glycosides

The invention relates to medicine, namely, neurology, orthopedics, acupuncture, manual therapy, and can be used for the treatment of muscle pain syndromes of various etiologies, for example, neurological manifestations of osteochondrosis, pathology articular ligament, and some diseases of internal organs
Up!