The inhibitor activity of esterified cholesterol transport protein, a prophylactic or therapeutic agent, derivatives of bis-(2-aminophenyl)disulfide or aminothiophenol

 

(57) Abstract:

The invention relates to an inhibitor of the activity of esterified cholesterol transport protein (HETB), comprising as active ingredient a compound represented by the formula (I), where R is a straight or branched alkyl group; a lower halogenating group; substituted or unsubstituted cycloalkyl group; substituted or unsubstituted cycloalkylcarbonyl group; substituted or unsubstituted aryl group, or substituted or unsubstituted heterocyclic group, X1X2X3and X4may be the same or different and each represents a hydrogen atom, halogen atom, lower alkyl group, lower halogenating group; a lower alkoxygroup; a cyano; a nitro-group; Y represents-CO -, and Z represents a hydrogen atom or mercaptohexanol group, or its pharmaceutically acceptable salt, or hydrate, or MES. Compounds represented by formula (I) can increase HDL cholesterol (HDL) and at the same time to reduce LDL (LDL) via selective inhibition activity HATB and therefore, as expected, can be used as a new type of preventive SS="ptx2">

The invention relates to a new inhibitor activity HATB (SETR), which includes as the active ingredient compound with bis-(2-AMINOPHENYL)disulfide structure, or 2-aminophenylthio structure and, in particular, to pharmaceutical compositions for the treatment or prevention of atherosclerosis or hyperlipidemia. This invention relates to the compound with bis-(2-AMINOPHENYL)disulfide structure or 2-aminophenylthio structure, prolekarstvom the compound, pharmaceutically acceptable salt, hydrate or solvate of these compounds.

Prior art

Based on the results of many epidemiological studies suggest that there is some relationship between atherosclerotic diseases and serum lipoproteins. For example, Badimon et al. (J. Clin. Invest. 85, 1234-1241 (1990)) reported that after intravenous injection of the fractions containing HDL (HDL) (high-density lipoprotein) and LOIT (VHDL) (LP (very high density) cholesterol-loaded rabbits, observed not only prevent the development of atherosclerotic change, but also regression of atherosclerotic lesions. Thus, from the point of view of mutual the Item may have antiatherosclerotic activity.

Recently it became known that there are proteins that transport lipids between serum lipoproteins, i.e., HATB (SETR) (esterified cholesterol transport protein). For the first time the presence of HATB specified Nichols and Smith in 1965 (J. Lipid Res. 6, 206 (1965)). Later protein cDNA was cloned Drayna et al. in 1987, the Molecular mass of protein in the form of a glycoprotein is 74000 Yes. It is about 58000 Yes after complete removal of sugar goals; cDNA of this protein consists of 1656 nucleotide residues and encodes 476 amino acid following the signal peptide of 17 amino acid residues. Since about 44% of these hydrophobic amino acids, protein is highly hydrophobic and prone to inactivation by oxidation. HATB synthesized in organs such as the liver, spleen, adrenal gland, adipose tissue, small intestine, kidney, skeletal muscle and myocardium. There is evidence that HETB is synthesized in the cells, like macrophages derived from human monocytes, lymphocytes, fat cells, epithelial cells of the small intestine, caso2cells and liver cells (e.g., HepG2 cells, derived from cells of human hepatoma). In addition to these tissues, it is also present in cerebrospinal fluid and Semliki, and choreopoem plexus sheep.

It became obvious that HATB involved in the metabolism of all lipoproteins in vivo and plays an important role in the reversible transfer of cholesterol. It attracts attention as a system that prevents the accumulation of cholesterol in peripheral cells and functions as a protective mechanism against atherosclerosis. With regard to HDL cholesterol, which plays an important role in the reversible transfer of cholesterol, a large number of epidemiological studies have shown that the decrease in EH (CE) (esterified cholesterol esters cholesterol) HDL in the blood is one of the risk factors for coronary artery disease (coronary heart disease). Activity HATB varies depending on animal species, and it became apparent that cholesterol loading does not cause atherosclerosis in animals with low activity of HATB, while atherosclerosis is easily produced in animals with high activity HATB. No HATB leads to high HDL-MIA + low LDL (low-density lipoprotein)-MIA and causes symptoms resistant to atherosclerosis. Thus, at the present time recognized the importance of HATB as mediators of migration AH in in HDL LDL blood foamy from it, absorbed in lipoprotein very low density lipoproteins (VLDL, VLDL). Then lonp is metabolized in the blood LDL via lipoprotein, intermediate density (BOB, IDL) through the action of lipoprotein lipase (LPL, LPL) and triglyceride lipase liver (TLP, HTGL). LDL is absorbed by the peripheral cell-mediated LDL receptor, and thus, CX enters the cells.

In contrast, the flow from the liver to peripheral cells there is another thread of cholesterol from peripheral cells to the liver, called reverse transfer of cholesterol. CX, accumulated in the peripheral cells, extracted HDL, tarifitsiruetsya on HDL cholesterol through the action of LCAT (Lecithin: cholesterol acyltransferase) with the formation of OH is transferred to the hydrophobic portion of the frame HDL, and HDL Matures into globular HDL particles. OH in HDL is transferred to UPS (Ares)-containing lipoproteins, such as lonp, BOB and LDL, with the assistance present in the blood of HATB. When exchanging TG is transferred to HDL cholesterol at a molar ratio of 1:1. OH that is transferred to UPS-containing lipoprotein, is absorbed by the liver via LDL receptor on it and, thus, cholesterol is transferred indirectly to the liver. There are also mechanisms through to the th macrophages, and so p. which is then absorbed directly by the liver via LDL receptor or receptor-cut. In another, liver cells do not absorb HDL particles, but selectively absorb only AH in HDL. In the following (the mechanism) HDL particles are absorbed by liver cells through so-called HDL receptor.

In the state in which the activity of HATB amplified, OH in HDL and decreases in OH lonp, BOB and LDL increases due to the increase in EH transfer from HDL. Increase in the absorption BOB and LDL in the liver lead to regulation by the type of negative communication (down -) regulation of LDL receptor and increases LDL in the blood. In contrast, in a state of deficit HATB, HDL removes cholesterol from peripheral cells via LCAT, gradually increases his size and possesses apoE (apoE). HDL, which becomes apoE-enriched, is absorbed by the liver via LDL receptor in the liver and catabolized. However, since the action of this mechanism in humans is not adequate, is holding a large HDL in the blood and, as a result, the depot of cholesterol in the liver becomes less. LDL receptor becomes regulated by the type of positive communication (up-regulated) and decreases LDL.

Therefore, by selective ingabire inhibitory effect. Thus, it is possible to predict the development of not existing to date medicines that are useful for the prevention or treatment of atherosclerosis or hyperlipidemia.

More recently there have been reports of chemical compounds that are designed to inhibit the activity of HATB.

For example, in Biochemical and Biophysical Research Communications 223, 42-47 (1996) describes derivatives of dithiodipyridine and derivatives substituted dithiobenzoate as compounds that can inactivate HATB by modification of cysteine residues. However, in the publication are not disclosed and are not supposed to compounds such as the compounds of this invention are bis-(2-AMINOPHENYL)disulfide structure, or 2-aminophenylthio structure.

In WO95/06626 described Wiedendiol-A and Wiedendiol-B inhibitor, such as activity HATB, but there is no description of the proposed compounds of this invention.

In addition, in JP-B-Sho 45-11132, JP-B-Sho 45-2892, JP-B-Sho 45-2891, JP-B-Sho 45-2731 and JP-B-Sho 45-2730 described mercaptoacetate, substituted higher fatty acids, such as o-itsearviointiin. However, in these publications only refer to atherosclerosis and preventive action, but there is no description testowy the th, pointing to the compounds of this invention.

There are several reports on compounds with bis-(2-AMINOPHENYL)disulfide structure, or 2-aminophenylthio structure similar to those claimed in this invention.

For example, in WO96/09406 described disulfide compounds such as 2-acetylaminophenol disulfide, etc., However, referred to in this publication compounds are compounds that are used for retrovirus, i.e., HIV-1 (HIV-1), and their use as inhibitors of the activity of HATB not disclosed. In addition, there is no indication, hinting at it's use.

In JP-F-Hei 8-253454 described diphenyldisulfide compounds such as 2,2'-di(pyrimidinamine)diphenyldisulfide, etc., However, referred to in this publication compounds are compounds that have an inhibitory effect on the production of IL-1 and the release of TNF, and not revealed their usefulness in relation to the activity inhibitors HATB. Even there is no description, hinting of such usefulness. In JP-A-Hei 2-155937 described bis-(acylaminoalkyl)disulfide compounds such as 2,2'-diacetylethylenediamine, etc., However, the connection in this publication relate to a method for vulcanized CA is and HATB. In addition, no description, hinting of such usefulness. In the claims set forth in the publication, WITH5-C12cycloalkyl and cycloalkenyl defined as R9and R10and in the specific examples described cyclohexyl and cyclohexenyl. However, in the publication presents sample, which confirms the connection, and no description of the General method of obtaining compounds.

In JP-A-Hei 2-501772 described derivatives acylaminopenicillin, such as o-pillolagiovanissima, etc., as intermediates for obtaining pirazolonovogo potowatomie. However, the invention described in this publication, refers to the photocell and is not intended the invention. In addition, this publication also describes 2-cyclohexanecarbonitrile as an example of combining group agent combinations, but no description of the examples which confirm the connection.

In JP-A-Hei 8-171167 described derivatives thiophenol or disulfide derivative, such as 2-acetylaminophenol. However, the invention described in this publication, refers to an emulsion of silver halide, and is not intended the invention.

In JP-A-Hei 4-233 the ublications described as agents of chain transfer and thus, the publication does not suggest the present invention. As specific examples of R3in X, Y described tsiklogeksilnogo group, but no description of the sample, confirming the use of the common way obtain.

In JP-A-Sho 63-157150 described aminophenylacetylene derivatives, such as o-pillolagiovanissima, etc., as stabilizers. However, the invention of this publication belongs to the solar cell and does not suggest the present invention. In the formulas set forth in this publication, cycloalkyl group is defined as R substituents V, or Y compounds, stabilizers, but the example that confirms the use and common method of production, is not described.

Bis-(AMINOPHENYL)disulfide derivatives described in JP-A-Hei 8-59900, JP-A-Hei 7-258472, JP-A-Hei 7-224028, JP-A-Hei 7-49554, JP-A-Hei 6-19037, JP-A-Hei 6-19024, JP-A-Hei 3-226750, JP-A-Hei 2-284146, JP-A-Hei 2-23338, JP-A-Hei 1-321432, JP-A-Hei 1-278543 and JP-B-Sho 47-357786. However, none of these publications not talking about their use as inhibitors of the activity of HATB and there is no description suggesting such use.

THE INVENTION

As described above, the present inventors have been actively conducted research to develop connections, which is to olsavica as new preventive or therapeutic agents for the treatment of atherosclerosis or hyperlipidemia, with a new mechanism of action that can increase HDL cholesterol and at the same time to reduce LDL, which is the subject of this invention.

This invention relates to compounds and medicines, are presented in the following (1) to(19), which have inhibitory effect on the activity of HATB.

(1) the Inhibitor activity HATB, comprising as active ingredient a compound represented by the formula (I)

< / BR>
where R represents the

a straight or branched C1-10alkyl group;

a straight or branched C2-10alkenylphenol group;

halogen-C1-4lower alkyl group;

substituted or unsubstituted WITH3-10cycloalkyl group;

substituted or unsubstituted C5-8cycloalkenyl group;

substituted or unsubstituted WITH3-10cycloalkyl C1-10alkyl group;

substituted or unsubstituted aryl group;

substituted or unsubstituted aracelio group or

substituted or unsubstituted 5 - or 6-membered heterocyclic group having 1-3 nitrogen atom, oxygen or sulfur,

X1X2, X3and X4may be the same or different and predstavlyayuschee alkyl group;

C1-4the lower alkoxygroup;

the cyano;

the nitro-group;

acyl group or aryl group,

Y is

-CO - or-SO2and

Z represents

a hydrogen atom or

mercaptohexanol group

it proletarienne derivative, pharmaceutically acceptable salt, hydrate or MES.

(2) the Inhibitor activity HATB, comprising as active ingredient the compound described above (1), where

R is

a straight or branched C1-10alkyl group;

a straight or branched C2-10alkenylphenol group;

halogen-C1-4lower alkyl group substituted by 1-3 halogen atoms selected from fluorine, chlorine and bromine;

WITH3-10cycloalkyl group, C5-8cycloalkenyl group or3-10cycloalkyl C1-10alkyl group, each of which may have 1-4 substituent selected from the group consisting of

straight or branched C1-10alkyl group,

straight or branched C2-10alkenylphenol group,

WITH3-10cycloalkyl group,

WITH5-8cycloalkenyl group,

WITH3-10cycloalkyl C1-10alkyl group,

aryl PU, selected from phenyl, biphenyl and naphthyl; or

aryl, Uralkaliy, or 5 - or 6-membered heterocyclic group with 1-3 nitrogen atoms, oxygen or sulfur, each of which may have 1-4 substituent selected from the group consisting of

straight or branched C1-10alkyl group,

straight or branched C2-10alkenylphenol group,

the halogen atom selected from fluorine, chlorine and bromine,

nitro and

halogen-C1-4lower alkyl group having a halogen atom selected from fluorine, chlorine, and bromine;

Z represents a hydrogen atom;

mercaptohexanol group selected from the group consisting of

C1-4lower alkoxymethyl group,

C1-4lower alkylthiomethyl group,

aralkylamines group having aryl group selected from phenyl, biphenyl and naphthyl,

aralkylamines group having aryl group selected from phenyl, biphenyl and naphthyl,

WITH3-10cycloalkylcarbonyl group,

WITH5-8cycloalkylcarbonyl group,

WITH3-10cycloalkyl C1-10alkoxymethyl group,

relaxometry group having aryl group selected from phenyl, biphenyl and nknow group,

alloctype,

aminocarbonylmethyl group,

thiocarbonyl group and

tigraphy,

it proletarienne derivative, pharmaceutically acceptable salt, hydrate or MES.

(3) the Inhibitor activity HATB, comprising as active ingredient the compound described above (2), which is represented by formula (I-1)

< / BR>
where R, X1, X2, X3, X4and Y are as described above (2) and

Z1is

a hydrogen atom;

the group represented by formula

< / BR>
where R, X1, X2, X3X4and Y are as described above;

-Y1R1,

where Y1represents-CO - or

-CS-, and

R1is

substituted or unsubstituted straight or branched C1-10alkyl group;

C1-4the lower alkoxygroup;

C1-4the lower allylthiourea;

substituted or an unsubstituted amino group;

substituted or unsubstituted raidgroup;

substituted or unsubstituted WITH3-10cycloalkyl group;

substituted or unsubstituted WITH3-10cycloalkyl C1-10alkyl group;

substituted or unsubstituted aryl g the ing group;

substituted or unsubstituted killigrew;

substituted or unsubstituted 5 - or 6-membered heterocyclic group having 1-3 nitrogen atom, oxygen or sulfur, or substituted or unsubstituted 5 - or 6-membered heteroallyl group; or

-S-R2,

where R2is

substituted or unsubstituted C1-4lower alkyl group or

substituted or unsubstituted aryl group,

it proletarienne derivative, pharmaceutically acceptable salt, hydrate or MES.

(4) the Inhibitor activity HATB, comprising as active ingredient the compound described above (3), where

R1is

a straight or branched C1-10alkyl group which may have 1-3 substituent selected from the group consisting of a halogen atom selected from fluorine, chlorine, and bromine, C1-4low alkoxygroup,

amino group which may be substituted C1-4lower alkyl, acyl or a hydroxyl group,

C1-4low allylthiourea,

carbamoyl,

hydroxyl group,

acyl group,

alloctype having acyl group,

carboxyl group and

alloctype, to which the SCP;

C1-4the lower allylthiourea;

amino - or raidgroup, which may have 1-2 substituent selected from the group consisting of

C1-4lower alkyl group,

hydroxyl group,

acyl group and

aryl group which may be substituted by lower C1-4alkoxygroup;

WITH3-10cycloalkyl group or3-10cycloalkyl C1-10alkyl group which may have substituents selected from the group consisting of

straight or branched C1-10alkyl group,

WITH3-10cycloalkyl group,

C5-8cycloalkenyl group,

aryl group,

amino group,

C1-4low alkylamino with C1-4the lower alkyl group and

alluminare having acyl group;

aryl group, aracelio group, arylalkyl group or killigrew, each of which may have 1-4 substituent selected from the group consisting of

C1-10alkyl group,

the halogen atom selected from fluorine, chlorine and bromine, nitro,

hydroxyl group,

C1-4low alkoxygroup,

C1-4low allylthiourea,

acyl group,

g is/BR> amino group which may be substituted C1-4lower alkyl or acyl group;

5 - or 6-membered heterocyclic group having 1-3 nitrogen atom, oxygen or sulfur, or a 5 - or 6-membered heteroallyl group which may have 1-4 substituent selected from the group consisting of

straight or branched C1-10alkyl group,

the halogen atom selected from fluorine, chlorine and bromine,

acyl group,

the carbonyl group and

halogen-C1-4lower alkyl group having a halogen atom selected from fluorine, chlorine and bromine; and

R2is

C1-4lower alkyl group which may have 1-3 substituent selected from the group consisting of

C1-4lower alkoxygroup,

amino group which may be substituted C1-4lower alkyl or acyl group,

C1-4low allylthiourea,

carbamoyl,

hydroxyl group,

carboxyl group,

acyl group and

5 - or 6-membered heterocyclic group having 1-3 nitrogen atoms, oxygen, or sulfur; or an aryl group which may have 1-4 substituent selected from the group consisting of

C1-4the lower alkyl groups/BR>C1-4low alkoxygroup,

C1-4low allylthiourea,

acyl group,

amino group which may be substituted C1-4lower alkyl or acyl group, and

halogen-C1-4lower alkyl group having a halogen atom selected from fluorine, chlorine and bromine,

it proletarienne derivative, pharmaceutically acceptable salt, hydrate or MES.

(5) the Inhibitor activity HATB, comprising as active ingredient the compound described above (1), which are selected from the group consisting of

bis-[2-(paulolino)phenyl]disulfide;

bis-[2-(2-propylpentanoate)phenyl]disulfide;

bis-[2-(1-methylcyclohexanecarboxylic)phenyl]disulfide;

bis-[2-(1-isopentenyltransferase)phenyl]disulfide

bis-[2-(1-isopentenyladenosine)phenyl]disulfide

N-(2-mercaptophenyl)-2,2-dimethylpropanamide;

N-(2-mercaptophenyl)-1-isopentenyladenosine;

N-(2-mercaptophenyl)-1-methylcyclohexanecarboxylic;

N-(2-mercaptophenyl)-1-isopentenyltransferase;

N-(2-mercaptophenyl)-1-isopropylcyclohexane;

N-(4,5-dichloro-2-mercaptophenyl)-1-isobutyltrimethoxysilane;

N-(2-mercapto-4-were)-1-isopentenyladenosine;

S-[2-(1-isopentenyladenosine)phenyl]thioacetate;

S-[2-(1-methylcyclohexanecarboxylic)phenyl]-2,2-dimethylthiophosphate;

S-[2-(paulolino)phenyl]phenylthiourea;

S-[2-(1-isopentenyladenosine)phenyl] -2,2-dimethylthiophosphate;

S-[2-(1-lisopenthefileasnormalsource)phenyl] -2-acetylamino-3-phenylthiophene;

S-[2-(1-isopentenyladenosine)phenyl] -3-pyridinedicarboxylate;

S-[2-(1-isopentenyladenosine)phenyl]CHLOROACETATE;

S-[2-(1-isopentenyladenosine)phenyl] methoxytyramine;

S-[2-(1-isopentenyladenosine)phenyl]thiopropionate;

S-[2-(1-isopentenyladenosine)phenyl] phenoxythioacetamide;

S-[2-(1-isopentenyladenosine)phenyl]-2-methylthiopropionate;

S-[2-(1-isopentenyladenosine)phenyl] -4-chlorophenoxyacetate;

S-[2-(1-isopentenyladenosine)phenyl] -cyclopropanecarboxylate;

S-[2-(1-isopentenyladenosine)phenyl] -2-acetyl-amino-4-carbamodithioate;

S-[2-(1-isopentenyladenosine)phenyl] -2-hydroxy-2-methylthiophenethylamine)phenyl]thioacetate;

S-[4,5-dichloro-2-(1-isopentenyladenosine)phenyl]-2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-isopentenyltransferase)phenyl]-2,2-dimethylthiophosphate;

S-[2-(1-isopentenyladenosine)-4-triptoreline] -2,2-dimethylthiophosphate;

O-methyl S-[2-(1-isopentenyladenosine)phenyl] montierbar;

S-[2-(1-methylcyclohexanecarboxylic)phenyl]-3-phenyldiethanolamine;

S-[2-(1-isopentenyladenosine)phenyl]-N-phenylthiocarbamide;

S-[2-(paulolino)-4-trifloromethyl]-2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-cyclopropanecarboxylate)phenyl]-2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(2-cyclohexylpropionate)phenyl] -2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-pentylcyclohexanecarboxylic)phenyl] -2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-cyclopropylacetylene)phenyl] -2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-cyclohexyloxycarbonyloxy)phenyl] -2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-isopropylcyclopentadienyl)phenyl]-2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-isopentenyladenosine)phenyl]-2,2-dimethylthiophosphate;

S-[4,5-DIH is benjamina)-4-nitrophenyl] -2,2-dimethylthiophosphate;

S-[4-cyano-2-(1-isopentenyladenosine)phenyl] -2,2-dimethylthiophosphate;

S-[4-chloro-2-(1-isopentenyladenosine)phenyl] -2,2-dimethylthiophosphate;

S-[5-chloro-2-(1-isopentenyladenosine)phenyl] -2,2-dimethylthiophosphate;

S-[4-fluoro-2-(1-isopentenyladenosine)phenyl] -2,2-dimethylthiophosphate;

S-[4,5-debtor-2-(1-isopentenyladenosine)phenyl]-2,2-dimethylthiophosphate;

S-[5-fluoro-2-(1-isopentenyladenosine)phenyl] -2,2-dimethylthiophosphate;

bis-[4,5-dichloro-2-(1-isopentenyladenosine)phenyl] disulfide;

2-tetrahydropyrimidin-2-(1-isopentenyladenosine)phenoldisulfonic;

N-(2-mercaptophenyl)-1-ethylcyclohexylamine;

N-(2-mercaptophenyl)-1-propylcyclohexanone;

N-(2-mercaptophenyl)-1-butylcyclohexanecarboxylic;

N-(2-mercaptophenyl)-1-isobutyltrimethoxysilane;

S-[2-(1-isopentenyladenosine)phenyl] cyclohexanecarboxylate;

S-[2-(1-isopentenyladenosine)phenyl]thiobenzoate;

S-[2-(1-isopentenyladenosine)phenyl] -5-carboxymefenamic;

S-[2-(1-isopentenyladenosine)-4-were] thiazolyl)cyclohexanecarboxylate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -2-methylthiopropionate;

S-[2-(1-isobutylacetophenone)phenyl]-2-methylthiopropionate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -1-acetylpiperidine-4-dicarboxylate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate]phenyl]thioacetate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -2,2-dimethylthiophosphate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate]phenyl]methoxytyramine;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -2-hydroxy-2-methylthiopropionate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -4-chlorophenoxyacetate;

S-[2-(1-isobutylacetophenone)phenyl] -4-chlorophenoxyacetate and

S-[2-(1-isobutylacetophenone)phenyl] -1-acetylpiperidine-4-dicarboxylate,

it proletarienne derivative, pharmaceutically acceptable salt, hydrate or MES.

(6) a Preventive or therapeutic agent for hyperlipidemia, comprising as active ingredient the compound described above (1) to(5), it proletarienne derivative, pharmaceutically acceptable salt, hydrate or MES.

(7) Preventive or terapevticheskojj (1) to(5), it proletarienne derivative, pharmaceutically acceptable salt, hydrate or MES.

(8) the Compound represented by formula (I-2)

< / BR>
where R' is

substituted or unsubstituted WITH3-10cycloalkyl group or a substituted or unsubstituted WITH5-8cycloalkenyl group;

X1X2, X3and X4are as described above (1); and

Z1' is

a hydrogen atom;

the group represented by formula

< / BR>
where R', X1, X2, X3and X4are as described above;

-Y1R1,

where Y1and R1same as above (3) or

-S-R2,

where R2same as above (3),

it proletarienne derivative, pharmaceutically acceptable salt, hydrate or MES.

(9) the Compound described above in (8), which is represented by formula (I-3)

< / BR>
where R" is

1-substituted-C-3-10cycloalkyl group or

1-substituted-C5-8cycloalkenyl group;

X1, X2, X3and X4are the same as described above (1); and

Z1" is

a hydrogen atom;

the group, not only is/BR>-Y1R1,

where Y1and R1are the same as described above (3); or

-S-R2,

where R2is the same as described above (3),

it proletarienne derivative, pharmaceutically acceptable salt, hydrate or MES.

(10) the Compound described above (8), which is represented by formula (II)

< / BR>
where R', X1X2, X3and X4are the same as described above (8);

it proletarienne derivative, pharmaceutically acceptable salt, hydrate or MES.

(11) the Compound described above (9), which is represented by formula (II-1)

< / BR>
where R, X1, X2, X3and X4are the same as described above (9);

it proletarienne derivative, pharmaceutically acceptable salt, hydrate or MES.

(12) the Compound described above (8), which is represented by formula (III)

< / BR>
where R', X1X2, X3and X4are the same as described above (8);

it proletarienne derivative, pharmaceutically acceptable salt, hydrate or MES.

(13) the Compound described above (9), which is represented by formula (III-1)

< / BR>
where R, X1X2, X3and X4

(14) the Compound described above (8), which is represented by formula (IV)

< / BR>
where R', X1, X2, X3, X4, Y1and R1are the same as described above (8);

it proletarienne derivative, pharmaceutically acceptable salt, hydrate or MES.

(15) the Compound described above (9), which is represented by formula (IV-1)

< / BR>
where R, X1, X2, X3X4, Y1and R1are the same as described above (9);

it proletarienne derivative, pharmaceutically acceptable salt, hydrate or MES.

(16) the Compound described above (8), which is represented by formula (V)

< / BR>
where R', X1, X2, X3, X4and R2are the same as described above (8);

it proletarienne derivative, pharmaceutically acceptable salt, hydrate or MES.

(17) the Compound described above (9) represented by formula (V-1)

< / BR>
where R, X1X2, X3, X4and R2are the same as described above (9);

it proletarienne derivative, pharmaceutically acceptable salt, hydrate or MES.

(18) the Compound described above (8), which isopentenyltransferase)phenyl]disulfide

bis-[2-(1-isopentenyladenosine)phenyl]disulfide

N-(2-mercaptophenyl)-1-isopentenyladenosine;

N-(2-mercaptophenyl)-1-methylcyclohexanecarboxylic;

N-(2-mercaptophenyl)-1-isopentenyltransferase;

N-(2-mercaptophenyl)-1-isopentenyladenosine;

N-(4,5-dichloro-2-mercaptophenyl)-1-isopentenyladenosine;

N-(4,5-dichloro-2-mercaptophenyl)-1-isopentenyltransferase;

N-(2-mercapto-5-were)-1-isopentenyladenosine;

N-(2-mercapto-4-were)-1-isopentenyladenosine;

S-[2-(1-isopentenyladenosine)phenyl]thioacetate;

S-[2-(1-methylcyclohexanecarboxylic)phenyl]-2,2-dimethylthiophosphate;

S-[2-(1-isopentenyladenosine)phenyl] -2,2-dimethylthiophosphate;

S-[2-(1-isopentenyladenosine)phenyl] -2-acetylamino-3-phenylthiophene;

S-[2-(1-isopentenyladenosine)phenyl] -3-pyridinedicarboxylate;

S-[2-(1-isopentenyladenosine)phenyl]CHLOROACETATE;

S-[2-(1-isopentenyladenosine)phenyl]methoxytyramine;

S-[2-(1-isopentenyladenosine)phenyl]thiopropionate;

S-[2-(1-isopentyl is citiprivate;

S-[2-(1-isopentenyladenosine)phenyl] -4-chlorophenoxyacetate;

S-[2-(1-isopentenyladenosine)phenyl] cyclopropanecarboxylate;

S-[2-(1-isopentenyladenosine)phenyl] -2-acetylamino-4-carbamodithioate;

S-[2-(1-isopentenyladenosine)phenyl] -2-hydroxy-2-methylthiopropionate;

S-[2-(1-isopentenyltransferase)phenyl]-2,2-dimethylpropionic;

S-[2-(1-isopentenyltransferase)phenyl]thioacetate;

S-[4,5-dichloro-2-(1-isopentenyladenosine)phenyl] -2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-isopentenyltransferase)phenyl] -2,2-dimethylthiophosphate;

S-[2-(1-isopentenyladenosine)-4-triptoreline] -2,2-dimethylthiophosphate;

O-methyl-3-[2-(1-isopentenyladenosine)phenyl] montierbar;

S-[2-(1-methylcyclohexanecarboxylic)phenyl]-S-phenyldiethanolamine;

S-[2-(1-isopentenyladenosine)phenyl]-N-phenylthiocarbamide;

S-[4,5-dichloro-2-(1-cyclopropanecarboxylate)phenyl]-2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-pentylcyclohexanecarboxylic)phenyl] -2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-cyclopropylacetylene enyl] -2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-isopropylcyclopentadienyl)phenyl]-2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-isopentenyladenosine)phenyl]-2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-isopentenyladenosine)phenyl] -2,2-dimethylthiophosphate;

S-[2-(1-isopentenyladenosine)-4-nitrophenyl] -2,2-dimethylthiophosphate;

S-[4-cyano-2-(1-isopentenyladenosine)phenyl] -2,2-dimethylthiophosphate;

S-[4-chloro-2-(1-isopentenyladenosine)phenyl]-2,2-dimethylthiophosphate;

S-[5-chloro-2-(1-isopentenyladenosine)phenyl]-2,2-dimethylthiophosphate;

S-[4-fluoro-2-(1-isopentenyladenosine)phenyl]-2,2-dimethylthiophosphate;

S-[4,5-debtor-2-(1-isopentenyladenosine)phenyl] -2,2-dimethylthiophosphate;

S-[5-fluoro-2-(1-isopentenyladenosine)phenyl] -2,2-dimethylthiophosphate;

bis-[4,5-dichloro-2-(1-isopentenyladenosine)phenyl]disulfide;

2-tetrahydropyrimidin-2-(1-isopentenyladenosine)phenoldisulfonic;

N-(2-mercaptophenyl)-1-ethylcyclohexylamine;

N-(2-mercaptophenyl)-1-propylcyclohexanone;

N-(2-mercaptophenyl)-1-butylcyclohexanecarboxylic;

The N;

S-[2-(1-isopentenyladenosine)phenyl]thiobenzoate;

S-[2-(1-isopentenyladenosine)phenyl] -5-carboxymefenamic;

S-[2-(1-isopentenyladenosine)-4-were]thioacetate;

bis-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate]phenyl]disulfide;

N-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxylate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -2-methylthiopropionate;

S-[2-(1-isobutylacetophenone)phenyl]-2-methylthiopropionate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -1-acetylpiperidine-4-dicarboxylate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate]phenyl]thioacetate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -2,2-dimethylthiophosphate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate]phenyl]methoxytyramine;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -2-hydroxy-2-methylpropionate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -4-chlorophenoxyacetate;

S-[2-(1-isobutylacetophenone)phenyl] -4-chlorophenoxyacetate and

S-[2-(1-isobutylacetophenone)phenyl] -1-acetylpiperidine-4-dicarboxylate,

it proletarienne derived, farmette active ingredient compound, the above-described (8)-(18), it proletarienne compound, pharmaceutically acceptable salt, hydrate or MES.

(20) the Use of compounds represented by the above formula (I), it procarcinogen derivative, pharmaceutically acceptable salt, hydrate or MES, to obtain inhibitor activity HATB.

(21) Use of the compound represented by the above formula (I), it procarcinogen compounds, pharmaceutically acceptable salt, hydrate or MES, to receive a prophylactic or therapeutic agent for hyperlipidemia.

(22) the Use of compounds represented by the above formula (I), it procarcinogen compounds, pharmaceutically acceptable salt, hydrate or MES, to receive a prophylactic or therapeutic agent for atherosclerosis.

(23) a Method of inhibiting the activity of HATS, including the introduction patients compounds represented by the above formula (I), it procarcinogen compounds, pharmaceutically acceptable salt, hydrate or MES.

(24) a Method for preventing or treating hyperlipidemia, comprising the administration to patients of the compounds represented by the above

(25) a Method of preventing or treating atherosclerosis, comprising the administration to patients of the compounds represented by the above formula (I), it procarcinogen compounds, pharmaceutically acceptable salt, hydrate or MES.

Used herein, the term "straight or branched C1-10alkyl group" means an alkyl group having 1-10 carbon atoms which may be straight or branched. Specific examples of such groups are methyl, ethyl, sawn, ISO-propyl, bucilina, isobutylene, second-bucilina, tert-bucilina, pentilla, isopentyl, neopentyl, tert-pencilina, 1-ethylbutyl, 2-ethylbutyl, 1-protivooterne, 1,1-dimethylbutyl, 1-isobutyl-3-methylbutyl, 1-ethylpentane, 1-propylpentyl, 1-isobutylphenyl, 2-ethylpentane, 2-isopropylaniline, 2-tert-butylaniline, 3-ethylpentane, 3-isopropylphenyl, 4-methylpentyl, 1,4-dimethylpentyl, 2,4-dimethylpentyl, 1-ethyl-4-methylpentyl, hexeline, 1-ethylhexyl, 1-propylhexedrine, 2-ethylhexyl, 2-isopropylpyridine, 2-tert-butylacrylate, 3-ethylhexyl, 3-isopropylethylene, 3-tert-butylacrylate, 4-ethylhexyl, 5-methylhexane, GA, 4-propylheptyl, 5-etilefrine, 6-methylheptane, anjilina, 1-atrakcyjna, 2-atrakcyjna, Danilina, 1-methylnonane, 2-methylnonane, decile, etc. groups. Preferred straight or branched alkyl group having 1-8 carbon atoms.

Used herein, the term "C1-4the lower alkyl group" means an alkyl group having 1-4 carbon atoms, and specifically includes methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, second-boutelou, tert-boutelou, etc. group.

The term "straight or branched C2-10Alchemilla group" means alkenylphenol group having 2-10 carbon atoms with at least one or more double bonds, which may be straight or branched. Specific examples of such groups are allyl, vinyl, Isopropenyl, 1-protanilla, 1-methyl-2-protanilla, 2-methyl-2-protanilla, 1-methyl-1-bucinellina, catilina, 1-methyl-3-bucinellina, 3-methyl-2-bucinellina, 1,3-dimethyl-2-bucinellina, 1-penttila, 1-methyl-2-penttila, 1-ethyl-3-penttila, 4-penttila, 1,3-pentadienyl, 2,4-pentadienyl, 1-examilia, 1-methyl-2-examilia, 3-examilia, 4-examilia, 1-BU is anilina, 5-leptanillinae, 6-leptanillinae, 1,3-heptadienal, 2,4-heptadienal, 1-octenidine, 2-octenidine, 3-octenidine, 4-octenidine, 5-octenidine, 6-octenidine, 7-octenidine, 1-noninline, 2-noninline, 3-noninline, 4-noninline, 5-noninline, 6-noninline, 7-noninline, 8-noninline, 9-dianiline, etc. groups. Preferred Alchemilla group having 2-8 carbon atoms which may be straight or branched.

The term "halogen atom" means fluorine atoms, chlorine and bromine.

The term "halogen-C1-4alkyl group" means the above C1-4lower alkyl group substituted by 1-3 Halogens, which may be the same or different. Specific examples of such groups are permetrina, chloromethylene, brometalia, deformational, dichloromethylene, triptoreline, trichloroethylene, chlorethylene, deperately, triptoreline, pentachloroaniline, bromopropylate, dichloropropylene, triptoreline, etc. groups. Preferred trifluoromethyl and chloroethyl.

The term "C1-4the lower alkoxy group" means an alkoxy group containing the above C1-4lower alkyl group. Examples are methoxy, ethoxy, UB> lower alkylthio group" means alkylthio group containing C1-4the lower alkyl group described above. Examples of such groups are methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, sec-butylthio, tert-butylthio, etc. group.

The term "C3-10cycloalkyl group" means cycloalkyl group having 3-10 carbon atoms, which may be monocyclic or polycyclic. Examples of it include cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo, cycloheptyl, cyclooctyl, octahydronaphthalene, decahydronaphthalene, bicyclo[2.2.1]heptylene, Adamantine, etc. groups. The preferred group having 5-7 carbon atoms, including cyclopentyl, cyclohexyl and cycloheptyl.

The term "C5-8cycloalkenyl group" means cycloalkenyl group having 5-8 carbon atoms with one or more double bonds in the ring. Examples of such groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctadiene, cyclopentadienyls, cyclohexadienyl, cycloheptenyl, cyclooctadiene, etc. groups. Preferred are groups with 5-7 carbon atoms, including the group" means the above-described straight or branched C1-10alkyl group substituted WITH the above3-10cycloalkyl group. Specific examples of this group include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexyltrichlorosilane, dicyclohexylmethyl, 1-cyclopentylmethyl, 1-cyclohexylethyl, 2-cyclopropylethyl, 2-cyclopentylmethyl, 2-cyclohexylethyl, 2-cyclohexylethyl, 1-cyclohexyl-1-methylethyl, 1-cyclohexylprop, 2-cyclopentylpropionyl, 3-cyclobutylmethyl, 3-cyclopentylpropionyl, 3-cyclohexylprop, 3-cycloheptylmethyl, 1-cyclopropyl-1-methylpropyl, 1-cyclohexyl-2-methylpropyl, 1-cyclopentylmethyl, 1-cyclohexylethyl, 3-cyclohexylmethyl, 4-cyclopropylmethyl, 4-cyclobutylmethyl, 4-cyclopentylmethyl, 1-cyclohexyl-1-methylbutyl, 1-cyclopentyl-2-ethylbutyl, 1-cyclohexyl-3-methylbutyl, 1-cyclopentylmethyl, 1-cyclohexylethyl, 1-cyclohexylmethyl, 2-cyclohexylethyl, 2-cyclohexenylmethyl, 3-cyclopentylmethyl, 1-cyclohexyl-4-methylpentyl, 5-cyclopentylmethyl, 1-cyclopentylmethyl, 1-cyclohexylethyl, 1-cyclopentylmethyl, 2-cyclopentyloxy, 2-cyclopropylethyl, 3-cyclopentyloxy, 1-cyclohexylethyl, 1-cyclopentyl-1-methylhept, 1-cyclohexyl-1,6-dimethylheptyl, 1-cycloheptylmethyl, 2-cyclopentylacetyl, 3-cyclohexylcyclohexanes, 1-cyclopentylacetyl, 2-cyclohexylethyl, etc. group.

"Aryl group" include phenyl, raftiline, antennae, phenanthroline, biphenylene, etc. groups. Preferred phenyl, raftiline and biphenylene group.

"Kalkilya group" means the above C1-4lower alkyl group substituted by one or more aryl groups described above. Examples of such groups include benzyl, benzhydryl, triteleia, fenetylline, 3-phenylpropyl, 2-phenylpropyl, 4-phenylbutyl, naphthylmethyl, 2-naphthylamine, 4-biphenylamine, 3-(4-biphenyl), sawn, etc., group.

"Arylalkylamine group" means alkenylphenol group having 2-4 carbon atoms, substituted by the above aryl group. Examples of such groups include 2-phenylidole, 3-phenyl-2-propylene, 3-phenyl-2-methyl-2-propylene, 4-phenyl-3-butenolide, 2-(1-naphthyl)vinyl, 2-(naphthyl)vinyl, 2-(4-biphenyl)vinyl, etc. group.

"Aaltio group" means aaltio group containing the above-described aryl group, and, in particular, includes phenylthio, naphthylthio, etc. group.

"Heterocyclic ring group" means a 5 - and 6-membered aromaticheskiye 1-4, preferably 1 to 3 heteroatoms selected from nitrogen atoms, oxygen or sulfur. Specific examples of such groups include aromatic heterocyclic rings, such as theatrically, tetrazolyl, dithiazole, oxadiazolidine, thiadiazolidine, triazoline, oxazolidine, pyrazolidine, pyrrolidine, pureline, thienyl, thetrainline, triazinyl, personilnya, pyridinoline, pyrimidinyl, peredelnye or similar groups, and non-aromatic heterocyclic ring, such as DIOXOLANYL, pyrrolidinyl, tetrahydrofuryl, tetrahydrothiophene, dithiazanine, thiodianiline, morpholino, morpholinyl, oxazinyl, teasingly, piperazinilnom, piperidine, piperidine, perylene, tipirneni or similar group. The preferred groups are aromatic heterocyclic (heteroaryl) group, including furyl, thienyl, pyrrolyl, pyridyl, etc., and non-aromatic heterocyclic group containing at least one nitrogen atom, including pyrrolidinyl, tetrahydrofuryl, piperazinilnom, piperidine, piperidine, etc. group.

"Heteroallyl group" means the above C1-4lowest alkyl the th, and, in particular, these include 2-thienylmethyl, 2-furylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 2-thienyl-2-ethyl, 3-furyl-1-ethyl, 2-pyridyl-3-through, etc. group.

"Acyl group", in particular, includes formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl, propiolic, methacryloyl, crotonoyl, benzoyl, Naftoli, toluoyl, hydrotropes, Acropol, cynnamoyl, furoyl, thenoyl, nicotinoyl, isonicotinoyl, glycolyl, lactol, glycerol, tropol, bansilal, salicyloyl, anisoyl, vanilloid, veratrol, piperonal, protocatechuic, galloyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cyclohexylcarbonyl, 1-methyl-cyclohexanecarbonyl, 1-isopentenyladenosine, 1-isopentenyladenosine, tert-butoxycarbonyl, methoxycarbonyl, etoxycarbonyl, 2-(1-isopentenyladenosine)phenylthiocarbamyl, etc. groups. Preferred are acetyl, tert-butoxycarbonyl, benzoyl, 1-methylcyclohexanol, 1-isopentenyladenosine, 1-isopentenyladenosine and 2-(1-isopentenyladenosine)phenylthiocarbamyl.

The term substituted or unsubstituted" "substituted or unsubstituted WITH3-10cycle the military WITH3-10cycloalkyl C1-10the alkyl group described for R, R1and so on, means that the group may be substituted by 1-4 substituents, which may be the same or different, and the position of substitution can be arbitrary without any restrictions. Specific examples of these groups are the above C1-10an alkyl group with straight or branched chain; the above WITH2-10Alchemilla group with a straight or branched chain; the above WITH3-10cycloalkyl group; the above WITH5-8cycloalkenyl group; the above WITH3-10cycloalkyl C1-10alkyl group; the above-described aryl group; amino group; C1-4lower alkylamino group, such as methylamino, ethylamino or similar group; acylamino group, such as acetylamino, propionamido, benzylamino, etc. groups; oxoprop; above kalkilya group; the above arylalkylamine group, etc., the Above-mentioned substituents are recommended as substituents for R. Among them preferred for R1are the above C1-10an alkyl group with straight or branched chain, described above WITH3-10cycloalkyl group, the above C5-8zsanna or unsubstituted" "substituted or unsubstituted aryl group, "5 - or 6-membered heterocyclic group containing 1-3 nitrogen atom, oxygen, or sulfur", "substituted or unsubstituted aranceles group", "substituted or unsubstituted arylalkylamines group", "substituted or unsubstituted of aristocraty" and "substituted or unsubstituted 5 - or 6-membered heteroallyl group" described relative to R, R1and so on, means that groups can be substituted 1-4, preferably 1-3, substituents which may be the same or different, and the position of substitution can be arbitrary without specific limitations. Examples of these groups include the above-described straight or branched C1-10alkyl group, preferably a straight or branched1-6aracelio group; the above-described straight or branched2-10alkenylphenol group, preferably a straight or branched C2-6alkenylphenol group; the above-described halogen atom; a nitro-group; the above-described amino group which may be substituted by the above C1-4lower alkyl group or the above-described acyl group; a hydroxyl group; the above C1-4the lower alkoxygroup; the above C1-4the lower allylthiourea; the above halogen-C1-41. Among them, preferred R are above C1-6an alkyl group with straight or branched chain, the above-described halogen atom and the nitro-group.

The term "substituted or unsubstituted" "substituted or unsubstituted straight or branched C1-10the alkyl group described for R1and so on, means that the group may be substituted by 1-3 substituents, which may be the same or different, and the position of substitution can be arbitrary without specific limitations. Examples of these groups are the above C1-4lowest alkoxygroup; the above C1-4lower alkyl group; the above-described amino group which may be substituted acyl or a hydroxyl group; the above-described lower C1-4allylthiourea; carnemolla group; a hydroxyl group; the above-described halogen atom; the above alloctype containing acyl group; carboxyl group; the above-described acyl group; the above alloctype containing aryl group which may be substituted, etc.

"Substituted or unsubstituted" "C1-4the lower alkyl group" described in the relation R2and so on, oz the provision of substitution can be arbitrary without specific limitations. Examples of the group include the above C1-4the lower alkoxygroup; the above amino group which may be substituted by the above C1-4lower alkyl group or the above-described acyl group; the above C1-4the lower allylthiourea; karbamoilnuyu group; a hydroxyl group; a carboxyl group; the above-described acyl group; the above heterocyclic group (particularly, an aromatic heterocyclic groups such as thienyl, or non-aromatic heterocyclic group such as tetrahydrofuryl), etc.

The term "substituted or unsubstituted" "substituted or unsubstituted amino and substituted or unsubstituted of raidgroup described in relation to R1that means that groups can be substituted by one or more, preferably 1 or 2, substituents which may be the same or different, and the position of substitution can be arbitrary without specific limitations. Examples of these groups are the above C1-4alkyl group; a hydroxyl group; the above-described acyl group; and the above aryl group which may be substituted by the above C1-4lowest alkoxygroup, etc.

1-4lowest alkoxymethyl; C1-4lowest alkylthiomethyl; aralkylamines; aralkylamines; C3-10cycloalkylcarbonyl; C5-8cycloalkylcarbonyl; C3-10cycloalkyl C1-10alkoxymethyl; aryloxyalkyl; killtimer; acyl; acyloxy; aminocarbonylmethyl; thiocarbonyl and tigraphy. Specific examples of them include C1-4lower alkoxymethyl group with the above C1-4lowest alkoxygroup; C1-4lower alkylthiomethyl group with the above C1-4lowest alkylthiol; uraleleketro group with the above aranceles group; aralkylamines group with the above aranceles group; C3-10cycloalkylcarbonyl group described above WITH3-10cycloalkyl group; C5-8cycloalkylcarbonyl group with the above C5-8cycloalkenyl group; C3-10cycloalkyl C1-10alkoxymethyl group described above WITH3-10cycloalkyl C1-10alkyl group; aryloxyalkyl group with videopix the above-described substituted or unsubstituted straight or branched C1-10alkyl group, the above-described halogen-C1-4lower alkyl group, the above C1-4the lower alkoxygroup, the above C1-4the lower allylthiourea, the above substituted or an unsubstituted amino group, the above substituted or unsubstituted raidgroup, the above substituted or unsubstituted WITH3-10cycloalkyl group, the above substituted or unsubstituted WITH3-10cycloalkyl C1-10alkyl group, the above substituted or unsubstituted aryl group, the above substituted or unsubstituted aracelio group, the above substituted or unsubstituted arylalkyl group, the above substituted or unsubstituted killigrew, the above substituted or unsubstituted 5 - or 6-membered heterocyclic group with 1-3 nitrogen atoms, oxygen, or sulfur, or the above-described substituted or unsubstituted 5 - or 6-membered heteroallyl group; alloctype containing the above-described substituted or unsubstituted straight or branched C1-10alkyl group, the above-described halogen-C1-4lower alkyl group, the above C1-4the lower alkoxygroup, the above C1-4the lower allylthiourea, the above substituted or unsubstituted WITH3-10cycloalkyl group, the above substituted or unsubstituted WITH3-10cycloalkyl C1-10alkyl group, the above substituted or unsubstituted aryl group, the above substituted or unsubstituted aracelio group, the above substituted or unsubstituted arylalkyl group, the above substituted or unsubstituted killigrew, the above substituted or unsubstituted 5 - or 6-membered heterocyclic group with 1-3 nitrogen atoms, oxygen, or sulfur, or the above-described substituted or unsubstituted 5 - or 6-membered heteroallyl group; aminocarbonylmethyl group which may be substituted by the above-described substituted or unsubstituted straight or branched C1-10alkyl group, the above-described halogen-C1-4lower alkyl group, the above C1-4lowest alkoxygroup, the above C1-4lowest alkylthiol, the above substituted or unsubstituted WITH3-10cycloalkyl group, the above substituted or unsubstituted WITH3-10cycloalkyl C1-10alkyl group, the above substituted or unsubstituted aryl group, wicheap Tilney group, the above substituted or unsubstituted 5 - or 6-membered heterocyclic group with 1-3 nitrogen atoms, oxygen, or sulfur, or the above-described substituted or unsubstituted 5 - or 6-membered heteroallyl group, thiocarbonyl group, containing the above-described substituted or unsubstituted straight or branched C1-10alkyl group, the above-described halogen-C1-4lower alkyl group, the above C1-4the lower alkoxygroup, the above C1-4the lower allylthiourea, the above substituted or an unsubstituted amino group, the above substituted or unsubstituted raidgroup, the above substituted or unsubstituted WITH3-10cycloalkyl group, the above substituted or unsubstituted WITH3-10cycloalkyl C1-10alkyl group, the above substituted or unsubstituted aryl group, the above substituted or unsubstituted aracelio group, the above substituted or unsubstituted arylalkyl group, the above substituted or unsubstituted killigrew, the above substituted or unsubstituted 5 - or 6-membered heterocyclic group with 1-3 nitrogen atoms, oxygen, or sulfur, or the above-described substituted or antamisen C1-4lower alkyl group or aryl group.

In particular, preferred as a straight or branched C1-10alkyl groups for R are methyl, ethyl, isopropyl, butyl, isobutyl, tert-butyl, heptyl, 1-propinball and 1-isobutyl-3-methylbutyl.

"C2-10alkenylphenol group with a straight or branched chain, called R, are preferably allyl, vinyl, Isopropenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-methyl-1-butenyl, crotyl, 1,3-dimethyl-2-butenyl, 1-pentenyl and 1-methyl-2-pentenyl.

"Halogen-C1-4the lower alkyl group" for R is C1-4lower alkyl group, particularly preferably a methyl group substituted by the above-described halogen atom, particularly preferably a fluorine atom and chlorine, and it is preferable triptorelin group.

"Substituted or unsubstituted WITH3-10cycloalkyl group" for R is C3-10cycloalkyl group (particularly preferably cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo, cycloheptanol, octahydronaphthalene, decahydronaphthalene, adamantly and bicyclo[2.2.1]heptylene), which may be substituted by 1-4 deputies is the super C1-8alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2,2-dimethylpropyl, 4-methylpentyl, 2-ethylbutyl or so on), the above-described straight or branched C2-10alkenylphenol group (particularly preferably C1-8alkenylphenol group such as 1-methylvinyl, 2-methylvinyl, 3-methyl-3-propenyl or similar), described above WITH3-10cycloalkyl group (particularly preferably3-7cycloalkyl groups, such as cyclopropyl, cyclopentyl, cyclohexyl, or similar ), described above WITH5-8cycloalkenyl group (particularly preferably5-6cycloalkenyl groups, such as cyclopentenyl, cyclohexenyl or similar), described above WITH3-10cycloalkyl C1-10alkyl group (particularly preferably3-7cycloalkyl C1-4alkyl groups, such as cyclopropylmethyl, 2-cyclopropylethyl, 2-cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl or so on), the above-described aryl group (particularly preferably phenyl groups), the carbonyl group, the above aranceles group (particularly preferably phenyl C1-4lower alkyl groups such as benzyl, phenethyl or etc.) and the above arylalkilether 2,2,3,3-tetramethylcyclopropane, 1-isopenicillin, 1-isopropylcyclohexane, 1-isobutylphenyl, 1-isopentenyladenine, 1-cyclohexylethylamine, cyclohexyl, 1-methylcyclohexyl, 1-ethylcyclohexyl, 1-propylcyclohexyl, 1-isopropylcyclohexane, 1-butylcyclohexyl, 1-isobutyryloxy, 1-pentylcyclohexyl, 1-isopentenyladenine, 1-(2,2-dimethylpropyl)cyclohexyl, 1-(4-methylpentyl)-cyclohexyl, 1-(2-ethylbutyl)cyclohexyl, 4-tert-butyl-1-isopentenyladenine, 1-cyclopropylmethyl, 1-bicyclohexyl, 1-phenylcyclohexyl, 1-cyclopropylmethoxy, 1-cyclohexylethylamine, 1-(2-cyclopropylethyl)cyclohexyl, 1-(2-cyclopentylmethyl)cyclohexyl, 1-(2-cyclohexylethyl)cyclohexyl, 4-methylcyclohexyl, 4-propylcyclohexyl, 4-isopropylcyclohexane, 4-tert-butylcyclohexyl, 4-pentylcyclohexyl, 4-bicyclohexyl, 1-isopentenyladenine, 3A-octahedrons, 4A-decahydronaphthalene, 1-substituted and 7,7-dimethyl-1-(2-oxo)-bicyclo[2.2.1] heptyl. Place of substitution is not particularly limited, but, in particular preferably in position 1. Can be used any of the above described replacement group, but preferred a straight or branched C1-10alkyl group.

Deputy for the "substituted or unsubstituted C5-8cycloalken/SUB> cycloalkyl group". In particular, it means cycloalkenyl group (especially cyclopentenyl and cyclohexenyl), which may have 1-4 substituent selected from the above-described straight or branched C1-10alkyl group (particularly preferably C1-8alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, 2,2-dimethylpropyl, 4-methylpentyl or so on), the above-described straight or branched C2-10alkenylphenol group (particularly preferably2-8Alchemilla group such as 1-methylvinyl, 2-methylvinyl, 3-methyl-3-propenyl and so on), described above WITH3-10cycloalkyl group (particularly preferably3-7cycloalkyl group, such as cyclopropyl, cyclopentyl, cyclohexyl, or similar ), the above C5-8cycloalkenyl group (particularly preferably C5-6cycloalkenyl group, such cyclopentenyl, cyclohexenyl or similar), described above WITH3-10cycloalkyl C1-10alkyl group (particularly preferably3-7cycloalkyl C1-4lower alkyl group, such as cyclopropylmethyl, 2-cyclopropylethyl, 2-cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl or similar), videopal group (particularly preferably phenyl C1-4lower alkyl group, such as benzyl, phenethyl or similar), and arylalkylamines group (particularly preferably 2-phenylphenyl). Preferred examples cycloalkenyl groups include 1-isopropyl-2-cyclopentenyl, 1-isopropyl-3-cyclopentenyl, 1-isobutyl-2-cyclopentenyl, 1-isobutyl-3-cyclopentenyl, 1-isopentyl-2-cyclopentenyl, 1-isopentyl-3-cyclopentenyl, 1-cyclohexylmethyl-2-cyclopentenyl, 1-cyclohexylmethyl-3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-methyl-2-cyclohexenyl, 1-methyl-3-cyclohexenyl, 1-ethyl-2-cyclohexenyl, 1-ethyl-3-cyclohexenyl, 1-propyl-2-cyclohexenyl, 1-propyl-3-cyclohexenyl, 1-isopropyl-2-cyclohexenyl, 1-isopropyl-3-cyclohexenyl, 1-butyl-2-cyclohexenyl, 1-butyl-3-cyclohexenyl, 1-isobutyl-2-cyclohexenyl, 1-isobutyl-3-cyclohexenyl, 1 pentyl-2-cyclohexenyl, 1 pentyl-3-cyclohexenyl, 1-isopentyl-2-cyclohexenyl, 1-isopentyl-3-cyclohexenyl, 1-(2,2-dimethylpropyl)-2-cyclohexenyl, 1-(2,2-dimethylpropyl)-3-cyclohexenyl, 1-(4-methylpentyl)-2-cyclohexenyl, 1-(4-methylpentyl)-3-cyclohexenyl, 1-cyclopropyl-2-cyclohexenyl, 1-cyclopropyl-3-cyclohexenyl, 1-cyclohexyl-2-cyclohexenyl, 1-cyclohexyl-3-cyclohexenyl, 1-phenyl-2-cyclohexenyl, 1-phenyl-3-cyclohexenyl, 1-cyclopropylmethyl the-cyclohexenyl, 1-(2-cyclopropylethyl)-2-cyclohexenyl, 1-(2-cyclopropylethyl)-3-cyclohexenyl, 1-(2-cyclopentylmethyl)-2-cyclohexenyl, 1-(2-cyclopentylmethyl)-3-cyclohexenyl, 1-(2-cyclohexylethyl)-2-cyclohexenyl and 1-(2-cyclohexylethyl)-3-cyclohexenyl. There are no particular restrictions on the position of substitution, but especially preferred position is position 1. You can use any of the above substituents, but particularly preferred is a straight or branched1-10an alkyl group or3-10cycloalkyl C1-4alkyl group.

"Substituted or unsubstituted WITH3-10cycloalkyl C1-10alkyl group" for R is C3-10cycloalkyl C1-10alkyl group (particularly preferably cyclohexylmethyl, 1-cyclohexylethyl, 1-cyclohexyl-1-methylethyl, 1-cyclohexyl-2-methylpropyl, 1-cyclohexyl-3-methylbutyl, 1-cyclohexylethyl, 1-cyclohexyl-4-methylpentyl and 1-cyclohexylethyl), C1-10an alkyl group which is straight or branched and which may have 1-4 substituent selected from the above C3-10cycloalkyl group (particularly preferably3-7cycloalkyl group, such as cyclopentyl or cyclohexyl), the above C1-10alkyl part. Preferred examples3-10cycloalkyl C1-10alkyl groups include cyclohexylmethyl, 1-cyclohexylethyl, cyclohexyltrichlorosilane, dicyclohexylmethyl, 1-cyclohexyl-1-methylethyl, 1-cyclohexyl-2-methylpropyl, 1-cyclohexyl-3-methylbutyl, 1-cyclohexyl-4-methylpentyl, 1-cyclohexylethyl and 1-cyclohexylethyl.

"Substituted or unsubstituted aryl group" for R is aryl group (particularly preferably phenyl group) which may have 1-4 substituent selected from the above-described straight or branched C1-6alkyl group (particularly preferably tert-bucilina group), the above-described halogen atom (particularly preferably fluorine and chlorine) and nitro group. Preferred examples of aryl groups are phenyl, 2-chlorophenyl, 4-nitrophenyl and 3,5-di-tert-butylphenyl.

"Substituted or unsubstituted aralkyl" for R means aracelio group (particularly preferably benzyl, benzhydryl, trityl), which may have substituents selected from the above atom Galaga alkyl group is straight or branched. There are no particular restrictions on the position of substitution. Straight or branched C1-4the lower alkyl part may be substituted. Preferred examples aranceles groups are benzyl, trityl.

"Substituted or unsubstituted 5 - or 6-membered heterocyclic group having 1-3 nitrogen atom, oxygen or sulfur, R is the above-described heterocyclic group which may have 1-4 substituent selected from the above-described straight or branched C1-6alkyl group (particularly preferably tert-bucilina group), the above-described halogen atom (particularly preferably fluorine and chlorine) and nitro group. The heterocyclic group preferably is an aromatic heterocyclic group, particularly preferably furyl, thienyl and pyridyl.

"Substituted or unsubstituted straight or branched C1-10alkyl group" for R is a straight or branched C1-10alkyl group which may have a Deputy, selected from the above-described halogen atom (particularly preferably fluorine and chlorine), the above C1-4low alkoxygroup (particularly preferably metoxygroup), an amino group, kotoryi group), the above-described acyl group (particularly preferably acetyl group) or a hydroxyl group, the above C1-4low allylthiourea (in particular preferably of metalcorp), carbamoyl, hydroxyl group, alloctype having the above-described acyl group (particularly preferably acetyloxy), carboxyl group, acyl group (particularly preferably methoxycarbonyl group) and alloctype having the above-described substituted or unsubstituted aryl group (particularly preferably fenoxaprop and 4 chlorophenoxy group). Preferred examples of alkyl groups include methyl, chloromethyl, ethyl, isopropyl, 1-methyl-2-pentyl, octyl, methoxyethyl, dimethylaminomethyl, acetamidomethyl, 1-acetylamino, 1-acetylamino-2-methylpropyl, 1-acetylamino-3-methylbutyl, 1-acetylamino-3-metaltipped, 1-acetylamino-3-carbamoylmethyl, 1-hydroxy-1-methylethyl, 1 atomic charges of-1-methylethyl, 4-carboxybutyl, 2-methoxycarbonylethyl, phenoxymethyl and 4-chlorphenoxamine.

The preferred "C1-4lowest alkoxygroup" for R is a methoxy group and tert-butoxypropan.

The preferred "C1-4lowest alkylthiophene" DL is which may have a Deputy, selected from the above C1-4lower alkyl group (particularly preferably ethyl, isopropyl and tert-butyl), the above-described acyl group (particularly preferably acetyl and benzoyl), and the above-described aryl group (particularly preferably phenyl and 4-methoxyphenyl) that can be substituted for the above1-4lowest alkoxygroup. Preferred examples of the amino group are ethylamino, isopropylamino, tert-butylamino, phenylamino and 4 methoxybenzylamine.

"Substituted or unsubstituted raidgroup" for R means raidgroup, which may have a Deputy, selected from the above C1-4lower alkyl group (particularly preferably methyl and ethyl), the above-described acyl group (particularly preferably acetyl and benzoyl), and the above-described aryl group (particularly preferably phenyl and 4-methoxyphenyl) that can be substituted for the above 1-4lowest alkoxygroup, and preferred is N,N'-diphenylurea.

"Substituted or unsubstituted WITH3-10cycloalkyl group" for R is C3-10cycloalkyl group (particularly preferably cyclopropyl and cyclohexyl), which is lastnosti preferably methyl, tert-butyl and isopentyl), an amino group, an amino group (particularly preferably methylamino, ethylamino, acetylamino, benzoylamino), which can be substituted for the above C1-4lower alkyl or acyl groups. Preferred examples cycloalkyl groups are cyclopropyl, cyclohexyl, 1-methylcyclohexyl, 1-isopentenyladenine, 1-aminocyclohexane, 1-acetylaminophenol and 4-tert-butylcyclohexyl.

"Substituted or unsubstituted WITH3-10cycloalkyl C1-10alkyl group" for R is C3-10cycloalkyl C1-10alkyl group which may have a Deputy, selected from the above C3-10cycloalkyl group (particularly preferably cyclopentyl and cyclohexyl), described above WITH5-8cycloalkenyl group (particularly preferably cyclopentenyl and cyclohexenyl) and the above-described aryl group (particularly preferably phenyl group), and in which C1-10alkyl portion is straight or branched. There are no particular restrictions on the position of substitution. Straight or branched C1-10alkyl part may be substituted. Preferred as3-10cycloalkyl C1-10alkyl UB> means aryl group (particularly preferably phenyl and naphthyl) which may have a Deputy, selected from the above-described straight or branched C1-6alkyl group (particularly preferably methyl and tert-bucilina group), the above-described halogen atom (particularly preferably fluorine and chlorine), nitro, hydroxyl group, the above C1-4low alkoxygroup (particularly preferably a methoxy group) and the above-described acyl group (particularly preferably 2-(1-isopentenyladenosine)phenylthiocarbamyl group). Preferred examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2,6-dimetilfenil, 2-methoxyphenyl, 2-nitrophenyl, 4-nitrophenyl, 3,5-di-tertbutyl-4-hydroxyphenyl and 4-[2-(1-isopentenyladenosine) phenylthiocarbamyl] phenyl.

"Substituted or unsubstituted kalkilya group" for R1means aracelio group (particularly preferably benzyl, phenethyl, 3-inproper, naphthylmethyl and biphenylyl), which may have a Deputy, selected from the above-described halogen atom (particularly preferably fluorine and chlorine), nitro, amino groups (in particular prepensionamento), which may be substituted by the above-described1-4lower alkyl group or the above-described acyl group, and hydroxyl group, and in which C1-4the lower alkyl group is straight or branched. There are no particular restrictions on the position of substitution. Straight or branched C1-4the lower alkyl part may be substituted. Preferred examples aranceles groups include benzyl, phenetyl, 3-phenylpropyl, 2-naphthylmethyl, 4-biphenylyl, benzhydryl, 2-chloroformate, 3-chloroformate, 4-chloroformate, 2-nitrophenyloctyl, 4-nitrophenolate, 2-pivaloyloxymethyl, 2-(1-methylcyclohexanecarboxylic)phenylmethyl, 2-tert-butoxycarbonylmethylene, 3-acetylaminophenol, 3-(1-methylcyclohexanecarboxylic) phenylmethyl-aminobenzyl-acetylaminobenzoic, -(1 methylcyclohexanecarboxylic)benzyl, -benzylaminopurine-aminophenethyl, -acetylaminophenol and 1-acetylamino-2-(4-hydroxyphenyl)ethyl.

"Substituted or unsubstituted arylalkylamine group" for R1means arylalkyl group (in particular, phenylphenyl), which may have a Deputy, selected from the above-described straight or branched C1-6lower alkyl group (in particular preferred is the group and hydroxyl group, and preferred is 2-fenilvinil group.

"Substituted or unsubstituted aristocrata for R1means killigrew (particularly preferably phenylthiourea), which may have a Deputy, selected from the above-described halogen atom (particularly preferably fluorine and chlorine), nitro group and amino group which may be substituted by the above C1-4lower alkyl group or the above-described acyl group (particularly preferably amino, acetylamino, paulolino, 1 methylcyclohexanecarboxylic and benzoylamine), hydroxyl group and the above-described halogen-C1-4lower alkyl group (particularly preferably triptorelin group). Preferable examples of aristocraty include phenylthio, 2-pihlajaniemi, 2-(1-methylcyclohexanecarboxylic)phenylthio and 2-(1-methylcyclohexanecarboxylic-4-trifluoromethyl)phenylthio.

"Substituted or unsubstituted 5 - or 6-membered heterocyclic ring group with 1-3 nitrogen atoms, oxygen or sulfur for R1mean heterocyclic ring group (particularly preferably an aromatic heterocyclic group, such as Perl deputies, selected from the above-described straight or branched C1-6alkyl group (particularly preferably a methyl group), halogen atom (particularly preferably fluorine and chlorine), the above-described acyl group (particularly preferably acetyl and benzoyl), and the carbonyl group. Preferred examples of them are 3-pyridyl, 1-methyl-4-piperidyl, 1-acetyl-4-piperidyl, 5-oxo-2-pyrrolidinyl, 1-acetyl-2-pyrrolidinyl and 1-benzoyl-2-pyrrolidinyl. Particularly preferred 4-piperideine group such as 1-methyl-4-piperideine or 1-acetyl-4-piperideine group.

"Substituted or unsubstituted 5 - or 6-membered heteroallyl group" for R1means above heteroallyl group (particularly preferably 2-anilina group), which may be substituted by the above-described straight or branched1-6alkyl group (particularly preferably a methyl group) and the above-described halogen atom (particularly preferably fluorine and chlorine). Preferred 2-anilina group.

"Substituted or unsubstituted C1-4the lower alkyl group" for R2means C1-4lower alkyl group (particularly preferably a methyl group), the cat is occhialino the methoxy group), amino group which may be substituted by the above C1-4lower alkyl or acyl group (particularly preferably dimethylaminopropoxy), the above C1-4low allylthiourea (in particular preferably of metalcorp), carbamoyl, hydroxyl group, carboxyl group, the above-described acyl group (particularly preferably methoxycarbonyl group) and the above-described heterocyclic group (particularly preferably an aromatic heterocyclic group, such as thienyl, or non-aromatic heterocyclic group, such as tetrahydrofuryl). It is preferable tetrahydropyrimidine group.

"Substituted or unsubstituted aryl group" for R2is the same as the group R1. Preferred examples are phenyl group, halogenated phenyl group, acylaminoalkyl phenyl group, etc.

"Halogen atom" for X1X2, X3and X4means a halogen atom, including fluorine, chlorine, bromine, etc., preferably fluorine and chlorine.

The preferred "C1-4the lower alkyl group for X1X2, X3and X4aulav> and X4means C1-4lower alkyl group (particularly preferably a methyl group), substituted by the above-described halogen atom (particularly preferably fluorine and chlorine). Preferred triptorelin group.

The preferred "C1-4lowest alkoxygroup" X1X2, X3and X4is the methoxy group.

Preferred "acyl group" for X1, X2, X3and X4is benzoline group.

Preferred "aryl group" for X1, X2, X3and X4is a phenyl group.

"1-substituted C3-10cycloalkyl group" for R" means cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, preferably C5-7cycloalkyl group, particularly preferably tsiklogeksilnogo group), which is substituted in position 1 by substituents selected from the above-described straight or branched C1-4alkyl group (particularly preferably C1-6alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, 2,2-dimethylpropyl, 4-methylpentyl or 2-ethylbutyl), videopia the Naya group, such as 1-methylvinyl, 2-methylvinyl or 3-methyl-3-propenyl), described above WITH3-10cycloalkyl (particularly preferably3-7cycloalkyl group, such as cyclopropyl, cyclopentyl or cyclohexyl), the above C5-8cycloalkenyl group (particularly preferably C5-6cycloalkenyl group, such as cyclopentenyl or cyclohexenyl), described above WITH3-10cycloalkyl C1-10alkyl group (particularly preferably3-7cycloalkyl C1-4lower alkyl group, such as cyclopropylmethyl, 2-cyclopropylethyl, 2-cyclopentylmethyl, cyclohexylmethyl or 2-cyclohexylethyl), the above-described aryl group (particularly preferably phenyl group), the above aranceles group (particularly preferably phenyl C1-4lower alkyl group, such as benzyl and phenethyl) and arylalkylamines group (particularly preferably 2-phenylphenyl). Preferred examples of the 1-substituted-C3-10cycloalkyl groups include 1-isopenicillin, 1-isopropylcyclohexane, 1-isobutylphenyl, 1-isopentenyladenine, 1-cyclohexylethylamine, 1-methylcyclohexyl, 1-ethylcyclohexyl, 1-propylcyclohexyl, 1-isopropylcyclohexane, logical, 1-(4-methylpentyl)cyclohexyl, 1-(2-ethylbutyl)cyclohexyl, 1-cyclopropylmethyl, 1-bicyclohexyl, 1-phenylcyclohexyl, 1-cyclopropylmethoxy, 1-cyclohexylethylamine, 1-(2-cyclopropylethyl)cyclohexyl, 1-(2-cyclopentylmethyl) cyclohexyl, 1-(2-cyclohexylethyl)cyclohexyl and 1-isopentenyladenine. Straight or branched C1-10an alkyl group is particularly preferred as the substituent in position 1.

"1-substituted-C5-8cycloalkenyl group" for R" means cycloalkenyl group (particularly preferably C5-6cycloalkenyl group, such as cyclopentenyl or cyclohexenyl), which is substituted in position 1 by substituents selected from the above-described straight or branched C1-10alkyl group (particularly preferably C1-8alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, 2,2-dimethylpropyl and 4-methylpentyl), the above-described straight or branched C2-10alkenylphenol group (particularly preferably2-8Alchemilla group such as 1-methylvinyl, 2-methylvinyl or 3-methyl-3-propenyl), described above WITH3-10cycloalkyl group (particularly preferably3-75-6cycloalkenyl group, such as cyclopentenyl or cyclohexenyl), described above WITH3-10cycloalkyl C1-10alkyl group (particularly preferably3-7cycloalkyl C1-4lower alkyl group, such as cyclopropylmethyl, 2-cyclopropylethyl, 2-cyclopentylmethyl, cyclohexylmethyl or 2-cyclohexylethyl), the above-described aryl group (particularly preferably phenyl group), the above aranceles group (particularly preferably phenyl C1-4lower alkyl group, such as benzyl or phenethyl) and above arylalkylamines group (particularly preferably 2-fenilvinil group). Preferred examples of the 1-substituted-C5-8cycloalkenyl groups include 1-isopropyl-2-cyclopentenyl, 1-isopropyl-3-cyclopentenyl, 1-isobutyl-2-cyclopentenyl, 1-isobutyl-3-cyclopentenyl, 1-isopentyl-2-cyclopentenyl, 1-isopentyl-3-cyclopentenyl, 1-cyclohexylmethyl-2-cyclopentenyl, 1-cyclohexylmethyl-3-cyclopentenyl, 1-methyl-2-cyclohexenyl, 1-methyl-3-cyclohexenyl, 1-ethyl-2-cyclohexenyl, 1-ethyl-3-cyclohexenyl, 1-propyl-2-cyclohexenyl, 1-propyl-3-cyclohexenyl, 1-isopropyl-2-cyclohexenyl, 1-isopropyl-3-cyclohexenyl, 1-butyl-2-cyclohexenyl, 1-butyl-3-cyclohexadienyl-2-cyclohexenyl, 1-isopentyl-3-cyclohexenyl, 1-(2,2-dimethylpropyl)-2-cyclohexenyl, 1-(2,2-dimethylpropyl)-3-cyclohexenyl, 1-(4-methylpentyl)-2-cyclohexenyl, 1-(4-methylpentyl)-3-cyclohexenyl, 1-cyclopropyl-2-cyclohexenyl, 1-cyclopropyl-3-cyclohexenyl, 1-cyclohexyl-2-cyclohexenyl, 1-cyclohexyl-3-cyclohexenyl, 1-phenyl-2-cyclohexenyl, 1-phenyl-3-cyclohexenyl, 1-cyclopropylmethyl-2-cyclohexenyl, 1-cyclopropylmethyl-3-cyclohexenyl, 1-cyclohexylmethyl-2-cyclohexenyl, 1-cyclohexylmethyl-3-cyclohexenyl, 1-(2-cyclopropylethyl)-2-cyclohexenyl, 1-(2-cyclopropylethyl)-3-cyclohexenyl, 1-(2-cyclopentylmethyl)-2-cyclohexenyl, 1-(2-cyclopentylmethyl)-3-cyclohexenyl, 1-(2-cyclohexylethyl)-2-cyclohexenyl and 1-(2-cyclohexylethyl)-3-cyclohexenyl. Straight or branched C1-10an alkyl group is particularly preferred as the substituent in position 1.

"Proletarienne derivative" refers to derivatives of the compounds of the present invention, which has a chemically or metabolically degradiruem group that exhibit pharmaceutical activity in the degradation by hydrolysis or solvolysis or under physiological conditions.

"Pharmaceutically acceptable salt" refers to any compound that predstavlyayou salts include salts of inorganic acids, such as hydrochloride, hydrobromide, hydroiodide, sulfates, nitrates, phosphates, carbonates, bicarbonates or perchlorate; organic acid salts such as formate, acetate, triptoreline, propionate, tartratami, glycolate, succinate, lactates, maleate, hydroxylate, methylmaleic, fumarate, adipate, tartratami, malaty, citrates, benzoate, cinnamate, ascorbates, salicylates, 2-acetoxybenzoic, nicotinate or isonicotinate; sulfonates, such as methanesulfonate, econsultancy, isothionate, bansilalpet, p-toluensulfonate or naphthalenesulfonate; salts of acidic amino acids, such as asparate or glutamate; alkali metal salts, such as salts of sodium or potassium, salts of alkaline earth metals such as magnesium salts or calcium salts; ammonium salts; salts of organic bases, such as trimethylamine, triethylamine, pyridine salts, picoline salts, salts dicyclohexylamine or salts of N,N'-dibenziletilendiaminom; and salts of amino acids such as lysine salt or salts of arginine. Depending on circumstances, can be used to hydrate or solvate with alcohols.

In particular 1-isobutyryloxy group, 1-(2-ethyl-butyl)tsiklogeksilnogo group and 1-isopentenyladenosine group about the especially preferred as X1X2, X3and X4and isobutylene group and 1-acetyl-4-piperidinecarboxylate group is especially preferred as z

The compound of the present invention inhibits the activity of HATB, and it is assumed that it represents the unknown in the traditional sense a new type of preventive or therapeutic agent for treatment of hyperlipidemia or atherosclerosis diseases.

When used as a pharmaceutical compound of this invention represented by formula (I) or its pharmaceutically acceptable salt may typically be used together with known pharmaceutically acceptable carriers, fillers, diluents, (dry) diluents, disintegrators, stabilizers, preservatives, buffers, emulsifiers, flavorings, dyes, classicisme that increase the viscosity by means of improving the taste of means, solubilization and other additives. In particular, the connection can be formulated in dosage forms such as tablets, pills, powders, granules, suppositories, injections, eye drops, liquid medicines, capsules, tablets (pellets), aerosols, elixirs, suspensions, etilenglikol, glyceroltrinitrate gelatin, lactose, carbohydrates such as starch, magnesium stearates, talc, lanolin and vaseline, and these dosage forms can be used orally or parenterally.

The abovementioned pharmaceutical preparations containing the compound of this invention represented by formula (I) or its pharmaceutically acceptable salt in an amount effective for inhibiting the activity of HATB and treatment of hyperlipidemia, atherosclerotic disease or similar diseases attributed to the activity of HATB. The person skilled in the art can easily determine the effective amount.

Doses can vary depending on the type and severity of diseases, the compounds to be used, route of administration, age, sex and body weight of patients. In the case of oral administration is usually desirable to use the compound (I) an adult individual in an amount of 1-1000 mg, in particular 50-800 mg / day.

The compound of this invention can be obtained using the following method, but it goes without saying that the method of obtaining the compounds of the present invention is not limited in this way (see diagram at the end of the description).

[Stase) can be synthesized by reacting compound (VI) (in the formula, X1X2, X3and X4such as described above) with the compound (XII) (in the formula, X represents a halogen atom and R and Y are as described above) in the presence of a base, such as pyridine, triethylamine, N-methylmorpholine or N-methylpiperazine, in an organic solvent such as methylene chloride, chloroform, toluene, ether, tetrahydrofuran, dioxane, diisopropyl ether, dimethoxyethane or hexane, water, or mixtures of these solvents, or in the absence of solvent, at a temperature of from cooling to heating.

The compound (III-2) can be synthesized from the compound (II-2) using the following stage 2.

[Stage 2]

The compound (III-2) (in the formula, R, X1, X2, X3, X4and Y are as described above) can be synthesized by allowing the compound (II-2) (in the formula, R, X1X2, X3, X4and Y are as described above) to react in the presence of a reducing agent such as sodium borohydride, lithium borohydride, sociallyengaged, triphenylphosphine, zinc or tin, in an organic solvent, such as methanol, ethanol, ether, dioxane, tetrahydrofuran, diisopropyl ether, dimethoxyethane, toluene, hexane, acetone, or Acadiana (II-2) or (IV-2) can be synthesized from compound (III-2), using the following stages 3 or 4.

[Stage 3]

The compound (II-2) (in the formula, R, X1, X2, X3, X4and Y are as described above) can be synthesized by allowing the compound (III-2) (in the formula, R, X1X2, X3, X4and Y are as described above) to react in the presence of oxidizing means, such as iodine, hydrogen peroxide, potassium permanganate or dimethylsulfoxide, in an organic solvent, such as methanol, ethanol, ether, dioxane, tetrahydrofuran, diisopropyl ether, dimethoxyethane, acetone, toluene, hexane, dimethylformamide or acetic acid, water or mixtures of these solvents, or in the absence of solvent, at a temperature of from cooling to heating.

[Stage 4]

The compound (IV-2) (in the formula R, R1X1, X2, X3, X4, Y and Y1are as described above) can be synthesized by reacting compound (III-2) (in the formula, R, X1, X2, X3, X4and Y are as described above) with galogenangidridy 1-YX (in the formula, R1X and Y such as described above), the isocyanate R1-NY (in the formula, R1and Y such as described above), galogenangidridy coal is you R1-S-YX (in the formula, R1X and Y such as described above), in the presence of a base, such as pyridine, triethylamine, N-methylmorpholine or N-methylpiperazine, in an organic solvent such as methylene chloride, chloroform, toluene, ether, dioxane, tetrahydrofuran, diisopropyl ether, dimethoxyethane or hexane, water, or mixtures of these solvents, or in the absence of solvent, at a temperature of from cooling to heating. Alternatively, the compound (IV-2) can be synthesized by reacting compound (III-2) with a carboxylic acid R1-COOH (in the formula, R1such as described above) or thiocarbonic acid R1-YSH (in the formula, R1and Y such as described above), using a bonding agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, dicyclohexylcarbodiimide, diphenylphosphoryl or carbonyldiimidazole, in the presence of an activating agent, if required, such as 1-hydroxybenzotriazole, hydroxysuccinimide or imide, N-hydroxy-5-norbornene-2,3-dicarboxylic acid, in an organic solvent, such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, carbon tetrachloride or toluene, or mixtures of these solvents, prreteen). In addition, the compound (IV-2) can be synthesized by reacting compound (III-2) with a carboxylic acid R1-COOH (in the formula, R1such as described above) in the presence of a base such as triethylamine or pyridine and in the presence of atilglukuronida or so on, in an organic solvent such as ethyl acetate, or tetrahydrofuran, or mixtures of these solvents, at a temperature of from cooling to heating. When R1has a carboxyl group, above this stage can be done using the appropriate ester, receiving the connection by acid hydrolysis, using a known method.

The compound (IV-2) can also be obtained in the future by holding stage 4 after the above stage 2 or below stage 7, or following stage 10, without isolating the compound (III-2).

The compound (V-2) can be synthesized by carrying out the following stages 5 or 5'. Stage 5 is suitable, especially when R2represents a lower alkyl group which may have substituents, and stage 5' suitable, especially when R2represents an aryl group which may have substituents.

[Stage 5]

The compound (V-2) (in the formula R, R2X-X (in the formula, R2and X such as described above) and the sulfur compound such as sodium thiosulfate, interact in an organic solvent, such as ethanol, methanol, tetrahydrofuran, dioxane, dimethoxyethane, acetone or acetonitrile, water or mixtures of these solvents at room temperature before heating, and adding the compound (III-2) (in the formula, R, X1, X2, X3X4and Y such as described above) and an aqueous solution of a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium bicarbonate, to the resulting solution at a temperature of from cooling with ice to heat.

[Stage 5']

The compound (V-2) (in the formula R, R2X1, X2, X3, X4and Y such as described above) can be synthesized by reacting R2-SH (in the formula, R2such as described above) with trimethylsilylimidazole in carbon tetrachloride at a temperature of from cooling with ice to room, adding to the resulting solution of the reaction mixture, representing the result of the interaction of the compound (II-2) (in the formula, R, X1, X2, X3, X4and Y such as described above) with sulfurylchloride in carbon tetrachloride in the presence of a base, takotna, and providing the opportunity to interact mixture.

In addition, the compound (III-2) can be synthesized using the following schema.

[Stage 6]

The compound (XI) (in the formula, R, X1X2, X3, X4and Y such as described above) can be synthesized by reacting compound (X) (in the formula, X1, X2, X3and X4such as described above) with the compound (XII) (in the formula, R, X, and Y such as described above) in the presence of a base, such as pyridine, triethylamine, N-methylmorpholine or N-methylpiperazine, in an organic solvent such as methylene chloride, chloroform, toluene, ether, dioxane, tetrahydrofuran, diisopropyl ether, dimethoxyethane or hexane, in water or in mixtures of these solvents, or in the absence of solvent, at a temperature of from cooling to heating.

[Stage 7]

The compound (III-2) (in the formula, R, X1X2, X3, X4and Y such as described above) can be synthesized, by subjecting compound (XI) (in the formula, R, X1, X2, X3, X4and Y such as described above) interaction in the presence of a base such as sodium acetate, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or bicarb the ether or diisopropyl ether, water or a mixture of these solvents, at a temperature of from ice cooling to heating.

In addition, the compound (III-2) can be synthesized according to the following scheme.

[Step 8]

The compound [VIII] (in the formula, R11and R12may be the same or different and represent a lower alkyl group such as methyl or ethyl, and X1X2, X3, X4are as described above) can be synthesized by reacting compound (VII) (in the formula, X1, X2, X3and X4such as described above) with the compound (XIII) (in the formula, R11and R12and X such as described above) in the presence of a base such as sodium hydride, triethylamine or N-methylmorpholine, in an organic solvent, such as dimethylformamide, tetrahydrofuran, dioxane or dimethoxyethane, or in mixtures of these solvents, at a temperature of from cooling to heating, and allowing the resulting product to react in an organic solvent, such as phenyl ether or sulpholane, or in mixtures of these solvents, or in the absence of a solvent under heating.

[Stage 9]

The compound (IX) (in the formula R, R11and R12X1, X2, X3, X4, X2, X3and X4such as described above) to interact in the presence of a reducing agent such as ferrous chloride of tin, zinc, iron, dithionite sodium, sodium sulfide or disulfide sodium, in an organic solvent such as ethyl acetate, acetic acid, methanol, ethanol, tetrahydrofuran, dioxane, diisopropyl ether, dimethoxyethane or toluene, water, or mixtures of these solvents, at a temperature of from cooling to heating, and by reacting the resulting product with the compound (XII) (in the formula, R, X and Y, such as described above) in the presence of a base, such as pyridine, triethylamine, N-methylmorpholine or N-methylpiperazine, in an organic solvent such as chloroform, methylene chloride, tetrahydrofuran, ether, dioxane, diisopropyl ether, dimethoxyethane, toluene or hexane, water, or mixtures of these solvents, or in the absence of solvent, at a temperature of from cooling to heating.

[Stage 10]

The compound (III-2) (in the formula, R, X1, X2, X3, X4and Y such as described above) can be obtained by allowing the compound (IX) (in the formula R, R11and R12X1X2, X3, X4and Y such as described above) collaboration is or sodium bicarbonate, in an organic solvent, such as methanol, ethanol, tetrahydrofuran, dioxane, dimethoxyethane, ether or diisopropyl ether, water or a mixture of these solvents, at a temperature of from cooling to heating.

In addition, the compound (VI) can be synthesized from compound (VIII) with the help of stage 11.

[Stage 11]

The compound (VI) (in the formula, X1, X2, X3and X4such as described above) can be synthesized by allowing the compound (VIII) (in the formula, R11and R12X1, X2, X3and X4such as described above) to react in the presence of a reducing agent such as ferrous chloride of tin, zinc, iron, ditional sodium, sodium sulfide and sodium disulfide, in an organic solvent such as ethyl acetate, acetic acid, methanol, ethanol, ether, tetrahydrofuran, dioxane, diisopropyl ether, dimethoxyethane and toluene, water or a mixture of these solvents, at a temperature of from cooling to heating, giving the resulting product to interact in the presence of a base such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate or sodium bicarbonate, in organic solvents, such as methane is ritala, at a temperature of from cooling to heating, and allowing the product to react in the presence of oxidizing means, such as iodine, hydrogen peroxide, potassium permanganate or dimethylsulfoxide, in an organic solvent, such as methanol, ethanol, ether, dioxane, tetrahydrofuran, diisopropyl ether, dimethoxyethane, acetone, toluene, hexane, dimethylformamide or acetic acid, water or mixtures of these solvents, or in the absence of solvent, at a temperature of from cooling to heating.

Thus obtained compound (I) can be extracted and cleaned using a well known method for separation and purification such as concentration, concentration under reduced pressure, extraction, crystallization, recrystallization or chromatography. The compound of this invention contains one or more stereoisomers due to the presence of asymmetric carbon. Such isomers and mixtures thereof, all included in the scope of this invention.

The best way of carrying out the invention

Below the present invention is explained in detail, referring to examples and the example test, but the present invention is not limited with this.

Example 1

Synthesis of bis-[2-(beer is carbonyl, Z = 2-(paulolino) phenylthio)

Step 1) a Mixture of bis-(2-AMINOPHENYL) disulfide (8.00 g), pyridine (6.5 ml) and chloroform (150 ml) was stirred at 0oWith and to it added dropwise pivaloate (83 ml). When you are finished adding the organic layer is washed with water and saturated salt solution. After drying the organic layer over anhydrous sodium sulfate and evaporation to obtain a solid substance. The thus obtained solid substance was washed with a mixture of ether-hexane and collected by filtration, obtaining the desired compound (of 11.15 g, yield: 83%).

Example 2

Synthesis of bis-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate]phenyl] disulfide (formula (I); R = 1-(2-ethylbutyl)cyclohexyl, X1X2, X3, X4= a hydrogen atom, Y = carbonyl, Z = 2-[1-(2-ethylbutyl)cyclohexanecarboxylate]phenylthio).

i) Suspension of 60% sodium hydride (980 mg) in tetrahydrofuran (80 ml) was stirred at room temperature and added dropwise a solution of tetrahydrofuran (10 ml) containing cyclohexanecarbonyl acid (3.00 g). After complete addition, the mixture is stirred for 1 hour and cooled to 0oC, followed by adding the mixture dropwise of a solution of cyclohexane (18.7 ml), containing 1.5 M esopoWith added dropwise a solution of tetrahydrofuran (10 ml) containing 1-bromo-2-ethylbutane (with 4.64 g). The solution is gradually warmed to room temperature and stirred over night. This reaction solution was added water and 10% solution of the hydrochloride and the solution extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After drying the resulting solution was concentrated, obtaining 1-(2-ethylbutyl)cyclohexanecarbonyl acid (3,17 g, yield: 64%).

ii) a Mixture of 1-(2-ethylbutyl)cyclohexanecarboxylic acid (1.50 g) obtained above in (i), oxalicacid of 0.85 ml), methylene chloride (20 ml) and a small amount of dimethylformamide is stirred at room temperature for 1 hour, concentrated under reduced pressure, obtaining 1-(2-ethylbutyl)cyclohexanecarbonitrile in the form of a crude product.

Stage 1) Solution of pyridine (20 ml) containing bis-(2-AMINOPHENYL)disulfide (825 mg), stirred at room temperature and added dropwise crude 1-(2-ethylbutyl)cyclohexanecarboxylate obtained above in (ii). After complete addition the solution is stirred over night at 100oC. After concentration under reduced giving the Ute saturated saline and dried over anhydrous sodium sulfate and then concentrated. The resulting residue is purified by using column chromatography on silica gel (manifesting solvent hexane: ethyl acetate = 15:1) to give the desired compound (667 mg, yield: 32%).

Examples 3-8

The compounds shown in tables 1 and 2, receive the same manner as in examples 1 and 2.

Compounds 1-1 through 1-19, are presented in tables 3 and 4 receive the same manner as in examples 1 and 2.

Example 9

Synthesis of N-(2-mercaptophenyl)-2,2-dimethylpropanamide (formula (I); R = tert-butyl, X1, X2, X3, X4= a hydrogen atom, Y = carbonyl, Z = hydrogen atom).

Step 2) a Mixture of bis-[2-(paulolino)phenyl]disulfide (300 mg) obtained in example 1 above, and methanol (0.4 ml) - tetrahydrofuran (4 ml) was stirred at room temperature. Add sodium borohydride (70 mg) and the resulting solution was refluxed for 4 hours. After cooling and addition of 10% hydrochloric acid, the resulting solution was extracted with ethyl acetate. The organic layer is washed with water and saturated saline and dried over anhydrous sodium sulfate. After drying, the solution is concentrated and the resulting residue is separated and purified by using column chromatog the od: 28%).

Example 10

Synthesis of N-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxylate (formula (I); R = 1-(2-ethylbutyl)cyclohexyl, X1, X2, X3, X4= a hydrogen atom, Y = carbonyl, Z = hydrogen atom).

Step 2) a Mixture of bis-[2-[1-(2-ethylbutyl) cyclohexanecarboxylate]phenyl] disulfide (667 mg) obtained in example 2 above, triphenylphosphine (577 mg), dioxane (8 ml) and water (4 ml) is stirred for 1 hour at 50oC. After the mixture allow to cool, add 1 N. aqueous sodium hydroxide. The aqueous layer was washed with hexane and neutralized with 10% hydrochloric acid solution. After extraction with ethyl acetate, the solution washed with saturated saline and dried over anhydrous sodium sulfate. After drying, the solution is concentrated and the resulting residue purified using column chromatography on silica gel (manifesting solvent hexane:ethyl acetate = 15:1), which results in obtaining the desired compound (378 mg, yield: 56%).

Example 11

Synthesis of N-(2-mercaptophenyl)-1-isopentenyladenosine (formula (I); R = 1-isopentenyladenine, X1, X2, X3, X4= a hydrogen atom, Y = carbonyl, Z = hydrogen atom).

Stage 6) N-[2-(1-UB>, X2, X3, X4= a hydrogen atom, Y = carbonyl).

A solution of pyridine (500 ml) containing 2-aminothiophenol (15,8 g), stirred at room temperature and added dropwise 2 equal volume of 1-isopentenyltransferase. After complete addition the solution is stirred for 2 hours at 60oAnd give him a chance to cool off. After removal of the pyridine under reduced pressure, water is added and the solution extracted with ethyl acetate. The organic layer was washed with aqueous solution of saturated sodium bicarbonate, hydrochloric acid and saturated saline solution in this order, and dried over anhydrous sodium sulfate. The resulting solution was concentrated under reduced pressure, obtaining the desired compound in the form of a crude oily material (60 g).

Stage 7) the Crude product obtained in stage 6 above (60 g) was dissolved in a mixed solvent of methanol (60 ml), tetrahydrofuran (60 ml) in an argon atmosphere. Add potassium hydroxide (24.2 g) and the solution stirred for 1 hour at room temperature. After stirring water (50 ml), the solution washed with hexane (50 ml) and the aqueous layer was acidified with acidic sodium sulfate, followed extract is the sodium atom and the solvent is removed by evaporation under reduced pressure. The obtained precipitated crystalline product is washed with pentane and collected by filtration, obtaining the desired compound (23.1 g, yield: 60%).

Examples 12-18

Compounds are presented in tables 6 and 7 receive the same manner as in example 11.

In addition, the compounds 11-1 and 11-2 are presented in table 8, receive the same manner as in example 11.

Example 19

Synthesis of N-(2-mercapto-5-methoxyphenyl)-1-methylcyclohexanecarboxylic (formula (I); R = 1-methylcyclohexyl, X1, X3, X4= hydrogen atom, X2= methoxy, Y = carbonyl, Z = hydrogen atom).

Step 8) S-(4-methoxy-2-nitrophenyl) - N,N'-dimethylthiocarbamate (formula (VIII); R11, R12= methyl, X1, X3, X4= hydrogen atom, X2= methoxy).

A solution of dimethylformamide (20 ml) containing 4-methoxy-2-NITROPHENOL (4,00 g), is added to a suspension of sodium hydride (1.04 g) in dimethylformamide (40 ml) at 0oWith under stirring. After complete addition, the mixture is stirred for 30 minutes at room temperature, then add dimethylthiocarbamate (3,65 g) and the solution stirred for 1 hour at 80oC. After the solution is allowed the opportunity to cool off, denim saline and dried over anhydrous sodium sulfate. The solution is concentrated and the thus obtained residue add a mixture of ether-hexane. The precipitated solid is collected by filtration, receiving a yellow solid (5,11 g, yield: 84%). Then to the resulting product (3.50 g) is added phenyl ether (10 ml). After stirring for 1 hour at 210oWith, the solution is allowed the opportunity to cool off. The resulting solution was purified using column chromatography on silica gel (manifesting solvent hexane: ethyl acetate = 7: 1-3:2) to give the desired compound (at 3.35 g, yield: 96%).

Stage 9) S-[2-(1-methylcyclohexanecarboxylic)-4-methoxyphenyl)-N,N'-dimethylthiocarbamate (formula (XI); R = 1-methylcyclohexyl, R11, R12= methyl, X1, X3, X4= hydrogen atom, X3= methoxy, Y = carbonyl).

A solution of ethyl acetate (75 ml) containing the compound (2.00 g) obtained in stage 8) above, and SnCl22H2O (3,65 g), stirred at room temperature overnight. To the solution was added ethyl acetate (100 ml) and then add aqueous sodium hydroxide. To the mixture of magnesium sulfate and the precipitated solid product is filtered off. The filtrate is concentrated and receiving S-(2-amino-4-methoxyphenyl)-N, N'-dimethylthiocarbamate (1.64 g, yield: 93%). After goblet 1-methylcyclohexanecarboxylic (1.39 g), followed by stirring for 1 hour. After removal of the solvent, water is added and the solution extracted with ethyl acetate. The organic layer is washed with water and saturated saline and dried over anhydrous sodium sulfate. Obtained by concentrating the residue purified using column chromatography on silica gel (manifesting solvent hexane: ethyl acetate = 3:1) to give the desired compound (2,41 g, yield: 95%).

Stage 10) the Compound obtained in stage 9) above, (250 g) are added to a solution containing potassium hydroxide (140 mg) and methanol (1.5 ml) - tetrahydrofuran (0.5 ml) and the mixture refluxed for 30 minutes. After cooling, water is added and the aqueous layer washed with hexane. The solution is acidified by adding aqueous acidic potassium sulfate, followed by extraction with ethyl acetate. The organic layer is washed with water and saturated saline and dried over anhydrous sodium sulfate. The residue obtained after concentration is purified by using column chromatography (manifesting solvent hexane:ethyl acetate = 40:1, obtaining the desired compound (104 mg, yield: 52%).

Examples 20-24

Compounds shown in table 9, receive the same manner as in example 19.

Connect the emer 25

Synthesis of S-[2-(1-isopentenyladenosine)phenyl] thioacetate (formula (I); R = 1-isopentenyladenine, X1X2, X3, X4= a hydrogen atom, Y = carbonyl, Z = acetyl).

Stage 4) acetylchloride (0.17 ml) is added dropwise in a solution of chloroform (10 ml) containing N-(2-mercaptophenyl)-1-isopentenyladenosine (600 mg) obtained in the same manner as in stage 2) of example 9, stage 7) of example 11 or under 10) of example 19, and pyridine (of 0.48 ml) at room temperature under stirring. The solution is stirred for 1 hour. The residue obtained after concentration, purified column chromatography on silica gel (manifesting solvent hexane:ethyl acetate = 12:1) to give the desired compound (666 mg, yield: 98%).

Example 26

Synthesis of S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate]phenyl]-2-methylthiopropionate (formula (I); R = 1-(2-ethylbutyl)cyclohexyl,1X2, X3, X4= a hydrogen atom, Y = carbonyl, Z = isobutyryl).

Stage 4) Isobutyramide (15.0 ml) is added dropwise in a solution of chloroform (300 ml) containing N-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxylic (43,72 g) obtained in example 10, and pyridine (27.7 ml) at room temperature poverty the product is filtered. The filtrate is concentrated and the resulting residue is purified column chromatography on silica gel (manifesting solvent hexane: ethyl acetate = 15: 1) to give the desired compound (50,72 g, yield: 95%).

Example 27

Synthesis of S-[2-(1-isobutylacetophenone)phenyl]-2-methylthiopropionate (formula (I); R = 1-isobutyryloxy, X1, X2, X3, X4= a hydrogen atom, Y = carbonyl, Z = isobutyryl).

Stage 4) Isobutyramide (0,92 ml) is added dropwise in a solution of chloroform (25 ml) containing N-(2-mercaptophenyl)-1-isobutyltrimethoxysilane (2.50 g) obtained in example 18, and pyridine (1.8 ml) at room temperature under stirring. The solution is stirred for 1 hour. The residue obtained after concentration, purified column chromatography on silica gel (manifesting solvent hexane:ethyl acetate = 15:1) to give the desired compound (2,94 g, yield: 95%).

Example 28

Synthesis of S-[2-[1-(2-ethylbutyl)cyclohexanecarbonitrile)phenyl]-1-acetylpiperidine-4-dicarboxylate (formula (I); R = 1-(2-ethylbutyl)cyclohexyl, X1X2, X3, X4= a hydrogen atom, Y = carbonyl, Z = 1-acetyl-4-piperidinylcarbonyl).

Stage 4) Solution of chloroform (10 ml), coderresult dropwise into a solution of chloroform (10 ml), contains 1-acetilsalicilico acid (500 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (616 mg) and 1-hydroxybenzotriazole (435 mg) at room temperature. The solution is stirred for 1 hour. After stirring, water is added and the solution extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The residue obtained after concentration, purified column chromatography on silica gel (manifesting solvent hexane:ethyl acetate = 4:1 - chloroform: methanol = 10:1) to give the desired compound (1.08 g, yield: 79%).

Example 28

The compound of example 28 (formula (I); R = 1-(2-ethylbutyl)cyclohexyl, X1X2, X3, X4= a hydrogen atom, Y = carbonyl, Z = 1-acetyl-4-piperidinylcarbonyl) synthesized using a different method of synthesis.

Stage 4) Triethylamine (541 ml) is added to a suspension of ethyl acetate (2 liters) containing 1-acetilsalicilico acid (331 g), in a stream of argon. The solution is stirred under ice cooling. Added dropwise an ethyl acetate solution (400 ml) containing ethylchloride (185 ml) and the mixture is then stirred for 100 min at a spontaneous rise in temperature. After cooled the Teal)-cyclohexanecarboxylate (618 g), obtained in example 10, and the reaction solution is then stirred for 15 minutes under ice cooling. After stirring 1 N. hydrochloric acid (1,3 liter), the organic layer washed successively with water, aqueous saturated sodium bicarbonate solution, water and saturated saline and dried over anhydrous sodium sulfate.

The residue obtained after concentration was dissolved in diisopropyl ether (2.5 liters) and the solution stirred for crystallization, obtaining the crude crystalline substance. Then crystalline substance is dissolved in diisopropyl ether (5.5 liters) under heating and the solution is stirred for crystallization, obtaining the desired compound (505 g, yield: 55%).

Examples 29-65

The compounds presented in tables 11-17, receive the same manner as in examples 25, 26, 27, 28 or 28'.

Connection with 25-1 on 25-109, are presented in tables 18 and 27 receive the same manner as in examples 25 to 28.

Example 66

Synthesis of 3-[4,5-sodium dichloro-2-(1-isopropylcyclopentadienyl)phenyl] -2,2-dimethylthiophosphate (formula (I); R = 1-isopropylcyclohexane, X1, X4= hydrogen atom, X2, X3= a chlorine atom, Y =PR-2-(1-isopropylcyclopentadienyl)phenyl]-N,N'-dimethylthiocarbamate (86 g), obtained in the same manner as in stage 9) of example 19, and potassium hydroxide (50 mg) is refluxed for 30 minutes. After the solution will allow to cool, add water and the aqueous layer washed with hexane. Then the aqueous layer was acidified with acidic potassium sulfate and extracted with chloroform (10 ml). To the obtained extract was added pyridine (90 μl) and then at room temperature under stirring to the extract add pivaloate (41 μl). The solution is stirred for 1 hour. After concentration the residue is purified column chromatography on silica gel (manifesting solvent hexane:ethyl acetate = 20:1) to give the desired compound (24 mg, yield: 27%).

Examples 67-81

The compounds presented in tables 28-30, receive the same manner as in example 66.

In addition, compounds with 66-1 on 66-53 presented in tables 31 through 35, receive the same manner as in example 66.

Example 82

Synthesis of bis-[4,5 dichloro-2-(1-isopropylcyclopentadienyl)phenyl] disulfide (formula (I); R = 1-isopentenyladenine, X1, X4= hydrogen atom, X2, X3= a chlorine atom, Y = carbonyl, Z = 4,5-dichloro-2-(1-isopenicillin is d (formula (III-2); R = 1-isopentenyladenine, X1X4= hydrogen atom, X2, X3= a chlorine atom, Y = carbonyl).

A solution of tetrahydrofuran (2 ml) - methanol (1 ml) containing S-[4,5-dichloro-2-(1-isopentenyladenosine)phenyl] -N, N'-dimethylthiocarbamate (400 g) obtained in the same manner as in stage 9) of example 19, and potassium hydroxide (180 mg) is refluxed for 2 hours and the mixture allow to cool. After adding water, the aqueous layer was washed with hexane, acidified with saturated aqueous solution of acid potassium sulfate and extracted with chloroform. The organic layer is washed with water and saturated saline and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration of the organic solvent is distilled off under reduced pressure, obtaining the crude compound.

Stage 3) Dimethylsulfoxide solution (5 ml) of the crude product obtained in stage 10) above is stirred for 2 hours at 130oWith the mixture and allow to cool. To the solution was added water, extracted with chloroform. The organic layer is washed with water and saturated saline and dried over anhydrous sodium sulfate actuarial hexane: ethyl acetate = 30:1), receiving the compound (200 mg, yield: 60%).

Connection 82-1, are presented in table 35, receive the same manner as in example 82.

Example 83

Synthesis of 2-tetrahydropyrimidin-2-(1-isopentenyladenosine)phenoldisulfonic (formula (I); R = 1-isopentenyladenine,1, X2, X3, X4= a hydrogen atom, Y = carbonyl, Z = 2-tetrahydrofurfurylamine).

Stage 5) Solution of ethanol (6 ml) - water (6 ml) containing tetrahydrofurfurylamine (3.0 g) and sodium thiosulfate (4,13 g), refluxed for 17 hours and the mixture allow to cool. The ethanol is removed under reduced pressure and obtain an aqueous solution of Bunte salts. An aqueous solution (1 ml) of N-(2-mercaptophenyl)-1-isopentenyladenosine (380 mg) obtained in example 11, and sodium hydroxide (50 mg) is added dropwise to the solution at 0oAnd the solution is stirred for 1.5 hours. After adding ether, the organic layer is successively washed with aqueous sodium hydroxide, water and saturated saline and dried over anhydrous sodium sulfate. The residue obtained is concentrated under reduced pressure, purified column chromatography on silica gel (developing rest the C phenyl-2-pillolagiovanissima (formula (I); R = tert-butyl, X1, X2, X3, X4= a hydrogen atom, Y = carbonyl, Z = penalty).

Stage 5') Trimethylsilylimidazole (202 mg) are added to a solution (5 ml) tetrachlorocuprate containing thiophenol (159 mg). The solution is stirred for 2 hours at room temperature. The precipitated imidazole filtered, obtaining a solution.

Then sulfurylchloride (97 mg) and triethylamine (1 drop) are sequentially added to a solution (5 ml) tetrachlorocuprate containing bis-[2-(paulolino)phenyl] disulfide (300 mg), obtained as in stage 1 of example 1 at 0oC. the Solution is stirred for 1.5 hours at the same temperature and added dropwise to the above solution was cooled in a bath of ice and salt and the mixture is continuously stirred for 2.5 hours. After completion of the reaction, water is added and the solution extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting residue is purified column chromatography on silica gel (manifesting solvent hexane: ethyl acetate = 12: 1) to give the desired compound (337 mg, yield: 74%).

Below are the results of f Examples]

(1) Obtaining donor lipoprotein

The potassium bromide (KBr) is added to the plasma of healthy subjects (40 ml) to bring the relative densities up to d=1,125 g/ml. Spend centrifugation in density gradient (227000 g, 4oC, 17 hours) to obtain a fraction with a relative density d>1,125 g/ml (HDL3HDL3fraction). Thus obtained fraction cialiswhat against SFR (PBS) solution [10 mm Na2HPO4/10 mm NaH2PO4/O 15 M NaCl/1 mm add (EDTA) (pH 7.4)]. Then tritium-labeled cholesterol (10 nm) (50,3 Curie/mm dissolved in 95% ethanol and gradually add in the above HDL3fraction under stirring. The solution is incubated for 18 hours at 37o[Tritium-labeled cholesterol tarifitsiruetsya on this procedure, due to the action of lecithin:cholesterol acyltransferase (LAT, LCAT), present on the surface of HDL3and is absorbed into the inner part of the HDL3as labeled with tritium cholesterylester (ester of cholesterol) [3H] CE, ([3H]EH)]. After incubation add CVG and the relative density was adjusted to d= 1,21 g/ml Spending centrifugation in density gradient (227000 g, 4oC, 17 hours) and collecting the fraction with d>to 1.21 g/ml of the resulting coat is-HDL3relative density: 1,125<d>1,21, the relative activity: 101000 R/min/nm (dpm/nm), which serves as a donor lipoprotein.

(2) obtaining the acceptor lipoprotein

Physiological saline solution (relative density d=1,006 g/ml) layer to the plasma of healthy subjects (100 ml). Spend centrifugation in density gradient (227000 g, 4oC, 17 hours) and collecting the fraction with a relative density d>1,006 g/ml KBR added to the thus obtained fraction to bring the relative densities up to d=1,063 g/ml and carry out the centrifugation in density gradient (227000 g, 4oC, 20 hours) to collect a fraction with a relative density d>1,063 g/ml thus Obtained fraction cialiswhat against the above SFR solution, receiving the fractions containing BOB and LDL (relative density: 1,006<d>1,063 g/ml, which serve as acceptor lipoprotein.

Test example 1: in vitro inhibition activity of HATB in whole plasma

Plasma containing [3H] OH-HDL3, (60000 p/min/ml), receive, adding donor lipoprotein obtained in the above (1), in plasma from healthy subjects. The sample solution receiving, using a 1:1 solution of N-IU is) and plasma contains [3H]OH-HDL3(100 ál), add in a microtube and incubated for 4 hours at 37oWith or 4oC. After cooling with ice, TBS solution [20 mm Tris/0.15 M NaCl (pH of 7.4)] containing 0.15 M chloride magic and 0.3% dextran sulfate (100 μl), added to each microprobing and mix well. After microtube will stand at 4oC for 30 minutes, perform centrifugation (8000 rpm, 4oC, 10 minutes) and determine the radioactivity of the obtained supernatant (HDL fraction) using a scintillation counter. The difference between values obtained after incubation at 4oWith the 37oIn the case of only solvent, accept as activity HATB or decrease (%) of measured values produced by the models take as the degree of inhibition (%) activity HATB. On the basis of the degree of inhibition (%) activity HATB, calculated IC50the value of each sample.

The results are presented in Tables 38-48.

Test Example 2: ex vivo inhibitory effect activity HATB plasma from transgenic mice

The samples are suspended in a 0.5% solution of methylcellulose and administered orally using a plastic probe, transgenic mice having entered cient Japan Hei 8-130660), which were subjected to starvation during the night. Blood is collected before the introduction, and 6 hours after the introduction of the activity is determined HATB in plasma, using the following method.

Donor lipoprotein ([3H] OH-HDL3containing of 0.21 µg cholesterol) obtained in the above (1), the acceptor lipoprotein obtained in the above (2) (containing 21 mg of cholesterol) and 0.9 μl of mouse plasma added to the microtube. The total volume was adjusted to 600 μl of the test tube/TBS solution [10 mm Tris/0.15 M NaCl (pH of 7.4)]. Microtube incubated for 15 hours at 37oWith or 4oC. and Then cooled with ice TBS solution (400 ál/tube) and 0.3% solution of dextran sulfate (100 µl/vial) containing 0.15 M magnesium chloride, added to the tubes and mixed well. After keeping micro test tubes for 30 minutes at 4oWith, spend centrifugation (8000 rpm, 4oC, 10 minutes) and determine the radioactivity of the obtained supernatant (HDL fraction) using a scintillation counter. The difference between the measured values obtained by incubation of plasma individual mice at 4oWith the 37oFrom before the introduction of the samples is taken as the activity of HATB or decrease (%) measured snny in Tables 38-48.

Industrial applicability

The results of the above tests show that the compounds (1) according to the present invention have excellent inhibitory effect on the activity of HATB. Thus, the compounds can reduce BOB, lonp and LDL, which cause atherosclerosis, and increase HDL, which has inhibitory effect on him, and therefore they can be used as a not widely known new type of preventive or therapeutic agent for hyperlipidemia. In addition, the connection can be used as a preventive or therapeutic agent for the treatment of atherosclerotic diseases.

1. The inhibitor activity of esterified cholesterol transport protein (HETB), comprising as active ingredient a compound represented by the formula (I)

< / BR>
where R is a straight or branched C1-10alkyl group; a halogen-C1-4lower alkyl group; a substituted or unsubstituted WITH3-10cycloalkyl group; C3-10cycloalkyl C1-10alkyl group; a substituted or unsubstituted aryl group; substituted or unsubstituted aracelio group or a substituted or nezamesov> and X4may be the same or different and represent a hydrogen atom; a halogen atom; C1-4lower alkyl group; a halogen-C1-4lower alkyl group; C1-4the lower alkoxygroup; cyano; or nitro-group;

Y represents-CO-;

Z represents C1-4lower alkoxymethyl group, C1-4lower alkylthiomethyl group, uraleleketro group having aryl group selected from phenyl, biphenyl and naphthyl, aralkylamines group having aryl group selected from phenyl, biphenyl and naphthyl, WITH3-10cycloalkylcarbonyl group, C5-8cycloalkylcarbonyl group3-10cycloalkyl C1-10alkoxymethyl group, aryloxyalkyl group having aryl group selected from phenyl, biphenyl and naphthyl, alltimelow group having aryl group selected from phenyl, biphenyl and naphthyl, acyl group, acyloxy group, aminocarbonylmethyl group, thiocarbonyl group, and tigroup,

pharmaceutically acceptable salt, hydrate or MES.

2. The inhibitor activity HATB containing as active ingredient a compound according to p. 1, where R is a straight or razvetvlennye from fluorine, chlorine and bromine; C3-10cycloalkyl group which may have 1-4 substituent selected from the group consisting of straight or branched C1-10alkyl group, straight or branched C2-10alkenylphenol group3-10cycloalkyl group, C5-8cycloalkenyl group3-10cycloalkyl C1-10alkyl group, aryl group selected from phenyl, biphenyl and naphthyl, the carbonyl group and aranceles group having aryl group selected from phenyl, biphenyl and naphthyl; WITH3-10cycloalkyl C1-10alkyl group, or aryl, aracelio or 5 - or 6-membered heterocyclic group containing 1 nitrogen atom, or sulfur, each of which may have 1-4 substituent selected from the group consisting of straight or branched1-10alkyl group, straight or branched C2-10alkenylphenol group, halogen atom selected from fluorine, chlorine and bromine, nitro and halogen-C1-4lower alkyl group having a halogen atom selected from fluorine, chlorine and bromine, pharmaceutically acceptable salt, hydrate or MES.

3. The inhibitor activity HATB, comprising as active ingredient the compound according to p. 2, which is represented by formula (I-1):
dstanley a hydrogen atom; the group represented by formula

< / BR>
where R, X1X2, X3, X4and Y are as described above;

-Y1R1where Y1represents-CO-; R1represents a substituted or unsubstituted straight or branched C1-10alkyl group; C1-4the lower alkoxygroup; C1-4the lower allylthiourea; substituted or an unsubstituted amino group; substituted or unsubstituted raidgroup; substituted or unsubstituted WITH3-10cycloalkyl group; C3-10cycloalkyl C1-10alkyl group; a substituted or unsubstituted aryl group; substituted or unsubstituted aracelio group; arylalkyl group; killigrew, where aryl represents phenyl; substituted or unsubstituted 5 - or 6-membered heterocyclic group having nitrogen atom, or 5 - membered heteroallyl group; or-S-R2where R2represents a substituted or unsubstituted C1-4lower alkyl group or a substituted or unsubstituted aryl group,

pharmaceutically acceptable salt, hydrate or MES.

4. The inhibitor activity HATB, comprising as active ingredient the compound according to p. 3, where R1is prameya from a halogen atom, selected from fluorine, chlorine and bromine, C1-4low alkoxygroup, an amino group which may be substituted C1-4lower alkyl, acyl or a hydroxyl group, a C1-4low allylthiourea, carbamoyl, hydroxyl group, acyl group, alloctype having acyl group, carboxyl group and alloctype, which may be substituted by a halogen atom selected from fluorine, chlorine and bromine; C1-4the lower alkoxygroup; C1-4the lower allylthiourea; amino - or raidgroup, which may have 1-2 substituent selected from the group consisting of C1-4lower alkyl groups, hydroxyl group, acyl group, and aryl group which may be substituted by lower C1-4alkoxygroup; C3-10cycloalkyl group which may have substituents selected from the group consisting of straight or branched1-10alkyl group, a C3-10cycloalkyl group, C5-8cycloalkenyl group, aryl group, amino group, C1-4low alkylamino with C1-4lower alkyl group, and alluminare having acyl group; C3-10cycloalkyl C1-10alkyl group, or aryl group, or aracelio GRU is s, the halogen atom selected from fluorine, chlorine and bromine, nitro, hydroxyl group, C1-4low alkoxygroup, C1-4low allylthiourea, acyl group, halogen-C1-4lower alkyl group having a halogen atom selected from fluorine, chlorine and bromine, and an amino group which may be substituted C1-4lower alkyl or acyl group; arylalkyl group; killigrew, where aryl represents phenyl; 5 - or 6-membered heterocyclic group having nitrogen atom, which may have 1-4 substituents selected from the group consisting of straight or branched C1-10alkyl group, halogen atom selected from fluorine, chlorine and bromine, 5-membered heteroaryl group, and R2represents C1-4lower alkyl group which may have 1-3 substituent selected from the group consisting of C1-4low alkoxygroup, an amino group which may be substituted C1-4lower alkyl or acyl group, C1-4low allylthiourea, carbamoyl, hydroxyl group, carboxyl group, acyl group and 5 - or 6-membered heterocyclic group having 1-3 nitrogen atom, oxygen or sulfur; or an aryl group which may have 1-4 replace the ora, chlorine and bromine, nitro, hydroxyl group, C1-4low alkoxygroup, C1-4low allylthiourea, acyl group, amino group which may be substituted C1-4lower alkyl or acyl group, and a halogen-C1-4lower alkyl group having a halogen atom selected from fluorine, chlorine and bromine, pharmaceutically acceptable salt, hydrate or MES.

5. The inhibitor activity HATB, comprising as active ingredient the compound under item 1, which is selected from the group consisting of

bis-[2-(paulolino)phenyl] disulfide;

bis-[2-(2-propylpentanoate)phenyl] disulfide;

bis-[2-(1-methylcyclohexanecarboxylic)phenyl)disulfide;

bis-[2-(1-isopentenyltransferase)phenyl] disulfide;

bis-[2-(1-isopentenyladenosine)phenyl] disulfide;

N-(2-mercaptophenyl)-2,2-dimethylpropanamide;

N-(2-mercaptophenyl)-1-isopentenyladenosine;

N-(2-mercaptophenyl)-1-methylcyclohexanecarboxylic;

N-(2-mercaptophenyl)-1-isopentenyltransferase;

N-(2-mercaptophenyl)-1-isopropylcyclohexane;

N-(4,5-dichloro-2-mercaptophenyl)-1-isopentenyladenosine;

N-(4,5-sodium dichloro-2-IU xamiga;

N-(2-mercapto-4-were)-1-isopentenyladenosine;

S-[2-(1-isopentenyladenosine)phenyl] thioacetate;

S-[2-(1-methylcyclohexanecarboxylic)phenyl] -2,2-dimethyl-thiopropionate;

S-[2-(paulolino)phenyl] phenylthiourea;

S-[2-(1-isopentenyladenosine)phenyl] -2,2-dimethylthiophosphate;

S-(2-(1-isopentenyladenosine)phenyl] -2-acetyl-amino-3-phenylthiophene;

S-[2-(1-isopentenyladenosine)phenyl] -3-pyridinedicarboxylate;

S-[2-(1-isopentenyladenosine)phenyl] CHLOROACETATE;

S-[2-(1-isopentenyladenosine)phenyl] methoxytyramine;

S-[2-(1-isopentenyladenosine)phenyl] thiopropionate;

S-[2-(1-isopentenyladenosine)phenyl] phenoxythioacetamide;

S-[2-(1-isopentenyladenosine)phenyl] -2-methylthiopropionate;

S-[2-(1-isopentenyladenosine)phenyl] -4-chlorophenoxyacetate;

S-[2-(1-isopentenyladenosine)phenyl] cyclopropanecarboxylate;

S-[2-(1-isopentenyladenosine)phenyl] -2-acetylamino-4-carbamodithioate;

S-[2-(1-isopentenyladenosine)phenyl] -2-hydroxy-2-methylthiophenethylamine)phenyl] thioacetate;

S-[4,5-dichloro-2-(1-isopentenyladenosine)-phenyl] -2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-isopentenyltransferase)-phenyl] -2,2-dimethylthiophosphate;

S-[2-(1-isopentenyladenosine)-4-trifloromethyl] -2,2-dimethylthiophosphate;

O-methyl S-[2-(1-isopentenyladenosine)phenyl] -montierbar;

S-[2-(1-methylcyclohexanecarboxylic)phenyl] -S-phenyldiethanolamine;

S-[2-(1-isopentenyladenosine)phenyl] -N-phenylthiocarbamide;

S-[2-(paulolino)-4-trifloromethyl] -2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-cyclopropanecarboxylate)-phenyl] -2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(2-cyclohexylpropionate)phenyl] -2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-pentylcyclohexanecarboxylic)phenyl] -2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-cyclopropylacetylene)phenyl] -2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-cyclohexyloxycarbonyloxy)phenyl] -2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-isopropylcyclopentadienyl)-phenyl] -2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-isopentenyladenosine)-phenyl] -2,2-dimethylthiophosphate;

hexacarbonyl)-4-nitrophenyl] -2,2-dimethylthiophosphate;

S-[4-cyano-2-(1-isopentenyladenosine)phenyl] -2,2-dimethylthiophosphate;

S-[4-chloro-2-(1-isopentenyladenosine)phenyl] -2,2-dimethylthiophosphate;

S-[5-chloro-2-(1-isopentenyladenosine)phenyl] -2,2-dimethylthiophosphate;

S-[4-fluoro-2-(1-isopentenyladenosine)phenyl] -2,2-dimethylthiazolidine;

S-[4,5-debtor-2-(1-isopentenyladenosine)-phenyl] -2,2-dimethylthiophosphate;

S-[5-fluoro-2-(1-isopentenyladenosine)phenyl] -2,2-dimethylthiophosphate;

bis-[4,5-dichloro-2-(1-isopentenyladenosine)-phenyl] disulfide;

2-tetrahydropyrimidin-2-(1-isopentenyladenosine)phenoldisulfonic;

N-(2-mercaptophenyl)-1-ethylcyclohexylamine;

N-(2-mercaptophenyl)-1-propylcyclohexanone;

N-(2-mercaptophenyl)-1-butylcyclohexanecarboxylic;

N-(2-mercaptophenyl)-1-isobutyltrimethoxysilane;

S-[2-(1-isopentenyladenosine)phenyl] cyclohexanecarboxylate;

S-[2-(1-isopentenyladenosine)phenyl] thiobenzoate;

S-[2-(1-isopentenyladenosine)phenyl] -5-carboxymefenamic;

S-(2-(1-isopentenyladenosine)-4-were] -Tilbury)cyclohexanecarboxylate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -2-methylthiopropionate;

S-[2-(1-isobutylacetophenone)phenyl] -2-methylthiopropionate;

S-[2-(1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -1-acetylpiperidine-4-dicarboxylate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] thioacetate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -2,2-dimethylthiophosphate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -methoxytyramine;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -2-hydroxy-2-methylthiopropionate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -4-chlorophenoxyacetate;

S-[2-(1-isobutylacetophenone)phenyl] -4-chlorophenoxyacetate and

S-[2-(1-isobutylacetophenone)phenyl] -1-acetylpiperidine-4-dicarboxylate,

its pharmaceutically acceptable salt, hydrate or MES.

6. The inhibitor activity HATB under item 1, its pharmaceutically acceptable salt, hydrate or of MES MES to obtain preventive or therapeutic agent for hyperlipidemia.

7. The inhibitor activity HATB under item 1, its pharmaceutically acceptable salt, hydrate or of MES MES to obtain prkticheski remedy for hyperlipidemia, comprising as active ingredient a compound according to any one of paragraphs. 1-5, its pharmaceutically acceptable salt, hydrate or MES.

9. Preventive or therapeutic agent for atherosclerosis, comprising as active ingredient a compound according to any one of paragraphs. 1-5, its pharmaceutically acceptable salt, hydrate or MES.

10. Derivatives of bis-(2-AMINOPHENYL)disulfide or aminothiophenol General formula (I-2)

< / BR>
where R' is substituted or unsubstituted WITH3-10cycloalkyl group; X1X2, X3, X4may be the same or different and represent a hydrogen atom, a halogen atom, a C1-4lower alkyl group, halogen-C1-4lower alkyl group, a C1-4the lower alkoxygroup, or the cyano or nitro-group;

Z1' represents a hydrogen atom; a group represented by the formula

< / BR>
where R', X1, X2, X3and X4have the meanings as described above;

-Y1R1where-Y1represents a group-CO-; R1represents a substituted or unsubstituted straight or branched C1-10alkyl group, a C1-4the lower alkoxygroup, C1-4the lower allylthiourea, Sahu3-10cycloalkyl group; C3-10cycloalkyl C1-10alkyl group; a substituted or unsubstituted aryl group; substituted or unsubstituted aracelio group; arylalkyl group; killigrew, where aryl represents phenyl; substituted or unsubstituted 5 - or 6-membered heterocyclic group having nitrogen atom, or 5-membered heteroallyl group; or-SR2where R2represents a substituted or unsubstituted C1-4lower alkyl group or a substituted or unsubstituted aryl group, where aryl represents phenyl,

pharmaceutically acceptable salt, hydrate or MES.

11. Connection on p. 10, which is represented by formula (I-3)

< / BR>
where R" represents a 1-substituted-C3-10cycloalkyl group;

X1X2, X3and X4are the same as specified in paragraph 10;

Z1" represents a hydrogen atom; a group represented by the formula

< / BR>
where R, X1X2, X3and X4are as described above;

-Y1R1where Y1and R1are as specified in paragraph 10; or-S-R2where R2so, as stated in paragraph 10,

its pharmaceutically reception is where R', X1, X2, X3and X4are as specified in paragraph 10,

its pharmaceutically acceptable salt, hydrate or MES.

13. Connection on p. 11, which is represented by formula (II-1)

< / BR>
where R, X1X2, X3and X4are as specified in paragraph (11,

its pharmaceutically acceptable salt, hydrate or MES.

14. Connection on p. 10, which is represented by formula (III)

< / BR>
where R', X1X2, X3and X4are as specified in paragraph 10,

its pharmaceutically acceptable salt, hydrate or MES.

15. Connection on p. 11, which is represented by formula (III-1)

< / BR>
where R, X1, X2, X3and X4are the same as indicated in paragraph 11,

its pharmaceutically acceptable salt, hydrate or MES.

16. Connection on p. 10, which is represented by formula (IV)

< / BR>
where R', X1, X2, X3, X4, Y1and R1are the same as indicated in paragraph 10,

its pharmaceutically acceptable salt, hydrate or MES.

17. Connection on p. 11, which is represented by formula (IV-1)

< / BR>
where R, X1, X2, X3, X4, Y1and R1avla. Connection on p. 10, which is represented by formula (V)

< / BR>
where R', X1X2, X3, X4, Y1and R2are the same as indicated in paragraph 10,

its pharmaceutically acceptable salt, hydrate or MES.

19. Connection on p. 11, which is represented by formula (V-1)

< / BR>
where R, X1, X2, X3X4and R2are the same as indicated in paragraph 11,

its pharmaceutically acceptable salt, hydrate or MES.

20. Connection on p. 10, which is selected from the group consisting of

bis-[2-(1-methylcyclohexanecarboxylic)phenyl] disulfide;

bis-[2-(1-isopentenyltransferase)phenyl] -disulfide;

bis-[2-(1-isopentenyladenosine)phenyl] -disulfide;

N-(2-mercaptophenyl)-1-isopentenyladenosine;

N-(2-mercaptophenyl)-1-methylcyclohexanecarboxylic;

N-(2-mercaptophenyl)-1-isopentenyltransferase;

N-(2-mercaptophenyl)-1-isopentenyladenosine;

N-(4,5-dichloro-2-mercaptophenyl)-1-isopentenyladenosine;

N-(4,5-dichloro-2-mercaptophenyl)-1-isopentenyltransferase;

N-(2-mercapto-5-were)-1-isopentenyladenosine;

N-(2-measurement is acetate;

S-[2-(1-methylcyclohexanecarboxylic)phenyl] -2,2-dimethylthiophosphate;

S-[2-(1-isopentenyladenosine)phenyl] -2,2-dimethylthiophosphate;

S-[2-(1-isopentenyladenosine)phenyl] -2-acetylamino-3-phenylthiophene;

S-[2-(1-isopentenyladenosine)phenyl] -3-pyridinedicarboxylate;

S-[2-(1-isopentenyladenosine)phenyl] CHLOROACETATE;

S-[2-(1-isopentenyladenosine)phenyl] methoxytyramine;

S-[2-(1-isopentenyladenosine)phenyl] -thiopropionate;

S-[2-(1-isopentenyladenosine)phenyl] phenoxythioacetamide;

S-[2-(1-isopentenyladenosine)phenyl] -2-methylthiopropionate;

S-[2-(1-isopentenyladenosine)phenyl] -4-chlorophenoxyacetate;

S-[2-(1-isopentenyladenosine)phenyl] cyclopropanecarboxylate;

S-[2-(1-isopentenyladenosine)phenyl)-2-acetylamino-4-carbamodithioate;

S-[2-(1-isopentenyladenosine)phenyl] -2-hydroxy-2-methylthiopropionate;

S-[2-(1-isopentenyltransferase)phenyl] -2,2-dimethylpropionic;

S-[2-(1-isopentenyltransferase)phenyl] thioacetate;

S-[4,5-dichloro-2-(1-isopentenyl enyl] -2,2-dimethylthiophosphate;

S-[2-(1-isopentenyladenosine)-4-triptoreline] -2,2-dimethylthiophosphate;

O-methyl 3-[2-(1-isopentenyladenosine)phenyl] montierbar;

S-[2-(1-methylcyclohexanecarboxylic)phenyl] -S-phenyldiethanolamine;

S-[2-(1-isopentenyladenosine)phenyl] -N-phenylthiocarbamide;

S-[4,5-dichloro-2-(1-cyclopropanecarboxylate)-phenyl] -2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-pentylcyclohexanecarboxylic)phenyl] -2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-cyclopropylacetylene)phenyl] -2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-cyclohexyloxycarbonyloxy)phenyl] -2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-isopropylcyclopentadienyl)-phenyl] -2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-isopentenyladenosine)-phenyl] -2,2-dimethylthiophosphate;

S-[4,5-dichloro-2-(1-isopentenyladenosine)phenyl] -2,2-dimethylthiophosphate;

S-[2-(1-isopentenyladenosine)-4-nitrophenyl] -2,2-dimethylthiophosphate;

S-[4-cyano-2-(1-isopentenyladenosine)phenyl] -2,2-dimethylthiophosphate;

S-[4-chloro-2-(1-isopentenyladenosine)phenyl] -2,2-dimethyldioctadecylammonium)phenyl] -2,2-dimethylthiophosphate;

S-[4,5-debtor-2-(1-isopentenyladenosine)-phenyl] -2,2-dimethylthiophosphate;

S-[5-fluoro-2(1-isopentenyladenosine)phenyl] -2,2-dimethylthiophosphate;

bis-[4,5-dichloro-2-(1-isopentenyladenosine)-phenyl] disulfide;

2-tetrahydropyrimidin-2-(1-isopentenyladenosine)phenoldisulfonic;

N-(2-mercaptophenyl)-1-ethylcyclohexylamine;

N-(2-mercaptophenyl)-1-propylcyclohexanone;

N-(2-mercaptophenyl)-1-butylcyclohexanecarboxylic;

N-(2-mercaptophenyl)-1-isobutyltrimethoxysilane;

S-[2-(1-isopentenyladenosine)phenyl] cyclohexanecarboxylate;

S-[2-(1-isopentenyladenosine)phenyl] thiobenzoate;

S-[2-(1-isopentenyladenosine)phenyl] -5-carboxymefenamic;

S-[2-(1-isopentenyladenosine)-4-were] -thioacetate;

bis-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -disulfide;

N-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxylate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -2-methylthiopropionate;

S-[2-(1-isobutylacetophenone)phenyl] -2-methylthiopropionate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarbonyl is cetate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -2,2-dimethylthiophosphate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -methoxytyramine;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -2-hydroxy-2-methylpropionate;

S-[2-[1-(2-ethylbutyl)cyclohexanecarboxylate] phenyl] -4-chlorophenoxyacetate;

S-(2-(1-isobutylacetophenone)phenyl] -4-chlorophenoxyacetate and

S-[2-(1-isobutylacetophenone)phenyl] -1-acetylpiperidine-4-dicarboxylate,

its pharmaceutically acceptable salt, hydrate or MES.

21. Pharmaceutical composition comprising as active ingredient a compound according to any one of paragraphs. 10-20, its pharmaceutically acceptable salt, hydrate or MES.

22. A method of inhibiting the activity of HATB, including the introduction patients inhibitor activity HATB under item 1, its pharmaceutically acceptable salt, hydrate or MES.

23. A method of inhibiting the activity of HATB on p. 22 for the prophylaxis or treatment of hyperlipidemia.

24. A method of inhibiting the activity of HATB on p. 22 for the prevention or treatment of atherosclerosis.

Priority points:

12.02.1997 on PP. 8-17;

05.06.1997 on PP. 5,18,19;
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Same patents:

The invention relates to a new process for the preparation of 2,3-pyridinecarboxamide formula (I), where R is hydrogen, C1-C6alkyl or C1-C6alkoxymethyl, R1means hydrogen, C1-C6alkyl, C(O)R2, phenyl, benzyl, R2means C1-C6alkyl, benzyl or phenyl, which is that the compound of formula (II), where R has the above meaning, R6means C1-C6alkyl, R7means OR8or NR9R10, R8means hydrogen, C1-C6alkyl, C(O)R11, phenyl, benzyl, R11means C1-C6alkyl, OR12, NR12, R13, benzyl or phenyl, R12and R13denote hydrogen, C1-C6alkyl, benzyl or phenyl, R9and R10denote hydrogen, C1-C6alkyl, benzyl or phenyl, is subjected to the interaction with the imide of maleic acid of the formula (III), where R1have the above values

The invention relates to the class of hydrazides of dicarboxylic acids, namely to a new biologically active isonicotinohydrazide tarakanovas acid formula

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The compound obtained by the interaction of the hydrazide of isonicotinic acid anhydride citramonum

The invention relates to a continuous method of hydrolysis of cyanopyridines in adiabatic conditions, which is a continuous Association of two or more of the supplied flow with formation of a reaction mixture containing cyano, water and a base, heating it to a temperature sufficient to initiate the hydrolysis of the cyano

The invention relates to a method for producing N-(2 - nitroxyethyl)-nicotinamide of formula I

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also known as nicorandil
The invention relates to physiologically active compounds and relates amidoalkylation and method of production thereof

The invention relates to Amida sulfamido and sulphonilecarbomide-2-carboxylic acids and their use in pharmaceutical compositions for the treatment of fibrosis

The invention relates to nitrogen-containing compounds that may constitute the active ingredient of the pharmaceutical composition active as an antagonist neirokinina, and more particularly to a derivative of arylpyrimidines and pharmaceutical compositions containing these compounds

The invention relates to 4-mercapto-benzoylpyridine formula (I), where R1denotes A; R2means And, unsubstituted or substituted by F, Cl, Br, phenyl, pyridyl; And - alkyl with 1-6 C-atoms, and their physiologically acceptable salts, methods for their production and pharmaceutical compositions based on them

The invention relates to sulfur-containing derivative of an aryl having antibacterial and antiviral activity, in particular Aristotelianism the following formula (I), their pharmaceutically acceptable salts and solvate, a pharmaceutical composition having antibacterial and antiviral activity, and method of treating bacterial or viral infections

The invention relates to pharmacy

The invention relates to new niftystories compounds of formula I, where R1and R2- H, -OH, -O(C1-C4alkyl), -OCOC6H5, -OCO(C1-C6alkyl), -OSO2(C4-C6alkyl); R3- 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, 1 hexamethyleneimino; intermediate compounds, which are suitable for easing symptoms of postmenopausal syndrome, including osteoporosis, hyperlipemia and estrogenzawisimy cancer, and inhibition of uterine fibroids, endometriosis and proliferation of aortic smooth muscle cells

The invention relates to medicine and relates to means for the treatment of hyperlipidemia and atherosclerosis, as well as correction of rheological properties of blood

The invention relates to medicine, namely to methods of prevention of fat embolism, and can be applied, in particular, the replacement of large joints
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