New glucitol derivative, prodrug and salt and therapeutic agent containing them for diabetes treatment

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns a new glucitol derivative of formula (I): wherein m represents an integer chosen from 1-3; each R1, R2, R3 and R4 are independently choose from hydrogen atom and benzyl groups; Ar1 represents a naphthyl group which can be substituted by one or more substitutes chosen from the group, consisting of C1-C6alkyl group or halogen atom; A represents 5-7-members aromatic heterocyclic group containing one or more heteroatoms independently chosen from oxygen atom and sulphur atom which can form a condensed cycle with an aromatic carbocycle or an aromatic heterocycle where A can be substituted by one or more Rb provided when A is a benzocondensed cycle containing two or more rings, the group -(CH2)m- is connected with a heterocycle in A; Each Rb is independently chosen from C1-C6alkyl group, halogen atom and C1-C6-alkoxy group; or to their pharmaceutically acceptable salts. These compounds are used as a Na+ cotransport inhibitor and exhibits ability to reduce blood sugar level.

EFFECT: invention covers a pharmaceutical composition based on these compounds and to the method for treatment and prevention of such diseases associated with hyperglycemia, as diabetes, diabetes complications and obesity.

12 cl, 4 tbl, 5 ex

 

The technical field

The present invention relates to the derivatives of glucitol, their prodrugs and their pharmaceutically acceptable salts, which are used as medicines. In particular, the present invention relates to the derivatives of glucitol, their prodrugs and their salts, which are applicable as a preventive or therapeutic agents for treatment of diabetes, as insulin-dependent diabetes (type I diabetes) and non-insulin-dependent diabetes (type II diabetes), diabetic complications and diseases such as obesity-induced hyperglycemia by inhibiting cotransporter 2 Na+-glucose (SGLT2).

The level of technology

In recent years, the number of patients with diabetes have increased as a result of Western manners, nutrition, chronic lack of exercise and so on. In diabetic patients due to chronic hyperglycemia is reduced as the secretion of insulin, and insulin sensitivity, and this leads to a further increase in the level of sugar in the blood affects the state of the disease. As therapeutic agents for diabetes used biguanide drugs, sulfonylurea drugs, drugs-glucosidase inhibitors, agents that increase resistentes is to insulin, and so on. However, as the side effects associated with these agents, there are reports of lactic acidosis in the case biguanide drugs, hypoglycemia in the case of sulfonylurea drugs, and diarrhea in the case of glucosidase inhibitors; and thus, the current situation is such that it is highly desirable to develop therapeutic agents for the treatment of diabetes, with a new mechanism of action that differs from the mechanism of action of these drugs.

It was reported (see non-patent document 1)that phlorizin, natural derivative of glucose, inhibits re-absorption of excess glucose in the kidneys by inhibiting retrieveimage of cotransporter 2 glucose (SGLT2), located on the site S1 renal proximal curved tubules, and activates the secretion of glucose for the manifestation reduce blood sugar levels, and since then has conducted an intensive study of therapeutic agents for treatment of diabetes on the basis of inhibition of SGLT2.

For example, in Japanese patent publication 2000-080041 A (patent document 1), international publication no WO 01/068660 (patent document 2), No. WO 04/007517 (patent document 3), and so forth, described compounds used as inhibitors of SGLT2. However, the problem is that when Perera Inom the introduction of these compounds are easily hydrolyzed under the action of glucosidase, present in the small intestine, or the like, and their pharmacological effect quickly disappears. If phlorizin reported that phloretin, the aglycone of phlorizin, inhibits the Transporter sugar lightweight type diffusion. For example, when injected intravenously phlorizin rat reported adverse effect of reducing the intracerebral concentration of glucose (reference, for example, non-patent document 2).

Then, in order to prevent such decomposition and increase the absorption efficiency of some attempts were made to translate such compounds in their prodrugs. With the introduction of prodrugs, it is desirable that the specified prodrug properly absorbed in the target organ or beside him, becoming active connection. However, as in the living organism there are various metabolic enzymes and individual variability is considerable, in many cases it is difficult to provide a stable action of the prodrug. In addition, an attempt was made transformation of the glycosidic bonds of the compounds in carbon-carbon bond (reference to patent documents 4 to 8). However, it is necessary to further improve the properties of the medicinal product, including activity, metabolic stability, and so forth.

Patent document 1: Japanese patent publication is the situation 2000-080041 A.

Patent document 2: international publication number WO 01/068660 summary.

Patent document 3: international publication number WO 04/007517 summary.

Patent document 4: the Patent publication U.S. 2001/041674 A.

Patent document 5: the Patent publication U.S. 2002/137903 A.

Patent document 6: international publication number WO 01/027128 summary.

Patent document 7: international publication number WO 02/083066 summary.

Patent document 8: international publication number WO 04/013118 summary.

Non-patent document 1: J. Clin. Invest.,93, 397-404 (1994).

Non-patent document 2: Stroke,14, 388 (1983).

Description of the INVENTION

The problem to be solved by the present invention

The present invention is to develop a derivative glucitol possessing suitable for drug properties. In particular, the present invention is to develop a derivative glucitol that reduce blood sugar levels and, in addition, possess appropriate properties as drugs, as prolonged effect, the metabolic stability and security.

In addition, the present invention is the development of pharmaceutical compositions used for the prevention or treatment of such diabetes, as inulinase iSky mellitus (type I diabetes) and non-insulin-dependent diabetes (type II diabetes), complications of diabetes and diseases such as obesity-induced hyperglycemia.

Solutions to problems

In the result of intensive research conducted by the authors of the present invention to solve the above described problems, found that derivatives of glucitol formula (I) possess excellent inhibitory activity against SGLT2, and the present invention was completed.

That is, according to one aspect of the present invention proposed a compound of formula (I):

in which

m is an integer selected from 1-3;

each of R1, R2, R3and R4independently selected from a hydrogen atom, a C1-C6alkyl group which may be substituted by one or more Ra, a7-C14aranceles group which may be substituted by one or more Rb,- C(=O)Rx;

Rx represents a C1-C6alkyl group which may be substituted by one or more Ra, and aryl group which may be substituted by one or more Rb, a heteroaryl group which may be substituted by one or more Rb, C1-C6alkoxygroup, which may be substituted by one or more Ra, or-NReRf;

Ar1represents naftalina group which may be substituted by one or more Rb;

And isone heteroaryl group, which may be substituted by one or more Rb, with the specified heteroaryl group may form a condensed cycle with aromatic carbocycle or aromatic heterocycle, provided that when a is benzododecinium cycle containing two or more rings, the group -(CH2)m- linked heterocycle in A;

each Ra is independently selected from a halogen atom, hydroxy-group, ceanography, nitro, carboxyl group, With1-C6alkoxygroup, which may be substituted by one or more Rc, an aryl group which may be substituted by one or more Rd, alloctype, which may be substituted by one or more Rd, a heteroaryl group which may be substituted by one or more Rd, heterokaryosis, which may be substituted by one or more Rd, mercaptopropyl,1-C6allylthiourea, which may be substituted by one or more Rc, C1-C6alkylsulfonyl group which may be substituted by one or more Rc, C1-C6alkylsulfonyl group which may be substituted by one or more Rc, -NRfRg,1-C6alkoxycarbonyl group which may be substituted by one or more Rc, and C1-C6alkylcarboxylic group which may be substituted by one or more Rc;

each of Rb, together with the IMO to choose from With 1-C6alkyl group which may be substituted by one or more Rc, C3-C8cycloalkyl group which may be substituted by one or more Rc, C7-C14aranceles group which may be substituted by one or more Rd, halogen atom, hydroxy-group, ceanography, nitro, carboxyl group, With1-C6alkoxycarbonyl group which may be substituted by one or more Rc, C1-C6alkoxygroup, which may be substituted by one or more Rc, an aryl group which may be substituted by one or more Rd, alloctype, which may be substituted by one or more Rd, a heteroaryl group which may be substituted by Rd, heterokaryosis, which may be substituted by one or more Rd, mercaptopropyl,1-C6allylthiourea, which may be substituted by one or more Rc, C1-C6alkylsulfonyl group which may be substituted by one or more Rc, C1-C6alkylsulfonyl group which may be substituted by one or more Rc, -NRfRg,1-C6alkylcarboxylic group which may be substituted by one or more Rc, C1-C3alkylenedioxy and heterocyclyl group;

each Rc is independently selected from a halogen atom, hydroxy-group, ceanography, nitro, carboxy who enoy group, With1-C6alkoxygroup, aryl group which may be substituted by one or more Rd, alloctype, which may be substituted by one or more Rd, a heteroaryl group which may be substituted by one or more Rd, heterokaryosis, which may be substituted by one or more Rd, an amino group, With1-C6alkylamino and di(C1-C6alkyl)amino;

each Rd is independently selected from C1-C6alkyl group which may be substituted by one or more halogen atoms, With7-C14aranceles group, halogen atom, hydroxy-group, ceanography, nitro, amino, C1-C6alkylamino and di(C1-C6alkyl)amino;

Re represents a hydrogen atom, a C1-C6alkyl group which may be substituted by one or more Rc, an aryl group which may be substituted by one or more Rd, or heteroaryl group which may be substituted by one or more Rd;

Rf represents a hydrogen atom or a C1-C6alkyl group which may be substituted by one or more Rc,

Rg represents a hydrogen atom, a C1-C6alkyl group which may be substituted by one or more Rc, C1-C6alkylcarboxylic group which may be substituted by one the or more Rc, aryl group which may be substituted by Rd, a heteroaryl group which may be substituted by one or more Rd, carbamoyl group1-C6alkoxycarbonyl group which may be substituted by one or more Rc, or1-C6alkylsulfonyl group which may be substituted by one or more Rc; or

Re and Rf, and Rf and Rg may form a 4-7-membered heterocycle together with the nitrogen atom to which they relate,

or its prodrug, or pharmaceutically acceptable salt.

According to another aspect of the present invention proposed a compound of formula (Ia):

in which A, R1, R2, R3, R4and m are same as defined above, or its prodrug, or pharmacologically acceptable salt.

According to further aspect of the present invention proposed a compound of formula (Ib):

in which A, Ar1, R1, R2, R3, R4and m are same as defined above, or its prodrug, or pharmaceutically acceptable salt.

According to another aspect of the present invention proposed a compound of formula (IC):

in which A, R1, R2, R3, R4and m are same as defined above, or its prodrug, or its pharmaceutical is Eski acceptable salt.

Preferably Rb in the present invention independently selected from C1-C6alkyl group, a C1-C6halogenoalkanes group, halogen atom, hydroxy-group, ceanography,1-C6alkoxygroup,1-C6allylthiourea,1-C6alkylsulfonyl group1-C6alkylsulfonyl group and1-C3alkylenedioxy.

Preferably, a represents a thienyl group or benzothiazoline group, these groups may be substituted by one or more Rb.

In addition, m in the present invention preferably is 1. In addition, each of R1, R2, R3and R4independently selected from a hydrogen atom and-C(=O)Rx, and Rx represents a C1-C6alkyl group which may be substituted by one or more Ra, or C1-C6alkoxygroup, which may be substituted by one or more Ra.

As the compounds included in the present invention, for example, can be given the following connection:

(2S,3R,4R,5S,6R)-2-[3-(benzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]-6-hydroxyethylacrylate-3,4,5-triol;

(2S,3R,4R,5S,6R)-2-[3-(5-toranzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]-6-hydroxyethylacrylate-3,4,5-triol;

(2S,3R,4R,5S,6R)-2-[3-(benzo[b]thiophene-2-ylmethyl)-4-methoxynaphthalene-1-yl]-6-hydroxymethyl who tetrahydropyran-3,4,5-triol;

(2R,3S,4R,5R,6S)-2-hydroxymethyl-6-[3-(5-methoxybenzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]tetrahydropyran-3,4,5-triol;

(2S,3R,4R,5S,6R)-2-[3-(5-ethylbenzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]-6-hydroxyethylacrylate-3,4,5-triol;

(2S,3R,4R,5S,6R)-2-[3-(5-chlorobenzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]-6-hydroxyethylacrylate-3,4,5-triol;

(2R,3S,4R,5R,6S)-2-hydroxymethyl-6-[3-(5-methylbenzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]tetrahydropyran-3,4,5-triol;

(2R,3S,4R,5R,6S)-2-hydroxymethyl-6-[3-(5-methylthiophene-2-ylmethyl)naphthalene-1-yl]tetrahydropyran-3,4,5-triol and

(2R,3S,4R,5R,6S)-2-hydroxymethyl-6-[3-(5-ethylthiophen-2-ylmethyl)naphthalene-1-yl]tetrahydropyran-3,4,5-triol.

According to further aspect of the present invention proposed a pharmaceutical composition containing the above compound, its prodrug or pharmaceutically acceptable salt, which is used as an inhibitor of cotransporter Na+-glucose.

According to further aspect of the present invention proposed a pharmaceutical composition containing the above compound, its prodrug or pharmaceutically acceptable salt, which is used for the prophylaxis or treatment of diabetes [e.g., insulin-dependent diabetes (type I diabetes) and non-insulin-dependent diabetes (type II diabetes)], diabetic complications caused by hyperglycemia, or obesity.

According to another TSA is KTU present invention, a method for prevention or treatment of diabetes [e.g., insulin-dependent diabetes (type I diabetes) and non-insulin-dependent diabetes (type II diabetes)], diabetic complications caused by hyperglycemia, or obesity, which comprises the administration to the patient an effective amount of the above compound, its prodrug, or pharmacologically acceptable salt.

In the above formulas (I), (Ia), (Ib) and (Ic) groups represented by R1, R2, R3and R4include, for example, a hydrogen atom, a C1-C6alkyl group, a C1-C6alkoxy With1-C6alkyl group, a C7-C14aracelio group1-C6alkylcarboxylic group7-C14aralkylamines group1-C6alkoxycarbonyl group and7-C14aracelikarsaalyna group. These groups may be substituted by one or more substituents, each of which is independently selected from a halogen atom, hydroxy-group, With1-C6alkoxygroup,1-C6alkylcarboxylic group, carboxyl group, amino group and substituted amino group. As R1, R2, R3and R4the preferred hydrogen or C1-C6acylcarnitine group, and particularly preferred hydrogen atom.

In the above formulas, Ar1may contain, for example, from about the nogo up to four identical or different substituents, for example, one to four substituents, each of which is independently selected from a halogen atom; a hydroxy-group; C1-C6alkyl group, a C3-C8cycloalkyl group1-C6alkyloxy and C1-C6allylthiourea (these four groups can contain from one to four substituents selected from halogen atom, hydroxy-group and amino group); methylendioxy; ceanography; C1-C6alkylsulfonyl group; C1-C6alkylsulfonamides; nitro group; carboxyl group; a substituted amino group; and 4-6-membered heterocyclyl group.

In the above formula A can contain, for example, from one to four identical or different substituents, for example, from one to four substituents, each of which is independently selected from a halogen atom; a hydroxy-group; C1-C6alkyl group, a C3-C8cycloalkyl group1-C6alkyloxy and C1-C6allylthiourea (these four groups can contain from one to four substituents, each of which is independently selected from a halogen atom, hydroxy-group and amino group); methylendioxy; ceanography; C1-C6alkylsulfonyl group; C1-C6alkylsulfonamides the dust; the nitro group; carboxyl group; a substituted amino group; a 5 - or 6-membered heteroaryl group; and a 4-6-membered heterocyclyl group.

The group presented And includes, for example, pyrrolidinyl group, indolenine group, pyridyloxy group, pinolillo group, izohinolinove group, thienyl group, benzothiazoline group, follow group, benzofuranyl group, thiazolidine group, benzothiazolyl group, isothiazolinone group, benzothiazolyl group, pyrazolidine group, indazolinone group, oxazolidinyl group, benzoxazolyl group, isoxazolyl group, benzisoxazole group, imidazolidinyl group, benzoimidazolyl group, triazolyl group, benzotriazolyl group, pyrimidinyl group, brazilrio group, personilnya group, pyridazinyl group, imidazopyridine group, triazolopyrimidine group and group pyrrolopyridine; and, in addition, preferable are a thienyl group, benzothiazoline group, furilla group and benzofuranyl group; and more preferred are a thienyl group and benzothiazoline group. When And represents benzoannelirovannykh cycle containing two or more rings, the group -(CH2)m- in the above formulas associated with heterocycle at A.

Used in the present description, the term "C 1-C6alkyl group" means a linear or branched alkyl group containing from 1 to 6 carbon atoms, and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl and 2-ethylbutyl; and preferred With1-C6alkyl groups include, for example, linear or branched alkyl groups containing from one to three carbon atoms; and particularly preferred are methyl and ethyl.

Used in the present description, the term "C3-C8cycloalkyl group" means a cyclic alkyl group containing 3 to 8 carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Used in the present description, the term "C1-C6alkoxygroup" means alkoxygroup, including linear or branched alkyl group containing from one to six carbon atoms, in the alkyl fragment, and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, n-pentox, 3 methylbutoxy, 2-methylbutoxy, 1 methylbutoxy, 1-telpro is hydroxy, n-hexyloxy, 4-methylphenoxy, 3 methylpentane, 2-methylpentane, 1 methylpentane and 3 ethylbutane.

Used in the present description, the term "C7-C14kalkilya group" means aracelio group containing from 7 to 14 carbon atoms and includes aryl group and includes, for example, benzyl, 1-phenethyl, 2-phenethyl, 1-naphthylmethyl and 2-naphthylmethyl.

Used in the present description, the term "C7-C14arancelaria" means arylalkylamine containing from 7 to 14 carbon atoms, which includes defined above aracelio group, and includes, for example, benzyloxy, 1-penetrate, 2-penetrate, 1 naphthalenyloxy and 2 naphthalenyloxy.

Used in the present description, the term "aryl group" means aryl group include aromatic hydrocarbon cycle, containing six to ten carbon atoms, and includes, for example, phenyl, 1-naphthyl and 2-naphthyl.

Used in the present description, the term "heteroaryl group" means a 5-to 10-membered aromatic heterocyclic group containing one or more heteroatoms independently selected from oxygen atom, nitrogen atom and sulfur atom, and includes, for example, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, Arcadia is alil, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, chinosol and ethanolic. Preferred heteroaryl groups are 5-6-membered heteroaryl group, as pyrrolidine group, pyrazolidine group, imidazolidinyl group and Peregrina group, and particularly preferred is pyrazolidine group.

Used in the present description, the term "alloctype" means alloctype, including defined above aromatic hydrocarbon group containing from six to ten carbon atoms, as the aryl fragment, and includes, for example, phenoxy, 1 naphthoxy and 2 naphthoxy.

Used in the present description, the term "heteroanalogues" means heteroepitaxy, including defined above 5-10-membered aromatic heterocyclic group containing one or more heteroatoms selected from oxygen atom, nitrogen atom and sulfur, as heteroaryl fragment, and includes, for example, forelocks, titilate, pyrrolidone, imidazolidine, pyrazolinone, oxazolidone, isoxazolidine, thiazolidine, isothiazolinone, oxadiazolidine, thiadiazolidine, triazolinone, tetrazolate, pyridyloxy, pyrimidinone, pyrazinone, pyridazinone, intolerance, hyalinelike is ethanolinduced. The preferred heteroarylboronic are 5-6-membered heterokaryosis.

Used in the present description, the term "C1-C6alkylamino" means alkylamino, including linear or branched alkyl group containing from one to six carbon atoms as the alkyl fragment, and includes, for example, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, isobutylamino, tert-butylamino, n-pentylamine, 3 methylbutylamine, 2-methylbutylamine, 1 methylbutylamine, 1 ethylpropylamine, n-hexylamino, 4-methylpentylamino, 3 methylpentylamino, 2-methylpentylamino, 1 methylpentylamino, 3-ethylbutylamine and 2 ethylbutylamine.

Used in the present description, the term "di(C1-C6alkyl)amino group" means dialkylamino, including linear or branched alkyl groups, each of which contains from one to six carbon atoms in the two alkyl fragments, which may be the same or different. "Di(C1-C6alkyl)amino group" includes, for example, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, methyl-n-butylamino, methyl-sec-butylamine, methylisobutylketone, tert-butylamino, ethyl-n-butylamino, ethyl-sec-butyl is Mino, ethylisopropylamine and ethyl-tert-butylamino.

Used in the present description, the term "C1-C6allylthiourea" means allylthiourea, including linear or branched alkyl group containing from one to six carbon atoms as the alkyl fragment, and includes, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, isobutyric, tert-butylthio, n-pentylthio, 3 methylbutyl, 2-methylbutyl, 1 methylbutyl, 1 ethylpropyl, n-hexylthio, 4-methylphenylthio, 3 methylphenylthio, 2-methylphenylthio, 1 methylphenylthio, 3-ethylbutyl and 2 ethylbutyl.

Used in the present description, the term "C1-C6alkylsulfonyl group" means alkylsulfonyl group (-SO-R), including linear or branched alkyl group containing from one to six carbon atoms as the alkyl fragment, and includes, for example, methylsulfinyl, ethylsulfinyl, n-propylsulfonyl, isopropylphenyl, n-butylsulfonyl, second-butylsulfonyl, isobutylamine, tert-butylsulfonyl, n-pentylaniline, 3-methylbutylamine, 2-methylbutylamine, 1-methylbutylamine, 1-ethylpropylamine, n-hexylaniline, 4-methylphenylsulfonyl, 3-methylphenylsulfonyl, 2-methylphenylsulfonyl, 1-methylphenylsulfonyl, 3-ethyl shall ethylsulfinyl and 2-ethylbutylamine.

Used in the present description, the term "C1-C6alkylsulfonyl group" means alkylsulfonyl group including linear or branched alkyl group containing from one to six carbon atoms as the alkyl fragment, and includes, for example, methylsulphonyl, ethylsulfonyl, n-propylsulfonyl, isopropylphenyl, n-butylsulfonyl, second-butylsulfonyl, isobutylamine, tert-butylsulfonyl, n-peterculter, 3-methylbutylamine, 2-methylbutylamine, 1-methylbutylamine, 1-ethylpropylamine, n-hexylsilane, 4-methylphenylsulfonyl, 3-methylphenylsulfonyl, 2-methylphenylsulfonyl, 1-methylphenylsulfonyl, 3-ethylbutylamine and 2-ethylbutylamine.

Used in the present description group-C(=O)-Rx" includes, for example, With1-C6alkylcarboxylic group7-C14aralkylamines group1-C6alkoxycarbonyl group and7-C14aracelikarsaalyna group. With1-C6acylcarnitine group includes, for example, acetyl group, propionyl group, butyryloxy group and pivaloyl, and particularly preferred is an acetyl group. With7-C14analceleberty group includes, for example, benzylcarbamoyl gr the PPU and naphthylethylenediamine group, and it is preferable benzylcarbamoyl group.

With1-C6alkoxycarbonyl group includes, for example, methoxycarbonyl group and ethoxycarbonyl group, and preferred is methoxycarbonyl group. With7-C14aracelikarsaalyna group includes, for example, benzyloxycarbonyl group and naphthylethylenediamine group, and preferred is benzyloxycarbonyl group.

Used in the present description, the term "halogen atom" includes, for example, fluorine atom, chlorine atom, bromine atom and iodine atom.

Used in the present description, the term "4-7-membered heterocycle" means a heterocycle, which may be fully saturated or partially or fully unsaturated, and contains one nitrogen atom and may further contain one or more heteroatoms independently selected from oxygen atom, nitrogen atom and sulfur atom, and includes, for example, azetidine, pyrrolidine, piperidine and morpholine, and is preferred piperidine.

Used in the present description, the term "aromatic carbon cycle" means 6-10-membered aromatic carbon cycle and includes, for example, benzene ring and naphthalene ring.

Used in the present description, the term "aromatic Goethe is acicl" means a 5-6-membered aromatic heterocycle, containing one or more heteroatoms independently selected from oxygen atom, nitrogen atom and sulfur atom, and includes, for example, pyrrole cycle, indole cycle, titanovyi cycle, benzothiophene cycle, furan cycle, benzofuranyl cycle, the pyridine cycle, quinoline cycle, isoquinoline cycle, thiazole cycle, benzothiazolyl cycle, isothiazol cycle, benzothiazolyl cycle, pyrazol cycle indazol cycle, oxazolyl cycle, benzoxazolyl cycle, isoxazolyl cycle, benzisoxazole cycle, imidazole cycle, benzoimidazolyl cycle, triazole cycle, benzotryazolyl cycle, pyrimidine cycle, orally cycle, pyrazinoic cycle and pyridazinones cycle.

Used in the present description, the term "substituted amino group" includes, for example, -NReRf where Re represents a hydrogen atom, a C1-C6alkyl group, a C1-C6alkylcarboxylic group, karbamoilnuyu group or1-C6alkoxycarbonyl group; Rf represents a hydrogen atom, or1-C6alkyl group; and Re and Rf may form a 4-7-membered heterocycle together with the nitrogen atom to which they relate).

Used in the present description, the term "C1-C3alkylenedioxy" means a divalent group represented by the formula: -O-(C1-C3kilen)-O - and include, for example, methylenedioxy, Ethylenedioxy and diethyleneoxide.

Used in the present description, the term "heterocyclyl group" means a 4-7-membered heterocyclyl group that contains one or more heteroatoms independently selected from oxygen atom, nitrogen atom and sulfur atom, and may be fully saturated or partially or fully unsaturated, and comprises, for example, azetidine, pyrrolidine, piperidinyl, piperazinil, pyrrolyl, imidazolyl, imidazolyl, pyrazolyl, pyrazolyl, oxazolyl, morpholinyl, thiomorpholine, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, hexamethylenimine, furyl, tetrahydrofuryl, thienyl, tetrahydrofuryl, DIOXOLANYL, and oxathiolanes dioxane. The position of substitution in heterocyclyl group is not particularly limited, as it is a substitutable position with the carbon atom or nitrogen atom.

In addition, the compounds of the present invention include the tautomers, mixtures of these different types of stereoisomers, optical isomers and individual isomers.

Compounds of the present invention sometimes form an acid additive salt. In addition, depending on the type of substituent sometimes they form salts with bases. Such salts include, for example, such an acid additive salt, as chloritoid Edna acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, nitric acid and phosphoric acid and such organic acids as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonate and econsultation; such acidic amino acids like aspartic acid and glutamic acid. In addition, salts formed with bases include salts with inorganic bases like sodium, potassium, magnesium, calcium and aluminium, salts with organic bases, as methylamine, ethylamine, and ethanolamine; salts with basic amino acids like lysine and ornithine; and ammonium salts.

In addition, the compounds of the present invention include hydrates and various pharmaceutically acceptable solvate, polymorph, and so on.

In addition, the compounds of the present invention is not limited to compounds which will be described in the following examples, and include all derivatives glucitol represented by the above formula (I)and their pharmaceutically acceptable salts.

In addition, the present invention includes compounds which are converted into compounds, performance is undertaken by the above formula (I), as a result of metabolism in vivo, and their pharmaceutically acceptable salts, that is, so-called prodrugs. Group comprising prodrugs of the compounds of the present invention include, for example, the groups described in Prog. Med., 5, 2157-2161 (1985), and groups described in the Development of Drugs,7(Molecular Designing), 163-198, Hirokawa Shoten, 1990.

Compounds of the present invention can be obtained by using various known methods of synthesis, depending on the features based on the type of main skeleton or Deputy. For example, in the case when the group is preferable protect with the appropriate protective group at the stage of starting compound or intermediate compounds from the point of view of the methodology of the specified protective group can be removed at a later stage, to obtain the desired compound. Groups that must be protected at the stage of receipt, include, for example, the hydroxy-group and carboxyl group, and the protective group for the specified groups include protective groups are described in Green and Wuts, Protective Groups in Organic Synthesis, 2nd edition. Used protective group and the reaction conditions for introducing and removing the protective group is chosen appropriately, according to known methods, as described in the above sources.

Compounds of the present invention possess Inga is yuusei activity against retrieveimage the glucose Transporter 2 (SGLT2) (J. Clin. Invest., 93, 397 (1994)), related to the re-absorption of glucose in the kidneys. When the inhibition of reabsorption of glucose is excreted excess glucose and hyperglycemia can be cured, not loading β-cells of the pancreas, having a therapeutic effect on diabetes and superior effect on insulin resistance.

Thus, according to one aspect of the present invention proposed drug for the prevention or treatment of diabetes, or a condition which can be alleviated by inhibiting SGLT2 activity, such as diabetes, diabetes-related diseases and complications of diabetes.

Used in the present description, the term "diabetes" includes type I diabetes, type II diabetes and other types of diabetes due to certain reasons. In addition, used in the present description, the term "diabetes-related disease" includes, for example, obesity, hyperinsulinism, impaired sugar metabolism, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipogranulomas, hypertension, congestive heart failure, edema, hyperuricemia and gout.

In addition, used in the present description, the term "complications of diabetes" includes both acute complications and chronic complications. Acute complications include, for example, hyperslices the Yu (ketoacidosis, and so on) and infectious diseases (such as diseases of the skin, soft tissue, biliary tract, respiratory system and urinary system), and "chronic complications" include, for example, the microangiopathy (nephropathy and retinopathy), arteriosclerosis, atherosclerosis, myocardial infarction, thrombosis of cerebral vessels and thrombosis of the lower Limbaugh artery), neuropathy (such as neuropathy sensory nerves, motor nerves and autonomic nerves) and gangrene of the feet. The main complication of diabetes includes, for example, diabetic retinopathy, diabetic nephropathy and diabetic neuropathy.

In addition, the compounds of the present invention can be used in combination with an agent for diabetes, a therapeutic agent for treating diabetic complications, a therapeutic agent for treatment of hyperlipidemia, a therapeutic agent for the treatment of hypertension or the like, the mechanism of action differs from the mechanism of action of inhibitors of SGLT2 activity. The combination of the compounds of the present invention with other agents can be expected additive effect compared with the effect obtained from each individual agent in the case of the above diseases.

"Therapeutic agents for the treatment of diabetes and therapeutic agents for treating diabetic complications"that can be used in the form of op is Tania, include, for example, amplifiers insulin sensitivity (such as an agonist of PPAR γ agonist PPAR α/γ agonist of PPAR-δ and PPAR agonist α/γ/δ), glucosidase inhibitors, biguanides medicines, activators of insulin secretion, insulin antagonists glukagonovykh receptors, kinase activators of insulin receptors, inhibitors tripeptidylpeptidase II inhibitors dipeptidylpeptidase IV inhibitors patientinitiated-1B, glycogen phosphorylase inhibitors, inhibitors of glucose-6-phosphatase, inhibitors of gluconeogenesis, inhibitors fruktozodifosfata, inhibitors piruvatdegidrogenazy, activators of glucokinase, D-chiroinositol inhibitors kinase glikogensintetazy 3, like peptide-1 analogues of like peptide-1, agonists of like peptide-1, amirin, the analogues of amerina, agonists of amerina, glucocorticoid receptor antagonists, inhibitors of 11β-hydroxysteroid dehydrogenase inhibitors alsoreported, inhibitors of protein kinase C antagonists of receptors for γ-aminobutyric acid, sodium channel antagonists, inhibitors of transcription factor NF-κB inhibitors of IKK-β inhibitors lipidperoxidation, inhibitors of N-acetylated-α-linked-acid-dipeptidase, insulin-like growth factor-I, platelet-derived growth factor (PDGF), analogues of platelet factor growth(PDGF), epidermal growth factor (EGF), factor nerve growth, derivatives of carnitine, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, vimolmal, sulodexide, Y-128, and TAR-428.

As therapeutic agents for the treatment of diabetes and therapeutic agents for the treatment of complications of diabetes are the following.

"Biguanide drugs" include, for example, hydrochloride Metformin and phenformin.

In a series of "activators of insulin secretion" sulfonylureas include, for example, gliburid (glibenclamide), glipizide, gliclazide and hlorpropamid and desulfonylation include, for example, nateglinide, Repaglinide and mitiglinide.

"Insulin" includes recombinant human insulin and insulin derived from animals and are divided into three groups according to duration of action, i.e. the type of immediate action (human insulin and human neutral insulin), intermediate type (aqueous suspension of insulin-human isovanillin, aqueous suspension of neutral human insulin-human isovanillin, water zinc suspension human insulin and water zinc suspension insulin) and type of long-term action (zinc crystalline suspension of human insulin).

"Glycosidase inhibitors" include, is for example, acarbose, voglibose and miglitol.

Agonists of PPAR γ "amplifiers insulin sensitivity include, for example, troglitazone, pioglitazone and rosiglitazone, and dual agonists, PPAR α/γ include, for example, MK-767 (KRP-297), tesaglitazar, LM-4156, LY 510929, DRF-4823 and TY-51501, and agonists of PPAR δ include, for example, GW-501516.

"Inhibitors tripeptidylpeptidase II include, for example, THE-139.

"Inhibitors dipeptidylpeptidase IV include, for example, NVP-DPP728A, LAF-237, MK-0431, P32/98 and TSL-225.

"Inhibitors alsoreported" include, for example, ascorbylpalmitate, tolrestat, epalrestat, fidarestat, sorbinil, ponalrestat, resurected and zenarestat.

"Antagonists of receptors for γ-aminobutyric acid" includes, for example, topiramate.

"Sodium channel antagonists include, for example, hydrochloride meksiletina.

"Inhibitors of transcription factor NF-κB include, for example, dukkipati.

"Inhibitors lipoperoxides" include, for example, terilization.

"Inhibitors of N-acetylated α-linked-acid-dipeptidase" include, for example, GPI-5693.

"Derivatives of carnitine include, for example, carnitine hydrochloride and levocetirizine.

"Therapeutic agents for the treatment of hyperlipidemia and therapeutic agents for the treatment of hypertension", which can use the AMB in combination, include, for example, inhibitors hydroxymethylglutaryl-coenzyme a-reductase fibrate compounds, agonists of the receptor β3-adrenaline, activators AMRS, inhibitors allgovernment A: cholesterol-acyltransferase, probucol, agonists of the receptors, thyroid hormone, inhibitors of cholesterol absorption, lipase inhibitors, inhibitors of microsome protein transfer of triglycerides, lipoxygenase inhibitors, inhibitors carnitinelongevity inhibitors stvalentines, activators of receptor low density lipoprotein, a derivative of nicotinic acid, bile acid adsorbents, inhibitors of Transporter nutrician bile acids, inhibitors of protein transfer cholesterolemic esters, angiotensin converting enzyme inhibitors, receptor antagonists angiotensin II inhibitors endotelinzawisimogo enzyme antagonists endothelioma receptors, diuretics, calcium antagonists, vasodilators, antihypertensive agents, blockers of the sympathetic activity, anti-hypertensive agents Central action, agonists α2-adrenergic receptors, protivotromboznoe agents, inhibitors of the formation of uric acid, stimulants urinary excretion of uric acid, agents, alkalizing urine, anorectic, agonists adiponectin receptor GPR40 agonists, antagoni what you GPR40.

As therapeutic agents for the treatment of hyperlipidemia and therapeutic agents for the treatment of hypertension as the following example shows.

"Inhibitors hydroxymethylglutaryl-coenzyme A-reductase inhibitor" includes, for example, fluvastatin, lovastatin, pravastatin, tseriwastatina and pitavastatin.

"Fibrate compounds include, for example, bezafibrat, beclobrate and benefibre.

"Inhibitors stvalentines" include, for example, SO-475, derivatives of α-phosphosulfate (described in U.S. patent No. 5712396).

"Allgovernment As: inhibitors of cholesterol-acyltransferase" include, for example, CI-1011, NTE-122, FCE-27677, RP 73163, MCC-147 and DPU-129.

"Activators of receptor low density lipoprotein" include, for example, MD-700, and LY-295427.

"Inhibitors of microsome protein transfer of triglycerides (MTP inhibitors)include, for example, the compounds given in the descriptions of U.S. patent No. 5739135, 5712279, 5760246 and so on.

"Anorectic" include, for example, adrenaline·noradrenergic agonists (mazindol, ephedrine, and so on), serotonin agonists (such selective inhibitors of serotonin reuptake, as fluvoxamine), adrenaline·serotonin agonists (sibutramine and so on), agonists of the receptor melanocortin 4 (MC4R) and α-melanocarcinoma hormones (α-sit), leptin, to the ain and amphetaminelike transcript (CART) and so on.

"Agonists of the receptors of thyroid hormones include, for example, liotironin sodium and levothyroxine sodium.

"Adsorption inhibitors of cholesterol include, for example, ezetimibe.

"Lipase inhibitors" include, for example, orlistat.

"Inhibitors carnitinelongevity" include, for example, etomoxir.

"Derivatives of nicotinic acid include, for example, nicotinic acid, nicotinamide, nicomol and nicorandil.

"Adsorbents bile acids" include, for example, cholestyramine, colestilan and hydrochloride colesevelam.

"Angiotensin converting enzyme inhibitors" include, for example, captopril, enalaprilat, alacepril and cilazapril.

"Antagonists of angiotensin II receptors" include, for example, candesartanzapomnit, losartan potassium and apresentadora.

"Inhibitors endotelinzawisimogo enzyme" includes, for example, CGS-31447 and CGS-35066.

"Antagonists endothelioma receptors" include, for example, L-749805, TBC-3214 and BMS-182874.

For example, in the treatment of diabetes and the like compounds of the present invention is preferably used together with at least one agent selected from the group comprising amplifiers insulin sensitivity (agonists of PPAR γ agonists, PPAR α/γ agonists, PPAR δ, PPAR α/γ/δ, and so forth), inhibitors of glycosidase, biguanide drugs, activators of insulin secretion, insulin and inhibitors dipeptidylpeptidase IV.

In addition, it is preferable that the compounds of the present invention was used together with at least one agent selected from the group comprising inhibitors hydroxymethylglutaryl-coenzyme a-reductase fibrate compounds, inhibitors stvalentines, inhibitors of acyl-coenzyme A: cholesterol-acyltransferase, activators of receptor low density lipoprotein inhibitors microsome protein transfer of triglycerides and anorectic.

Drugs of the present invention can enter the systemic or local, or oral, or parenteral (e.g., rectally, subcutaneously, intramuscularly, intravenously or transdermally).

Compounds of the present invention, which are used as pharmaceutical preparations can be in the form of solid compositions, liquid compositions and other compositions, and choose the most suitable desired shape. Drugs of the present invention can be obtained by introducing a pharmaceutically suitable carrier in the compounds of the present invention. Specifically, the compounds of the present invention add the most commonly used excipient, filler, svyazivalsa the substance, baking powder, agent for the coating agent for sugar coating, a pH regulator, solubilizers agent or an aqueous or nonaqueous solvent to obtain tablets, pills, capsules, granules, powders for dusting, powders, liquids and solutions, emulsions, suspensions, solutions for injections or the like by means of the commonly used methods for obtaining pharmaceutical compositions. Excipients and fillers include, for example, lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, Arabic gum, olive oil, sesame oil, cacao butter, ethylene glycol and other commonly used substances.

In addition, the compounds of the present invention can be prepared medicines, receiving clathrate compounds with α-, β - or γ-cyclodextrin or methylated-cyclodextrin.

The dose of the compounds of the present invention varies depending on the disease, condition of the disease, weight, age, sex, and method of administration, and is preferably from 0.1 to 1000 mg/kg/day, more preferably from 0.1 to 200 mg/kg/day and may be given once a day, or separately, several times a day.

Compounds of the present invention can be synthesized, for example, using the methods of obtaining below.

Compounds of the present invention with naziroute way shown in scheme 1.

Scheme 1

in which R11and R12similar to the substituents on the Ar1defined above, and And are the same as defined above.

That is, the compound (III) are alkyllithium (for example, n-butyllithium or the like), and then injected into interaction with the compound (II)to give compound (IV), and then celanova reagent (for example, triethylsilane or the like) to act on the compound (IV) in the presence of acid (e.g., triperoxonane acid complex of boron TRIFLUORIDE-diethyl ether or the like), getting derived mating (V), and then perform dibenzylamine reaction of catalytic hydrogenation in the presence of a palladium catalyst, in the way it uses acid Lewis (tribromide boron, trichloride boron complex trichloride boron-dimethyl sulfide complex of boron TRIFLUORIDE-diethyl ether and ethanthiol, a complex of boron TRIFLUORIDE-diethyl ether and dimethyl sulfide or the like) or the like, obtaining the compound (VI). In addition, the compound (II) can be synthesized, for example, by the method described in the source [Carbohydr. Res., 260, 243 (1994)], as the compound (III) can be synthesized, for example, by the method described in patent documents (international publication no WO 01/27128 and # WO 04/013118).

Connection nastoyascheevremya can also be obtained by the method of scheme 2.

Scheme 2

in which R11and R12similar to the substituents on the Ar1defined above, And the same as defined above, and X1and X2are halogen atoms.

That is, the compound (VII) act alkyllithium (for example, n-butyllithium or the like), and then injected into interaction with the compound (II)to give compound (VIII), and then celanova reagent (for example, triethylsilane or the like) to act on the compound (VIII) in the presence of acid (e.g., triperoxonane acid complex of boron TRIFLUORIDE-diethyl ether or the like), getting derived compounds (IX). The compound (IX) is converted into a compound (X) in suitable conditions of halogenation (for example, N-bromosuccinimide, bromine, bromovalerate or the like, when X1is a bromine atom), and then the compound (X) enter into interaction with heteroarylboronic (A-X2in the presence of a suitable palladium catalyst, and then carry out dibenzylamine reaction of catalytic hydrogenation in the presence of a palladium catalyst, in the way it uses the Lewis acid (tribromide boron, trichloride boron complex trichloride boron-dimethyl sulfide complex of boron TRIFLUORIDE is-diethyl ether and ethanthiol, the complex of boron TRIFLUORIDE-diethyl ether and dimethyl sulfide or the like) or the like, obtaining the compound (VI) of the present invention. In addition, the compound (VII) can be synthesized, for example, by the method described in patent document (international publication number WO 04/013118).

The above intermediate compound (X) can be obtained as follows.

Scheme 3

in which R11and R12similar to the substituents on the Ar1defined above, And the same as defined above, P is a protective group for a hydroxy-group, and X1is a halogen atom.

That is, the hydroxy-group of the compound (XII) protect with a suitable protective group P (for example, tert-butyldimethylsilyloxy group, tetrahydropyranyloxy group or the like), and then the obtained compound are suitable alkyllithium (for example, n-butyllithium or the like), and after that enter into interaction with the compound (II), obtaining the derivative of the compound (XIII). Then to compound (XIII) are celanova reagent (for example, triethylsilane or the like) in the presence of acid (e.g., triperoxonane acid complex of boron TRIFLUORIDE-diethyl ether or the like), getting derived compounds (XIV). This is followed by the removal of protection, olucha compound (XV), and after that, the obtained compound is subjected to galogenirovannyie in suitable conditions (conditions using N-bromosuccinimide, bromine, chetyrehpostovye carbon or the like)to give compound (X).

Compounds of the present invention can also be obtained by the method according to scheme 4.

Scheme 4

in which R11and R12similar to the substituents on the Ar1defined above; each of R13independently selected from C1-C6alkyl groups (for example, butilkoi group or the like), And are the same as defined above, and X is a halogen atom.

If necessary, the compound (XVI) are acid anhydride (for example, anhydride triperoxonane acid or the like) in the presence of a suitable base (e.g. sodium acetate or the like), and then injected into interaction with the compound (XVII) in the presence of a suitable Lewis acid (for example, a complex of boron TRIFLUORIDE-diethyl ether or the like)to give compound (XVIII). Then the compound (XVIII) enter into interaction with sexualcardiologist (for example, hexabutylditin or the like) in the presence of a suitable palladium catalyst, obtaining a derivative of the compound (XIX), which is then injected into the interaction with A-CH2-X (where a similar is n defined above, and X is a halogen atom) in the presence of a suitable palladium catalyst, obtaining a derivative of the compound (XX).

Then carry out dibenzylamine reaction of catalytic hydrogenation in the presence of a palladium catalyst, in the way it uses the Lewis acid (tribromide boron, trichloride boron complex trichloride boron-dimethyl sulfide complex of boron TRIFLUORIDE-diethyl ether and ethanthiol, a complex of boron TRIFLUORIDE-diethyl ether and dimethyl sulfide or the like)to give compound (VI).

The method of obtaining the compounds of the present invention is not limited in the ways described. Compounds of the present invention can also be obtained, for example, with the appropriate combination of stages included in schemes 1-4.

EXAMPLES

The content of the present invention will be explained in more detail using the following examples and experimental examples, but the present invention is not limited to their content.

Each abbreviation in the following examples has the following value.

NMR: nuclear magnetic resonance (internal standard TMS);

MS: the value obtained by the method of mass spectrometric analysis;

HPLC: high performance liquid chromatography;

NMR, MS and HPLC was carried out using the following equipment.

NMR: JOEL JNM-EX-270 (270 MG is) or Bruker ARX 300 (300 MHz);

MS: LCQ from Thermo Finigan or Micromass ZQ, or Quattro micro from the Waters;

HPLC: 2690/2996 (detector) from the Waters.

Example 1

(2S,3R,4R,5S,6R)-2-[3-(benzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]-6-hydroxyethylacrylate-3,4,5-triol

(1) Synthesis of (benzo[b]thiophene-2-yl)-(4-does not depend-2-yl)methanol

Under nitrogen atmosphere a solution of n-utility in hexane (1.6 M, 2,04 ml of 3.27 mmol) was added dropwise to a solution of benzothiophene (0,48 g, 3.58 mmol) in anhydrous THF (10 ml) at -78°C for 5 minutes. The reaction solution was stirred at -78°C for 10 minutes and then at room temperature for 20 minutes. To the obtained reaction mixture was added dropwise a solution of 4-does not depend-2-carbaldehyde (0,73 ml, 3.11 mmol) in anhydrous THF (5 ml) at -78°C and stirred at -78°C for two hours. To the reaction mixture were added saturated aqueous solution of ammonium chloride and was extracted with the mixture of diethyl ether, the organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After filtration the solvent is kept under reduced pressure, and the obtained residue was column purified flash chromatography on silica gel [n-hexane:ethyl acetate (10:1)], getting mentioned in the title compound (1.0 g, 75,6%).

1H-NMR (CDCl3) δ: 2,72 (1H, d, J=3,9 Hz), to 6.22 (1H, d, J=3.6 Hz), 7,17 (1H, s), 7,25 was 7.36 (2H, m), 7,52-of 7.70 (3H, m),to 7.77 (1H, d, J=7.5 Hz), 7,83 (1H, d, J=7.8 Hz), to 7.84 (1H, s), 7,92 (1H, s), 8,21 (1H, d, J=8,1 Hz).

(2) Synthesis of 2-(4-does not depend-2-ylmethyl)benzo[b]thiophene

In a stream of nitrogen triethylsilane (of 0.48 ml, a 3.01 mmol) and a complex of boron TRIFLUORIDE-diethyl ether (0,34 ml, a 2.71 mmol) was added dropwise to a solution of (benzo[b]thiophene-2-yl)-(4-does not depend-2-yl)methanol (1.0 g, a 2.71 mmol) in methylene chloride (30 ml) at 0°C. the Reaction mixture was stirred at room temperature for three hours, was added 50%aqueous solution of methanol (1 ml) and then added to her water and was extracted with a mixture of methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride and was dried (anhydrous magnesium sulfate)and the solvent is then drove away under reduced pressure. The obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:40)], getting mentioned in the title compound (0,82 g, 85,6%).

1H-NMR (CDCl3) δ: 4,34 (2H, s), 7,05 (1H, s), 7.23 percent-7,33 (2H, m), of 7.48-to 7.59 (2H, m), 7,66-7,79 (5H, m), 8,19 (1H, d, J=8,1 Hz).

(3) Synthesis of (3R,4S,5S,6R)-2-[3-(benzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]-3,4,5-trebaseleghe-6-benzyloxypyrrolidine-2-ol

Under nitrogen atmosphere a solution of n-butylate in hexane (1.6 M, 1,58 ml of 2.53 mmol) was added dropwise to a solution of 2-(4-does not depend-2-ylmethyl)benzo[b]thiophene (0,81 g to 2.29 mmol) in anhydrous THF (15 ml) at -78°C for five minutes. The reaction is th the mixture was stirred at -78°C for 5 minutes, and then added to it dropwise a solution of 3,4,5-trebaseleghe-6-benzyloxypyrrolidine-2-it (1,36 g, 2,52 mmol) in anhydrous THF (10 ml) at -78°C. and stirred the reaction solution at -78°C for 2 hours. To the obtained reaction mixture was added saturated aqueous solution of ammonium chloride and was extracted with diethyl ether, the organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After filtration the solvent is kept under reduced pressure, and the obtained residue was column purified flash chromatography on silica gel [n-hexane:ethyl acetate (10:1)], getting mentioned in the title compound (1.4 g, 75%).

1H-NMR (CDCl3) δ: 3,47 (1H, d, J=10.5 Hz), 3,52 (1H, s), 3,74 (1H, d, J=10,2 Hz), 3,98 (1H, d, J=9.0 Hz), 4,10-to 4.28 (4H, m), 4,35 (2H, s), 4,46 (1H, d, J=11.7 Hz), 4,59 (1H, d, J=12 Hz), was 4.76 (1H, d, J=10,8 Hz), 4,88 (2H, s), equal to 4.97 (1H, d, J=10,8 Hz), of 6.66 (2H, d, J=7,2 Hz), 6,94 (2H, t, J=7.5 Hz), 7,05 (2H, d, J=7.5 Hz), 7,21-7,33 (18H, m), 7,42 (1H, t, J=7.5 Hz), a 7.62 (1H, d, J=7,2 Hz), to 7.68 (1H, d, J=7.8 Hz), 7,75 (1H, s), 7,80 (1H, d, J=7.8 Hz), 7,89 (1H, d, J=1,8 Hz), 8,63 (1H, d, J=8.7 Hz).

MS (ESI+): 836 [M+Na]+.

(4) Synthesis of (2S,3R,4R,5S,6R)-2-[3-(benzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]-3,4,5-trebaseleghe-6-benzyloxyacetophenone

In a stream of nitrogen triethylsilane (0,34 ml of 2.06 mmol) and a complex of boron TRIFLUORIDE-diethyl ether (0,24 ml, 1,89 mmol) was added dropwise to a solution of (3R,4S,5S,6R)-2-[3-(benzo[b]t the Hairdryer-2-ylmethyl)naphthalene-1-yl]-3,4,5-trebaseleghe-6-benzyloxypyrrolidine-2-ol (1.4 g, 1,72 mmol) in methylene chloride (15 ml) at 0°C. the Reaction mixture was stirred at room temperature for two hours, and then was added water and was extracted with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride and was dried (anhydrous magnesium sulfate), the solvent is then drove away under reduced pressure. The obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:10)], getting mentioned in the title compound (1.1 g, 80.2 per cent).

1H-NMR (CDCl3) δ: 3,42 (1H, d, J=10,2 Hz), 3,66-of 3.96 (6H, m), 4.09 to (1H, d, J=10,2 Hz), 4,37 (2H, s), 4,51 (1H, d, J=12.3 Hz), 4,63 (1H, d, J=12 Hz), 4,69 (1H, d, J=10,8 Hz), 4,87-4,96 (4H, m), 6,50 (2H, d, J=7,2 Hz), of 6.96 (2H, t, J=7,8, 7,2 Hz), 7,03 (1H, s), 7,06 (1H, d, J=7.5 Hz), 7,21-7,30 (17H, m), 7,37 is 7.50 (2H, m), 7,60 (2H, s), to 7.68 (1H, d, J=7.8 Hz), 7,74 (1H, s), 7,82 (1H, d, J=7.5 Hz), scored 8.38 (1H, d, J=8,4 Hz).

MS (ESI+): 820 [M+Na]+.

(5) Synthesis of (2S,3R,4R,5S,6R)-2-[3-(benzo[b]thiophene-2-ylmethyl)-naphthalene-1-yl]-6-hydroxyethylacrylate-3,4,5-triol

In a stream of nitrogen dimethyl sulfide (3.5 ml) and a complex of boron TRIFLUORIDE - diethyl ether (1.75 ml of 13.8 mmol) was added dropwise to a solution of (2S,3R,4R,5S,6R)-2-[3-(benzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]-3,4,5-trebaseleghe-6-benzyloxyacetophenone (1.1 g, 1.38 mmol) in anhydrous methylene chloride (30 ml) at 0°C. and stirred the reaction mixture at room temperature for three days. Doba is ranged to her water (10 ml) and the resulting mixture was extracted with methylene chloride. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After filtration the solvent is kept under reduced pressure, and the obtained residue was column purified flash chromatography on silica gel [methylene chloride:methanol (30:1)], getting mentioned in the title compound (0.35 g, 58.2 per cent).

1H-NMR (CD3OD) δ: 3,63-3,51 (3H, m), 3,69-3,81 (2H, m), 3,90 (1H, d, J=12 Hz), and 4.40 (2H, s), the 4.90 (1H, d, J=9.3 Hz), 7,11 (1H, s), 7,20-7,30 (2H, m), 7,44-7,49 (2H, m), of 7.64-7,74 (4H, m), 7,81 (1H, d, J=8,4 Hz), 8,27 (1H, d, J=8,1 Hz).

MS (ESI+): 459 [M+Na]+.

Example 2

(2S,3R,4R,5S,6R)-2-[3-(5-toranzo[b]thiophene-2-ylmethyl)-naphthalene-1-yl]-6-hydroxyethylacrylate-3,4,5-triol

(1) Synthesis of 1-(2,2-dimethoxymethylsilyl)-4-fermental

In a stream of nitrogen 4-fermentation (2.5 ml, and 23.4 mmol) and 2-bromo-1,1-dimethoxyethane (3.0 ml, of 25.7 mmol) was added to a solution of sodium methylate in methanol (0.5 M, 74,9 ml, or 37.4 mmol) under cooling with ice and stirred the reaction mixture at the same temperature for 10 minutes, and then heated and boiled under reflux for five hours. The reaction mixture was concentrated under reduced pressure and added cold water. The mixture was extracted with ether. The organic layer was washed saturated aqueous sodium chloride and then dried over sodium sulfate. After the filtering process is Italy drove away under reduced pressure, and the resulting residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:20)], getting mentioned in the title compound (4.52 g, 89%).

1H-NMR (CDCl3) δ: 3,05 (2H, d, J=5.4 Hz), the 3.35 (6H, s), of 4.49 (1H, t, J=5.4 Hz), 6,85 (2H, t, J=9.0 Hz), 7,31 (2H, DD, J=8,7, 5,1 Hz).

(2) Synthesis of 5-toranzo[b]thiophene

In nitrogen atmosphere polyphosphoric acid (10 g) was added to the anhydrous chlorobenzene (150 ml). To the resulting solution while boiling under reflux was added 1-(2,2-dimethoxymethylsilyl)-4-torbenson (4.0 g, 18.5 mmol) for 1.5 hours and boiled under reflux the resulting solution over night. The reaction mixture was cooled to room temperature, and then separated the organic layer. To the layer of polyphosphoric acid was added water and was extracted with methylene chloride. All the obtained organic layers were washed with water and saturated aqueous sodium chloride and dried over sodium sulfate. After filtration the solvent is kept under reduced pressure, and the obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:50)], getting mentioned in the title compound (420 mg, 15%).

1H-NMR (CDCl3) δ: 7,10 (1H, dt, J=8,7, 2.4 Hz), 7,27 (1H, DD, J=12,6, 7,2 Hz), 7,45-rate of 7.54 (2H, m), to 7.77 (1H, DD, J=8,7, 4,8 Hz).

(3) Synthesis of 4-does not depend-2-carbaldehyde

Under nitrogen atmosphere a solution of oxalicacid in methylene chloride (2.0 M 4,88 ml) was diluted with methylene chloride (40 ml) was added dropwise dimethyl sulfoxide (0.9 ml, 12.7 mmol) at -78°C. To this solution was added dropwise a solution of (4-does not depend-2-yl)methanol (1,15 g, 4,88 mmol), synthesized according to the source [J. Med. Chem., 37, 2485(1993)] in methylene chloride (10 ml) for 10 minutes. This reaction mixture was stirred at -78°C for 15 minutes and at -45°C for one hour and then was added to it drop wise addition of triethylamine (4.0 ml, of 29.3 mmol) and stirred at 0°C for 30 minutes. To this reaction solution was added saturated aqueous solution of ammonium chloride and the resulting solution was extracted with methylene chloride. The organic layer was washed with water and saturated aqueous sodium chloride and dried over sodium sulfate. After filtration the solvent is kept under reduced pressure, and the obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:20)], getting mentioned in the title compound (890 mg, 78%).

1H-NMR (CDCl3) δ: 7,66 (1H, t, J=7,7 Hz), 7,78 (1H, t, J=8.0 Hz), 8,21 (1H, d, J=8.0 Hz), 8,27-8,33 (3H, m), 10,11 (1H, s).

(4) Synthesis of (4-does not depend-2-yl)-(5-toranzo[b]thiophene-2-yl)methanol

In a stream of nitrogen a solution of n-butylate in hexane (1.6 M, 1,68 ml, 2.68 mmol) was added dropwise to the races the thief 5-toranzo[b]thiophene (410 mg, 2.68 mmol) in THF (10 ml) and stirred the reaction solution at the same temperature for 10 minutes. To this solution was added dropwise a solution of 4-does not depend-2-carbaldehyde (600 mg, 2.55 mmol) in THF (5 ml) at -78°C. the resulting mixture was stirred at the same temperature for two hours, and then was added a saturated aqueous solution of ammonium chloride and the mixture was extracted with ether. The organic layer was washed with a saturated aqueous solution of sodium chloride and was dried (anhydrous magnesium sulfate)and the solvent is then drove away under reduced pressure. The obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:10)], getting mentioned in the title compound (680 mg, 69%).

1H-NMR (CDCl3) δ: 2,75 (1H, d, J=3,9 Hz), of 6.20 (1H, d, J=3.6 Hz),? 7.04 baby mortality (1H, dt, J=9,0, 2.4 Hz), 7,11 (1H, s), 7,33 (1H, DD, J=9,3, 2.7 Hz), of 7.48-7,63 (2H, m), 7,68 (1H, DD, J=8,7, 4,8 Hz), 7,82-7,94 (3H, m), 8,21 (1H, d, J=8,4 Hz).

(5) Synthesis of 2-(4-does not depend-2-ylmethyl)-5-toranzo[b]thiophene

In a stream of nitrogen triethylsilane (of 0.18 ml, 2,11 mmol) and a complex of boron TRIFLUORIDE-diethyl ether (0.25 ml, 1.94 mmol) was added dropwise to a solution of (4-does not depend-2-yl)-(5-toranzo[b]thiophene-2-yl)methanol (260 mg, of 0.65 mmol) in methylene chloride (10 ml) at 0°C and stirred the mixture at room temperature for two hours. Was added a saturated aqueous solution of sodium bicarbonate, and ek is was tragically a mixture of methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride and was dried (anhydrous magnesium sulfate)and the solvent is then drove away under reduced pressure. The obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:100)], getting mentioned in the title compound (520 mg, 80%).

1H-NMR (CDCl3) δ: 4,32 (2H, s), 7,02 (2H, dt, J=9,0, 2.4 Hz), 7,25-of 7.82 (7H, m), to 8.20 (1H, d, J=9.0 Hz).

(6) Synthesis of (3R,4S,5S,6R)-3,4,5-trebaseleghe-6-benzoyloxymethyl-2-[3-(5-toranzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]tetrahydropyran-2-ol

In a stream of nitrogen a solution of n-butylate in hexane (1.6 M, of 0.97 ml, 1.55 mmol) was added dropwise to a solution of 2-(4-does not depend-2-ylmethyl)-5-toranzo[b]thiophene (520 mg, of 1.41 mmol) in THF (15 ml) at -78°C. and stirred the reaction mixture at the same temperature for 10 minutes. To this solution was added dropwise a solution of 3,4,5-trebaseleghe-6-benzyloxypyrrolidine-2-it (835 mg, 1.55 mmol) in THF (3 ml). The mixture was stirred at -78°C for one hour and added a saturated aqueous solution of ammonium chloride to stop the reaction. The reaction mixture was extracted with ether, and the organic layer was washed with a saturated aqueous solution of sodium chloride and was dried (anhydrous magnesium sulfate), the solvent is then drove away under reduced pressure. The obtained residue was purified kolonen the th flash chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:20)], getting listed in the title compound (770 mg, 66%).

1H-NMR (CDCl3) δ: 3,48 (1H, d, J=10,8 Hz), 3,52 (1H, in), 3.75 (1H, d, J=10,2 Hz), 4,00 (1H, d, J=10.5 Hz), of 4.05 (1H, d, J=10.5 Hz), 4,10-to 4.28 (4H, m), 4,34 (2H, s), 4,47 (1H, d, J=12.0 Hz), 4,59 (1H, d, J=12.0 Hz), 4,76 (1H, d, J=10,8 Hz), 4,88 (2H, s), equal to 4.97 (1H, d, J=10,8 Hz), to 6.67 (1H, d, J=6.9 Hz), 6,94-7,07 (4H, m), 7,22-7,37 (19H, m), the 7.43 (1H, t, J=7.5 Hz), EUR 7.57 (1H, DD, J=8,7, 4,8 Hz), of 7.75 (1H, s), 7,80 (1H, d, J=8.1 Hz), 7,87 (1H, s)8,64 (1H, d, J=8.7 Hz).

(7) Synthesis of (3R,4R,5S,6R)-3,4,5-trebaseleghe-6-benzoyloxymethyl-2-[3-(5-toranzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]tetrahydropyran

In a stream of nitrogen triethylsilane (0,19 ml of 1.21 mmol) and a complex of boron TRIFLUORIDE-diethyl ether (0,14 ml, 1.11 mmol) was added to a solution of (3R,4R,5S,6R)-3,4,5-trebaseleghe-6-benzoyloxymethyl-2-[3-(5-toranzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]tetrahydropyran-2-ol (770 mg, of 0.93 mmol) in methylene chloride (10 ml) at 0°C. the Reaction mixture was stirred at room temperature for two hours, and then was added a saturated aqueous solution of sodium bicarbonate. The resulting mixture was extracted with methylene chloride, and the organic layer was washed saturated aqueous sodium chloride, then dried over sodium sulfate. The solvent is kept under reduced pressure, and the obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:20)], getting mentioned in the title compound (550 mg, 73%).

1H-NMR(CDCl 3) δ: 3,43 (1H, d, J=10,2 Hz), 3,79-3,93 (6H, m), 4,10 (1H, d, J=10.5 Hz), 4,35 (2H, s), 4,51 (1H, d, J=12.0 Hz), to 4.62 (1H, d, J=12.3 Hz), 4,69 (1H, d, J=10,8 Hz), 4,89 to 4.92 (4H, m), 6,50 (2H, d, J=7,2 Hz), 6,94-7,07 (5H, m), 7,21-to 7.59 (20H, m), 7,74 (1H, s), 7,83 (1H, d, J=8.1 Hz), scored 8.38 (1H, d, J=8,4 Hz).

(8) Synthesis of (2S,3R,4R,5S,6R)-2-[3-(5-toranzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]-6-hydroxyethylacrylate-3,4,5-triol

In a stream of nitrogen dimethyldisulfide (1,72 ml) and a complex of boron TRIFLUORIDE-diethyl ether (0,86 ml, 6.8 mmol) was added to a solution of (3R,4R,5S,6R)-3,4,5-trebaseleghe-6-benzoyloxymethyl-2-[3-(5-toranzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]tetrahydropyran (550 mg, of 0.68 mmol) in methylene chloride (15 ml) under cooling with ice. The reaction mixture was stirred at room temperature for 2.5 days, then was added a saturated aqueous sodium hydrogen carbonate solution under ice cooling and was extracted with a mixture of methylene chloride. The organic layer was washed saturated aqueous sodium chloride and then dried over sodium sulfate and then the solvent is kept at reduced pressure. The obtained residue was purified column chromatography on silica gel [eluting solution = methylene chloride:methanol (40:1)], getting mentioned in the title compound (140 mg, 46%).

1H-NMR (CD3OD) δ: 3,51-of 3.80 (5H, m), 3,90 (1H, d, J=6.0 Hz), 4,39 (2H, s), the 4.90 (1H, d, J=9.6 Hz), 7,01 (1H, dt, J=8,7, and 2.1 Hz), to 7.09 (1H, s), 7,37 (1H, dt, J=8,7, and 2.1 Hz), 7,44-7,49 (2H, s), 7,63-7,73 (3H, m), 7,80 (1H, d, J=6.0 Hz), of 8.28 (1H, d, J=8.7 G is).

MS (ESI+): 477 [M+Na]+.

Example 3

(2S,3R,4R,5S,6R)-2-[3-(benzo[b]thiophene-2-ylmethyl)-4-methoxynaphthalene-1-yl]-6-hydroxyethylacrylate-3,4,5-triol

(1) Synthesis of 2,4-dibromo-1-methoxynaphthalene

In a nitrogen atmosphere to a solution of 1-methoxynaphthalene (15.3 g, 96,4 mmol) in methylene chloride (450 ml) was added bromine (9,88 ml, 192,8 mmol) at room temperature for 10 minutes. The reaction mixture was stirred at room temperature for two hours, then was added a saturated aqueous solution of Na2S2O5and was extracted with a mixture of methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride and was dried (anhydrous magnesium sulfate)and the solvent is then drove away under reduced pressure, obtaining specified in the header connection (29,4 g, 98%).

1H-NMR (CDCl3) δ: 4,00 (3H, s), to 7.59-the 7.65 (2H, m), to $ 7.91 (1H, s), 8,12-to 8.20 (2H, m).

(2) Synthesis of 4-bromo-1-methoxynaphthalene-2-carbaldehyde

In a stream of nitrogen a solution of n-butylate in hexane (1.6 M, 56,9 ml, to 91.1 mmol) was added dropwise to a solution of 2,4-dibromo-1-methoxynaphthalene (30,3 g, with 95.9 mmol) in THF (1800 ml) at -78°C. and stirred the reaction mixture at the same temperature for 30 minutes. To this mixture was added N,N-dimethylformamide (8,9 ml, or 115.1 mmol) at -78°. The mixture was stirred at the same temperature for three hours, and then added to it on yenny aqueous solution of ammonium chloride and the mixture was extracted with ether. The organic layer was washed with a saturated aqueous solution of sodium chloride and was dried (anhydrous magnesium sulfate)and the solvent is then drove away under reduced pressure. The obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:8)], getting mentioned in the title compound (3,85 g, 15%).

1H-NMR (CDCl3) δ: 4,15 (3H, s), of 7.64-7,79 (2H, m), 8,16 (1H, s), compared to 8.26-8,29 (2H, m), 10,52 (1H, s).

(3) Synthesis of benzo[b]thiophene-2-yl-(4-bromo-1-methoxynaphthalene-2-yl)methanol

In a stream of nitrogen a solution of n-butylate in hexane (1.6 M, 6.2 ml 9,90 mmol) was added dropwise to a solution of benzothiophene (1,33 g, for 9.90 mmol) in THF (20 ml) at -78°C. and stirred the reaction mixture at the same temperature for 10 minutes. To this mixture was added dropwise a solution of 4-bromo-1-methoxynaphthalene-2-carbaldehyde (2.5 g, 9.43 mmol) in THF (30 ml) at -78°C. the Reaction mixture was stirred at the same temperature for two hours, and then was added a saturated aqueous solution of ammonium chloride and the mixture was extracted with ether. The organic layer was washed with a saturated aqueous solution of sodium chloride and was dried (anhydrous magnesium sulfate)and the solvent is then drove away under reduced pressure. The obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:4)], receiving specified in the header connect the out (3.12 g, 83%).

1H-NMR (CDCl3) δ: is 3.08 (1H, d, J=4,8 Hz), 3,91 (3H, s), to 6.58 (1H, d, J=4,1 Hz), 7,14 (1H, s), 7,28-to 7.35 (2H, m), EUR 7.57-of 7.69 (3H, m), to 7.77-7,81 (1H, m), 7,95 (1H, s), 8,10-of 8.25 (2H, m).

(4) Synthesis of 2-(4-bromo-1-methoxynaphthalene-2-ylmethyl)benzo[b]thiophene

In a stream of nitrogen triethylsilane (2,48 ml of 15.5 mmol) and the complex of boron TRIFLUORIDE-diethyl ether (1.08 ml, 8,54 mmol) was added dropwise to a solution of benzo[b]thiophene-2-yl-(4-bromo-1-methoxynaphthalene-2-yl)methanol (3.1 g, 7,76 mmol) in methylene chloride (60 ml) at 0°C. and stirred the reaction mixture at room temperature for two hours, and then was added a 50%aqueous solution of methanol and, in addition, was added to her water (30 ml). The resulting mixture was extracted with methylene chloride, the organic layer was washed with a saturated aqueous solution of sodium chloride and was dried (anhydrous magnesium sulfate)and the solvent is then drove away under reduced pressure. The obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:50)], getting mentioned in the title compound (2.38 g, 80%).

1H-NMR (CDCl3) δ: 3,95 (3H, s)to 4.41 (2H, s),? 7.04 baby mortality (1H, s), 7,22-7,33 (2H, m), 7,56 to 7.75 (5H, m), 8,13-8,21 (2H, m).

(5) Synthesis of (3R,4R,5S,6R)-2-[3-(benzo[b]thiophene-2-ylmethyl)-4-methoxynaphthalene-1-yl]-3,4,5-trebaseleghe-6-benzyloxypyrrolidine-2-ol

In a stream of nitrogen a solution of n-butylate in hexane (1.6 M, 1,09 ml of 1.75 mmol) was added dropwise to restore-(4-bromo-1-methoxynaphthalene-2-ylmethyl)benzo[b]thiophene (610 mg, to 1.59 mmol) in THF (9 ml) at -78°C. the Reaction mixture was stirred at the same temperature for five minutes and to this solution was added dropwise a solution of 3,4,5-trebaseleghe-6-benzyloxypyrrolidine-2-it (940 mg, about 1.75 mmol) in THF (3 ml) and stirred the reaction mixture at -78°C for two hours. Was added thereto, a saturated aqueous solution of ammonium chloride to stop the reaction. The reaction mixture was extracted with ether, and the organic layer was washed with a saturated aqueous solution of sodium chloride and was dried (anhydrous magnesium sulfate), the solvent is then drove away under reduced pressure. The obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:6)], getting mentioned in the title compound (859 mg, 64%).

1H-NMR (CDCl3) δ: 3,45-to 4.98 (20H, m), 6,66-to 7.67 (27H, m), 7,87 (1H, s), 8,16 (1H, d, J=7.5 Hz), 8,63 (1H, d, J=8.7 Hz).

(6) Synthesis of (3R,4R,5S,6R)-2-[3-(benzo[b]thiophene-2-ylmethyl)-4-methoxynaphthalene-1-yl]-3,4,5-trebaseleghe-6-benzyloxyacetophenone

In a stream of nitrogen triethylsilane (0.33 ml, 2.04 mmol) and a complex of boron TRIFLUORIDE-diethyl ether (0,14 ml, 1.12 mmol) was added dropwise to a solution of (3R,4R,5S,6R)-2-[3-(benzo[b]thiophene-2-ylmethyl)-4-methoxynaphthalene-1-yl]-3,4,5-trebaseleghe-6-benzyloxypyrrolidine-2-ol (859 mg, of 1.02 mmol) in methylene chloride (17 ml) at 0°C. the Reaction mixture is displaced is ivali at room temperature for one hour, and then added to it water (20 ml). The resulting mixture was extracted with methylene chloride, the organic layer was washed saturated aqueous sodium chloride and dried over sodium sulfate. The solvent is kept under reduced pressure, and the obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:10)], getting mentioned in the title compound (517 mg, 61%).

1H-NMR (CDCl3) δ: 3,52-4,89 (20H, m), 6,51 (2H, d, J=7.5 Hz), 6,93-to 7.67 (26H, m), 8,18 (1H, d, J=8.7 Hz), 8,39 (1H, d, J=8.7 Hz).

(7) Synthesis of (2S,3R,4R,5S,6R)-2-[3-(benzo[b]thiophene-2-ylmethyl)-4-methoxynaphthalene-1-yl]-6-hydroxyethylacrylate-3,4,5-triol

In nitrogen atmosphere dimethyldisulfide (1.6 ml) and a complex of boron TRIFLUORIDE-diethyl ether (0,79 ml, 6,23 mmol) was added to a solution of (3R,4R,5S,6R)-2-[3-(benzo[b]thiophene-2-ylmethyl)-4-methoxynaphthalene-1-yl]-3,4,5-trebaseleghe-6-benzyloxyacetophenone (515 mg, of 0.62 mmol) in methylene chloride (10 ml) under cooling with ice. The reaction mixture was stirred at room temperature for three days, then added water (10 ml) under cooling with ice and was extracted with a mixture of methylene chloride. The organic layer was washed saturated aqueous sodium chloride and then dried over sodium sulfate, then the solvent is kept at reduced pressure. The obtained residue was purified column chromatograph is she on silica gel [eluting solution = methylene chloride:methanol (20:1)], getting listed in the title compound (82 mg, 28%).

1H-NMR (CD3OD) δ: 3,49-are 3.90 (7H, m), of 3.94 (3H, m), 4,48 (2H, d, J=6.0 Hz), 7,11 (1H, s), 7,22-7,76 (7H, m), 8,16-8,19 (1H, m), 8,33-at 8.36 (1H, m).

MS (ESI-): 465 [M-1]-.

Example 4

(2R,3S,4R,5R,6S)-2-hydroxymethyl-6-[3-(5-methoxybenzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]tetrahydropyran-3,4,5-triol

(1) Synthesis of 1-(2,2-dimethoxymethylsilyl)-4-methoxybenzene

In nitrogen atmosphere 4-methoxybenzoyl (3,07 ml to 25.0 mmol) and 2-bromo-1,1-dimethoxyethane (of 3.25 ml, 27.5 mmol) was added to a solution of sodium methylate in methanol (0.5 M, 80,0 ml, 40.0 mmol) under cooling with ice. The reaction mixture was stirred at the same temperature for 10 minutes and then was heated to boiling under reflux for five hours. The reaction mixture was concentrated under reduced pressure and added cold water. The resulting mixture was extracted with ether, the organic layer was washed saturated aqueous sodium chloride and then dried over sodium sulfate. After filtration the solvent is kept under reduced pressure, and the obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:20)], getting mentioned in the title compound (5.30 g, 93%).

1H-NMR (CDCl3) δ: 3,00 (2H, d, J=5.6 Hz), to 3.33 (6H, s), 3,70 (3H, s), 4,47 (1H, t, J=5.6 Hz), 6,85 (2H, d, J=8,8 Hz), 7,39 (2H, d, J=8,8 Hz).

(2) Synthesis of 5-methoxybenzo[b]thiophene

In the atmosphere of nitrogen to dry chlorobenzene (150 ml) was added polyphosphoric acid (10 g). To the mixture was added 1-(2,2-dimethoxymethylsilyl)-4-methoxybenzo (5,2 g, 22.7 mmol) by boiling under reflux for 1.5 hours and kept boiling under reflux overnight. The reaction mixture was cooled to room temperature, and then separated the organic layer. To the layer of polyphosphoric acid was added water and the resulting solution was extracted with methylene chloride. All the obtained organic layers were washed with water and saturated aqueous sodium chloride and dried over sodium sulfate. After filtration the solvent is kept under reduced pressure, and the obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:40)], getting mentioned in the title compound (1.1 g, 30%).

1H-NMR (CDCl3) δ: 3,51 (3H, s), 7,00 (1H, DD, J=8,8, 2.4 Hz), 7,26 (2H, m), 7,44 (1H, d, J=5.5 Hz), 7,73 (1H, d, J=8,8 Hz).

(3) Synthesis of (4-does not depend-2-yl)-(5-methoxybenzo[b]thiophene-2-yl)methanol

In a stream of nitrogen a solution of n-butylate in hexane (1.6 M, 1,48 ml, 2.36 mmol) was added dropwise to a solution of 5-methoxybenzo[b]thiophene (388 mg, 2.36 mmol) in THF (6 ml) at -78°C. and stirred the reaction solution at the same temperature for 10 minutes. To Dan the th solution was added dropwise a solution of 4-does not depend-2-carbaldehyde (530 mg, 2.25 mmol) in THF (4 ml). The reaction mixture was stirred at the same temperature for two hours, and then was added a saturated aqueous solution of ammonium chloride and was extracted with a mixture of ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and was dried (anhydrous magnesium sulfate)and the solvent is then drove away under reduced pressure. The obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:10)], getting mentioned in the title compound (725 mg, 77%).

1H-NMR (CDCl3) δ: 2,62 (1H, d, J=4.0 Hz), 3,83 (3H, s), from 6.22 (1H, d, J=3.8 Hz), to 6.95 (1H, DD, J=8,8, 2,5 Hz), 7,10 (1H, s), to 7.15 (1H, d, J=2.5 Hz), 7,52-the 7.65 (3H, m), 7,83-7,88 (2H, m), to 7.93 (1H, s), by 8.22 (1H, d, J=8,1 Hz).

(4) Synthesis of 2-(4-does not depend-2-ylmethyl)-5-toranzo[b]thiophene

In a stream of nitrogen (4-does not depend-2-yl)-(5-methoxybenzo[b]thiophene-2-yl)methanol (260 mg, of 0.65 mmol) was added dropwise to a solution of trimethylsilylacetamide ones (0.46 ml, 3,26 mmol) in acetonitrile (10 ml) at 0°C for two hours and stirred the reaction mixture at the same temperature for one hour. Was added a saturated aqueous solution of sodium bicarbonate and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium thiosulfate and saturated aqueous sodium chloride and was dried (anhydrous magnesium sulfate), and then the solvent is thenali under reduced pressure. The obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:10)], getting mentioned in the title compound (130 mg, 52%).

1H-NMR (CDCl3) δ: a-3.84 (3H, s), 4,32 (2H, s)6,91 (2H, DD, J=8,8, 2,5 Hz), 6,98 (1H, s), 7,14 (1H, d, J=2.5 Hz), 7,51-to 7.61 (3H, m), 7,70-7,79 (3H, m), 8,19 (1H, d, J=8,2 Hz).

(5) Synthesis of (2R,3S,4R,5R)-3,4,5-trebaseleghe-2-benzoyloxymethyl-6-[3-(5-methoxybenzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]tetrahydropyran-6-ol

In a stream of nitrogen a solution of n-utility in hexane (1.6 M, at 0.31 ml, 0.50 mmol) was added dropwise to a solution of 2-(4-does not depend-2-ylmethyl)-5-methoxybenzo[b]thiophene (173 mg, 0.45 mmol) in THF (15 ml) at -78°C. stirred the reaction mixture at the same temperature for 10 minutes and was added to this solution a solution of 3,4,5-trebaseleghe-6-benzyloxypyrrolidine-2-she (267 mg, 0.50 mmol) in THF (2 ml). The reaction solution was stirred at -78°C for one hour and then was added a saturated aqueous solution of ammonium chloride to stop the reaction. The resulting reaction solution was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous solution of sodium chloride and was dried (anhydrous magnesium sulfate)and the solvent is then drove away under reduced pressure. The obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:4)], receiving indicated the data in the title compound (279 mg, 73%).

1H-NMR (CDCl3) δ: 3.46 in-3,50 (2H, m), 3,74 (1H, d, J=a 10.6 Hz), 3,82 (3H, s), 4,00 (1H, d, J=10.4 Hz), of 4.05 (1H, d, J=10.4 Hz), 4,10-to 4.28 (4H, m), 4,34 (2H, s), 4,47 (1H, d, J=11,9 Hz), 4,59 (1H, d, J=11,9 Hz), was 4.76 (1H, d, J=10,8 Hz), 4,88 (2H, s), 4,96 (1H, d, J=10,8 Hz), to 6.67 (1H, d, J=7,3 Hz), 6,88-6,98 (4H, m),? 7.04 baby mortality-to 7.09 (2H, m), 7,21-7,35 (16H, m), 7,42 (1H, t, J=7.2 Hz), 7,53 (1H, d, J=8,8 Hz), of 7.75 (1H, s), 7,79 (1H, d, J=8.0 Hz), 7,88 (1H, d, J=1.6 Hz), 8,65 (1H, d, J=8.7 Hz).

(6) Synthesis of (2R,3S,4R,5R)-3,4,5-trebaseleghe-2-benzoyloxymethyl-6-[3-(5-methoxybenzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]tetrahydropyran

In a stream of nitrogen, trimethylsilane (0,093 ml of 0.58 mmol) and a complex of boron TRIFLUORIDE-diethyl ether level (0.041 ml, 0.32 mmol) was added to a solution of (2R,3S,4R,5R)-3,4,5-trebaseleghe-2-benzoyloxymethyl-6-[3-(5-methoxybenzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]tetrahydropyran-6-ol (245 mg, 0.29 mmol) in methylene chloride (3 ml) at 0°C. the Reaction mixture was stirred at room temperature for one hours, and then was added a saturated aqueous solution of sodium bicarbonate. The resulting mixture was extracted with methylene chloride, the organic layer was washed saturated aqueous sodium chloride and dried over sodium sulfate. The solvent is kept under reduced pressure, and the obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:6)], getting mentioned in the title compound (271 mg, 80%).

1H-NMR (CDCl3) δ: 3,42 (1H, d, J=10,2 Hz), 3,6-3,99 (9H, m), 4.09 to (1H, d, J=9.9 Hz), 4,35 (2H, s)to 4.52 (1H, d, J=and 12.2 Hz), 4,63 (1H, d, J=and 12.2 Hz), 4,69 (1H, d, J=10,8 Hz), 4,87-4,96 (4H, m), 6,50 (2H, d, J=7,3 Hz), to 6.88 (1H, DD, J=7,2, 2.4 Hz), 6,95-of 6.99 (3H, m), 7,05-7,10 (2H, m), 7,21-7,30 (15H, m), 7,37 is 7.50 (2H, m), 7,53 (1H, d, J=8,8 Hz), 7,60 (1H, s), 7,74 (1H, s), 7,82 (1H, d, J=7,7 Hz), of 8.37 (1H, d, J=8,2 Hz).

(7) Synthesis of (2R,3S,4R,5R,6S)-2-hydroxymethyl-6-[3-(5-methoxybenzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]tetrahydropyran-3,4,5-triol

In a stream of nitrogen dimethyldisulfide (0,66 ml) and a complex of boron TRIFLUORIDE-diethyl ether (0.33 ml, 2,62 mmol) was added to a solution of (2R,3S,4R,5R)-3,4,5-trebaseleghe-2-benzoyloxymethyl-6-[3-(5-methoxybenzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]tetrahydropyran (217 ml, 0,262 mmol) in methylene chloride (4 ml) under cooling with ice. The reaction mixture was stirred at room temperature for three days, then was added a saturated aqueous sodium hydrogen carbonate solution under ice cooling and was extracted with a mixture of methylene chloride. The organic layer was washed saturated aqueous sodium chloride and dried over sodium sulfate, then the solvent is kept under reduced pressure, and the obtained residue was purified column chromatography on silica gel [eluting solution = methylene chloride:methanol (30:1)], getting mentioned in the title compound (85 mg, 65%).

1H-NMR (CD3OD) δ: 3,51-3,63 (3H, m), 3,69-of 3.80 (5H, m), 3,90 (1H, d, J=11,6 Hz), 4,37 (2H, s), the 4.90 (1H, d, J=9.5 Hz), 6.87 in (1H, DD, J=8,8, 2,5 Hz),? 7.04 baby mortality (1H, s), 7,19 (1H, d, J=2.4 Hz), 7,43-7,49 (2H, m), 57 (1H, d, J=8,8 Hz), 7,63 (1H, s), 7,73 (1H, s), 7,79-of 7.82 (1H,m), of 8.27 (1H, d, J=9,3 Hz).

MS (ESI+): 489 [M+Na]+.

Example 5

(2S,3R,4R,5S,6R)-2-[3-(5-ethylbenzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]-6-hydroxyethylacrylate-3,4,5-triol

(1) Synthesis of 1-(2,2-dimethoxymethylsilyl)-4-ethylbenzene

In nitrogen atmosphere 4-ethylbenzoyl (3,50 ml, and 25.4 mmol) and 2-bromo-1,1-dimethoxyethane (3,3 ml of 27.9 mmol) was added to a solution of sodium methylate in methanol (0.5 M, 81,4 ml of 40.7 mmol) under cooling with ice. The reaction mixture was stirred at the same temperature for 10 minutes and then was heated to boiling under reflux for five hours. The reaction mixture was concentrated under reduced pressure and added cold water. The resulting mixture was extracted with ether, the organic layer was washed saturated aqueous sodium chloride and dried over sodium sulfate. After filtration the solvent is kept under reduced pressure, and the obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:20)], getting mentioned in the title compound (5.31g, 93%).

1H-NMR (CDCl3) δ: 1,22 (3H, t, J=7,6 Hz), 2,62 (2H, q, J=7,6 Hz), is 3.08 (2H, d, J=5.6 Hz), to 3.36 (6H, s), 4,51 (1H, t, J=5.6 Hz), 7,12 (2H, d, J=8,3 Hz), 7,32 (2H, d, J=8,3 Hz).

(2) Synthesis of 5-ethylbenzo[b]thiophene

In the atmosphere of nitrogen to dry chlorobenzene (150 ml) we use the and polyphosphoric acid (10 g). To the resulting solution was added 1-(2,2-dimethoxymethylsilyl)-4-ethylbenzene (5.31g, 23.5 mmol) by boiling under reflux for 1.5 hours and kept heated to the boil under reflux overnight. The reaction mixture was cooled to room temperature, and then separated the organic layer. To the layer of polyphosphoric acid was added water and the resulting mixture was extracted with methylene chloride. All the obtained organic layers were washed with water and saturated aqueous sodium chloride and dried over sodium sulfate. After filtration the solvent is kept under reduced pressure, and the obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:20)], getting mentioned in the title compound (0,98 g, 26%).

1H-NMR (CDCl3) δ: of 1.29 (3H, t, J=7,6 Hz), was 2.76 (2H, q, J=7,6 Hz), 7.18 in-7,28 (2H, m), 7,40 (1H, d, J=5.4 Hz), to 7.64 (1H, s), 7,78 (1H, d, J=8,3 Hz).

(3) Synthesis of (4-does not depend-2-yl)-(5-ethylbenzo[b]thiophene-2-yl)methanol

In a stream of nitrogen a solution of n-butylate in hexane (1.6 M, 1,44 ml of 2.30 mmol) was added dropwise to a solution of 5-ethylbenzo[b]thiophene (373 mg, 2,30 mmol) in THF (15 ml) at -78°C. and stirred the reaction solution at the same temperature for 5 minutes. To this mixture was added dropwise a solution of 4-does not depend-2-carbaldehyde (515 mg, 2,19 mmol) in THF (5 ml) at -78°C and displaced ivali the resulting mixture at the same temperature for two hours and at -20°C for 30 minutes, and then was added a saturated aqueous solution of ammonium chloride and was extracted with a mixture of ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and was dried (anhydrous magnesium sulfate), the solvent is then drove away under reduced pressure. The obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:9)], getting mentioned in the title compound (780 mg, 90%).

1H-NMR (CDCl3) δ: 1,24 (1H, t, J=7,6 Hz), 2,63 (1H, d, J=3.1 Hz), 2,73 (2H, q, J=7,6 Hz), 6,23 (1H, d, J=3.1 Hz), 7,14 (2H, s), 7,52-of 7.70 (4H, m), 7,83-to 7.93 (3H, m), by 8.22 (1H, d, J=8,3 Hz).

(4) Synthesis of 2-(4-does not depend-2-ylmethyl)-5-ethylbenzo[b]thiophene

In a stream of nitrogen triethylsilane (0.63 ml, 3.93 mmol) and a complex of boron TRIFLUORIDE-diethyl ether (0,27 ml of 2.16 mmol) was added to a solution of (4-does not depend-2-yl)-(5-ethylbenzo[b]thiophene-2-yl)methanol (780 mg, a 1.96 mmol) in methylene chloride (20 ml) at 0°C. and stirred the reaction mixture at room temperature for three hours. To the resulting solution were added methanol (10 ml) and water (30 ml) and was extracted with a mixture of methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride and was dried (anhydrous magnesium sulfate)and the solvent is then drove away under reduced pressure. The obtained residue was purified column chromatography on silica gel [eluting solution = n-hexane], receiving is shown in the title compound (460 mg, 62%).

1H-NMR (CDCl3) δ: 1,27 (1H, t, J=7,6 Hz), 2,73 (2H, q, J=7,6 Hz), 4,34 (2H, s), 7,10 (1H, s), 7,13 (1H, d, J=7,6 Hz), of 7.48-7,79 (7H, m), 8,19 (1H, d, J=8,3 Hz).

(5) Synthesis of (3R,4R,5S,6R)-3,4,5-trebaseleghe-6-benzoyloxymethyl-2-[3-(5-ethylbenzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]tetrahydropyran-2-ol

In a stream of nitrogen a solution of n-butylate in hexane (1.6 M, or 0.83 ml of 1.33 mmol) was added dropwise to a solution of 2-(4-does not depend-2-ylmethyl)-5-ethylbenzo[b]thiophene (460 mg, to 1.21 mmol) in THF (15 ml) at -78°C. the Reaction mixture was stirred at the same temperature for five minutes and was added to this solution dropwise a solution of 3,4,5-trebaseleghe-6-benzyloxypyrrolidine-2-it (844 mg, 1.57 mmol) in THF (5 ml). The reaction solution was stirred at -78°C for five minutes, then was added a saturated aqueous solution of ammonium chloride to stop the reaction. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium chloride and was dried (anhydrous magnesium sulfate), the solvent is then drove away under reduced pressure. The obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:9)], getting mentioned in the title compound (1,06 mg, 100%).

1H-NMR (CDCl3) δ: of 1.25 (3H, t, J=7,6 Hz), of 2.72 (2H, q, J=7,6 Hz), 4,35 (2H, s), 3,45-4,78 (12H, m), 4,89 (2H, s), 4.92 in-to 4.98 (1H, m), to 6.67 (2H, d, J=7,2 Hz), 6,94 (2H, t, J=7.2 Hz), 7,01-7,44 (21H, m),to 7.59 (1H, d, J=8,3 Hz), of 7.75 (1H, s), 7,79 (1H, d, J=7.9 Hz), 7,89 (1H, d, J=1.7 Hz), to 8.62 (1H, d, J=8.6 Hz).

(6) Synthesis of (3R,4R,5S,6R)-3,4,5-trebaseleghe-2-benzoyloxymethyl-6-[3-(5-ethylbenzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]tetrahydropyran

In a stream of nitrogen triethylsilane (0,60 ml of 3.78 mmol) and a complex of boron TRIFLUORIDE-diethyl ether (0.17 ml, of 1.32 mmol) was added dropwise to a solution of (3R,4R,5S,6R)-3,4,5-trebaseleghe-6-benzoyloxymethyl-2-[3-(5-ethylbenzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]tetrahydropyran-2-ol (1.06 g, of 1.26 mmol) in methylene chloride (20 ml) at -40°C. the Reaction mixture was stirred at 0°C within one hour, and then was added a 50%aqueous solution of methanol (20 ml). The resulting mixture was extracted with methylene chloride, the organic layer was washed saturated aqueous sodium chloride and dried over sodium sulfate. The solvent is kept under reduced pressure, and the obtained residue was purified column chromatography on silica gel [eluting solution = ethyl acetate:n-hexane (1:9)], getting mentioned in the title compound (670 mg, 65%).

1H-NMR (CDCl3) δ: 1.26 in (3H, t, J=7,6 Hz), 2,71 (2H, q, J=7,6 Hz), 3,42 (1H, d, J=10.3 Hz), 3,60-4,00 (6H, m), 4.09 to (1H, d, J=10.3 Hz), 4,35 (2H, s), 4,46-4,72 (3H, m), 4,82-to 4.98 (4H, m), 6,50 (2H, d, J=7,2 Hz), 6,85 is 7.85 (27H, m), of 8.37 (1H, d, J=8,2 Hz).

(7) Synthesis of (2R,3S,4R,5R,6S)-2-hydroxymethyl-6-[3-(5-ethylbenzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]tetrahydropyran-3,4,5-triol

In nitrogen atmosphere dimethyldisulfide (2.66 ml) is a complex of boron TRIFLUORIDE-diethyl ether (of 1.03 ml, to 8.12 mmol) was added to a solution of (3R,4R,5S,6R)-3,4,5-trebaseleghe-2-benzoyloxymethyl-6-[3-(5-ethylbenzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]tetrahydropyran (670 mg, 0.81 mmol) in methylene chloride (4 ml) under cooling with ice. The reaction mixture was stirred at room temperature for 1.5 days, then was added a 50%aqueous solution of methanol (20 ml) under cooling with ice and was extracted with a mixture of methylene chloride. The organic layer was washed saturated aqueous sodium chloride and dried over sodium sulfate, and the solvent is then drove away under reduced pressure. The obtained residue was purified column chromatography on silica gel [eluting solution = methylene chloride:methanol (50:1)], getting mentioned in the title compound (119 mg, 32%).

1H-NMR (CD3OD) δ: 1.26 in (3H, t, J=7,6 Hz), 2,71 (2H, q, J=7,6 Hz), 3.45 points-of 3.65 (3H, m), 3,66-3,82 (2H, m)to 3.89 (1H, d, J=12.1 Hz), 4,39 (2H, s), the 4.90 (1H, d, J=9.6 Hz), 7,05-to 7.15 (2H, m), 7,40-of 7.55 (3H, m), 7,58-7,66 (2H,, m), 7,37 (1H, s), 7,78-a 7.85 (1H, m), 8,24-8,32 (1H, m).

MS (ESI+): 487 [M+Na]+.

The structure of the compounds of the above examples are shown in table 1.

Table 1
Connection 1
Connection 2
Connection 3
Connection 4

Connection 5

By the same method as in the examples described above, obtained compounds of the present invention, are shown in table 2, using appropriate starting compounds and reagents.

Table 2
Connection 61H-NMR (CD3OD) δ: 3,50-3,63 (3H, m), 3,69-of 3.80 (2H, m)to 3.99 (1H, DD, J=11,7, 1.9 Hz), and 4.40 (2H, s), the 4.90 (1H, d, J=9.6 Hz), to 7.09 (1H, s), 7,21 (1H, DD, J=8,6, 2.0 Hz), 7,42-7,51 (2H, m), 7,62-7,74 (4H, m), 7,79-7,83 (1H, m), of 8.28 (1H, m).
MS (ESI+): 493 [M+Na]+
Connection 71H-NMR (CD3OD) δ: is 2.37 (3H, s), of 2.56 (1H, users), of 3.45 (1H, m), 3,54-3,90 (5H, m), and 4.40 (2H, s), to 4.81 (1H, d, J=9,2 Hz), 6.89 in (1H, s), 7,02 (1H, DD, J=8,4, 1.5 Hz), 7,35-7,45 (3H, m), of 7.48 (1H, s), 7,54 (1H, d, J=8,4 Hz), the 7.65 (1H, s), 7,71 for 7.78 (1H, m), 8,11 (1H, m).
MS (ESI+): 473 [M+Na]+
Compound 81H-NMR (CD3OD) δ: of 2.38 (3H, s), 3,51-3,63 (3H, m), 3,69-3,81 (2H, m), 3,90 (1H, d, J=12.1 Hz), 4,22 (2H, s), 4,88 (1H, d, J=9.6 Hz), 6,56 (1H, d, J=3,4 Hz), 6,63 (1H, d, J=3,4 Hz), 7,39-of 7.48 (2H, m), EUR 7.57 (1H, s), to 7.64 (1H, s), 7,78 (1H, d, J=9.5 Hz), of 8.25 (1H, d, J=9.5 Hz).
MS (ESI+): 423 [M+Na]+
Connection 91H-NMR (CD3OD) δ: of 1.23 (3H, t, J=7.5 Hz), a 2.75 (2H, q, J=7.5 Hz), 3,51-3,63 (3H, m), 3,69-3,81 (2H, m)to 3.89 (1H, d, J=12.0 Hz), to 4.23 (2H, s), 4,89 (1H, d, J=9.0 Hz), 6,56 (1H, s), of 6.65 (1H, s), 7,42 was 7.45 (2H, m), EUR 7.57 (1H, s), the 7.65 (1H, s), 7,78 (1H, d, J=8,4 Hz), of 8.25 (1H, d, J=9.0 Hz).
MS (ESI-): 413 [M-1]-

Experimental example 1

Test to confirm inhibitory effect on cotransporter Na+-human glucose (SGLT1 and SGLT2)

(1) preparation of expression vector of human SGLT1

PCR PCR was performed using KOD+DNA polymerase (product of Toyobo Co., Ltd.), when using a cDNA library derived from the small intestine of man (product of Clontech) as the template, using a synthetic primer DNA for amplification of cDNA human SGLT1. Then this amplificatory fragment cloned into the vector pcRII-Topo using a kit for cloning Topo TA Cloning Dual Promoter (product of Invitrogen)and introduced into competent cells of E. coli (TOP10, the product of Invitrogen), and clones that were resistant to ampicillin, proliferated in the LB medium containing ampicillin (50 mg/l). From proliferating E. coli was isolated plasmid in the usual way (see Maniatis et al., Molecular Cloning). Using this plasmid as template, PCR was carried out using KOD+DNA polymerase using the synthesized primer DNA, which introduced the restriction sites of enzymes for amplification of cDNA SGLT1 human (fragment with the added restriction site Eco RI in the upper part and the restriction site Hind III in the lower part). This amplificatory fragment was subjected to digestion with Eco RI and Hind III to bind digested fragments with restriction sites of the expression vector pcDNA 3.1(-) (product of Invitrogen) using the set for accelerated ligating DNA (product of Roche Diagnostics). The associated expression vector was introduced into competent E. coli cells (DH5α, product Invitrogen) and proliferated in containing the ampicillin LB medium, receiving the vector in the expression of SGLT1 person in the usual way.

(2) Obtaining the expression vector of human SGLT2

PCR was performed using KOD+DNA polymerase (product of Toyobo Co., Ltd.), when using a cDNA library derived from human kidney (product of Clontech) as the template, using a synthetic primer DNA for amplification of cDNA human SGLT2. Then this amplifier the bath fragment cloned into the vector pcRII-Topo using a kit for cloning Topo TA Cloning Dual Promoter (product of Invitrogen) and introduced into competent cells of E. coli (TOP10, the product of Invitrogen), and clones that showed resistance to ampicillin, proliferated in the LB medium containing ampicillin (50 mg/l). From proliferating E. coli in the normal way were isolated plasmid. Using this plasmid as template, PCR was carried out using KOD+DNA polymerase using the synthesized primer DNA, which introduced the restriction sites of enzymes for amplification of cDNA human SGLT2 (fragment with the added restriction site Xho I in the upper part and the restriction site Hind III in the lower part). This amplificatory fragment was subjected to digestion Xho I and Hind III to bind digested fragments with restriction sites of the expression vector pcDNA 3.1(-) when using the set for accelerated ligating DNA. The associated expression vector was introduced into competent E. coli cells (DH5α) and proliferated in containing the ampicillin LB medium, receiving the vector in the expression of SGLT2 person in the usual way.

(3) Obtaining stably expressing SGLT1 human cells and stably expressing SGLT2 human cells

The expression vector of human SGLT1 or SGLT2 expression vector man, digested with restriction enzymes Pvu I, was introduced into cells Cho-K1 using FuGene (Roche Diagnostics). After the introduction of this gene, the cells were incubated in DMEM (Gibco)containing penicillin (50 U/ml, about the SPS Sigma), streptomycin (50 mg/l, product of Sigma), Geneticin (200 mg/l, product of Nacalai Tesque), and 20%whey fruit cow in the presence of 5% CO2at 37°C for approximately three weeks, receiving Genticin-resistant clones. These clones were selected cells stably Express human SGLT1 or SGLT2 person, and received when using activity retrieveimage absorption of sugar (methyl-α-D-glucopyranosid) as the index.

(4) Determination of the activity of inhibiting the uptake of methyl-α-D-glucopyranoside

Cells SNO, stably expressing human SGLT1 or cells SNO, stably expressing human SGLT2, were sown in 96-well plates with a density of 30,000 to 40,000 cells/well and incubated for four to six days. Then the environment of the culture of the tablet was removed and added to the buffer pre-treatment (a buffer containing 140 mm choline chloride, 2 mm potassium chloride, 1 mm calcium chloride, 1 mm magnesium chloride, 10 mm 2-[4-(2-hydroxyethyl)-1-piperazinil]econsultancy and Tris(hydroxymethyl)aminomethane, and having a pH 7.4) in an amount of 150 μl per well, and then left to stand at 37°C for 20 minutes. Buffer pre-treatment was removed and was again added to the buffer pre-treatment in the amount of 50 μl per well, and then left to stand at 37°C for 20 minutes. To 100 ml of a buffer (the buffer is, containing 140 mm sodium chloride, 2 mm potassium chloride, 1 mm calcium chloride, 1 mm magnesium chloride, 1 mm methyl-α-D-glucopyranoside, 10 mm 2-[4-(2-hydroxyethyl)-1-piperazinil]econsultancy and Tris(hydroxymethyl)aminomethane, and having a pH 7.4)was added and stirred 6.3 ml of methyl-α-D-(U-14C)glucopyranoside (200 MCI/l, product of Amersham Pharmacia Biotech), receiving buffer absorption, and dissolving the test compound in the buffer absorption, and the resulting solution was used as a buffer to determine the inhibitory activity. In addition, as a control was used buffer absorption, does not contain the test compound. In addition, to determine the underlying absorption in the absence of the test compound and sodium, similarly prepared and used to determine the basic buffer absorption, containing 140 mm choline chloride instead of sodium chloride. Buffer pre-treatment was removed from the wells of the culture of the tablet and was added to the buffer to determine the inhibitory activity of 35 µl per well and left to stand at 37°C for 45 minutes. After this buffer to determine the inhibitory activity was removed and added to the washing buffer (buffered solution containing 140 mm choline chloride, 2 mm potassium chloride, 1 mm calcium chloride, 1 mm magnesium chloride, 1 mm methyl-α-D-glucopyranoside, 10 mm 2-[4-(hydroxyethyl)-1-piperazinil]econsultancy and Tris(hydroxymethyl)aminomethane, and having a pH 7.4) in an amount of 300 μl per well and immediately removed. This washing operation was repeated again and the solution was added to dissolve the cells (1 M sodium hydroxide and 0.1% sodium lauryl) in an amount of 30 μl per well to dissolve the cells. There was added 15 μl of 2 M hydrochloric acid, 40 μl of the obtained solution was transferred into a Luma-tablet (product Packard) and left to stand at room temperature overnight to evaporate the solvent. The radioactivity of the sample in the tablet was determined using a Topcount (Packard production). The concentration of the test compound (the value of the IC50), which inhibits 50% of absorption, assuming the value obtained when deriving the basic absorption from the reference absorption, 100%, was calculated from the curve of concentration-inhibition using computational software (Elfir ver.3). In the compounds of the present invention showed a remarkable inhibitory effect against SGLT2. The values of the IC50for inhibition of SGLT2 presented compounds of the present invention are shown in table 3.

Table 3
Test connectionIC50(nm)
Example 1 18
Example 818

Experimental example 2

The test to determine the half-life from blood in rats

The test compound was administered intravenously to male SD rats (8-weeks old, Japan SLC), and made the blood withdrawal after 2 minutes, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 8 hours after administration, respectively. The obtained blood was centrifuged, receiving the plasma. Plasma sample (0.01 ml) and water (0.4 ml) were placed in a test tube with phenytoin (250 ng) as internal standard, was added there diethyl ether (2 ml) and the resulting solution was stirred for five minutes, then centrifuged for 10 minutes, the organic layer was separated and subjected to drying with nitrogen, and the mobile phase was added to the obtained solid substance for its dissolution and took the resulting solution as a sample to determine.

The sample for determination was injected in HPLC-mass spectrometer and were used to define the following terms.

Column: ODS (2,0×150 mm)

Mobile phase: acetonitrile/10 mm ammonium acetate = 4/6 (about./about.)

Flow rate: 0.2 ml/min

The volume of injected sample: 10 ál

Mass analysis: ESI (+)

Concentrated plasma, obtained by HPLC-MS were subjected to neki momu analysis using WinNonlin standard, made Pharsight Corporation for calculation of pharmacokinetic parameters. The half in the final layer are shown in table 4.

Table 4
(Dosage: 10 mg/kg)
Test connectionThe elimination half-life (h)
Example 18,21

The possibility of industrial use

In the present invention proposed connection glucitol, which have an excellent effect for inhibiting the activity of SGLT2, prodrug, or their pharmaceutically acceptable salts. In addition, the compounds of the present invention is applicable as a preventive or therapeutic agents for diabetes, diabetes-related diseases or diabetic complications.

1. The compound of formula (I)

in which
m is an integer selected from 1-3;
each of R1, R2, R3and R4independently selected from a hydrogen atom and a benzyl group;
Ar1represents naftalina group which may be substituted by one or more Deputy selected from the group consisting of C1/sub> -C6alkyl group, or halogen atom;
A is a 5-7-membered aromatic heterocyclic group containing one or more heteroatoms independently selected from oxygen atom and sulfur atom, which may form a condensed cycle with aromatic carbocycle or aromatic heterocycle, where a may be substituted by one or more Rb, provided that when a is benzododecinium cycle containing two or more rings, the group -(CH2)m- linked heterocycle in A;
each Rb is independently selected from C1-C6alkyl group, halogen atom and C1-C6-alkoxygroup;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1 of formula (Ia)

in which A, R1, R2, R3, R4and m are same as defined in claim 1.
or its pharmaceutically acceptable salt.

3. The compound according to claim 1 of formula (Ib)

in which A, Ar1, R1, R2, R3, R4and m are same as defined in claim 1,
or its pharmaceutically acceptable salt.

4. The compound according to claim,1 in which a represents a thienyl group or benzothiazoline group, where these groups may be substituted by one or more
Rbor its pharmaceutically acceptable salt.

5. Joint who according to claim 1, in which m is 1, or its pharmaceutically acceptable salt.

6. The compound according to claim 1, chosen from:
(2S,3R,4R,5S,6R)-2-[3-(benzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]-6-hydroxyethylacrylate-3,4,5-triol;
(2S,3R,4R,5S,6R)-2-[3-(5-toranzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]-6-hydroxyethylacrylate-3,4,5-triol-;
(2R,3S,4R,5R,6S)-2-hydroxymethyl-6-[3-(5-methoxybenzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]tetrahydropyran-3,4,5-triol;
(2S,3R,4R,5S,6R)-2-[3-(5-ethylbenzo[b]thiophene-2-ylmethyl) naphthalene-1-yl]-6-hydroxyethylacrylate-3,4,5-triol;
(2S,3R,4R,5S,6R)-2-[3-(5-chlorobenzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]-6-hydroxyethylacrylate-3,4,5-triol;
(2R,3S,4R,5R,6S)-2-hydroxymethyl-6-[3-(5-methylbenzo[b]thiophene-2-ylmethyl)naphthalene-1-yl]tetrahydropyran-3,4,5-triol;
(2R,3S,4R,5R,6S)-2-hydroxymethyl-6-[3-(5-methylthiophene-2-ylmethyl)naphthalene-1-yl]tetrahydropyran-3,4,5-triol and (2R,3S,4R,5R,6S)-2-hydroxymethyl-6-[3-(5-ethylthiophen-2-ylmethyl)naphthalene-1-yl]tetrahydropyran-3,4,5-triol, or their pharmaceutically acceptable salts.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or its pharmaceutically acceptable salt, which is used as an inhibitor of cotransporter Na+-glucose.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or its pharmaceutically acceptable salt, which is used for the prophylaxis or treatment of diabetes, complicated the th diabetes, called hyperglycemia, or obesity.

9. The pharmaceutical composition of claim 8, where diabetes is an insulin-dependent diabetes (type I diabetes) or non-insulin-dependent diabetes (type II diabetes).

10. A method of preventing or treating diabetes, diabetic complications caused by hyperglycemia, or obesity, which comprises the administration to a patient a therapeutic amount of a compound according to any one of claims 1 to 6, or its pharmaceutically acceptable salt.

11. The method according to claim 10, in which diabetes is an insulin-dependent diabetes (type I diabetes) or non-insulin-dependent diabetes (type II diabetes).



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula , where R1 is -O-X, where X is -(CH2)m-(CR9R10)p-(CH2)n-Z-(CH2)q-W, where m, n and q are independently equal to zero or assume values from 1 to 5; p equals 0 or 1; R9 and R10 are independently hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or cycloalkyl; or R9 and R10 together represent alkylene, which together with the carbon atom to which the are bonded, form an aryl; Z is a bond or O, W is aryl; R2 is hydrogen; L is a bond; R3 is hydrogen; R4 is hydrogen; R5 and R6 are independently hydrogen; R7 is hydrogen, halogen, hydroxy, trifluromethyl, lower alkyl, lower alkoxy, alkanoyl, alkyloxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, acylamino, carbamoyl, carboxy, alkoxycarbonyl; or R5 and R6 together represent -(CH2)1-2-; Y is -(CH2)r-, -O-(CH2)r, -(CH2)r-O-, where r equals zero or assumes values from 1 to 3; Q together with atoms to which it is bonded form an aryl, pyridyl, pyrimidinyl, thienyl, furyl, pyrroliyl or indolyl ring; or to its pharmaceutically acceptable salts. The invention also relates to a method of inhibiting rennin activity in mammals, to a pharmaceutical composition, as well as to application.

EFFECT: obtaining new biologically active compounds with inhibitory activity towards renin.

23 cl, 52 ex

FIELD: chemistry.

SUBSTANCE: invention claims compounds of the formula (I) with radicals as described in the claim, and medicine with inhibition effect on glycine absorption, based on compound of the formula (I) .

EFFECT: medicine for diseases treatment where glycine absorption inhibition can be effective.

21 cl, 1 tbl, 173 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means -lower alkyl, -CH2-aryl, -cycloalkyl, -(CH2)3, -OC(=O)CH3, -lower alcohol, -lower alkyl-R10, -CH2COOH or -CH2CH2OCH2CH3; R2 means -lower alkyl, -CH2-aryl, -lower alcohol, -CH2C(=O)-NH2 or lower alkyl-R10 wherein at least one radical among R1 or R2 means -CH3; R3 means -COOH, -lower alkyl-COOH, -lower alcohol, -CH2OCH2, -CH2NH2, -CHNHSO2R11, -C(=O)-R12, -(CH2)nNHC(=O)-R13, -(CH2)mC(=O)N-(R15)(R16), -C(=NH)-R17 or -(CH2)n-R18; R4 means hydrogen atom (-H), -lower alkoxy group, -O-C(R7R8)C(=O)-R19, -halogen atom, -SCH3, -C=CHC(=O)-R10, -CH2CH2C(=O)-R10, -O-lower alcohol, -OCH2CH(OH)CH2N=N±N-, -OCH2CH2OCH2CH2Cl, -NHC9=O)-CH2-lower alkyl, -O(CH2)n-cycloalkyl, -O-lower alkene or 5-membered unsaturated heterocyclic ring comprising one heteroatom representing sulfur (S) or oxygen (O) atom; R5 and R6 mean independently -H, -halogen atom or -lower alkoxy group; R7 and R8 mean independently -H or -CH3; R10 means 5-6-membered saturated heterocyclyl comprising 1 or 2 heteroatoms, such as N and O, and this group is bound with other moiety of molecule by a ring N atom; R11 means -CF3, -lower alkyl, -CH2Cl, -CH2CF3 or -R12; R12 means 5-6-membered saturated substituted or unsubstituted heterocyclic ring comprising 1 heteroatom, such as N, O and S wherein substituted ring represents heterocyclic ring substituted with -OH or -phenyl; R13 means -lower alkyl, -lower alkoxy group or -(CH2)nR14; R14 means 5-6-membered saturated or unsaturated heterocyclic ring comprising 1 and 2 heteroatoms, that are chosen from group comprising N and O; R15 means -H, -lower alkyl, -OH, -lower alkoxy group or -CH2COOCH2CH3; R17 means -lower alkoxy group, -NH2 or -N-lower alkyl; R18 means saturated or unsaturated 5-membered substituted or unsubstituted heterocyclic ring comprising from 1 to 4 heteroatoms, such as N, O and S wherein substituted ring represents heterocyclic ring that is substituted by one or two cyclic carbon atoms by =O, or it is substituted by cyclic N atom by -lower alcohol or -lower alkyl; R19 means -OH, -NHCH(CH3)2, -N(CH3)CH2-aryl, -N(CH3)-lower alkyl, 1-(aryl-(CH2)n-)-[1,4]-diazin-4-yl or 5-6-membered saturated heterocyclyl and optionally substituted with lower alkyl comprising 1 or 2 heteroatoms, such as N and O; m = 0, 1 or 2; n = 0 or 1, and their pharmaceutically acceptable salts and esters. Also, invention relates to a pharmaceutical composition possessing inhibitory activity with respect to GFAT and containing the effective amount of compound of the formula (I). Invention provides expanding assortment of agents possessing inhibitory activity with respect to GFAT. Proposed compounds can be used as inhibitors of GFAT, and pharmaceutical composition possessing inhibitory activity with respect to GFAT containing above said compound of the formula (I) also.

EFFECT: valuable biochemical properties of compounds and pharmaceutical composition.

25 cl, 134 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new 1-(p-thienylbenzyl)-imidazoles of the formula (I): , wherein indicated residues represent the following values: R(1) means halogen atom, (C1-C4)-alkoxyl, (C1-C8)-alkoxyl wherein one carbon atom can be replaced with heteroatom oxygen atom (O); R(2) means CHO; R(3) means aryl; R(4) means hydrogen halogen atom; X means oxygen atom; Y means oxygen atom or -NH-; R(5) means (C1-C6)-alkyl; R(6) means (C1-C5)-alkyl in their any stereoisomeric forms and their mixtures taken in any ratios, and their physiologically acceptable salts. Compounds are strong agonists of angiotensin-(1-7) receptors and therefore they can be used as a drug for treatment and prophylaxis of arterial hypertension, heart hypertrophy, cardiac insufficiency, coronary diseases such as stenocardia, heart infarction, vascular restenosis after angioplasty, cardiomyopathy, endothelial dysfunction or endothelial injures, for example, as result of atherosclerosis processes, or in diabetes mellitus, and arterial and venous thrombosis also. Invention describes a pharmaceutical composition based on above said compounds and a method for their applying also.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 19 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

The invention relates to new imidazole derivative of the formula (I):where R1represents phenyl or pyridinyl, substituted by substituents selected from the group comprising (1) phenyl, (2) furyl, thienyl, (3) halogen, (4) halogen(lower)alkyl, (5) lower alkylthio, (6) nitro, (7) lower alkenyl, optionally substituted phenyl, (8) lower quinil, optionally substituted phenyl, (9) lower alkoxy, optionally substituted cyclo(lower)alkyl or phenyl, (10) lower alkyl, optionally substituted, phenyloxy or (11) amino, optionally substituted protected carboxyla; R2represents lower alkyl; R3represents halogen or lower alkyl; R4represents (1) lower alkenyl, optionally substituted phenyl, (2) phenyl, optionally substituted lower alkyl or lower alkenyl, (3) lower alkyl or (4) thienyl, optionally substituted with halogen; a represents a lower alkylene and L represents a simple bond, a lower albaniles or lower alkylene, optionally substituted phenyl or pyridinyl, or-X-CH2- where X represents O or NR5where R5represents hydrogen or n is

The invention relates to the field of organic chemistry, specifically to new connections: dicyanodiamide, namely aralen-bis(2-aminothiophene-3-carbonitrile)am General formula

where R represents

Connection most effectively can be used as monomers for obtaining polyamides, polyazomethines and politician with phenylanaline groups with high values of viscosity and conductivity

The invention relates to new substituted phenyl derivatives, which are strong blockers chlorine ion channels and as such are useful in the treatment of sickle cell anemia, cerebral edema that accompanies ischemia or tumor, diarrhea, hypertension (diuretic), osteoporosis and to reduce the intraocular pressure for the treatment of disorders such as glaucoma

The invention relates to piperazine derivatives of General formula I, in which R1denotes pyridyl or phenyl, unsubstituted or once substituted Ph or 2 - or 3-Tiepolo, R2indicates Ph1or Het

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is offered application of dipeptidylpeptidase IV inhibitor (DPP-IV inhibitor), preferentially (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyanopyrrolidine or its pharmaceutically acceptable salt, for treatment of cardiovascular diseases or injures, renal diseases or damages, cardiac insufficiency or related diseases, related method and pharmaceutical composition of the same purpose.

EFFECT: compound reduces both hypertrophy of blood vessel wall and aortic ventricle, causes endothelium mediated increase of vasorelaxation, and risk of hypostasis in prolonged application in comparison with other DPPs-IV.

26 cl, 4 ex

Hypoglycemic agent // 2385717

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns medicine, namely pharmacology, hypoglycemic agents influencing the glucose blood content in treating the diseases associated with metabolic disorders, such as pancreatic diabetes. The agent expressing hypoglycemic activity, characterised by that it contains N-isopropylamide-2-(1-phenylethyl)aminoethanesulphacid hydrochloride in effective amount.

EFFECT: invention renders more expressed hypoglycemic action.

2 cl, 3 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compounds of formula (I) and their pharmaceutically acceptable salts or esters having agonistic effect on PPARδ and/or PPARα, where X1 is selected from a group which includes O and CH2, R1 denotes hydrogen or C1-C7alkyl, R2 denotes C1-C7alkyl, or if X1 denotes CH2, then R2 denotes hydrogen, R3 denotes hydrogen or C1-C7alkyl, R4 and R8 are independently selected from a group which includes hydrogen, C1-C7alkyl, C1-C7alkoxy, halogen, R5, R6 and R7 are independently selected from a group which includes hydrogen, C1-C7alkoxy, halogen, where one of R5, R6 and R7 denotes , where X2 denotes O, R10 denotes hydrogen, R11 denotes hydrogen, one of R12 or R13 is selected from a group which includes hydrogen, C1-C7alkyl and fluoro(C1-C7)alkyl, and the other denotes an unshared electron pair, R14 denotes hydrogen, R15 denotes 4-trifluoromethoxyphenyl, and n equals 1, 2 or 3. The invention also relates to pharmaceutical compositions containing such compounds.

EFFECT: increased effectiveness of the compounds.

23 cl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

or

or to their pharmaceutically acceptable salts, where ring A, R2, R3, R4 and X are as defined in the description. The disclosed compounds are useful as 11βHSD1 inhibitor. The invention also relates to a pharmaceutical composition, an agent for treating or preventing pathology related to glucocorticoids, a 11βHSD1 inhibitor containing the disclosed compound or its pharmaceutically acceptable salt, and use of the disclosed compounds.

EFFECT: compounds are highly effective.

40 cl, 48 tbl, 191 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical composition of fast release includes granules obtained by granulation from melt. Granules contain DPP-IV inhibitor and meltable hydrophobic component with ratio from 1:1 to 1:10 (per dry weight). At least 90% of granule surface are covered with meltable hydrophobic component. Granules release approximately 50% of DPP-IV inhibitor during 30 minutes after peroral introduction of medication. DPP-IV inhibitor is N-(substituted glicyl)-2-cyanopyrrolodin or its pharmaceutically acceptable salt. Preferably DPP-IV is (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyanopyrrolidin.

EFFECT: composition for fast release according to invention possesses improved stability in presence of moisture in comparison with known compositions for controlled or prolonged release.

20 cl, 9 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula : in which R1 represents a hydrogen atom or alkyl optionally substituted with (1) aralkyloxy group, (2) aroyl, (3) isoquinolinyl or (4) aryl, optionally substituted with an alkoxy group; the solid line and the dashed line between A1 and A2 represent a double bond (A1=A2) or a single bond (A1-A2); A1 is a group of formula C(R4), and A2 is a nitrogen atom when the solid line and the dashed line between A1 and A2 represents a double bond (A1=A2); A1 is a group of formula C=O, and A2 is a group of formula N(R5) when the solid line or the dashed line between A1 and A2 represent a single bond (A1-A2); R2 represents alkyl optionally substituted with a cyano group, aryl optionally substituted with an alkoxy group, aralkyl optionally substituted with a halogen atom, a cyano group, an alkoxy group, an alkyl or carbamoyl or alkynyl; R3 represents a hydrogen atom, a halogen atom, cyano, formyl, carboxyl, alkyl optionally substituted with (1) amino group optionally substituted with alkyl, or (2) alkoxy group, aryl optionally substituted with an alkoxy group, tetrazolyl, alkylcarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, where heteroaryl is a 4-6-member monocyclic radical containing 1-2 heteroatoms selected from a nitrogen atom or oxygen atom, alkoxycarbonyl, carbamoyl optionally substituted with alkyl, cycloalkyl or cycloalkylalkyl, hydroxyl, alkoxy group or a group of formula: -Rd-C(O)O-Re, where Rd represents a single bond, and Re represents a group of formula: -CH(R4a)OC(O)R4b, where R4a represents alkyl or R4b represents cycloalkyloxy or aryloxy; R represents a hydrogen atom, hydroxyl, cyano, alkyl, carbamoyl, carboxyl, aryloxy optionally substituted with an alkoxy group or carbamoyl, alkylsulfonyl, alkylcarbonyl or alkoxycarbonyl; R5 represents a hydrogen atom or alkyl; -Y represents a group of formula (A) given below: in which m1 equals 2, and R6 is absent, or to pharmaceutically acceptable salts of the said compounds. The invention also relates to compounds of formula (VI), to pharmaceutical compositions, to a dipeptidyl peptidase IV inhibitor, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds with dipeptidyl peptidase IV inhibition properties.

20 cl, 76 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention relates to compounds of general formula (I) and their pharmaceutically acceptable salts and pharmaceutically acceptable asters, possessing activity with respect to LXRα and/or LXRβ receptors. Compounds can be applied for treatment and prevention of diseases mediated by LXRα and/or LXRβ receptors, namely: increased level of lipids and cholesterol level, atherosclerotic diseases, diabetes, metabolic syndrome, dyslipidermia, sepsis, inflammatory diseases, pancreatitis, liver cholestasis/fibrosis, and diseases which include inflammatory component, such as Alzheimer's disease and reduced/improvable cognitive function. In general formula n represents integer number from 0 to 3; R1 is independently selected from group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, -OR11, pyperidinyl and -N(R11)(R11), where R11 is independently selected from lower alkyl and H, X1, X2, X3 and X4 are independently selected from nitrogen and carbon, on condition that, not more than two of X1, X2, X3 and X4 can simultaneously represent nitrogen, and in case when two of X1, X2, X3 and X4 represent nitrogen, n represents 0,1 or 2; k represents integer number 0 or 1; R2 represents H; R3 represents H, lower alkyl or halogen; R4 represents aryl, heteroaryl, lower alkylaryl or lower alkylheteroaryl, each of which is optionally substituted with substituents in amount from one to five, which are independently selected from group consisting of halogen, lower alkyl, -OR41, lower alkinyl and NR42R43, where R41 represents lower alkyl, R42 and R43 independently on each other represent hydrogen or lower alkyl, or NR42R43 represents pyrrolidinyl, or R4 represents lower alkyl; R5 is selected from group, heteroaryl, consisting of and , said aryl and heteroaryl being optionally substituted in one or more positions with one or more substituents, independently selected from group consisting of H, halogen, lower alkyl and (CH2)VR53, where R51 is selected from group consisting of H, lower alkyl, lower alkenyl and lower alkylaryl, said lower alkylaryl is optionally substituted in one or more positions with one or more lower alkyl, -CN, halogen, group -COOR54 and group -CH2OR54, where R54 represents lower alkyl or H; R52 represents lower alkyl or -H; R53 represents H, lower alkyl, C3-C6-cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -CONH2 or -CH2OR55, where R55 is independently selected from group consisting of lower alkyl, -H, -C(O)aryl or -C(O)-lower alkyl, and R56 is selected from group consisting of H, lower alkyl, -C(O)CF3, -C(O)aryl, -C(O)-lower alkyl and lower alkylaryl, and where said aryl and lower alkylaryl are optionally substituted in one or more positions with one or more lower alkyl, halogen, group COOR57 and group -CH2OR57, where R57 represents lower alkyl or -H, or R55 and R56 together with atom to which they are bound, form ring system; or R53 represents aryl, which can be optionally substituted with benzyloxy, carboxy, lower alkoxycarbonyl, hydroxy-(lower alkyl), halogen, carbamoyl, (lower alkyl)carbamoyl, di-(lower alkyl)carbamoyl, m represents integer number from 0 to 2; v represents integer number from 0 to 4; where term "lower alkyl" separately or in combination with other groups refers to branched or linear monovalent alkyl radical, containing from one to six carbon atoms, where term "aryl" separately or in combination with other groups refers to phenyl or naphthyl, and where term "hetyeroaryl" refers to aromatic 5- or 6-member ring, which can include 1-3 heteroatoms selected from nitrogen, oxygen and/or sulphur, and which can be condensed with phenyl group.

EFFECT: increase of compound application efficiency.

38 cl, 5 dwg, 137 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) which are protein tyrosine kinase 1B(PTP-1B) inhibitors and can be used in medicinal preparations for treating and preventing diseases related to high concentration of glucose in blood, for example diabetes and obesity. In formula (I) X is a X-1 group or X-2: , where R1 and R2 are each independently selected from a group consisting of hydrogen, lower alkyl, alkoxy-lower alkyl and hydroxyl-lower alkyl, under the condition that, R1 and R2 both represent hydrogen; R3, R4, R6 and R7 are each independently selected from a group consisting of hydrogen, lower alkyl; lower alkyl substituted with halogen or hydroxy; lower alkoxy; lower alkoxy substituted with halogen, hydroxy or lower alkoxy; hydroxyl, halogen, lower alkylthio, lower alkylsufanyl, lower alkylsufanyl, aminosufonyl, cyano, nitro, carbamoyl, lower mono- or dialkylcarbamoyl, lower alkanoyl, benzoyl, phenyl, phenyl substituted with halogen, phenyloxy, lower mono- or dialkylamino, hydroxy-substituted lower alkylamino, lower alkanoylamino, lower alkylsulfonylamino, heterocycloalkyl, hydroxy-substituted heterocycloalkyl, heterocyclyloxy, heterocyclylcarbonyl; where each heterocycloalkyl in the said values represents a 5-6-membr ring containing 1-2 heteroatoms selected from nitrogen and oxygen, and which can be substituted with lower alkyl or phenyl-lower alkyl; carboxyl, lower alkoxycarbonyl and a substitute of formula: ; R8 is selected from a group consisting of hydrogen, lower alkylthio, halogen, alkoxy-lower alkoxy, lower alkoxy, halogen-lower alkyl, hydroxy-lower alkyl; represents a 5-member heteroaromatic ring containing 1 or 2 heteroatoms selected from a group consisting of hydrogen, sulphur and nitrogen; R8 and R9 each independently represents hydrogen or lower alkyl.

EFFECT: novel compounds have useful biological properties.

31 cl, 7 dwg, 152 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel hexafluoroisopropanol substituted derivatives of cyclohexane of formula (I) with LXRα- and/or LXRβ agonist modulation properties, as well as to their pharmaceutically acceptable salts. In formula (I) R1 denotes hydrogen, lower alkyl, fluoro-lower alkyl, lower alkyl-carbonyl, fluoro-lower alkyl-carbonyl, phenyl-lower alkyl, C3-C6-cycloalkyl-lower alkyl, C3-C6-cycloalkylcarbonyl or C3-C6-cycloalkyl-lower alkyl-carbonyl; R2 denotes hydrogen or lower alkyl; R3 denotes lower alkyl, phenyl-lower alkyl, where phenyl is possibly substituted with lower alkoxycarbonyl, lower alkoxycarbonyl, or if X represents a single bond and m is not equal to 0, R3 can also denote a hydroxy group; R4 denotes phenyl or heterocyclyl, where heterocyclyl is a five-member aromatic heterocyclic ring containing two heteroatoms selected from nitrogen and sulphur, optionally substituted with 1-3 substitutes independently selected from a group which includes lower alkyl and halogen; X denotes a single bond, SO2, CO or C(O)O; m equals 0, 1, 2 or 3; n equals 0 or 1. The invention also relates to a pharmaceutical composition containing formula (I) compounds.

EFFECT: novel compounds have useful biological properties.

20 cl, 35 ex

FIELD: chemistry.

SUBSTANCE: small peptides of formula X1-X2-X3-X4-X5-X6-X7-R1, containing 7-12 amino acid residues are proposed.

EFFECT: said peptides are MC4 receptor agonists and are therefore useful in treating obesity and related diseases.

31 cl, 2 tbl, 82 ex

FIELD: chemistry; biochemistry.

SUBSTANCE: invention relates to compounds of general formula (II) and pharmaceutically acceptable salts thereof, and to use and a pharmaceutical composition based on the said compounds. In formula (II) compounds, A is a heteroaromatic 5-member cyclic system containing one group X selected from a group consisting of S and O; Z1 and Z2 independently represent O; R2 is OR6; R6 is H; R8 is hydrogen or (C1-C6)alkyl; E is phenyl which is optionally substituted with 1-4 substitutes in form of halogen; Y is phenyl which is optionally substituted with 1-2 substitutes selected from halogen, (C1-C6)alkoxy or halogen((C1-C6))alkyloxy; m equals 0; n equals 0; q equals 0; t equals 0; or pharmaceutically acceptable salts thereof.

EFFECT: obtaining aromatic compounds of formula (II) for inhibiting dehydroorotate dehydrogenase.

6 cl, 22 ex

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