Substituted piperazine compounds and their using as inhibitors of aliphatic acids oxidation

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and R8 represent hydrogen atom or (C1-C6)-alkyl; T represents oxygen atom; V represents N<; X1 represents phenyl substituted with 1-2 substitutes chosen from group comprising (C1-C6)-alkyl, (C1-C6)-alkoxy-group, halogen atom, cyano-group or trifluoromethyl; X2 represents a bicyclic heteroaryl comprising 7 carbon atoms and 1-2 heteroatoms chosen from oxygen (O), nitrogen (N) and sulfur (S) atoms optionally substituted with (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl or phenyl substituted with halogen atom; Y represents monocyclic heteroarylenyl comprising 3-5 carbon atoms and 1-3 heteroatoms chosen from N and O; Z1 and Z2 represent independently (C1-C4)-alkylene. Compounds of the formula (I) are used in preparing a pharmaceutical composition used in treatment of morbid state in mammal that can be relieved using inhibitor of oxidation of aliphatic acids. Also, invention relates to a pharmaceutical composition inhibiting oxidation of aliphatic acids and comprising at least one pharmaceutically acceptable excipient and the therapeutically effective dose of compound of the formula (I). Invention provides using substituted piperazine compounds as inhibitors of oxidation of aliphatic acids.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

19 cl, 22 ex

 

The present invention relates to new heterocyclic derivatives, in particular derivatives of piperazine and piperidine derivatives and their use in the treatment of various painful conditions, in particular cardiovascular diseases such as atrial and ventricular arrhythmias, intermittent claudication, Prinzmetal's angina (variant), stable and unstable angina, angina, caused by physical exercise, congestive heart disease, ischemia, perfusion abnormalities, diabetes, myocardial infarction, and to increase HDL (high lipid density in the plasma by reducing the level of LDL (low density lipids). This invention relates also to processes for their preparation and pharmaceutical compositions containing such compounds.

It is known that some classes piperazinone compounds useful for the treatment of cardiovascular diseases, including arrhythmia, angina, myocardial infarction and related diseases such as intermittent claudication. For example, U.S. patent No. 4567264 discloses a class of substituted piperazinone compounds, 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 their use in the above conditions.

Despite demand the properties, demonstrate ranolazine, which is very effective cardiac therapeutic agent and which is believed to act as an inhibitor of fatty acid oxidation, there remains a need for compounds that have therapeutic properties similar to the properties of ranolazine, but are more powerful and have greater half-life.

The objective of this invention is to provide new substituted piperazinone and been the analogs of piperidine compounds, which are inhibitors of fatty acid oxidation with a good therapeutic half-life. Thus, the first aspect of the present invention relates to compounds of formula I

where R1, R2, R3, R4, R5, R6, R7and R8represent hydrogen, lower alkyl or-C(O)R;

in which R stands for-OR9or-NR9R10where R9and R10represent hydrogen or lower alkyl; or

R1and R2, R3and R4, R5and R6, R7and R8taken together with the carbon to which they are attached represent a carbonyl; or

R1and R5or R1and R7or R3and R5or R3and R7taken together form a bridging group -(CR12R13)n-, in which n is 1, 2, and 3, and R12and R13independently represent hydrogen or lower alkyl;

provided that the maximum number of carbonyl groups is equal to 2;

the maximum number of groups-C(O)NR9R10equals 1;

the maximum number of bridging groups is 1;

T is oxygen, sulfur or NR11in which R11represents hydrogen or lower alkyl;

V is-N<, -CH< or -- N-CH<;

X1represents hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

X2represents optionally substituted aryl or optionally substituted heteroaryl;

Y represents an optionally substituted monocyclic heteroaryl;

Z1and Z2independently represent a substituted C1-4alkylen.

The second aspect of the present invention relates to pharmaceutical preparations containing a therapeutically effective amount of the compounds of formula I and at least one pharmaceutically acceptable excipient.

The third aspect of the present invention relates to a method of using compounds of formula I in the treatment of a disease or condition in a mammal that is amenable to treatment with an inhibitor of fatty acid oxidation. Such diseases include the (but not limited to) protection of skeletal muscle from damage as a result of injury, alternating lameness, shock, and cardiovascular diseases including atrial and ventricular fibrillation, angina Prinzmetala (option), stable angina, angina, caused by physical exercise, congestive heart disease, diabetes, myocardial infarction, and increased level of HDL in the plasma by reducing LDL levels. The compounds of formula I can also be used for the preservation of donor tissue and organs used in transplants.

A fourth aspect of the present invention relates to a method for producing compounds of formula I.

Among the compounds of formula I, one preferred class consists of compounds in which V represents nitrogen, in particular such compounds in which Z1and Z2represent the lowest alkylene, especially methylene, and T represents oxygen. A preferred group of this class include such compounds in which R1, R2, R3, R4, R5, R6, R7and R8independently selected from hydrogen and methyl, in particular, where R1, R2, R3, R4, R5, R6, R7and R8all represent hydrogen, or R1, R2, R3, R5, R6, R7and R8- all represent hydrogen and R4represents methyl. A preferred subgroup includes those compounds in which X1presented yet optionally substituted aryl or optionally substituted heteroaryl, especially, where X1represents optionally substituted phenyl. Within this subgroup preferably, when X2represents optionally substituted phenyl or optionally substituted bicyclic heteroaryl, in particular, when X2is optionally substituted bicyclic heteroaryl.

More preferred within this subgroup are those compounds in which Y represents biradical, a derivative of pyrazole, 1,2-oxazole, 1,3-oxazole, 1,3-thiazole, 1,2,4-oxadiazolyl or 1,3,4-oxadiazole, especially, where X1represents phenyl, optionally substituted lower alkyl, lower alkoxy, halogen or trifluoromethyl, and X2selected from 2-methylbenzo-1,3-thiazol-5-yl, 2-cyclohexylamino-1,3-thiazol-5-yl, 2-phenylbenzo-1,3-thiazol-5-yl, 2-phenylbenzo-1,3-oxazol-5-yl or 2-methoxyphenyl. Most preferred are those compounds in which X2selected from 2-methylbenzo-1,3-thiazol-5-yl, and X1-Y is 3-(4-tert-butylphenyl)-1,2,4-oxadiazol-5-yl, or X1-Y is 5-(4-triptoreline)-1,2,4-oxadiazol-3-yl, or X1-Y is 5-(4-chlorophenyl)-1,2-oxazol-3-yl, or X1-Y is 5-(4-triptoreline)isoxazol-3-yl, or X1-Y represents 2-(4-triptoreline)oxazol-4-yl.

Definitions and basic parameters

The term "alkyl" otnositsa monologically branched or unbranched saturated hydrocarbon chain, having from 1 to 20 carbon atoms. Examples denoted by this term are such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-decyl, tetradecyl and the like.

The term "substituted alkyl" refers to:

1) an alkyl group as defined above having from 1 to 5 substituents, preferably from 1 to 3 substituents selected from the group consisting of alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxylic, aaltio, heteroaromatic, heterocyclic, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonyl, heteroaromatic, heterocyclic, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl. Until there are no restrictions in the definition, all substituents may be optionally additionally substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2; or

2) an alkyl group as defined above, and which is interrupted by 1-5 atoms is or in groups, independently selected from oxygen, sulfur and-NRa-, where Raselected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, quinil, aryl, heteroaryl and heterocyclyl. Until then, until there are no restrictions in the definition, all substituents may be optionally additionally substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2; or

3) an alkyl group as defined above, and which has from 1 to 5 substituents defined above and is also interrupted by 1-5 atoms or groups as defined above.

The term "lower alkyl" refers to monologically branched or unbranched saturated hydrocarbon chain, having from 1 to 6 carbon atoms. Examples marked with this term, are groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl and the like.

The term "substituted lower alkyl" refers to lower alkyl as defined above having from 1 to 5 substituents, preferably from 1 to 3 substituents, as defined for the substituents of the alkyl or lower alkyl group, as defined above that is interrupted by 1-5 atoms as defined for substituted al the sludge, or a lower alkyl group, as defined above, which is from 1 to 5 substituents as defined above and is also interrupted by 1-5 atoms, as defined above.

The term "alkylene" refers to biradicaloid branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 20 carbon atoms, more preferably 1-10 carbon atoms, and more preferably 1-6 carbon atoms. Examples marked with this term, are groups such as methylene (-CH2-), ethylene (-CH2CH2-), isomers of propylene (e.g.,- CH2CH2CH2- , and-CH(CH3)CH2-) and the like.

The term "lower alkylene" refers to biradicaloid branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 6 carbon atoms.

The term "substituted alkylene" refers to:

1) alkalinous group as defined above having from 1 to 5 substituents selected from the group comprising alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxylic, aaltio, heteroaromatic, heterocyclic, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonyl, heteroaromatic, Goethe is iillil, heterocyclics, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl. Until there are no restrictions in the definition, all substituents may be optionally additionally substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2; or

2) alkalinous group that is defined above and which is interrupted by 1-5 atoms or groups independently chosen from oxygen, sulfur and-NRa-, where Raselected from hydrogen, optionally substituted alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl, or groups selected from carbonyl, carboxyester, carboxyamide and sulfonyl, or

3) alkalinous group that is defined above, and which has from 1 to 5 substituents as defined above and is also interrupted by 1-20 atoms as defined above. Examples of the substituted alkylenes are chlormethine (-CH(Cl)-), aminoethyl (-CH(NH2)CH2-), methylaminoethanol (-CH(NHMe)CH2-)isomers of 2-carboxypropyl(-CH2CH(CO2H)CH2-), ethoxyethyl(-CH2CH2OCH2CH2-), ethylmethylamine(-CH2CH2N(CH3)CH2/sub> CH2-), 1 ethoxy-2-(2-ethoxyethoxy)ethane (-CH2CH2O-CH2CH2-OCH2CH2-Och2CH2-) and the like.

The term "aralkyl" refers to an aryl group covalently associated with alkalinous group, where the aryl and alkylene defined above. "Optionally substituted aralkyl" denotes optionally substituted aryl group covalently linked with optionally substituted alkalinous group. Examples of such Uralkalij groups are benzyl, phenylethyl, 3-(4-methoxyphenyl)propyl and the like.

The term "alkoxy" refers to the group R-O-, where R is optionally substituted alkyl or optionally substituted cycloalkyl or R is a group-Y-Z, in which Y represents optionally substituted alkylene, and Z represents optionally substituted of alkenyl, optionally substituted quinil; or optionally substituted cycloalkenyl, where the alkyl, alkenyl, quinil, cycloalkyl and cycloalkenyl such as here defined. The preferred alkoxygroup are optionally substituted group alkyl-O - and include as an example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentox, n-hexose, 1,2-Dimethylbutane, triptoreline and the like.

The term "alkylthio" refers to the group R-S-, where R is defined as for alkoxy.

The term "lceil" refers to monologically branched or unbranched unsaturated hydrocarbon group, preferably having from 2 to 20 carbon atoms, more preferably from 2 to 10 carbon atoms, even more preferably from 2 to 6 carbon atoms and having 1-6 double bonds, preferably 1 double bond (vinyl). Preferred alkeneamine groups include ethynyl or vinyl(-CH=CH2), 1-propylene or allyl (-CH2CH=CH2), isopropylene (-C(CH3)=CH2), bicyclo[2.2.1]hepten and the like. When alkenyl attached to the nitrogen, the double bond may not be in the alpha-position to the nitrogen.

The term "lower alkenyl" refers to alkenyl, as defined above, containing 2-6 carbon atoms.

The term "substituted alkenyl" refers to alkenylphenol group, which is defined here above, having from 1 to 5 substituents and preferably 1 to 3 substituents selected from the group comprising alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxylic, aaltio, heteroaromatic, heterocyclic, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonyl, heteroaromatic, heterocyclic, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl and-SO2-heteroaryl. what about those long while there are no restrictions in the definition, all substituents may be optionally additionally substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "quinil" refers to monoarticular unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms, more preferably from 2 to 10 carbon atoms and even more preferably from 2 to 6 carbon atoms, and having at least 1 and preferably 1-6 places acetylenic unsaturation (triple bond). Preferred alkyline group include ethinyl (-CH≡), propargyl (or prop-1-in-3-yl, -CH2CH≡) and such. When quinil attached to the nitrogen triple bond may not be in the alpha-position to the nitrogen.

The term "substituted quinil" refers to alkenylphenol group as defined above having from 1 to 5 substituents and preferably 1 to 3 substituents selected from the group comprising alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxylic, aaltio, heteroaryl is about, heterocyclic, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonyl, heteroaromatic, heterocyclic, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl and-SO2-heteroaryl. Until the determination there are no other restrictions, all substituents may be optionally additionally substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "aminocarbonyl" denotes the group-C(O)NRR where each R independently represents hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or where both groups R are connected, forming a heterocyclic group (for example, morpholino). Until the determination there are no other restrictions, all substituents may be optionally additionally substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "acylamino" refers to the group-NRC(O)R where each R independently represents hydrogen, alkyl, aryl, heteroaryl or gets recycler. Until the determination there are no other restrictions, all substituents may be optionally additionally substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "acyloxy" refers to a group-O(O)s-alkyl, -O(O)s-cycloalkyl, -O(O)C-aryl, -O(O)s-heteroaryl and-O(O)C-heterocyclyl. Until the determination there are no other restrictions, all substituents may be optionally additionally substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "aryl" means an aromatic carbocyclic group of from 6 to 20 carbon atoms having a single ring (e.g. phenyl)or multiple rings (e.g., biphenyl), or multiple condensed (fused) rings (e.g., naphthyl or until). Preferred arily include phenyl, naphthyl and the like. Until in the definition of aryl substituent are no other restrictions, such aryl groups can be optionally substituted by 1-5 substituents, preferably 1-3 substituents, select the tion from the group includes alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxylic, aaltio, heteroaromatic, heterocyclic, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonyl, heteroaromatic, heterocyclic, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl and-SO2-heteroaryl. Until the determination there are no other restrictions, all substituents may be optionally additionally substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "aryloxy" refers to the group aryl-O-, where aryl group such as defined above, and includes optionally substituted aryl group, which is also defined above. The term "aristeo" refers to a group R-S-, where R is as defined for aryl.

The term "amino" denotes the group-NH2.

The term "substituted amino" denotes the group-NRR where each R is independently selected from the group comprising hydrogen, alkyl, cycloalkyl, carboxylic (n is an example, benzyloxycarbonyl), aryl, heteroaryl and heterocyclyl, provided that both groups R are hydrogen or the group-Y-Z, in which Y represents optionally substituted alkylene and Z denotes alkenyl, cycloalkenyl or quinil. Until the determination there are no other restrictions, all substituents may be optionally additionally substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "carboxylic" denotes the group-C(O)O-alkyl, -C(O)O-cycloalkyl, where the alkyl and cycloalkyl such as here defined, and can be optionally additionally substituted by alkyl, alkenyl, quinil, alkoxy, halogen, CF3, amino, substituted amino, cyano or-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "cycloalkyl" denotes a cyclic alkyl group of 3-20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include as examples of patterns with a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like, or structure with many rings, such as adamantyl and bicyclo[2.2.1]GE is tan, or cyclic alkyl groups, which are condensed with aryl groups, for example, indan and the like.

The term "substituted cycloalkyl" means cycloalkyl group having from 1 to 5 substituents, and preferably 1-3 substituent selected from the group comprising alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxylic, aaltio, heteroaromatic, heterocyclic, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonyl, heteroaromatic, heterocyclic, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl. Until the determination there are no other restrictions, all substituents may be optionally additionally substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "halogen" or "halo" refers to fluorine, bromine, chlorine and iodine.

The term "acyl" denotes the group-C(O)R, in which R represents hydrogen, optionally substituted alkyl, optionally alseny cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.

The term "heteroaryl" refers to an aromatic group (i.e. unsaturated)comprising from 1 to 15 carbon atoms and from 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur, at least one ring.

Until the definition of heteroaryl substituent are no other restrictions, such heteroaryl groups can be optionally substituted by 1-5 substituents, preferably 1 to 3 substituents selected from the group comprising alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxylic, aaltio, heteroaromatic, heterocyclic, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonyl, heteroaromatic, heterocyclic, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl. Until the determination there are no other restrictions, all substituents may be optionally additionally substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted am the but cyano and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2. Such heteroaryl groups can have a single ring (e.g., pyridyl, furyl, oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl) or multiple condensed rings (e.g., bicyclic heteroaryl group, such as indolizinyl, benzothiazolyl, benzoxazolyl, sensational and the like). Examples of nitrogen heterocycles and heteroaryl include (but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, hemolysin, isoquinoline, quinoline, phthalazine, naftemporiki, cinoxacin, hinzelin, cinnolin, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazol, fenesin, isoxazol, phenoxazin, phenothiazines, imidazolidin, imidazolyl and the like, and N-alkoxysilane heteroaryl compounds.

The term "heteroaryl" or "heteroaromatic" refers to biradical heteroaryl group as defined above. This term presents examples of such groups as 3,5-[1,2,4]oxadiazolyl, 2,4-[1,3]oxazinyl, 2,5-[1,3]oxazinyl, 3,5-isoxazolyl, 3,4-pyrazolyl, 3,5-pyrazolyl and the like. For example, 3,5-[1,2,4]oxadiazolyl in the context of the compounds of formula I is represented as:

Until in the definition of g is tervailing or heteroarenes Deputy no other restrictions such heteroarenes groups can be optionally substituted by 1-5 substituents, preferably 1 to 3 substituents selected from the group comprising alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxylic, aaltio, heteroaromatic, heterocyclic, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonyl, heteroaromatic, heterocyclic, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl and-SO2-heteroaryl. Until the determination there are no other restrictions, all substituents may be optionally additionally substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "heteroaromatic" denotes the group heteroaryl-O-.

The term "heterocyclyl" means manordeilo saturated or partially unsaturated group having a single ring or a lot of condensed rings, having from 1 to 40 carbon atoms and from 1 to 10 heteroatoms, preferably from 1 to 4 heteroatoms, you the security of nitrogen, sulfur, phosphorus and/or oxygen in the ring.

Until the determination of heterocyclic substituent, there are no other restrictions, such heterocyclic groups can be optionally substituted by 1-5, and preferably 1-3 substituents selected from the group comprising alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxylic, aaltio, heteroaromatic, heterocyclic, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonyl, heteroaromatic, heterocyclic, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl. Until the determination there are no other restrictions, all substituents may be optionally additionally substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2. Heterocyclic groups can have a single ring or a lot of condensed rings. Preferred heterocyclic groups include tetrahydrofuranyl, morpholino, piperidinyl and the like.

Those who min "thiol" refers to the group-SH.

The term "substituted, alkylthio" denotes the group-S-substituted alkyl.

The term "heteroaromatic" denotes the group-S-heteroaryl, where heteroaryl group such as defined above including optionally substituted heteroaryl group defined above.

The term "sulfoxide" refers to a group-S(O)R, in which R represents alkyl, aryl or heteroaryl.

The term "substituted sulfoxide" refers to a group-S(O)R, in which R is substituted alkyl, substituted aryl or substituted heteroaryl, which is defined above.

The term "sulfon" denotes the group-S(O)2R, in which R represents alkyl, aryl or heteroaryl.

The term "substituted sulfon" denotes the group-S(O)2R, in which R is substituted alkyl, substituted aryl or substituted heteroaryl, which is defined above.

The term "keto" refers to the group-C(O)-. The term "thiocarbonyl" denotes the group-C(S)-. The term "carboxy" refers to a group-C(O)-HE.

The expression "optional" or "optionally" means that the described event or circumstance may occur or not occur and that the description includes instances when the specified event or circumstance occurs and instances where it does not occur.

Have in mind that the expression "a compound of formula I includes compounds Yes the tion of the invention, they are revealed, and their pharmaceutically acceptable salts, pharmaceutically acceptable esters and prodrugs of such compounds.

The expression "therapeutically effective amount" denotes an amount of the compounds of formula I, which is sufficient for effective treatment, as defined above, with the introduction in need of such treatment to the mammal. A therapeutically effective amount varies depending on the patient and subject to the treatment of painful conditions, weight and age of the patient, the severity of the condition, the route of administration and the like, it is easily determined by the expert in this field.

The term "therapy" or "treatment" means the treatment of a disease in a mammal, including:

(i) preventing the disease, i.e. ensuring circumstances in which the clinical symptoms not to develop;

(ii) inhibiting the disease, i.e. the suspension of development of clinical symptoms; and/or

(iii) facilitation of the disease, i.e. ensuring the regression of clinical symptoms.

In many cases, the compounds of this invention are capable of forming salts of the acids and/or bases, due to the presence of amino and/or carboxyl groups or similar groups. The expression "pharmaceutically acceptable salts" refers to salts that retain the biological effective is the motion and properties of the compounds of formula I and which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts of the accession of the bases can be obtained from inorganic and organic bases. Salts, derivatives of inorganic bases include, as examples only salts of sodium, potassium, lithium, ammonium, calcium and magnesium. Salts derived from organic bases include, but are not limited to, the salts of primary, secondary and tertiary amines, such as alkylamines followed, diallylamine, triallylamine, substituted alkylamines followed, di(substituted alkyl)amines, three(substituted alkyl)amines, alkenylamine, dialkanolamine, trialkylamine, substituted alkanolamine, di(substituted alkenyl)amines, three(replaced alkenyl)amines, cyclooctylamine, di(cycloalkyl)amines, three(cycloalkyl)amines, substituted cycloalkene, disubstituted cyclooctylamine, tizamidine cyclooctylamine, cyclooctylamine, di(cycloalkenyl)amines, three(cycloalkenyl)amines, substituted cycloalkenyl, disubstituted cycloalkenyl, tizamidine cyclooctylamine, arylamine, diarylamino, triarylamine, heteroaromatic, digitalairlines, triethanolamine, heterocyclic amines, diheterocyclanes amines, trilateration amines, mixed di - and triamine, where at least two of the substituents on Amina different and selected from the group comprising alkyl, substituted alkyl, alkenyl, replaced alkenyl, cycloalkyl, alseny cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic group and the like.

Specific examples of suitable amines include are given only as examples Isopropylamine, trimethylamine, diethylamine, three(isopropyl)amine, three(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, geranamine, choline, betaine, Ethylenediamine, glucosamine, N-alkylguanine, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine and the like.

Pharmaceutically acceptable salt accession acids can be obtained from inorganic and organic acids. Salts, derivatives of inorganic acids include salts of hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include the salts of acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, almond acid, methanesulfonic acid, econsultancy acid, para-toluensulfonate acid, salicylic acid and the like.

Used herein, the expression "pharmaceutically acceptable wear the spruce" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and agents that slow down the absorption, and the like. The use of such media and agents for pharmaceutically active substances is well known in this field. With the exception of those cases when conventional medium or agent is incompatible with the active ingredient and it is supposed to be used in pharmaceutical compositions. The composition can also include additional active ingredients.

The term "inhibitors of fatty acid oxidation" refers to compounds that inhibit the production of ATP from oxidation of fatty acids and, therefore, stimulate the production of ATP through the oxidation of glucose and lactate. In the heart of the production of ATP occurs mainly via the metabolism of fatty acids. The metabolism of glucose and lactate provides a smaller part of ATP. However, the formation of ATP from fatty acids is less effective against oxygen consumption than the formation of ATP from oxidation of glucose and lactate. Thus, inhibitors of fatty acid oxidation in the result produces more energy per molecule of the consumed oxygen, allowing the heart to work more efficiently.

Nomenclature

The name and numbering of the compounds Dunn is th invention is illustrated in a typical example, the compounds of formula I, in which R1, R2, R3, R4, R5, R6, R7and R8represent hydrogen, T is oxygen, X1is 4-tert-butylphenyl, X2is 2-methylbenzothiazol-5-yl, Y is 1,2,4-oxadiazole, and Z1and Z2represent methylene:

and which is called 3-[4-({3-[4-(tert-butyl)phenyl](1,2,4-oxadiazol-5-yl)}methyl)piperazinil]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol.

The synthesis of compounds of formula I

One way of preparing compounds of formula I are represented by reaction scheme I.

where R1, R2, R3, R4, R5, R6, R7, R8, T, X1X2, Y, Z1and Z2such as defined above, Hal represents halogen, and t-but denotes a tertiary butyl.

Educt

Compounds of formula (1), (2) and (4) are either commercially available or can be obtained by conventional means, well known specialist in this field.

For example, the precursor compounds of the formula (4), where R1and R5taken together, represent a bridging methylene group, that is,

is commercially available [(1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane] or it can be obtained by the method disclosed in J. Org. Chem., 990, 55, 1684-7. Similarly, the precursor compounds of the formula (4), where R1and R5taken together, represent a bridging ethylene group, and the precursor compounds of the formula (4), where R1and R7taken together, represent a bridging ethylene group, can be obtained according to the published method disclosed in J. Med. Chem., 1974, 17, 481-7. The precursor compounds of the formula (4), where R1, R2, R3, R4, R5, R6and R7represent hydrogen and R8represents-C(O)NH2from piperazine-2-carboxamide, commercially available compounds.

Step 1 - Obtaining the compounds of formula (3)

The compound of the formula (3) are usually obtained by reacting the compounds of formula (1), for example 5-hydroxy-2-methylbenzothiazole, with the epoxide of formula (2). Usually two compounds are mixed in an inert solvent, preferably a ketone, for example acetone, in the presence of tertiary organic bases or inorganic bases, preferably calcium carbonate at a temperature of about the boiling point under reflux for about 8-48 hours, preferably over night. When the interaction is essentially finished, produce the product of formula (3) in the usual ways, for example by filtration, removal of solvent under reduced pressure followed chromatographically on silica gel. In the alternative case, after filtration, the product may crystallize from the filtrate.

Stage 2 - Obtaining the compounds of formula (5)

Further, the compound of formula (3) is subjected to interaction with a protected piperazine of the formula (4). Usually two compounds are mixed in an inert solvent, preferably a halogenated solvent such as methylene chloride, optionally in the presence of a catalyst, for example triftoratsetata ytterbium (III). In the presence of a catalyst interaction is conducted at about 0-30°C, preferably at room temperature for about 8-48 hours, preferably over night. In the absence of catalyst the mixture is refluxed during the same time period in ethanol in the presence of triethylamine. When the interaction is essentially finished, produce the product of formula (5) in the usual ways, for example by removing the solvent under reduced pressure followed by chromatography of the residue on silica gel.

Stage 3 - Obtaining the compounds of formula (6)

Further, the compounds of formula (5) remove the protection via hydrolysis of the tert-butyl ether complex. Typically, the compound of formula (5) is dissolved in a mixture of inert solvent, preferably a halogenated solvent such as methylene chloride, and a strong acid, such as triflorus the Oh of the acid.

The interaction is conducted at about 0-30°C, preferably at a temperature of about room for about 8-48 hours, preferably over night. When the interaction is essentially finished, produce the product of formula (6) in the usual ways, for example by adding a base to remove excess acid and removing the solvent under reduced pressure.

Stage 4 - Obtaining the compounds of formula I

Further, the compound of formula (6) is subjected to interaction with the compound of the formula (7) (X1-Y-Z1-Hal), for example 3-(4-triptoreline)-5-chloromethyl-1,2,4-oxadiazole. Usually two compounds are mixed in an inert solvent, preferably proton solvent, for example ethanol, in the presence of an inorganic or tertiary organic base, preferably triethylamine. The interaction is conducted at about 30-100°C, preferably near the boiling point under reflux for about 8-48 hours, preferably over night. When the interaction is essentially finished, produce the product of formula I by conventional means, for example by removing the solvent under reduced pressure followed by chromatography.

An alternative synthesis of compounds of formula I, where Y is derived 1,2,4-oxadiazole shown in reaction scheme II.

Soy is inania formula (9) are obtained by known reactions by reacting the nitrile of the formula X 1CN with hydroxylaminopurine in ethanol in the presence of a tertiary base, preferably triethylamine at a temperature of approximately 0°C.

The compound of formula (9) is subjected to interaction with chlororesorcinol formula (10), such as chloracetamide, in an inert solvent, for example dichloromethane, at a temperature of from about -10 to -30°With subsequent interaction at a temperature of about 85°receiving the connection formula (11).

Then the compound of formula (11) is subjected to interaction with the compound of the formula (6) in a similar manner as shown in reaction scheme I. alternatively, you can spend interaction of the compounds of formula (11) with tert-butyldimethylchlorosilane, which then removes the protection of the normal ways (acidic conditions). Next, the thus obtained compound is subjected to interaction with the epoxide of formula (3)as shown in reaction scheme I, receiving the compound of formula I.

This allows us to obtain the compound of formula I, in which the 3-substituted [1,2,4]oxadiazol-5-yl attached to the piperazine. To obtain the corresponding 5-substituted derivative [1,2,4]oxadiazol-3-yl spend the interaction of the compounds of formula (9a) with a derivative of a carboxylic acid X1C(O)Cl, receiving 3-chloromethylene derived [1,2,4]oxadiazol formula (11a), which then experience the t interaction with the compound of the formula (6), receiving the compound of the formula I in which Y represents a 5-substituted [1,2,4]oxadiazol-3-yl, as shown in reaction scheme III.

Chloromethylene compound of formula (9a) are obtained by known reactions by the interaction of chloroacetonitrile with hydroxylaminopurine in aqueous conditions in the presence of a base, preferably sodium carbonate at a temperature of approximately 0°C.

Thus obtained 2-chloracetamide formula (9a) is subjected to interaction with the acid chloride of the acid of formula X1C(O)Cl in the presence of a base, preferably a proprietary tertiary base in an inert solvent, for example toluene, at a temperature of about room during the night. The product is isolated and heated at about 80-120°C for about 2-3 days. When the interaction is essentially completed, produce a product of formula (11a) in the usual way.

Further, the compound of formula (11a) is subjected to interaction with the compound of the formula (6)obtained as shown above. Usually two compounds are mixed in an inert solvent, preferably proton solvent, for example ethanol, in the presence of an inorganic or tertiary organic base, preferably triethylamine. The interaction is conducted at about 30-100°C, preferably about ambient temperature the fish boil under reflux for about 24 to 72 h, preferably within 48 hours When the interaction is essentially completed, produce a product of formula I by conventional means, for example by removing the solvent under reduced pressure followed by chromatography.

Alternatively, you can spend interaction of the compounds of formula (11) with tert-butyldimethylchlorosilane, which then removes the protection conventional methods (acid conditions). Next, the thus obtained compound is subjected to interaction with the epoxide of formula (3)as shown in reaction scheme I, receiving the compound of formula I.

To obtain compounds of the formula I in which Y represents optionally substituted oxazole, apply a slightly different sequence of interactions, as shown in reaction scheme IV.

Stage 1

The compound of the formula X1C(O)Cl is subjected to interaction with commercially available methyl 2-amino-3-hydroxypropanoate (12). Typically, the two compounds are mixed in an inert solvent, for example dichloromethane, in the presence of an inorganic or tertiary organic base, preferably triethylamine. The first interaction is conducted at about 0°C for 5 min, and then at a temperature of about room within 30 minutes When the interaction is essentially finished, highlight the product f is rmula (13) in the usual way, for example by removing the solvent under reduced pressure followed by chromatography.

Stage 2

Further, the compound of formula (13) cyclist by interacting with diisopropylcarbodiimide or the like in the presence of triphenylphosphine, receiving 4-carboxymethyl-1,3-oxazoline of the formula (14). The interaction is carried out in an inert solvent, for example tetrahydrofuran, at a temperature of about room within 1-5 days. When the interaction is essentially completed, produce a product of formula (14) in the usual ways, for example by removing the solvent under reduced pressure followed by chromatography.

Stage 3

Then oxazoline of the formula (14) is transformed into 4-carboxymethyl-1,3-oxazoline derivative of the formula (15) by interaction with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in an inert solvent, for example toluene, at a temperature of about the boiling point under reflux for 1-2 days. When the interaction is essentially completed, produce a product of formula (15) in the usual ways, for example by removing the solvent under reduced pressure followed by chromatography.

Stage 4

Then carboxymethyl group of compounds of formula (15) restore normal ways to hydroxymethylene group receiving compound of the formula (16), for example, by reduction with sociallyengaged in the air is " thinner, for example tetrahydrofuran, at a temperature of approximately 0°C. When the interaction is essentially completed, produce a product of formula (16) in the usual ways, for example by quenching the excess of reducing agent with water, extraction with an inert solvent, e.g. ethyl acetate, removal of the solvent under reduced pressure followed by chromatography. Thus obtained hydroxymethylene compound of the formula (16) is subjected to interaction with a reagent capable of converting a hydroxyl group into a leaving group, for example, by conversion into the chloride by conventional means or preferably by interaction with sulphonylchloride, for example interaction with methanesulfonamido with receiving nelfinavir. Then this mesilate is subjected to interaction with the compound of the formula (6) in a similar manner as shown in reaction scheme I, receiving the compound of the formula I in which Y represents optionally substituted oxazol.

To obtain compounds of the formula (8)in which Y represents optionally substituted pyrazole, used another sequence of interactions, as shown in reaction scheme V.

Stage 1

Commercially available iodine compound of the formula X1I put the interaction with n-butyllithium at a temperature of from about -50 to -80°the inert solvent, for example diethyl ether, for approximately 1 h To thus obtained anion type three(n-butyl)stannane and approximately 1 h to give a mixture to warm to room temperature. When the interaction is essentially finished, produce the product of formula (17) in the usual ways, for example by blanking the excess of reducing agent ammonium chloride in water, extraction with an inert solvent, for example ether, and solvent removal under reduced pressure.

Stage 2

Further derived tin of formula (17) is mixed with optionally substituted pyrazole derivative of formula (18). These compounds are commercially available or they can get well-known in this field means. The interaction is carried out in an inert solvent, for example acetonitrile, in the presence of triphenylarsine, copper iodide and Pd-fired at a temperature of about 60-100°C for 1-3 days. When the interaction is essentially completed, produce a product of formula (19) in the usual ways, for example by filtration, removal of solvent under reduced pressure and chromatography of the residue.

The compounds of formula (7), in which Y represents optionally substituted isoxazol receive, as shown in reaction scheme VI.

Stage 1

The vinyl derivative of formula (20) is subjected to interaction with ethyl 2-chlor(hydroxyimino)acetate (21) in an inert solvent, for example tetrahydrofuran, in the presence of a tertiary base, such as triethylamine, in a period of about 0.5 to 4 hours When the interaction is essentially finished, highlight the product formula (22) in the usual way.

Stage 2

Further, the compound of formula (22) is transformed into 4-carboxyethyl-1,2-oxazoline derivative of the formula (23) by reaction with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in an inert solvent, for example toluene, at a temperature of about the boiling point under reflux for 1-2 days. When the interaction is essentially completed, produce a product of formula (23) in the usual ways, for example by removing the solvent under reduced pressure followed by chromatography.

Stage 3

Next carboxyaniline group of compounds of formula (23) to restore normal ways to hydroxymethylene group receiving compound of the formula (24), for example by reduction with sodium borohydride in an inert solvent, for example ethanol, at a temperature of approximately 0°C for 2-8 hours When the interaction is essentially completed, produce a product of formula (24) in the usual ways, for example by quenching the excess of reducing agent with water, extraction with an inert solvent, e.g. ethyl acetate, removal of the solvent under reduced pressure followed by chromatography.

Stage 4

Next hydroxymethylene group of compounds of formula (24) is transformed into chloromethylene group in the usual way, for example using thionyl chloride, receiving the compound of formula (25). The interaction is carried out in an inert solvent, for example dichloromethane, at a temperature of approximately 0°C for about 5 min, then stirred the mixture overnight at room temperature. When the interaction is essentially completed, produce a product of formula (25) in the usual ways, for example by removing the solvent under reduced pressure.

Further, the compound of formula (25) is subjected to interaction with piperazinone derivative of the formula (6) in a similar manner as shown in reaction scheme I, receiving the compound of the formula I in which Y represents optionally substituted isoxazol.

General applicability

The compounds of formula I effective in the treatment of conditions which are known to be responsive to the introduction of inhibitors of fatty acid oxidation, including the protection of skeletal muscle from damage as a result of trauma, alternating lameness, shock, and cardiovascular diseases including atrial and ventricular fibrillation, angina Prinzmetala (option), stable angina, ischemia and perfusion abnormalities in heart, kidney, liver and brain, angina, caused by physical exercise, congestive heart disease and myocardial infarction. Recently it was shown that inhibitors of fatty acid oxidation change the level of the glucose in patients with diabetes, providing, thus, a new method of treatment of diabetes and, in particular, ensuring effective treatment of angina in diabetic patients. It is also shown that inhibitors of fatty acid oxidation increase the levels of HDL and lower the LDL levels in mammals, providing, thus, a method for the treatment of coronary arterial disease. The compounds of formula I can also be used to save the donor tissue and organs used in transplants, and you can type in conjunction with thrombolytic agents, anticoagulants and other agents.

Investigation

The research activity carried out as described in the patents and patent applications identified above and in the examples below, and in ways that are understandable to experts in this field.

The pharmaceutical composition

The compounds of formula I is usually administered in the form of pharmaceutical compositions. Thus, the present invention relates to pharmaceutical compositions which contain as active ingredient one or more compounds of the formula I or their pharmaceutically acceptable salts or esters, and one or more pharmaceutically acceptable excipient, carrier, including inert solid diluents and fillers; diluents, including sterile aqueous solution and various organic solvents; agents that enhance p is anzania; agents that promote dissolution, and adjuvants. The compounds of formula I can be entered by themselves or in combination with other therapeutic agents. Such compositions produced by methods known in the pharmaceutical field (see, for example, Remington''s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985) and "Modern Pharmaceutics", Marcel Dekker, Inc. 3th Ed. (G. S. Banker & C. T. Rhodes, Eds.).

Route of administration

Compositions of the compounds of formula I can be taken as a single dose or multiple doses by any suitable means of administration of agents having similar applicability, for example, as described in the patents and patent applications, incorporated herein by reference, including rectal, transbukkalno, intranasal and transdermal routes of administration by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, locally, in the form of inhalation or by the insertion or blowing device, such as, for example, a stent or injected into the artery cylindrical polymer.

One of the ways of administration is parenteral, in particular by injection. Forms, which can include new compositions of the present invention for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as Elik the Ira, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical carriers. Usually for injections is used as aqueous solutions at physiological solution, but in the context of the present invention, they are less preferred. You can also use ethanol, glycerin, propylene glycol, liquid polyethylene glycol and the like and suitable mixtures), cyclodextrin derivatives and vegetable oils. The proper fluidity can be maintained, for example, using a coating such as lecithin, by maintaining the required particle size in the case of dispersion and by applying surfactants. It is possible to realize the prevention of the action of microorganisms using various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like.

Sterile injectable solutions, get, including the compound of formula I in the required amount in the appropriate solvent with various other ingredients as listed above, if required, followed by sterilization by filtration. Dispersion usually get, including the various sterilized active ingredients into a sterile vehicle, which contains the basic dispersion medium and other necessary ingredients from above. In the case of sterile powders for received what I sterile solutions for injection, the preferred methods of obtaining methods are vacuum drying and freeze-drying, which give a powder of the active ingredient plus any additional desired ingredient from a previous solution, sterilized by filtration.

The compound of the formula I can be introduced into the stent, for example, by diffusion, or be applied to the stent, for example, in the form of a gel, using techniques known to experts in this area, in light of the present invention.

Another way of introducing the compounds of the formula I is oral ingestion. You capsules, or tablets intersolubility coating, or the like. Upon receipt of pharmaceutical compositions that include at least one compound of formula I, the active ingredient is usually diluted with filler and/or included in such media, which may be in the form of a capsule, sachet, paper or other container. If the excipient serves as a diluent, it may be in the form of solid, semi-solid or liquid material (as described above), which acts as a filler, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, pellets, sachets, those capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, containing, for example, up to 10% of the mass. active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, Arabic gum, calcium phosphate, alginates, tragakant, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The preparations may additionally include lubricants, such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspendresume agents; preservatives, such as methyl - and propylhydroxybenzoate; sweetening agents and flavoring agents.

The compounds of this invention can be prepared in such a way as to ensure rapid, prolonged or delayed release of the active ingredient after administration to the patient, applying well-known in this field of technique. System with controlled release of drugs for oral administration include osmotic delivery system and dissolving system containing tanks with a polymer coating or preparations with a matrix of drug-polymer. Examples of systems with controlled release described in U.S. patent No. 3845770, 4326525, 4902514 and 5616345. Other preparations for the use of the texts in the methods of the present invention use the device for transdermal delivery ("patches"). Such plasters for transdermal delivery can be used to provide continuous or discontinuous injection of the compounds of the present invention in controlled amounts. Design and application patches for transdermal delivery of pharmaceutical agents is well known in this field. See, for example, U.S. patent No. 5023252, 4992445 and 5001139. It is possible to construct such patches for continuous, pulsed or required delivery of pharmaceutical agents.

The composition is preferably made in the form of a standard dosage forms. The expression "standard dosage form" refers to physically discrete units suitable as the standard dose for patients of humans and other mammals, each unit contains a predetermined quantity of the active substance, designed to provide the required therapeutic effect, in combination with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule). The compounds of formula I effective in a wide dosage range and are typically administered in pharmaceutically effective amounts. Preferably the dosage unit for oral administration contain 1 mg to 2 g of compound of formula I, and for parenteral administration, preferably from 0.1 to 700 mg of the compounds of formula I. However, the pleasant, that actually enter the amount of the compounds of formula I is determined by the physician in light of the specific circumstances, including the subject to the treatment condition, the chosen route of administration, the specific input connection and its relative activity, the age, weight and response of the individual patient, the severity of the patient's symptoms and the like.

For solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient, receiving the solid composition of the preliminary preparation containing a homogeneous mixture of the compounds of the present invention. Looking at the data of the composition of the preliminary preparations as homogeneous, suppose that the active ingredient is dispersed evenly within the composition so that the composition can easily be divided into standard dosage forms equal efficiency, such as tablets, pills and capsules.

Pills and tablets of the present invention may have a coating or can be prepared in such a way as to provide a dosage form with prolonged action or form, protected from the acidic conditions of the stomach. For example, the tablet or pill may contain internal dosed component and an outer dosage component, the latter forms a shell on top of the first. Two components can be R sdeleni intersolubility layer, which serves to counteract the destruction in the stomach and permits the inner component to pass intact into the duodenum or to be released with delay. For such intersolubility layers, you can use a variety of substances; these substances include a number of polymeric acids and mixtures of polymeric acids with such substances as shellac, cetyl alcohol and cellulose acetate.

Compositions for inhalation and insufflate include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents or their mixtures and powders. Liquid and solid compositions may contain suitable pharmaceutically acceptable excipients, which are described previously. For local or General steps preferably compositions for oral or breathing through the nose. The composition in the preferred pharmaceutically acceptable solvents can be sprayed using inert gases. Sprayable solutions can be applied in the form of inhalation directly from the spraying device or spray device can be attached to the face mask awning or breathing machine with intermittent positive pressure. Compositions in the form of solutions, suspensions or powders can be entered preferably orally or through the nose from devices that deliver the drug on the walking way.

The following examples are included to demonstrate preferred variants of the present invention. Specialists in this field should appreciate that the methods disclosed in the following examples represent techniques that were developed by the applicants of the present invention, and work well when applying this invention, and, therefore, we can assume that they are the preferred options for its use. However, experts in this area should be assessed in light of the present disclosure that you can make a lot of changes in the specific embodiments which are disclosed and still obtain a like or similar results in the scope of this invention.

EXAMPLE 1

Obtaining the compounds of formula (3)

A. Obtaining the compounds of formula (3)in which T is oxygen, X2is 2-methylbenzothiazol-5-yl and Z2represents a methylene

A mixture of the compounds of formula (1) 2-methylbenzothiazol-5-ol (6.0 g, 36 mmol), compounds of the formula (2) (S)-(+)-epichlorohydrin (20 ml, 182 mmol) and potassium carbonate (20 g, 144 mmol) in acetone (100 ml) is refluxed and allowed to mix overnight. The solution is allowed to cool and filtered through Celite 512. The filtrate is evaporated in vacuum, obtaining oil. This oil chromatographic on silica gel, elwira a mixture of 20% ethyl acetate/GE the San, getting 2-methyl-5-(S)-(oxiran-2-ylethoxy)benzothiazole as a white solid (6.2 g, 28 mmol).

C. Obtaining the compounds of formula (3)in which T is oxygen, X2is 2-phenylbenzoxazole-5-yl and Z2represents a methylene

Similarly, using the above method 1A, but replacing 2-methylbenzothiazol-5-ol 2-phenylbenzoxazole-5-ol, obtain the connection formula (3), where X2is 2-phenylbenzoxazole-5-yl, T is oxygen and Z2is methylene, namely 2-phenyl-5-(oxiran-2-ylethoxy)benzoxazol.

Similarly receive the following compounds of formula (3):

2-methoxy-1-(oxiran-2-ylethoxy)benzene and

2-fluoro-1-(oxiran-2-ylethoxy)benzene.

C. Obtaining the compounds of formula (3) with different T, X2and Z2

Similarly, using the above method 1A, but not necessarily replacing 2-methylbenzothiazol-5-ol with other compounds of formula (1), and optionally replacing (S)-(+)-epichlorohydrin other compounds of formula (2), substituted appropriately, given the following compounds of formula (3):

2-methyl-5-(R)-(oxiran-2-ylethoxy)benzothiazole;

2-methyl-5-(RS)-(oxiran-2-ylethoxy)benzothiazole;

2-methoxy-1-(oxiran-2-ylethoxy)benzene;

2-chloro-1-(oxiran-2-ylethoxy)benzene;

2-methyl-5-(oxiran-2-ylethoxy)benzothiazole;

2-fluoro-1-(oxiran-2-ylethoxy)benzo is;

4-methoxy-1-(oxiran-2-ylethoxy)benzene;

8-fluoro-1-(oxiran-2-ylethoxy)naphthalene;

1-fluoro-2-(oxiran-2-ylethoxy)naphthalene;

2-ethyl-4-(oxiran-2-ylethoxy)thiazole;

4-methyl-2-(oxiran-2-ylethoxy)imidazole;

2-methyl-5-(oxiran-2-ylethoxy)benzimidazole and

2-phenyl-5-(oxiran-2-ylethoxy)benzimidazole.

D. Obtaining the compounds of formula (3) with different T, X2and Z2

Similarly, using the above method 1A, but not necessarily replacing 2-methylbenzothiazol-5-ol with other compounds of formula (1), and optionally replacing (S)-(+)-epichlorohydrin other compounds of formula (2), substituted as appropriate, obtain other compounds of formula (3).

EXAMPLE 2

Obtaining the compounds of formula (5)

A. Obtaining the compounds of formula (5), in which R1, R2, R3, R4, R5, R6, R7and R8represent hydrogen, T is oxygen, X2is 2-methylbenzothiazol-5-yl and Z2represents a methylene

To a solution of the compounds of formula (3) 2-methyl-5-(oxiran-2-ylethoxy)benzothiazole (6.2 g, 28 mmol) and the compounds of formula (4) tert-butyl 1-piperidinecarboxylate (5.7 g, 31 mmol) in methylene chloride (200 ml) add triftorbyenzola ytterbium (III) (1.73 g, 28 mmol). The resulting solution was allowed to mix at room temperature the re during the night. The solvent is evaporated in vacuum, receiving semi-solid substance that chromatographic on silica gel, elwira a mixture of 5% methanol/methylene chloride, getting tert-butyl ester 4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazine-1-carboxylic acid as a clear oil (9.5 g, 23 mmol).

C. Obtaining the compounds of formula (5), in which R1, R2, R3, R4, R5, R6, R7and R8represent hydrogen, T is oxygen, X2is 2-phenylbenzoxazole-5-yl and Z2represents a methylene

Similarly, using the above method 2A, but replacing 2-methylbenzothiazol-5-yl 2-phenylbenzoxazole-5-yl, get compound of formula (3), where X2is 2-phenylbenzoxazole-5-yl, T is oxygen and Z2is methylene, namely tert-butyl ester 4-[2-hydroxy-3-(2-phenylbenzoxazole-5-yloxy)propyl]piperazine-1-carboxylic acid.

Similarly receive the following compounds of formula (3):

tert-butyl ester 4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazine-1-carboxylic acid and

tert-butyl ester 4-[2-hydroxy-3-(2-pertenece)propyl]piperazine-1-carboxylic acid.

C. Obtaining the compounds of formula (5) with different R1, R2, R3, R4, R5, R6, R7and R8, T, X2and Z2

Similar is about, using the above method 2A, but optionally replacing 2-methyl-5-(oxiran-2-ylethoxy)benzothiazole other compounds of formula (3), and optionally replacing tert-butyl 1-piperidinecarboxylate other compounds of formula (4)are the following compounds of formula (5):

tert-butyl ester 4-[2-hydroxy-4-(2-methoxyphenoxy)butyl]piperazine-1-carboxylic acid;

tert-butyl ester 4-[2-hydroxy-4-(2-pertenece)butyl]piperazine-1-carboxylic acid;

4-[2-hydroxy-4-(2-methylbenzothiazol-5-yloxy)butyl]piperazine-1-carboxylic acid;

4-[2-hydroxy-3-(2-pertenece)propyl]piperazine-1-carboxylic acid;

4-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperazine-1-carboxylic acid;

4-[2-hydroxy-3-(8-fornuft-1 yloxy)propyl]piperazine-1-carboxylic acid;

4-[2-hydroxy-3-(1-fornuft-2-yloxy)propyl]piperazine-1-carboxylic acid;

4-[2-hydroxy-3-(2-utiltity-4-yloxy)propyl]piperazine-1-carboxylic acid;

4-[2-hydroxy-3-(4-Mei-4-yloxy)propyl]piperazine-1-carboxylic acid;

4-[2-hydroxy-3-(2-methylbenzimidazole-5-yloxy)propyl]piperazine-1-carboxylic acid and

4-[2-hydroxy-3-(2-phenylbenzimidazol-5-yloxy)propyl]piperazine-1-carboxylic acid.

D. Obtaining the compounds of formula (5) with different R1, R2, R3, R4, R5, R6, R7and R8, T, X2and Z2

Similarly, using the above method 2A, but optionally replacing 2-methyl-5-(oxiran-2-ylethoxy)benzothiazole other compounds of formula (3), and optionally replacing tert-butyl 1-piperidinecarboxylate other compounds of formula (4)obtain other compounds of formula (5).

EXAMPLE 3

Obtaining the compounds of formula (6)

A. Obtaining the compounds of formula (6)in which R1, R2, R3, R4, R5, R6, R7and R8represent hydrogen, T is oxygen, X2is 2-methylbenzothiazol-5-yl, and Z2represents a methylene

A solution of the compounds of formula (5) tert-butyl ester 4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazine-1-carboxylic acid (2.0 g, 4.9 mmol) and a mixture of 25% triperoxonane acid/methylene chloride (20 ml) was allowed to mix at room temperature over night. The solvent is evaporated in vacuum, obtaining oil. This oil is diluted with acetone (20 ml) and add solid potassium carbonate until the termination of foaming. The resulting mixture was allowed to mix overnight. The solution is filtered through Celite 512 and the filtrate is evaporated in vacuum, obtaining oil. The oil is placed in a high vacuum at night, getting 1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-improper-2-ol in the form of a clear viscous oil (3.4 g, 3 mmol).

C. Obtaining the compounds of formula (6)in which R1, R2, R3, R4, R5, R6, R7and R8represent hydrogen, T is oxygen, X2is 2-phenylbenzoxazole-5-yl and Z2represents a methylene

Similarly, using the above method 3A, but replacing tert-butyl ester 4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazine-1-carboxylic acid tert-butyl ester 4-[2-hydroxy-3-(2-phenylbenzoxazole-5-yloxy)propyl]piperazine-1-carboxylic acid, to obtain the compound of formula (6), where R1, R2, R3, R4, R5, R6, R7and R8represent hydrogen, X2is 2-phenylbenzoxazole-5-yl, T is oxygen and Z2is methylene, namely 1-(2-phenylbenzoxazole-5-yloxy)-3-piperazine-1-improper-2-ol.

Similarly receive the following compounds of formula (6):

1-(2 - methoxyphenoxy)-3-piperazine-1-improper-2-ol and

1-(2-pertenece)-3-piperazine-1-improper-2-ol.

C. Obtaining the compounds of formula (6) with different R1, R2, R3, R4, R5, R6, R7and R8, T, X2and Z2

Similarly, using the above method 3A, but replacing tert-butyl ester 4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazine-1-carboxylic acid with other compounds form the s (5), get the following compounds of formula (6):

1-(2-methoxyphenoxy)-4-piperazine-1-ivatan-3-ol;

1-(2-chlorophenoxy)-4-piperazine-1-ivatan-3-ol;

1-(2-methylbenzothiazol-5-yloxy)-4-piperazine-1-ivatan-3-ol;

1-(2-pertenece)-3-piperazine-1-improper-2-ol;

1-(4-methoxyphenoxy)-3-piperazine-1-improper-2-ol;

1-(8-fornuft-1 yloxy)-3-piperazine-1-improper-2-ol;

1-(1-fornuft-2-yloxy)-3-piperazine-1-improper-2-ol;

1-(2-utiltity-4-yloxy)-3-piperazine-1-improper-2-ol;

1-(4-Mei-4-yloxy)-3-piperazine-1-improper-2-ol;

1-(2-methylbenzimidazole-5-yloxy)-3-piperazine-1-improper-2-ol and

1-(2-phenylbenzimidazol-5-yloxy)-3-piperazine-1-improper-2-ol.

D. Obtaining the compounds of formula (6) with different R1, R2, R3, R4, R5, R6, R7, R8, T, X2and Z2

Similarly, using the above method 3A, but replacing tert-butyl ester 4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazine-1-carboxylic acid with other compounds of formula (5)obtain other compounds of formula (6).

EXAMPLE 4

Obtaining the compounds of formula I

A. Obtaining the compounds of formula I in which R1, R2, R3, R4, R5, R6, R7and R8represent hydrogen, T is oxygen, X1is 4-tert-butylphenyl, X2is 2-methylbenzothiazol-yl, Y is 1,2,4-oxadiazol and Z1and Z2represent methylene

A solution of the compounds of formula (6) 1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-improper-2-ol (75 mg, 0.14 mmol) and 3-(4-tert-butylphenyl)-5-chloromethyl-1,2,4-oxadiazole (40 mg, 0.16 mmol) in a mixture of 10% trimethylamine/ethanol heated to 73°and left to mix overnight. The solvent is evaporated under reduced pressure and the obtained residue chromatographic way PTSH (3% methanol/methylene chloride). The resulting oil was diluted with methylene chloride and placed in a high vacuum at night, getting 3-{4-[3-(4-tert-butylphenyl)-[1,2,4]oxadiazol-5-ylmethyl]piperazine-1-yl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol as a white solid (52 mg, 0.09 mmol).

C. Obtaining the compounds of formula I in which R1, R2, R3, R4, R5, R6, R7and R8represent hydrogen, T is oxygen, X1is 4-tert-butylphenyl, X2is 2-phenylbenzoxazole-5-yl, Y is 1,2,4-oxadiazol, Z1and Z2represent methylene

Similarly, using the above method 4A, but replacing 1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-improper-2-ol, 1-(2-phenylbenzoxazole-5-yloxy)-3-piperazine-1-improper-2-ol, obtain the connection formula I, where R1, R2, R3, R , R5, R6, R7and R8represent hydrogen, X1is 4-tert-butylphenyl, X2is 2-phenylbenzoxazole-5-yl, Y is 1,2,4-oxadiazol, T is oxygen and Z1and Z2both represent methylene, namely 3-{4-[3-(4-tert-butylphenyl)-[1,2,4]oxadiazol-5-ylmethyl]piperazine-1-yl}-1-(2-phenylbenzoxazole-5-yloxy)propan-2-ol.

Similarly receive the following compounds of formula I:

3-{4-[3-(3,5-dimethylisoxazol-4-yl)-[1,2,4]oxadiazol-5-ylmethyl]piperazine-1-yl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

3-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

3-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;3-{4-[5-(3-triptoreline)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

3-{4-[5-(4-triptoreline)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

3-[4-(2-methyl-1,3-thiazole-4-ylmethyl)piperazine-1-yl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

3-[4-(5-methylisoxazol-3-ylmethyl)piperazine-1-yl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

3-{4-[2-(4-triptoreline)-1,3-thiazole-4-ylmethyl]piperazine-1-yl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

3-{4-[3-(4-chlorophenyl)-[1,2,4]oxadiazol-5-ylmethyl]piperazine-1-yl}-1-(2-methylbenz the thiazole-5-yloxy)propan-2-ol;

3-{4-[2-(3,5-dimethyl-1,2-oxazol-4-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-phenylbenzoxazole-5-yloxy)propan-2-ol;

3-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-phenylbenzoxazole-5-yloxy)propan-2-ol;

3-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-phenylbenzoxazole-5-yloxy)propan-2-ol;

3-{4-[5-(3-triptoreline)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-phenylbenzoxazole-5-yloxy)propan-2-ol;

3-{4-[5-(4-triptoreline)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-phenylbenzoxazole-5-yloxy)propan-2-ol;

3-[4-(2-methyl-1,3-thiazole-4-ylmethyl)piperazine-1-yl]-1-(2-phenylbenzoxazole-5-yloxy)propan-2-ol;

3-[4-(5-methylisoxazol-3-ylmethyl)piperazine-1-yl]-1-(2-phenylbenzoxazole-5-yloxy)propan-2-ol;

3-{4-[2-(4-triptoreline)-1,3-thiazole-4-ylmethyl]piperazine-1-yl}-1-(2-phenylbenzoxazole-5-yloxy)propan-2-ol;

3-{4-[5-(4-chlorophenyl)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-phenylbenzoxazole-5-yloxy)propan-2-ol;

3-{4-[3-(3,5-dimethylisoxazol-4-yl)-[1,2,4]oxadiazol-5-ylmethyl]piperazine-1-yl}-1-(2-methoxyphenoxy)propan-2-ol;

3-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-methoxyphenoxy)propan-2-ol;

1-{4-[5-(5-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-3-(2-methoxyphenoxy)propan-2-ol;

3-{4-[5-(3-triptoreline)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-methoxyphenoxy)propan-ol;

3-{4-[3-(3,5-dimethylisoxazol-4-yl)-[1,2,4]oxadiazol-5-ylmethyl]piperazine-1-yl}-1-(2-pertenece)propan-2-ol;

3-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-pertenece)propan-2-ol;

3-{4-[5-(5-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-pertenece)propan-2-ol;

3-{4-[5-(3-triptoreline)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-pertenece)propan-2-ol.

C. Obtaining the compounds of formula I with various R1, R2, R3, R4, R5, R6, R7, R8, T, X1X2, Z1and Z2

Similarly, using the above method 4A, but optionally replacing 1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-improper-2-ol with other compounds of formula (6), and optionally replacing 3-(4-tert-butylphenyl)-5-chloromethyl-1,2,4-oxadiazol other compounds of formula (7), given the following compounds of formula (I):

3-{4-[5-(4-tert-butylphenyl)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

3-{4-[5-(4-tert-butylphenyl)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-methoxyphenoxy)butane-3-ol;

3-{4-[5-(4-tert-butylphenyl)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-chlorophenoxy)butane-3-ol;

3-{4-[5-(4-tert-butylphenyl)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-methylbenzothiazol-5-yloxy)-4-piperazine-1-yl-butane-3-ol;

3-{4-[5-(4-tert-butylphenyl)-[1,2,4]acadias the l-3-ylmethyl]piperazine-1-yl}-1-(2-pertenece)-3-piperazine-1-yl-propan-2-ol;

3-{4-[5-(4-tert-butylphenyl)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-pertenece)propan-2-ol;

3-{4-[5-(3-triptoreline)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(4-methoxyphenoxy)propan-2-ol;

3-{4-[5-(4-tert-butylphenyl)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(8-fornuft-1 yloxy)propan-2-ol;

3-{4-[5-(4-chlorophenyl)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(1-fornuft-2-yloxy)propan-2-ol;

3-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-utiltity-4-yloxy)propan-2-ol;

3-{4-[5-(4-Mei-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;

3-{4-[5-(2-methylbenzimidazole-5-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol and

3-{4-[3-(2-phenylbenzimidazol-2-yl)-[1,2,4]oxadiazol-5-ylmethyl]piperazine-1-yl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol.

D. Obtaining the compounds of formula I with various R1, R2, R3, R4, R5, R6, R7, R8, T, X1X2, Z1and Z2

Similarly, using the above method 4A, but optionally replacing 1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-improper-2-ol with other compounds of formula (6), and optionally replacing 3-(4-tert-butylphenyl)-5-chloromethyl-1,2,4-oxadiazol other compounds of formula (7), obtain other compounds of formula I.

EXAMPLE 5

Alta is native obtaining the compounds of formula I

Obtaining the compounds of formula I in which R1, R2, R3, R4, R5, R6, R7and R8represent hydrogen, T is oxygen, X1is 3-forfinal, X2is 2-methylbenzothiazol-5-yl, Y is 1,2,4-oxadiazol and Z1and Z2represent methylene

A. Obtaining 2-chloracetamide: hydroxylamine hydrochloride (85 g, 1,22 mol) in water (250 ml) is treated with sodium carbonate (60 g, of 0.58 mol) and cool the solution to 0aboutC. After 2 hours add chloroacetonitrile (100 g, 1,32 mol) and the reaction mixture is allowed to interact for 2 more hours. The resulting paste was filtered, washed with a minimum amount of cold H2O and dried, obtaining 2-chloracetamide (55,0 g, 42%).

Century 2-Chloracetamide (1 g, 9.2 mmol) in toluene (5 ml) at 0aboutWith N2is treated with a solution of N,N-diisopropylethylamine (3.2 ml, 18.4 mmol) in toluene (5 ml). After 5 minutes, slowly add a solution of 3-tormentilla (1,49 g, 9,39 mmol) in toluene (5 minutes) for 20 minutes, the Reaction mixture was left to warm to room temperature over night. The reaction is quenched with aqueous sodium bicarbonate (˜100 ml) and extracted with ethyl acetate (CH ml). The combined organic extracts dried over MgSO4filter and remove the solvent in vacuo give crude n is megalocnus product, which is used in the next stage without additional purification.

C.

The intermediate product from the previous stage is dissolved in toluene (10 ml) and shaken on a J-KemTMblock 110°C for 60 hours, the Reaction mixture was concentrated and subjected to flash chromatography (hexane-EtOAc 98:2 to 90:10)to give compound of formula (12A) of 3-(chloromethyl)-5-(3-forfinal)-1,2,4-oxadiazol (242 mg, 12%).

The formula I. 3-(Chloromethyl)-5-(3-forfinal)-1,2,4-oxadiazol (242 mg, of 1.02 mmol) and the compound of formula (6) 1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-improper-2-ol (309 mg, 1.0 mmol) in EtOH (8 ml) is treated with Et3N (0.5 ml, of 3.57 mmol) and refluxed at 90aboutWith J-Kemblock within 48 hours the Reaction product is concentrated and purified by way of flash chromatography (EtOAc-MeOH 90:10)to give the compound of formula I

3-(4-{[5-(3-forfinal)(1,2,4-oxadiazol-3-yl)]methyl}piperazinil)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol.

D. Obtaining the compounds of formula I with various R1, R2, R3, R4, R5, R6, R7, R8, T, X1X2, Z1and Z2

Similarly, following the above procedure of example 5, but optionally replacing 1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-improper-2-ol with other compounds of formula (6), and optionally replacing 3-perbenzoate other chloramide the AMI acids, get other compounds of formula I.

EXAMPLE 6

Alternative obtaining the compounds of formula I

Obtaining the compounds of formula I in which R1, R2, R3, R4, R5, R6, R7and R8represent hydrogen, T is oxygen, X1is 3-forfinal, X2is 2-methylbenzothiazol-5-yl, Y is 1,2,4-oxadiazole, and Z1and Z2represent methylene

A. 3-Perbenzoate (3.2 ml, 30 mmol) and hydroxylamine hydrochloride (4.6 g, 65,8 mmol) in ethanol (30 ml) at 0°treated with triethylamine (9.6 ml, 69 mmol). The solution is allowed to warm to room temperature and then shaken at 80°J-Kemblock during the night. After cooling, add ethyl acetate (40 ml) and the precipitate is filtered and washed with ethyl acetate (˜100 ml). The filtrate was washed with a saturated solution of salt, dried (MgSO4), filtered and concentrated. The crude product (3-forfinal(hydroxyimino)methylamine (4,96 g, 107%), compound of formula (9), used in the next stage without additional purification.

Century (3-Forfinal(hydroxyimino)methylamine (4,96 g is 32.2 mmol) in dichloroethane (45 ml) cooled to -20°and add drop by drop diisopropylethylamine (22.5 ml, 130 mmol). The solution is stirred for 10 min at -20°With, then add drop by drop chlorocatechol (1.25 ml, 141 mmol) for ˜5 min. the Solution deep black left to warm to room temperature and then shaken on J-Kemblock at 85°With during the night. After cooling, the reaction mixture was diluted with dichloromethane (˜200 ml), washed with water (x2) and a saturated solution of salt, dried (MgSO4), filtered and concentrated to a black oil. The oil is dissolved in a mixture of hexane/ethyl acetate 9:1 and filtered through a layer of SiO2. This layer is washed first with a mixture of hexane/ethyl acetate 9:1, then ethyl acetate. The combined filtrates are concentrated and the product 5-(chloromethyl)-3-(3-forfinal)-1,2,4-oxadiazol, the compound of formula (11), used in the next stage without additional purification.

C. 5-(chloromethyl)-3-(3-forfinal)-1,2,4-oxadiazole (300 mg, of 1.41 mmol) and the compound of formula (6) 1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-improper-2-Olu (291 mg, of 0.94 mmol) in EtOH (20 ml, anhydrous) add diisopropylethylamine (0,329 mg, 1,89 mmol) and the reaction mixture is shaken on a J-KemTMblock overnight at 90°C. After cooling to room temperature the solution is concentrated to an oil and purified on IscoTMCombi Flash Si 10X, using column Redi Sep (10 g), elwira with ethyl acetate, then with a gradient to a mixture of ethyl acetate/methanol 4:1, obtaining the compound of formula I is 3-(4-{[3-(3-forfinal)(1,2,4-oxadiazol-5-yl)]methyl}piperazinil)-1-(2-methylbenzothiazol-5-yloxy)propane-2-the l (136 mg, 30%).

D. Obtaining the compounds of formula I with various R1, R2, R3, R4, R5, R6, R7, R8, T, X1X2, Z1and Z2

Similarly, following the above procedure of example 6, but optionally replacing 1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-improper-2-ol with other compounds of formula (6), and optionally replacing 3-perbenzoate other NITRILES, obtain other compounds of formula I.

EXAMPLE 7

Obtaining the compounds of formula I

Obtaining the compounds of formula I in which R1, R2, R3, R4, R5, R6, R7and R8represent hydrogen, T is oxygen, X1is 4-triptoreline, X2is 2-methylbenzothiazol-5-yl, Y is 1,3-oxazol, Z1and Z2represent methylene

A. Obtaining the compounds of formula (13)

Hydrochloride methyl 2-amino-3-hydroxypropanoate (hydrochloride of the methyl ester of L-serine, 1,71 g, 11 mmol) is stirred in dichloromethane (20 ml) at 0°and add triethylamine (and 2.79 ml, 20 mmol), and then add drop by drop 4-cryptomathematical (1,486 ml, 11 mmol). The mixture was stirred at 0°C for 30 min, then partitioned between dichloromethane and water, dried over magnesium sulfate and Phi is trout. From the filtrate to remove the solvent under reduced pressure and the residue purified by way of column chromatography, obtaining the compound of formula (13) of methyl 3-hydroxy-2-{[4-(trifluoromethyl)phenyl]carbylamine}propanoate.

C. Obtaining the compounds of formula (14)

To a solution of methyl 3-hydroxy-2-{[4-(trifluoromethyl)phenyl]carbylamine}of propanoate (to 2.57 g, 8,83 mmol) in tetrahydrofuran (30 ml) is added triphenylphosphine (2.55 g, 9,71 mmol). The mixture is cooled to 0°and slowly add diisopropylethylamine (1,91 ml, 9,71 mmol). The mixture is stirred at room temperature for 2 days. From the filtrate to remove the solvent under reduced pressure and the residue purified by way of column chromatography, obtaining the compound of formula (14) methyl 2-[4-(trifluoromethyl)phenyl]-1,3-oxazoline-4-carboxylate.

C. Obtaining the compounds of formula (15)

A solution of methyl 2-[4-(trifluoromethyl)phenyl]-1,3-oxazoline-4-carboxylate (1,33 g, to 4.87 mmol) in toluene (60 ml) was stirred at 55°until complete dissolution of the original substance. Then add parts of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.53 g, 24,365 mmol) and the resulting solution was stirred at 75°within 36 hours the Solvent is evaporated under reduced pressure and the residue purified by way of column chromatography, obtaining the connection form is s (15) of methyl 2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-carboxylate.

D. Obtaining the compounds of formula (16)

A solution of methyl 2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-carboxylate (1.365 mmol) in tetrahydrofuran (20 ml) cooled to 0°and add drop by drop sociallyengaged in tetrahydrofuran (1.365 mmol). The reaction mixture was stirred at 0°C for 30 min, slowly quenched with water, and then add a solution of ammonium chloride. The resulting mixture was filtered through celite and washed with ethyl acetate. The filtrate is washed with saturated salt solution, dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by chromatography, obtaining {2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}methane-1-ol, the compound of formula (16).

E. Obtaining the compounds of formula I

A solution of {2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}methane-1-ol (0,19 g, 0.78 mmol) in tetrahydrofuran (15 ml) cooled to 0°and add triethylamine (0.33 ml, 2.34 mmol), and then drop methanesulfonanilide (of 0.12 ml, 1.56 mmol). The mixture is stirred for 1 h at 0°With, then add water and extracted the product with ethyl acetate. The organic layer is dried over sodium sulfate and removed from the filtrate solvent under reduced pressure, obtaining {2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}methyl methylsulfonate, mesyl derivative compounds of formula (15).

This mesyl derivative (0.2 g, 0.78 mmol) is then mixed with tert-butyldimethylchlorosilane (0,29 g, 1.56 mmol) and triethylamine (0.33 ml, 2.34 mmol) in ethanol (20 ml) and the mixture refluxed for 2 hours to Remove the solvent under reduced pressure and the residue is divided between ethyl acetate and water. The organic layer is dried over sodium sulfate and removed from the filtrate the solvent, obtaining tert-butyl 4-({2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}methyl)piperidinecarboxylate.

Then remove the protective group BOC by treatment with 4N hydrochloric acid in dioxane at room temperature over night, getting 4-(piperazinylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol in the form of its hydrochloride salt.

This compound (40 mg, 0,115 mmol) is dissolved in ethanol and added dropwise N,N-diisopropylethylamine (0,08 ml) and the compound of formula (6) 1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-improper-2-ol (25 mg, 0,115 mmol). The mixture is stirred at 85°during the night, then remove the solvent under reduced pressure and the residue purified by the method of preparative TLC, elwira 5% methanol in dichloromethane, getting 1-(2-methylbenzothiazol-5-yloxy)-3-[4-({2-[4-(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methyl)piperazinil]propan-2-ol, the compound of formula I.

F. Obtaining the compounds of formula I with various R1, R2, R3, R4, R5, R6, R7, R8, T, X1X2 , Z1and Z2

Similarly, following the above procedure of example 7, but optionally replacing 1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-improper-2-ol with other compounds of formula (6), and optionally replacing 4-permitidentifier other anhydrides of acids, obtain other compounds of formula I.

EXAMPLE 8

Obtaining the compounds of formula I

Obtaining the compounds of formula I in which R1, R2, R3, R4, R5, R6, R7and R8represent hydrogen, T is oxygen, X1is 4-formationl, X2is 2-cyclohexylbenzothiazole-5-yl, Y is N-pyrazole, Z1is ethylene and Z2represents a methylene

A. To a solution of 4-periodontal (2,22 g, 10 mmol) in ether at -78aboutWith added slowly n-utility (5 ml of a 2.5m solution). The reaction mixture was stirred for 1 h at -78°then add three(n-butyl)albahari and the mixture is stirred for another 1 h at -78°C. the Mixture is allowed to warm to room temperature, then quenched with a solution of ammonium chloride, diluted with ether, washed with saturated salt solution, dried over sodium sulfate, filtered and removed from the filtrate solvent under reduced pressure, obtaining the compound of formula (17) 4-fluoro-(tri-n-butyl)albabenshal as liquid.

C. a Mixture of compounds of formula (18) 1-(2-chloroethyl)-4-moderate (2.0 g, 6.3 mmol) and 4-fluoro-(tri-n-butyl)avobenzone (2.9 g, 7.6 mmol) in dry acetonitrile is stirred for 10 min under nitrogen. To this solution add triphenylarsine (385 mg, of 1.26 mmol), copper iodide (120 mg, to 0.63 mmol) and 10% palladium on coal (250 mg) and the mixture is heated at 80°C for 48 hours the Mixture is cooled, filtered through celite, washed with dichloromethane and removed from the filtrate solvent under reduced pressure. The residue is subjected to flash chromatography, elwira dichloromethane and receiving the compound of formula (19) 1-(2-chloroethyl)-4-(4-forfinal)pyrazole.

C. Next, 1-(2-chloroethyl)-4-(4-forfinal)pyrazole subjected to interaction with the compound of the formula (6) 1-(2-cyclohexylbenzothiazole-5-yloxy)-3-piperazine-1-improper-2-I as shown above, obtaining 1-(2-cyclohexylbenzothiazole-5-yloxy)-2-(4-{2-[4-(4-forfinal)pyrazolyl]ethyl}piperazinil)Ethan-1-ol.

D. Obtaining the compounds of formula I with various R1, R2, R3, R4, R5, R6, R7, R8, T, X1X2, Z1and Z2

Similarly, following the above procedure of example 8, but optionally replacing 4-periodental other compounds of formula X1I, optionally replacing 1-(2-chloroethyl)-4-iterator other optionally substituted pyrazoles, and optionally replacing 1-(2-cyclog silbersattel-5-yloxy)-3-piperazine-1-improper-2-I other compounds of formula (6), get other compounds of formula I.

EXAMPLE 9

Obtaining the compounds of formula I

Obtaining the compounds of formula I in which R1, R2, R3, R4, R5, R6, R7and R8represent hydrogen, T is oxygen, X1is 4-triptoreline, X2is 2-methylbenzothiazol-5-yl, Y is isoxazol, Z1and Z2represent methylene

A. To a mixture of the compounds of formula (20) 1-(trifluoromethyl)-4-vinylbenzene (2.0 g, 11,27 mmol) and the compounds of formula (21) ethyl 2-chloro-2-(hydroxyimino)acetate (2,11 g, 13,52 mmol) in anhydrous THF added drop by drop a solution of triethylamine (3.0 ml) in tetrahydrofuran at room temperature. The mixture is stirred overnight under N2. Thus obtained white precipitate is filtered off and washed twice with tetrahydrofuran (10 ml). Removed from the filtrate solvent under reduced pressure and the residue partitioned between water and ethyl acetate (20 ml:20 ml, about./vol.), extragere three times with 20 ml of ethyl acetate. The combined organic layers washed with aqueous ammonium chloride and dried over MgSO4receiving the compound of formula (22) ethyl 5-[4-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-3-carboxylate.

C. a Solution of ethyl 5-[4-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-3-carboxylate (3.3 grams) is stirred is OleOle (15 ml) and then add parts of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1,00 g), and then part of the molecular sieves 3A and the resulting mixture was stirred at 75°C for 2 days. After cooling, add ether and the mixture is filtered through a layer of anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the residue purified by way of column chromatography, obtaining the compound of formula (23) ethyl 5-[4-(trifluoromethyl)phenyl]isoxazol-3-carboxylate.

C. Ethyl 5-[4-(Trifluoromethyl)phenyl]isoxazol-3-carboxylate (130 mg) was dissolved in ethanol (10 ml), cooled to 0°and add to stir the solution borgerende (26 mg) parts. The mixture is stirred at room temperature for 4 h, then add excess water. The solvent is evaporated under reduced pressure and the residue purified by the method of preparative thin-layer chromatography, elwira a mixture of 5% methanol/ethyl acetate, obtaining the compound of formula (24) {5-[4-(trifluoromethyl)phenyl]isoxazol-3-yl}methane-1-ol.

D. {5-[4-(Trifluoromethyl)phenyl]isoxazol-3-yl}methane-1-ol (200 mg) is dissolved in dry dichloromethane (10 ml) and cooled to 0°C. the Solution is stirred while adding a solution of thionyl chloride (2,74 ml) in dichloromethane (25 ml), then allowed to warm to room temperature and stirred over night. The solvent is evaporated under reduced pressure and the residue purified by the method of preparative thin-layer chromatography, elwira mixture is Yu 30% ethyl acetate/hexane, receiving the compound of formula (25) 3-(chloromethyl)-5-[4-(trifluoromethyl)phenyl]isoxazol.

E. To a solution of 1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-improper-2-ol hydrochloride (50 mg) in tert-butanol at room temperature is added triethylamine (60 μl) and the mixture is stirred at room temperature for 5 minutes To this mixture is added 3-(chloromethyl)-5-[4-(trifluoromethyl)phenyl]isoxazol (26 mg) and the mixture was stirred at 100°With during the night. The solvent is removed under reduced pressure, the residue is dissolved in 1 ml of methanol and purified by the method of preparative thin-layer chromatography, elwira a mixture of 5% methanol/dichloromethane, receiving the compound of formula I 1-(2-methylbenzothiazol-5-yloxy)-3-[4-({5-[4-trifluoromethyl)phenyl]isoxazol-3-yl}methyl)piperazinil]propan-2-ol.

F. Obtaining the compounds of formula I with various R1, R2, R3, R4, R5, R6, R7, R8, T, X1X2, Z1and Z2

Similarly, following the above procedure of example 9, but optionally replacing 1-(trifluoromethyl)-4-vinylbenzyl other compounds of formula (20), and optionally replacing 1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-improper-2-ol hydrochloride other compounds of formula (6), obtain other compounds of formula I.

EXAMPLE 10

Applying the methods of the above examples 1-9 are given the following joint the formula I, also presented their biological activity:

The following examples illustrate the obtaining of a typical pharmaceutical preparations containing the compound of formula I, such as compound obtained according to example 4.

EXAMPLE 11

Get hard gelatin capsules containing the following ingredients:

IngredientQuantity (mg/capsule)
The active ingredient30,0
Starch305,0
Magnesium stearate5,0

The above ingredients are mixed and filled with a mixture of hard gelatin capsules.

EXAMPLE 12

Get the drug in tablet form, using the following ingredients:

IngredientQuantity (mg/tablet)
The active ingredient25,0
Microcrystalline cellulose 200,0
Colloidal silicon dioxide10,0
Stearic acid5,0

The components are mixed and pressed, receiving tablets.

EXAMPLE 13

Get the drug for inhalation in the form of a dry powder containing the following components:

IngredientWeight (%)
The active ingredient5
Lactose95

The active ingredient is mixed with the lactose and the mixture is added to the device for inhalation of a dry powder.

EXAMPLE 14

Tablets, each containing 30 mg of active ingredient, was prepared as follows:

IngredientQuantity (mg/tablet)
The active ingredient30,0
Starch45,0
Microcrystalline cellulose35,0
Polyvinylpyrrolidone (as

10% solution in sterile water)
4,0
Natrocarbonatite4,5
Magnesium stearate0,5
Talc1,0
Only120 mg

Active Ingram is ient, starch and cellulose sieved through sieve No. 20 mesh. U.S. and thoroughly mix. The solution of polyvinylpyrrolidone is mixed with the obtained powders, which are then sieved through a sieve of 16 mesh. USA. Thus obtained granules are dried at 50-60aboutC and sieved through a sieve of 16 mesh. USA. Then add natrocarbonatite, magnesium stearate and talc, previously passed through sieve No. 30 mesh. USA, to the granules which, after mixing is pressed on the machine to obtain tablets, receiving tablets, each weighing 120 mg

EXAMPLE 15

Suppositories, each containing 25 mg of active ingredient, was prepared as follows:

IngredientNumber
The active ingredient25 mg
Glycerides of saturated fatty acids to2000 mg

The active ingredient is sifted through a sieve No. 60 mesh. USA and suspended in the glycerides of saturated fatty acids, previously melted using the minimum heat needed. The mixture is then poured into the form to obtain suppositories with a nominal capacity of 2.0 g and allow it to cool.

EXAMPLE 16

Suspensions, each containing 50 mg of active ingredient 5.0 ml dose, receive the following way:

IngredientNumberThe active ingredient50.0 mgXanthan gum4.0 mgThe sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%)50.0 mgSucrose1,75 gSodium benzoate10.0 mgFlavoring and coloringat the discretionPurified waterto 5.0 ml

The active ingredient, sucrose and xanthan resin are mixed and sieved through sieve No. 10 mesh. USA and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose in water. Sodium benzoate, flavoring and coloring diluted with some water and add with stirring. Then add enough water to get the required amount.

EXAMPLE 17

Preparation for subcutaneous injection can be obtained as follows:

IngredientNumber
The active ingredient5.0 mg
Corn oil1.0 ml

EXAMPLE 18

The preparation for injection gender is given, having the following composition:

IngredientNumber
The active ingredient2.0 mg/ml
Mannitol, USP50 mg/ml
Gluconic acid, USPas required (pH 5-6)
Water (distilled, sterile)how much you want to 1.0 ml
Gaseous nitrogen, NFas needed

EXAMPLE 19

Preparation for local use are having the following composition:

IngredientGrams
The active ingredient0,2-10
Span 602,0
Tween 602,0
Mineral oil5,0
Petrolatum0,10
Methylparaben0,15
Propylparaben0,05
BHA (bottled hydroxyanisol)0,01
Waterhow much you want to 100 g

All of the above ingredients, except water, are combined and heated to 60aboutWith under stirring. Then add a sufficient quantity of water at 60aboutAnd the intensity of the active stirring, amblyraja ingredients, and then add water as needed up to 100 g

EXAMPLE 20

The composition of prolonged action

IngredientRange weight (%)Predpochtite. range (%)Naiboa. (%)
The active ingredient50-9570-9075
Microcrystalline cellulose (filler)1-355-1510,6
Copolymer of methacrylic acid1-355-12,510,0
Sodium hydroxide0,1-100,2-0,60,4
The hypromellose0,5-5,01-32,0
Magnesium stearate0,5-5,01-32,0

Sustained-release preparations of this invention was prepared as follows: compound, the pH-dependent binder and optional fillers, thoroughly mix (dry). Then mixed in the dry mixture granularit in the presence of an aqueous solution of a strong base, which is sprayed into the mixed powder. The granulate is dried, sieved, mixed with optional lubricants such as talc or magnesium stearate) is pressed into tablets. Preferred aqueous solutions of strong bases are solutions of hydroxides of alkali metals such as sodium hydroxide or potassium, preferably sodium hydroxide, in water (optionally containing up to 25% miscible with water, solvents such as lower alcohols).

The resulting tablets may not necessarily be covered with a film forming agent for identification, masking the taste and increase the ease of swallowing. Forming a film agent is typically present in an amount of from 2 to 4% by weight of the tablet. Suitable agents that make up the film, well known to specialists in this field and include hypromellose, cationic methacrylate copolymers (copolymers of dimethylaminoethylmethacrylate/methyl-butylmethacrylate - Eudragit® E Röhm. Pharma) and the like. The agents forming the film may optionally contain dyes, plasticizers and other ingredients.

Obtained by pressing the tablets preferably have a hardness sufficient to withstand compression 8 Kp. Tablet size depends primarily on the number of connections per tablet. Tablets include from 300 to 1100 mg of the compound in the form of free base. Preferably the tablets include 400-600 mg free base, 650-850 mg and 900-1100 mg

To affect the dissolution rate, Regulus shall have time during which the powder containing this compound, mixed wet. Preferably, the total time of mixing the powder, i.e. the time during which the powder is subjected to the action of sodium hydroxide solution, ranged from 1 to 10 min, and more preferably from 2 to 5 minutes After pelleting the particles removed from the pellet and placed in a fluidized bed dryer for drying at a temperature of about 60°C.

EXAMPLE 21

Research on mitochondria

Allocate mitochondria of rat heart way Nedergard and Cannon (Methods in Enzymol., 55, 3, 1979).

Oxidation of Palmitoyl COA: oxidation of Palmitoyl COA is carried out in a total volume of 100 µl, containing the following agents: 110 mm KCl, 33 mm Tris buffer with pH 8, 2 mm KPi, 2 mm MgCl2, 0.1 mm EDTA, 14,7 μm fat-free BSA, 0.5 mm malic acid, 13 mm carnitine, 1 mm ADP, 52 µg of mitochondrial protein and 16 μm 1-C14, Palmitoyl COA (specific activity 60 of the ICJ/mmol; 20 mccu/ml (using 5 ál of the study). The compounds of this invention added to the DMSO solution at the following concentrations: 100 μm, 30 μm and 3 μm. In each study using the control DMSO. After 15 min of enzymatic reaction at 30°the mixture is centrifuged (20000 g for 1 min) and add 70 ál of supernatant to a column of silicic acid and activated reversed phase (approximately 0.5 ml of silicic acid Column elute 2 ml of water and using 0.5 ml of eluent for counting of scintillations to determine the number of 14captured in the form of14-bicarbonate ion.

In this study, the compounds of this invention demonstrate activity as inhibitors of fatty acid oxidation.

EXAMPLE 22

The perfusion solution

Perfusion according to Langendorff carried out using a solution of Krebs-Henseleit containing (mm): NaCl To 118.0, KCl 4.7 in, KH2PO41,2, MgSO41,2, CaCl22,5, NaHCO3of 25.0 and glucose of 5.5 or 11 (Finegan and others, 1996). Working heart perfusion solution consists of a solution of Krebs-Henseleit with the addition of palmitate (0.4 or 1.2 mm), previously associated with 3% bovine serum albumin (BSA, essentially not containing fatty acids), and insulin (100 mked/ml). Palmitate is first dissolved in a mixture of ethanol/water (40%/60%)containing 0.5-0.6 g Na2CO3on g palmitate. After heating for evaporation of ethanol, the mixture was added to a mixture of 3% BSA-Krebs-Henseleit (without glucose) and leave overnight for dialysis (threshold 8000 MM) in 10 volumes of a solution of Krebs-Henseleit that does not contain glucose. The next day added to a solution of glucose, filter the mixture through a glass microfibre filter (GF/C, Whatman, Maidstone, England) and stored on ice or in the refrigerator until use. In the perfusion apparatus of the perfusion solution is constantly saturated with oxygen using a gas mixture of 95% CO2/5% O2maintaining aerobic conditions.

Protocols perfusion of the heart

Rats give anesthesia of the Penta is barbitala (60 mg/kg, intraperitoneally), quickly remove the heart and placed in chilled on ice, a solution of Krebs-Henseleit. Then in the hearts quickly insert the cannula through the remainder of the aorta and begin perfusion according to Langendorff constant pressure (60 mm Hg), continue perfusion for 10 min period equilibrium. During the period equilibrium cut the pulmonary artery and removes the excess fat and lung tissue to open the pulmonary vein. Introducing the cannula into the left atrium and is connected to a line preload, coming from oxygenation camera. After a 10-minute period equilibrium hearts connect to a working system (constricting line Langendorff and opening line of advanced and further load) and spend perfusion at 37°under aerobic conditions at a constant preload of the left atrium (11.5 mm Hg) and then load the aorta (80 mm RT. Art.). Camera matching is filled with air so as to support the pressure of 50-60 mm Hg perfusion solution delivered in oxygenation the chamber via a peristaltic pump from a backup camera, which collects the flow from the aorta and coronary flow, as well as excess from the oxygenator.

Usually heart perfusion in aerobic conditions within 60 minutes Hearts set the pulse rate of 300 beats/min at each phase of the perfusion Protocol (if the need is about, regulate voltage) except for the initial 5 min of perfusion, when hearts allow pulsate spontaneously.

At the end of the perfusion Protocol hearts quickly frozen using Wollenberger clamps cooled to liquid nitrogen temperature. Frozen tissue is ground up and store the obtained powders at -80aboutC.

Myocardial mechanical function

Measure systolic and diastolic aortic pressure using the pressure sensor Sensonor (Horten Norway)connected to the line coming out of the aortic flow and coupled with accumulation system data AD Instruments. Measure the cardiac output, aortic flow and coronary flow (cardiac output minus aortic flow) (ml/min)using an ultrasonic flow sensors inside the lines connected to the ultrasonic flow meter Transonic T206. The work of the left ventricle per minute (LV), calculated as cardiac output multiplied by the generated left ventricular pressure (aortic systolic pressure - pressure pre-load), use as a permanent indicator mechanical features. Hearts exclude, if LV-work is reduced by more than 20% within a 60-minute period during aerobic perfusion.

Myocardial oxygen consumption and cardiac efficiency

Measurement atrio-venous difference in oxygen content is and perfusion solution and multiplied by cardiac output provides a measure of oxygen consumption. Atrial oxygen (mm Hg) measured in the perfusion solution in the line pre-load or just before entering the left atrium. Venous oxygen content measured in the perfusion solution emerging from the pulmonary artery and passing through the sensors About2inside lines and meters Microelectrodes Inc., Bedford, NH. Cardiac efficiency as cardiac work, divided by the consumption of oxygen.

Measurement of glucose metabolism and fatty acids

To determine the rate of production3H2O and14CO2of [3H/14C]glucose on a dedicated working rat model allows direct and continuous measurement of the speed of glycolysis and glucose oxidation. In the alternative case, the measurement of production3H2Of [5-3H]palmitate provides a direct and continuous measurement of the velocity of oxidation of palmitate. Double-labeled substrates allow the simultaneous measurement of the rate of glycolysis and glucose oxidation or the rate of fatty acid oxidation and glucose oxidation. At different points in time during the Protocol selected 3-ml sample of the perfusion solution from the introduction holes recirculating perfusion apparatus for analysis3H2O and14CO2and directly placed under mineral oil to studies on the accumulation of metal the symbolic value of products. The perfusion solution supply [3H/14C]glucose or [5-3H]palmitate approximately to the specific activity 20 disintegrations per minute/mol. The average rate of glycolysis and glucose oxidation calculated from the linear cumulative time-dependent accumulation of products between 15 and 60 min aerobic perfusion. The rate of glycolysis and glucose oxidation is expressed as the number of moles of metabolized glucose/min/g dry weight.

Measurement of myocardial glycolysis

The rate of glycolysis is measured directly, as described previously (Saddik &Lopaschuk, 1991) quantitative determination of3H2Oh, freed from radioactively labeled with [5-3H]glucose on enolase stage of glycolysis. Samples of the perfusion solution taken at different points in time Protocol perfusion.3H2About separated from the perfusion solution, passing the sample perfusion solution through the column containing anion exchange resin Dowex 1-x4 (200-400 mesh.). 90 g/l of Dowex 0,4M mixture of potassium tetraborate is stirred overnight, after which 2 ml of the suspension is loaded into a separating column and long washed dH2About to remove tetraborate. As found, the column exclude 98-99,6% of [3H]glucose (Saddik &Lopaschuk, 1996). Samples of the perfusion solution (100 μl), each, loaded onto the column and washed with 1.0 ml dH2O. the Resulting liquid is collected in a 5 ml scintillation fluid Ecolite (ICN, Radichemicals, Irvine, CA) and shall count for 5 min in a scintillation counter Beckman LS 6500 using the auto correction double (3H/14C) quenching. The average rate of glycolysis for each phase of perfusion is expressed as µmol metabolized glucose/min/g dry weight, as described above.

Measurement of myocardial glucose oxidation

Oxidation of glucose is also determined directly, as described previously (Saddik &Lopaschuk, 1991), by measuring the14CO2of [14C]glucose, vswobozdauschego at a certain level of pyruvaldehyde and the Krebs cycle. Measure gaseous14CO2leaving oxygenation camera, and [14C]bicarbonate held in solution. Samples of the perfusion solution taken at different points in time Protocol perfusion. Gas14CO2collect missing leaving the oxygenator gas through gamingindustry trap (20-50 ml depending on the duration of perfusion). Samples of the perfusion solution (2×1 ml), kept under oil to prevent out-gassing during equilibration with atmospheric CO2introducing research tubes 16×150 mm containing 1 ml of 9N H2SO4. This process releases of the perfusion solution14CO2present as the N14CO3-. Test tubes in duplicate capacityv who have rubber plugs, connected to a 7-ml scintillation vials containing a piece of filter paper 2×5 cm, saturated 250 μl of gamingrelated. Then remove scintillation vials with filter paper and add scintillation fluid Ecolite (7 ml). Shall count samples according to standard methods, as described above. The average rate of oxidation of glucose for each phase of perfusion is expressed as µmol metabolized glucose/min/g dry weight, as described above.

Measurement of myocardial fatty acid oxidation

The rate of oxidation of palmitate measured directly, as described previously (Saddik and Lopaschuk, 1991), on the quantitative definition of3H2O released from the radioactively labeled [5-3H]palmitate.3H2O is separated from [5-3H]palmitate conducting a successive extraction of the chloroform:methanol (1,88 ml in 1:2 vol./about.) samples buffer volume of 0.5 ml and then adding of 0.625 ml of chloroform and of 0.625 ml of 2M KCl solution:HCl. The aqueous phase is removed and treated with a mixture of chloroform, methanol and KCl:HCl (1:1:0.9 to about./about). Samples with a double repetition is withdrawn from the aqueous phase for counting in a liquid scintillator and the oxidation rate is determined taking into account the dilution factor. It took place in more than 99% of cases the extraction and release3H2O from [5-3H]palmitate. The average rate of oxidation of p is limitata for each phase of perfusion is expressed as µmol metabolized palmitate/min/g dry weight, as explained above.

The ratio of the mass of dry materials to damp

Frozen ventricles were crushed under liquid nitrogen using a mortar and pestle. Determine from the dry to the wet produce, weighing a small amount of frozen tissue of the heart, re-weighing the same fabric after 24-48 h of air drying and taking the ratio of the two masses. From this ratio it is possible to calculate the total weight of the dry fabric. This ratio is used for normalization relatively gram dry mass velocity of glycolysis, glucose oxidation and turnover of glycogen, as well as the content of metabolites.

In this study, the compounds of this invention demonstrate activity as inhibitors of fatty acid oxidation.

Although the present invention is described with reference to specific options, the person skilled in the art it is clear that it is possible to make various changes and replacement of equivalents, without departing from the essence and scope of this invention. In addition, it is possible to make various modifications to adapt a particular situation, material, consider the composition, method, stage or stages of the way to the objective, spirit and scope of the present invention. I believe that all such modifications are included within the scope of appended here claims. All cited patents and the public is tion is incorporated herein by reference.

LINKS

1. Finegan BA, Gandhi M, Lopaschuk GD, Clanachan AS, 1996. Antecedent ischemia reverses effects of adenosine on glycolysis and mechanical function of working hearts. American Journal of discrimination 271: H2116-25.

2. Saddik M, Lopaschuk GD, 1991. Myocardial triglyceride turnover and contribution to energy substrate utilization in isolated working rat hearts. Journal of Biological Chemistry 266:8162-8170.

1. The compound of the formula

where R1, R2, R3, R4, R5, R6, R7and R8represent hydrogen or C1-6alkyl

T is oxygen;

V represents N<;

X1represents phenyl, substituted with 1-2 substituents selected from the group comprising C1-6alkyl, C1-6alkoxy, halogen, cyano or trifluoromethyl;

X2represents a bicyclic heteroaryl, including 7 carbon atoms and 1-2 heteroatoms selected from O, N and S, optionally substituted C1-6the alkyl, C3-6cycloalkyl, phenyl and phenyl substituted by halogen; Y represents a monocyclic heteroaryl, containing 3-5 carbon atoms and 1-3 heteroatoms selected from N and O; and

Z1and Z2independently represent1-4alkylen.

2. The compound according to claim 1, where R1, R2, R3, R4, R5, R6, R7and R8independently selected from hydrogen and methyl.

3. The compound according to claim 1, where Y represents biradical, a derivative of pyrazole, ,2-oxazole, 1,3-oxazole, 1,3-thiazole, 1,2,4-oxadiazolyl or 1,3,4-oxadiazole.

4. The compound according to claim 3, where X2is 2-methylbenzo-1,3-thiazol-5-yl, 2-cyclohexylamino-1,3-thiazol-5-yl, 2-phenylbenzo-1,3-thiazol-5-yl or 2-phenylbenzo-1,3-oxazol-5-yl.

5. The compound according to claim 4, where R1, R2, R3, R4, R5, R6, R7and R8all represent hydrogen.

6. The compound according to claim 5, where Z1and Z2both represent methylene.

7. The connection according to claim 6, where X1represents phenyl, optionally substituted C1-6the alkyl, C1-6alkoxy, halogen or trifluoromethyl.

8. The connection according to claim 7, where X1-Y is 3-(4-tert-butylphenyl)-1,2,4-oxadiazol-5-yl, and X2is 2-methylbenzo-1,3-thiazol-5-yl, namely 3-{4-[3-(4-tert-butylphenyl)-[1,2,4]oxadiazol-5-ylmethyl]piperazine-1-yl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol.

9. The connection according to claim 7, where X1-Y is 5-(4-triptoreline)-1,2,4-oxadiazol-3-yl, X2is 2-methylbenzo-1,3-thiazol-5-yl, namely 3-{4-[5-(4-(trifluoromethyl)phenyl)-[1,2,4]oxadiazol-3-ylmethyl]piperazine-1-yl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol.

10. The connection according to claim 7, where X1-Y is 5-(4-chlorophenyl)-1,2-oxazol-3-yl and X2is 2-methylbenzo-1,3-thiazol-5-yl, namely 3-(4-{[5-(4-chlorophenyl)isoxazol-3-yl]methyl}piperazinil)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol.

11. The connection according to claim 7, where X1-Y is 5-(4-(trifluoromethyl)phenyl)isoxazol-3-yl and X2is 2-methylbenzo-1,3-thiazol-5-yl, namely (2S)-1-(2-methylbenzothiazol-5-yloxy)-3-[4-({5-[4-(trifluoromethyl)phenyl]isoxazol-3-yl}methyl)piperazinil]propan-2-ol.

12. The connection according to claim 7, where X1-Y represents 2-(4-(trifluoromethyl)phenyl)oxazol-4-yl and X2is 2-methylbenzo-1,3-thiazol-5-yl, namely 1-(2-methylbenzothiazol-5-yloxy)-3-[4-({2-[4-(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methyl)piperazinil]propan-2-ol.

13. The connection according to claim 6, where one of R1, R2, R3, R4, R5, R6, R7and R8represent methyl, and the others are hydrogen.

14. The connection indicated in paragraph 13, where Z1and Z2both represent methylene.

15. The connection 14, where X1represents phenyl, optionally substituted C1-6the alkyl, C1-6alkoxy, halogen or trifluoromethyl.

16. The connection indicated in paragraph 15, where R4is methyl, and R1, R2, R3, R5, R6, R7and R8represent hydrogen.

17. Connection P16, where X1-Y is 5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl and X2is 2-methylbenzo-1,3-thiazol-5-yl, namely (2S)-3-[(2S)-2-methyl-4-({5-[4-(trifluoromethyl)phenyl)(1,2,4-oxadiazol-3-yl)}methyl)piperazinil]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol.

18. When is the change of the connection according to claim 1 to obtain a pharmaceutical composition for the treatment of painful conditions in a mammal, which can be facilitated by using an inhibitor of fatty acid oxidation.

19. The pharmaceutical composition inhibiting the oxidation of fatty acids comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound according to claim 1.



 

Same patents:

FIELD: organic chemistry, medicine, hematology, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): in all their stereoisomeric forms and their mixtures taken in any ratio and their physiologically acceptable salts possessing properties of inhibitors of factor Xa and/or factor VIIa, and to a medicinal agent based on thereof. Also, invention relates to a method for synthesis of these compounds and their using for preparing pharmaceutical agents for inhibition of activity of factor Xa and/or factor VIIa or for their effect on blood coagulation or fibrinolysis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 1 tbl, 276 ex

FIELD: chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (1): and their salts wherein values R1, k, Ar, n, j, Y, R and R2 are determined in the invention claim. Novel compounds are able to modulate activity of chemokine receptors. Also, invention relates to using indicated compounds for treatment of human immunodeficiency virus or feline immunodeficiency virus and to a pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 100 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of bipiperidine of the formula (I): , wherein X means a direct bond, -CH2-, -CH2-CH2- or -CHR9-; R1 means optionally R10- and/or R11-substituted phenyl, optionally R10- and/or R11-substituted heteroaryl, N-oxide of optionally R10- and/or R11-substituted heteroaryl or optionally R10- and/or R11-substituted naphthyl; R2 has one of values given for R1, or it means optionally R10-substituted (C1-C6)-alkyl, optionally R10-substituted (C3-C6)-cycloalkyl, optionally R10-substituted adamantyl; R3 has one of values given for R1; each radical among R4, R5, R6 and R7 means hydrogen atom; R8 means hydrogen atom or (C1-C6)-alkyl; R9 means (C1-C6)-alkyl or (C3-C6)-cycloalkyl; R10 represents from 1 to 4 substitutes chosen independently from (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C2-C6)-alkoxyalkyl, (C1-C6)-halidealkyl, (C3-C6)-cycloalkyl, phenyl, heteroaryl, heteroaryl N-oxide, fluorine, chlorine, bromine, iodine atoms, hydroxyl, groups -OR9, -CONH2, -CONHR9, -CONR9R9, -COOH, -CF3, -CHF2, -CN, -NH2, -NHR9, -NHC(O)R9, -NR9C(O)R9; R11 represents two adjacent substitutes that form anellated 4-7-membered nonaromatic ring optionally comprising up to two heteroatoms chosen independently from nitrogen oxygen and sulfur atoms; Y means a direct bond, -C(O)-, -S(O2)-, -CH2-. Proposed compounds can be in free form as a salt. Compounds of the formula (I) and their salts possess antagonistic activity with respect to CCR5-receptors and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 6 tbl, 83 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nicotine- or isonicotine-benzothiazole of general formulas (IA) and (IB) their pharmaceutically acceptable acid-additive salts and a medicinal agent based on thereof. In compounds of general formula (IA) and (IB) R1 means phenyl, piperidine-1-yl or morpholine; A means -O-; R means -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-O-lower alkyl, -(CH2)n-O-(CH2)n-O-lower alkyl, lower alkyl, -(CH2)n-morpholinyl, -(CH2)n-phenyl, -(CH2)n-N(R''), -(CH2)n-pyridinyl, -(CH2)n-CF3, -(CH2)n-2-oxopyrrolidinyl or (C4-C6)-cycloalkyl; R'' mean(s) independently of one another hydrogen atom or lower alkyl; n= 1 or 2; A means -N(R')-; R means lower alkyl, (C4-C6)-cycloalkyl, -(CH2)n-O-lower alkyl, -(CH2)n-pyridinyl, -(CH2)n-piperidinyl, -(CH2)n-phenyl, -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-morpholinyl or -(CH2)n-N(R'')2; R' and R'' mean independently of one another hydrogen atom or lower alkyl; n = 1 or 2; or A means -CH2-; R means -N(R'')-(CH2)m-O-lower alkyl, -N(R'')2, S-lower alkyl, or R means azethidinyl, pyrrolidinyl or piperidinyl that are substituted optionally with hydroxy-group or lower alkoxy-group; or R means morpholinyl, -N(R'')-(CH2)m-(C4-C6)-cycloalkyl, -N(R'')-(CH2)m-C(O)-O-lower alkyl, -O-(CH2)m-O-lower alkyl or alkoxy-group; R'' mean(s) independently of one another hydrogen atom or lower alkyl; m = 1, 2 or 3; or A means -S-; R means lower alkyl, or A-R mean in common piperazinyl substituted with alkyl, -C(O)-lower alkyl or oxo-group, or group A-R means piperidinyl substituted with lower alkoxy-group or hydroxy-group, or group A-R means morpholinyl substituted with lower alkyl, or group A-R means (C4-C6)-cycloalkyl, azethidine-1-yl optionally substituted with hydroxy-group or lower alkoxy-group, or group A-R means thiomorpholinyl-1,1-dioxo-group, tetrahydropyrane or 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Proposed compounds can be used in treatment of diseases mediated by adenosine A2A-receptors, for example, Alzheimer disease, some depressive states, toxicomania and Parkinson's disease.

EFFECT: valuable medicinal properties of compounds and agent.

37 cl, 10 sch, 109 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 18 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention elates to derivatives of benzothiazole of the general formula (I): wherein R means hydrogen atom, -(CH2)n-phenyl optionally substituted with a substitute chosen from the following group: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, trifluoromethyl or -N(R')-C(O)-(lower)-alkyl, -(CH2)n-pyridinyl optionally substituted with (lower)-alkyl, -(CH2)n-(C3-C6)-cycloalkyl optionally substituted with hydroxy-group, -(CH2)n-benzo[1,3]dioxolyl, -(CR'2)-thiophenyl, -(CR'2)n-thiazolyl optionally substituted with (lower)-alkyl, -(CH2)n-C(O)-thiophenyl optionally substituted with halogen atom, -(CH2)-furanyl optionally substituted with (lower)-alkyl, -(CHR')n-benzofuran-1-yl, -(CH2)n-benzo[b]thiophenyl, -(CH2)n-N(R')-C(O)-phenyl optionally substituted with halogen atom or (lower)-alkoxy-group. -(CH2)n-C(O)-phenyl optionally substituted with (lower)-alkoxy-group, -(CH2)n-C(O)-2,3-dihydrobenzo[1,4]dioxine-6-yl, -(CH2)n-N(R')-C(O)-pyridinyl, -(CH2)n-tetrahydrofuranyl, -CH-biphenyl, -CH-(phenyl)pyridinyl, -(CH2)n-1-oxo-(CH2)n-CH-(phenyl)tetrahydropyranyl, -(CH2)n-1-oxo-1,2,3,4-tetrahydroquinoline-3-yl or -(CH2)n-S-[1,3,4]thiadiazol-2-yl optionally substituted with amino-group; R' means hydrogen atom or (lower)-alkyl and independently of one another in case R'2; n = 0, 1, 2, 3 or 4. Also, invention relates to a medicament possessing high affinity to adenosine A2A-receptors and high selectivity with respect to A1-receptors and comprising one or more derivatives of benzothiazole of the formula (I) and pharmaceutically acceptable excipients. Invention provides using derivatives of benzothiazole as ligands of adenosine receptors.

EFFECT: valuable medicinal properties of compounds and medicament.

13 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-oxo-1-pyrrolidine of the formula (I) or their pharmaceutically acceptable salts wherein X means -CA1NR5R6 or -CA1-R8 wherein A1 and A2 mean independently oxygen atom; R1 means hydrogen atom (H), (C1-C20)-alkyl, (C6-C10)-aryl or -CH2-R1a wherein R1a means (C6-C10)-aryl; R3 means H, -NO2, nitrooxy-group, C≡N, azido-group, -COOH, amido-group, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C6-C10)-aryl, thiazolyl, oxazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, pyrimidinyl, triazolyl, pyridinyl, -COOR11, -COR11 wherein R11 means (C1-C12)-alkyl; R3a means H, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl or (C6-C10)-aryl; R5 and R6 are similar or different and each means independently H, (C1-C6)-alkyl, and R8 means -OH and wherein each alkyl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, isothiocyanate, -OH, -NO2, -CN, azido-group, (C3-C6)-cycloalkyl and (C6-C10)-aryl;, and wherein each (C6-C10)-aryl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, -NH2, -NO2, azido-group, (C1-C6)-alkoxy-group, (C1-C6)-alkyl and (C1-C6)-halogenalkyl, and wherein each alkenyl can be substituted independently with at least one substitute chosen from halogen atom and -OH, and under condition that at least one radical among R and R3a differs from H, and when compound represent a mixture of possible isomers then X means -CONR5R6; A2 means oxygen atom, and R1 means H, -CH3, -C2H5, -C3H7, and when each R1 and R3a means H and A2 means oxygen atom and X means -CONR5R6 then R3 differs from -COOH, -CH, -COOR11, amido-group, naphthyl, phenyl rings substituted with (C1-C6)-alkoxy-group or halogen atom in para-position in naphthyl or phenyl ring. Compounds of the formula (I) can be used in pharmaceutical compositions for treatment of epilepsy, epileptogenesis, convulsions, epileptic seizures, essential tremor and neuropathic pain.

EFFECT: improved method of synthesis, valuable medicinal properties of derivatives and pharmaceutical compositions.

27 cl, 3 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1):

and their salts wherein ring A comprises optionally heteroatom oxygen (O); dotted lines represent the optional unsaturation; R1 represents (C1-C4)-alkoxy-group; R2 and R3 represent independently hydrogen atom (H), optionally halogenated (C1-C4)-alkyl, optionally substituted aromatic group, or R2 and R3 in common can form substituted or unsubstituted 5-7-membered ring condensed with ring E; k = 0-4; L1 represents a covalent bond or (C1-C6)-alkyl optionally comprising nitrogen atom (N); X represents unsubstituted or substituted carbon © atom or N, or represents O or sulfur (S) atom; Ar represents phenylene; each n = 0-2 independently; each R represents independently H or (C1-C6)-alkyl; Y represents optionally substituted aromatic or heteroaromatic group or 5-11-membered heterocyclic group comprising 1-4 heteroatoms cgosen from N, O and S that are bound with chemokine receptors comprising CXCR4 and CCR5, and elicit the protective affect against damage of host-cells by human immunodeficiency virus (HIV).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds 2,6-di-tert.-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazole-4-yl}phenol, 2,6-di-tert.-butyl-4-[4-(hydroxymethyl)-1,3-oxazole-2-yl]phenol, 4-methylphenyl-2-[4-(1,1-biphenyl-4-yl)-1H-imidazole-2-yl]ethylcarbamate and others or their pharmaceutically acceptable salts. Also, invention relates to using these compounds for preparing a medicinal agent possessing one of the following three activities: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulating activity with respect to sodium channels. Proposed derivatives of thiazole, oxazole or imidazole possess one of the following species of pharmacological activity: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulation of sodium channels.

EFFECT: valuable biochemical and biological properties of derivatives.

34 cl, 119 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I) wherein p, R1, R2, R3 and A are determined in the invention description, their individual isomers and their pharmaceutically acceptable salts. Proposed compounds possess antagonistic effect with respect to muscarinic receptors that allows their using in treatment and prophylaxis of diseases yielding to treatment with muscarinic receptor antagonist. Also, invention describes a pharmaceutical composition containing these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 22 ex

FIELD: organic chemistry, medicine, hematology, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): in all their stereoisomeric forms and their mixtures taken in any ratio and their physiologically acceptable salts possessing properties of inhibitors of factor Xa and/or factor VIIa, and to a medicinal agent based on thereof. Also, invention relates to a method for synthesis of these compounds and their using for preparing pharmaceutical agents for inhibition of activity of factor Xa and/or factor VIIa or for their effect on blood coagulation or fibrinolysis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 1 tbl, 276 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of derivatives of indolinone of the general formula (VI): wherein R1, R2, R3 and R4 are chosen independently from group consisting of hydrogen atom (H) and halogen atom; each R5 means independently (C1-C12)-alkyl; R6 means -NR8-(CH2)mR9, -NR10R11 under condition that from 1 to 4 groups -CH2- can be substituted optionally with -OH; R8 means H; R9 means -NR10R11 wherein R10 and R11 mean (C1-C12)-alkyl, or R10 and R11 in common with nitrogen atom to which they are bound can form a heterocyclic group chosen from morpholinyl, pyrrolidinyl and piperidinyl under condition that the heterocyclic group can be substituted optionally with morpholino-group; J means -NH; L means carbon atom (C), and group -C(O)R6 is bound with L; K and M means -CR5; m = 1, 2, 3 or 4; p = 2. Method for synthesis of these compounds involves the addition reaction of compound of the general formula (III): wherein R* means R with compound of the formula (IV): wherein values R1, R2, R3 and R4 are given above with amine of the general formula (V): HR6 (V) wherein R6 is given above to form indolinone of the general formula (VI). Method provides synthesis of indolinone derivatives with the yield 25-85%.

EFFECT: improved method of synthesis.

20 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I): or its pharmaceutically acceptable salts or esters hydrolyzed in vivo and possessing properties of selective inhibitor of cyclin-dependent kinases, such as CDK-2, and inhibiting proliferation of cells. Compounds can be used in preparing medicinal agents used in treatment of cancer diseases. In compounds of the formula (I) R1 represents halogen atom; p = 0 or 1; R2 represents sulfamoyl or group B-E-; q = 0 or 1 wherein p + q = 1; R3 represents hydrogen atom, (C1-C6)-alkyl wherein R3can be substituted optionally at carbon atom with one or some M; R4 represents (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl wherein R4 can be substituted optionally with one or some M; or R3 and R4 taken with nitrogen atom to which they are bound form heterocyclic ring substituted optionally at carbon atom with one or some M wherein if indicated heterocyclic ring comprises group -NH then nitrogen atom can be substituted optionally with group chosen from Q; B is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein B can be substituted optionally at carbon atom with one or some D and wherein indicated heterocyclic group comprises group -NH- then nitrogen atom can be substituted optionally with group chosen from G; E represents -S(O)r- or -N(Ra)SO2- wherein Ra represents hydrogen atom or (C1-C6)-alkyl and r = 2; D is chosen independently from halogen atom, nitro-, cyano-, hydroxy-, amino-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N-(C1-C6)-alkylamino-, N,N-((-C1-C6)-alkyl)2-amino-, (C1-C6)-alkanoylamino-group, (C1-C6)-alkyl-S(O)a wherein a = 0-2, wherein D can be substituted optionally at carbon atom with one or some V; M is chosen independently from halogen atom, nitro-, cyano-, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N,N-((C1-C6)-alkyl)2-amino-group, (C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkyl or heterocyclic group wherein M can be substituted optionally at carbon atom with one or some P; P, X and Y are chosen independently from hydroxy-group, methyl, methoxy-, dimethylamino-group; G and Q are chosen independently from (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkoxycarbonyl wherein Q can be substituted optionally at carbon atom with one or some X. Also, invention relates to methods for synthesis of compounds, preparing pharmaceutical compositions based on thereof and to a method for inhibition of proliferation of cells.

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

15 cl, 2 sch, 133 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel aromatic compounds that can be used in treatment of diseases or pathological states accompanying by inflammation, for example, chronic inflammation diseases. Invention describes compound of the formula (II): wherein G means phenyl, pyridinyl, pyrazolyl and wherein G is substituted with one or some groups R1, R2 or R3; Ar means naphthyl; X means (C5-C8)-cycloalkyl or cycloalkenyl optionally substituted with 1-2 oxo-groups, phenyl, furanyl, pyridinyl or pyrazolyl; Y means a bond or saturated either unsaturated branched or unbranched (C1-C4)-carbon chain wherein one or some methylene groups are optionally and independently substituted with oxygen (O) or nitrogen (N) atoms; Y is optionally substituted with oxo-group; Z means phenyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, morpholinyl, thiomorpholinyl, piperidinyl, piperidinonyl, piperazinyl, pentamethylenesulfoxidyl wherein each of them is optionally substituted with 1-3 (C1-C6)-alkyls or group -CONH2, (C1-C6)-alkyl, nitrile, hydroxy-group, (C1-C6)-alkoxy-group, secondary or tertiary amine wherein amine nitrogen is bound covalently with (C1-C3)-alkyl or (C1-C5)-alkoxyalkyl, tetrahydrofuranyl-(C1-C3)-alkyl, nitrile-(C1-C3)-alkyl, carboxamide-(C1-C3)-alkyl; R1 means independently in each case (C1-C10)-alkyl which is optionally partially or completely halogenated and optionally substituted with 1-3 hydroxy-groups, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl wherein each of them is optionally substituted with 1-3 groups -CN, halogen atom, (C3-C6)-alkynyl branched or unbranched carbon chain and one or some methylene groups is optionally replaced for atom O and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R2 means branched or unbranched (C1-C6)-alkyl that is optionally partially or completely halogenated, branched or unbranched (C1-C4)-alkoxy-group that in each case is optionally partially or completely halogenated, halogen atom, (C1-C6)-alkoxy-group, hydroxy-group, mono- or di-(C1-C4)-alkyl-amino-group, group -OR6, nitro-group or group mono- or di-(C1-C4)-alkyl-amino-S(O)2 that is optionally partially or completely halogenated, or group -H2NSO2; R3 in each case means independently phenyl, pyridinyl, pyrimidyl, pyrrolidinyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, (C1-C4)-alkynyl group or branched or unbranched (C1-C6)-alkoxy-group wherein each of them is optionally partially halogenated, -OR18 or (C1-C6)-alkyl optionally substituted with group -OR18, amino-group or mono- either di-(C1-C5)-alkyl-amino-group, (C2-C6)-alkynyl branched or unbranched carbon chain wherein one or some methylene groups are optionally replaced for atom O, and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R6 means (C1-C4)-alkyl that is optionally partially or completely halogenated; in each case R18 means independently hydrogen atom, (C1-C4)-alkyl; W means atom O, and its pharmaceutically acceptable derivatives. Also, invention describes a pharmaceutical composition containing these compounds and a method for treatment of disease mediated by cytokines and based on indicated compounds. Invention provides synthesis of novel compounds possessing valuable biological properties.

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

12 cl, 1 tbl, 38 ex

FIELD: organic chemistry, insecticides.

SUBSTANCE: invention describes compound of the formula (I): wherein B represents oxygen atom (O) or -NR1; J represents 5-membered heteroaromatic ring representing group of the formula (J-1): optionally substituted with 1-2 radicals R5 wherein Q represents -NR5; each X, Y and Z represents independently nitrogen atom (N), -CH or - CR5; B1 represents O; R2 represents hydrogen atom (H) or (C1-C6)-alkyl optionally substituted with one halogen atom, or (C2-C6)-alkynyl; or R1 and R2 taken in common form a binding chain consisting of 2-3 members and comprising at least one carbon atom, optionally comprising one carbon atom as -C(=O), optionally substituted with R3 wherein R3 represents (C1-C2)-alkyl; each R represents independently H, (C1-C6)-alkyl, halogen atom or -CN; each R5 represents independently (C1-C6)-halogenalkyl or halogen atom, or each ring is substituted with one R6; each R6 represents independently halogen atom; n represents a whole number 1 or 2. Also, invention describes a composition used for control of insects and comprising the biologically effective dose of compound of the formula (I) and at least one additional component chosen from group comprising surface-active substances, solid and liquid diluting agents, and methods for control of insects with using compositions based on compounds of the formula (I) and compounds of the formula (I). Proposed compounds of the formula (I) possess insecticide activity and can be used in agriculture.

EFFECT: valuable insecticide properties of compounds and compositions.

11 cl, 26 tbl, 4 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel oxazolidinones of the general formula (I): , their pharmaceutically acceptable salts, hydrates and salt hydrates that inhibit factor Xa selectively and possess anti-thrombosis effect. Also, invention relates to a method for synthesis of these compounds (variants) and using the known substituted oxazolidinones of the general formula (A): as agent inhibiting factor Xa selectively and possessing anti-thrombosis effect, and to a medicinal agent based on at least one compound of the formula (I) or at least one compound of the general formula (A). Values of substitutes R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are given in the invention claim.

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

10 cl, 2 tbl, 252 ex

FIELD: chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (1): and their salts wherein values R1, k, Ar, n, j, Y, R and R2 are determined in the invention claim. Novel compounds are able to modulate activity of chemokine receptors. Also, invention relates to using indicated compounds for treatment of human immunodeficiency virus or feline immunodeficiency virus and to a pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 100 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds represented by the general formula (I): and their pharmaceutically acceptable salts and esters possessing agonistic activity with respect to peroxisome proliferator receptors PPARα and/or PPARγ, to a pharmaceutical composition based on thereof and their using for preparing medicines wherein R1 means thiophenyl or phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkoxy-group, (C1-C8)-alkyl and (C1-C8)-alkyl substituted with one-three halogen atoms; R2 means hydrogen atom or (C1-C8)-alkyl; R3 means phenoxy-, (C2-C8)-alkenyloxy- or (C1-C8)-alkoxy-group; R4 means hydrogen atom or (C1-C8)-alkyl wherein one of substitutes R5 and R6 means compound of the formula and another one means hydrogen atom and wherein the bond between carbon atoms Ca and Cb means a carbon-carbon simple or double bond; R7 means hydrogen atom or (C1-C8)-alkyl; R8 means hydrogen atom or (C1-C8)-alkyl being any of A and A1 means nitrogen atom and another means oxygen or sulfur atom; n means 1, 2 or 3.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

30 cl, 1 tbl, 14 sch, 86 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula: or their pharmaceutically acceptable salts wherein Ra - R8a mean phenyl; R8b means pyridyl, or R8 means naphthyl; R1 means hydrogen atom; R2 - R9, R10, R11 mean substituted phenyl; R9, R10, R11 mean substituted pyridyl or pyrimidyl; R9, R10, R11 mean substituted pyridyl-N-oxide or pyrimidyl-N-oxide; R12, R13 mean substituted oxazolyl, naphthyl, fluorenyl, compounds of formulae , or ; R3 means hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C6)-alkyl; R8 means phenyl; R8 means phenyl-(C1-C6)-alkyl, or R8 means thienyl-(C1-C6)-alkyl; R4, R5, R7 and R13 mean independently hydrogen atom or (C1-C6)-alkyl; R6 means hydrogen atom or (C1-C6)-alkyl; R8 means 1-3 substitutes that mean independently hydrogen atom, halogen atom, (C1-C6)-alkoxyl or -CF3; R8a means 1-3 substitutes that mean independently hydrogen atom, halogen atom, -CF3, -CF3O, -CN; R14 means phenyl, -NHCOCF3 and imidazolyl; R8b means 1-3 substitutes that mean independently hydrogen atom or halogen atom; R9 and R10 mean independently (C1-C6)-alkyl, halogen atom, -NR17R18, -OH, -CF3 and -OCH3; R11 means R9, hydrogen atom, phenyl, -NO2, -CN, -CH2F, -CHF2, -CHO, -CN=NOR17, pyridyl, pyridyl-N-oxide, pyrimidinyl, pyrazinyl, -N(R17)CONR18R19, -NHCONH-(chloro-(C1-C6)-alkyl), -NHCONH-((C3-C10)-cycloalkyl-(C1-C6)-alkyl), -NHCO-(C1-C6)-alkyl, -NHCOCF3, -NHSO2N-((C1-C6)-alkyl)2, -NHSO2-(C1-C6)-alkyl, -N(SO2CF3)2, -NHCO2-(C1-C6)-alkyl, (C3-C10)-cycloalkyl, -SR20, -OSO2-(C1-C6)-alkyl, -SO2CF3, hydroxy-(C1-C6)-alkyl, -CONR17R18, -CON(CH2CH2-O-CH3)2, -OCONH-(C1-C6)-alkyl, -Si(CH3)3 or -B(OC(CH3)2)2; R12 means (C1-C)-alkyl or R14-phenyl; R14 means 1-3 substitutes that mean independently hydrogen, (C1-C6)-alkyl, -CF3, -CO2R17, -CN, (C1-C6)-alkoxyl and halogen atom; R15 and R16 mean independently hydrogen atom and (C1-C6)-alkyl, or R15 and R16 mean in common (C2-C5)-alkylene group and in common with carbon atom to which they are bound form (C3-C6)-spiran ring; R17, R18 and R19 mean independently hydrogen atom or (C1-C6)-alkyl; R20 means (C1-C6)-alkyl. Also, invention describes pharmaceutical compositions containing these compounds and using novel compounds as CCR5 antagonists in treatment of HIV infection, arthritis, asthma, cerebrospinal sclerosis and other diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

29 cl, 30 tbl, 31 ex

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