1-thio-d-glucitol derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to novel 1-thio-D-glucitol compounds of formula I or to pharmaceutically acceptable salts thereof or hydrates of the compound or salts: , [where R1, R2, R3 and R4 are identical or different, and each is a hydrogen atom, C1-C6-alkyl group), A is -(CH2)n-, -CONH(CH2)n-, -O- or -(CH2)nCH=CH- (where n is an integer from 0 to 3, Ar1 is an arylene group, heteroarylene group, which is an unsaturated 5-9-member mono- or bicyclic group, containing 1-2 heteroatoms, selected from S and N, Ar2 is an aryl group or heteroaryl group which is an unsaturated 5-9-member mono- or bicyclic group containing 1-2 heteroatoms selected from O, S and N, and R5, R6, R7, R8, R9 and R10 are identical or different, and each is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) C1-8-alkyl group, optionally substituted with hydroxyl group(s), (v) -(CH2)m-Q {where m is an integer from 0 to 4, and Q is -CO2H, -ORc1, -CO2Ra3, -SRe1, -NHRa6 or -NRa7Ra7 (where each of Ra3, Ra6 and Ra7 is a C1-6-alkyl group, Rc1 is a C1-6-alkyl group, and Rc1 is a C1-6-alkyl group)}, (vi) -O-(CH2)m'-Q' {where m' is an integer from 1 to 4, and Q' is a hydroxyl group,-CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12 (where each of Ra8, Ra10 and Ra12 is a C1-6-alkyl group)}, (vii) -ORf {where Rf is C3-7-cycloalkyl group or tetrahydropyranyl group)}, (viii) morpholine group, (ix) phenyl group, (x) pyridyl group]. The invention also relates to 1-thio-D-glucitol compounds of formulae IA, II, III, IV, to a pharmaceutical agent, to methods of obtaining 1-thio-D-glucitol compounds, as well as to compounds of formulae XIII, XIV.

EFFECT: obtaining novel biologically active compounds which are inhibitors of sodium-dependent co-transporter-2-glucose.

25 cl, 140 ex, 3 tbl

 

The technical FIELD

The present invention relates to derivatives of 1-thio-D-glucitol that inhibit the activity of sodium-dependent co-glucose Transporter (SGLT2), which is associated with the reabsorption of glucose in the kidneys.

PRIOR art

It is believed that chronic hyperglycemia decreases the secretion of insulin and, in addition, reduced insulin sensitivity, which further causes an increase in levels of glucose in the blood leads to deterioration in diabetes. Hyperglycemia is a major risk factor for diabetic complications. Thus, it is believed that maintaining normal blood sugar levels improves insulin sensitivity and inhibits the beginning of the development of complications in diabetes. To date in the treatment of diabetes are the biguanides, sulfonylureas, glycosidase inhibitors and agents that improve insulin sensitivity. However, there are reports of adverse reactions or side effects such as lactic acidosis, when using biguanides, hypoglycemia when using the sulfonylureas, as well as diarrhea and serious violations of liver function using glycosidase inhibitors. Therefore, there is an urgent need to develop drugs for the treatment of diabetes, which would have IU is aNISM actions different from the mechanisms of action of commonly used for this drug.

It was shown that phlorizin, which is a derivative of glucose, isolated from natural products, inhibits the reabsorption of excess levels of glucose in the kidney and initiates the excretion of glucose, showing antihyperglycemics action (non-patent documents 1 and 2). Further, this reabsorption of glucose is attributed to the sodium-dependent co-glucose Transporter 2 (SGLT2), present at site S1 proximal renal tubules (non-patent document 3). Since it has been shown that the introduction of phlorizin, specific SGLT inhibitor, in rats with diabetes increases the secretion of glucose in the urine and causes antihyperglycemics action, SGLT2-specific inhibitors are considered as a new target molecules for therapeutic intervention with diabetes.

Against this background, explored a number of related phlorizin compounds and have been described O-arylpyrazole (patent documents 1-11). However, oral administration of O-arylpyrazole their glycosidic bond is hydrolyzed under the action of β-glycosidase present in the small intestine, and in unmodified form they are low efficiency of absorption. Thus, their proletarienne forms are now under study.

It was published is about the message about the connections which are O-arylpyrazole transformed into chemically stable C-arylpyrazole (patent document 12). There are reports also of compounds in which the sugar residue is directly linked to the aryl or heteroaryl as described above (patent documents 13-15). However, C-arylpyrazole, which are described in these documents (patent documents 12-15), in many cases are amorphous substances, and, thus, their pharmaceutical production is problematic (patent document 12). For this reason, these compounds need to be subjected to crystallization with the corresponding amino acids such as phenylalanine and Proline (U.S. patent US6774112). Accordingly, a need exists for compounds that are extremely crystallinity, and treatment, storage and pharmaceutical production of which is facilitated, and which can easily be included in the composition of medicinal products.

There are reports about how the production of derivatives of aryl-5-thio-β-D-glucopyranoside (O-aryl-5-thio-β-D-glucoside) or heteroaryl-5-thio-β-D-glucopyranoside (O-heteroaryl-5-thio-β-D-glucoside), in which 5-thioglucose and aryl or heteroaryl linked through β-glucoside (patent documents 16-17). There are reports also of SGLT-inhibitory effect of these compounds (patent the e documents 18-19). However, according to the publication (patent document 16) the nature of the glycosylation reaction greatly depends on the type of sugar, and reaction conditions that promote glycosylation of glucose, are very different and cannot be used against thioglucose.

Thus, there is no way of producing derivatives of 1-thio-D-glucitol, in which 5-thioglucose and aryl or heterocycle directly connected to each other, and there are no publications about derivatives of 1-thio-D-glucitol. Some of the compounds described in patent documents 1 to 15, have already been subjected to clinical trials and it is likely that in the future there will be new drugs for the treatment of diabetes, which will be commercially available. However, in the process of clinical trials on human development of such tools for several reasons it may be difficult, and in this regard, there remains a need for a group of compounds that have the same mechanism of action, but having a new, previously unknown, the structure of the skeleton.

Non-patent document 1: Rossettl, L., et al. J. Clin. Invest., Vol. 80, 1037, 1987

Non-patent document 2: Rossetti, L., et al. J. Clin. Invest., Vol. 79, 1510, 1987

Non-patent document 3: Kanai, Y., et al. J. Clin. Invest., Vol. 93, 397, 1994

Patent document 1: Publication of the European patent application No. 0850948

Patent document is t 2: Publication of the European patent application No. 0598359

Patent document 3: international publication No. WO 01/068660

Patent document 4: international publication No. WO 01/016147

Patent document 5: international publication No. WO 01/074834

Patent document 6: international publication No. WO 01/074835

Patent document 7: international publication No. WO 02/053573

Patent document 8: international publication No. WO 2/068439

Patent document 9: international publication No. WO 02/068440

Patent document 10: international publication No. WO 02/036602

Patent document 11: international publication No. WO 02/088157

Patent document 12: international publication No. WO 01/027128

Patent document 13: Publication of patent application U.S. No. US2001/0041674

Patent document 14: international publication No. WO 04/013118

Patent document 15: international publication No. WO 04/080990

Patent document 16: international publication No. WO 04/014930

Patent document 17: international publication No. WO 04/089966

Patent document 18: international publication No. WO 04/014931

Patent document 19: international publication No. WO 04/089967

Description of the INVENTION

PROBLEMS THAT are solved by USING the PRESENT INVENTION

One of the objects of the present invention associated with the provision of new, not previously known compounds 1-thio-D-glucitol that inhibit the activity is ü sodium-dependent co-glucose Transporter 2 (SGLT2), associated with the reabsorption of glucose in the kidneys, stimulate the secretion of sugar in the urine and have antihyperglycemics action. Another object of the present invention is linked to a very selective SGLT2 inhibitor activity. Another object of the present invention is the provision of a compound that has an exceptional crystallinity and cleaning, storage and pharmaceutical manufacture is facilitated and which is easily subject to inclusion in the composition of medicines. Another object of the present invention associated with the provision of a method for obtaining compounds of 1-thio-D-glucitol and obtain its derivatives.

APPROACHES TO PROBLEM SOLVING

The authors of the present invention conducted a thorough search and investigation in an attempt to find a solution to the above problems. As a result, they invented a method of obtaining a direct binding of the aryl or heterocycle with 5-thio-glucose and found that the derived 1-thio-D-glucitol obtained in this way has the exclusive inhibitory activity against SGLT2. This discovery has enabled me to complete the present invention. It was found also that the derived 1-thio-D-glucitol according to the invention has satisfactory crystallinity. Thus, this derivative does not require joint crystallization with amine is a acid or other, does not require treatment, storage, and pharmaceutical production of this derivative is easy, and besides, it is suitable for use as a medicine.

Embodiments of the derived 1-thio-D-glucitol according to the invention (hereinafter referred to as "compound according to the present invention will be described below.

One of the embodiments of the present invention relates to the connection 1-thio-D-glucitol following formula I or its pharmaceutically acceptable salt, or hydrate of the compound, or a hydrate of the salt.

[where R1, R2, R3and R4the same or different, and each represents a hydrogen atom, a C1-6is an alkyl group, -CO2Ra2, -CORb1or C7-12-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, -NO2and-OMe (where Ra2represents a C1-6is an alkyl group, and Rb1represents a C1-6is an alkyl group, a C7-10-aracelio group or phenyl group),

A represents -(CH2)n-, -CNH(CH2)n-, -HCO(CH2)n-, -O-, -S-, -NH - or -(CH2)nCH=CH- (where n denotes an integer from 0 to 3)

Ar1represents Allenova group, heteroarenes group or heterocyclochain the second group,

Ar2represents an aryl group, heteroaryl group, or geterotsyklicescoe group, and

R5, R6, R7, R8, R9and R10the same or different, and each represents:

(i) a hydrogen atom,

(ii) a halogen atom,

(iii) a hydroxyl group,

(iv) C1-8is an alkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom and a hydroxyl group,

(v) -(CH2)m-Q {where m denotes an integer from 0 to 4, and Q represents-CHO, -NH2, -NO2, -CN, -CO2H, -SO3H, -or SIGc1, -CO2Ra3, -CONH2, -CNHRA4, -CONRa5Ra5, -CRd1, -CRd2, -SRe1, -SORe2, -SO2RE3, -NHC(=O)H, -NHCRd3, -NHC2Rd4, -NHCONH2, -NHSO2RE4-The othera6or-NRa7Ra7(where Ra3, Ra4, Ra5, Ra6and Ra7each represents a C1-6is an alkyl group, Rc1represents a C1-6is an alkyl group, optionally substituted atom(s) halogen, Rd1, Rd2, Rd3and Rd4each represents a C1-6is an alkyl group, a C7-10-aracelio group, phenyl group or a C3-7-cycloalkyl group, and Re1, Re2, Re3and Re4each represents a C1-6-al the ilen group, phenyl group or taillow group)},

(vi) -O-(CH2)m'-Q' {where m' denotes an integer from 1 to 4, and Q' represents a hydroxyl group, -CO2H, -or SIGc2, -CO2Ra8, -CONH2, -CONHRA9, -CNRa10Ra10, -NH2-The othera11, -NRa12Ra12or-NHCO2Rd5(where Ra8, Ra9, Ra10, Ra11and Ra12each represents a C1-6is an alkyl group, Rc2represents a C1-6is an alkyl group, optionally substituted atom(s) halogen, and Rd5represents a C1-6is an alkyl group, a C7-10-aracelio group, phenyl group or a C3-7-cycloalkyl group)},

(vii) -ORf{where Rfrepresents a C3-7-cycloalkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa13(where Ra13represents a C1-6is an alkyl group); aryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa14(where Ra14represents a C1-6is an alkyl group); C7-10-aracelio group, optionally substituted by one or more substituents which, selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa15(where Ra15represents a C1-6is an alkyl group); or geterotsyklicescoe group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa16(where Ra16represents a C1-6is an alkyl group)},

(viii) otherg{where Rgrepresents a C7-10-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa17(where Ra17represents a C1-6is an alkyl group)},

(ix) C3-7-cycloalkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa18(where Ra18represents a C1-6is an alkyl group),

(x) aryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa19(where Ra19represents a C1-6is an alkyl group),

(xi) C7-10-Araki is inuu group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa20(where Ra20represents a C1-6is an alkyl group),

(xii) heteroaryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa21(where Ra21represents a C1-6is an alkyl group),

(xiii) geterotsyklicescoe group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa22(where Ra22represents a C1-6is an alkyl group),

(xiv) C2-6-alkenylphenol group or

(xv) C2-6-alkylamino group].

Another embodiment of the present invention relates to the connection 1-thio-D-glucitol following formula IA or pharmaceutically acceptable salt or hydrate of the compound or a hydrate of the salt.

[where R1, R2, R3and R4the same or different, and each represents a hydrogen atom, a C1-6is an alkyl group, -CO2Ra2, -CORb1or C7-12-aracelio group, optionally substituted one who does more substituents, selected from the group consisting of a halogen atom, -NO2and-OMe (where Ra2represents a C1-6is an alkyl group, and Rb1represents a C1-6is an alkyl group, a C7-10-aracelio group or phenyl group),

A represents -(CH2)n-, -CNH(CH2)n-, -HCO(CH2)n-, -O-, -S-, -NH - or -(CH2)nCH=CH- (where n denotes an integer from 0 to 3)

Ar1represents Allenova group, heteroarenes group or geteroseksualbnogo group,

Ar2represents an aryl group, heteroaryl group, or geterotsyklicescoe group, and

R5', R6', R7', R8', R9'and R10'the same or different, and each represents:

(i) a hydrogen atom,

(ii) a halogen atom,

(iii) a hydroxyl group,

(iv) C1-8is an alkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom and a hydroxyl group,

(v) -(CH2)m-Q {where m denotes an integer from 0 to 4, and Q represents-CHO, -NH2, -NO2, -CN, -CO2H, -SO3H, -or SIGc1, -CO2Ra3, -CONH2, -CNHRA4, -CONRa5Ra5, -CRd1, -CRd2, -SRe1, -SORe2, -SO2RE3, -NHC(=O)H, -NHCRd3, -NHC2Rd4, -NHCONH2, -NHSO2RE4-The othera6or-NRa7 Ra7(where each Ra3, Ra4, Ra5, Ra6and Ra7represents a C1-6is an alkyl group, Rc1represents a C1-6is an alkyl group, optionally substituted atom(s) halogen, Rd1, Rd2, Rd3and Rd4each represents a C1-6is an alkyl group, a C7-10-aracelio group, phenyl group or a C3-7-cycloalkyl group, and each Re1, Re2, Re3and Re4represents a C1-6is an alkyl group, phenyl group or taillow group)},

(vi) -O-(CH2)m'-Q' {where m' denotes an integer from 1 to 4, and Q' represents a hydroxyl group, -CO2H, -or SIGc2, -CO2Ra8, -CONH2, -CONHRA9, -CNRa10Ra10, -NH2-The othera11, -NRa12Ra12or-NHCO2Rd5(where Ra8, Ra9, Ra10, Ra11and Ra12each represents a C1-6is an alkyl group, Rc2represents a C1-6is an alkyl group, optionally substituted atom(s) halogen, and Rd5represents a C1-6is an alkyl group, a C7-10-aracelio group, phenyl group or a C3-7-cycloalkyl group)},

(vii) -ORf{where Rfrepresents a C3-7-cycloalkyl group, optionally substituted by one or more substituents selected and the group, consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa13(where Ra13represents a C1-6is an alkyl group); aryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa14(where Ra14represents a C1-6is an alkyl group); or C7-10-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa15(where Ra15represents a C1-6is an alkyl group);

(viii) otherg{where Rgrepresents a C7-10-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa17(where Ra17represents a C1-6is an alkyl group)},

(ix) C3-7-cycloalkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa18(where Ra18represents a C1-6is an alkyl group),

(x) aryl group, optionally substituted ar is them or more substituents, selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa19(where Ra19represents a C1-6is an alkyl group),

(xi) C7-10-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa20(where Ra20represents a C1-6is an alkyl group),

(xii) heteroaryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa21(where Ra21represents a C1-6is an alkyl group), or

(xiii) geterotsyklicescoe group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa22(where Ra22represents a C1-6is an alkyl group)].

The first specific embodiment of the present invention pertain to compounds 1-thio-D-glucitol formula I or IA where Ar1represents Allenova group, or their pharmaceutically acceptable salts, or hydrates of salts.

One of the above embodiments of the present invention relates to the connection 1-thio-D-glucitol is and formulas I or IA, where Ar1represents fenelonov group or Neftyanoy group, or its pharmaceutically acceptable salt, or hydrate of the compound or a hydrate salts.

Another embodiment of the present invention relates to the connection 1-thio-D-glucitol or its pharmaceutically acceptable salt or hydrate of the compound, or a hydrate of the salt, where A represents -(CH2)n-, -CONH(CH2)n-, -O - or -(CH2)nCH=CH- (where n denotes an integer from 0 to 3).

Another embodiment of the present invention relates to the connection 1-thio-D-glucitol or its pharmaceutically acceptable salt, or hydrate of the compound, or a hydrate of the salt, where A represents a-CH2-.

Another embodiment of the present invention relates to the connection 1-thio-D-glucitol or its pharmaceutically acceptable salt, or hydrate of the compound, or a hydrate of the salt, where Ar2represents a phenyl group, thienyl group, a benzo[b]tiffaniejoy group, thieno[2,3-b]tiffaniejoy group, benzofuranyl group, benzothiazolyl group, indolenine group, pyrrolidino group, imidazolidinyl group, pyrazolidine group, pyridyloxy group, pyrimidinyl group, personilnya group or isoxazolyl group.

The first specific embodiment of the present invention relates in particular to the connection 1-thio-D-glucitol following the shape of the s II or its pharmaceutically acceptable salt, or the hydrate of the compound or the salt hydrate (hereinafter referred to as "the first concrete embodiment (1)"):

[where R1, R2, R3and R4the same or different, and each represents a hydrogen atom, a C1-6is an alkyl group, -CO2Ra2, -CORb1or C7-12-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, -NO2and-OMe (where Ra2represents a C1-6is an alkyl group, and Rb1represents a C1-6is an alkyl group, a C7-10-aracelio group or phenyl group),

at least one of RA, RB, Rcand RDrepresents a hydrogen atom, and the rest of them are the same or different, and each represents:

(i) a hydrogen atom,

(ii) a halogen atom,

(iii) a hydroxyl group,

(iv) C1-8is an alkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom and a hydroxyl group,

(v) -(CH2)m-QAnd{where m denotes an integer from 0 to 4, and QArepresents-NH2, -CO2H, -ORc1, -CO2Ra3, -CONH2, -CONHRa4, -CONRa5Ra5, -CORd1, -OCORd2, -SRe1, -SORe2, -SO2Re3, -NHC(=O)H, -NHCOR d3, -NHCO2Rd4, -NHCONH2, -NHSO2Re4-The othera6or-NRa7Ra7(where Ra2, Ra3, Ra4, Ra5, Ra6and Ra7each represents a C1-6is an alkyl group, Rc1represents a C1-6is an alkyl group, optionally substituted atom(s) halogen, Rd1, Rd2, Rd3and Rd4each represents a C1-6is an alkyl group, a C7-10-aracelio group, phenyl group or a C3-7-cycloalkyl group, and each Re1, Re2, Re3and Re4represents a C1-6is an alkyl group, phenyl group or taillow group)},

(vi) -O-(CH2)m'-Q' {where m' denotes an integer from 1 to 4, and Q' represents a hydroxyl group, -CO2H, -or SIGc2, -CO2Ra8, -CONH2, -CONHRA9, -CNRa10Ra10, -NH2-The othera11, -NRa12Ra12or-NHCO2Rd5(where Ra8, Ra9, Ra10, Ra11and Ra12each represents a C1-6is an alkyl group, Rc2represents a C1-6is an alkyl group, optionally substituted atom(s) halogen, and Rd5represents a C1-6is an alkyl group, a C7-10-aracelio group, phenyl group or a C3-7-cycloalkyl group)},

(vii) -ORf{where Rfrepresents a C3-7-cloulkili group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa13(where Ra13represents a C1-6is an alkyl group); aryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa14(where Ra14represents a C1-6is an alkyl group); C7-10-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa15(where Ra15represents a C1-6is an alkyl group)};

(viii) otherg{where Rgrepresents a C7-10-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa17(where Ra17represents a C1-6is an alkyl group)},

(ix) aryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa19(where RA19represents a C1-6-alkyl which the Rupp), or

(x) geterotsyklicescoe group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa22(where RA22represents a C1-6is an alkyl group), and

RE, RFand RGthe same or different, and each represents:

(i) a hydrogen atom,

(ii) a halogen atom,

(iii) a hydroxyl group,

(iv) C1-8is an alkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom and a hydroxyl group,

(v) -(CH2)m-Q {where m denotes an integer from 0 to 4, and Q represents-CHO, -NH2, -NO2, -CN, -CO2H, -SO3H, -or SIGc1, -CO2Ra3, -CONH2, -CNHRA4, -CONRa5Ra5, -CRd1, -CRd2, -SRe1, -SORe2, -SO2RE3, -NHC(=O)H, -NHCRd3, -NHC2Rd4, -NHCONH2, -NHSO2RE4-The othera6or-NRa7Ra7(where Ra3, Ra4, Ra5, Ra6and Ra7each represents a C1-6is an alkyl group, Rc1represents a C1-6is an alkyl group, optionally substituted atom(s) halogen, Rd1, Rd2, Rd3and Rd4each represents a C1-6is an alkyl group, a C7-10-aracelio gr the PPU, phenyl group or a C3-7-cycloalkyl group, and each Re1, Re2, Re3and Re4represents a C1-6is an alkyl group, phenyl group or taillow group)},

(vi) -O-(CH2)m'-Q' {where m' denotes an integer from 1 to 4, and Q' represents a hydroxyl group, -CO2H, -or SIGc2, -CO2Ra8, -CONH2, -CONHRA9, -CNRa10Ra10, -NH2-The othera11, -NRa12Ra12or-NHCO2Rd5(where Ra8, Ra9, Ra10, Ra11and Ra12each represents a C1-6is an alkyl group, Rc2represents a C1-6is an alkyl group, optionally substituted atom(s) halogen, and Rd5represents a C1-6is an alkyl group, a C7-10-aracelio group, phenyl group or a C3-7-cycloalkyl group)},

(vii) -ORf{where Rfrepresents a C3-7-cycloalkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa13(where Ra13represents a C1-6is an alkyl group); aryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa14 (where Ra14represents a C1-6is an alkyl group); C7-10-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa15(where Ra15represents a C1-6is an alkyl group); or geterotsyklicescoe group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa16(where Ra16represents a C1-6is an alkyl group)},

(viii) otherg{where Rgrepresents a C7-10-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa17(where Ra17represents a C1-6is an alkyl group)},

(ix) C3-7-cycloalkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa18(where Ra18represents a C1-6is an alkyl group),

(x) aryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom is, hydroxyl group, a C1-6is an alkyl group and-ORa19(where Ra19represents a C1-6is an alkyl group),

(xi) C7-10-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa20(where Ra20represents a C1-6is an alkyl group),

(xii) heteroaryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa21(where Ra21represents a C1-6is an alkyl group),

(xiii) geterotsyklicescoe group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa22(where Ra22represents a C1-6is an alkyl group),

(xiv) C2-6-alkenylphenol group or

(xv) C2-6-alkylamino group].

Another embodiment of the present invention relates to the connection 1-thio-D-glucitol formula II or its pharmaceutically acceptable salt or hydrate of the compound or the salt hydrate (hereinafter referred to as "the first concrete embodiment (1)-1"), in which

RAand Rceach represents and what Ohm hydrogen

RBrepresents a hydrogen atom, halogen atom, hydroxyl group, C1-8is an alkyl group, -O-(CH2)m'-Q' {where m' denotes an integer from 1 to 4, and Q' represents a hydroxyl group, -CO2H, -ORc2, -CO2RA8, -CONH2, -CONHRA9, -CONRa10Ra10, -NH2-The otherA11, -NRA12RA12or-NHCO2Rd5(where each RA8, RA9, Ra10, RA11and RA12represents a C1-6is an alkyl group, Rc2represents a C1-6is an alkyl group, optionally substituted atom(s) halogen, and Rd5represents a C1-6is an alkyl group, a C7-10-aracelio group, phenyl group or a C3-7-cycloalkyl group)}, orf1{where Rf1represents a C1-6is an alkyl group, optionally substituted atom(s) halogen, or C7-10-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa15(where RA15represents a C1-6is an alkyl group),

RDrepresents a hydrogen atom, halogen atom, hydroxyl group, C1-8is an alkyl group or-ORf2{where Rf2represents a C1-6is an alkyl group, optional the nutrient substituted atom(s) halogen, or C7-10-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa15(where RA15represents a C1-6is an alkyl group),

REand RFthe same or different, and each represents a hydrogen atom, halogen atom, hydroxyl group, C1-8is an alkyl group or-ORc3(where Rc3represents a C1-6is an alkyl group, optionally substituted atom(s) halogen), and

RGrepresents:

(i) a hydrogen atom,

(ii) a halogen atom,

(iii) a hydroxyl group,

(iv) C1-8is an alkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom and a hydroxyl group,

(v) -(CH2)m-Q {where m denotes an integer from 0 to 4, and Q represents-CHO, -NH2, -NO2, -CN, -CO2H, -SO3H, -or SIGc1, -CO2Ra3, -CONH2, -CNHRA4, -CONRa5Ra5, -CRd1, -CRd2, -SRe1, -SORe2, -SO2RE3, -NHC(=O)H, -NHCRd3, -NHC2Rd4, -NHCONH2, -NHSO2RE4-The othera6or-NRa7Ra7(where Ra3, Ra4, Ra5, Ra6and Ra7each represents a C1-6is an alkyl group, Rc represents a C1-6is an alkyl group, optionally substituted atom(s) halogen, Rd1, Rd2, Rd3and Rd4each represents a C1-6is an alkyl group, a C7-10-aracelio group, phenyl group or a C3-7-cycloalkyl group, and each Re1, Re2, Re3and Re4represents a C1-6is an alkyl group, phenyl group or taillow group)},

(vi) -O-(CH2)m'-Q' {where m' denotes an integer from 1 to 4, and Q' represents a hydroxyl group, -CO2H, -or SIGc2, -CO2Ra8, -CONH2, -CONHRA9, -CNRa10Ra10, -NH2-The othera11, -NRa12Ra12or-NHCO2Rd5(where Ra8, Ra9, Ra10, Ra11and Ra12each represents a C1-6is an alkyl group, Rc2represents a C1-6is an alkyl group, optionally substituted atom(s) halogen, and Rd5represents a C1-6is an alkyl group, a C7-10-aracelio group, phenyl group or a C3-7-cycloalkyl group)},

(vii) -ORf{where Rfrepresents a C3-7-cycloalkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa13(where Ra13the submitted is a C 1-6is an alkyl group); aryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa14(where Ra14represents a C1-6is an alkyl group); C7-10-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa15(where Ra15represents a C1-6is an alkyl group); or geterotsyklicescoe group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa16(where Ra16represents a C1-6is an alkyl group)},

(viii) otherg{where Rgrepresents a C7-10-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa17(where Ra17represents a C1-6is an alkyl group)},

(ix) C3-7-cycloalkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6-alkyl the group and-OR a18(where Ra18represents a C1-6is an alkyl group),

(x) aryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa19(where Ra19represents a C1-6is an alkyl group),

(xi) C7-10-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa20(where Ra20represents a C1-6is an alkyl group),

(xii) heteroaryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa21(where Ra21represents a C1-6is an alkyl group), or

(xiii) geterotsyklicescoe group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa22(where Ra22represents a C1-6is an alkyl group).

Another embodiment of the present invention relates to the connection 1-thio-D-glucitol or its pharmaceutically acceptable salt or hydrate of the compound or the salt hydrate (referred to as the hereinafter as "the first concrete embodiment (1)-2"), in which

RBrepresents a hydrogen atom, a C1-6is an alkyl group, -ORf1(where Rf1represents a C1-6is an alkyl group, optionally substituted atom(s) halogen), or a halogen atom, and

RDrepresents a hydrogen atom, a hydroxyl group or-ORf1{where Rf1represents a C1-6is an alkyl group, optionally substituted atom(s) halogen, or C7-10-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa15(where RA15represents a C1-6is an alkyl group)}.

Another embodiment of the present invention relates to the connection 1-thio-D-glucitol or its pharmaceutically acceptable salt or hydrate joint, or salt hydrate according to the first specific embodiment (1)-1 or the first specific embodiment (1)-2, where

RGrepresents a

(i) a hydrogen atom,

(ii) a halogen atom,

(iii) a hydroxyl group,

(iv) C1-8is an alkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom and a hydroxyl group,

(v) CO2H,

(vi) -ORc1,

(vii) -CO2Ra3,

(viii) -CONH2,

(ix) -CONR a4,

(x) -CONRa5Ra5,

(xi) -CORd1,

(xii) -OCORd2,

(xiii) -SRe1,

(xiv) -SORe2,

(xv) -SO2Re3,

(xvi) -othera6,

(xvii) -NRa7Ra7(where each Ra3, RA4, Ra5, Ra6and RA7represents a C1-6is an alkyl group, Rc1represents a C1-6is an alkyl group, optionally substituted atom(s) halogen, Rd1and Rd2each represents a C1-6is an alkyl group, a C7-10-aracelio group, phenyl group or a C3-7-cycloalkyl group, and Re1, Re2and Re3each represents a C1-6is an alkyl group, phenyl group or taillow group)

(xviii) -O-(CH2)m'-Q' {where m' denotes an integer from 1 to 4, and Q' represents a hydroxyl group, -CO2H, -ORc2, -CO2RA8, -CONH2, -CONHRA9, -CONRa10Ra10, -NH2-The otherA11or-NRA12RA12(where RA8, Ra9, Ra10, Ra11and RA12each represents a C1-6is an alkyl group, and Rc2represents a C1-6is an alkyl group, optionally substituted atom(s) halogen)},

(xix) -ORf{where Rfrepresents a C3-7-cycloalkyl group, optionally substituted by one or more substituents, selected from the group comprised the soup from a halogen atom, hydroxyl group, a C1-6is an alkyl group and-ORA13(where RA13represents a C1-6is an alkyl group); aryl group, optionally substituted by one or more substituents selected from the group consisting of halogen atom, hydroxyl group, C1-6is an alkyl group and-ORA14(where RA14represents a C1-6is an alkyl group); C7-10-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA15(where Ra15represents a C1-6is an alkyl group); or geterotsyklicescoe group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA16(where RA16represents a C1-6is an alkyl group)},

(xx) aryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA19(where RA19represents a C1-6is an alkyl group),

(xxi) C7-10-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, g is drakeley group, C1-6is an alkyl group and-ORA20(where Ra20represents a C1-6is an alkyl group),

(xxii) heteroaryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa21(where Ra21represents a C1-6is an alkyl group), or

(xxiii) geterotsyklicescoe group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA22(where RA22represents a C1-6is an alkyl group).

Another embodiment of the present invention relates to the connection 1-thio-D-glucitol or its pharmaceutically acceptable salt or hydrate of the compound or the salt hydrate according to the first specific embodiment (1)-1 or the first specific embodiment (1)-2, where

RGrepresents a

(i) a hydrogen atom,

(ii) a halogen atom,

(iii) a hydroxyl group,

(iv) C1-8is an alkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom and a hydroxyl group,

(v) CO2H,

(vi) -ORc1,

(vii) -CO2Ra3,

(viii) -CONH2,

(ix) -CONHRa4,

(x) -CONRa5Ra5,

xi) -COR d1,

(xii) -OCORd2,

(xiii) -SRe1,

(xiv) -SORe2,

(xv) -SO2Re3,

(xvi) -othera6,

(xvii) -NRa7Ra7(where each Ra3, RA4, Ra5, Ra6and RA7represents a C1-6is an alkyl group, Rc1represents a C1-6is an alkyl group, optionally substituted atom(s) halogen, Rd1and Rd2each represents a C1-6is an alkyl group, a C7-10-aracelio group, phenyl group or a C3-7-cycloalkyl group, and Re1, Re2and Re3each represents a C1-6is an alkyl group, phenyl group or taillow group)

(xviii) -O-(CH2)m'-Q' {where m' denotes an integer from 1 to 4, and Q' represents a hydroxyl group, -CO2H, -ORc2, -CO2RA8, -CONH2, -CONHRA9, -CONRa10Ra10, -NH2-The otherA11or-NRA12RA12(where RA8, Ra9, Ra10, Ra11and RA12each represents a C1-6is an alkyl group, and Rc2represents a C1-6is an alkyl group, optionally substituted atom(s) halogen)},

(xix) -ORf2{where Rf2represents a C3-7-cycloalkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C 1-6is an alkyl group and-ORA13(where RA13represents a C1-6is an alkyl group); or geterotsyklicescoe group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA16(where RA16represents a C1-6is an alkyl group)}, or

(xx) geterotsyklicescoe group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA22(where RA22represents C1-6is an alkyl group).

The first specific embodiment of the present invention also relates in particular to the connection 1-thio-D-glucitol following formula III or its pharmaceutically acceptable salt, or hydrate of the compound or the salt hydrate (hereinafter referred to as "the first concrete embodiment (2)"):

[where R1, R2, R3and R4the same or different, and each represents a hydrogen atom, a C1-6is an alkyl group, -CO2Ra2, -CORb1or C7-12-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, -NO2and-OMe (where Ra2depict is to place a C 1-6is an alkyl group, and Rb1represents a C1-6is an alkyl group, a C7-10-aracelio group or phenyl group),

RHand RIthe same or different, and each represents a hydrogen atom, halogen atom, hydroxyl group, C1-8is an alkyl group or-ORf1{where Rf1represents a C1-6is an alkyl group, optionally substituted atom(s) halogen, or C7-10-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA15(where RA15represents a C1-6is an alkyl group)},

Ar3represents a thienyl group, a benzo[b]tiffaniejoy group, thieno[2,3-b]tiffaniejoy group, benzofuranyl group, benzothiazolyl group, indolenine group, pyrrolidino group, imidazolidinyl group, pyrazolidine group, pyridyloxy group, pyrimidinyl group, personilnya group or isoxazolyl group,

R8Aand R9athe same or different, and each represents a hydrogen atom, halogen atom, hydroxyl group, C1-8is an alkyl group or-ORc3(where Rc3represents a C1-6is an alkyl group, optionally substituted atom(s) halogen), and

R10arepresents a hydrogen atom or aryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORa19(where RA19represents a C1-6is an alkyl group or heteroaryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA21(where RA21represents a C1-6is an alkyl group)].

A second specific embodiment of the present invention relates to the connection 1-thio-D-glucitol formula I or IA in which Ar1represents heteroarenes group, or its pharmaceutically acceptable salt or hydrate of the compound or a hydrate of the salt.

A second specific embodiment of the present invention, furthermore, relates to the connection 1-thio-D-glucitol or its pharmaceutically acceptable salt, or hydrate of the compound, or a hydrate of the salt, where A represents -(CH2)n- (where n denotes an integer from 0 to 3).

A second specific embodiment of the present invention relates in particular to the connection 1-thio-D-glucitol following formula IV or its pharmaceutically acceptable salt or hydrate of the compound or a hydrate of the salt.

[where R1, R2, R3and R4the same or different, and each represents a hydrogen atom, a halogen atom, a C1-6is an alkyl group, -CO2RA2, -CORb1or C7-12-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, -NO2and-OMe (where Ra2represents a C1-6is an alkyl group, and Rb1represents a C1-6is an alkyl group, a C7-10-aracelio group or phenyl group),

Ar4represents thienylene group, benzo[b]thienylene group or piridinovy group,

R20aand R21athe same or different, and each represents a hydrogen atom, halogen atom, hydroxyl group, C1-8is an alkyl group or-ORc3(where Rc3represents a C1-6is an alkyl group, optionally substituted atom(s) halogen), and

RJand RKthe same or different, and each represents a hydrogen atom, a halogen atom, a C1-8is an alkyl group or-ORc3(where Rc3represents a C1-6is an alkyl group, optionally substituted atom(s) halogen), and

RLrepresents a

(i) a hydrogen atom,

(ii) a halogen atom,

(iii) a hydroxyl group,

(iv) C1-8is an alkyl group, neo is Astelin substituted by one or more substituents, selected from the group consisting of a halogen atom and a hydroxyl group,

(v) CO2H,

(vi) -ORc1,

(vii) -CO2Ra3,

(viii) -CONH2,

(ix) -CONHRa4,

(x) -CONRa5Ra5,

(xi) -CORd1,

(xii) -OCORd2,

(xiii) -SRe1,

(xiv) -SORe2,

(xv) -SO2Re3,

(xvi) -othera6,

(xvii) -NRa7Ra7(where each Ra3, RA4, Ra5, Ra6and RA7represents a C1-6is an alkyl group, Rc1represents a C1-6is an alkyl group, optionally substituted atom(s) halogen, Rd1and Rd2each represents a C1-6is an alkyl group, a C7-10-aracelio group, phenyl group or a C3-7-cycloalkyl group, and Re1, RE2and Re3each represents a C1-6is an alkyl group, phenyl group or taillow group)

(xviii) -O-(CH2)m'-Q' {where m' denotes an integer from 1 to 4, and Q' represents a hydroxyl group, -CO2H, -ORc2, -CO2RA8, -CONH2, -CONHRA9, -CONRa10Ra10, -NH2-The otherA11or-NRA12RA12(where RA8, Ra9, Ra10, Ra11and RA12each represents a C1-6is an alkyl group, and Rc2represents a C1-6is an alkyl group, optionally substituted atom(s) halogen},

(xix) -ORf2{where Rf2represents a C3-7-cycloalkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA13(where RA13represents a C1-6is an alkyl group); or geterotsyklicescoe group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA16(where RA16represents a C1-6is an alkyl group)}, or

(xx) geterotsyklicescoe group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and ORA22(where RA22represents a C1-6is an alkyl group].

Another embodiment of the present invention relates to the connection 1-thio-D-glucitol following formula IV or its pharmaceutically acceptable salt, or hydrate of the compound, or a hydrate of the salt, in which RLrepresents a hydrogen atom, a halogen atom, a C1-8is an alkyl group or-ORc3(where Rc3represents a C1-6is an alkyl group, optionally substituted atom(s) halogen-free).

The following embodiment of the pharmaceutical the ski means include a connection according to the present invention:

One of the embodiments of the present invention includes any of the compounds 1-thio-D-glucitol, their pharmaceutically acceptable salts or hydrates of the compounds or hydrates of the salts described above.

Another embodiment of the present invention is connected with the inhibitor activity of the sodium-dependent co-Transporter-2 glucose, an inhibitor containing the compound 1-thio-D-glucitol, its pharmaceutically acceptable salt or hydrate of the compound or a hydrate of the salt.

Another embodiment of the present invention is an inhibitor containing any of the above compounds 1-thio-D-glucitol, their pharmaceutically acceptable salts or hydrates of the compounds or hydrates of the salts and used as a drug for the prophylaxis or treatment of diabetes, is associated with diabetes or a complication caused by diabetes.

Another embodiment of the present invention relates to a pharmaceutical preparation containing any of the above compounds 1-thio-D-glucitol, their pharmaceutically acceptable salts or their hydrates in combination with at least one pharmaceutical agent selected from the group consisting of increasing sensitivity to insulin agents are selected from the group consisting of PPAR-γ agonists, PPAR-α/γ agonists, PPAR-δ agonists and PPAR-α/γ/δ agonists; inhibitors of glycosidase; big is andow; substances that accelerate the secretion of insulin; insulin; inhibitors of dipeptidylpeptidase IV.

Another embodiment of the present invention relates to a pharmaceutical preparation containing any of the above compounds 1-thio-D-glucitol, their pharmaceutically acceptable salts or their hydrates in combination with at least one of the pharmaceutical agents selected from the group consisting of inhibitors hydroxymethylglutaryl-CoA-reductase, fibrate compounds, inhibitors of squalene synthase, inhibitors of acyl-CoA:cholesterylester, amplifiers receptors low-density lipoprotein, inhibitors of microsome protein-carrier of triglycerides and anorectics.

The following embodiments are modifications of the method of obtaining the compounds according to the invention.

One of the embodiments of the present invention relates to a method for obtaining compounds of 1-thio-D-glucitol following formula I or its pharmaceutically acceptable salt, or hydrate of the compound or a hydrate of the salt.

includes the following stages: adding thiolactone following formula VIII to more than one equivalent of Grignard reagent following formula IX, to obtain the compounds V, reconnection V and, if necessary, removing the protection obtained in the result of the connection, in accordance with the following scheme:

[where R11, R12, R13and R14the same or different, and each represents a C1-6is an alkyl group, -SiRa13, -CH2CH=CH2or C7-12-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, -NO2and OMe (where RA1represents a C1-6is an alkyl group), X represents a halogen atom, and Ar1, Ar2, R5, R6, R7, R8, R9and R10represent values that are defined in formula I.

Another embodiment of the present invention is associated with such as described above, in which up to the stage of adding the Grignard reagent of the formula IX to thiolactone formula VIII to obtain a compound V was added from about 0.8 to 1.2 equivalents of R30MgX (R30represents a C1-8is an alkyl group or a C3-7-cycloalkyl group, and X represents a halogen atom) to thiolactone formula VIII.

Another embodiment of the present invention relates to a method for obtaining compounds of 1-thio-D-glucitol following formula I or its pharmaceutically acceptable salt, or hydrate of the compound or the salt:

where the method includes the stage of (1) adding to the compound of formula X reagent of formula XI to obtain a compound XII, and stage (2) additional reconnection XII, if Y is a hydroxyl group, to obtain β-stereoselective compounds in which Y represents hydrogen, and the stage of removing the foam compound obtained in stage (1) or (2)if necessary, according to the following scheme:

where Y represents a hydrogen atom or a hydroxyl group (provided that when Y represents a hydrogen atom, the 1-position is S-configuration),

R11, R12, R13and R14the same or different, and each represents a C1-6is an alkyl group, -SiRa13, -CH2CH=CH2or C7-12-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, -NO2and OMe (where RA1represents a C1-6is an alkyl group), Ar2, R8, R9and R10have the same meanings as in formula I, and RA, RB, Rcand RDhave the same meaning as in the formula II,

Aa represents-CH(W)(CH2)n'-, -CONH(CH2)n - or-CH=CH- (where W represents a hydrogen atom or hydroxyl group, n means an integer from 0 to 3, and n' denotes an integer from 0 to 2),

Ea represents-CHO, -CO2H or-CH2X, and

Da represents -(CH2 )n Li, -(CH2)'n MgX, -CH2PPh3+X-, -CH2PO(ORA23), -(CH2)nNH2or SnBu4(where X represents a halogen atom, Ra23represents a C1-6is an alkyl group, n denotes an integer from 0 to 3, and n' denotes an integer from 0 to 2),

provided that if Ea represents-CHO, compound X, where Da represents -(CH2)n Li, -(CH2)'n MgX, -CH2PPh3+X-or-CH2PO(ORA23), interacts with the reagent XI, to obtain compounds XII, in which Aa represents-CH(W)(CH2)n - or-CH=CH-,

if Ea represents-CO2H, the compound X is condensed with reagent XI, where Da represents -(CH2)nNH2to obtain compounds XII, in which Aa represents-CONH(CH2)n-, or

if Ea represents-CH2X, the connection X condensed with reagent XI, where Da represents-SnBu4to obtain compounds XII, in which Aa represents-CH2.

The following embodiments are intermediate compounds formed in the process of obtaining compounds according to the present invention.

The embodiment of the present invention relates to the connection of the following formula XIII or its salt, or hydrate of the compound or a hydrate of the salt.

[where Y represents a hydrogen atom or a hydroxyl group (provided that when Y represents a hydrogen atom, then the position 1 is in S-configuration), and

R21, R22, R23and R24the same or different, and each represents a C1-6is an alkyl group, -SiRa13, -CH2CH=CH2-CO2RA2, -CORb1or C7-12-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, -NO2and-OMe (where each of Ra1and RA2represents a C1-6is an alkyl group, and Rb1represents a C1-6is an alkyl group, a C7-10-aracelio group or phenyl group), provided that if Y is a hydrogen atom, R21, R22, R23and R24are not simultaneously a hydrogen atom; and other symbols are the same as in the above formula I]. The compound of formula XIII where Y represents a hydrogen atom, and R21- R24are substituents other than-SiRa13or-CH2CH=CH2partially coincides with the above compound of the present invention. Because the previous connection is functioning not only as an intermediate connection, but also as an end product, which is active compounds is receiving or dosage form.

Another embodiment of the present invention relates to the connection of the following formula XIV or its salt or hydrate of the compound or a hydrate of the salt.

[where Y represents a hydrogen atom or a hydroxyl group (provided that when Y represents a hydrogen atom, then the position 1 is in S-configuration), and

E represents-CHO, -CO2H, -CO2RA24(where RA24represents a C1-6is an alkyl group), -CH2Mand(where Mandrepresents a hydroxyl group or a halogen atom), 1,3-dioxolane-2-ilen group or 1,3-dioxane-2-ilen group,

R21, R22, R23and R24have the same meaning as in formula XIII, and

RA, RB, Rcand RDhave the same value as in formula II].

Another embodiment of the present invention relates to the connection of the following formula XV or its salt or hydrate of the compound or a hydrate of the salt.

[where Ar5represents a thienyl group, a benzo[b]tiffaniejoy group, benzofuranyl group, benzothiazolyl group, pyridyloxy group or phenyl group,

G1represents a halogen atom

G2represents a halogen atom or hydroxyl group, and G2'represents a halogen atom alumette with G 2forms oxoprop,

G3Arepresents a hydrogen atom; a halogen atom; a hydroxyl group; C1-8is an alkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom and a hydroxyl group; -SRa25; -Separator R s oa25; -SO2Ra25; -ORh1(where Ra25represents a C1-6is an alkyl group, and Rh1represents a C1-6is an alkyl group or a C7-10-aracelio group, optionally substituted atom(s) halogen); aryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-or SIGa19(where Ra19represents a C1-6is an alkyl group); or heteroaryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-or SIGa21(where Ra21represents a C1-6is an alkyl group),

G3band G3cthe same or different, and each represents a represents a hydrogen atom, halogen atom, hydroxyl group, C1-8is an alkyl group or-ORc3(where Rc3represents a C1-6is an alkyl group, it is not necessarily samewe the s atom(s) halogen),

G4represents a C1-6is an alkyl group, optionally substituted by halogen atoms or by a halogen atom, and

Rh2represents a C1-6is an alkyl group or a C7-10-aracelio group, in which each of the substituents optionally substituted atom(s) halogen.

EMBODIMENTS of the INVENTION

What follows is a more detailed description of the present invention, but the examples are given to illustrate the invention, not limit the scope of the invention.

Definitions of terms used in the invention and examples for explanations of these terms are used, but without limitation, to illustrate the description and scope of the present invention.

The term "aryl group" is used to denote a monocyclic or condensed polycyclic aromatic hydrocarbon group having 6 to 15 carbon atoms, and examples of such groups are phenyl group, naftalina group (including 1-naftalina group and 2-naftalina group), pentylaniline group, angenlina group, indayla group, atulananda group, heptylaniline group and fluoroaniline group. Preferred are a phenyl group, naftalina group, angenlina group, indayla group and atulananda group, and more preferred are naftalina group and anilina group.

The term "heteroaryl group" denotes monocyclic or aromatic heterocyclic group condensed rings containing one or more heteroatoms selected from O, S and N. If the aromatic heterocyclic group is condensed ring, it includes partially hydrogenated monocyclic group. Examples of such heteroaryl groups are pyrazolidine group, thiazolidine group, isothiazolinone group, thiadiazolyl group, imidazolidinyl group, furilla group, thienyl group, oxazoline group, isoxazolyl group, pyrrolidine group, imidazolidinyl group, (1,2,3)- and (1,2,4)-thiazolidine group, tetrataenia group, Pernilla group, Peregrina group, pyrimidinyl group, piratininga group, pyridazinyl group, kinolinna group, izochinolina group, benzofuranyl group, isobenzofuranyl group, indayla group, isoindolyl group, indazolinone group, benzoimidazolyl group, benzotriazolyl group, benzoxazolyl group, benzothiazolyl group, benzo[b]teofilina group, thieno[2,3-b]teofilina group, (1,2)and (1,3)-pentoxifylline group, chromadorina group, 2-oxaprotiline group, benzothiadiazole group, hyalinella group, phthalazinone the th group, naphthyridinone group, khinoksalinona group, chinadaily group, indolenine group and carbazolyl group.

The term "heterocytolysine group" is used to denote geteroseksualnoe group having from 3 to 12 atoms and containing one or more heteroatoms selected from O, S and N. This group also includes, for example, a cyclic amino group containing one or more nitrogen atoms in the ring and optionally containing one or more oxygen atoms and sulfur atoms. Examples geteroseksualnoe group include morpholinopropan, piperidinyloxy group, piperazinilnom group, 1-pyrrolidinyloxy group, sepanlou group, thiomorpholine, oxalanilide group, ossanlou group, DIOXOLANYL group and dioxinlike group.

The term "Allenova group" is used to denote a divalent aromatic cyclic group associated with a 5-tissahamy balance with one hand and linked with-A - on the other hand. Examples Allenova groups are fenelonov group, naftalanovaja group (including 1-Neftyanoy group and 2-Neftyanoy group), panteleymonov group, inderena group, indreleia group, Suleymanova group, heptageniidae group and ftorhinolonovy group. The preferred groups are fenelonov group, naphthyl the new group, Ingenieria group, indreleia group and Suleymanova group, and more preferred are naftalanovaja group and fenelonov group.

The term "heteroarenes group" is used to denote a divalent aromatic heterocyclic group that is associated with 5-tissahamy balance with one hand and linked with-A - on the other hand. Examples heteroarenes groups are pyrazolidinone group, titlyanova group, isothiazolinone group, thiadiazolidine group, imidazolidinone group, Torrenova group, taylena group, oxazolidinone group, isoxazolidinone group, pyrrolidinone group, imidazolidinone group, (1,2,3)- and (1,2,4)-triazolinone group, TetraSociology group, pernerova group, piridinovy group, pyrimidinylidene group, piratininga group, peridiniella group, Hinayana group, izohinolinove group, benzofuranyl group, isobenzofuranyl group, Intellinova group, isoindoline group, indazolinone group, benzoimidazolyl group, benzothiazolylthio group, benzoxazolinone group, benzothiazolylthio group, benzo[b]teofilina group, kremenliev group, 2-oxoprolinuria group, benzothiazolylthio group, finalizer.java group, phthalazinone the th group, naphthyridinone group, khinoksalinona group, girasolereale group, sinolingua group and kurbanalieva group.

The term "literoticalolita group" is used to denote a divalent geteroseksualnoe ring group associated with 5-tissahamy balance with one hand and linked with-A - on the other hand. Examples of such geteroseksualbnogo groups include morpholinylmethyl group, piperidinyloxy group, piperazinylmethyl group, pyrrolidinylcarbonyl group, AspireRevo group, thiomorpholine group, oxalanilide group, oksanalove group, DIOXOLANYL group and dioxooleana group.

In the compound of the present invention, depending on the type Ar1not all of the three substituents R5, R6and R7can be included in this group.

The term "C1-6is an alkyl group" is used to denote an alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, and examples of such groups are methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, tert-bucilina group, sec-bucilina group, n-pencilina group, tert-Amelina group, 3-methylbutyl group, neopentylene group and n-exilda group.

The term "C2-6 -Alchemilla group" is used to denote an aliphatic hydrocarbon group with a straight or branched chain, having from 2 to 6 carbon atoms, and examples of such groups are Attila group, protanilla group and bucinellina group.

The term "C2-6-Alchemilla group" is used to denote an aliphatic hydrocarbon group with a straight or branched chain, having a triple bond and from 2 to 6 carbon atoms, and examples of such groups are etinilnoy group, proponila group and Butyrina group.

The term "halogen atom" means a fluorine atom, chlorine atom, bromine atom or iodine atom.

The term "C7-10-kalkilya group" is used to denote arylalkyl group having 7 to 10 carbon atoms, and examples of such groups are benzyl group and phenylethylene group.

The term "C7-12-kalkilya group optionally substituted", as used in the definitions of R1- R4, R11- R14and R21- R24refers to substituted or unsubstituted aranceles group having from 7 to 12 carbon atoms. Substituents for C7-12-aranceles groups are one or more substituents selected from the group consisting of a halogen atom, -NO2and-OMe. Preferred substituents are chlorine atom, -NO2and-OMe. Example of the substituted C 7-12-aranceles groups include 4-methoxybenzyl group, 3,4-dimethoxybenzyl group, 4-chloraniline group and 4-nitrobenzyloxy group.

The term "C1-8is an alkyl group optionally substituted" is used to denote a substituted or unsubstituted alkyl group having from 1 to 8 carbon atoms. Vice-C1-8-alkyl groups are one or more substituents selected from the group consisting of a halogen atom and a hydroxyl group. The preferred number of the replacement of the halogen atoms is from 1 to 6, more preferably from 1 to 4. Preferred halogen atoms are chlorine atom, a fluorine atom, and more preferred is a fluorine atom. The preferred number of the replacement of hydroxyl groups is from 1 to 6, more preferably from 1 to 3. Examples of substituted C1-8-alkyl groups include triptorelin group, deformational group, 1,1,1-triptorelin group, 1,1,1-triptorelin group, 1,1,1-triptorelin group, 1,3-dittocam-2-ilen group, hydroxymethylene group, hydroxyethylene group (such as 1-hydroxyethylene group), hydroxypropyl group and hydroxybutyl group. The preferred groups are triptorelin group, deformational group, 1,1,1-triptorelin group, 1,3-dittocam-2-ilen the group, hydroxymethylene group and hydroxyethylene group. More preferred groups are triptorelin group, deformational group, 1,1,1-triptorelin group, hydroxymethylene group and hydroxyethylene group.

The term "C3-7-cycloalkyl group" is used to mean a cyclic alkyl group having 3 to 7 carbon atoms, and examples of such groups are cyclopropyl group, cyclobutyl group, cyclopentenone group, tsiklogeksilnogo group and cycloheptyl group. Cyclopropyl group, cyclobutyl group, cyclopentenone group and tsiklogeksilnogo group are preferred, and cyclopropyl group and cyclobutyl group are more preferred.

The term "C1-6is an alkyl group, optionally substituted atom(s) halogen" refers to substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms. The number of replacement of the halogen atoms is 1 or more atoms. The preferred number of the replacement of the halogen atoms is from 1 to 6, more preferred from 1 to 4. Preferred halogen atoms are chlorine atoms and fluorine, and more preferred is a fluorine atom. Examples of substituted C1-6-alkyl groups include triptorelin group, deformational group and 1,1,1-trip ratelow group.

The term "C3-7-cycloalkyl group, optionally substituted" refers to substituted or unsubstituted cycloalkyl group having from 3 to 7 carbon atoms. Substituents for cycloalkyl groups are one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA13(orA18) (RA13and RA18each represents a C1-6is an alkyl group).

The term "aryl group optionally substituted" is used to denote a substituted or unsubstituted aryl group. Substituents for the aryl group are one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA14(orA19) (each of RA14and RA19represents a C1-6is an alkyl group). Preferred substituents are a halogen atom, a hydroxyl group, a C1-4is an alkyl group, a methoxy group and ethoxypropan. Examples of substituted aryl groups include 4-chloraniline group, 4-florfenicol group, 4-hydroxyphenyl group and 4-metoksifenilny group.

The term "C7-10-kalkilya group optionally substituted" is used to denote a substituted or unsubstituted aranceles group, Meuse is from 7 to 10 carbon atoms. Substituents for Uralkaliy groups are one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA15(orA17or ORA20) (each of RA15, RA17and RA20represents a C1-6is an alkyl group). Preferred substituents are a halogen atom, a hydroxyl group, a C1-4is an alkyl group, a methoxy group and ethoxypropan. Examples of substituted C7-10-aranceles groups include 4-methoxybenzyl group, 3,4-dimethoxybenzyl group, 4-chloraniline group and 4-chlorophenylalanine group.

The term "heteroaryl group optionally substituted" is used to denote a substituted or unsubstituted heteroaryl group. Substituents for heteroaryl groups are one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA21(RA21represents a C1-6is an alkyl group). Preferred substituents are a halogen atom, a C1-4is an alkyl group, a methoxy group and ethoxypropan. More preferred substituents are methyl group and ethyl group. Examples of substituted heteroaryl groups include 4-methylthiazole-2-ilen group, 2-m is terpyridine-5-ilen group, 1-methylpyrazole-4-ilen group, 1-aripirazole-4-ilen group, 1-methylpyrrolidinyl group, 2-methylimidazolidine group and 4-methoxystyrene group.

The term "heterocytolysine group optionally substituted" is used to denote a substituted or unsubstituted geteroseksualnoe group. Substituents for geteroseksualnoe groups are one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA16(orA22), each of RAa16and RA22represents a C1-6is an alkyl group). Preferred substituents are a halogen atom, and C1-4is an alkyl group, more preferred are methyl group and ethyl group. Examples of substituted geteroseksualnoe groups are 4-methylpiperazin-1-ilen group and 4-ethylpiperazin-1-ilen group.

The term "pharmaceutically acceptable salt" is used to denote salts of alkali metals, alkaline earth metals, ammonium or alkylamine, salts of mineral acids or salts of organic acids. Examples of such salts include sodium salt, potassium salt, calcium salt, ammonium salt, an aluminium salt, salt of triethylamine, acetate, propionate, butyrate, format, triptorelin, maleate, tartarate, citrate, stearate, succinate, those who succinate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, aconsultant, 2-hydroxyethanesulfonic, bansilalpet, paratoluenesulfonyl, laurylsulphate, malate, aspartate, glutamate, adipat, salt cysteine, salt of N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, Hydriodic, nicotinate, oxalate, picrate, thiocyanate, undecanoate, salt of acrylic polymer, salt carboxyvinyl polymer.

The term "salt" is used to denote salts of alkali metals, alkaline earth metals, ammonium or alkylamine, salts of mineral acids or salts of organic acids, but, in addition to pharmaceutically acceptable salts, include, and other salts.

Since some of the compounds and intermediates according to the present invention may have chiral center, they may be represented as diastereoisomers or enantiomers. Some of the compounds and intermediates according to the present invention can also be provided, such as keto-enol the tautomers. Moreover, some of the compounds and intermediates according to the present invention can be represented as geometric isomers (E-form, Z-form). Thus, the compounds and intermediate compounds according to the present invention include all of the above individual isomers and see the sea.

As will be shown in the test examples below, the compounds according to the present invention capable of inhibiting the activity of sodium-dependent co-Transporter-2 glucose (SGLT2)associated with the reabsorption of glucose in the kidneys, and can provide an exceptional the pharmaceutical agents that are effective for the prevention or treatment of diabetes, diseases associated with diabetes, or complications caused by diabetes.

In addition, the compounds according to the invention, as will be shown in detail below, exclusive in the sense that possess high crystallinity, easy to clean, easy to store, the production of a pharmaceutical preparation and are suitable to use as a drug. As for the compounds of the present invention, the compounds of formulas I, IA, II, III and IV, in which R1- R4are hydrogen, possess high crystallinity.

Many of the compounds of glucitol are amorphous substances in the manufacturing process of pharmaceuticals in need of crystallization together with the appropriate amino acids such as phenylalanine and Proline (patent application U.S. US6774112). However, the compounds according to the invention, containing glucitol converted to 1-thio-glucitol have a high Krista is personality and need not be co-crystallization with amino acids.

For example, glucitol connection Ha presented in the patent application U.S. US6515117, in the form of glassy substances have low crystallinity. On the other hand, the connection Xb according to the invention are the connection 1-thio-glucitol and represent a colorless crystalline powder having a melting point 79,0-83,0°C.

The preferred embodiment of the compounds of the present invention are listed below.

In formulas I and IA preferred examples of A are -(CH2)n- (where n denotes an integer from 0 to 3, preferably n=1 or 2), -CONH(CH2)n- (where n denotes an integer from 0 to 3, preferably n=0) or -(CH2)nCH=CH- (where n denotes an integer from 0 to 3, preferably n=0 or 1) and-O-.

A more preferred example is A-CH2-.

In formulas I and IA, the preferred position for connection A-Ar2is the meta-position to tishara.

Preferred embodiments of compounds of formula II according to the present invention will be presented below.

In the formula (II) RAand Rcpreferably are hydrogen atoms.

The preferred substitute for RBis a hydrogen atom, halogen atom, hydroxyl group, C1-8is an alkyl group or-O-(CH2)m'-Q' {where m' denotes an integer from 1 to 4, preferably m'=1, and Q' Ave dstanley a hydroxyl group, -CO2H, -ORc2, -CO2RA8, -CONH2, -CONHRA9, -CONRa10Ra10, -NH2-The otherA11, -NRA12RA12or NHC2Rd5(where each of RA8, RA9, Ra10, RA11and RA12represents a C1-6is an alkyl group, Rc2represents a C1-6is an alkyl group, optionally substituted atom (atoms) halogen, and Rd5represents a C1-6is an alkyl group, a C7-10-aracelio group, phenyl group, or a C3-7-cycloalkyl group)}; or

-ORf1{where Rf1represents a C1-6is an alkyl group, optionally substituted atom (atoms) halogen; or C7-10-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA15(where RA15represents a C1-6is an alkyl group)}.

RBpreferably represents a hydrogen atom, a C1-6is an alkyl group, a halogen atom, a C1-6-alkoxygroup or-O-CH2-Q' [where Q' represents a-CO2H or-CO2RA8(RA8defined above)], and especially preferred methyl group, a chlorine atom or a methoxy group.

The preferred substitute for RDis a hydrogen atom,a halogen atom, hydroxyl group, a C1-8is an alkyl group, orf2{where Rf2represents a C1-6is an alkyl group, optionally substituted atom(s) halogen; or C7-10-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA15(where RA15represents a C1-6is an alkyl group)}.

RDpreferably represents a hydrogen atom, a hydroxyl group or a C1-6-alkoxygroup and particularly preferably a hydroxyl group or a methoxy group.

Preferred substituents for REand RFthe same or different, and each represents a hydrogen atom, a halogen atom, a C1-8is an alkyl group or-ORc3(where Rc3represents a C1-6is an alkyl group, optionally substituted atom(s) halogen.

Preferably, REand RFare hydrogen atoms or fluorine atoms.

The preferred substitute for RGis a hydrogen atom, a halogen atom, a hydroxyl group or a C1-8is an alkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom and a hydroxyl group.

Preferred of them ablauts is a halogen atom, hydroxyl group or a C1-8is an alkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom and a hydroxyl group. Especially preferred are methyl group, ethyl group, isopropyl group or hydroxymethylene group.

Other preferred substituents for RGare-CO2H, -ORc1, -CO2Ra3, -CONH2, -CONHRa4, -CONRa5Ra5, -CRd1, -OCRd2, -SRe1, -SORe2, -SO2Re3-The othera6or-NRa7Ra7(where each of Ra3, Ra4, Ra5, Ra6and Ra7represents a C1-6is an alkyl group, Rc1represents a C1-6is an alkyl group, optionally substituted atom(s) halogen, each Rd1and Rd2represents a C1-6is an alkyl group, a C7-10-aracelio group, phenyl group or a C3-7-cycloalkyl group, and each of Re1, RE2and RE3represents a C1-6is an alkyl group, phenyl group or taillow group).

Preferred of them are-CO2H, -ORc1, -CO2RA3, -SRE1and-NRA7RA7(where Rc1, Ra3, Re1and RA7such as defined above). Especially preferred are a methoxy group ethoxypropan, isopropylacetate, materialgroup and-CO2Me.

Other preferred substitute for RGis-O-(CH2)m'-Q' {where m' denotes an integer from 1 to 4, preferably m'=1 or 2, and Q' represents a hydroxyl group, -CO2H, -ORc2, -CO2RA8, -CONH2, -CONHRA9, -CONRa10Ra10, -NH2-The otherA11or-NRA12RA12(where each of RA8, RA9, Ra10, RA11and RA12represents a C1-6is an alkyl group, and Rc2represents a C1-6is an alkyl group, optionally substituted atom(s) halogen)}.

Preferred of them are-O-CH2CO2Me, -O-CH2CO2H, -O-CH2CONMe2, -O-CH2CH2OH and-O-CH2CH2NMe2.

Other preferred substitute for RGis-ORf2{where Rf2represents a C3-7-cycloalkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA13(where Ra13represents a C1-6is an alkyl group); or geterotsyklicescoe group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6-alkyl the group and-OR A16(where RA16represents a C1-6is an alkyl group)}, or geterotsyklicescoe group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA22(where RA22represents a C1-6is an alkyl group).

Preferred of them are-O-C3-7-cycloalkyl group, -O-heterocytolysine group and heterocytolysine group. Especially preferred are tetrahydropyranyloxy, cyclopentyloxy and morpholinopropan.

The preferred embodiment of the compounds of formula III according to the present invention are presented below.

In the formula (III), Ar3preferably represents a thienyl group, a benzo[b]tiffaniejoy group, thieno[2,3-b]tiffaniejoy group, benzofuranyl group, benzothiazolyl group, indolenine group, pyrrolidino group, imidazolidinyl group, pyrazolidine group, pyridyloxy group, pyrimidinyl group, personilnya group or isoxazolyl group.

R8A, R9aand R10awhich substituents for Ar3group, the same or different and each preferably represents a hydrogen atom, halogen atom, hydroxyl group, C1-8is an alkyl group or a C1-6/sub> -alkoxygroup.

If Ar3represents a thienyl group, it is preferable that at least one of R8A, R9aand R10arepresented an aryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA19(where RA19represents a C1-6is an alkyl group, or heteroaryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA21(where Ra21represents a C1-6is an alkyl group), and each of the other two represents a hydrogen atom, a halogen atom, a C1-8is an alkyl group or a C1-6-alkoxygroup.

The preferred embodiment of the compounds of formula (IV) according to the present invention are presented below.

In the formula (IV) Ar4preferably represents thienylene group, benzo[b]thienylene group or piridinovy group. Preferably, each of R20a, R21a, RJand RKwhich substituents for Ar4the group consisted of a hydrogen atom, a halogen atom, a C1-8is an alkyl group or a C1-6-alkoxygroup. Preferably, RL is the same as any of the following preferred substituents RG.

Preferred specific compounds for the present invention are presented below.

(1S)-1,5-Anhydrous-1-[3-(4-active compounds)phenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[3-(4-ethoxybenzyl)phenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[3-[(1-benzothieno-2-yl)methyl]-4-methoxyphenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[4-chloro-3-(4-ethoxybenzyl]phenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[3-(4-ethoxybenzyl)-4-methoxyphenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[3-[(1-benzothieno-2-yl)methyl]-4-chlorophenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[3-[(1-benzothieno-2-yl)methyl]phenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[3-(4-ethoxybenzyl]-6-methoxyphenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[3-[(1-benzothieno-2-yl)methyl]-6-methoxyphenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[3-(4-ethoxybenzyl)-6-hydroxyphenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[4,6-dimethoxy-3-(4-ethoxybenzyl]phenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[3-(4-ethoxybenzyl)-4-forfinal]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[3-(4-ethoxybenzyl)-4-hydroxyphenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[4-chloro-3-(2,5-debtor-4-ethoxybenzyl)phenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[4-chloro-3-(3-fluoro-4-ethoxybenzyl)phenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[4-chloro-3-(3-chloro-4-ethoxybenzyl)phenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[3-(4-ethoxybenzyl)-4-were]-1-thio-D-gluco the ol

(1S)-1,5-Anhydrous-1-[4-chloro-3-(3,4-dimethoxybenzyl)phenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[4-chloro-3-(4-methoxybenzyl)phenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[3-(4-ethoxybenzyl)-6-methoxy-4-were]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[3-(4-tert-butylbenzyl)-4-chlorophenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[4-chloro-3-(2-fluoro-4-ethoxybenzyl)phenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[3-[(1-benzothieno-2-yl)methyl]-4,6-acid]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[4-chloro-3-(4-methylbenzyl)phenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[4-chloro-3-(4-methylthiophenyl)phenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[4-chloro-3-(4-hydroxybenzyl)phenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[4-chloro-3-(4-active compounds)phenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[4-chloro-3-(4-isopropylbenzyl)phenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[4-chloro-3-(4-ethoxymethylene)phenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[3-(4-ethoxybenzyl)-6-hydroxy-4-were]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[3-[(1-benzofuran-2-yl)methyl]-4-chlorophenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[4-chloro-3-(4-ethoxybenzyl)-6-methoxyphenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[3-(4-ethoxybenzyl)-4,6-dihydroxyphenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[3-(4-active compounds)-6-methoxy-4-were]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[4-chloro-3-(4-active compounds)-6-methoxyphenyl]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[4-chloro-3-(4-isopropylbenzyl)-6-methoxyphenyl]-1-thio-D-gluc the tol

(1S)-1,5-Anhydrous-1-[3-(4-methylbenzyl)-6-methoxy-4-were]-1-thio-D-glucitol

(1S)-1,5-Anhydrous-1-[3-(4-isopropylbenzyl)-6-methoxy-4-were]-1-thio-D-glucitol.

Intermediate compounds of formula XV according to the present invention is characterized by the fact that we have a Deputy ORh2. The existence of such a substituent creates the advantage that the yield and selectivity in the synthesis of this intermediate compound is higher than in the case of compounds deprived of such Deputy.

In particular, in the production method of the intermediate compounds of formula XV (for example, in scheme 8, below), the reaction of the Friedel-gives high output. If the desired product is a compound of formula XV, in which Ar5is a phenyl group in the para-position to the linker, formed only para-substituted products and several positional isomers (ortho-substituted products)generated using this method.

In addition, these intermediate compounds of formula XV according to the present invention, as the compound in which G2'is oxoprop together with G2(corresponds to the connection O figure 8), and the compound in which G2'and G2are halogen atoms (corresponding to compound IIA in Scheme 8), have a good crystallochemistry in many cases and can be easily cross stylizowane in a colorless powder.

The preferred embodiment of the compounds of formula XV according to the present invention are presented below.

If Ar5represents a phenyl group, then G3apreferably represents a hydroxyl group; C1-8is an alkyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom and a hydroxyl group; -SRA25; -SORA25; -SO2RA25; orhl(where Ra25represents a C1-6is an alkyl group, and Rhlrepresents a C1-6is an alkyl group or a C7-10-aracelio group, optionally substituted atom(s) halogen), and more preferably represents a C1-8is an alkyl group, optionally substituted atom(s) halogen), -SMe, -SOMe, -SO2Me or C1-6-alkoxygroup, optionally substituted by halogen atom, or benzyloxy, optionally substituted by a halogen atom. The preferred position of the substitution G3Ais the para-position to the linker. The other designations are the same as in formula XV, but more preferably, if G3band G3cthe same or different, and each represents a hydrogen atom or a fluorine atom.

If Ar5represents a benzo[b]tiffaniejoy group, benzofuranyl group, benzothiazolyl GRU is PU or pyridyloxy group, each of G3A, G3band G3cpreferably represents a hydrogen atom, halogen atom, hydroxyl group, C1-8is an alkyl group or a C1-6-alkoxygroup.

If Ar5represents a thienyl group, then GA3preferably represents an aryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA19(where RA19represents a C1-6is an alkyl group); or heteroaryl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6is an alkyl group and-ORA21(where RA21represents a C1-6is an alkyl group), and G3band G3cthe same or different, and each represents a hydrogen atom, a halogen atom, a C1-8is an alkyl group or a C1-6-alkoxygroup.

Ar5preferably is a phenyl group.

Various methods for producing compounds according to the present invention will be described in detail in the following examples, which are given to illustrate the invention but not to limit. There is a message stating that derivatives of D-glucitol can be synthesized with the use of the cation C-arylpropionate, which can be obtained by adding one equivalent argillite or aryl Grignard reagent to the derivatives of glycolate (patent document 12). However, 1-thio-glucitol according to the invention could not be obtained in the conditions described above. Applicants in the result of careful studies have found that 1-thio-glucitol can be obtained in the following conditions.

Method 1 obtain the compounds according to the present invention

The compound of formula V obtained from the compounds of formula IIA (aglycone) and the compounds of formula VIII (thiolactone) using the methods presented in schemes 1-3. Then the compound of formula V was restored and, if needed, was shot protection, as shown in figure 4, whereby was obtained a compound of formula I. the Method of synthesis of compounds of formula IIA (aglycone) are presented on figures 5-8, and the method of synthesis of compounds of formula VIII (thiolactone) is shown in figure 9.

Scheme 1: Reaction of formation of carbon-operadas communication between the aglycone and 5-tishara

Scheme 1

where X represents a halogen atom, in particular bromine atom, iodine or chlorine, Ar1represents aryl, heteroaryl or geterotsyklicescoe group, and other symbols correspond to the values specified for them above.

As long as the ANO in figure 1, the connection can be obtained by adding thiolactone (compound VIII) to the Grignard reagent derived from an aryl halide, halide heteroaryl or halide geterotsiklicheskie (compound IIA) and magnesium. A certain amount of Grignard reagent was added to about 2 or more equivalents of thiolactone, more preferably, from about 2 equivalents to about 2.2 equivalents, to obtain approximately 1 equivalent of the desired compound V. For this reaction, the preferred reaction temperature from -20°C to 25°C. To obtain a Grignard reagent as solvent used diethyl ether, tetrahydrofuran or dimethyl ether of diethylene glycol (diglyme). As a catalyst can be used iodine or 1,2-dibromethane. The necessary reaction temperature from 25°C to 150°C, preferably from 40°C to 100°C.

Ability, heterogeneity or generalcausality synthesized by reaction of compounds IIA and lithium reagent is selected from n-utility, tert-utility and musicality (2,4,6-trimethylaniline) at a temperature of from -78°C to -20°C, cannot interact with the compound VIII. Therefore, to obtain a Grignard reagent, which can interact with the compound VIII, was added magnesium bromide (MgBr2to abilitiy, heteroaryl the Yu or literoticalolita. In this reaction the solvent used diethyl ether, tetrahydrofuran or the like, and the preferred reaction temperature is from -20°C to 25°C.

Scheme 2: Reaction of 2 the formation of carbon-carbon linkages between aglycone and 5-tishara

Scheme 2

where Ar1represents aryl, heteroaryl or geterotsyklicescoe group and the other symbols correspond to the values specified for them above.

As shown in scheme 2, compound V can also be synthesized by adding a metal halide, such as iodide, copper (I) or cesium chloride to abilitiy, heterogeneity or literoticalolita that can be obtained in the manner described above, with the formation of the complex (compound (II')by Parametrierung, and the interaction of this complex with the compound VIII. The preferred reaction temperature in the process of obtaining such a lithium reagent is a temperature from -78°C to -20°C. as a solvent in this reaction is used, diethyl ether, tetrahydrofuran or other. Then the lithium reagent was added dropwise to a suspension of copper iodide or cesium chloride and diethyl ether, the received complex II'. Maintained the reaction temperature from -78°C to 0°C, preferably from -25°Sre 0°C. Then add thiolactone VIII under the same conditions as in scheme 1, or complex II' added to thiolactone VIII, in the received connection V.

Scheme 3: Reaction 3 the formation of carbon-carbon linkages between aglycone and 5-tishara

Scheme 3

where Ar1represents aryl, heteroaryl or geterotsyklicescoe group, R30represents a C1-8is an alkyl group or a C3-7-cycloalkyl group, and other symbols correspond to the values specified for them above.

The method shown in scheme 3, can reduce the number of equivalents of compound IIA, which is necessary in the case of reaction with thiolactone VIII. Taking into account the fact that thiolactone VIII cannot communicate with 1 equivalent of Grignard reagent, was added from about 0.8 to about 1.2 equivalents, preferably added from about 0.9 to about 1.0 equivalent to R30MgX to thiolactone VIII. As halide C1-8-alkylamine in this case used the chloride Isopropylamine, bromide Isopropylamine or chloride tert-butylamine. As halide C3-7-cycloalkane used, for example, chloride cyclohexylamine. As solvents used diethyl the IDF, tetrahydrofuran or other. The preferred reaction temperature is from -20°C to 25°C. Then was added the Grignard reagent IX obtained from compound IIA, then thiolactone selectively reacts with the Grignard reagent IX, not interacting with R30MgX added initially, resulting in the received connection required V. the Amount of Grignard reagent IX regulated depending on the number of connections V. Use approximately 1 equivalent of Grignard reagent IX enough to get about 1 equivalent of the desired connection. The preferred solvent is diethyl ether or tetrahydrofuran, and the preferred reaction temperature is from -20°C to 25°C.

In accordance with the method described above, the number of equivalents of expensive compound IIA can be reduced, which allows to synthesize 1-thio-glucitol more efficiently.

Scheme 4: Reaction of recovery and response unprotect

Scheme 4

where the symbols correspond to the values specified for them above.

Further, as shown in scheme 4, compound V was previously restored to the possibility of β-stereoselective synthesis of compound XIII according to the invention. Eligible and reducing agents for this reaction are Et 3SiH, (i-Ph3SiH or Ph2SiHl, and BF3·Et2O, CF3COOH or InCl3the so-called Lewis acid. As a solvent used chloroform, dichloromethane, acetonitrile, ethyl acetate, diethyl ether, 1,4-dioxane, tetrahydrofuran or a mixture of these solvents. α-Compounds resulting from the reaction of recovery, are formed as by-products, with access from a few percent up to 15%. However, by combining the reagents or solvents, it is possible to increase the output of products. Preferred reducing agents for this reaction are Et3SiH or i-Pr3SiH, more preferable Et3SiH. The preferred reagent is a Lewis acid, such as BF3·Et2O or CF3COOH, is preferred BF3·Et2O. the Necessary temperature to the reaction temperature from -60°C to 25°C, preferably from -40°C to 0°C. in Addition, an important choice of solvent, and a suitable solvent for this reaction is acetonitrile or a mixture comprising acetonitrile, such as acetonitrile-chloroform or acetonitrile-dichloromethane.

R21- R24removed from OR21- -OR24compounds XIII according to the invention by appropriate methods, where the substituents are transformed into hydroxyl groups for further gaining the compounds Ia according to the invention.

If R21, R22, R23and R24are benzyl groups, or 4-methoxybenzylidene groups, R21- R24you can remove, for example, by catalytic hydrogenation in a hydrogen atmosphere, using a catalyst like palladium catalyst on charcoal, palladium hydroxide, or platinum-palladium on charcoal. As a solvent in this reaction used methanol, ethanol, isopropanol, ethyl acetate and acetic acid. Alternative, R21- R24can be removed with the use of such Lewis acids as BCl3, BCl3·Me2S, BBr3, AlCl3, CF3COOH or TfOH. Examples of solvents used in this reaction include chloroform, dichloromethane, acetonitrile, diethyl ether, tetrahydrofuran and anisole. The recommended reaction temperature is from -78°C to 40°C.

If R21, R22, R23and R24are allyl groups (-CH2CH=CH2), t-BuOK in dimethyl sulfoxide causes isomerization of (-CH=CHCH3), after which samaritane group can be removed using hydrochloric acid or HgCl2/HgO. Alternative, R21- R24can be removed using, for example, Pd(PPh3)4, PdCl2or palladium on charcoal, in the presence of organic acids, such as acetic acid is, hydrate p-toluensulfonate acid, or N,N'-dimethylbarbituric acid. As solvents for this reaction used acetonitrile, diethyl ether or tetrahydrofuran. The recommended reaction temperature is from 25°C to 100°C.

Figure 5: Method 1 synthesis aglionby part

Scheme 5

where A' represents -(CH2)n'- (n' denotes an integer from 0 to 2), -CH=CH-or-C≡C-, Ar1represents aryl, heteroaryl or geterotsyklicescoe group and the other symbols correspond to the values specified for them above.

If A represents -(CH2)n- (n means an integer from 1 to 3) and an intermediate connection connection IIA, this compound can be synthesized as described in international patent publication WO 0127128. Alternatively, the intermediate compound (IId) can be obtained according to scheme 5.

Compound IIA was converted to the Grignard reagent, using 1 equivalent of magnesium according to the method described above. Alternatively, compound IIA was converted into monoacrylate, using 1 equivalent of n-utility or tert-utility. Then, a commercially available compound IIb was added to the Grignard reagent or monoacrylate, resulting in the received connection IIc. As a solvent in this reaction using the and, diethyl ether or tetrahydrofuran. The preferred reaction temperature is a temperature from -78°C to 25°C.

Then the connection IIc restored, namely by reaction with Et3SiH, (i-Pr3SiH or Ph2SiHCl, for example, in the presence of a Lewis acid, resulting in the received connection IId. As the Lewis acid in the reaction used BF3·Et2O, CF3COOH or InCl3. As a solvent used chloroform, dichloromethane, acetonitrile or a mixture of these solvents. The preferred solvent mixture containing acetonitrile, such as acetonitrile-chloroform or acetonitrile-dichloromethane. The reaction temperature in this reaction is from -60°C to 25°C, preferably from -30°C to 25°C.

Scheme 6: synthesis Method 2 aglionby part

Scheme 6

where M represents-O - or-NH-, Ar1represents aryl, heteroaryl or geterotsyklicescoe group, and other symbols correspond to the values specified for them above.

Compound IIe connected with airborne acid, heteroarylboronic acid or derivative heterocyclizations acid IIf, using a palladium catalyst or a copper catalyst, in the presence of a base, so you can get the connection IIA, where A I is is-O - or-NH-. As the palladium catalyst, for example, used Pd2(OAc)2Pd(dba)2, palladium on charcoal, dba:dibenzylideneacetone or Pd(PPh3)4. As the copper catalyst is preferred Cu(OAc)2. As the base used, for example, t-BuOK, Na2CO3, K2CO3, KOH, pyridine or triethylamine. As a solvent in this reaction used chloroform, dichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane or dimethoxyethane.

Scheme 7: synthesis Method 3 aglionby part

Scheme 7

where Ar1represents aryl, heteroaryl or geterotsyklicescoe group, and other symbols correspond to the values specified for them above.

The reaction of the Friedel-performed using compound IIg and IIh, in the received connection IIi. As the Lewis acid used in this reaction AlCl3, CF3COOH or EtAlCl2. As a solvent used chloroform, dichloromethane or toluene. Maintained the reaction temperature from -30°C to 60°C, preferably from -15°C to 25°C. Next, the connection IIj can be obtained using the recovery method according to the scheme 5. Then carried out the selective position bromination of compound IIj using bromine, bromide, hydroxide is I, bromide of potassium, hydrogen bromide or N-bromosuccinimide (NBS), which received the compound IIA. As the solvent for this reaction, the preferred chloroform, dichloromethane, CF3COOH or acetic acid. The preferred solvent mixture NBS-CF3COOH-H2SO4.

Scheme 8: synthesis Method 3 aglionby part

Scheme 8

where Ar1represents aryl, heteroaryl or geterotsyklicescoe group, and other symbols correspond to the values specified for them above.

If the substituents R5and R9source materials IIk or IIn are, for example, alkoxygroup, the reaction according to scheme 7, may result in deterioration of the selective position of the synthesized, which reduces the efficiency of obtaining the desired product. In this case, as shown in scheme 8, the first stage was completed the process of halogenation, next was the reaction of Friedel and crafts reaction recovery. This method is preferred because it can provide a high yield of compound IIA. The conditions for each reaction coincide with the conditions of the reactions according to scheme 7.

Scheme 9: Synthesis of thiolactone

Scheme 9

where the legend corresponds to the value is reported, specified for them above.

Compound VIII can be synthesized according to the methods described in Yuasa, H., et al., J. Chem. Soc. Perkin Trans. 1, 2763, 1990. Alternatively, compound VIII can be synthesized according to scheme 9, below.

Hydroxyl group in 1-position of compound IIIa (which can be obtained according to the international Publication WO 04/106352) was protected using a protective group which is stable in Ostuni conditions and capable of removing protection in neutral and acidic conditions. For example, for the synthesis of compounds IIIb this hydroxyl group was protected tetrahydropyranyloxy group using 3,4-dihydro-2H-Piran (3,4-DHP) and monohydrate p-toluensulfonate acid or pyridinedicarboxylate (PPTS). As a solvent in this reaction used N,N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, chloroform, dichloromethane or toluene.

Then acetyl group of compound IIIb was removed. The removal of acetyl groups were performed using bases, such as sodium methoxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate or triethylamine. As a solvent used methanol, ethanol or aqueous methanol. Then, in the result of the interaction of R11-R14X and, for example, benzylbromide, benzylchloride, allylbromide or under the conditions in prisutstvie is of a suitable base, received connection IIIc. Examples of suitable bases are triethylamine, N-ethyl-N,N-Diisopropylamine, pyridine, potassium carbonate, calcium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium methoxide and t-BuOK. Preferred for this reaction bases are potassium carbonate, calcium carbonate, cesium carbonate and sodium hydride. As a solvent in this reaction used N,N-dimethylformamide, tetrahydrofuran, dioxane or dimethoxyethane. Maintained the reaction temperature from -20°C to 25°C.

Then the protective group at position 1 of compound IIIc was removed, receiving the connection IIId. For example, THP group can be removed by exposure to compounds IIIc in PPTS in methanol or ethanol. And, finally, the connection IIId was treated with a suitable oxidizing agent, to deliver thiolactone VIII. The preferred oxidizing agent for this reaction is dimethylsulfoxide anhydride, peridinin dess-Martin, or IBX, and the reaction temperature is from 0°C to 40°C.

Method 2 for obtaining compounds according to the present invention

Compound I according to the present invention, where A represents -(CH2)n- (n means an integer from 1 to 3)can also be synthesized by the method shown in scheme 10. Another method of obtaining synthetic intermediate compounds VA on with the Birmingham 10 shown in scheme 11.

Figure 10: Method 2 obtain the compounds of formula I

Scheme 10

where Ar1represents an aryl or heteroaryl group, Y represents a bromine atom in the compound IIr or MgBr or Li in the IIs connection, and the other symbols correspond to the values specified for them above.

Commercially available compound IIp together with etilenglikolem and monohydrate p-toluensulfonate acid was boiled under reflux in toluene or benzene, receiving the connection IIq. The duration of the reaction is from 1 to 24 hours, and it is desirable to carry out the dehydration operation using the process of boiling unit Dean-Stark or similar. Then received a Grignard reagent compounds IIq method similar to the method described in the above Example get 1, and then added thiolactone VIII, resulting in the compound IVa.

Further explanations refer to one of the methods for obtaining the compounds I according to the present invention from compound IVa. First I removed ethylenically connection group IVa acid, receiving the connection IVb. The acid in the reaction used hydrochloric acid, monohydrate p-toluensulfonate acid, acetic acid, perchloric acid or Ph3CBF4. The solvent used is methanol, ethanol, acetone, dichloromethane, water or a mixture of these solvents. The preferred reaction temperature is from 25°C to 100°C.

Next, compound IVb was added to the Grignard reagent or organolithium IIs, which can be obtained from which is commercially available derivative of bromine IIr by the method described in the above Example, a 1 in scheme 4, the receiving connection IVc. As the solvent used in this reaction, diethyl ether, tetrahydrofuran or dimethoxyethane. Maintained the reaction temperature from -78°C to 25°C.

Then restored the hydroxyl group in the compound IVc in a manner similar to the method described in the above Example, obtaining 1, scheme 4, receiving compound I according to the present invention.

Compound I according to the present invention can also be synthesized from compounds IVa the other way. Restored hydroxyl group tishara compounds IVa, and then deleted ethylenically connection group IVa, receiving the connection VA. The reaction conditions for these reactions coincide with the methods described above. Then compound VA was added to the IIs connection, which is a Grignard reagent or organolithium, receiving the connection Vx. Then to restore the hydroxyl group carried out the reaction of the compound Vx with Et3SiH, (i-Pr3/sub> SiH or Ph2SiHCl, in the presence of a Lewis acid, resulting in the compound I. as a Lewis acid in this reaction used BF3·Et2O, CF3COOH or InCl3. As a solvent used chloroform, dichloromethane, acetonitrile or a mixture of these solvents. Preferred is a mixture of solvents including acetonitrile, such as acetonitrile-chloroform or acetonitrile-dichloromethane. Maintained the reaction temperature from -60°C to 100°C, preferably from -10°C to 60°C.

Figure 11: the Method of synthesis of intermediate compounds VA

Scheme 11

where Ar1represents an aryl or heteroaryl group, and other symbols correspond to the values specified for them above.

The intermediate connection VA can also be synthesized by treatment of compounds Va n-BuLi, and further adding N,N-dimethylformamide, as shown in scheme 11. As a solvent in this reaction used tetrahydrofuran or ether. The preferred reaction temperature is from -78°C to 25°C.

Method 3 for obtaining compounds according to the present invention

Compound I according to the present invention, where A represents a-CH2-, and R8represents a functional group such as-CO dor-C02Rain particular, can be synthesized by way of the connection Steele ('espinet, P., et al. Angew. Chem. Int. Ed. Engl. vol. 43, 4704, 2004; Stille, J.K., Angew. Chem. Int. Ed. Engl. vol. 25, 508, 1986), as shown to connect Vb to Scheme 12, or as shown for the intermediate IVf in Scheme 13.

Figure 12: Method 3 for obtaining compounds of formula I

Scheme 12

where Ar1represents an aryl or heteroaryl group, Y' represents a chlorine atom or a bromine atom, and other symbols correspond to the values specified for them above.

Commercially available IIa was converted to the Grignard reagent by the method described in the above-mentioned production method of 1, Scheme 5, using 1 equivalent of magnesium Alternate, compound IIa was converted into complex ate using i-PrMgCl-LiCl (Kitagawa, K., et al. Angew. Chem. Int. Ed. Engl. vol. 39, 2481, 2000; Knochel, P., et al. Angew. Chem. Int. Ed. Engl. vol. 43, 3333, 2004). Compound VIII was added to the obtained reagent, resulting in the connection of the IVd. Then the hydroxyl group of compound IVd was restored by the method similar to that described in the method of obtaining 1, scheme 4, the received connection Va. Further, the compound Va was treated with Bu6Sn2and palladium catalyst so that it was possible to obtain a connection Vb. As palladium cat who lyst used in this reaction Pd 2(OAc)2Pd(dba)2or Pd(PPh3)4. The preferred solvent is toluene, and the reaction was carried out at a temperature from 60°C to 120°C.

Then the connection Vb and connection IIt was treated with palladium catalyst, and as a result received compound I of the present invention. As the palladium catalyst used in this reaction Pd2(OAc)2Pd(dba)2Pd(PPh3)4or PdCl2(PPh3)2. As a solvent used toluene, tetrahydrofuran or N,N-dimethylformamide, and maintained the reaction temperature from 40°C to 120°C.

Scheme 13

where Ar1represents an aryl or heteroaryl group, and other symbols correspond to the values specified for them above.

Compound I according to the invention can also be obtained by reaction of the Steele intermediate IVf and ORGANOTIN compounds IIz, as shown in figure 13.

The intermediate connection IVf can be obtained in the following way:

First, the hydroxyl group of compound IVb was restored under the same conditions as in figure 4, resulting in the connection IVe. Then hydroxymethylene connection group IVe bromisovali, thus obtaining the intermediate connection IVf. In the process the synthesized use the Wali such compositions as PPh 3-CBr4or PPh3N-bromosuccinimide. Alternatively, hydroxymethylene connection group I've been sulfurously chloride methanesulfonyl, chloride p-toluensulfonyl or chloride trifloromethyl, in the presence of a base, and then bromisovali using NaBr or LiBr. As the solvent used in this reaction, chloroform, dichloromethane, acetonitrile, diethyl ether, tetrahydrofuran or dioxane. Preferred for use in this reaction grounds are Na2CO3, K2CO3, KOH, pyridine or triethylamine.

Method 4 for obtaining compounds according to the present invention

Compound I according to the present invention, where A represents -(CH2)n"- (n" denotes an integer from 0 to 2), -O - or-NH-, can be synthesized using the method of connection Suzuki (Bellina, F., et al. Synthesis, vol. 15, 2419, 2004, Miyaura, N., et al. Chem. Rev., vol. 95, 2457, 1995), as shown in figure 14 for the case of a Vc connection.

Scheme 14: Method 4 for obtaining compounds of formula I

Scheme 14

where Ar1represents an aryl or heteroaryl group, A represents-O - or-NH-, A'is a bond, -CH2- or-CH=CH-, R1krepresents a C1-6is an alkyl group, and other symbols correspond to the values that are specified for either the above.

To join Va in tetrahydrofuran was added n-utility, and then the resulting mixture was subjected to three(C1-6-alkoxy)borane (B(OR1k)) at the reaction temperature -78°C to 25°C. and Then was treated with hydrochloric or similar acid and resulted derived Vc boric acid.

Further, the Vc connection and connection IIu was treated with palladium catalyst, in the presence of a suitable base, resulting in received compound I according to the present invention. Examples of solvents used in the reaction are dioxane, acetonitrile, toluene, dimethoxyethane, tetrahydrofuran, N,N-dimethylformamide, dimethoxyethane/water, ethanol/water and toluene/ethanol. As grounds for this reaction, the preferred t-BuOK, Na2CO3, K2CO3, KOH, pyridine or triethylamine.

As the palladium catalyst can be used in this reaction, palladium on charcoal, Pd2(OAc)2Pd(dba)2Pd(PPh3)4and PdCl2(PPh3)2. If the reaction involved the connection IIu, in which A'represents-CH=CH-, then the obtained reaction product may be converted into a compound of formula I, where A represents-C2H4-by the way, based on catalytic hydrogenation, as described in the production method of 1, scheme 4.

Ispolzuemogo, described in the production method of 1, scheme 6, it is possible to obtain a compound I according to the present invention (A = -O - or-NH-) of the Vc connection and connection IIv.

Method 5 for obtaining compounds according to the present invention

Compound I according to the present invention, where A is-CONH(CH2)n -, or-NHCO(CH2)n- (n means an integer from 0 to 3), was obtained using the intermediate Vd shown in figure 15, or intermediate compounds Vf, shown in Scheme 16.

Scheme 15: 5 Way of obtaining the compounds of formula I

Scheme 15

where Ar1represents an aryl or heteroaryl group, and other symbols correspond to the values specified for them above.

Connection IIy were processed using the ate complex i-PrBu2MgLi, which was obtained from n-BuLi and i-PrMgCl or i-PrMgBr, receiving organometallics reagent IIaa. This reagent IIaa was added to thiolactone VIII, resulting in the received connection IVg. Then, the hydroxyl group was restored according to the conditions described in scheme 4, and then tert-butyl ester was subjected to acid hydrolysis, getting a carboxylic acid derivative Vd. As a solvent in this reaction used dioxane, acetonitrile, toluene, dimethoxyethane, tetrahydrofuran, N,N-digitiform the Ministry of foreign Affairs, dimethoxyethane/water, ethanol/water or toluene/ethanol. As the acid used formic acid, hydrochloric acid or CF3COOH. Alternatively, the carboxylic acid derivative Vd can be synthesized by the influence of n-BuLi in connection Va, and then ozonation carbon dioxide. As a solvent in this reaction used tetrahydrofuran or diethyl ether, and maintained the reaction temperature from -78°C to 25°C.

Further, the connection Vd and Amin IIw were subjected to condensation-dehydration, as a result received the Ib connection according to the present invention. As a solvent in this reaction used chloroform, dichloromethane or N,N-dimethylformamide. Preferred agents for condensation-dehydration are N,N-disclocation (DCC), N-ethyl-N'-3-dimethylaminopropiophenone hydrochloride (WSC), N,N-carbonyldiimidazole (CDI) or WSC/1-hydroxybenzotriazole monohydrate. Maintained the reaction temperature from 0°C to 60°C.

Diagram 16: the Way 5' obtain the compounds of formula I

Scheme 16

where Ar1represents an aryl or heteroaryl group, and other symbols correspond to the values specified for them above.

As shown in scheme 16, the connection Vd in the solvent was subjected to SOCl2or (COCl)2,to obtain a CHL is rangered connection Vd. As a solvent in this reaction used chloroform or dichloromethane. In the presence of n-Bu4NBr on the acid chloride was affected by sodium azide, getting derived acid azide compounds Vd. It is derived together tert-butanol was heated under reflux, in the received connection Ve. Chloroform or toluene are the preferred solvents for this reaction. Tert-butoxycarbonyl group (Boc) connection Ve removed by treatment with a suitable acid, resulting in the connection of Vf. The preferred acid for use in this reaction include hydrochloric acid or CF3COOH.

Then the connection Vf and carboxylic acid IIx were subjected to condensation-dehydration, resulting in the connection of the Ic according to the invention. Preferred solvents for this reaction include chloroform, dichloromethane or N,N-dimethylformamide. Preferred agents for condensation-dehydration are N,N-disclocation (DCC), N-ethyl-N'-3-dimethylaminopropiophenone hydrochloride (WSC), N,N-carbonyldiimidazole (CDI) or WSC/1-hydroxybenzotriazole monohydrate. The reaction temperature was maintained in the range from 0°C to 60°C.

If the substituents R5, R6, R7, R8, R9or R10on aryl, heteroaryl or heterocyclicamines ring connection is according to the invention are hydroxyl group or amino group, the transformation by substitution can be carried out by alkylation or acylation. An example in which the Deputy is a hydroxyl group shown in scheme 17. In the reaction of hydroxyl group with methylbromide, in the presence of a base, received connection Id. As a solvent in this reaction used dioxane, acetonitrile, toluene, dimethoxyethane, tetrahydrofuran or N,N-dimethylformamide. For use as a base in this reaction, the preferred Na2CO3, K2CO3, KOH, pyridine or triethylamine.

Then methoxycarbonyl group hydrolyzed via a method known in this field, making the connection Id in the carboxylic acid. Alternatively, the connection Id was subjected to condensation-dehydration, using primary or secondary amine, as a result, the connection Id was transformed into amide derivative. In addition, alternatively, the carbonyl group of compound Id was restored, resulting in making the connection Id in alcohol.

Scheme 17

The connection according to the present invention has the ability to inhibit the activity retrieveimage co-Transporter-2 glucose (SGLT2). (J. Clin. Invest., vol. 93, 397, 1994), associated with the reabsorption of glucose in the kidneys.

Inhibiting SGLT2, the connection according to this is the overarching invention can inhibit the reabsorption of sugar and excess sugar from the body, it allows to treat diabetes. Thus, this connection can be used for correction of hyperglycemia without depletion of β-cells of the pancreas caused by the toxicity of glucose and improve insulin resistance.

Therefore, the present invention relates to a medicinal product for the prevention or treatment of diseases or conditions that can improve with inhibition activity (SGLT2), for example, diabetes, diseases associated with diabetes, or complications caused by diabetes.

Used herein, the term "diabetes" includes type 1 diabetes, type 2 diabetes and other types of diabetes due to other causes.

The term "disease associated with diabetes include obesity, hyperinsulinemia, abnormal metabolism of sugar, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, abnormal lipid metabolism, hypertension, acute heart failure, edema, hyperuricemia and gout.

Used herein, the term "complication caused by diabetes" is divided into acute and chronic complication complication.

The term "acute complication includes hyperglycemia (diabetic ketoacidosis etc) and infection (infectious skin disease, infection soft tissue, infection of the biliary tract, infection of the respiratory tract and urinary tract infection).

the Term "chronic complication includes microangiopathy (nephropathy, retinopathy), arteriosclerosis (atherosclerosis, myocardial infarction, cerebral infarction, obstructive arteriosclerosis of the lower limbs, etc.), nerve damage (sensitive nerve, radial nerve, autonomic nerve, etc.) and gangrene of the legs.

The main complications are diabetic retinopathy, diabetic nephropathy and diabetic neuropathy.

The connection according to the present invention can also be used in combination with drugs other than SGLT2 activity inhibitors with different mechanisms of action, such as a drug for the treatment of diabetes, drug treatment for complications caused by diabetes, a drug for the treatment of hyperlipidemia and drug treatment for hypertension. Combining the compound according to the invention with other drugs, you can expect additional result due to the combined use, in comparison with the results obtained in the individual application for the treatment of the above diseases.

The terms "drug for diabetes treatment and drug treatment for complications caused by diabetes, which can be used include insulinsensitizing agents (PPARγ agonist is, PPARα/γ agonist, PPARδ agonists and PPARα/γ/δ agonists, etc.), glycosidase inhibitors, the biguanides, substances that accelerate the secretion of insulin, the insulin receptor antagonists of glucagon, accelerators insulin receptor kinase inhibitors tripeptidylpeptidase II inhibitors dipeptidylpeptidase IV, protein inhibitors tyrosinosis 1B, glycogen phosphorylase inhibitors, inhibitors of glucose-6-phosphatase, inhibitors of gluconeogenesis, inhibitors fruktozodifosfata, inhibitors piruvatdegidrogenazy, activators of glucokinase, D-chiroinositol inhibitors glikogensintetazy kinase 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-hydroxysteroiddehydrogenase inhibitors alsoreported, inhibitors of protein kinase C antagonists of the receptor γ-aminobutyric acid antagonists, sodium channel inhibitors of transcription factor NF-κ, IKKβ inhibitors, inhibitors of liquid peroxidase inhibitors N-azetilirovannah α-linked acidic dipeptidase, insulin-like growth factor-I, platelet-derived growth factor (PDGF), analogues of platelet-derived growth factor (PDGF), epidermal growth factor (EGF), nerve growth factor, derivatives of carnitine, uridine, 5-hydroxy-1-metil dantoin, EGB-761, vikraman, sulodexide, Y-128, and TAK-428.

The following pharmaceuticals are examples of medicines for diabetes, medicines for the treatment of complications of diabetes:

Examples of "the biguanide is Metformin hydrochloride, phenformin.

From "accelerators insulin secretion to the sulfonylureas are gliburid (glibenclamide), glipizide, gliclazide and hlorpropamid, and to desulfonylation include nateglinide, Repaglinide and mitiglinide.

"Insulin" includes human insulin, created by methods of genetic engineering, and the insulin of animal origin. These drugs are divided into three types, depending on the length of their actions, namely, fast acting type (human insulin human neutral insulin), the interim action (suspension of insulin and insulin-Isfana person, the suspension of neutral insulin isophane insulin human zinc suspension human insulin zinc suspension insulin) and type of prolonged action (zinc suspension human crystalline insulin).

The term "field of glycosidase inhibition inhibitors" include acarbose, voglibose and miglitol.

The term "insulin sensitizing agents" refers to agonists of PPAR-γ, such as troglitazone, PI is glitazone and rosiglitazone, dual agonists of PPAR-α/γ, such as MK-767 (KRP-297), tesaglitazar, LM4156, LY510929, DRF-4823 and TY-51501, and PPAR-δ to agonists such as GW-501516, etc.

"Inhibitors tripeptidylpeptidase II" refer UCL-139 etc.

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

"Inhibitors alsoreported" are ascorbylpalmitate, tolrestat, epalrestat, fidarestat, sorbinil, ponalrestat, resurected and zenarestat.

"Antagonists of the receptor γ-aminobutyric acid" refers topiramate etc.

"Antagonists, sodium channel are meksiletin hydrochloride etc.

"Inhibitors of transcription factor NF-κ" refer to dukkipati etc.

"Inhibitors of liquid peroxidase" are tirilazad mesylate etc.

"Inhibitors of N-azetilirovannah α-linked acidic dipeptidase" are GPI-5693 etc.

"Derivative of carnitine" include carnitine, levocetirizine hydrochloride etc.

Examples of "medicines for the treatment of hyperlipidemia and medicines for the treatment of hypertension, which can be used as a companion drugs are inhibitors hydroxymethylglutaryl-CoA reductase, fibrate compounds, agonists β3-adrenergic receptor, AMPK activators, inhibitors of acyl-CoA:cholesterylester, probucol, agonists of receptors th the Mona thyroid gland, inhibitors of cholesterol absorption, lipase inhibitors, inhibitors of microsomal protein carrier of triglycerides, lipoxygenase inhibitors, inhibitors carnitinelongevity, inhibitors of squalene synthase, amplifiers receptors low-density lipoprotein, derivatives of nicotinic acid, bile acid adsorbents, inhibitors vector matriculating bile acids, inhibitors of protein-vectors of ester cholesterol, inhibitors of angiotensin-converting enzyme antagonists of angiotensin II receptor inhibitors endotelinzawisimogo enzyme, receptor antagonists endothelin, diuretics, calcium antagonists, antihypertensive agents, sympathicolysis tools, antihypertensive agents Central action, agonists α2-adrenergic receptors, antiplatelet funds inhibitors ureagenesis, stimulants excretion of uric acid, agents, alkalizing urine, anorectic, AGE inhibitors, agonists of receptors adiponectin, GPR40 agonists and antagonists GPR40.

Drug for the treatment of hyperlipidemia and drug treatment for hypertension presents the following examples of pharmaceutical products.

"Inhibitors hydroxymethylglutaryl-CoA reductase" refers fluvastatin, lovastatin, pravastatin,tseriwastatina and pitavastatin.

To "vibratrim compounds" refer bezafibrat, beclobrate and benefibre.

"Inhibitors of squalene synthase" are the SO-475 and derivatives of α-phosphosulfate (USP 5712396).

"Inhibitors of acyl-CoA:cholesterylester" are CI-1011, NTE-122, FCE-27677, RP 73163, MCC-e DPU-129.

"Amplifiers receptors low-density lipoprotein" refers MD-700 and LY-295427.

"Inhibitors of microsomal protein carrier of triglycerides (MTP inhibitors)" include compounds described in patent applications USP 5739135, USP 5712279 and USP 5760246.

Examples of "anorectics are adrenergic-noradrenergic agents (for example, mazindol, and ephedrine), serotonergic agents (selective inhibitors of back capture of serotonin, for example, fluvoxamine), adrenergic - serotonergic agent such as sibutramine, etc.), agonists of the receptor melanocortin 4 (MC4R), α-melanocytestimulating hormone (α-MCH), leptin and transcripts regulated by cocaine and amphetamine (CART).

Examples of agonists hormone receptor thyroid gland are nutritition and nutriceutical.

Examples of inhibitors of cholesterol absorption" is ezetimib.

Examples of the lipase inhibitor is orlistat.

An example of an inhibitor carnitinelongevity is etomoxir.

Examples of derivatives of nicotinic acid are nicoti the OIC acid, nicotinamide, nicomol and nicorandil.

Examples of "bile acid adsorbents are cholestyramine, colestilan and hydrochloride colesevelam.

Examples of "angiotensin converting enzyme" are captoril, enalaprilat, alacepril and cilazapril.

Examples of antagonists of angiotensin II receptors" are candesartanzapomnit, losartan potassium, apresentadora and olmesartanonline.

Examples of "inhibitors endotelinzawisimogo enzyme are CGS-31447 and CGS-35066.

Examples of antagonists endothelioma receptor" are L-749805, TBC-3214 and BMS-182874.

In the treatment of diabetes and other diseases associated with diabetes, for example, you need to take into account that the connection according to the present invention is preferably used in combination with at least one drug selected from the group consisting of insulin-sensitizing components (PPAR-γ agonists, PPAR-α/γ agonists, PPAR-δ agonists, PPAR-α/γ/δ agonists, etc.), glycosidase inhibitors, biguanides, substances that accelerate the secretion of insulin, insulin inhibitors dipeptidylpeptidase IV.

Alternatively, you need to take into account that the connection according to the present invention is preferably used in combination with at least one drug selected from the group consisting of inhibitors hydroxymethylglutaryl-CoA-reductase, fibrate compounds, inhibitors of squalene synthase, inhibitors of acyl-CoA:cholesterylester, amplifiers receptors low-density lipoprotein, inhibitors of microsomal protein carrier of triglycerides and anorectics.

The pharmaceutical agents according to the present invention it is possible to enter systemically or locally via the oral route of administration or parenteral route of administration, for example, intrarectal, subcutaneous, intramuscular, intravenous or percutaneous.

Compounds according to the present invention can be used as pharmaceutical agents in such form, as a solid composition, a liquid composition, or can be used for any other composition, and the optimal shape is selected depending on the needs. The pharmaceutical agent according to the present invention can be produced by mixing a pharmaceutically acceptable carrier with the compound according to the present invention. More specifically, the connection according to the present invention was added excipient, is a bulking agent, a binder agent, disintegrator, covering substance, sweetened covering substance, a pH regulator, a solvent reagent or an aqueous or anhydrous solvent, any of which is widely used. The resulting mixture can be formed, is using the conventional technology of pharmaceutical production, in such dosage forms as tablets, pills, capsules, granules, powder, solution or liquid, emulsion, suspension or injectable dosage form. Examples of excipient agent and the filler is lactose, ministerof, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cacao butter, ethylene glycol or any other commonly used materials.

Alternatively, the connection according to the present invention may be pharmaceutically manufactured through formation of compounds with α-, β - or γ-cyclodextrin or methylated-cyclodextrin.

The dose of a compound according to the present invention varies depending on the disease, symptoms, body weight, age or sex of the patient, or the method of administration to a patient. For adults, the preferred dose is from 0.1 to 1000 mg/kg body weight/day, more preferably from 0.1 to 200 mg/kg body weight/day, which you can enter once a day or split the dose into several methods.

EXAMPLES

Examples of receipt

Here are examples of obtaining aglionby fragments of the compounds of the present invention.

Example obtain 1

Synthesis of 2,3,4,6-Tetra-O-benzyl-5-thio-D-glucono-1,5-lactone

3,4-Dihydro-2H-Piran (1.5 ml, 16.5 mmol) and the monohydrate para-toluensulfonate acid (104 mg, 0,549 mmol) was added the solution of 2,3,4,6-Tetra-O-acetyl-5-thio-D-glucopyranose (2.0 g, 5,49 mmol) in chloroform (40 ml) and stirred at room temperature for one hour. To the reaction mixture were added saturated aqueous sodium bicarbonate solution and was extracted with chloroform, and then the organic layer was washed with brine, dried over anhydrous magnesium sulfate. The desiccant of otfiltrovana, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1)to give tetrahydro-2H-Piran-2-yl-2,3,4,6-Tetra-O-acetyl-5-thio-D-glucopyranose (2,56 g) as a pale yellow amorphous substance.

Then 25% (by weight) solution of sodium methoxide (of 0.11 ml, 0.55 mmol) in methanol was added to a solution of tetrahydro-2H-Piran-2-yl-2,3,4,6-Tetra-O-acetyl-5-thio-D-glucopyranose (2.5 g) in methanol (40 ml) and was stirred for three hours. Next was added a small amount of dry ice to neutralize the reaction mixture, then the reaction mixture was concentrated. The obtained residue was dissolved in N,N-dimethylformamide (20 ml). The resulting solution was added dropwise to a suspension of sodium hydride (1.3 g, from 32.9 mmol; 60% in oil) and N,N-dimethylformamide (4 ml)while cooling in an ice bath. Then the reaction mixture was stirred at room temperature for 20 minutes, cooled to 4°C was added benzyl bromide (5.6 g, from 32.9 mmol). Yes is it the reaction mixture was stirred at room temperature for 12 hours, was added methanol (5 ml) and was stirred for 30 minutes. To the reaction mixture was added ice water, was extracted with a mixture of ethyl acetate, then the organic layer was washed with brine, dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=6:1), receiving tetrahydro-2H-Piran-2-yl 2,3,4,6-Tetra-O-benzyl-5-thio-D-glucopyranose (3,36 g, 96% for the three stages).

A mixture of tetrahydro-2H-Piran-2-yl-2,3,4,6-Tetra-O-benzyl-5-thio-D-glucopyranose (3,30 g of 5.15 mmol), para-toluensulfonate pyridinium (518 mg, of 2.06 mmol) and ethanol (58 ml) was stirred at a temperature of 80°C for two hours. The reaction mixture was cooled to room temperature, and the solvent was concentrated. The obtained residue was dissolved in ethyl acetate. Then, the solution was washed with saturated aqueous sodium bicarbonate solution and a salt solution, then dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1)to give 2,3,4,6-Tetra-O-benzyl-5-thio-D-glucopyranose (2,89 g, Quant.) in the form of colorless crystal.13C NMR (125 MHz, CHLOROFORM-d) δ 41,3, 67,8, 71,6, 73,0, 73,2, 75,6, 76,2, 81,9, 82,9, 84,4, 127,5, 127,7, 127,8, 127,9, 128,0, 128,3, 128,4,128,5, 137,8, 138,3, 138,8.

A mixture of 2,3,4,6-Tetra-O-benzyl-5-thio-D-glucopyranose (2,82 g 5,07 mmol), dimethyl sulfoxide (47 ml) and acetic anhydride (39 ml) was stirred at room temperature for 12 hours. To the reaction mixture were added ice water and was extracted with a mixture of ethyl acetate, then the organic phase is washed with water, saturated aqueous sodium bicarbonate and salt solution, then dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=6:1), obtaining mentioned in the title compound as a colorless oily substance. (2.3 g, 82%).

1H NMR (200 MHz, CHLOROFORM-d) δ ppm 3,70 (d, J=4,8 Hz, 2H), 3,86-was 4.02 (m, 2H), 4.09 to 4,22 (m, 2H), 4,40-and 4.68 (m, 7H), of 4.83 (d, J=11,4 Hz, 1H), 7,12-7,41 (m, 20H).

Example of getting 2

Synthesis of 2,3,4,6-Tetra-O-(4-methoxybenzyl)-5-thio-D-glucono-1,5-lactone

The synthesis was carried out by a method similar to that described in example obtain 1 using chloride 4-methoxybenzyl instead of benzyl bromide.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,60-3,66 (m, 2H), of 3.77-3,81 (m, 12H), 3,81-3,91 (m, 2H), 4,01-to 4.15 (m, 2H), 4,29-4,58 (m, 7H), 4,74 (d, J=11.2 Hz, 1H), 6,78-of 6.90 (m, 8H), 7.03 is-7,10 (m, 2H), 7,11-7,30 (m, 6H).

Example of getting 3

Synthesis of 1-bromo-3-(4-ethoxybenzyl)benzene

2.6 M solution of n-b is tilletiaceae (5.8 ml) was added to a mixture of 4-bromophenetole (2,87 g, 0,0143 mol) and tetrahydrofuran (30 ml) at -78°C. Then the mixture was stirred for 0.5 hours, the solution was added 3-bromobenzaldehyde (2.65 g, 0,0143 mol) in tetrahydrofuran (15 ml) and then was stirred for 15 minutes, heating the mixture to room temperature. Next, to the reaction mixture were added saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=7:1 - 5:1), receiving (3-bromophenyl)(4-atocopherol)methanol (3.94 g, 90%) as a colorless oily substance.

Then Et3SiH (4.09 to ml, 0,0256 mol) and BF3·Et2O (1,47 ml, 0,0116 mol), was added to a solution of (3-bromophenyl)(4-ethoxyphenyl)methanol (to 3.92 g, 0,0128 mol) in chloroform (22 ml) at a temperature of -60°C. and Then was stirred for one hour, then the reaction mixture was heated to room temperature. Next, to the reaction mixture were added saturated aqueous solution of sodium carbonate and was extracted with chloroform, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained is output as the result of evaporation of the solvent under reduced pressure, was purified by column chromatography on silica gel (hexane:ethyl acetate=50:1), obtaining specified in the header connection (2,84 g, 76%)as a colorless oily substance.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.40 (t, J=7.0 Hz, 3H), 3,88 (s, 2H), 4,01 (kV, J=7,0 Hz, 2H), 6,83 (d, J=8,9 Hz, 2H), 7,07 (d, J=8,9 Hz, 2H), 7,09-to 7.18 (m, 2H), 7,29-7,34 (m, 2H).

Example 4

Synthesis of 2-(5-bromo-2-methoxybenzyl)-1-benzothiophene

1.6 M solution of n-utilitiesman (30,5 ml) was added to a mixture of benzo[b]thiophene (6.6 g, 0,049 mol) and tetrahydrofuran (66 ml) at -78°C. Then stirred for 0.5 hours, the reaction mixture was added a solution of 5-bromo-2-methoxybenzaldehyde (10.0 g, 0,047 mol) in tetrahydrofuran (50 ml), then was stirred for 5 minutes and the reaction mixture was heated to room temperature. Then to the reaction mixture were added saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate, the organic phase was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=6:1), obtaining (1-benzothieno-2-yl)(5-bromo-2-methoxyphenyl)methanol (11.3 g, 69%) as a pale yellow crystal.

Then Et3SiH (10.3 ml, 0,0642 mol) and BF3·Et 2O (4,10 ml, 0,0321 mol), was added to a solution of (1-benzothieno-2-yl)(5-bromo-2-methoxyphenyl)methanol (1.2 g, 0,0321 mol) in chloroform (110 ml) at -15°C. the mixture was stirred for 0.5 hours, was added saturated aqueous sodium bicarbonate solution. The mixture was extracted with chloroform, and the organic phase was washed with brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=30:1), obtaining specified in the header connection (9,84 g,92%) as a yellow crystal.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm of 3.84 (s, 3H), 4,17 (s, 2H), 6,76 (d, J=8.7 Hz, 1H), 7,01 (s, 1H), 7,19-7,37 (m, 4H), of 7.65 (d, J=7.8 Hz, 1H), 7,73 (d, J=7.8 Hz, 1H).

EI 332, 334 (M+M+2).

Example of getting 5

Synthesis of 2-(5-bromo-2-Chlorobenzyl)-1-benzothiophene

Oxalyl chloride (3,78 ml, 0,0441 mmol) and N,N-dimethylformamide (0.06 ml) was added to a solution of 5-bromo-2-chlorbenzoyl acid (10.0 g, 0,0425 mol) in chloroform (20 ml). Then the reaction mixture was stirred at room temperature for one day, then the reaction mixture is evaporated under reduced pressure. The obtained yellow oily substance was dissolved in chloroform (20 ml). This solution was added dropwise to a mixture of N,O-dimethoxyphenethylamine hydrochloride (4,56 g, 0,068 mol), triethylamine (12.3 ml, 0,0882 mol) and chloroform (50 ml) over 15 minutes while maintaining the reaction temperature is from 5°C to 10°C. and Then was stirred for 15 minutes, the reaction mixture was heated to room temperature. Next, to the reaction mixture were added water (20 ml), separated the organic layer, then washed the organic layer with saturated aqueous sodium bicarbonate and the salt solution and dried over anhydrous magnesium sulfate. The desiccant was filtered, then the solvent is evaporated under reduced pressure, obtaining 5-bromo-2-chloro-N-methoxy-N-methylbenzamide (11,8 g of 99.7%) as a colorless crystal. The obtained substance was used in the next reaction without further purification.

LiAlH4(1.47 g, 0,0388 mol) was added in small portions to a solution of 5-bromo-2-chloro-N-methoxy-N-methylbenzamide (10.8 g, 0,0388 mol) in tetrahydrofuran (108 ml)while maintaining the temperature does not exceed -10°C. the Reaction mixture was stirred at -15°C for one hour, and was carefully added to saturated aqueous solution of ammonium chloride, and the precipitated insoluble fraction was filtered through celite. Next, the filtrate was extracted with ethyl acetate, the organic layer washed with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate, salt solution and then dried over anhydrous magnesium sulfate. The desiccant was filtered, the solvent evaporated under reduced pressure, receiving 5-bromo-2-chlorobenzaldehyde (8,1 g, 95%) as a pale yellow crystal. The obtained substance was used in the next reaction without further purification.

1.6 M solution of n-utilitiesman (26,9 ml) was added to a mixture of benzo[b]thiophene (5.8 g, 0,043 mol) and tetrahydrofuran (58 ml) at -78°C for more than 20 minutes. Then was stirred for 0.5 hours, to the mixture was added a solution of 5-bromo-2-chlorobenzaldehyde (9.0 g, 0,041 mol) in tetrahydrofuran (50 ml) and was stirred for a further five minutes. The reaction mixture was heated to room temperature. Next, to the reaction mixture were added saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate, the organic phase was washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1), obtaining (1-benzothieno-2-yl)(5-bromo-2-chlorophenyl)methanol (10.3 g, 71%) as a pale yellow oily substance.

Next Et3SiH (9,2 ml, 0,058 mol) and BF3·Et2O (3.6 ml, 0,029 mol), was added to a solution of (1-benzothieno-2-yl)(5-bromo-2-chlorophenyl)methanol (10.2 g, 0,0288 mol) in chloroform (110 ml) at -15°C. the Reaction mixture was heated to room temperature the tours and was stirred at this temperature for ten hours. Then to the reaction mixture were added saturated aqueous sodium bicarbonate solution, the organic phase was separated, washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=60:1), obtaining mentioned in the title compound as a colorless oily substance (5.5 g, 56%).

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 4,30 (s, 2H), 6,98-7,06 (m, 1H), 7,22-7,37 (m, 4H), 7,43 (d, J=2.3 Hz, 1H), of 7.64-7,71 (m, 1H), 7,72-7,80 (m, 1H).

EI 336 (M+), 338 (M+2), 340 (M+4).

An example of obtaining 6

Synthesis of 1-(benzyloxy)-2-bromo-4-(4-ethoxybenzyl)benzene

Benzylbromide (3.1 ml, was 0.026 mol) was added to a mixture of 3-bromo-4-hydroxybenzaldehyde (5.0 g, 0,025 mol), tetrabutylammonium iodide (0,92 g, 2.5 mmol), potassium carbonate (6.9 g, 0,050 mol) and N,N-dimethylformamide (70 ml) at room temperature and was stirred for 2.5 hours. A mixture of ice water (100 ml) was poured into the reaction mixture and the resulting solution was stirred for one hour. The precipitate was filtered and dried, obtaining 4-benzyloxy-3-bromobenzaldehyde (7,1 g, 98%) as a pale yellow powder.

Next, 1.6 M solution of n-utilitiesman (22.9 ml) was added to a mixture of 4-bromophenetole (7,3 g 0,037 mol) and tetrahydrofuran (70 ml) at t is mperature -78°C. Then was stirred for 0.5 hours, the solution was added 4-benzyloxy-3-bromobenzaldehyde (7.0 g, 0,024 mol) in tetrahydrofuran (70 ml) and then was stirred for 15 minutes and the reaction mixture was heated to room temperature. Then to the reaction mixture were added saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate, the organic phase was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1)to give [4-(benzyloxy)-3-bromophenyl](4-ethoxyphenyl)methanol (8.7 g, 86%) as a colorless oily substance.

Next Et3SiH (6,7 ml 0,042 mol) and BF3·Et2O (2.7 ml, 0,021 mol) were added sequentially to a solution of [4-(benzyloxy)-3-bromophenyl](4-ethoxyphenyl)methanol (8.7 g, 0,021 mol) in chloroform (90 ml) at -15°C. the resulting mixture was stirred for one hour, then the reaction mixture was heated to room temperature. Then the reaction mixture was added saturated aqueous solution of sodium carbonate and was extracted with chloroform, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained in rez is ltate evaporation of the solvent under reduced pressure, was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1), obtaining mentioned in the title compound as a colorless oily substance (8.8 g, Quant.).

1H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.40 (t, J=7.0 Hz, 3H), 3,82 (s, 2H), 4.00 points (kV, J=7,0 Hz, 2H), 5,12 (s, 2H), 6,78-6,87 (m, 3H), 6,98-7,10 (m, 3H), 7,27-to 7.50 (m, 6H).

Example of getting 7

Synthesis of 1-bromo-3-(4-ethoxybenzyl)-4-methoxybenzene

The synthesis was carried out by a method similar to that described in the example of a 3, using 5-bromo-2-methoxybenzaldehyde and 4-bromophenetole.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.40 (t, J=7.0 Hz, 3H), 3,79 (c, 3H), 3,85 (c, 2H), 4,01 (kV, J=7,0 Hz, 2H), 6,72 (d, J=8.6 Hz, 1H), for 6.81 (d, J=8.7 Hz, 2H), to 7.09 (d, J=8.7 Hz, 1H), 7,13 (d, J=2.5 Hz, 1H), 7,27 (DD, J=8,6, 2.5 Hz, 1H).

Example obtain 8

Synthesis of 1-bromo-3-(4-ethoxybenzyl)-6-methoxybenzoyl

The synthesis was carried out by a method similar to that described in the example of a 3, using 3-bromo-4-methoxybenzaldehyde and 4-bromophenetole.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.40 (t, J=7.0 Hz, 3H), 3,83 (c, 2H), 3,86 (c, 3H), 4,01 (kV, J=7,0 Hz, 2H), 6,78-6,85 (m, 3H), 7.03 is-7,10 (m, 3H), 7,35 (d, J=2.2 Hz, 1H).

EI 320, 322 (M+M+2).

Example of getting 9

Synthesis of 2-(3-bromobenzyl)-1-benzothiophene

The synthesis was carried out by a method similar to that described in example 4, using 3-bromobenzaldehyde and benzo[b]thiophene.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 4,19 (c, 2H), 7,02 (c, 1H), 7,15-7,47 (m, 6 H) 7,65-of 7.70 (m, 1H), 7,71-to 7.77 (m, 1H).

EI 302, 304 (M+M+2).

Example 10

Synthesis of 2-(3-bromo-4-methoxybenzyl)-1-benzothiophene

The synthesis was carried out by a method similar to that described in example 4, using 3-bromo-4-methoxybenzaldehyde and benzo[b]thiophene.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,89 (c, 3H), 4,15 (c, 2H), 6,86 (d, J=8,4 Hz, 1H), 7,01 (c, 1H), 7,16-7,35 (m, 3H), of 7.48 (d, J=1.9 Hz, 1H), of 7.64-of 7.70 (m, 1H), 7,71-to 7.77 (m, 1H).

EI 332, 334 (M+M+2).

Example of getting 11

Synthesis of 1-bromo-3-(4-ethoxybenzyl)-4,6-dimethoxybenzene

The synthesis was carried out by a method similar to that described in the example of a 3, using 5-bromo-2,4-dimethoxybenzaldehyde and 4-bromophenetole.

1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.39 in (t, J=7.0 Hz, 3H), 3,80 (c, 2H), 3,82 (c, 3H), 3,88 (c, 3H), 4.00 points (kV, J=7,0 Hz, 2H), 6,47 (c, 1H), 6.75 in-6,85 (m, 2H), 7,02 for 7.12 (m, 2H), 7,17 (c, 1H).

EI 350, 352 (M+M+2).

Example 12

Synthesis of 1-bromo-3-(4-ethoxybenzyl)-4-fermental

The synthesis was carried out by a method similar to that described in the example of a 3, using 5-bromo-2-forbindelse and 4-bromophenetole.

1H NMR (200 MHz, CHLOROFORM-d) δ ppm of 1.40 (t, J=7.0 Hz, 3H), 3,88 (c, 2H), 4,01 (kV, J=7,0 Hz, 2H), 6,79-of 6.96 (m, 3H), 7,05-7,16 (m, 2H), 7,19-to 7.32 (m, 2H).

EI 309, 311 (M+M+2).

Example of getting 13

Synthesis of 1-(benzyloxy)-4-bromo-2-(4-ethoxybenzyl)benzene

The synthesis was carried out by a method similar to that described in the example of a 6, using 3-b is ω-2-hydroxybenzaldehyde.

1H NMR (200 MHz, CHLOROFORM-d) δ ppm of 1.40 (t, J=6.8 Hz, 3H), 3,90 (c, 2H), 4,01 (kV, J=6,8 Hz, 2H), 5,03 (c, 2H), 6,72-6,85 (m, 3H), 7,02-7,13 (m, 2H), 7,15-the 7.43 (m, 7H).

Example of getting 14

Synthesis of 1-bromo-4-chloro-3-(4-ethoxy-2,5-diferensial)benzene

Oxalyl chloride (1.89 ml, 0,0220 mol) and N,N-dimethylformamide (0,03 ml) was added to 5-bromo-2-chlorbenzoyl acid (5.0 g, 0,0212 mol) in chloroform (10 ml) and was stirred for three hours. The yellow oil obtained by evaporation of the solvent under reduced pressure, then dissolved in chloroform (10 ml). To this solution was added 2.5-differenital (3.4 g, 0,0214 mol) and then batch was added aluminium chloride (2.9 g, 0,0214 mol) at a temperature of -10°C for five minutes. Next, the reaction mixture was stirred at 5°C for two hours, was added ice-cold water. This mixture was extracted with chloroform three times. Then the combined organic layer washed with 1 M hydrochloric acid, water, salt solution and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1)to give (5-bromo-2-chlorophenyl)(4-ethoxy-2,5-differenl)methanon (5,59 g, 70%) as a colorless crystal.

Then Et3SiH (5,93 ml, 0,0371 mol) and BF3·Et 2O and 2.83 ml, 0,0224 mol) were added sequentially to a solution of (5-bromo-2-chlorophenyl)(4-ethoxy-2,5-differenl)methanone (5,58 g, 0,0149 mol) in chloroform-acetonitrile (1:1; 60 ml) at 4°C. the Reaction mixture was heated to room temperature, was stirred for 12 hours and still was stirred at 45°C for three hours. Next, to the reaction mixture were added saturated aqueous solution of sodium carbonate and was extracted with chloroform, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1), obtaining mentioned in the title compound as a colorless oily substance (3.8 g, 71%).

1H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.46 (t, J=7.0 Hz, 3H), 3,98 (c, 2H), 4,08 (kV, J=7,0 Hz, 2H), of 6.71 (DD, J=11,3, 7,1 Hz, 1H), PC 6.82 (DD, J=11,3, 7,1 Hz, 1H), 7.18 in-7,38 (m, 3H).

EI 360 (M+), 362 (M+2), 364 (M+4).

Example get 15

Synthesis of 1-bromo-4-chloro-3-(4-ethoxy-3-terbisil)benzene

The synthesis was carried out by a method similar to that described in the example of a 14, using 5-bromo-2-chlorbenzoyl acid and 2-florfenicol.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.44 (t, J=7.0 Hz, 3H), 3,97 (c, 2H), 4.09 to (kV, J=7,0 Hz, 2H), 6,79-to 6.95 (m, 3H), 7.18 in-7,35 (m, 3H).

p> EI 342 (M+), 344 (M+2), 346 (M+4).

Example 16

Synthesis of 1-bromo-4-chloro-3-(3-chloro-4-ethoxybenzyl)benzene

The synthesis was carried out by a method similar to that described in the example of a 14, using 5-bromo-2-chlorbenzoyl acid and 2-chlorphenyl.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.46 (t, J=7.0 Hz, 3H), 3.96 points (c, 2H), 4,08 (kV, J=7,0 Hz, 2H), 6,85 (d, J=8,4 Hz, 1H), 6,95-7,03 (m, 1H), 7,18 (d, J=2.2 Hz, 1H), 7.23 percent-7,33 (m, 3H).

Example of getting 17

Synthesis of 1-bromo-3-(4-ethoxybenzyl)-4-methylbenzene

The synthesis was carried out by a method similar to that described in the example of a 14, using 5-bromo-2-methylbenzoic acid (synthesized as described in International patent publication WO 0127128) and phenetol.

1H NMR (200 MHz, CHLOROFORM-d) δ ppm of 1.40 (t, J=7.0 Hz, 3H), 2,18 (c, 3H), 3,86 (c, 2H), 4.00 points (kV, J=7,0 Hz, 2H), 6,76-6,87 (m, 2H), 6,94-7,07 (m, 3H), 7,17-7,30 (m, 2H).

EI 304 (M+), 306 (M+2).

Example of getting 18

Synthesis of 1-bromo-4-chloro-3-(2,4-dimethoxybenzyl)benzene

The synthesis was carried out by a method similar to that described in the example of a 14, using 5-bromo-2-chlorbenzoyl acid and 1,3-dimethoxybenzene.

1H NMR (200 MHz, CHLOROFORM-d) δ ppm 3,79 (c, 3H), 3,80 (c, 3H), 3,95 (c, 2H), 6,36-6,53 (m, 2H), 6,94 (d, J=8,4 Hz, 1H), 7,13-7,28 (m, 3H).

Example of getting 19

Synthesis of 1-bromo-4-chloro-3-(4-methoxybenzyl)benzene

The synthesis was carried out by a method similar to that described in the example of a 14, using 5-the rum-2-chlorbenzoyl acid and anisole.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,80 (c, 3H), 3,99 (c, 2H), PC 6.82-6.89 in (m, 2H), 7,06-7,13 (m, 2H), 7,19-7,30 (m, 3H).

Example of getting 20

Synthesis of 1-bromo-4-chloro-3-(4-tert-butylbenzyl)benzene

The synthesis was carried out by a method similar to that described in the example of a 14, using 5-bromo-2-chlorbenzoyl acid and tert-butylbenzoyl.

1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1,31 (c, 9 H), a 4.03 (c, 2H), 7,11 (d, J=7.9 Hz, 2H), 7,22-7,37 (m, 5H).

Example of getting 21

Synthesis of 1-bromo-4-chloro-3-(4-methylbenzyl)benzene

The synthesis was carried out by a method similar to that described in the example of a 14, using 5-bromo-2-chlorbenzoyl acid and toluene.

1H NMR (200 MHz, CHLOROFORM-d) δ ppm 2,33 (c, 3H), was 4.02 (c, 2H), 7.03 is-7,16 (m, 4H), 7.18 in-7,32 (m, 3H).

EI 294 (M+), 296 (M+2).

Example of getting 22

Synthesis of 1-bromo-4-chloro-3-(4-methylthiophenyl)benzene

The synthesis was carried out by a method similar to that described in the example of a 14, using 5-bromo-2-chlorbenzoyl acid and thioanisole.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2,47 (c, 3H), 4,01 (c, 2H), 7,06-7,14 (m, 2H), 7,17-to 7.32 (m, 5H).

An example of retrieving 23

Synthesis of 1-bromo-4-chloro-3-(4-active compounds)benzene

The synthesis was carried out by a method similar to that described in the example of a 14, using 5-bromo-2-chlorbenzoyl acid and ethylbenzene.

1H NMR (200 MHz, CHLOROFORM-d) δ ppm of 1.23 (t, J=7.7 Hz, 3H), 2.63 in (kV, J=7.7 Hz, 2H), was 4.02 (c, 2H),? 7.04 baby mortality-to 7.18 (m, 4H), 7.18 in-7,32 (m, 3H)

EI 308 (M+), 310 (M+2).

Example of getting 24

Synthesis of 1-bromo-4-chloro-3-(4-isopropylbenzyl)benzene

The synthesis was carried out by a method similar to that described in the example of a 14, using 5-bromo-2-chlorbenzoyl acid and cumin.

1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1,22 (c, 3H), 1.26 in (c, 3H), 2,79-of 2.97 (m, 1H), was 4.02 (c, 2H), 7,05-to 7.32 (m, 7H).

EI 322 (M+), 324 (M+2).

Example get 25

Synthesis of 2-(5-bromo-2-Chlorobenzyl)benzofuran

The synthesis was carried out by a method similar to that described in example getting 5 using benzofuran instead of benzothiophene.

1H NMR (200 MHz, CHLOROFORM-d) δ ppm 4,20 (c, 2H), 6,40-6,46 (m, 1H), 7,13-rate of 7.54 (m, 7H).

EI 319 (M+), 321 (M+2).

Example of getting 26

Synthesis of 1-bromo-3-(4-ethoxybenzyl)-6-methoxy-4-methylbenzoyl

To a mixture of 4-methoxy-2-methylbenzoic acid (10 g, to 0.060 mol), Fe (0.20 g, 3.61 mmol) and chloroform (10 ml) was added dropwise bromine (a 3.87 ml, 0,076 mol) at 5°C. Then the reaction mixture was heated to room temperature, the mixture was stirred over night. Then was added chloroform (600 ml)and this suspension was washed with 10% sodium hydrosulphate (200 ml × 2) and the salt solution and dried over anhydrous magnesium sulfate. The desiccant was filtered, then pale yellow powder obtained by evaporating the solvent under reduced pressure, recrystallized twice from methane is a, receiving 5-bromo-4-methoxy-2-methylbenzoic acid (4,96 g, 34%).

Altenative, 5-bromo-4-methoxy-2-methylbenzoic acid can be synthesized from 4'-hydroxy-2'-methylacetophenone, as the source material. Potassium carbonate (determined as 0.720 mg, to 5.21 mmol) and methyliodide (0,542 g is 3.82 mmol) was added to a solution of 4'-hydroxy-2'-methylacetophenone (0,552 g, 3,47 mmol) in acetone (10 ml) and stirred at room temperature for 12 hours. Then add methyliodide (0.24 g, of 1.73 mmol) and the mixture is boiled under reflux for two hours. The reaction mixture was heated to room temperature, then the solvent is evaporated under reduced pressure. Further to the residue was added chloroform, the insoluble fraction was filtered and the filtrate was concentrated, obtaining 4'-methoxy-2'-methylacetophenone (0,57 g). Then to a solution of 4'-methoxy-2'-methylacetophenone (0.21 g, of 1.27 mmol) in acetone (4 ml) - water (4 ml) was added Oxon (0,79 g of 1.27 mmol) and NaBr (0,13 g of 1.27 mmol) and stirred at room temperature for one hour. Later in the reaction mixture were added water and ethyl acetate, the organic layer was separated and washed with water, saturated aqueous sodium carbonate and the salt solution and dried over anhydrous magnesium sulfate. The desiccant was filtered, then the solvent is evaporated under reduced pressure, obtaining a mixture of 4:1 (0.28 g) 5'-bromo-4'-meth is XI-2'-methylacetophenone and 3'-bromo-4'-methoxy-2'-methylacetophenone. Then to the mixture 4:1 (0.26 g) 5'-bromo-4'-methoxy-2'-methylacetophenone and 3'-bromo-4'-methoxy-2'-methylacetophenone was added 5% NaOCl solution (3 ml) and potassium hydroxide (0,92 g) and boiled under reflux for 2.5 hours. The reaction mixture was cooled to room temperature, then the reaction mixture was acidified using 2 M HCl. Then the mixture was extracted with ethyl acetate, the organic phase is washed with 1 M HCl, the salt solution and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure, washed with methanol, receiving 5-bromo-4-methoxy-2-methylbenzoic acid (112 mg) as colorless powder.

Then specified in the header connection (5,80 g) was synthesized from 5-bromo-4-methoxy-2-methylbenzoic acid (4,93 g, 0,0201 mol) and phenetole manner similar to that described in the example of a 14.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.40 (t, J=7.0 Hz, 3H), 2,19 (c, 3H), 3,82 (c, 2H), a 3.87 (c, 3H), 4.00 points (kV, J=7,0 Hz, 2H), of 6.71 (c, 1H), 6,77-6,83 (m, 2H), 6,95? 7.04 baby mortality (m, 2H), 7,24 (c, 1H).

EI 335 (M+), 337 (M+2).

Example of getting 27

Synthesis of 1-bromo-4-chloro-3-(4-ethoxybenzyl)-6-methoxybenzoyl

A suspension of 2-bromo-5-chlorophenol (2.85 g, 13.7 mmol, synthesized as described in International patent publication WO 0109122), potassium carbonate (1.89 g, 13.7 mmol), n-Bu4NI (50 mg, 0,137 mmol), under the conditions (1,28 ml, 20,6 m is ol) and N,N-dimethylformamide (8.0 ml) was stirred for two hours. Added ice water and the resulting mixture was extracted twice with ethyl acetate. The combined organic phase was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=95:5)to give 2-bromo-5-chloroanisole (2,94 g, 97%) as a colorless oily substance. Next, oxalyl chloride (1.23 ml, 15.1 mmol) and N,N-dimethylformamide (2 drops) was added to 4-ethoxybenzoyl acid (2.28 g, 13.7 mmol) in chloroform (8 ml) and was stirred for five hours. The yellow oil obtained by evaporation of the solvent under reduced pressure, was dissolved in chloroform (5 ml). To this solution was added a solution of 2-bromo-5-chloroanisole (2,94 g, 13.3 mmol) in chloroform (10 ml) and then added in portions aluminium chloride (2,07 g of 15.5 mmol) at a temperature of -10°C with an interval of five minutes. The reaction mixture was stirred at 5°C for one hour, then the reaction mixture was heated to room temperature and was stirred for 13 hours. The reaction mixture was poured into ice water and was extracted three times with chloroform. Then washed with 1 M hydrochloric acid, water, salt solution, the combined organic layer was dried over anhydrous is magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography NH type silica gel (hexane:ethyl acetate=9:1)to give (5-bromo-2-chloro-6-methoxyphenyl)(4-ethoxyphenyl)methanon (1,53 g, 31%) as a colorless crystal.

Then Et3SiH (of 1.62 ml, 10.1 mmol) and BF3·Et2O (0,772 ml, 6,09 mmol) were added sequentially to a solution of (5-bromo-2-chloro-6-methoxyphenyl)(4-ethoxyphenyl)methanone (1.50 g, 4,06 mmol) in chloroform-acetonitrile (1:1; 16 ml) at a temperature of -5°C. the Reaction mixture was heated to room temperature and was stirred for 16 hours. Next, to the reaction mixture were added saturated aqueous solution of sodium carbonate and was extracted with chloroform, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=20:1), obtaining mentioned in the title compound as a colorless oily substance (1.48 g, 99%).

1H NMR (200 MHz, CHLOROFORM-d) δ ppm of 1.40 (t, J=7.0 Hz, 3H), a 3.87 (c, 3H), 3,93 (c, 2H), 4,01 (kV, J=7,0 Hz, 2H), 6,77-6,87 (m, 2H), 6.90 to (c, 1H), 7.03 is for 7.12 (m, 2H), 7,29 (c, 1 H).

EI 354 (M+), 356 (M+2), 358 (M+4).

Example of getting 28

The synthesis was carried out by a method similar to that described in the example of a 27 using 4-ethylbenzoyl acid instead of 4-ethoxybenzoyl acid.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1,22 (t, J=7,6 Hz, 3H), 2,62 (kV, J=7,6 Hz, 2H), a 3.87 (c, 3H), 3,97 (c, 2H), 6,91 (c, 1H),? 7.04 baby mortality-to 7.18 (m, 4H), 7,32 (c, 1H).

EI 338, 340, 342 (M+M+2, M+4).

An example of obtaining 29

Synthesis of 1-bromo-4-chloro-3-(4-isopropylbenzyl)-6-methoxybenzoyl

The synthesis was carried out by a method similar to that described in the example of a 27 using 4-isopropylbenzoic acid instead of ethoxybenzoyl acid.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1,24 (d, J=7,0 Hz, 6H), 2,82-to 2.94 (m, 1H), a 3.87 (c, 3H), 3,97 (c, 2H), 6,91 (c, 1H), 7,05-7,20 (m, 4H), 7,33 (c, 1H).

EI 352, 354, 356 (M+M+2, M+4).

Example 30

Synthesis of 1-benzyloxy-2-bromo-4-(4-ethoxybenzyl)-5-methylbenzol

The synthesis was carried out by a method similar to that described in the example of a 3, using 4-benzyloxy-3-bromo-6-methylbenzaldehyde instead of 3 bromobenzaldehyde.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.40 (t, J=7.0 Hz, 3H), 2,17 (c, 3H), 3,82 (c, 2H), 4.00 points (kV, J=7,0 Hz, 2H), 5,12 (c, 2H), 6,76 (c, 1H), 6,77-6,85 (m, 2H), of 6.96-7,05 (m, 2H), 7,27 (c, 1H), 7,30-7,44 (m, 3H), 7,45-7,53 (m, 2H).

EI 410 (M+), 412 (M+2).

An example of retrieving 31

Synthesis of 1-bromo-2,4-(dibenzyline)-5-(4-ethoxybenzyl)benzene

A suspension of 5-bromo-2,4-dihydroxybenzoic acid (5.0 g, 0,0215 mol), potassium carbonate (9.8 g, 0,0710 mol), n-Bu4NI (79 mg, 0.21 mmol), benzyl bromide (8,4 ml, 0,0710 mol) and N,N-dimethylformamide (40,0 ml) was stirred for 60 hours. Added ice water and the resulting mixture was extracted twice with ethyl acetate. The combined organic phase was washed with brine and dried over anhydrous magnesium sulfate.

The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure, was dissolved in tetrahydrofuran (150 ml). The resulting solution was cooled to -15°C and was added in small portions LiAlH4(1.22 g, 0,0323 mol). The mixture is then stirred at a temperature of -5° C for 1.5 hours, then was added LiAlH4(0,41 g to 0.011 mol). The reaction mixture was stirred at 5° C for one hour and was carefully added to saturated aqueous solution of ammonium chloride, and the resulting insoluble fraction was filtered through celite. Then the filtrate was extracted with ethyl acetate, the organic layer washed with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate and salt solution and then dried over anhydrous magnesium sulfate. The desiccant was filtered, then the solvent is evaporated under reduced pressure, obtaining 5-bromo-2,4-(dibenzyline)benzyl alcohol (12.1 g), which was used in the next reaction without purification.

Manganese dioxide (IV) (13,1 g, 0,150 mol) was added to a solution of 5-bro who -2,4-(dibenzyline)benzyl alcohol (12.1 g) in toluene (150 ml). This mixture was stirred at room temperature for 15 hours and further stirred at a temperature of 80°C for four hours and at a temperature of 100°C for two hours. Next was added manganese dioxide (IV) (4.0 g) and the mixture was stirred at 100°C for four hours. The reaction mixture was cooled to room temperature and the insoluble fraction was filtered through celite. The solid substance obtained by concentration of the filtrate, recrystallized from a solvent mixture of hexane - ethyl acetate, receiving 5-bromo-2,4-(dibenzyline)benzaldehyde (3.6 g, 43%) as a colorless powder.

Then specify in the title compound was synthesized by the method described in the example of a 3, using 5-bromo-2,4-(dibenzyline)benzaldehyde instead of 3-bromobenzaldehyde.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.40 (t, J=7.0 Hz, 3H), 3,84 (c, 2H), 4,01 (kV, J=7,0 Hz, 2H), 4,96 (c, 2H), 5,07 (c, 2H), 6,53 (c, 1H), 6.75 in-PC 6.82 (m, 2H), 7,02-7,10 (m, 2H), 7,20-of 7.48 (m, 11H).

EI 525 (M+), 527 (M+2).

Example of getting 32

Synthesis of 1-bromo-2-methoxy-4-methyl-5-(4-methylbenzyl)benzene

Oxalyl chloride (3,43 ml, 0,0400 mmol) and N,N-dimethylformamide (2 drops) was added to a solution of 4-methoxy-2-methylbenzoic acid (5.0 g, 0,0300 mol) in chloroform (60 ml). The reaction mixture was stirred at room temperature for one hour, then the solvent is evaporated under reduced Yes the tion. The obtained yellow oily substance was dissolved in chloroform (60 ml). In terms of cooling in an ice bath to this solution was added toluene (3,52 ml, 0,0330 mol) and aluminum chloride (8,02 g, 0,0601 mol) and the reaction mixture was stirred for three hours and a half, continuing the cooling of the reaction mixture in an ice bath. It was further added to the reaction mixture 5% hydrochloric acid and was extracted with chloroform, the organic phase is washed with 10% hydrochloric acid, water, saturated aqueous sodium bicarbonate and the salt solution and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=15:1)to give (4-methoxy-2-were)(4-were)methanon (4.26 deaths grams of 58.9%) as a yellow oily substance.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2,39 (c, 3H), 2,42 (c, 3H), 3,86 (c, 3H), 6,74 (DD, J=8,5, of 2.56 Hz, 1H), for 6.81 (d, J=2.6 Hz, 1H), 7,21-7,27 (m, 2H), 7,31 (d, J=8,4 Hz, 1H), of 7.64-7,71 (m, 2H).

ESI m/z = 263 (M+Na)

Et3SiH (8.5 ml, 0,0531 mol) was added dropwise to a mixture of solutions of 4-methoxy-2-were)(4-were)methanone and BF3·Et2O (4.5 ml, 0,0354 mol) in chloroform (8 ml) and acetonitrile (32 ml), cooling in an ice bath. The reaction mixture was heated to room temperature and displacement is ivali at 50°C for one hour. Then to the reaction mixture were added saturated aqueous solution of sodium bicarbonate and was extracted with ethyl acetate, the conditions of cooling in an ice bath, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=15:1)to give 4-methoxy-2-methyl-1-(4-methylbenzyl)benzene (3,89 g, 97%) as a colorless oily substance.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2,21 (c, 3H), 2,31 (c, 3H), 3,78 (c, 3H), 3,88 (c, 2H), 6,65-6,74 (m, 2H), 6,97-7,03 (m, 3H), 7.03 is-7,11 (m, 2H).

EI 226 (M+)

Br2was added dropwise to a solution of 4-methoxy-2-methyl-1-(4-methylbenzyl)benzene in acetic acid (35 ml), under conditions of cooling in an ice bath. The reaction mixture was stirred at 110°C for two hours. Then to the reaction mixture was added water, in conditions of cooling in an ice bath, and extracted with ethyl acetate, the organic phase is washed with saturated aqueous sodium bicarbonate solution and the salt solution and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (GE is San:ethyl acetate=15:1), getting listed in the title compound as a yellow oily substance (4,21 g, 80%).

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2,20 (c, 3H), 2,31 (c, 3H), 3,85 (c, 2H), a 3.87 (c, 3H), of 6.71 (c, 1H), 6,94-7,11 (m, 4H), 7,26 (c, 1H).

EI 304 (M+), 306 (M+2).

An example of obtaining 33

Synthesis of 1-bromo-2-methoxy-4-methyl-5-(4-active compounds)benzene

Specified in the title compound was synthesized by a method similar to that described in the example of a 32 using ethylbenzene instead of toluene.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1,22 (t, J=7,6 Hz, 3H), 2,20 (c, 3H), 2,61 (kV, J=7,6 Hz, 2H), 3,85 (c, 2H), a 3.87 (c, 3H), of 6.71 (c, 1H), 6,97-7,14 (m, 4H), 7,27 (c, 1H).

EI 318 (M+).

An example of retrieving 34

Synthesis of 1-bromo-2-methoxy-4-methyl-5-(4-isopropylbenzyl)benzene

Specified in the title compound was synthesized by a method similar to that described in the example of a 32 using cumin instead of toluene.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1,22 (c, 3H), 1,24 (c, 3H), 2,21 (c, 3H), 2,81 of 2.92 (m, 1H), 3,85 (Sirs, 2H), a 3.87 (c, 3H), of 6.71 (c, 1H), 6,98-7,06 (m, 2H), 7,10-7,16 (m, 2 H), 7,28 (c, 1H).

EI 322 (M+), 334 (M+2).

Example of getting 35

Synthesis of 2-(4-active compounds)phenol

1-Bromo-4-ethylbenzene (6,69 g, being 0.036 mol) was added to a suspension of magnesium (17,2 g) and tetrahydrofuran (50 ml) and boiled under reflux. Subsequently, the solution was added 1-bromo-4-ethylbenzene (97.9 g, 0,529 mol) in tetrahydrofuran (300 ml) for two hours at room temperature the re. Then was stirred at room temperature for 1.5 hours, the reaction mixture was cooled to 4°C and the solution was added 2-benzyloxybenzaldehyde (100 g, 0,471 mol) in tetrahydrofuran (100 ml) for one hour. After this was stirred for two hours, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate, the organic phase was washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=95:5)to give (2-benzyloxyphenyl)(4-ethylphenyl)methanol (152 g) as a colourless solid.

1H-NMR(CDCl3) δ of 1.23 (t, J=7,6 Hz, 3H), 2,64 (kV, J=7,6 Hz, 2H), 2,90 (d, J=5.6 Hz, 1H), to 5.03 (s, 2H), 6,03 (d, 1H, J=5.6 Hz), 6.90 to-7,37 (m, 12H).

Then a mixture of (2-benzyloxyphenyl)(4-ethylphenyl)methanol (78,5 g), 10% palladium on charcoal (5,2 g), conc. hydrochloric acid (10.4 ml) and methanol (850 ml) was stirred in hydrogen atmosphere at room temperature for 24 hours. The insoluble fraction was filtered, then the filtrate is evaporated under reduced pressure and then the residue person to distil under reduced pressure, obtaining specified in the header connection (56,8 g) in sidebusting oil.

1H-NMR(CDCl3) δ ppm to 1.21 (t, J=7.7 Hz, 3H), 2,62 (kV, J=7.7 Hz, 2H), 4.00 points (c, 2H), with 4.64 (s, 1H), 6,77-to 7.18 (m, 8H).

EI 213 (M+H).

Example of getting 36

Synthesis of 3-(4-ethyleneoxy)-bromine benzol

A suspension of 3-bromophenol (2.3 g, 13.3 mmol), 4-ethylvinylbenzene acid (1.0 g, to 6.67 mmol), molecular sieve 4Å (14,7 g), Cu(OAc)2(1,21 g, to 6.67 mmol) and chloroform (25 ml) was stirred at room temperature for three minutes, and added to it triethylamine (3.6 ml) and pyridine (2.7 ml). The insoluble fraction was filtered through celite, and then the mixture was stirred for 15 hours. The filtrate was concentrated, then the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=95:5), receiving specified in the title compound (1.89 g) as a colorless oily substance.

EI 276 (M+), 278 (M+2).

An example of retrieving 37

Synthesis of 3-bromo-5-(4-ethoxybenzyl)pyridine

A solution of 3,5-dibromopyridine (5 g, 0,0211 mol) in tetrahydrofuran (25 ml) was added dropwise to a mixture of 1 M solution isopropylated magnesium in tetrahydrofuran (21.1 ml) and tetrahydrofuran (10 ml) at 4°C for 15 minutes. Then was stirred at room temperature for 2.5 hours, the reaction mixture was added 4-ethoxybenzaldehyde (2,93 ml, 0,0211 mol) and was stirred over the next 1.5 hours. Then to the reaction mixture was added water, slaveholding in an ice bath and extracted with ethyl acetate, the organic phase was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1)to give (5-bromopyridin-3-yl)(4-ethoxyphenyl)methanol (5.0 g, 77%) as a yellow oily substance.

Then triperoxonane acid (12.5 ml, rate £ 0.162 mol) was added dropwise to a solution of (5-bromopyridin-3-yl)(4-ethoxyphenyl)methanol (2.5 g, 8,11 mmol) in chloroform and Et3SiH (5,1 ml of 40.6 mmol) at 4°C and was stirred at room temperature for 2.5 hours. To the reaction mixture was added water and was extracted with chloroform. It was further washed with brine, the organic phase was dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1), obtaining mentioned in the title compound in the form of colorless needle-like formations (1,83 g, 77%).

1H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.41 (t, J=6,99 Hz, 3H), 3,90 (c, 2H), was 4.02 (q, J=6,99 Hz, 2H), 6,85 (d, J=to 8.70 Hz, 2H), 7,07 (d, J=to 8.70 Hz, 2H), to 7.59 (t, J=2,02 Hz, 1H), 8,40 (c, 1H), charged 8.52 (c, 1H).

ESI m/z = 292 (M+H), 294 (M+2+H).

An example of retrieving 38

Synthesis of 1-bromo-3-[(2E, or Z)3-(4-ethylphenyl)prop-2-EN-1-yl]benzene

To a mixture of (4-active compounds)triphenylphosphonium chloride (3,52 g, 8,44 mmol) and tetrahydrofuran (20 ml) was added 2 M Diisopropylamine Li (a solution of heptane/tetrahydrofuran/ethylbenzene, of 4.2 ml, 8.4 mmol)in terms of cooling in an ice bath and stirred at room temperature for one hour. This solution was added dropwise to a solution of (3-bromophenyl)acetaldehyde (0.56 g of 2.81 mmol) in tetrahydrofuran (10 ml) and stirred at room temperature for one hour. Then to the reaction mixture were added saturated aqueous solution of ammonium chloride, under conditions of cooling in an ice bath, and extracted with ethyl acetate, the organic phase was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:chloroform=20:1), obtaining specified in the header connection (0,41 g, 50%, E/Z mixture) as a colorless oily education.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1,17-of 1.30 (m, J=7,41, 7,41, 7,41 Hz, 3H), 2,56-of 2.72 (m, 2H), 3,47-3,68 (m, 2H), 5,70-6,63 (m, 2H),? 7.04 baby mortality-7,46 (m, 8H).

EI 300, 302 (M+M+2).

An example of retrieving 39

Synthesis of 3-bromo-7-(4-methylbenzyl)-1-benzothiophene

To a solution of 7-(4-methylbenzyl)-1-benzothiophene (1.24 g, 5,20 mmol) in acetonitrile (30 ml) was added the N-bromosuccinimide (1.01 g, 5,72 mmol) and stirred at room temperature for two hours. The solvent is evaporated under reduced pressure and diluted with ethyl acetate. Then washed with 20 wt.% aqueous sodium thiosulfate solution and a salt solution, the organic phase was dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=100:1 - 50:1), getting listed in the title compound (0,92 g, 56%) as a colorless powder.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2,31 (c, 3H), 4,12-4.26 deaths (m, 2H), 7,07-of 7.23 (m, 5H), 7,37-to 7.50 (m, 2H), 7,72 (d, J=7,46 Hz, 1H).

EI 316, 318 (M+M+2).

Example 1

Synthesis of 2,3,4,6-Tetra-O-benzyl-1-C-[3-(4-active compounds)phenyl]-5-thio-D-glucopyranose

A mixture of magnesium (55 mg, 2.25 mmol), 1-bromo-3-(4-active compounds)benzene (496 mg, of 1.80 mmol, synthesized as described in International patent publication WO 0127128), and tetrahydrofuran (2.0 ml) was boiled under reflux for one hour. Next, the reaction mixture was stirred at room temperature for one hour and then cooled to 0°C. To this solution was added dropwise a solution of 2,3,4,6-Tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (500 mg, of 0.901 mmol) in tetrahydrofuran (5.0 ml) and displaced ivali at room temperature for one hour. Then to the reaction mixture were added saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate, the organic phase was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1), obtaining mentioned in the title compound (440 mg, 65%) as a colorless oily substance.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1,19 (t, J=7,6 Hz, 3H), 2,59 (kV, J=7,6 Hz, 2H), 3.04 from (c, 1H), 3,48 is 3.57 (m, 1H), 3,64 (DD, J=10,1, 2.7 Hz, 1H), 3,74 (d, J=10.1 Hz, 1H), 3,88-4,17 (m, 6H), to 4.41 (d, J=10.1 Hz, 1H), to 4.52 (c, 2H)and 4.65 (d, J=10,7 Hz, 1H), 4,81-of 4.95 (m, 3H), 6,67-6,74 (m, 2H), 7.03 is-7,21 (m, 10H), 7,22 and 7.36 (m, 14H), 7,47-EUR 7.57 (m, 2H).

ESI m/z = 773 (M+Na).

Example 2

Synthesis of 2,3,4,6-Tetra-O-benzyl-1-C-[3-(4-active compounds)phenyl]-5-thio-D-glucopyranose through complex ate

A mixture of 1-bromo-3-(4-active compounds)benzene (1.0 g, 3.63 mmol) and diethyl ether (10 ml) was cooled to -78°C and added to it a solution of 2.6 M n-utility hexane (1.4 ml) in an argon atmosphere. Then was stirred for 20 minutes, then the reaction mixture was heated to -20°C and was stirred for 45 minutes. The resulting solution was added dropwise to a suspension of CuI (347 mg, 1.82 mmol) in diethyl ether (10 ml)using a cannula. Suspension, acquired a black color in the process poupelin the th add, was heated to -9°C. Upon completion pocataligo add the suspension was stirred at -15°C for 15 minutes and added dropwise a solution of 2,3,4,6-Tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (671 mg, 1,21 mmol) in diethyl ether (4.0 ml)and the resulting mixture was stirred for 20 minutes. Next, to the reaction mixture were added saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate, the organic phase was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1), obtaining mentioned in the title compound (1.0 g) as a colorless oily substance. The NMR spectrum corresponds to the NMR spectrum, shown in example 1.

Example 3

Synthesis of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-(4-active compounds)phenyl]-1-thio-D-glucitol

To a solution of 2,3,4,6-Tetra-O-benzyl-1-C-[3-(4-active compounds)phenyl]-5-thio-D-glucopyranose (410 mg, 0,546 mmol) in dichloromethane (20 ml), was added Et3SiH (0,523 ml of 3.28 mmol) and BF3·Et2O (0,276 ml of 2.18 mmol) at a temperature of -18°C and was stirred for 0.5 hours. Then to the reaction mixture were added saturated aqueous solution of bicarbonate of soda which I and was extracted with chloroform, the organic phase was washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1), obtaining mentioned in the title compound (250 mg, 62%) as colorless powder.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1,19 (t, J=7,6 Hz, 3H), 2,59 (kV, J=7,6 Hz, 2H), 3,05-and 3.16 (m, 1H), 3,53 (t, J=8,9 Hz, 1H), 3,67-3,99 (m, 8H), 4,47 (d, J=10.0 Hz, 1H), 4.53-in (c, 2H), 4,60 (d, J=10,7 Hz, 1H), 4,85-4,94 (m, 3H), 6,62-6,69 (m, 2H), 7,00-7,20 (m, 10 H), 7,22 and 7.36 (m, 16H).

ESI m/z = 757 (M+Na).

TPL 100,0-102,5°C.

Example 4

Synthesis of (1S)-1,5-anhydrous-1-[3-(4-active compounds)phenyl]-1-thio-D-glucitol

1 M solution of BBr3in dichloromethane (4,08 ml) was added dropwise to a solution of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-(4-active compounds)phenyl]-1-thio-D-glucitol (200 mg, 0,272 mmol) in dichloromethane (20 ml) at -78°C. the resulting mixture was stirred at this temperature for 2.5 hours, then the mixture was sequentially added methanol (5.0 ml) and pyridine (3.0 ml). The reaction mixture was heated to room temperature and concentrated. The obtained residue was purified by column chromatography on silica gel (chloroform:methanol=10:1), obtaining mentioned in the title compound (23 mg, 23%) as bestwe the aqueous amorphous substance.

1H NMR (300 MHz, METHANOL-d4) δ ppm 1,19 (t, J=7,6 Hz, 3H), 2,58 (kV, J=7,6 Hz, 2H), 2.95 and-3,03 (m, 1H), 3,20 of 3.28 (m, 1H), 3,60 (DD, J=10,3, 9.0 Hz, 1H), 3,70-of 3.78 (m, 3H), 3,88-3,98 (m, 3H), 7,09 (Sirs, 5H), 7,17-of 7.23 (m, 3H).

ESI m/z = 397 (M+Na), 373 (M-H).

Example 5

Synthesis of 2,3,4,6-Tetra-O-benzyl-1-C-[2-methoxy-4-methyl-(4-ethoxybenzyl)phenyl]-5-thio-D-glucopyranose

Five drops of 1,2-dibromoethane was added to a mixture of magnesium (41 mg, 1,67 mmol), 1-bromo-3-(4-ethoxybenzyl)-6-methoxy-4-methylbenzene (0.51 g, is 1.51 mmol) and tetrahydrofuran (2 ml). Then this mixture is boiled under reflux for one hour, then to obtain a Grignard reagent, the reaction mixture was cooled at room temperature. 1.0 M solution of Isopropylamine magnesium in tetrahydrofuran (1,40 ml) and the resulting Grignard reagent was added dropwise to a solution of 2,3,4,6-Tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (0,76 g, 1.38 mmol) in tetrahydrofuran (5 ml), under conditions of cooling in an ice bath, and then the mixture was stirred for 30 minutes. Next, to the reaction mixture were added saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate, the organic phase was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure, was purified through a column of chromatogr is the philosophy on silica gel (hexane:ethyl acetate=4:1), receiving (from 0.76 g, 68%) of a yellow oily specified in the header of the connection.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1,37 (t, J=6,92 Hz, 3H), 2,21 (c, 3H), 3,51-4,20 (m, 12H), 3,85-to 3.89 (m, 3H), 4,51 (c, 2H)and 4.65 (d, J=of 10.72 Hz, 1H), 4,71 (d, J=5,75 Hz, 1H), 4,78-4,99 (m, 3H), 6,59-the 7.43 (m, 26H).

Example 6

Synthesis of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-methoxy-4-methyl-5-(4-ethoxybenzyl)phenyl]-1-thio-D-glucitol

To a solution of 2,3,4,6-Tetra-O-benzyl-1-C-[2-methoxy-4-methyl-5-(4-ethoxybenzyl)phenyl]-5-thio-D-glucopyranose (840 mg, 1.04 mmol) in acetonitrile (18 ml) was added sequentially Et3SiH (0,415 ml, 2,60 mmol) and BF3·Et2O (0,198 ml, 1.56 mmol) at a temperature of -18°C and was stirred for one hour. Then the reaction mixture was added saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate, the organic phase was washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1), obtaining mentioned in the title compound (640 mg, 77%).

1H NMR (600 MHz, CHLOROFORM-d) δ ppm of 1.35 (t, J=6,88 Hz, 3H), 2,21 (c, 3H), 3,02-is 3.21 (m, 1H), 3,55 (t, J=9,40 Hz, 1H), 3,71 (c, 1H), 3,74-of 3.97 (m, 10H), 4,01 (c, 1H), 4,45-4,56 (m, 3H), 4,60 (d, J=10,55 Hz, 2H), 4,86 (c, 2H), the 4.90 (d, J=10,55 Hz, 1H), 6,58-6,76 (m, 5H), of 6.90 (d, J=7,34 Hz, 1H), 7,097,19 (m, 5H), 7.23 percent-to 7.35 (m, 15H).

ESI m/z = 812 (M+NH4).

Example 7

Synthesis of (1S)-1,5-anhydrous-1-[3-(4-ethoxybenzyl)-6-methoxy-4-were]-1-thio-D-glucitol

A mixture of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-methoxy-4-methyl-5-(4-ethoxybenzyl)phenyl]-1-thio-D-glucitol (630 mg, 0,792 mmol), 20% palladium hydroxide on charcoal (650 mg) and ethyl acetate (10 ml) - ethanol (10 ml) was stirred in hydrogen atmosphere at room temperature for 66 hours. The insoluble fraction of the reaction mixture was filtered through celite and the filtrate was concentrated. The obtained residue was purified by column chromatography on silica gel (chloroform:methanol=10:1), obtaining specified in the header colorless powdery compound (280 mg, 81%) as a 0.5 hydrate.

1H NMR (600 MHz, METHANOL-d4) δ ppm of 1.35 (t, J=6.9 Hz, 3H), 2,17 (c, 3H), 2,92-a 3.01 (m, 1H), 3,24 (t, J=8,71 Hz, 1H), 3,54-of 3.60 (m, 1H), and 3.72 (DD, J=11,5, 6.4 Hz, 1H), 3,81 (c, 3H), 3,83 (c, 2H), 3,94 (DD, J=11,5, and 3.7 Hz, 1H), 3,97 (kV, J=6,9 Hz, 2H), 4,33 (c, 1H), 6,77 (d, J=8,3 Hz, 2H), 6,76 (c, 1H), 6,99 (d, J=8,3 Hz, 2H), 7,10 (c, 1H).

ESI m/z = 452 (M+NH4+), 493 (M+CH3CO2-). So 155,0-157,0°C. Anal. Rasch. for C23H30O6S·0,5H2O: C, 62,28; H, 7,06. Found: C, 62,39; H, 7,10.

Example 8

Synthesis of 2,3,4,6-Tetra-O-benzyl-1-C-[2-(benzyloxy)-5-(4-ethoxybenzyl)phenyl]-5-thio-D-glucopyranose

Three drops of 1,2-dibromethane dobavlyali mixture of magnesium (175 mg, 7.20 mmol), 1-(benzyloxy)-2-bromo-4-(4-ethoxybenzyl)benzene (to 2.29 g, USD 5.76 mmol) and tetrahydrofuran (6.0 ml) and the mixture was boiled under reflux for one hour. The reaction mixture was cooled to room temperature and a solution of 2,3,4,6-Tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (1.6 g, 2.9 mmol) in tetrahydrofuran (5.0 ml) was added dropwise to this solution and stirred at room temperature for one hour. Then to the reaction mixture were added saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate, the organic phase was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=6:1), obtaining mentioned in the title compound (1.48 g, 59%) as pale yellow powder.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm to 1.38 (t, J=7.0 Hz, 3H), 3,48-3,71 (m, 2H), of 3.77-4,10 (m, 9 H), 4,51 (Sirs, 2H), 4,59-4,74 (m, 2H), 4,77-4,94 (m, 3H), 5,09 (c, 2H), 6,64-7,40 (m, 32 H).

ESI m/z = 895 (M+Na).

Example 9

Synthesis of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-(4-ethoxybenzyl)phenyl]-1-thio-D-glucitol

To a solution of 2,3,4,6-Tetra-O-benzyl-1-C-[2-(benzyloxy)-5-(4-ethoxybenzyl)phenyl]-5-thio-D-glucopyranose (850 mg, 0,974 mmol) in chlorofo the IU (8.0 ml) and acetonitrile (8.0 ml) was added sequentially Et 3SiH (0,933 ml of 5.84 mmol) and BF3·Et2O (0,494 ml, 3.90 mmol) at -20°C and was stirred for one hour. Next, to the reaction mixture were added saturated aqueous sodium bicarbonate solution and was extracted with chloroform, the organic phase was washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=8:1), obtaining mentioned in the title compound (810 mg, 97%) as a colorless powder.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.36 (t, J=7.0 Hz, 3H), 3.04 from-3,18 (m, 1H), 3,54 (t, J=8,4 Hz, 1H), 3,65 is 3.76 (m, 1H), of 3.77-4,06 (m, 8H), 4,40-to 4.73 (m, 5H), a 4.83-5,12 (m, 5H), 6,62-6,87 (m, 5 H), 6,92-7,46 (m, 27H).

ESI m/z = 879 (M+Na).

Example 10

Synthesis of (1S)-1,5-anhydrous-1-[5-(4-active compounds)-2-hydroxyphenyl]-1-thio-D-glucitol

A mixture of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-(4-ethoxybenzyl)phenyl]-1-thio-D-glucitol (810 mg, 0,954 mmol), 20% palladium hydroxide on charcoal (800 mg) and ethyl acetate (5.0 ml) - ethanol (5.0 ml) was stirred in hydrogen atmosphere at room temperature for 46 hours. Insoluble precipitation reaction mixture was filtered through celite and the filtrate was concentrated. The obtained residue was purified by means the PTO column chromatography on silica gel (chloroform:methanol=10:1 - 5:1), obtaining specified in the header colorless powdery compound (202 mg, 53%) as of 0.7-hydrate.

1H NMR (300 MHz, METHANOL-d4) δ ppm 1,37 (t, J=7.0 Hz, 3H), 2,94 was 3.05 (m, 1H), 3,22-3,29 (m, 1H), 3,60 (m, 1H), 3,69-3,88 (m, 4H), 3,90-Android 4.04 (m, 3H), 4,33 (d, J=a 10.6 Hz, 1H), of 6.71 (d, J=8,2 Hz, 1H), 6,76-of 6.90 (m, 3H), 7.03 is-to 7.15 (m, 3H).

ESI m/z = 429 (M+Na), 405 (M-H). TPL 145,0-150,s. Anal. Rasch. for C22H28O6S·0,7H2O: C, 61,00; H, 6,86. Found: C, 60,81; H, 6.89 In.

Example 11

Synthesis of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[4-chloro-3-(4-ethoxy-2-methylbenzyl)phenyl]-1-thio-D-glucitol

Five drops of 1,2-dibromoethane was added to a mixture of magnesium (1,11 g of 45.7 mmol), 2-(5-bromo-2-chlorophenyl)-1,3-dioxolane (for 9.64 g of 36.5 mmol) and tetrahydrofuran (20 ml), and the mixture is boiled under reflux for two hours. The reaction mixture was cooled to room temperature and was added to this solution dropwise a solution of 2,3,4,6-Tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (10,14 g of 36.5 mmol) in tetrahydrofuran (15 ml) and stirred at room temperature for 30 minutes. Then to the reaction mixture were added saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate, the organic phase was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure, cleaned the if via column chromatography on silica gel (hexane:ethyl acetate=4:1 - 3:1)to give 2,3,4,6-Tetra-O-benzyl-1-C-[4-chloro-3-(1,3-dioxolane-2-yl)phenyl]-5-thio-D-glucopyranose (11,81 g, 87%) as a colorless amorphous substance.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,06 (c, 1H), 3,47-to 3.58 (m, 1H), 3,64 (DD, J=10,0, 2,9 Hz, 1H), 3,83-is 4.21 (m, 9 H), 4,48-4,56 (m, 3H), of 4.66 (d, J=a 10.6 Hz, 1H), 4,82-equal to 4.97 (m, 3H), 6,15 (c, 1H), 6,77 (DD, J=7,9, 1.5 Hz, 2H), 7,08-7,21 (m, 5H), 7.23 percent-7,37 (m, 14H), 7,55 (DD, J=8,4, 2.5 Hz, 1H), 7,92 (d, J=2.5 Hz, 1H).

Then 6 M hydrochloric acid solution (120 ml) was added to a solution of 2,3,4,6-Tetra-O-benzyl-1-C-[4-chloro-3-(1,3-dioxolane-2-yl)phenyl]-5-thio-D-glucopyranose (6,01 g, 8,12 mmol) in tetrahydrofuran (50 ml), cooling in an ice bath and stirred at room temperature for two days. To the reaction mixture were added ice water and was extracted with ethyl acetate, and the organic phase was washed with saturated aqueous sodium bicarbonate solution, salt solution and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1)to give 2,3,4,6-Tetra-O-benzyl-1-C-(4-chloro-3-formylphenyl)-5-thio-D-glucopyranose (4,53 g, 80%) of colorless amorphous substance.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,14 (c, 1H), 3.43 points-to 3.58 (m, 1H), 3,63 (DD, J=10,0, 2.6 Hz, 1H), a 3.87-4,16 (m, 5H), of 4.45-4.72 in (m,4 H), 4,80-of 5.05 (m, 3H), 6.73 x (d, J=7.8 Hz, 2H), 7,02-the 7.43 (m, 19H), 7,74 (DD, J=8,4, 2.5 Hz, 1H), of 8.06 (d, J=2.5 Hz, 1H), accounted for 10.39 (c, 1H).

Then 2.6 M solution of n-utilitiesman (1.6 ml) was added to a mixture of 1-bromo-4-ethoxy-2-methylbenzene (0,94 g, 4,37 mmol) and tetrahydrofuran (12 ml) at -78°C. this was stirred for one hour, to the mixture was added a solution of 2,3,4,6-Tetra-O-benzyl-1-C-(4-chloro-3-formylphenyl)-5-thio-D-glucopyranose (1.52 g, to 2.18 mmol) in tetrahydrofuran (10 ml) and then was stirred for 20 minutes, and the reaction mixture was heated to room temperature. Then to the reaction mixture were added saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate, the organic phase was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1)to give 2,3,4,6-Tetra-O-benzyl-1-C-{4-chloro-3-[(4-ethoxy-2-were)(hydroxy)methyl]phenyl}-5-thio-D-glucopyranose (1,72 g, 95%) as a yellow amorphous diastereomeric mixture.

Then to a solution of 2,3,4,6-Tetra-O-benzyl-1-C-{4-chloro-3-[(4-ethoxy-2-were)(hydroxy)methyl]phenyl}-5-thio-D-glucopyranose (1,72 g of 2.06 mmol) in acetonitrile (20 ml) was added sequentially Et3SiH (1,98 ml, 12.4 mmol) and BF3·Et2O (1,04 ml of 8.27 mmol), y is s cooling in an ice bath. Then was stirred for one hour, the reaction mixture was heated to room temperature and was stirred for three hours. Next, to the reaction mixture were added saturated aqueous solution of sodium carbonate and was extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1)to give (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[4-chloro-3-(4-ethoxy-2-methylbenzyl)phenyl]-1-thio-D-glucitol (1.01 g, 61%) as a colorless powder.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.40 (t, J=7.0 Hz, 3H), 2,14 (c, 3H), 3,01-of 3.12 (m, 1H), 3,48 (t, J=8,9 Hz, 1H), 3,65-4,06 (m, 10H), 4,46-br4.61 (m, 4H), 4.80 to 4,91 (m, 3H), return of 6.58 (DD, J=8,2, 2.5 Hz, 1H), 6,68-6,76 (m, 2H,), for 6.81 (d, J=8,4 Hz, 1H), 6,98 (d, J=2.2 Hz, 1H), 7,10-7,39 (m, 21H).

Example 12

Synthesis of (1S)-1,5-anhydrous-1-[4-chloro-3-(4-ethoxy-2-methylbenzyl)phenyl]-1-thio-D-glucitol

To a solution of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[4-chloro-3-(4-ethoxy-2-methylbenzyl)phenyl]-1-thio-D-glucitol (0,99 g of 1.23 mmol) in anisole (10 ml) was added AlCl3(0,83 g, to 6.19 mmol) at room temperature and was stirred for 30 minutes. To the reaction mixture were added ice water and was extracted with ethyl acetate, and the organic phase p is washed 1 M hydrochloric acid, saturated aqueous sodium bicarbonate, salt solution and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (chloroform:methanol=10:1), obtaining mentioned in the title compound (55 mg, 10%) as a colorless amorphous substance.

1H NMR (300 MHz, METHANOL-d4) δ ppm 1,37 (t, J=6.9 Hz, 3H), 2,17 (c, 3H), 2,90-a 3.01 (m, 1H), 3,14-3,24 (m, 1H), 3,54 (DD, J=10,3, and 9.2 Hz, 1H), 3,60 is 3.76 (m, 3H), 3,86-4,06 (m, 5H), of 6.66 (DD, J=8,6, 2.7 Hz, 1H), 6.75 in (d, J=3.0 Hz, 1H), 6,85-to 6.95 (m, 2H), 7,19 (DD, J=8,2, 2.2 Hz, 1H), 7,35 (d, J=8,2 Hz, 1H).

ESI m/z = 461 (M+Na), 437 (M-H).

Example 13

Synthesis of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-[4-(4-tetrahydropyranyloxy)benzyl]phenyl]-1-thio-D-glucitol

2.6 M solution of n-utilitiesman (0.8 ml) was added to a mixture of 1-bromo-4-(4-tetrahydropyranyloxy)benzene (0,545 g, 2,12 mmol) and tetrahydrofuran (6 ml) at -78°C. Then stirred for 1.5 hours, was added a solution of 2,3,4,6-Tetra-O-benzyl-1-C-(3-formylphenyl)-5-thio-D-glucopyranose (0,70 g, 1.06 mmol) in tetrahydrofuran (8 ml) and further stirred for three hours, and the reaction the mixture was heated to room temperature. Then to the reaction mixture were added saturated aqueous solution of sodium carbonate and was extracted with etilize is that the organic layer was washed with brine, dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1)to give 2,3,4,6-Tetra-O-benzyl-1-C-[3-[(4-(4-tetrahydropyranyloxy)phenyl)(hydroxy)methyl]phenyl]-5-thio-D-glucopyranose (0,67 g, 76%).

Then to a solution of 2,3,4,6-Tetra-O-benzyl-1-C-[3-[(4-(4-tetrahydropyranyloxy)phenyl)(hydroxy)methyl]phenyl]-5-thio-D-glucopyranose (0,67 g, 0,802 mmol) in acetonitrile (8 ml) was added sequentially Et3SiH (0,78 ml of 4.90 mmol) and BF3·Et2O (0,41 ml of 3.27 mmol) at -15°C. this was stirred for one hour, the reaction mixture was heated to room temperature and was stirred for three hours. Then to the reaction mixture were added saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1), obtaining mentioned in the title compound (0,37 g, 57%) as a colorless powder.

1H NMR (300 MHz, CHLOROFORM-) δ ppm 1,66-of 1.81 (m, 2H), 1,88-2,02 (m, 2H), 3,05 is 3.15 (m, 1H), 3,47-3,59 (m, 3H), 3,64-4,00 (m, 10 H), 4,33 was 4.42 (m, 1H), 4,46 (d, J=9,95 Hz, 1H), to 4.52 (c, 2H), 4,60 (d, J=10,41 Hz, 1H), 4,84-is 4.93 (m, 3H), 6,60 is 6.67 (m, 2H), 6,72-6,79 (m, 2H), 6,99-7,19 (m, 8H), 7,20-7,35 (m, 16H).

ESI m/z=824 (M+NH4).

Example 14

Synthesis of (1S)-1,5-anhydrous-1-[3-[4-(4-tetrahydropyranyloxy)benzyl]phenyl]-1-thio-D-glucitol

Specified in the header of the amorphous compound (18 mg) was obtained by the method similar to that described in example 7 from (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-[4-(4-tetrahydropyranyloxy)benzyl]phenyl]-1-thio-D-glucitol.

Example 15

Synthesis of 2,3,4,6-Tetra-O-allyl-1-C-[4-chloro-5-(4-ethoxybenzyl)-2-methoxyphenyl]-5-thio-D-glucopyranose

Three drops of 1,2-dibromoethane was added to a mixture of magnesium (171 mg, 7.03 mmol), 1-bromo-4-chloro-3-(4-ethoxybenzyl)-6-methoxybenzene (2.0 g, 5,62 mmol) and tetrahydrofuran (5 ml) and the resulting mixture was boiled under reflux for 30 minutes. The reaction mixture was cooled to room temperature and to this solution was added dropwise a solution of 2,3,4,6-Tetra-O-allyl-5-thio-D-glucono-1,5-lactone (1.5 g, 4,22 mmol) in tetrahydrofuran (20 ml) and stirred at room temperature for two hours. Then to the reaction mixture were added saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous is magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=6:1 → 5:1), getting listed in the title compound (1,41 g, 53%) as a pale yellow oil.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.39 in (t, J=7.0 Hz, 3H), 3,36-3,47 (m, 1H), 3,49-4,10 (m, 17H), 4,10-of 4.44 (m, 4H), 4,84 is equal to 4.97 (m, 2H), 5.08 to to 5.35 (m, 5H), 5,42-the ceiling of 5.60 (m, 1H), 5,75-6,07 (m, 3H), 6,78 (d, J=8.6 Hz, 2H), 6,92 (c, 1H), 7,03 (d, J=8.6 Hz, 2H), 7,32 (Sirs, 1H).

ESI m/z = 653 (M+Na), 655 (M+2+Na).

Example 16

Synthesis of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-allyl-1-[4-chloro-5-(4-ethoxybenzyl)-2-methoxyphenyl]-1-thio-D-glucitol

To a solution of 2,3,4,6-Tetra-O-allyl-1-C-[4-chloro-5-(4-ethoxybenzyl)-2-methoxyphenyl]-5-thio-D-glucopyranose (1,41 g of 2.23 mmol) in chloroform (20 ml) - acetonitrile (20 ml) was added sequentially Et3SiH (2,16 ml of 13.4 mmol) and BF3·Et2O (1.13 ml, of 8.92 mmol) at -15°C and was stirred for one hour. Then to the reaction mixture were added saturated aqueous sodium bicarbonate solution and was extracted with chloroform, the organic phase was washed with brine, dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1), getting listed in the title compound (895 mg, 65%) as colorless powder.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.39 in (t, J=7.0 Hz, 3H), 2.95 and totaling 3.04 (m, 1H), 3,21-3,30 (m, 1H), 3,41-with 3.79 (m, 5H), 3,81 (c, 3H), 3,84-4,20 (m, 8H), 4,25 was 4.42 (m, 4H), 4,81-4,91 (m, 2H), 5,09-5,33 (m, 6H), 5,34-5,52 (m, 1H), 5,79-6,04 (m, 3H), 6,78 (d, J=8,9 Hz, 2H), 6.87 in (c, 1H), 7,03 (d, J=8,9 Hz, 2H), 7,21 (Sirs, 1H).

ESI m/z = 637 (M+Na), 639 (M+2+Na).

Example 17

Synthesis of (1S)-1,5-anhydrous-1-[4-chloro-5-(4-ethoxybenzyl)-2-methoxyphenyl]-1-thio-D-glucitol

A mixture of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-allyl-1-[4-chloro-5-(4-ethoxybenzyl)-2-methoxyphenyl]-1-thio-D-glucitol (100 mg, 0,163 mmol), tetrakis(triphenylphosphine)palladium (38 mg, 0,0325 mmol), N,N'-dimethylbarbituric acid (203 mg, 1.3 mmol) and tetrahydrofuran (1.0 ml) was stirred in argon atmosphere at a temperature of 90°C for 1.5 hours. Then the reaction mixture was cooled to room temperature, was added a saturated aqueous solution of sodium carbonate and was extracted with ethyl acetate, the organic phase was washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (chloroform:methanol=10:1→5:1), getting listed in the title compound (63 mg, 85%) as colorless powder.

1H NMR (600 MHz, METAL-d 4) δ ppm of 1.35 (t, J=6.9 Hz, 3H), 2,92-3,00 (m, 1H), up 3.22 (t, J=8,9 Hz, 1H), 3,53-3,59 (m, 1H), and 3.72 (DD, J=11,7, 6,7 Hz, 1H), 3,82 (c, 3H), 3,88-3,95 (m, 3H), 3,99 (kV, J=6,9 Hz, 2H), 6,79 (d, J=8.7 Hz, 2H), 6,98 (c, 1H), 7,06 (d, J=8,71 Hz, 2H), 7,20 (c, 1H).

ESI m/z = 477 (M+Na), 479 (M+2+Na), 453 (M-H), 455 (M+2-H).

TPL 177,0 debt-179.0°C.

Example 18

Synthesis of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[4-chloro-3-(tert-butoxycarbonyl)phenyl]-1-thio-D-glucitol

2.6 M solution of n-utility hexane (1,72 ml) was added to a mixture of 1.0 M solution of Isopropylamine magnesium in tetrahydrofuran (2,23 ml) and tetrahydrofuran (9 ml) at a temperature of -5°C. Then stirred for 0.5 hours, the reaction mixture was cooled to -78°C was added a solution of tert-butyl 5-bromo-2-chlorobenzoate(542 mg, of 1.86 mmol) in tetrahydrofuran (4.0 ml). Next was stirred for one hour, was added a solution of 2,3,4,6-Tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (430 mg, 0,798 mmol) in tetrahydrofuran (3.0 ml) and then was stirred for 15 minutes. Then to the reaction mixture were added saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1)to give 2,3,4,6-Tetra-O-Ben the Il-1-C-[4-chloro-3-(tert-butoxycarbonyl)phenyl]-5-thio-D-glucopyranose (60 mg, 10%).

ESI m/z = 789 (M+Na), 791 (M+2+Na).

Then to a solution of 2,3,4,6-Tetra-O-benzyl-1-C-[4-chloro-3-(tert-butoxycarbonyl)phenyl]-5-thio-D-glucopyranose (60 mg, 0,0782 mmol) in chloroform (1.0 ml) - acetonitrile (1.0 ml) was added sequentially Et3SiH (0,031 ml of € 0.195 mmol) and BF3·Et2O (0,015 ml, 0,117 mmol) at -40°C. Then stirred for 1.5 hours, to the reaction mixture were added saturated aqueous solution of sodium carbonate and the organic solvent was concentrated under reduced pressure. Then the residue was extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1), obtaining mentioned in the title compound (26 mg, 44%).

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.61 of (c, 9H), 3,06-is 3.21 (m, 1H), 3,51-to 3.64 (m, 1H), 3,66-of 3.77 (m, 1H), 3,78-4,06 (m, 5H), 4,48-of 4.67 (m, 4H), 4,84-of 4.95 (m, 3H), 6.75 in (DD, J=7,54, 1,79 Hz, 2H), 7,08-7,20 (m, 5H), 7.24 to 7,46 (m, 15H), to 7.77 (d, J=2,02 Hz, 1H).

ESI m/z = 768 (M+Na), 770 (M+2+Na).

Example 19

Synthesis of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[4-chloro-3-[[(4-ethylphenyl)amino]carbonyl]phenyl]-1-thio-D-glucitol

To a solution of (1S)-1,5-anhydrous-1-[4-chloro-5-(4-ethoxybenzyl)-2-methoxyphenyl]-1-thio-D-glucitol (30 mg, 0,040 m is ol) in tetrahydrofuran (2.0 ml) was added concentrated hydrochloric acid (1.0 ml), then the reaction mixture was stirred at room temperature for 24 hours and at 40°C for a further two hours and then added ethyl acetate. The resulting mixture was washed with water, salt solution and dried over anhydrous magnesium sulfate. The desiccant was filtered, then the solvent is evaporated under reduced pressure, obtaining the (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[4-chloro-3-carboxyphenyl]-1-thio-D-glucitol.

Next, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (13 mg, 0,069 mmol) and 1-hydroxybenzotriazole (9 mg, 0,069 mmol) was added to a solution of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[4-chloro-3-carboxyphenyl]-1-thio-D-glucitol and 4-ethylaniline (13 mg, 0.104 g mmol) in chloroform. Then was stirred at room temperature for 21 hours, the reaction mixture was diluted with chloroform and the organic phase was washed with saturated aqueous sodium bicarbonate solution, salt solution and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1)to give the above anilidowe compound (22 mg).

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 in (t, J=7,15 Hz, 3H), 2,65 (kV, J=to 7.67 Hz, 1H), 3,06-3,24 (m, 1H), 3,50-3,61 (m, 1H), 3,71 (DD, J=9,87, 3,03 Hz, 1H), 3,78-4.09 to (m, 6H), 4,5 (c, 2H), to 4.62 (t, J=10,34 Hz, 2H), 4,84-to 4.98 (m, 3H), 6.75 in-6,85 (m, 2H), 7,08-7,56 (m, 25H), 7,72 (d, J=2,02 Hz, 1H).

ESI m/z = 769 (M-H). Pale yellow powder.

Example 20

Synthesis of (1S)-1,5-anhydrous-1-[4-chloro-3-[[(4-ethylphenyl)amino]carbonyl]phenyl]-1-thio-D-glucitol

Triftormetilfullerenov acid (0.1 ml) was added to a mixture of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[4-chloro-3-[[(4-ethylphenyl)amino]carbonyl]phenyl]-1-thio-D-glucitol (20 mg, of 0.025 mmol), triperoxonane acid (0.5 ml), dimethyl sulfide (0.3 ml), m-cresol (0,08 ml) and ethicial (0,02 ml) at -15°C. and Then was stirred for 15 minutes and to the mixture was added saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, salt solution and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (chloroform:methanol=10:1), obtaining mentioned in the title compound (6 mg, 54%) as a colorless powder.

1H NMR (600 MHz, METHANOL-d4) δ ppm of 1.23 (t, J=EUR 7.57 Hz, 3H), 2,64 (kV, J=7,79 Hz, 2H), 3.00 and-of 3.07 (m, 1H), 3.27 to (t, J=8,71 Hz, 1H), 3,59-to 3.64 (m, 1H), of 3.73-3,82 (m, 2H), 3,89 (d, J=to 10.09 Hz, 1H), 3,95 (DD, J=of 11.69, 3,44 Hz, 1H), 7,20 (d, J=8,25 Hz, 2H), 7,47 (c, 2H), 7,53 (c, 1H), 7,56 (d, J=8,71 Hz, 2H).

ESI m/z = 438 (M+Na), 440 (M+2+N). Colorless powder.

Example 21

Synthesis of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-(hydroxymethyl)phenyl]-1-thio-D-glucitol

To a solution of 2,3,4,6-Tetra-O-benzyl-1-C-(3-formylphenyl)-5-thio-D-glucopyranose (4.0 g, 6.05 mmol) in chloroform (35 ml) - acetonitrile (35 ml) was added sequentially Et3SiH (5.8 ml, 36,3 mmol) and BF3·Et2O (3,1 ml, and 24.2 mmol) at -15°C. Then stirred for 1.5 hours, the reaction mixture was added saturated aqueous sodium bicarbonate solution and was extracted with chloroform, the organic phase is washed with saturated aqueous sodium bicarbonate, salt solution and dried over anhydrous magnesium sulfate. The desiccant was filtered, the solid viseslava obtained by evaporation of the solvent under reduced pressure, washed with hexane:ethyl acetate=10:1, getting mentioned in the title compound (3.2 g, 77%) as a colorless powder.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,07-3,18 (m, 1H), 3,55 (t, 1H), and 3.72 (DD, 1H), 3,78-4,01 (m, 5H), 4,46-4,69 (m, 6H), 4,87-4,96 (m, 3H), 6,69 (DD, J=7,69, 1,48 Hz, 2H), 7,07 was 7.45 (m, 22H).

Example 22

Synthesis of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-(methyl bromide)phenyl]-1-thio-D-glucitol

Methanesulfonanilide (0,018 ml) and triethylamine (0,021 ml) was added to a solution of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-(hydroxymethyl)phenyl]-thio-D-glucitol (100 mg, 0,155 mmol) in tetrahydrofuran (1.5 ml) at 4°C. the Reaction mixture was stirred at room temperature for three hours and was diluted with ethyl acetate. Then washed the reaction mixture with saturated aqueous sodium bicarbonate solution and the salt solution, the mixture was dried over anhydrous magnesium sulfate. The desiccant was filtered and then the solvent is evaporated under reduced pressure, obtaining the (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-(methanesulfonylaminoethyl)phenyl]-1-thio-D-glucitol (150 mg). Next, a mixture of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-(methanesulfonylaminoethyl)-1-thio-D-glucitol (150 mg), LiBr (40 mg, 0,466 mmol) and acetone (3 ml) was stirred at room temperature for two hours. Then the reaction mixture was concentrated and added ethyl acetate and water. Then the organic layer was separated, washed his salt solution and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1), obtaining mentioned in the title compound (70 mg, 64%).

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,06-3,17 (m, 1H), 3,55 (t, J=8,94 Hz, 1H), and 3.72 (DD, 1H), 3,78-was 4.02 (m, 5H), to 4.41 with 4.65 (m, 6H), 4,85-4,96 (m, 3H), 6,66-6,72 (m, J=7,46, 2,02 Hz, 2H), 7,10-7,51 (m, 22H).

ESI m/z = 726 (M+NH4+), 728 (M+2+ NH +).

Example 23

Synthesis of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-[(1-methyl-1H-pyrrol-2-yl)methyl]phenyl]-1-thio-D-glucitol

A mixture of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-(methyl bromide)phenyl]-1-thio-D-glucitol (200 mg, 0,282 mmol), 1-methyl-2-(tributylstannyl)-lH-pyrrole (208 mg, 0,564 mmol), Tris(dibenzylideneacetone)diplegia (38 mg, 0,0423 mmol), 2(dicyclohexylphosphino)biphenyl (36 mg, 0,0987 mmol), KF (67 mg, of 1.16 mmol), CsCO3(257 mg, 0,792 mmol) and 1,4-dioxane (5 ml) was stirred at 60°C for eight hours. Then the insoluble fraction was filtered, the residue obtained by concentration of the filtrate was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1), obtaining mentioned in the title compound (190 mg, 95%).

1H NMR (300 MHz, CHLOROFORM-d) δ ppm, 3.04 from-and 3.16 (m, 1H), 3,32 (c, 3H), 3,53 (t, J=to 8.70 Hz, 1H), 3,67 of 3.75 (m, 1H), 3.75 to 4.00 points (m, 7 H), 4,46-4,56 (m, 3H), 4,60 (d, J=10,57 Hz, 1H), 4,84-4,96 (m, 3H), of 5.89 (DD, J=to 3.73, 1,55 Hz, 1H), 6,04 (t, J=3,03 Hz, 1H), of 6.49-is 6.54 (m, 1H), 6,70 (DD, J=7,62, 1,71 Hz, 2H), 7,05-to 7.18 (m, 7 H), 7,22 and 7.36 (m, 14H), 7,39-7,46 (m, 1H).

ESI m/z = 710 (M+H), 732 (M+Na).

Example 24

Synthesis of (1S)-1,5-anhydrous-1-[3-[(1-methyl-lH-pyrrol-2-yl)methyl]phenyl]-1-thio-D-glucitol

Triftormetilfullerenov acid (0.2 ml) was added to a mixture of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-[(1-methyl-lH-pyrrol-2-yl)methyl]phenyl]-1-thio-D-glucitol (190 mg), referencesee acid (1.0 ml), dimethyl sulfide (0.6 ml), m-cresol (0,08 ml) and ethicial (0.04 ml) at -15°C. and Then was stirred for 15 minutes, then to the mixture was added saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, salt solution and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (chloroform:methanol=10:1), obtaining mentioned in the title compound (16 mg, 17%) as a colorless powder.

1H NMR (300 MHz, METHANOL-d4) δ ppm 2,92 was 3.05 (m, 1H), 3,19-3,29 (m, 1H), 3,39 (c, 3H)and 3.59 (t, J=for 9.64 Hz, 1H), 3,68-a 3.83 (m, 3H), 3,86-was 4.02 (m, 3H), 5,80-by 5.87 (m, 1H), 5,94 (t, J=3,11 Hz, 1H), 6,55 (d, J=1,87 Hz, 1H), 7,03 (DD, J=6,99, 1,71 Hz, 1H), 7,12-7,28 (m, 3H).

ESI m/z = 372 (M+Na).

Example 25

Synthesis of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-[(4-methoxy-lH-indol-1-yl)methyl]phenyl]-1-thio-D-glucitol

To a solution of 4-methoxyindole (83 mg, 0,564 mmol) in N,N-dimethylformamide (1.0 ml) was added sodium hydride (22 mg, 0,564 mmol; 60% in oil) and stirred at room temperature for 20 minutes. To this solution was added a solution of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-(methyl bromide)phenyl]-1-thio-D-glucitol (200 mg, 0,282 mmol) in N,N-DIMET formamide (2.0 ml), was stirred at room temperature for three hours and added water. The resulting solution was extracted with ethyl acetate and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1), obtaining mentioned in the title compound (290 mg).

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,05-3,14 (m, 1H), 3.46 in of 3.56 (m, 1H), 3,66-3,74 (m, 1H), 3,76-to 3.92 (m, 5 H), 3,95 (c, 3H), 4,46 (d, J=10,10 Hz, 1H), to 4.52 (c, 2H), 4,59 (d, J=10,57 Hz, 1H), 4,84-is 4.93 (m, 3H), 5.25 in (d, J=2,49 Hz, 2H), 6,46-7,39 (m, 29H).

ESI m/z = 793 (M+NH4).

Example 26

Synthesis of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-[(4-hydroxyphenyl)methyl]phenyl]-1-thio-D-glucitol

Specified in the title compound (253 mg) as a colourless oil was obtained from (4-bromophenoxy)-tert-butyldimethylsilyl (2.17 g) and 2,3,4,6-Tetra-O-benzyl-1-C-(3-formylphenyl)-5-thio-D-glucopyranose (2.50 g) in a manner similar to that described in example 11.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,03 is 3.15 (m, 1H), 3,52 (t, J=8,78 Hz, 1H), 3,66-3,74 (m, 1H), 3.75 to of 3.97 (m, 6H), 4,43-4,55 (m, 3H), 4,56-4,74 (m, 3H), 4,84-4,94 (m, 3H), 6,62-6,70 (m, 4H), 7,00 (d, J=to 8.70 Hz, 2H), 7,06-7,20 (m, 6H), 7,21-7,41 (m, 16H).

ESI m/z = 740 (M+NH4).

Example 27

Synthesis of (1S)-1,5-anhydrous-23,4,6-Tetra-O-benzyl-1-[3-[4-(2-methoxy-2-acetoxy)benzyl]phenyl]-1-thio-D-glucitol

To a solution of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-[(4-hydroxyphenyl)methyl]phenyl]-1-thio-D-glucitol (364 mg, 0,504 mmol) in N,N-dimethylformamide (5 ml) was added potassium carbonate (91 mg, 0,660 mmol) and methylbromide (0,058 ml, 0,610 mmol) at 4°C and was stirred at room temperature for five hours. Then to the mixture was added water and was extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1), obtaining mentioned in the title compound as a colorless oily substance (334 mg, 83%).

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,05 is 3.15 (m, 1H), 3,52 (t, J=8,94 Hz, 1H), 3,66 of 3.75 (m, 1H), 3.75 to 3,98 (m, 10H), to 4.41 with 4.64 (m, 6H), a 4.83-of 4.95 (m, 3H), 6,60-6,79 (m, 4H), 6,98-7,19 (m, 8H), 7,22 and 7.36 (m, 16H).

ESI m/z = 817 (M+Na).

Example 28

Synthesis of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-[4-(carboxymethoxy)benzyl]phenyl]-1-thio-D-glucitol

To a solution of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-[[4-(ethoxycarbonylmethoxy)phenyl]methyl]phenyl]-1-thio-D-glucitol (180 mg, 0,226 mmol) in a mixture of water-methanol-tetrahydrofuran (1:3:3, and 1.4 ml) was added monohydrate of lithium hydroxide (11 mg, 0.27 mmol) and stirred at room is the temperature for 30 minutes. The reaction mixture was acidified by adding 10% HCl and the resulting residue was extracted with ethyl acetate. Then the organic layer was washed with brine and dried over anhydrous magnesium sulfate, the desiccant was filtered and the solvent evaporated under reduced pressure, obtaining mentioned in the title compound (149 mg, 84%) as a colorless powder.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.04 from is 3.15 (m, 1H), 3.46 in-to 3.58 (m, 1H), 3,66-of 3.96 (m, 7H), to 4.41-of 4.54 (m, 3H), 4,55-4,63 (m, 3H), 4,82-of 4.95 (m, 3H), of 6.65 (DD, J=8,00, 1,48 Hz, 2H), 6,76 (d, J=8,86 Hz, 2H), 7,00 was 7.36 (m, 24H).

ESI m/z =798 (M+NH4), 779 (M-H).

Example 29

Synthesis of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-[4-[2-(dimethylamino)-2-oksidoksi)benzyl]phenyl]-1-thio-D-glucitol

To a solution of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-[4-(carboxymethoxy)benzyl]phenyl]-1-thio-D-glucitol (149 mg, 0,191 mmol) in chloroform (2 ml) was added 2 M solution of dimethylamine (0,19 ml, 0,382 mmol) in tetrahydrofuran, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0,229 mmol) and 1-hydroxybenzotriazole (31 mg, 0,229 mmol). Then was stirred at room temperature for 1.5 hours, the reaction mixture was diluted with chloroform and the organic phase is washed with water, salt solution and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced is the t, was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2), getting mentioned in the title compound (128 mg, 83%).

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2,96 (c, 3H), 3,05 (c, 3H), 3,06-3,14 (m, 1H), 3,52 (t, J=8,86 Hz, 1H), 3,68-3,74 (m, 1H), 3,76-of 3.96 (m, 7H), of 4.44-of 4.54 (m, 3H), 4,56-4,63 (m, 3H), 4,85-is 4.93 (m, 3H), of 6.65 (DD, J=7,93, of 1.55 Hz, 2H), 6,76-6,83 (m, 2H), 7,01-to 7.18 (m, 8H), 7,22-7,35 (m, 16H).

ESI m/z = 825 (M+NH4).

Example 30

Synthesis of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-[[[4-(2-N,N-dimethylaminoethyl)oxy]phenyl]methyl]phenyl]-1-thio-D-glucitol

To a solution of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-[4-[2-(dimethylamino)-2-oksidoksi]benzyl]phenyl]-1-thio-D-glucitol (88 mg, 0,109 mmol) in tetrahydrofuran (2 ml) was added 1.2 M balancerationality complex (0.54 ml) at 4°C and was stirred at room temperature for two hours. The reaction mixture was cooled to 4°C, was added methanol and concentrated. Next was added 1,4-dioxane (1.0 ml) and 6 M HCl (0.5 ml) to the resulting residue and stirred at 40°C for two minutes. For alkalinization mixture to it was added 2 M aqueous sodium hydroxide solution and was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure is, was purified by column chromatography on NH-type silica gel (hexane:ethyl acetate=1:1), obtaining mentioned in the title compound (43 mg, 50%) as a colourless solid.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2,35 (c, 6H), 2,68-of 2.81 (m, 2H), 3.04 from-and 3.16 (m, 1H), 3,52 (t, J=to 8.70 Hz, 1H), 3,66 is 3.76 (m, 1H), 3,76-4,10 (m, 9H), 4,47 (d, J=10,10 Hz, 1H), to 4.52 (c, 2H), 4,60 (d, J=of 10.72 Hz, 1H), 4,84-4,94 (m, 3H), of 6.65 (DD, J=7,85, 1,32 Hz, 2H), 6,72-for 6.81 (m, 2H), 7,00-to 7.18 (m, 8 H), 7,20 was 7.36 (m, 16 H).

ESI m/z = 794 (M+H).

Example 31

Synthesis of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-[[[4-(2-hydroxyethyl)oxy]phenyl]methyl]phenyl]-1-thio-D-glucitol

To a solution of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-[4-(2-methoxy-2-oksidoksi)benzyl]phenyl]-1-thio-D-glucitol (102 mg, 0,128 mmol) in tetrahydrofuran (2.5 ml) was added LiAlH4(12 mg, 0,321 mmol) at 4°C and was stirred for 2.5 hours. Then was added dropwise water, 28% solution of ammonium was filtered and the insoluble fraction. The filtrate was extracted with ethyl acetate and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered, the solvent evaporated under reduced pressure, obtaining mentioned in the title compound (100 mg) as a colorless crystal.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,06-3,14 (m, 1H), 3,52 (t, J=8,86 Hz, 1H), 3,67-3,74 (m, 1H), of 3.77-Android 4.04 (m, 11H), 4,47 (d, J=9,95 Hz, 1H), to 4.52 (c, 2H), 4,60 (d, J=of 10.72 Hz, 1H), 4,86-is 4.93 (m, 3H), 6,62-,68 (m, 2H), 6.73 x-6,79 (m, 2H), 7,02-to 7.18 (m, 8H), 7,21-7,35 (m, 16H).

ESI m/z = 784 (M+NH4).

Example 32

Synthesis of 2,3,4,6-Tetra-O-allyl-1-C-[5-(4-ethoxybenzyl)pyridine-3-yl]-5-thio-D-glucopyranose

The Grignard reagent was obtained from 3-bromo-5-(4-ethoxybenzyl)pyridine (1,83 g, 6.26 mmol) in a manner similar to that described in example 15, and is listed in the title compound (508 mg, 29%) was obtained as a brown oily substance.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.40 (t, J=6,99 Hz, 3H), 2,98-3,18 (m, 1H), 3,29-3,47 (m, 2H), 3,56-of 4.05 (m, 12H), 4,06-4,43 (m, 4H), 4,77-4,91 (m, 2H), 5,07 lower than the 5.37 (m, 7H), 5,79-6,04 (m, 3H), for 6.81 (d, J=8,86 Hz, 2H),? 7.04 baby mortality (d, J=8,86 Hz, 2H), 7,72 (c, 1H), to 8.41 (d, J=1,86 Hz, 1H), to 8.70 (d, J=2,18 Hz, 1H).

ESI m/z = 568 (M+H), 590 (M+Na).

Example 33

Synthesis of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-allyl-1-[5-(4-ethoxybenzyl)pyridine-3-yl]-1-thio-D-glucitol

Specified in the title compound as a colorless oily substance (137 mg, 28%) was obtained from 2,3,4,6-Tetra-O-benzyl-1-C-[5-(4-ethoxybenzyl)pyridine-3-yl]-5-thio-D-glucopyranose (508 mg, 0,894 mmol) in a manner similar to that described in example 16.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.40 (t, J=6,99 Hz, 3H), 2.93 which is a 3.06 (m, 1H), 3,25 (t, J=8,94 Hz, 1H), 3,30-3,44 (m, 1H), 3,49-of 4.05 (m, 12H), is 4.15 (DD, J=12,05, 5,98 Hz, 1H), 4,24 was 4.42 (m, 3H), 4.80 to to 4.92 (m, 2H), 5.08 to 5,42 (m, 7H), 5,78-6,03 (m, 3H), for 6.81 (d, J=to 8.70 Hz, 2H), 7,03 (d, J=to 8.70 Hz, 2H), of 7.48 (c, 1H), 8,42 (DD, J=16,16, 2,18 Hz, 2H).

ESI m/z = 552 (M+H).

Example 34

Synthesis of (1S)-1,5-anhydrous-1-[5-(4-ethoxybenzyl)pyridine-3-yl]-1-thio-D-glucitol

Specified in the title compound (71 mg, 73%) as a colorless powder was obtained from (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-allyl-1-[5-(4-ethoxybenzyl)pyridine-3-yl]-1-thio-D-glucitol (137 mg, 0,248 mmol) in a manner similar to that described in example 17.

1H NMR (600 MHz, METHANOL-d4) δ ppm of 1.36 (t, J=7.18 in Hz, 3H), 3,01 was 3.05 (m, 1H), 3,23-of 3.27 (m, 1H), 3,60 (DD, J=10,32, to 8.94 Hz, 1H), 3,71-of 3.78 (m, 2H), 3,84 (d, J=10,55 Hz, 1H), 3,92-of 3.97 (m, 3H), 3,99 (kV, J=7.18 in Hz, 2H), 6,82-6,85 (m, 2H), 7,10-7,13 (m, 2H), to 7.64 (t, J=e 2.06 Hz, 1H), 8,28 (d, J=to 2.29 Hz, 1H), 8.34 per (d, J=to 2.29 Hz, 1H).

ESI m/z = 392 (M+Na), 390 (M-H).

Example 35

Synthesis of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-allyl-1-[5-(4-active compounds)thiophene-2-yl]-1-thio-D-glucitol

Specified in the title compound (890 mg, 94%) as a yellow oily substance was obtained from 2-bromo-5-(4-active compounds)thiophene (1.0 g, 3,55 mmol) in a manner similar to that described in examples 15 and 16.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1,22 (t, J=a 7.62 Hz, 3H), 2,62 (kV, J=a 7.62 Hz, 2H), 2.91 in-3,03 (m, 1H), 3,20 (t, J=9,01 Hz, 1H), 3,43-with 3.79 (m, 5H), 3,90-4,07 (m, 6H), 4.09 to 4,18 (m, 1H), 4,24-to 4.41 (m, 3H), 4.92 in-5,02 (m, 2H,), 5,09-5,32 (m, 6H), 5,50-to 5.66 (m, 1H), 5,79-6,05 (m, 3H), of 6.61 (d, J=3,57 Hz, 1H), 6,85 (d, J=3.42 Hz, 1H), 7,07-7,16 (m, 4H).

ESI m/z = 563 (M+Na).

Example 36

Synthesis of (1S)-1,5-anhydrous-1-[5-(4-active compounds)thiophene-2-yl]-1-thio-D-glucitol

Specified in the title compound (570 mg, 92%) as a colorless powder p which were given of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-allyl-1-[5-(4-active compounds)thiophene-2-yl]-1-thio-D-glucitol (890 mg, of 1.64 mmol) in a manner similar to that described in example 17.

1H NMR (300 MHz, METHANOL-d4) δ ppm of 1.20 (t, J=a 7.62 Hz, 3H), 2,60 (kV, J=a 7.62 Hz, 2H), 2,92-3,03 (m, 1H), 3,19 (t, J=8,86 Hz, 1H), 3,50-3,63 (m, 2H), and 3.72 (DD, J=11,58, of 6.45 Hz, 1H), 3,93 (DD, J=11,50, to 3.73 Hz, 1H), a 4.03 (t, J=equal to 4.97 Hz, 3H), 6,58 is 6.67 (m, 1H), 6,83 (d, J=3,57 Hz, 1H), 7,08-7,17 (m, 4H).

ESI m/z = 403 (M+Na), 379 (M-H).

Example 37

Synthesis of 2,3,4,6-Tetra-O-benzyl-1-C-{3-[(E or Z)-2-(4-ethylphenyl)vinyl]phenyl}-5-thio-D-glucopyranose

To a mixture of (4-active compounds)triphenylphosphonium chloride (1.64 g, 3.93 mmol) and tetrahydrofuran (20 ml) was added 2 M solution Diisopropylamine (heptane/tetrahydrofuran/ethylbenzene, 2.0 ml, 4.0 mmol), in terms of cooling in an ice bath and stirred at room temperature for one hour. To the resulting solution was added dropwise a solution (10 ml) 2,3,4,6-Tetra-O-benzyl-1-C-(3-formylphenyl)-5-thio-D-glucopyranose (0.52 g, 786 mmol) in tetrahydrofuran and stirred at room temperature for one hour. Then to the reaction mixture were added saturated aqueous solution of ammonium chloride, under conditions of cooling in an ice bath, and extracted with ethyl acetate, the organic phase was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromate is graphy on silica gel (hexane:ethyl acetate=6:1 - 3:1), obtaining specified in the header connection (0,49 g, 82%, E/Z mixture) as a colorless oily substance.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.10 is to 1.32 (m, 3H), 2,48-to 2.74 (m, 2H), 2,90-3,10 (m, J=38,55 Hz, 1H), 3,47-3,71 (m, 2H), 3,78-is 4.21 (m, 5H), to 4.41-to 4.73 (m, 4 H), 4.80 to 4,99 (m, 3H), 6,50-of 6.99 (m, 3H), 7.03 is-to 7.61 (m, 27H).

ESI m/z = 785 (M+Na).

Example 38

Synthesis of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-{3-[(E or Z)-2-(4-ethylphenyl)vinyl]phenyl}-1-thio-D-glucitol

To a solution of 2,3,4,6-Tetra-O-benzyl-1-C-{3-[(E or Z)-2-(4-ethylphenyl)vinyl]phenyl}-5-thio-D-glucopyranose (0,49 g, 642 mmol) in acetonitrile (20 ml)was added sequentially Et3SiH (0.35 ml, 1.92 mmol) and BF3·Et2O (0,20 ml, 1.28 mmol) at a temperature of -10°C and was stirred for 10 minutes at the same temperature. Then to the reaction mixture were added saturated aqueous solution of sodium carbonate and was extracted with ethyl acetate, the organic phase was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=8:1), obtaining mentioned in the title compound (0.31 g, 66%, E/Z mixture) as colorless powder.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.13 to 1.31 (m, 3H), 2,46-of 2.72 (m, 2H), 3.04 from-3,18 (m, 1H), 3,47-3,62 (m, 1H), 3,68-was 4.02 (m, 6 H), 4,45-of 4.66 (m, 4 H), 4,8-4,96 (m, 3H), of 6.49-to 6.80 (m, 3H), 6,92 to 7.62 (m, 27H).

ESI m/z = 769 (M+Na).

Example 39

Synthesis of (1S)-1,5-anhydrous-1-{3-[2-(4-ethylphenyl)ethyl]phenyl}-1-thio-D-glucitol

20% (by weight) of palladium hydroxide on charcoal (300 mg) was added to a solution (5 ml) of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-{3-[(E or Z)-2-(4-ethylphenyl)vinyl]phenyl}-1-thio-D-glucitol (0,30 g, 401 mmol) in ethanol and the atmosphere outside the system was replaced with hydrogen. Was stirred at room temperature for three days, the insoluble fraction in the system was removed by filtration through celite. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (chloroform:methanol=10:1), obtaining mentioned in the title compound (13 mg, 8%) as a colorless powder.

1H NMR (300 MHz, METHANOL-d4) δ ppm of 1.20 (t, J=1,62 Hz, 3H), 2,59 (kV, J=1,62 Hz, 2H), 2,85 (c, 4H), 2.95 and-of 3.07 (m, 1H), 3,21 of 3.28 (m, 1H), 3,54-3,68 (m, 1H), 3,69-a 3.83 (m, 3H), of 3.95 (DD, J=11,42, the 3.65 Hz, 1H), 7,00-7,11 (m, 5 H), 7,13-7,28 (m, 3H).

ESI m/z = 411 (M+Na), 387 (M-H).

Example 40

Synthesis of 2,3,4,6-Tetra-O-allyl-1-C-{3-[(2E, or Z)-3-(4-ethylphenyl)prop-2-EN-1-yl]phenyl}-5-thio-D-glucopyranose

Five drops of 1,2-dibromoethane was added to a mixture of magnesium (1,11 g of 45.7 mmol), 1-bromo-3-[(2E, or Z)-3-(4-ethylphenyl)prop-2-EN-1-yl)benzene (0,401 g of 1.33 mmol) and tetrahydrofuran (7 ml) and the mixture is boiled with bratim refrigerator for 1.5 hours. The reaction mixture was cooled to room temperature and to this solution was added dropwise a solution of 2,3,4,6-Tetra-O-allyl-5-thio-D-gluconolactone (0,38 g, 1.06 mmol) in tetrahydrofuran (5 ml) and stirred at room temperature for 30 minutes. To the reaction mixture were added saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate, the conditions of cooling in an ice bath, the organic phase was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1), obtaining mentioned in the title compound as a colorless oily substance (42 mg, 7%).

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1,16-of 1.30 (m, 3H), 2,55-of 2.72 (m, 2H), 2,90-3,03 (m, 1H), 3,31-of 4.44 (m, 16H), 4,82-4,94 (m, 2H), 5,09-5,49 (m, 6 H), 5,80-6,05 (m, 5H), 6,29-of 6.45 (m, 1H), 7,08-to 7.32 (m, 6H), 7,42-7,52 (m, 2H).

ESI m/z = 599 (M+Na), 575 (M-H).

Example 41

Synthesis of (1S)-2,3,4,6-Tetra-O-allyl-1,5-anhydrous-1-{3-[(2E, or Z)-3-(4-ethylphenyl)prop-2-EN-1-yl]phenyl}-1-thio-D-glucitol

To a solution of 2,3,4,6-Tetra-O-allyl-1-C-{3-[(2E, or Z)-3-(4-ethylphenyl)prop-2-EN-1-yl]phenyl}-5-thio-D-glucopyranose (42 mg, 72 μmol) in acetonitrile (3 ml) was added sequentially Et3SiH (35 μl, 218 mmol) and BF3·Et2O (20 µl, 145 the KMOL) at a temperature of -10°C and was stirred for 10 minutes at the same temperature. Then to the reaction mixture were added saturated aqueous solution of sodium carbonate and was extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1 - 8:1), getting listed in the title compound (28 mg, 70%) as a colorless oily substance.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1,17-of 1.30 (m, J=7,62, 7.62mm, a 7.62 Hz, 3H), 2.57 m-a 2.71 (m, 2H), 2.95 and was 3.05 (m, 1H), 3,26 (t, J=8,86 Hz, 1H), 3,50 (d, J=6,68 Hz, 2H), to 3.58-3,91 (m, 5H), 3,94-is 4.21 (m, 3H), 4,23-of 4.44 (m, 3H), 4,84-of 4.95 (m, 2H), 5,09-5,52 (m, 8H), 5,71-6,46 (m, 6H), 7,09-7,29 (m, 8H).

ESI m/z = 583 (M+Na).

Example 42

Synthesis of (1S)-1,5-anhydrous-1-{3-[(2E, or Z)-3-(4-ethylphenyl)prop-2-EN-1-yl]phenyl}-1-thio-D-glucitol

To a solution of (1S)-2,3,4,6-Tetra-O-allyl-1,5-anhydrous-1-{3-[(2E, or Z)-3-(4-ethylphenyl)prop-2-EN-1-yl]phenyl}-1-thio-D-glucitol (26 mg, 46 μmol) in tetrahydrofuran (3 ml) was added tetrakis(triphenylphosphine)palladium (11 mg, 9 mmol) and 1,3-dimethylbarbituric acid (58 mg, 370 μmol) and boiled under reflux in for 2.5 hours. Then to the reaction mixture were added saturated aqueous solution of sodium carbonate and was extracted with ethyl acetate, the conditions of cooling in an ice bath, the organization of the definition phase was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (chloroform:methanol=10:1). Further purification was performed by column chromatography on silica gel (NH silica gel, chloroform:methanol=9:1), obtaining mentioned in the title compound (13 mg, 72%).

1H NMR (300 MHz, METHANOL-d4) δ ppm 1,14-of 1.27 (m, J=7,98, 7,98, 7,98 Hz, 3H), 2,54 of 2.68 (m, 2H), 2.95 and was 3.05 (m, 1H), 3,22-3,30 (m, 1H), 3,51 (d, J=6,37 Hz, 1H), 3,56-3,68 (m, 2H), 3,70-a 3.83 (m, 3H), of 3.95 (DD, J=11,35, of 3.57 Hz, 1H), 5,72-6,59 (m, 2H), 7,07-7,30 (m, 8H).

ESI m/z = 423 (M+Na), 399 (M-H).

Example 43

Synthesis of (1S)-1,5-anhydrous-1-{3-[3-(4-ethylphenyl)propyl]phenyl}-1-thio-D-glucitol

20% (by weight) of palladium hydroxide on charcoal (20 mg) was added to a solution of (1S)-1,5-anhydrous-1-{3-[(2E, or Z)-3-(4-ethylphenyl)prop-2-EN-1-yl]phenyl}-1-thio-D-glucitol (13 mg, 32 μmol) in ethanol (2 ml) and the atmosphere outside the system was replaced with hydrogen. Then was stirred at room temperature for two days, the insoluble fraction in the system was removed by filtration through celite. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (chloroform:methanol=9:1), obtaining mentioned in the title compound (8 mg, 62%) as bescot the CSOs powder.

1H NMR (600 MHz, METHANOL-d4) δ ppm of 1.20 (t, J=EUR 7.57 Hz, 3H), 1,87-of 1.94 (m, 2H), 2,56-2,63 (m, 6H), 2,98-3,03 (m, 1H), 3,26 (t, J=of 8.25 Hz, 1H), 3,59-to 3.64 (m, J=10,32, to 8.94 Hz, 1H), 3,71-3,82 (m, 3H), of 3.95 (DD, J=11,46, to 3.67 Hz, 1H), 7,05 for 7.12 (m, 5H), 7,14-7,25 (m, 3H).

ESI m/z = 425 (M+Na), 401 (M-H).

Example 44

Synthesis of 2,3,4,6-Tetra-O-allyl-1-C-[7-(4-methylbenzyl)-1-benzothieno-3-yl]-5-thio-D-glucopyranose

Five drops of 1,2-dibromoethane was added to a mixture of magnesium (77 mg, 3,19 mmol), 3-bromo-7-(4-methylbenzyl)-1-benzothiophene (0,92 g, 2,90 mmol) and tetrahydrofuran (5 ml) and the resulting mixture was boiled under reflux for 30 minutes. The reaction mixture was cooled to room temperature and was added dropwise a solution of 2,3,4,6-Tetra-O-allyl-5-thio-D-glucono-1,5-lactone (0.51 g, 1,45 mmol) in tetrahydrofuran (5 ml) under conditions of cooling in an ice bath and then stirred at room temperature for 30 minutes. Then to the reaction mixture were added saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate, the organic phase was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1), obtaining mentioned in the title compound (0,76 g, 89%) as a yellow oily the substances.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2,31 (c, 3H), 3,21 (DD, J=11,81, the 6.06 Hz, 1H), 3,29 (c, 1H), 3.46 in-3,93 (m, 6H), 3.96 points-was 4.02 (m, J=4,66 Hz, 2H), 4,15-4.26 deaths (m, 4H), 4,30 (d, J=5,75 Hz, 2H), 4,42 (DD, J=12,12, 5,91 Hz, 1H), 4,57-4,78 (m, 2H), 5,10-of 5.40 (m, 7H), 5,80-between 6.08 (m, 3H), 7,05-7,17 (m, 5H), 7,32 (m, 1H), 7,63 (c, 1H), 8,19 (d, J=7,46 Hz, 1H).

ESI m/z = 615 (M+Na), 591 (M-H).

Example 45

Synthesis of (1S)-2,3,4,6-Tetra-O-allyl-1,5-anhydrous-1-[7-(4-methylbenzyl)-1-benzothieno-3-yl]-1-thio-D-glucitol

Specified in the title compound (86%) was synthesized by a method similar to that described in example 16 from 2,3,4,6-Tetra-O-allyl-1-C-[7-(4-methylbenzyl)-1-benzothieno-3-yl]-5-thio-D-glucopyranose.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2,31 (c, 3H), 2,99-3,10 (m, 1H), 3.27 to is 3.40 (m, 2H), 3,66-a 3.87 (m, 5H), 4.00 points (d, J=5,75 Hz, 2H), 4,15-4.26 deaths (m, 4H), or 4.31 (d, J=6,84 Hz, 2H), and 4.40 (DD, J=12,05, of 5.83 Hz, 1H), 4.63 to-4,82 (m, 2H,), 5,09 lower than the 5.37 (m, 7H), 5,80-6,07 (m, 3H),? 7.04 baby mortality-7,17 (m, 5H), 7,32 (m, 1H), 7,41 (c, 1H), 7,89 (d, J=to 7.93 Hz, 1H).

ESI m/z = 599 (M+Na).

Example 46

Synthesis of (1S)-1,5-anhydrous-1-[7-(4-methylbenzyl)-1-benzothieno-3-yl]-1-thio-D-glucitol

Specified in the title compound (76%) was synthesized in the form of a colourless powder in a manner similar to described in example 17, from (1S)-2,3,4,6-Tetra-O-allyl-1,5-anhydrous-1-[7-(4-methylbenzyl)-1-benzothieno-3-yl]-1-thio-D-glucitol.

1H NMR (300 MHz, METHANOL-d4) δ ppm 2.26 and (c, 2H), 3,03-3,14 (m, 1H), 3,32 is 3.40 (m, 1H), 3,62-and 3.72 (m, 1H), of 3.77 (DD, J=11,50, 6,37 Hz, 1H), 3,93-4,06 (m, 2H), 4,14 (c, 2H), 4,32 (d, J=10,26 Hz, 1H), 7,01-7,17 (m, 5 H), 7,33 (t, 1H), of 7.48 (c, 1H, of 7.90 (d, J=7,31 Hz, 1H).

ESI m/z = 439 (M+Na), 415 (M-H).

Compounds of the present invention, are presented in the following tables, obtained using procedures similar to those described in the examples above, using appropriate starting compounds and reagents. Compounds of the present invention obtained in the examples above, are also presented in table 1.

Table 1
Connection # The structural formulaNMR, MS, TPL, elemental analysis
Connection 11H NMR (300 MHz, CHLOROFORM-d) δ ppm 1,19 (t, J=7,6 Hz, 3H), 2,59 (kV, J=7,6 Hz, 2H), 3,05-and 3.16 (m, 1H), 3,53 (t, J=8,9 Hz, 1H), 3,67-3,99 (m, 8H), 4,47 (d, J=10.0 Hz, 1H), 4.53-in (c, 2H), 4,60 (d, J=10,7 Hz, 1H), 4,85-4,94 (m, 3H), 6,62-6,69 (m, 2H), 7,00-7,20 (m, 10H), 7,22 and 7.36 (m, 16H). ESI m/z = 757 (M+Na). TPL 100,0-102,5°C.
Connection 21H NMR (300 MHz, CHLOROFORM-d) δ ppm to 1.38 (t, J=6,99 Hz, 3H), 2,93-3,17 (m, 1H), 3,52 (t, J=8,86 Hz, 1H), 3,64 is 3.76 (m, 1H), 3,76-4,07 (m, 9H), to 4.46 (d, J=9,95 Hz, 1H), to 4.52 (c, 2H), 4,60 (d, J=10,57 Hz, 1H), a 4.83-equal to 4.97 (m, 3H), 6,59-to 6.80 (m, 4H), 6,97-7,21 (m, 8H), 7,22-7,39 (m, 16H). ESI m/z = 773 (M+Na).
Connection 31H NMR (600 MHz, CHLOROFORM-d) δ ppm to 1.38 (t, J=6,88 Hz, 3H), 3.00 and is 3.15 (m, 1H), 3,50 (t, J=8,94 Hz, 1H), 3,70 (DD, J=9,86, 2,98 Hz, 1H), 3.75 to of 3.80 (m, 2H), 3,82-3,99 (m, 6H), 4,06 (d, J=15,59 Hz, 1H), 4,47-a 4.53 (m, 3H), 4,59 (d, J=10,55 Hz, 1H), 4,82-4,88 (m, 2H), 4,89 (d, J=10,55 Hz, 1H), 6,70 (d, J=6,88 Hz, 2H), 6,74 (d, J=8,71 Hz, 2H), 7,03 (d, J=8,71 Hz, 2H), 7,09-7,37 (m, 21H). ESI m/z = 807 (M+Na). TPL 126,0-USD 128.0°C. Colourless powder.
Connection 41H NMR (600 MHz, CHLOROFORM-d) δ ppm 1,37 (t, J=6,88 Hz, 3H), 3,05-3,11 (m, 1H), 3,50 (t, J=8,94 Hz, 1H), 3,70 (DD, J=9,63, a 2.75 Hz, 1H), 3,76-a-3.84 (m, 6H), 3,84-to 3.92 (m, 3H), 3,92-3,99 (m, 3H), of 4.45 (d, J=to 10.09 Hz, 1H), to 4.52 (c, 2H), 4,59 (d, J=10,55 Hz, 1H), 4,85 (c, 2H), 4,89 (d, J=11,00 Hz, 1H), 6,67 to 6.75 (m, 4H), 6,83 (d, J=of 8.25 Hz, 1H), 7,02-to 7.18 (m, 8H), 7,22-7,35 (m, 14H), ESI m/z = 803 (M+Na).
Connection 51H NMR (600 MHz, CHLOROFORM-d) δ ppm 1,37 (t, J=7,11 Hz, 3H), of 3.07-3.15 in (m, 1H), 3,54 (t, J=9,17 Hz, 1H), 3,62-3,99 (m, 11H), 4,47-to 4.62 (m, 6H), 4,84-is 4.93 (m, 3H), 6,61-7,41 (m, 27H). ESI m/z = 803 (M+Na).
Connection 61H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.36 (t, J=6,92 Hz, 3H), 2,97-3,17 (m, 1H), 3,47-3,62 (m, 1H), 3,62 of 3.75 (m, 1H), 3,76-a 4.03 (m, 8H), 4,40-of 4.67 (m, 5H), 4,82-5,12 (m, 5H), 6,62-7,42 (m, 32H). ESI m/z = 879 (M+Na).
Connection 71H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.35 (t, J=6,92 Hz, 3H), 3,06 is 3.15 (m, 1H), 3,52 (t, J=8,86 Hz, 1H), 3,64-3,98 (m, 14H), 4,45-to 4.62 (m, 4H), 4,71 (c, 2H), 4,84-is 4.93 (m, 3H), 6,45 (c, 1H), 6,63-6,72 (m, 4H), 6,99-7,34 (m, 17H), 7,37 (d, J=4,35 Hz, 4H). ESI m/z = 828 (M+NH4)Gelte oil.
Compound 81H NMR (300 MHz, CHLOROFORM-d) δ ppm 1,38 (t, 1=of 6.99 Hz, 3H), 3,03-3,13 (m, 1H), 3.46 in-3,54 (m, 1H), 3,66-4,00 (m, 10H), 4,45-a 4.53 (m, 3H), 4,59 (d, J=of 10.72 Hz, 1H), 4,84-is 4.93 (m, 3H), 6,65-6,77 (m, 4H), of 6.96-7,34 (m, 23H). ESI m/z = 791 (M+Na). Colorless powder.
Connection 91H NMR (300 MHz, CHLOROFORM-d) δ ppm to 1.38 (t, J=6,92 Hz, 3H), 3,02-3,14 (m, 1H), 3,51 (t, J=to 8.70 Hz, 1H), 3,66-of 4.05 (m, 10H), 4,47 (d, J=10,26 Hz, 1H), to 4.52 (c, 2H), 4,59 (d, J=10,41 Hz, 1H), a 4.83-4,94 (m, 3H), of 5.06 (c, 2H), 6,64-6,74 (m, 4H), 6,84-6,91 (m, 1H), of 6.96-7,38 (m, 27H). ESI m/z = 874 (M+NH4). Colorless powder.
Connection 101H NMR (600 MHz, CHLOROFORM-d) δ ppm was 1.43 (t, J=6,88 Hz, 3H), 3,06-of 3.12 (m, 1H), 3,51 (t, J=8,94 Hz, 1H), 3,70 (DD, J=9,63, a 2.75 Hz, 1H), 3.75 to-3,81 (m, 2H), 3,83-4,06 (m, 8H), 4,49-4,55 (m, 3H), 4,59 (d, J=10,55 Hz, 1H), 4,84-4,94 (m, 3H), 6,63 (DD, J=10,55, to 6.88 Hz, 1H), 6,69 (d, J=6,88 Hz, 2H), 6,77 (DD, J=11,23, 7,11 Hz, 1H), 7,08-7,38 (m, 20H). ESI m/z = 843 (M+Na). Be the color powder.
Connection 111H NMR (600 MHz, CHLOROFORM-d) δ ppm of 1.40 (t, J=7,11 Hz, 3H), 3,01-3,11 (m, 1H), 3,50 (t, J=8,94 Hz, 1H), 3,69 (DD, J=9,63, a 2.75 Hz, 1H), 3.75 to of 3.80 (m, 2H), 3,81-3,95 (m, 4H), 3,99-4,07 (m, 3H), 4,49-a 4.53 (m, 3H), 4,58 (d, J=10,55 Hz, 1H), 4,82-is 4.93 (m, 3H), 6,65-of 6.90 (m, 5H), 7,09 and 7.36 (m, 21H). ESI m/z = 825 (M+Na). Colorless powder.
Connection 121H NMR (600 MHz, CHLOROFORM-d) δ ppm of 1.42 (t, J=6,88 Hz, 3H), 3,05-and 3.16 (m, 1H), 3,50 (t, J=8,94 Hz, 1H), 3,69 (DD, J=of 10.09, a 2.75 Hz, 1H), of 3.73-3,81 (m, 2H), 3,82-3,95 (m, 4H), was 4.02 (q, J=7.03 is Hz, 2H), 4,48-of 4.54 (m, 3H), 4,58 (d, J=10,55 Hz, 1H), 4,82-of 4.90 (m, 3H), 6,63 to 6.75 (m, 3H), 6,91 (DD, J=8,25, to 2.29 Hz, 1H), 7,07 and 7.36 (m, 22H). ESI m/z = 841 (M+Na).
Connection 131H NMR (300 MHz, CHLOROFORM-d) δ ppm to 1.38 (t, J=6,99 Hz, 3H), 2,22 (c, 3H), 3,06-3,14 (m, 1H), 3,52 (t, J=8,86 Hz, 1H), 3,68-4,00 (m, 10H), 4,46-of 4.54 (m, 3H), 4,60 (d, 1=of 10.72 Hz, 1H), 4,84-is 4.93 (M, 3H), 6,67-6,76 (m, 4H), 6,92-6,98 (m, 2H), 7,08-7,35 (m, 21H). ESI m/z = 782 (M+Na). Colorless powder.
The connection 141H NMR (600 MHz, CHLOROFORM-d) δ ppm 3,01-3,13 (m, 1H), 3,49 (t, J=8,94 Hz, 1H), 3,65 at 3.69 (m, 1H), 3,71 (c, 3H), of 3.73-of 3.78 (m, 2H), 3,76 (c, 3H), 3,80-of 3.96 (m, 4H), 4,01-4,07 (m, 1H), 4,45-a 4.53 (m, 3H), 4,59 (d, J=Hz 11,00, 1H), 4,8-to 4.92 (m, 3H), 6,30 (DD, 1=8,25, to 2.29 Hz, 1H), 6,41 (d, J=to 2.29 Hz, 1H), of 6.71 (d, J=of 8.25 Hz, 1H), at 6.84 (d, J=of 8.25 Hz, 1H), 7,10-7,35 (m, 21H). ESI m/z = 818 (M+NH4).
The connection 151H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,01-and 3.16 (m, 1H), 3,50 (t, 1=8,86 Hz, 1H), 3,66-and 3.72 (m, 1H), 3,76 (c, 3H), 3,76-3,99 (m, 6H), was 4.02-to 4.14 (m, 1H), 4,46-a 4.53 (m, 3H), 4,59 (d, J=l0,72 Hz, 1H), 4,82-of 4.95 (m, 3H), 6,63-PC 6.82 (m, 4H), 7,01 and 7.36 (m, 23H). ESI m/z = 788 (M+NH4).
The connection 161H NMR (600 MHz, CHLOROFORM-d) δ ppm of 1.35 (t, J=6,88 Hz, 3H), 2,21 (c, 3H), 3,02-is 3.21 (m, 1H), 3,55 (t, J=9,40 Hz, 1H), 3,71 (c, 1H), 3,74-of 3.97 (m, 10H), 4,01 (c, 1H), 4,45-4,56 (m, 3H), 4,60 (d, J=10,55 Hz, 2H), 4,86 (c, 2H), the 4.90 (d, J=10,55 Hz, 1H), 6,58-6,76 (m, 5H), of 6.90 (d, J=7,34 Hz, 1H), 7,09-7,19 (m, 5H), 7.23 percent-to 7.35 (m, 15H). ESI m/z = 812 (M+NH4). Colorless powder.
Connection 171H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.39 in (t, J=6,99 Hz, 3H), 2,18 (c, 3H), 2,93-is 3.08 (m, 1H), 3.27 to (t, J=9,01 Hz, 1H), 3,50-of 3.77 (m, 6H), 3,80 (c, 3H), 3,83-of 4.05 (m, 6H), 4,08-4,51 (m, 5H), 4,82-of 4.95 (m, 2H), 5,06-of 5.34 (m, 6H), 5,38-to 5.58 (m, 1H), 5,77-6,07 (m, 3H), 6,66 (c, 1H), 6.75 in (d, J=to 8.70 Hz, 2H), 6,94 (d, J=to 8.70 Hz, 2H), 7,16 (c, 1H). ESI m/z = 617 (M+Na).
The connection 181H NMR (300 MHz, CHLOROFORM-d) δ ppm 1,2 (c, 9H), 2,93-3,20 (m, 1H), 3,51 (t, J=8,94 Hz, 1H), 3,63-3,93 (m, 6H), 3,93-a 4.03 (m, 1H), 4,06-4,17 (m, 1H), 4,45-of 4.54 (m, 3H), 4,59 (d, J=10,57 Hz, 1H), 4,84-is 4.93 (m, 3H), 6,69 (DD, J=8,00, 1,48 Hz, 2H),? 7.04 baby mortality-7,38 (m, 25H). ESI m/z = 819 (M+Na). Colorless powder.
Connection 191H NMR (300 MHz, CHLOROFORM-d) δ ppm to 1.38 (t, J=6,99 Hz, 3H), 3,03 is 3.15 (m, 1H), 3,50 (t, J=8,86 Hz, 1H), 3,65-4,06 (m, 10H), 4,46-to 4.62 (m, 4H), 4,82-is 4.93 (m, 3H), 6,45-of 6.61 (m, 2H), 6,69 (d, J=8,08 Hz, 2H), 6,91 (t, J=8,63 Hz, 1H), 7,08-7,38 (m, J=1,00 Hz, 21H). A colorless oil.
The connection 201H NMR (300 MHz, CHLOROFORM-d) δ ppm 2,25-2,31 (c, 3H), 3.04 from-3,13 (m, 1H), 3.46 in-3,54 (m, 1H), 3,66 is 4.13 (m, 8H), 4,47-a 4.53 (m, 3H), 4,59 (d, J=11,04 Hz, 1H), 4,84 to 4.92 (m, 3H), 6,67-6,72 (m, 2H), 7,02 (c, 4H), 7,08-7,35 (m, 21H). ESI m/z = 772 (M+NH4), 774 (M+2+NH4). Colorless powder.
Connection 211H NMR (600 MHz, CHLOROFORM-d) δ ppm 2,42 (c, 3H), 3,05-of 3.12 (m, 1H), 3,51 (t, J=8,94 Hz, 1H), 3,70 (DD, J=9,86, 2,98 Hz, 1H), 3,74-3,82 (m, 2H), 3,82-to 3.92 (m, 3H), 3,93-4,01 (m, 1H), 4,07 (d, J=15,13 Hz, 1H), 4,48-of 4.54 (m, 3H), 4,59 (d, J=10,55 Hz, 1H), 4,82-to 4.87 (m, 2H), 4,89 (d, J=10,55 Hz, 1H), 6,70 (d, J=7,34 Hz, 2H), 7,00-7,38 (m, 25H). ESI m/z = 804 (M+NH4). Colorless powder.
The connection 22 1H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.29 (d, J=the 6.06 Hz, 6H), 3.04 from-3,14 (m, 1H), 3,50 (t, J=to 8.70 Hz, 1H), 3,65-4,11 (m, 8H), to 4.38-4.63 to (m, 5H), a 4.83-4.92 in (m, 3H), 6,65-6,77 (m, 3H), 6,99-7,37 (m, 24H). ESI m/z = 821 (M+Na). Yellow powder.
The connection 231H NMR (300 MHz, CHLOROFORM-d) δ ppm 1,19 (t, J=rate of 7.54 Hz, 3H), 2,58 (kV, J=to 7.77 Hz, 2H), 3.04 from-3,13 (m, 1H), 3,50 (t, J=to 8.70 Hz, 1H), 3,66-to 4.14 (m, 8H), 4,46-a 4.53 (m, 3H), 4,59 (d, J=of 10.72 Hz, 1H), 4,84 to 4.92 (m, 3H), 6,66-6,72 (m, 2H), 7,00 was 7.36 (m, 25H). ESI m/z = 791 (M+Na). Pale yellow powder.
Connection 241H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18 to (c, 3H), 1,21 (c, 3H), 2.77-to 2,89 (m, 1H), 3,05-3,13 (m, 1H), 3,51 (t, J=8,86 Hz, 1H), 3,66-to 4.15 (m, 8H), 4,46-of 4.54 (m, 3H), 4,59 (d, J=of 10.72 Hz, 1H), a 4.83-4.92 in (m, 3H), 6,69 (DD, J=7,85, 1,32 Hz, 2H), 7,06 (c, 4H), 7,08 and 7.36 (m, 21H). ESI m/z = 805 (M+Na). Colorless powder.
The connection 251H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.40 (t, J=6,99 Hz, 3H), 2,14 (c, 3H), 3,01-of 3.12 (m, 1H), 3,48 (t, J=8,86 Hz, 1H), 3,65-4,06 (m, 10H), 4,46-br4.61 (m, 4H), 4.80 to 4,91 (m, 3H), return of 6.58 (DD, J=8,24, 2,49 Hz, 1H), 6,68-6,76 (m, 2H,), for 6.81 (d, J=8,39 Hz, 1H), 6,98 (d, J=2,18 Hz, 1H), 7,10-7,39 (m, 21H). Colorless powder.
The connection 261H NMR (300 MG IS, CHLOROFORM-d) δ ppm 3,14 (c, 1H), 3.43 points-to 3.58 (m, 1H), 3,63 (DD, J=9,95, of 2.64 Hz, 1H), a 3.87-4,16 (m, 5H), of 4.45-4.72 in (m, 4H), 4.80 to of 5.05 (m, 3H), 6.73 x (d, J=to 7.77 Hz, 2H), 7,02-the 7.43 (m, 19H), 7,74 (DD, J=8,39, 2,49 Hz, 1H), 8,06 (d, J=2,49 Hz, 1H), accounted for 10.39 (c, 1H). Colourless amorphous substance.
Connection 271H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,06 (c, 1H), 3,47-to 3.58 (m, 1H), 3,64 (DD, J=there is a 10.03, 2,88 Hz, 1H), 3,83-is 4.21 (m, 9H), 4,48-4,56 (m, 3H), of 4.66 (d, J=10,57 Hz, 1H), 4,82-equal to 4.97 (m, 3H), 6,15 (c, 1H), 6,77 (DD, J=7,85, 1,48 Hz, 2H,), 7,08-7,21 (m, 5H), 7.23 percent-7,37 (m, 14H), 7,55 (DD, J=8,39, 2,49 Hz, 1H), 7,92 (d, J=2,49 Hz, 1H). ESI m/z = 761 (M+Na). Colourless amorphous substance.
The connection 281H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.36 (t, J=6,92 Hz, 3H), 2,17 (c, 3H), 3.04 from-3,19 (m, 1H), 3,47-4,17 (m, 10H), 4,42-of 4.66 (m, 5H), 4,77-5,12 (m, 5H), 6,55-7,51 (m, 31H). ESI m/z = 893 (M+Na). A colorless oil.
The connection 291H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.35 (t, J=6,99 Hz, 3H), 3,01-and 3.16 (m, 1H), 3,53 (t, J=9,01 Hz, 1H), 3,65-3,74 (m, 1H), 3,78 (c, 3H), 3,81-4,08 (m, 8H), 4,43-4,56 (m, 4H), 4,59 (d, J=10,88 Hz, 1H), 4,85 (c, 2H), 4,89 (d, J=of 10.72 Hz, 1H), of 6.68 (DD, J=to 7.77, 1,71 Hz, 4H), 6.89 in (c, 1H), 7,00 (d, J=8,39 Hz, 2H), 7,06-7,20 (m, 5H), 7,21-7,38 (m, 14H). ESI m/z = 837 (M+Na).
The connection 30 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.39 in (t, J=6,99 Hz, 3H), 2.95 and totaling 3.04 (m, 1H), 3,21-3,30 (m, 1H), 3,41-with 3.79 (m, 5H), 3,81 (c, 3H), 3,84-4,20 (m, 8H), 4,25 was 4.42 (m, 4H), 4,81-4,91 (m, 2H), 5,09-5,33 (m, 6H), 5,34-5,52 (m, 1H), 5,79-6,04 (m, 3H), 6,78 (d, J=8,86 Hz, 2H), 6.87 in (c, 1H), 7,03 (d, J=to 8.70 Hz, 2H), 7,21 (Sirs, 1H). ESI m/z = 637 (M+Na), 639 (M+2+Na).
The connection 311H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.36 (t, J=6,99 Hz, 3H), 3,03-3,17 (m, 1H), 3.46 in-a 4.03 (m, 10H), of 4.44-to 4.62 (m, 5H), 4,76-5,04 (m, 7H), 6,47 (c, 1H), 6,61-of 6.78 (m, 4H), 6,94-7,37 (m, 31H). A colorless oil.
The connection 321H NMR (300 MHz, CHLOROFORM-d) δ ppm was 1.15 (t, J=rate of 7.54 Hz, 3H), 2,22 (c, 3H), 2,54 (kV, J=rate of 7.54 Hz, 2H), 3,06-and 3.16 (m, 1H), 3,49-4,07 (m, 11H), 4,45 with 4.65 (m, 5H), 4,84-4,94 (m, 3H), 6,69-6,76 (m, 3H), 6,94 (c, 4H), 7,07-7,19 (m, 5H), 7,22-7,35 (m, 14H). ESI m/z = 801 (M+Na). A colorless oil.
The connection 331H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14 in (t, J=7,Hz, 3H), 2,54 (kV, J=8,13 Hz, 2H), 3,06-and 3.16 (m, 1H), 3,53 (t, J=8,78 Hz, 1H), 3,64 is 4.13 (m, 10H), 4,46 with 4.65 (m, 5H), a 4.83-of 4.95 (m, 3H), 6,64-6,72 (m, 2H), 6.87 in-7,35 (m, 24H). ESI m/z = 821 (M+Na). A colorless oil.
The connection 341H NMR (300 MHz, CHLOROFORM-d) δ ppm 0,34-0,38 (m, 9H), 0,47 (c, 9H), 0,5 (c, 9H), 0,53 (c, 9H), and 1.56 (t, J=rate of 7.54 Hz, 3H), 2,96 (kV, J=7,51 Hz, 2H), 3,30 is-3.45 (m, 1H), 3,63 (t, J=8,16 Hz, 1H), 3,82-4,08 (m, 3H), 4,14 (c, 3H), 4,29 (DD, J=10,41, to 3.73 Hz, 1H), 4,35 (d, J=3,57 Hz, 2H), 4,73 (d, J=10,96 Hz, 1H), 7,20 (c, 1H), 7,42-7,51 (m, 4H), 7.62mm (c, 1H). ESI m/z = 749 (M+Na).
The connection 351H NMR (300 MHz, CHLOROFORM-d) δ ppm was 1.15 (d, J=at 6.84 Hz, 6H), 2,72-to 2.85 (m, 1H), 3,06 is 3.15 (m, 1H), 3,53 (t, J=9,17 Hz, 1H), 3,64-4,11 (m, 10H), of 4.44-4,63 (m, 5H), a 4.83-is 4.93 (m, 3H), to 6.67 (d, J=of 7.69 Hz, 2H), 6.89 in (s, 1H), 6,94 and 7.36 (m, 23H). A colorless oil.
Soedinenie1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2,21 (c, 3H), 2,24 (c, 3H), 3,07-3,18 (m, 1H), 3,55 (t, J=8,39 Hz, 1H), 3,64-4,07 (m, 10H), 4,47 with 4.64 (m, 5H), 4,84-4,94 (m, 3H), 6,69-6,77 (m, 3H), 6,91 (c, 4H), 7,07-7,20 (m, 5H), 7,22 and 7.36 (m, 14H). ESI m/z = 787 (M+Na). Colourless amorphous substance.
The connection 371H NMR (300 MHz, CHLOROFORM-d) δ ppm 1,15 (c, 3H), 1,17 (c, 3H), 2.23 to (c, 3H), 2,70-of 2.86 (m, 1H), 3,03-3,20 (m, 1H), 3,55 (t, J=8,94 Hz, 1H), 3,64-4,08 (m, 10H), 4,43-of 4.66 (m, 5H), 4.80 to 4,95 (m, 3H), 6,67-of 6.78 (m, 3H), 6,95 (c, 4H), 7,05-7,19 (m, 5H), 7,21-7,37 (m, 14H). ESI m/z = 815 (M+Na). Pale yellow amorphous substance.
Compound 381H NMR (300 MHz, CHLOROFORM-d) δ ppm 126 (t, J=7,15 Hz, 3H), 2,65 (kV, J=to 7.67 Hz, 1H), 3,06-3,24 (m, 1H), 3,50-3,61 (m, 1H), 3,71 (DD, J=9,87, 3,03 Hz, 1H), 3,78-4.09 to (m, 6H), to 4.52 (c, 2H), to 4.62 (t, J=10,34 Hz, 2H), 4,84-to 4.98 (m, 3H), 6.75 in-6,85 (m, 2H), 7,08-7,56 (m, 25H), 7,72 (d, J=2,02 Hz, 1H). ESI m/z = 796(M-H). Pale yellow powder.
Connection 391H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,06 be 3.29 (m, 1H), of 3.77-4,12 (m, 8H), 4,46-and 4.68 (m, 4H), 4,84-5,00 (m, 2H), 7,01 was 7.45 (m, 23H).
The connection 401H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.61 of (c, 9H), 3,06-is 3.21 (m, 1H), 3,51-to 3.64 (m, 1H), 3,66-of 3.77 (m, 1H), 3,78-4,06 (m, 5H), 4,48-of 4.67 (m, 4H), 4,84-of 4.95 (m, 3H), 6.75 in (DD, J=7,54, 1,79 Hz, 2H), 7,08-7,20 (m, 5H), 7.24 to 7,46 (m, 15H), to 7.77 (d, J=2,02 Hz, 1H). ESI m/z = 768 (M+NH4).
The connection 411H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.13 to 1.31 (m, 3H), 2,46-of 2.72 (m, 2H), 3.04 from-3,18 (m, 1H), 3,47-3,62 (m, 1H), 3,68-was 4.02 (m, 6H), 4,45-of 4.66 (m, 4H), 4,85-4,96 (m, 3H), of 6.49-to 6.80 (m, 3H), 6,92 to 7.62 (m, 27H). ESI m/z = 769 (M+Na). Colorless powder.
The connection 421H NMR (300 MHz, CHLOROFORM-d) δ ppm 1,22 (t, J=a 7.62 Hz, 3H), 2,62 (kV, J=a 7.62 Hz, 2H), 2.91 in-3,03 (m, 1H), 3,20 (t, J=9,01 Hz, 1H), 3,43-with 3.79 (m, 5H), 3,90-4,07 (m, 6H), 4.09 to 4,18 (m, 1H), 4,24-to 4.41 (m, 3H), 4.92 in-5,02 (m, 2H,), 5,09-5,32 (m, 6H), 5,50-to 5.66 (m, 1), 5,79-6,05 (m, 3H), of 6.61 (d, J=3,57 Hz, 1H), 6,85 (d, J=3.42 Hz, 1H), 7,07-7,16 (m, 4H). ESI m/z = 563 (M+Na). A yellow oil.
The connection 431H NMR (300 MHz, CHLOROFORM-d) δ ppm to 1.21 (t, J=a 7.62 Hz, 3H), 2,61 (kV, J=7,56 Hz, 2H), 3,06 is 3.15 (m, 1H), 3,53 (t, J=8,94 Hz, 1H), 3,68-3,98 (m, 8H), 4,47-of 4.54 (m, 3H), br4.61 (d, J=10,41 Hz, 1H), 4,87-4,94 (m, 3H), 6,61 is 6.67 (m, 2H), 7,01-7,39 (m, 26H). ESI m/z = 757 (M+Na). Colorless powder.
The connection 441H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.91 in-3,03 (m, 1H), 3,19 is 3.40 (m, 2H), 3,56-a 3.87 (m, 6H), 3,92-was 4.02 (m, 4H), 4,11-4,20 (m, 1H), 4,25-4,43 (m, 3H), 4.63 to-and 4.68 (m, 2H), 4.80 to of 4.95 (m, 2H), 5,09-of 5.48 (m, 7H), 5,81-6,04 (m, 3H), 7,00-7,39 (m, 8H). ESI m/z = 554 (M+NH4). Pale yellow oil.
The connection 451H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.61 of (c, 9H), 3,06-is 3.21 (m, 1H), 3,51-to 3.64 (m, 1H), 3,66-of 3.77 (m, 1H), 3,78-4,06 (m, 5H), 4,48-of 4.67 (m, 4H), 4,84-of 4.95 (m, 3H), 6.75 in (DD, J=7,54, 1,79 Hz, 2H), 7,08-7,20 (m, 5H), 7.24 to 7,46 (m, 15H), to 7.77 (d, J=2,02 Hz, 1H). ESI m/z = 759 (M+Na).
The connection 461H NMR (300 MHz, DMSO-d6) δ ppm to 1.21 (t, J=rate of 7.54 Hz, 3H), 2,65 (kV, 2H), to 3.58 (t, J=8,86 Hz, 1H), 3,69-of 3.85 (m, 3H), 3,89-4,16 (m, 3H), to 4.41-to 4.62 (m, 5H), 4,78-4,85 (m, 3H), of 6.65 (d, J=a 7.62 Hz, 2H), 7,01 for 7.12 (m, 3H, 7,16-7,22 (m, 2H), 7,26-7,35 (m, 15H), 7,40-7,71 (m, 6H). ESI m/z = 743 (M+Na). Colorless powder.
Connection 471H NMR (300 MHz, CHLOROFORM-d) δ ppm 1,66-of 1.81 (m, 2H), 1,88-2,02 (m, 2H), 3,05 is 3.15 (m, 1H), 3,47-3,59 (m, 3H), 3,64-4,00 (m, 10H), 4,33 was 4.42 (m, 1H), 4,46 (d, J=9,95 Hz, 1H), to 4.52 (c, 2H), 4,60 (d, J=10,41 Hz, 1H), 4,84-4,93 (m, 3H), 6,60 is 6.67 (m, 2H), 6,72-6,79 (m, 2H), 6,99-7,19 (m, 8H), 7,20-7,35 (m, 16H). ESI m/z = 824 (M+NH4). Colorless powder.
The connection 481H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.56 to of 1.66 (m, 2H), 1,68-of 1.92 (m, 6H), 3,06-3,14 (m, 1H), 3,52 (t, J=8,86 Hz, 1H), 3,67-3,74 (m, 1H), 3.75 to 3,98 (m, 7H), 4,42-4,70 (m, 5H), a 4.83-is 4.93 (m, 3H), 6,61 to 6.75 (m, 4H), 6,98-7,19 (m, 8H), 7,19-7,34 (m, 16H). ESI m/z = 808 (M+NH4). Colorless powder.
The connection 491H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,00-3,13 (m, 3H), 3,30-3,44 (m, 4H), 3,67-to 3.89 (m, 5H), 3,94-of 4.05 (m, 3H), 4,15-4,24 (m, 1H), 4,33 (d, J=5,75 Hz, 2H), 4,37-to 4.46 (m, 1H), 4,77-to 4.87 (m, 2H), 5,10-of 5.45 (m, 7H), 5,81-6,06 (m, 3H), 7,19-7,39 (m, 7H), 7,53 (DD, J=8,63, and 1.63 Hz, 1H), of 7.70 (d, J=a 7.62 Hz, 1H), 7,82 (d, J=8,39 Hz, 1H), 8,08 (c, 1H). ESI m/z = 593(M+Na). Colorless powder.
The connection 501H NMR (300 MHz, CHLOROFORM-d) δ ppm 2,98-3,18 (m, 5H), 3,40-was 4.02(m, 12H), 4,36-of 4.66 (m, 5H), 4,81 is equal to 4.97 (m, 3H), 6,58 is 7.50 (m, 28H). FAB m/z = 791 (M). A colorless oil.
The connection 511H NMR (300 MHz, CHLOROFORM-d) δ ppm 2,88 (c, 6H), 3,05-316 (m, 1H), 3,41-4,01 (m, 8H), 4,39 with 4.64 (m, 5H), 4,84-of 4.90 (m, 3H), 6,52-7,37 (m, 28H). ESI m/z = 772 (M+Na). A colorless oil.
The connection 521H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,05 is 3.15 (m, 1H), 3,52 (t, J=8,94 Hz, 1H), 3,66 of 3.75 (m, 1H), 3.75 to 3,98 (m, 10H), to 4.41 with 4.64 (m, 6H), a 4.83-of 4.95 (m, 3H), 6,60-6,79 (m, 4H), 6,98-7,19 (m, 8H), 7,22 and 7.36 (m, 16H). ESI m/z = 817 (M+Na). A colorless oil.
The connection 531H NMR (300 MHz, CHLOROFORM-d) δ ppm 2,96 (c, 3H), 3,05 (c, 3H), 3,06-3,14 (m, 1H), 3,52 (t, J=8,86 Hz, 1H), 3,68-3,74 (m, 1H), 3,76-of 3.96 (m, 7H), of 4.44-of 4.54 (m, 3H), 4,56-4,63 (m, 3H), 4,85-is 4.93 (m, 3H), of 6.65 (DD, J=7,93, of 1.55 Hz, 2H), 6,76-6,83 (m, 2H), 7,01-to 7.18 (m, 8H), 7,22-7,35 (m, 16H). ESI m/z = 825 (M+NH4). Colorless solid.
The connection 541H NMR (300 MHz, CHLOROFORM-d) δ ppm 2,35 (c, 6H), 2,68-of 2.81 (m, 2H), 3.04 from-and 3.16 (m, 1H), 3,52 (t, J=to 8.70 Hz, 1H), 3,66 is 3.76 (m, 1H), 3,76-4,10 (m, 9H), 4,47 (d, J=10,10 Hz, 1H), to 4.52 (c, 2H), 4,60 (d, J=of 10.72 Hz, 1H), 4,84-4,94 (m, 3H), of 6.65 (DD, J=7,85, 1,32 Hz, 2H), 6,72-for 6.81 (m, 2H), 7,00-to 7.18 (m, 8H), 7,20 and 7.6 (m, 16H). ESI m/z = 794 (M+H). Colorless solid.
The connection 551H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,06-3,14 (m, 1H), 3,52 (t, J=8,86 Hz, 1H), 3,67-3,74 (m, 1H), of 3.77-Android 4.04 (m, 11H), 4,47 (d, J=9,95 Hz, 1H), to 4.52 (c, 2H), 4,60 (d, J=of 10.72 Hz, 1H), 4,86-is 4.93 (m, 3H), 6,62 of 6.68 (m, 2H), 6.73 x-6,79 (m, 2H), 7,02-to 7.18 (m, 8H), 7,21-7,35 (m, 16H). ESI m/z = 784 (M+NH4). Colorless solid.
The connection 561H NMR (600 MHz, CHLOROFORM-d) δ ppm 3,03-of 3.12 (m, 1H), 3,50 (t, J=9,17 Hz, 1H), 3,70 (DD, J=9,86, 2,98 Hz, 1H), 3,76-a-3.84 (m, 2H), 3,86 (c, 3H), a 3.87-to 3.92 (m, 2H), 3,94 (d, J=to 10.09 Hz, 1H), 4,13-4,18 (m, 1H), 4,22-4,27 (m, 1H), to 4.46 (d, J=to 10.09 Hz, 1H), 4,51 (c, 2H), 4,59 (d, J=10,55 Hz, 1H), 4,85 (c, 2H), 4,89 (d, J=11,00 Hz, 1H), 6,69 (d, J=6,88 Hz, 2H), 6.87 in (d, J=9,17 Hz, 1H), 6,94 (c, 1H), 7,01 (t, J=EUR 7.57 Hz, 2H), to 7.09 (t, J=7,34 Hz, 1H), 7,12-7,16 (m, J=9,17 Hz, 2H), 7,20 (t, J=EUR 7.57 Hz, 1H), 7.23 percent-7,35 (m, 16H), 7,54 (d, J=7,79 Hz, 1H), to 7.67 (d, J=8,71 Hz, 1H). ESI m/z = 815 (M+Na). TPL 133,0-135°C. Colourless powder.
Connection 571H NMR (600 MHz, CHLOROFORM-d) δ ppm 3,02-3,14 (m, 1H), 3,51 (t, J=8,94 Hz, 1H), 3,70 (DD, J=9,63, a 2.75 Hz, 1H), 3,76-to 3.92 (m, 4H), of 3.96 (d, J=10,55 Hz, 1H), 4,24-4,30 (m, 1H), 4,32-4,39 (m, 1H), 4,48-of 4.54 (m, 3H), 4,58 (d, J=10,55 Hz, 1H), 4,81-4,91 (m, 3H), 6,70 (d, J=7,34 Hz, 2H), 6,95 (c, 1H), 7,07 (t, J=EUR 7.57 Hz, 2H), 7,11-7,42 (m, 21H), 7,56 (d, J=7,79 Hz, 1H), 7,68 (d, J=7,79 Hz, 1H). ESI m/z= 819 (M+Na). TPL 140,0-143,0°C. Colourless powder.
The connection 581H NMR (600 MHz, CHLOROFORM-d) δ ppm is 3.08-3,14 (m, 1H), 3,53 (t, J=8,94 Hz, 1H), 3,71 (DD, J=9,63, a 2.75 Hz, 1H), of 3.77-3,88 (m, 2H), 3,88-of 3.97 (m, 3H), 4,16-of 4.25 (m, 2H), 4,48 (d, J=9,63 Hz, 1H), to 4.52 (c, 2H), 4,59 (d, J=11,00 Hz, 1H), 4,85-4,91 (m, 3H), to 6.67 (d, J=6,88 Hz, 2H), 6,97 (c, 1H), 7.03 is-to 7.09 (m, J=6,65, of 6.65 Hz, 2H), 7,10-7,16 (m, 3H), 7,19-7,42 (m, 19H), EUR 7.57 (d, J=7,79 Hz, 1H), 7,68 (d, J=of 8.25 Hz, 1H). ESI m/z = 785 (M+Na). Pale yellow solid.
Connection 591H NMR (600 MHz, CHLOROFORM-d) δ ppm 3,09 is 3.15 (m, 1H), 3,53-to 3.58 (m, 1H), 3,66-3,74 (m, 1H), 3,81 (c, 4H), 3,91 (t, J=9,63 Hz, 2H), 3,98-Android 4.04 (m, 1H), 4.09 to 4,19 (m, 2H), 4,48-of 4.54 (m, 3H), 4,58-of 4.67 (m, 2H), a 4.83-4.92 in (m, 3H), 6,69 (d, J=6,88 Hz, 2H), 8,84-6,94 (m, 2H), 7,07-7,35 (m, 21H), 7,45-7,66 (m, 3H). ESI m/z = 815 (M+Na). Colorless powder.
The connection 601H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,06-3,18 (m, 1H), 3,54 (t, J=9,17 Hz, 1H), 3,63-or 4.31 (m, 13H), of 4.44 with 4.64 (m, 5H), 4,82-of 4.95 (m, 3H), 6,47 (c, 1H), 6,72 (d, J=was 9.33 Hz, 2H), 6,88 (c, 1H), 7,00-7,52 (m, 22H), 7,58-to 7.67 (m, 1H). ESI m/z = 845 (M+Na). Colourless amorphous substance.
The connection 611H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,03-,15 (m, 1H), 3.46 in of 3.56 (m, 1H), 3,66-was 4.02 (m, 6H), 4,11-the 4.29 (m, 2H), 4,48-4,63 (m, 4H), of 4.83-is 4.93 (m, 3H), 6,28 (c, 1H), of 6.71 (DD, J=8,16, 1,32 Hz, 2H),? 7.04 baby mortality-7,19 (m, 6H), 7,22-the 7.43 (m, 19H). ESI m/z = 798 (M+NH4). Pink powder.
The connection 621H NMR (300 MHz, CHLOROFORM-d) δ ppm of 3.07-3.15 in (m, 1H), 3,53 (t, J=8,94 Hz, 1H), 3,68 of 3.75 (m, 1H), 3,78-4,00 (m, 5H), 4,07-4,17 (m, 2H), 4,46-of 4.54 (m, 3H), 4,60 (d, J=10,57 Hz, 1H), 4,86-is 4.93 (m, 3H), 6,65-of 6.71 (m, J=7,54, 1,94 Hz, 2H), 6.75 in (d, J=3,89 Hz, 1H), 7,06-7,17 (m, 7H), 7.24 to 7,40 (m, 17H), 7,47-7,53 (m, 1H), 7,58-the 7.65 (m, 1H), 8,48-charged 8.52 (m, 1H). ESI m/z = 790 (M+H). Colorless powder.
Connection 631H NMR (300 MHz, CHLOROFORM-d) δ ppm 1,22 (t, J=a 7.62 Hz, 3H), 2,62 (kV, J=a 7.62 Hz, 2H), 2.91 in-3,03 (m, 1H), 3,20 (t, J=9,01 Hz, 1H), 3,43-with 3.79 (m, 5H), 3,90-4,07 (m, 6H), 4.09 to 4,18 (m, 1H), 4,24-to 4.41 (m, 3H), 4.92 in-5,02 (m, 2H,), 5,09-5,32 (m, 6H), 8,50-to 5.66 (m, 1H), 5,79-6,05 (m, 3H), of 6.61 (d, J=3,57 Hz, 1H), 6,85 (d, J=3.42 Hz, 1H), 7,07-7,16 (m, 4H). ESI m/z = 611 (M+Na). A yellow oil.
The connection 641H NMR (300 MHz, CHLOROFORM-d) δ ppm of 3.53 (t, J=8,86 Hz, 1H), 3,66 is 3.76 (m, 1H), 3,67-3,74 (m, 1H), of 3.77-4.00 points (m, 5H), 4,18 (c, 2H), 4,45-of 4.54 (m, 3H), 4,60 (d, J=10,57 Hz, 1H), 4,86-4,94 (m, 3H), to 6.67 (DD, J=8,00, 1,32 Hz, 2H,), 6,90 (c, 1H), 7.03 is-7,41 (m, 24H). ESI m/z = 791 (M+Na).
The connection 651H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.04 from-and 3.16 (m, 1H), 3,32 (c, 3H), 3,53 (t, J=to 8.70 Hz, 1H), 3,67 of 3.75 (m, 1H), 3.75 to 4.00 points (m, 7H), 4,46-4,56 (m, 3H), 4,60 (d, J=10,57 Hz, 1H), 4,84-4,96 (m, 3H), of 5.89 (DD, J=to 3.73, of 1.55 Hz, 1H), 6,04 (t, J=3,03 Hz, 1H), of 6.49-is 6.54 (m, 1H), 6,70 (DD, J=7,62, 1,71 Hz, 2H), 7,05-to 7.18 (m, 7H), 7,22 and 7.36 (m, 14H), 7,39-7,46 (m, 1H). ESI m/z = 710 (M+H), 732 (M+Na).
Compound 661H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,06-3,17 (m, 1H), 3,54 (t, J=8,78 Hz, 1H), 3,68 of 3.75 (m, 1H), of 3.77-4,01 (m, 5H), 4,43 (c, 2H), 4,46-4,56 (m, 3H), 4,60 (d, J=10,57 Hz, 1H), 4,85-4,94 (m, 3H), to 6.67 (DD, J=7,93, 1,40 Hz, 2H,), 7,00-7,19 (m, 6H), 7,21-7,51 (m, 18H), 7,71 (d, J=7,31 Hz, 1H), of 7.97 (d, J=8,08 Hz, 1H). ESI m/z = 764 (M+H), 786 (M+Na).
Connection 671H NMR (300 MHz, CHLOROFORM-d) δ ppm of 1.40 (t, J=6,99 Hz, 3H), 2.93 which is a 3.06 (m, 1H), 3,25 (t, J=8,94 Hz, 1H), 3,30-3,44 (m, 1H), 3,49-of 4.05 (m, 12H), is 4.15 (DD, J=12,05, 5,98 Hz, 1H), 4,24 was 4.42 (m, 3H), 4.80 to to 4.92 (m, 2H), 5.08 to 5,42 (m, 7H), 5,78-6,03 (m, 3H), for 6.81 (d, J=to 8.70 Hz, 2H), 7,03 (d, J=to 8.70 Hz, 2H), of 7.48 (c, 1H), 8,42 (DD, J=16,16, 2,18 Hz, 2H). ESI m/z = 552 (M+H).
The connection 681H NMR (300 MHz, CHLOROFORM-d) δ ppm 2,31 (c, 3H), 2,99-3,10 (m, 1H), 3.27 to is 3.40 (m, 2H), 3,66-a 3.87 (m, 5H), 4.00 points (d, J=5,75 Hz, 2H), 4,15-4.26 deaths (m, 4H), or 4.31 (d, J=6,84 Hz, 2H), and 4.40 (DD, J=12,05, of 5.83 Hz, 1H), 4.63 to-4,82 (m, 2H,), 5,09 lower than the 5.37 (m, 7H), 5,80-6,07 (m, 3H),? 7.04 baby mortality-7,17 (m, 5H), 7,32 (m, 1H), 7,41 (c, 1H), ,89 (d, J=to 7.93 Hz, 1H). ESI m/z = 599 (M+Na). Yellow powder.
Connection 691H NMR (300 MHz, CHLOROFORM-d) δ ppm 2,28 (c, 3H), 3,07-and 3.16 (m, 1H), 3,53 (t, J=8,78 Hz, 1H), 3,68-of 3.97 (m, 6H), 4,49-4,63 (m, 5H), 4,86-4,91 (m, 2H), 4,99 (d, J=3,11 Hz, 2H), of 6.68 (DD, J=7,85, 1,63 Hz, 2H), 6,76 (d, J=1,24 Hz, 1H), 6,92-7,00 (m, 2H), 7,08-7,19 (m, 6H), 7.23 percent-7,44 (m, 15H). ESI m/z = 711 (M+H).
The connection 701H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,05-3,14 (m, 1H), 3.46 in of 3.56 (m, 1H), 3,66-3,74 (m, 1H), 3,76-to 3.92 (m, 5H), 3,95 (c, 3H), 4,46 (d, J=10,10 Hz, 1H), to 4.52 (c, 2H), 4,59 (d, J=10,57 Hz, 1H), 4,84-is 4.93 (m, 3H), 5.25-inch (d, J=2,49 Hz, 2H), 6,46-7,39 (m, 29H). ESI m/z = 793 (M+NH4).
Connection 711H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,05-3,17 (m, 1H), 3,47-of 3.60 (m, 1H), 3,66-3,99 (m, 6H), 4,15 (c, 1H), 4,43-4,70 (m, 5H), 4,84-of 4.95 (m, 3H), 6,60-of 6.73 (m, 2H), 6,97-7,20 (m, 6H), 7,19-7,49 (m, 17H), 7,78-7,87 (m, 1H), at 8.36-8,43 (m, 1H), 8,65-8,73 (m, 1H). ESI m/z = 708 (M+H), 730 (M+Na). Pale yellow powder.
Soedinenie1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,05 is 3.15 (m, 1H), 3,52 (t, J=8,94 Hz, 1H), 3,66 of 3.75 (m, 1H), 3.75 to 4,01 (m, 5H), 4,28 (c, 2H), 4,46 (d, J=9,79 Hz, 1H), to 4.52 (c, 2H), 4,60 (d, J=of 10.72 Hz, 1H), 4,85-of 4.95 (m, 3H), 6,55-6,62 (m, 2H), 6,98-7,37 (m, 22H), 7,49 (c, 1H), 8,5 (d, J=equal to 4.97 Hz, 2H). ESI m/z = 731 (M+Na). 709 (M+H).
Connection 731H NMR (300 MHz, CHLOROFORM-d) δ ppm 3,05-and 3.16 (m, 1H), 3,48-to 3.58 (m, 1H), 3,66 of 3.75 (m, 1H), of 3.77-3,99 (m, 5H), 4,15 (c, 2H), 4,45-4,55 (m, 3H), 4,60 (d, J=10,57 Hz, 1H), 4,84-4,P5 (m, 3H), 6,62 (d, J=6,84 Hz, 2H), 7,02-7,19 (m, 6H), 7,20-7,42 (m, 16H), at 8.36 (d, J=2,64 Hz, 1H), 8,40-of 8.47 (m, 1H), 8,67 (c, 1H). ESI m/z = 731 (M+Na).
The connection 741H NMR (300 MHz, METHANOL-d4) δ ppm 1,19 (t, J=7,6 Hz, 3H), 2,58 (kV, J=7,6 Hz, 2H), 2.95 and-3,03 (m, 1H), 3,20 of 3.28 (m, 1H), 3,60 (DD, J=10,3, 9.0 Hz, 1H), 3,70-of 3.78 (m, 3H), 3,88-3,98 (m, 3H), 7,09 (Sirs, 5H), 7,17-of 7.23 (m, 3H). SI m/z = 397 (M+Na), 373 (M-H).
Connection 751H NMR (300 MHz, METHANOL-d4) δ ppm of 1.35 (t, J=7.0 Hz, 3H), 2,92-3,03 (m, 1H), 3,19 of 3.28 (m, 1H)and 3.59 (DD, J=10,2, 9.1 Hz, iH), 3,69-of 3.78 (m, 3H), 3,88 (c, 2H), 3,90-Android 4.04 (m, 3H), to 6.80 (d, J=8.7 Hz, 2H),? 7.04 baby mortality-7,11 (m, 3H), 7,14-7,25 (m, 3H). ESI m/z = 413 (M+Na), 389 (M-H).
The connection 761H NMR (300 MHz, METHANOL-d4) δ ppm of 1.36 (t, J=7.0 Hz, 3H), 2,94-3,03 (m, 1H), up 3.22 (t, J=8,2 Hz, 1H), only 3.57 (DD, J=10,3, 9.0 Hz, 1H), 3,65-of 3.78 (m, 3H), 3,89-of 4.05 (m, 5H), to 6.80 (d, J=8.7 Hz, 2H), was 7.08 (d, J=8.7 Hz, 2H), 7,16-of 7.23 (m, 2H), to 7.32 (d, 1H). ESI m/z = 447, 449 (M+Na). TPL 79,0-83°C.
Connection 771H NMR (300 MHz, METHANOL-d4) δ ppm of 1.35 (t, J=7.0 Hz, 3H), 2.91 in-a 3.01 (m, 1H), 3,18-of 3.25 (m, 1H), only 3.57 (DD, J=10,3, 9.0 Hz, 1H), 3,68 is 3.76 (m, 3H), 3,79 (c, 3H), 3,84 (c, 2H), 3,89-was 4.02 (m, 3H), 6,76 (d, J=8.7 Hz, 2H), to 6.88 (d, J=8.7 Hz, 1H), 7.03 is-7,11 (m, 3H), 7,17 (DD, J=8,6, and 2.3 Hz, 1H). ESI m/z = 443 (M+Na). 419 (M-H), TPL 89,0-95°C.
The connection 781H NMR (600 MHz, METHANOL-d4) δ ppm 1,33 (t,J=7,1 Hz, 3H), 2,90 are 2.98 (m, 1H), up 3.22 (t, J=8,9 Hz, 1H), 3,51-3,61 (m, 1H), 3,65-3,74 (DD, J=11,5, 6.4 Hz, 1H), 3,76-a-3.84 (m, 6H), 3,91 (DD, J=11,5, and 3.7 Hz, 1H), 3.96 points (kV, J=7,1 Hz, 2H), or 4.31 (Sirs, 1H), 6,77 (d, J=8.7 Hz, 2H), 6,85 (d, J=8.7 Hz, 1H), 7,00 (DD, J=8,7, 2.3 Hz, 1H),? 7.04 baby mortality (d, J=8.7 Hz, 2H), 7,16 (Sirs, 1H). ESI m/z = 443 (M+Na). TPL 130,0-130,5°C.
Connection 791H NMR (300 MHz, METHANOL-d4) δ ppm 1,37 (t, J=7.0 Hz, 3H), 2,94 was 3.05 (m, 1H), 3,22-3,29 (m, 1H), 3,60 (m, 1H), 3,69-3,88 (m, 4H), 3,90-Android 4.04 (m, 3H), 4,33 (d, J=a 10.6 Hz, 1H), of 6.71 (d, J=8,2 Hz, 1H), 6,76-of 6.90 (m, 3H), 7.03 is-to 7.15 (m, 3H). ESI m/z = 429 (M+Na). 405 (M-H), TPL 145,0 150°C.
The connection 801H NMR (300 MHz, METHANOL-d4) δ ppm of 1.34 (t, J=7.0 Hz, 3H), 2,88-2,99 (m, 1H), up 3.22 (t, J=8,8 Hz, 1H), 3,51-3,59 (m, 1H), 3,66-with 3.79 (m, 4H), 3,81 (c, 3H), 3,84(c, 3H), 3,88-4,01 (m, 3H), 4,21-4,32 (m, 1H), 6,57 (c, 1H), 6.75 in (d, J=8.7 Hz, 2H), 7,03 (c, 1H),? 7.04 baby mortality (d, J=8.7 Hz, 2H). ESI m/z = 449 (M+Na). TPL 158,0-160,0°C.
Connection 811H NMR (300 MHz, METHANOL-d4) δ ppm of 1.35 (t, J=7.0 Hz, 3H), 2.91 in-3,03 (m, 1H), 3,19-of 3.25 (m, 1H), to 3.58 (DD, J=10,3, 9.0 Hz, 1H), 3,68-with 3.79 (m, 3H), 3,86-Android 4.04 (m, 5H), 6,77-PC 6.82 (m, 2H), 6,95? 7.04 baby mortality (m, 1H), 7,07 for 7.12 (m, 2H), 7,15-7,24 (m, 2H). ESI m/z = 431 (M+Na). TPL 60,0-65,0°C.
The connection 821H NMR (300 MHz, METHANOL-d4) δ ppm of 1.35 (t, J=6.9 Hz, 3H), 2,89 are 2.98 (m, 1H), 3,16-3,24 (m, 1H), of 3.56 (DD, J=10,2, 9.0 Hz, 1H), 3,60 is 3.76 (m, 3H), 3,83 (Sirs, 2H), 3,88-3,95 (m, 1H), 3,98 (kV, J=6,9 Hz, 2H), 6,69-to 6.80 (m, 3H), of 6.96? 7.04 baby mortality (m, 2H,), 7,06-to 7.15 (m, 2H). ESI m/z = 424 (M+NH4), 405 (M-H).
Connection 831H NMR (600 MHz, METHANOL-d4) δ ppm of 1.40 (t, J=7,1 Hz, 3H), 2,94 totaling 3.04 (m, 1H), 3,23 (t, J=8,9 Hz, 1H), to 3.58 (DD, J=10,3, a 8.9 Hz, 1H), 3,67-with 3.79 (m, 3H), of 3.94 (DD, J=11,5, 3.2 Hz, 1H), 3.96 points-Android 4.04 (m, 2H), 4,07 (kV, J=7,1 Hz, 2H), 6,79 (DD, J=11,2, 7,1 Hz, 1H), 6.87 in (DD, J=11,2, 7,1 Hz, 1H), 7,20 (d, J=2.3 Hz, 1H), 7,24 (DD, J=8,3, 2.3 Hz, 1H), 7,35 (d, J=8,3 Hz, 1H). ESI m/z = 483 (M+Na), 459 (M-H). TPL 72,0-76,0°C.
The connection 841H NMR (600 MHz, METHANOL-d4
Connection 851H NMR (600 MHz, METHANOL-d4) δ ppm of 1.40 (t, J=6.9 Hz, 3H), 2,96-3,03 (m, 1H), 3,23 (t, J=8,9 Hz, 1H), to 3.58 (DD, J=10,3, a 8.9 Hz, 1H), 3,68-of 3.80 (m, 3H), of 3.94 (DD, J=11,7, 3,4 Hz, 1H), 3.96 points-Android 4.04 (m, 2H), 4,06 (kV, J=6,9 Hz, 2H), 6,93 (d, J=8.5 Hz, 1H), 7,05 (DD, J=8,5, 2.3 Hz, 1H), 7,16 (d, J=2.3 Hz, 1H), 7,20-7,27 (m, 2H), 7,34 (d, J=7.8 Hz, 1H). ESI m/z = 481 (M+Na), 483 (M+2+Na), 485 (M+4+Na), 457 (M-H), 459 (M+2-H), 461 (M+4-H). TPL 79,0-82,0°C. Anal. Rasch. for C21H24ClO5S·0,5H2O: C, 53,84; H, 5,39. Found: C, 53,64; H, 5,39.
Connection 861H NMR (300 MHz, METHANOL-d4) δ ppm of 1.35 (t, J=6.9 Hz, 3H), 2,17 (c, 3H), 2,93-3,03 (m, 1H), 3,19 of 3.28 (m, 1H)and 3.59 (DD, J=10,2, 9.0 Hz, 1H), 3,68-with 3.79 (m, 3H), 3,89 (Sirs, 2H), 3,93 (DD, J=7,9, and 3.7 Hz, 1H), of 3.97 (q, 2H), 6,74-PC 6.82 (m, 2H), of 6.96? 7.04 baby mortality (m, 2H), 7,05-to 7.15 (m, 3H). ESI m/z = 422 (M+NH4), 403 (M-H).
Connection 871H NMR (600 MHz, METHANOL-d4) δ ppm 2,94-3,00 (m, 1H), 3,17-3,24 (m, 1H), 3,55 (DD, J=10,3, a 8.9 Hz, 1H), 3,61 of 3.75 (m, 4H), of 3.77 (c, 3H), 3,78 (c, 3H), 3,88-3,98 (m, 2H), 6.42 per (DD, J=8,3,,3 Hz, 1H), of 6.52 (d, J=2.3 Hz, 1H), make 6.90 (d, J=8,3 Hz, 1H), to 7.09 (d, J=2.3 Hz, 1H), 7,16 (DD, J=8,3, 2.3 Hz, 1H), 7,30 (d, J=8,3 Hz, 1H). ESI m/z = 463 (M+Na), 465 (M+2+Na), 439 (M-H).
The connection 881H NMR (600 MHz, METHANOL-d4) δ ppm 2,96-a 3.01 (m, 1H), 3,21-of 3.25 (m, 1H), only 3.57 (DD, J=10,3, a 8.9 Hz, 1H), 3,66-3,74 (m, 3H), 3.75 to (c, 3H), 3,93 (DD, J=11,5, and 3.7 Hz, 1H), 3,98-of 4.05 (m, 2H), PC 6.82 (d, J=8.7 Hz, 2H), to 7.09 (d, J=8.7 Hz, 2H), 7.18 in-7,22 (m, 2H), 7,32 (d, J=8,3 Hz, 1H). ESI m/z = 428 (M+NH4+), 430 (M+2+NH4+), 409 (M-H), 411 (M+2-H). TPL 71,0-74,0°C. Anal. Rasch. for C20H23ClO5S: C, 58,46; H, 5,46. Found: C, 58,35, H, 5,55.
Connection 891H NMR (600 MHz, METHANOL-d4) δ ppm of 1.35 (t, J=6.9 Hz, 3H), 2,17 (c, 3H), 2,92-a 3.01 (m, 1H), 3,24 (t, J=8,71 Hz, 1H), 3,54-of 3.60 (m, 1H), and 3.72 (DD, J=11,5, 6.4 Hz, 1H), 3,81 (c, 3H), 3,83 (c, 2H), 3,94 (DD, 1=11,5, and 3.7 Hz, 1H), 3,97 (kV, J=6,9 Hz, 2H), 4,33 (c, 1H),6,77 (d, J=8,3 Hz, 2H), 6,76 (c, 1H), 6,99 (d, J=8,3 Hz, 2H), 7,10 (c, 1H). ESI m/z = 452 (M+NH4+), 493 (M+CH3CO2-). TPL 155,0-157,0°C. Anal. Rasch. for C23H30O6S·0,5H2O: C, 62,28; H, 7,06. Found: C, 62,39; H, 7,10.
Connection 901H NMR (300 MHz, METHANOL-d4) δ ppm 1,29 (c, 9H), 2,90 was 3.05 (m, 1H), 3,23 (t, J=8.7 Hz, 1H), to 3.58 (DD,J=10,1, 8,7 Hz, 1), 3,64-of 3.80 (m, 3H), of 3.94 (DD, J=11,4, 3.5 Hz, 1H), 4.04 the (c, 2H), 7,10 (d, J=8,2 Hz, 2H), 7,16-7,37 (m, 5H). ESI m/z = 454 (M+NH4+), 456 (M+2+NH4+), 435 (M-H), 437 (M+2-H). TPL 94,0-100,0°C. Anal. Rasch. for C23H29ClO4S: C, 63,22; H, 6,69. Found: C, 62,82; H, 6,64.
Connection 911H NMR (300 MHz, METHANOL-d4) δ ppm of 1.36 (t, J=7.0 Hz, 3H), 2.93 which was 3.05 (m, 1H), 3,18-of 3.27 (m, 1H), to 3.58 (DD, J=10,3, 9.0 Hz, 1H), 3,67-of 3.78 (m, 3H), 3,89-Android 4.04 (m, 5H), 6,58-6,69 (m, 2H), 6,97 (t, 1=a 8.9 Hz, 1H), 7,11-7,24 (m, 2H), 7,33 (d, 1H). ESI m/z = 465 (M+Na), 441 (M-H).
The connection 921H NMR (300 MHz, METHANOL-d4) δ ppm 2,28 (c, 3H), 2,94-to 3.02 (m, 1H), 3,18-3,26 (m, 1H), only 3.57 (DD, J=10,2, a 8.9 Hz, 1H), 3,65-of 3.77 (m, 3H), 3,93 (DD, J=11,4, and 3.7 Hz, 1H), was 4.02 (c, 2H), 7,02-7,10 (m, 4H), 7,16-7,24 (m, 2H), 7,29-7,35 (m, 1H). ESI m/z = 412, 414 (M+Na). 393 (M-H).
Connection 931H NMR (600 MHz, METHANOL-d4) δ ppm 2,43 (c, 3H), 2.95 and-3,03 (m, 1H), 3,23 (t, J=8.7 Hz, 1H), to 3.58 (DD, J=10,3, a 8.9 Hz, 1H), 3,68-of 3.77 (m, 3H), 3,93 (DD, J=11,5, 3.2 Hz, 1H), EUR 4.00-4.09 to (m, 2H), 7,09-7,13 (m, 2H), 7,15-7,19 (m, 2H), 7,21 (DD, J=to 8.3, 2.3 Hz, 1H), 7.23 percent (d, J=2.3 Hz, 1H), 7,33 (d, J=8,3 Hz, 1H). ESI m/z = 449 (M+Na), 451 (M+2+Na), 425 (M-H), 427 (M+2-H).
Connection 94 1H NMR (300 MHz, METHANOL-d4) δ ppm 2.93 which was 3.05 (m, 1H), 3,18 of 3.28 (m, 1H), 3,54-to 3.64 (m, 1H), 3,66-of 3.78 (m, 3H), 3,89-3,99 (m, 3H), 6,69 (d, J=8.6 Hz, 2H), 6,99 (d, J=8.6 Hz, 2H), 7,15-7,22 (m, 2H), 7,31 (d, 1H). ESI m/z = 419 (M+Na), 395 (M+H).
Connection 951H NMR (300 MHz, METHANOL-d4) δ ppm of 1.20 (t, J=a 7.62 Hz, 3H), 2,59 (kV, J=a 7.62 Hz, 2H), 2,94-3,03 (m, 1H), 3,18-of 3.27 (m, 1H), only 3.57 (DD, J=10,26, 9,01 Hz, 1H), 3,66-of 3.78 (m, 3H), 3,93 (DD, J=11,50, of 3.57 Hz, 1H), 4,03 (c, 2H), 7,06-7,11 (m, 4H), 7,17-7,25 (m, 2H), 7,33 (d, J=8,08 Hz, 1H). ESI m/z = 431,433 (M+Na), 407 (M-H).
Connection 961H NMR (300 MHz, METHANOL-d4) δ ppm 1,20 (c, 3H), 1,22 (c, 3H), was 2.76 of 2.92 (m, 1H), 2,94-3,03 (m, 1H), 3,19-of 3.27 (m, 1H), to 3.58 (DD, J=10,1, and 9.2 Hz, 1H), 3,66-with 3.79 (m, 3H), of 3.94 (DD, J=11,4, 3.6 Hz, 1H), 4,03 (c, 2H), 7,06-to 7.15 (m, 4H), 7,17-7,26 (m, 2H), 7,33 (d, 1H). ESI m/z = 445,447 (M+Na), 421 (M-H).
Connection 971H NMR (300 MHz, METHANOL-d4) δ ppm 1,37 (t, J=6.9 Hz, 3H), 2,17 (c, 3H), 2,90-a 3.01 (m, 1H), 3,14-3,24 (m, 1H), 3,54 (DD, J=10,3, and 9.2 Hz, 1H), 3,60 is 3.76 (m, 3H), 3,86-4,06 (m, 5H), of 6.66 (DD, J=8,6, 2.7 Hz, 1H), 6.75 in (d, J=3.0 Hz, 1H), 6,85-to 6.95 (m, 2H), 7,19 (DD, J=8,2, 2.2 Hz, 1H), 7,35 (d, J=8,2 Hz, 1H). ESI m/z = 461 (M+Na), 437 (M-H). Anal. Rasch. for C22H27O5ClS·0,6H2O: C, 58,59; H, 6,33. Found: C, 58,28; H, 6,10.
Connection 98 1H NMR (300 MHz, METHANOL-d4) δ ppm of 1.35 (t, J=7.0 Hz, 3H), 2,08 (c, 3H), 2,92 totaling 3.04 (m, 1H), 3,22-of 3.27 (m, 1H)and 3.59 (DD, J=10,3, a 8.9 Hz, 1H), 3,69-3,88 (m, 4H), 3,89-a 4.03 (m, 3H), 4,29 (d, J=10,57 Hz, 1H), 6,60 (c, 1H), 6.73 x-to 6.80 (m, 2H), 6,95-7,02 (m, 2H),? 7.04 baby mortality (c, 1H). ESI m/z = 443 (M+Na), 419 (M-H). TPL USD 183.0-187,0°C. Anal. Rasch. for C22H28O6S·0,5H2O: C, 61,00; H, 6,86. Found: C, 60,81; H, 6.89 In.
Connection 991H NMR (600 MHz, METHANOL-d4) δ ppm of 1.35 (t, J=6.9 Hz, 3H), 2,92-3,00 (m, 1H), up 3.22 (t, J=8,9 Hz, 1H), 3,53-3,59 (m, 1H), and 3.72 (DD, J=11,7, 6,7 Hz, 1H), 3,82 (c, 3H), 3,88-3,95 (m, 3H), 3,99 (kV, J=6,9 Hz, 2H), 6,79 (d, J=8.7 Hz, 2H), 6,98 (c, 1H), 7,06 (d, J=8,71 Hz, 2H), 7,20 (c, 1H). ESI m/z = 477 (M+Na), 479 (M+2+Na), 453 (M-H), 455 (M+2-H). TPL 177,0 debt-179.0°C. Anal. Rasch. for C22H27ClO6S·0,7H2O: C, 56,95; H, 6,10. Found: C, 56,89; H, 5,98.
Connection 1001H NMR (600 MHz, METHANOL-d4) δ ppm of 1.35 (t, J=7,1 Hz, 3H), 2,89 are 2.98 (m, 1H), 3,19-3,26 (m, 1H), 3,52-to 3.58 (m, 1H), 3,68-with 3.79 (m, 4H), to 3.92 (DD, J=11,5, and 3.7 Hz, 1H), 3,97 (kV, J=7,1 Hz, 2H), 4,21 (d, J=10.1 Hz, 1H), 6,32 (c, 1H), 6,76 (d, J=8.7 Hz, 2H), 6,91 (c, 1H), was 7.08 (d, J=8.7 Hz, 2H). ESI m/z = 445 (M+Na), 421 (M-H), TPL of 186.0-190,0°C.
Soedinenie 1H NMR (300 MHz, METHANOL-d4) δ ppm 1,19 (t, J=7,6 Hz, 3H), 2,17 (c, 3H), 2,58 (kV, J=7,6 Hz, 2H), 2.91 in-to 3.02 (m, 1H), 3,19 of 3.28 (m, 1H), to 3.58 (DD, J=10,3, and 9.2 Hz, 1H), 3,67-to 3.89 (m, 7H), of 3.94 (DD, J=11,5, and 3.7 Hz, 1H), 4,25-4,39 (m, 1H), 6,76 (c, 1H), of 6.96-to 7.09 (m, 4H), 7,12 (c, 1H). ESI m/z = 441 (M+Na), 417 (M-H).
Connection 1021H NMR (300 MHz, METHANOL-d4) δ ppm of 1.23 (t, J=7,6 Hz, 3H), 2,62 (kV, J=7,6 Hz, 2H), 2,93-of 3.07 (m, 1H), 3.27 to (t, J=8,8 Hz, 1H), 3,60 (t, 1H), 3,70-4.09 to (m, 8H), 4,25-4,39 (m, 1H), 6,99-to 7.18 (m, 5H), 7,27 (c, 1H). ESI m/z = 461 (M+Na). Anal. Rasch. for C22H27ClO5S·H2O: C, 56,70; H, 6,50; Found: C, 56,40; H, 6,45.
Connection 1031H NMR (600 MHz, METHANOL-d4) δ ppm to 1.21 (d, J=7,3 Hz, 6H), 2,79-is 2.88 (m, 1H), 2,94-a 3.01 (m, 1H), 3,23 (t, J=8,9 Hz, 1H), 3,53-3,61 (m, 1H), 3,69 is 3.76 (m, 2H), 3,82 (c, 3H), 3,91-was 4.02 (m, 3H), 4,24 is 4.36 (m, 1H), 6,99 (c, 1H), 7,05-7,14 (m, 4H), 7,24 (c, 1H). ESI m/z = 475 (M+Na).
The connection 1041H NMR (600 MHz, METHANOL-d4) δ ppm 2,16 (c, 3H), and 2.27 (c, 3H), 2,94-2,99 (m, 1H), 3,24 (m, 1H), 3,55-of 3.60 (m, 1H), and 3.72 (DD, J=11,5, 6.4 Hz, 1H), of 3.77-3,90 (m, 6H), of 3.94 (DD, J=11,5, and 3.7 Hz, 1H), 6,76 (c, 1H), 6,97 (m, 2H), 7,00? 7.04 baby mortality (m, 2H,), 7,11 (c, 1H). ESI m/z = 427 (M+Na), 403 (M-H).
Connection 105 1H NMR (600 MHz, METHANOL-d4) δ ppm 1,20 (c, 3H), 1,21 (c, 3H), 2,17 (c, 3H), 2,80-of 2.86 (m, 1H), 2,94-2,99 (m, 1H), 3,25 (m, 1H), to 3.58 (DD, J=10,1, and 9.2 Hz, 1H), and 3.72 (DD, J=11,2, 6,6 Hz, 1H), of 3.77-3,91 (m, 6H), of 3.94 (DD, J=11,5, and 3.7 Hz, 1H), 6,76 (c, 1H), 7,00 (d, J=8,3 Hz, 2H), was 7.08 (d, J=8,3 Hz, 2H), 7,13 (c, 1H). ESI m/z = 455 (M+Na), 431 (M-H).
The connection 1061H NMR (600 MHz, METHANOL-d4) δ ppm of 1.23 (t, J=EUR 7.57 Hz, 3H), 2,64 (kV, J=7,79 Hz, 2H), 3.00 and-of 3.07 (m, 1H), 3.27 to (t, J=8,71 Hz, 1H), 3,59-3-64 (m, 1H), of 3.73-3,82 (m, 2H), 3,89 (d, J=to 10.09 Hz, 1H), 3,95 (DD, J=of 11.69, 3,44 Hz, 1H), 7,20 (d, J=8,25 Hz, 2H), 7,47 (c, 2H), 7,53 (c, 1H), 7,56 (d, J=8,71 Hz, 2H). ESI m/z = 438 (M+H), 440 (M+2+H). Colorless powder.
Connection 1071H NMR (300 MHz, METHANOL-d4) δ ppm 1,20 (t, 1=a 7.62 Hz, 3H), 2,59 (kV, J=a 7.62 Hz, 2H), 2,85 (c, 4H), 2.95 and-of 3.07 (m, 1H), 3,21 of 3.28 (m, 1H), 3,54-3,68 (m, 1H), 3,69-a 3.83 (m, 3H), of 3.95 (DD, J=11,42, the 3.65 Hz, 1H), 7,00-7,11 (m, 5H), 7,13-7,28 (m, 3H). ESI m/z = 411 (M+Na), 387 (M-H). Colorless powder.
The connection 1081H NMR (600 MHz, METHANOL-d4) δ ppm of 1.20 (t, J=EUR 7.57 Hz, 3H), 1,87-of 1.94 (m, 2H), 2,56-2,63 (m, 6H), 2,98-3,03 (m, 1H), 3,26 (t, J=of 8.25 Hz, 1H), 3,59-to 3.64 (m, J=10,32, to 8.94 Hz, 1H), 3,71-3,82 (m, 3H), of 3.95 (DD, J=11,46, to 3.67 Hz, 1H), 7,05 for 7.12 (m, 5H), 7,14-7,25 (m, 3H). ESI m/z = 425 (M+Na), 401 (M-H). Colorless powder.
Obedinenie 109 1H NMR (600 MHz, METHANOL-d4) δ ppm 1,19 (t, J=7,79 Hz, 3H), 2,58 (kV, J=7,79 Hz, 2H), 2,96-to 3.02 (m, 1H), 3,22-of 3.27 (m, 1H)and 3.59 (DD, J=10,32, to 8.94 Hz, 1H), 3,70-of 3.77 (m, 3H), 3,88-of 3.97 (m, 3H), 7,08 (c, 4H), 7,14 (d, J=7,79 Hz, 2H), 7,25 (d, J=7,79 Hz, 2H). ESI m/z = 397 (M+Na), 373 (M-H). Colorless powder.
The connection 1101H NMR (300 MHz, METHANOL-d4) δ ppm 2,94-3,03 (m, 1H), 3,20 of 3.28 (m, 1H), 3,54-the 3.65 (m, 1H), 3,68-of 3.78 (m, 3H), 3,89-3,98 (m, 3H), 4,55 (c, 2H), 7,05-7,11 (m, 2H), 7,12-7,28 (m, 7H). ESI m/z = 377 (M+H), 375 (M-H). Pale yellow powder.
Connection 1111H NMR (300 MHz, METHANOL-d4) δ ppm 1,14-of 1.27 (m, 3H), 2,54 of 2.68 (m, 2H), 2.95 and was 3.05 (m, 1H), 3,22-3,30 (m, 1H), 3,51 (d, J=6,37 Hz, 1H), 3,56-3,68 (m, 2H), 3,70-a 3.83 (m, 3H), of 3.95 (DD, J=11,35, of 3.57 Hz, 1H), 5,72-6,59 (m, 2H), 7,07-7,30 (m, 8H), ESI m/z = 423 (M+Na), 399 (M-H). A yellow oil.
The connection 1121H NMR (600 MHz, METHANOL-d4) δ ppm of 1.23 (t, J=EUR 7.57 Hz, 3H), 2.63 in (kV, J=7,79 Hz, 2H), 2.95 and totaling 3.04 (m, 1H), 3,23 (t, J=8,71 Hz, 1H), 3,56-3,61 (m, 1H), 3,69-of 3.78 (m, 3H), of 3.94 (DD, J=11,46, to 3.67 Hz, 1H), at 6.84 (DD, J=8,02, 2,52 Hz, 1H), 6,91 (d, J=of 8.25 Hz, 2H), 6,95-6,98 (m, 1H), was 7.08 (d, J=7,79 Hz, 1H), 7,18 (d, J=8,71 Hz, 2H), 7,27 (t, J=7,79 Hz, 1H). ESI m/z = 399 (M+Na). 375 (M-H).
Connection 1131H NMR (300 MHz, METHANOL-d4) δ ppm of 1.29 (t, J=a 7.62 Hz, 3H), 2,71 (kV, J=a 7.62 Hz, 2H), 3,01 is 3.15 (m, 1H), 3,28-to 3.36 (m, 1H), 3,62-4,07 (m, 5H), 7,22-7,66 (m, 8H). ESI m/z = 383 (M+Na), 359 (M-H). Colourless amorphous substance.
The connection 1141H NMR (300 MHz, METHANOL-d4) δ ppm 2,94-3,03 (m, 1H), 3,20 of 3.28 (m, 1H), 3,55-to 3.64 (m, 1H), 3,69-with 3.79 (m, 3H), a 3.87 (c, 3H), 3,90-3,98 (m, 1H), 4,03 (c, 2H), 7,08-7,14 (m, 1H), 7.18 in-7,35 (m, 5H), 7,89-to 7.95 (m, 2H). ESI m/z = 427 (M+Na), 403(M-H). Pale yellow powder.
Connection 1151H NMR (300 MHz, METHANOL-d4) δ ppm 1.61 of to 1.76 (m, 2H), 1.93 and-2,05 (m, 2H), 2,94-3,03 (m, 1H), 3,20-of 3.27 (m, 1H), 3,51-to 3.64 (m, 3H), 3,68-with 3.79 (m, 3H), 3,84-3,98 (m, 5H), 4,45-of 4.54 (m, 1H), for 6.81-to 6.88 (m, 2H),? 7.04 baby mortality-7,13 (m, 3H), 7,14-7,25 (m, 3H). ESI m/z = 469 (M+Na), 445(M-H). Pale yellow oil.
The connection 1161H NMR (600 MHz, METHANOL-d4) δ ppm 1.57 in-1,67 (m, 2H), 1,72-to 1.82 (m, 4H), 1,84-of 1.94 (m, 2H), 2.95 and-to 3.02 (m, 1H), 3,21 of 3.28 (m, 1H), 3,60 (DD, J=10,32, to 8.94 Hz, 1H), 3,70-of 3.80 (m, 3H), a 3.87 (c, 2H), 3,91-of 3.97 (m, 1H), 4,71-of 4.77 (m, 1H), 6.73 x-6,79 (m, 2H), 7.03 is-7,10 (m, 3H), 7,15-7,24 (m, 3H). ESI m/z = 453 (M+Na). Colorless powder.
Connection 117 1H NMR (600 MHz, METHANOL-d4) δ ppm 2,96-3,00 (m, 1H), 3,21-3,26 (m, 1H)and 3.59 (DD, J=of 10.09, 9,17 Hz, 1H), 3,71-with 3.79 (m, 3H), 3,82-a 3.87 (m, 2H), 3,88 (c, 2H), 3,94 (DD, J=11,46, to 3.67 Hz, 1H), 3,98-was 4.02 (m, 2H), 6,82-to 6.88 (m, 2H), 7,05 for 7.12 (m, 3H), 7,15-7,24 (m, 3H). ESI m/z = 429 (M+Na), 405(M-H). Colorless powder.
The connection 1181H NMR (600 MHz, METHANOL-d4) δ ppm 2,97 (c, 3H), 2,99 totaling 3.04 (m, 1H), 3,07 (c, 3H), 3,63-3,68 (m, 1H), 3,74-3,82 (m, 3H), 3,88-of 3.94 (m, 3H), 4,74 (c, 2H), 6.87 in (d, J=8,71 Hz, 2H), 7,06-7,14 (m, 3H), 7,16-7,24 (m, 3H). Colorless powder.
Connection 1191H NMR (300 MHz, METHANOL-d4) δ ppm of 1.35 (t, J=6,99 Hz, 3H), 2,92-3,00 (m, 1H), 3,17-of 3.25 (m, 1H), only 3.57 (DD, J=10,18, which is 9.09 Hz, 1H), 3,68-of 3.78 (m, 6H), 3,88-was 4.02 (m, 5H), 4,68 (c, 2H), 6.73 x-to 6.80 (m, 3H), 7,09-to 7.18 (m, 4H). ESI m/z = 501 (M+Na). 477 (M-H).
Connection 1201H NMR (300 MHz, METHANOL-d4) δ ppm of 1.35 (t, J=6,99 Hz, 3H), 2.91 in-3,00 (m, 1H), 3,17-of 3.25 (m, 1H), only 3.57 (DD, J=10,26, 9,01 Hz, 1H), 3,66-of 3.77 (m, 3H), 3 88-4,03 (m, 5H), 4,63 (c, 2H), 6.73 x-PC 6.82 (m, 3H), 7,07-7,19 (m, 4H). ESI m/z = 487 (M+Na), 463(M-H). Colorless crystal
Connection 1211 H NMR (600 MHz, METHANOL-d4) δ ppm 2,34 (c, 6H), was 2.76 (t, J=5.50 Hz, 2H), 2,96-a 3.01 (m, 1H), up 3.22 (t, J=8,71 Hz, 1H), only 3.57 (DD, J=10,32, to 8.94 Hz, 1H), 3,68 is 3.76 (m, 3H), 3,93 (DD, J=11,46, to 3.67 Hz, 1H), 4,01 (c, 2H), 4,07 (t, J=5.50 Hz, 2H), 6,83-6,87 (m, 2H), 7,08 for 7.12 (m, 2H), 7.18 in-of 7.23 (m, 2H), 7,32 (d, J=of 8.25 Hz, 1H). ESI m/z = 468 (M+H), 470 (M+2+H). Colorless powder.
The connection 1221H NMR (600 MHz, METHANOL-d4) δ ppm 2,96-a 3.01 (m, 1H), 3,22-3,26 (m, 1H)and 3.59 (DD, J=of 10.09, 9,17 Hz, 1H), 3,71-with 3.79 (m, 6H), 3,89 (c, 2H), 3,94 (DD, J=11,46, to 3.67 Hz, 1H), 4,66 (c, 2H), for 6.81-6,85 (m, 2H), 7,05-7,13 (m, 3H), 7,16-of 7.23 (m, 3H). ESI m/z = 457 (M+Na). Pale yellow oil.
Connection 1231H NMR (600 MHz, METHANOL-d4) δ ppm 2,98-of 3.07 (m, 2H), 3,07-3,13 (m, 1H), 3.33 and is 3.40 (m, 3H), of 3.69 (DD, J=of 10.09, 9,17 Hz, 1H), 3,80 (DD, J=of 11.69, of 6.65 Hz, 1H), 3,94 (DD, J=of 10.09, 8,71 Hz, 1H), 4,00 (DD, J=11,46, to 3.67 Hz, 1H), Android 4.04 (d, J=10,55 Hz, 1H), 7,14-7,20 (m, 1H), 7,21-7,29 (m, 5H), 7,30-7,35 (m, 1H), 7,51 (DD, J=8,48, 1.60 Hz, 1H), 7,69 (d, J=of 8.25 Hz, 1H), to 7.84 (d, J=of 8.25 Hz, 1H), 8,13 (c, 1H). ESI m/z = 433 (M+Na). Pale yellow powder.
The connection 1241H NMR (600 MHz, METHANOL-d4) δ ppm 2,92-of 2.97 (m, 1H), 3,17-up 3.22 (m, 1H), 3,55 (DD, J=of 10.09, 9,17 Hz, 1H), 3,66 of 3.75 (m, 3H), 3,90 (DD, J=11,46, to 3.67 Hz, 1H), 3,99 (c, 2H), 7,07 (d, J=7,79 Hz, 1H), 7,15-of 7.23 (m, 3H), 7,27 (d, J=of 8.25 Hz, 2H), 7,88 (d, J=of 8.25 Hz, 2H). Pale yellow is the OE oil.
Connection 1251H NMR (600 MHz, METHANOL-d4) δ ppm 2,94-3,00 (m, 1H), 3.04 from-3,11 (m, 4H), 3,19-of 3.25 (m, 1H), 3,54-3,61 (m, 1H), 3,69-of 3.77 (m, 3H), of 3.77-3,81 (m, 4H), 3,85 (c, 2H), 3,90-3,95 (m, 1H), 6,84-6,91 (m, 2H), 7.03 is-to 7.09 (m, 2H), 7,13 and 7.36 (m, 4H). ESI m/z = 454 (M+Na). Colorless powder.
Connection 1261H NMR (600 MHz, METHANOL-d4) δ ppm 2,85 (c, 6H), 2,93-a 3.01 (m, 1H), 3,19-of 3.25 (m, 1H), only 3.57 (DD, J=10,1, and 9.2 Hz, 1H), 3,68-of 3.78 (m, 3H), 3,82 (c, 2H), 3,89-3,95 (m, 1H), 6,67-6,74 (m, 2H), 6,99-7,07 (m, 2H), 7,11-7,26 (m, 4H). ESI m/z = 412 (M+Na). Colorless powder.
Connection 1271H NMR (600 MHz, METHANOL-d4) δ ppm 2.91 in are 2.98 (m, 1H), 3,17-of 3.23 (m, 1H), of 3.56 (t, J=9.6 Hz, 1H), 3,67-of 3.78 (m, 3H), 3,82 (c, 3H), 3,91 (DD, J=11,5, and 3.7 Hz, 1H), 4,11-4,20 (m, 2H), 6,92 (d, J=7.8 Hz, 1H), 6,98 (c, 1H), 7,16-7,26 (m, 4H), of 7.60 (d, J=7.8 Hz, 1H), 7,68 (d, J=7.8 Hz, 1H). ESI m/z = 455 (M+Na), 431 (M-H), TPL 91,0-105,0°C.
Connection 1281H NMR (300 MHz, METHANOL-d4) δ ppm 2.93 which was 3.05 (m, 1H), 3,20-of 3.27 (m, 1H), to 3.58 (DD, J=10,3, 9.0 Hz, 1H), 3,69-a 3.83 (m, 2H), 3,93 (DD, J=11,5, 3.6 Hz, 1H), 4,35 (c, 2H), 7,01-7,05 (m, 1H), 7,19-to 7.32 (m, 3H), 7,35-7,41 (m, 2H), 7,63-to 7.77 (m, 2H). ESI m/z = 459 (M+Na), 461 (M+2+Na), 435 (M-H). TPL 105,0-115,0°C.
Connection 1291H NMR (300 MHz, METHANOL-d4) δ ppm 2.95 and was 3.05 (m, 1H), 3,21-to 3.36 (m, 1H), 3,60 (DD, J=10,3, 9.0 Hz, 1H), 3,70-3,81 (m, 3H), 3,90-3,98 (m, 1H), 4,23 (c, 2H), 7,06 (c, 1H), 7,19-7,34 (m, 6H), 7,62 to 7.75 (m, 2H). ESI m/z = 425 (M+Na). TPL 159,5-160,0°C.
The connection 1301H NMR (300 MHz, METHANOL-d4) δ ppm 2,92-a 3.01 (m, 1H), 3,25 (t, J=8,9 Hz, 1H), 3,52-the 3.65 (m, 1H), and 3.72 (DD, J=11,4, 6.5 Hz, 1H), 3,76-a 3.87 (m, 4H), 3,93 (DD, J=11,4, 3.6 Hz, 1H), 4,16 (Sirs, 2H), or 4.31-4,43 (m, 1H), 6,92 (d, J=8.6 Hz, 1H), 7,03 (c, 1H), 7,12-7,35 (m, 4H), to 7.59 for 7.78 (m, 2H). ESI m/z = 455 (M+Na). TPL 97,5-98,0°C.
Connection 1311H NMR (300 MHz, METHANOL-d4) δ ppm 2,89-3,00 (m, 1H), up 3.22 (m, 1H), 3,51-of 3.96 (m, 10H), Android 4.04-4,19 (m, 2H), 6,62 (c, 1H), 6,97 (c, 1H), 7,17-7,28 (m, 3H), 7,58-7,73 (m, 2H). ESI m/z = 485 (M+Na), 461 (M-H).
Connection 1321H NMR (300 MHz, METHANOL-d4) δ ppm 2,94 was 3.05 (m, 1H), 3,18 of 3.28 (m, 1H), to 3.58 (DD, J=10,2, a 8.9 Hz, 1H), 3,66-a 3.83 (m, 3H), of 3.94 (DD, J=11,5, 3.6 Hz, 1H), 4.16 the 4,32 (m, 2H), 6,40 (c, 1H), 7,10-7,51 (m, 7H). ESI m/z = 443 (M+Na), 445 (M+2+Na).
Connection 133 1H NMR (300 MHz, METHANOL-d4) δ ppm 2,96 totaling 3.04 (m, 1H), 3,22-3,29 (m, 1H), 3,56-to 3.64 (m, 1H), 3,70-3,81 (m, 3H), of 3.94 (DD, J=11,42, the 3.65 Hz, 1H), 4,21 (c, 2H), 6,94-6,97 (m, 1H), 7.18 in-7,33 (m, 4H), of 7.36-the 7.43 (m, 1H), 7.62mm (d, J=to 3.73 Hz, 1H), 7,85-of 7.90 (m, 1H), of 7.96-8,03 (m, 1H), 8,44-8,49 (m, 1H). ESI m/z = 430 (M+H). Yellow powder.
Connection 1341H NMR (300 MHz, METHANOL-d4) δ ppm 2.95 and-a 3.06 (m, 1H), 3,22-3,29 (m, 1H), 3,57-3,66 (m, 1H), 3,70-a 3.83 (m, 3H), of 3.95 (DD, J=11,50, to 3.73 Hz, 1H), 4,12 (c, 2H), 6,79 (d, J=3,57 Hz, 1H), 7,14 and 7.36 (m, 8H), of 7.48-EUR 7.57 (m, J=8,32, 1,17 Hz, 2H). ESI m/z = 451 (M+Na), 427 (M-H). Colorless powder. Anal. Rasch. for C23H24O4S2·0,3H2O: C, 63,57; H, 5,72 Found: C, 63,89; H, 5,63.
Connection 1351H NMR (300 MHz, METHANOL-d4) δ ppm 2.95 and totaling 3.04 (m, 1H), 3,20 of 3.28 (m, 1H), 3,54-to 3.64 (m, 1H), 3,69-3,81 (m, 3H), of 3.94 (DD, J=11,35, of 3.57 Hz, 1H), 4,19 (c, 2H), 7,00 (c, 1H), 7,14 (d, J=ceiling of 5.60 Hz, 1H), 7,16-7,33 (m, 4H), 7,37 (DD, J=5,13, 0,47 Hz, 1H). ESI m/z = 431 (M+Na), 407(M-H). Colorless powder.
Connection 1361H NMR (300 MHz, METHANOL-d4) δ ppm 2,92 was 3.05 (m, 1H), 3,19 3,29 (m, 1H), 3,39 (c, 3H)and 3.59 (t, J=for 9.64 Hz, 1H), 3,68-a 3.83 (m, 3H), 3,86-was 4.02 (m, 3H), 5,80-by 5.87 (m, 1H), 5,94 (t, J=3,11 Hz, 1H), 6,55 (d, J=1,87 Hz, 1H), 7,03 (DD, J=6,99, 1,71 Hz, 1H), 7,12-7,28 (m, 3H). ESI m/z = 372 (M+Na).
Connection 1371H NMR (300 MHz, METHANOL-d4) δ ppm 2.95 and was 3.05 (m, 1H), 3,21 of 3.28 (m, 1H), 3,55-3,66 (m, 1H), 3,69-a 3.83 (m, 3H), of 3.94 (DD, J=11,50, of 3.57 Hz, 1H), of 4.44 (c, 2H), 7.24 to 7,52 (m, 6H), a 7.85-to 7.95 (m, 2H).
Connection 1381H NMR (600 MHz, METHANOL-d4) δ ppm of 1.36 (t, J=7.18 in Hz, 3H), 3,01 was 3.05 (m, 1H), 3,23-of 3.27 (m, 1H), 3,60 (DD, J=10,32, to 8.94 Hz, 1H), 3,71-of 3.78 (m, 2H), 3,84 (d, J=10,55 Hz, 1H), 3,92-of 3.97 (m, 3H), 3,99 (kV, J=7.18 in Hz, 2H), 6,82-6,85 (m, 2H), 7,10-7,13 (m, 2H), to 7.64 (t, J=e 2.06 Hz, 1H), 8,28 (d, J=to 2.29 Hz, 1H), 8.34 per (d, 3=to 2.29 Hz, 1H). ESI m/z = 392 (M+H), 390 (M-H). Colorless powder.
Connection 1391H NMR (300 MHz, METHANOL-d4) δ ppm of 1.20 (t, J=a 7.62 Hz, 3H), 2,60 (kV, J=a 7.62 Hz, 2H), 2,92-3,03 (m, 1H), 3,19 (t, J=8,86 Hz, 1H), 3,50-3,63 (m, 2H), and 3.72 (DD, J=11,58, of 6.45 Hz, 1H), 3,93 (DD, J=11,50, to 3.73 Hz, 1H), a 4.03 (t, J=equal to 4.97 Hz, 3H), 6,58-6,67 (m, 1H), 6,83 (d, J=3,57 Hz, 1H), 7,08-7,17 (m, 4H). ESI m/z = 403 (M+Na), 379 (M-H). Colorless powder. Anal. Rasch. for C19H24O4S2: C, 59,97; H, 6,36. Found: C, 59,93; H, 6,33.
The connection 1401H NMR (300 MHz, METHANOL-d4) δ ppm 2.26 and (c, 2H), 3,03-3,14 (m, 1H), 3,32 is 3.40 (m, 1H), 3,62-and 3.72 (m, 1H), of 3.77 (DD, J=11,50, 6,37 Hz, 1H), 3,93-4,06 (m, 2H) 4,14 (c, 2H), 4,32 (d, J=10,26 Hz, 1H), 7,01-7,17 (m, 5H), 7,33 (t, 1H), of 7.48 (c, 1H), of 7.90 (d, J=7,31 Hz, 1H). ESI m/z = 439 (M+Na). 415 (M-H). Colorless powder.

Test Example 1

After receiving 50 μl of the suspension of membrane vesicles to the brush border of rat kidney (protein concentration: 4 mg/ml) (membrane vesicles brush border, brush border membrane of vehicle: BBMV) according to the method described in the publication (Anal. Biochem., Vol. 201, Clause 301, 1984), this suspension was preincubated at 37°C for two minutes, and then thereto was added 150 μl of the reaction mixture, which was a mixture of test compounds dissolved in DMSO (the final concentration of DMSO: 1%), 100 mm mannitol, 100 mm NaSCN or KSCN, 10 mm HEPES/Tris, pH 7,4, D-glucose (final concentration: 0.1 mm) and 1 µci D-[6-3H]-glucose (Amersham). After keeping the reaction mixture at a temperature of 37°C for five seconds, for braking the reaction to the reaction mixture were added 1 ml of stopping the reaction, ice-cold solution (150 mm NaCl, 10 mm HEPES/Tris pH of 7.4, 0.3 mm of phlorizin) and membrane of the brush border vesicles (BBMV) were immediately separated by high speed centrifugation, using membrane filter (HAWP02500 with pore size, amounting to 0.45 μm, Millipore). Membrane filter three times washed with 4.5 ml of stopping the reaction of the frozen solution. After the membrane is sufficiently dry out, measured the radioactivity in the liquid Scintilla the ion radioactivity counter (Beckman) for the quantitative determination of the absorbed glucose in membrane vesicles to the brush border membrane filter.

Calculate the concentration at which the uptake of glucose inhibited by 50% (the value of the IC50taking the absorption rate of glucose without added compounds for 100%.

The results are shown in Table 2.

Table 2
Connection # IC50(µm)
Connection 751,600
The connection 760,320
Connection 790,220
Connection 1270,350
Connection 1280,790

Test Example 2

Human cloning and human SGLT1 and SGLT2 their introduction in expressing vector

The sequence of human SGLT1 (NM_000343) was subjected to reverse transcription on the basis of mRNA derived from the small intestine of man, then amplified, and then introduced into the vector pCMV-tag5A production of Stratagene Corporation. The sequence of human SGLT2 (NM_003041) was obtained from mRNA of human kidney using the above technology, and then introduced into the vector pcDNA3.1+hygro productions the Invitrogen Corporation. The identity of each cloned sequence was confirmed at the level of expressed sequence.

Obtaining cells CHO-k1, stably expressing human SGLT1 and human SGLT2

Cells CHO-K1 was transfusional expression vectors of human and human SGLT1 SGLT2 using lipofectamine 2000 (Invitrogen Corporation). SGLT-expressing cells cultured in the presence of geneticin (SGLT1) or hygromycin B (SGLT2) at a concentration of 500 μg/ml with the aim of selecting resistant strains. Cells were obtained based on the measure of their specific activity absorption of sugar in the next system.

Test sodium-dependent inhibition of sugar absorption into the cells

In the test, the sodium-dependent inhibitory activity of the takeover of sugar were used cells, stably expressing human SGLT1 and human SGLT2. Cells were incubated in 1 ml of buffer solution for pre-treatment (140 mm holdingarea, 2 mm KCl, 1 mm CaCl2, 1 mm MgCl2, 10 mm HEPES/5 mm Tris, pH of 7.4) for 20 minutes. Buffer solution for pre-treatment was removed and added to 200 μl of buffer, which is absorbed (methyl-α-D-glucopyranosid containing [14C]methyl-α-D-glucopyranosid (0.1 mm for inhibition of SGLT1, 1 mm for inhibition of SGLT2), 140 mm NaCl, 2 mm KCl, 1 mm CaCl2, 1 mm MgCl210 mm HEPES/5 mm Tris, a pH of 7.4)containing a test compound, and the reaction of absorption was carried out at 37°C for 30 minutes (SGLT1) or within one hour (SGLT2). After the reaction, the cells were twice washed with 1 ml buffer for washing (10 mm methyl-α-D-glucopyranoside, 140 mm holdingarea, 2 mm KCl, 1 mm CaCl2, 1 mm MgCl2, 10 mm HEPES/5 mm Tris, pH 7,4) and was dissolved in 400 μl of 0.2 M NaOH solution. After adding Aquazole 2 (Perkln Elmer Corporation) and thorough mixing was measured radioactivity in a liquid scintillation counter (Beckman Coulter Corporation). The buffer into which is absorbed, not containing the test compounds used in the control group. Another buffer solution, which is absorbed, containing choline chloride instead of Sodium chloride was also prepared to determine the underlying absorption.

To determine the value of the IC50the test compound used in the six acceptable concentrations, and calculated the concentration at which there is inhibition of the uptake of glucose by 50% (the value of the IC50), compared with the absorption of glucose in the control group (100%). The results of this test are shown in table 3.

Table 3
Connection # Human SGLT2 (µm) Human SGLT1 (µm)SGLT1/SGLT2
The connection 741,19015,312,8
Connection 752,83027,4the 9.7
The connection 760,0801,214,6
Connection 770,6908,0the 11.6
The connection 781,040120,0115,4
Connection 790,3702,77,2
The connection 800,1902,915,2
Connection 810,6006,510,9
The connection 823,78015,04,0
Compound 8 0,0301,548,7
The connection 840,1702,112,5
Connection 851,2706,14,8
Connection 86to 0.0601,118,3
The connection 880,0800,22,8
Connection 890,0656,397,5
Connection 910,1101,715,5
The connection 920,0300,27,7
Connection 930,0210,421,0
Connection 940,2500,31,3
Connection 950,0280,622,3
Connection 960,0627,3116,3
Connection 980,0150,16,5
Connection 99to 0.0325,6178,6
Connection 1001,5204,42,9
Connection 1010,0402,663,1
Connection 1020,0403,586,6
Connection 1030,06923,9347,9
The connection 1040,0341,029,8
Connection 1050,093of 17.0 182,5
Connection 1271,1200,70,6
Connection 1280,1400,64,4
Connection 1293,00012,84,3
The connection 1302,120>10-
Connection 1310,8904,1the 4.7
Connection 1320,4974,48,9
Connection 1342,910--
Connection 13833,000--
Connection 139114,000--

INDUSTRIAL APPLICABILITY

The present invention relates to compounds 1-thio-D-GL is citola, that possess the property of inhibiting the activity of sodium-dependent co-glucose Transporter (SGLT2) and the effect of hypoglycemia by enhancing the excretion of glucose in urine and, thus, with the opportunity for therapeutic drugs against diabetes, which has a new, not used in normal practice, the skeleton. In addition, derivatives of 1-thio-D-glucitol according to the invention have good crystallinity, and therefore, they can be used without the prior joint crystallization with amino acids, etc. and besides, they are easily cleaned, stored and included in pharmaceutical preparations and are suitable for use as a pharmaceutical product.

1. Connection 1-thio-D-glucitol the following formula I, or its pharmaceutically acceptable salt, or hydrate of the compound or the salt:

where R1, R2, R3and R4the same or different, and each represents a hydrogen atom, a C1-6is an alkyl group,
And represents -(CH2)n-, -CONH(CH2)n-, -O - or -(CH2)nCH=CH-
(where n denotes an integer from 0 to 3)
Ar1represents Allenova group, heteroarenes group represents an unsaturated 5 to 9 membered mono - or bicyclic group, sotiriadou-2 heteroatom, selected from S and N,
Ar2represents an aryl group or heteroaryl group represents an unsaturated 5 to 9 membered mono - or bicyclic group containing 1-2 heteroatoms selected from O, S and N, and
R5, R6, R7, R8, R9and R10the same or different, and each represents a
(i) a hydrogen atom,
(ii) a halogen atom,
(iii) a hydroxyl group,
(iv) C1-8is an alkyl group, optionally substituted hydroxyl group(s),
(v) -(CH2)m-Q {where m denotes an integer from 0 to 4, and
Q represents-CO2H, -ORc1, -CO2Ra3, -SRe1-The othera6or-NRa7Ra7(where each of Ra3, Ra6and Ra7represents a C1-6is an alkyl group, Rc1represents a C1-6is an alkyl group, and Rc1represents a C1-6is an alkyl group)},
(vi) -O-(CH2)m'-Q' {where m' denotes an integer from 1 to 4, and Q' represents a hydroxyl group, -CO2H, -CO2Rq8, -CONRa10Ra10, -NRal2Ral2(where each of Ra8, Ra10and Ra12represents a C1-6is an alkyl group)},
(vii) -ORf{where Rfrepresents a C3-7-cycloalkyl group or tetrahydropyranyloxy group)},
(viii) morpholinopropan,
(ix) phenyl group,
(x) pyridinio the group.

2. Connection 1-thio-D-glucitol the following formula IA, or pharmaceutically acceptable salt, or hydrate of the compound or the salt:

where R1, R2, R3and R4the same or different and each represents a hydrogen atom, a C1-6is an alkyl group,
And represents -(CH2)n-, -CONH(CH2)n-, -O - or -(CH2)nCH=CH- (where n denotes an integer from 0 to 3)
Ar1represents Allenova group, heteroarenes group represents an unsaturated 5 to 9 membered mono - or bicyclic group containing 1-2 heteroatoms selected from S and N, or geteroseksualbnogo group,
Ar2represents an aryl group or heteroaryl group represents an unsaturated 5 to 9 membered mono - or bicyclic group containing 1-2 heteroatoms selected from O, S and N, and
R5', R6', R7', R8', R9'and R10'the same or different and each represents a
(i) a hydrogen atom,
(ii) a halogen atom,
(iii) a hydroxyl group,
(iv) C1-8is an alkyl group, optionally substituted hydroxyl group(s),
(v) -(CH2)m-Q {where m denotes an integer from 0 to 4, and
Q represents-CO2H, -ORc1, -CO2Ra3, -SRe1-The othera6or-NRa7Ra7
(where each of R a3, Ra6and Ra7represents a C1-6is an alkyl group,
Rc1represents a C1-6is an alkyl group, and Re1represents a C1-6is an alkyl group)},
(vi) -O-(CH2)m'-Q' {where m' denotes an integer from 1 to 4, and
Q' represents a hydroxyl group, -CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12(where each of Ra8, Ra10and Ra12represents a C1-6is an alkyl group)},
(vii) -ORf{where Rfrepresents a C3-7-cycloalkyl group)},
(viii) morpholinopropan,
(ix) phenyl group,
(x) pyridyloxy group.

3. Connection 1-thio-D-glucitol, or its pharmaceutically acceptable salt, or hydrate of the compound or salt according to claim 2, where Ar1represents Allenova group.

4. Connection 1-thio-D-glucitol, or its pharmaceutically acceptable salt, or hydrate of the compound or salt according to claim 2, where Ar1represents fenelonov group or Neftyanoy group.

5. Connection 1-thio-D-glucitol, or its pharmaceutically acceptable salt, or hydrate of the compound or salt according to claim 4, where a represents a-CH2-.

6. Connection 1-thio-D-glucitol, or its pharmaceutically acceptable salt, or hydrate of the compound or salt according to any one of claims 1 to 5, where Ar2represents a phenyl group, thienyl the ing group, benzo[b]tiffaniejoy group, thieno[2,3-b]tiffaniejoy group, benzofuranyl group, benzothiazolyl group, indolenine group, pyrrolidino group, imidazolidinyl group, pyrazolidine group, pyridyloxy group, pyrimidinyl group, personilnya group or isoxazolyl group.

7. Connection 1-thio-D-glucitol following formula II, or its pharmaceutically acceptable salt, or hydrate of the compound or the salt:

where R1, R2, R3and R4the same or different and each represents a hydrogen atom, a C1-6is an alkyl group,
at least one of RARB, RCand RDrepresents a hydrogen atom, and the other of RARB, RCand RDthe same or different, and each represents a
(i) a hydrogen atom,
(ii) a halogen atom,
(iii) a hydroxyl group,
(iv)1-8is an alkyl group,
(v) -(CH2)m-QA{where m denotes an integer from 0 to 4, and QArepresents-CO2H, -ORc1, -CO2Ra3, -SRe1-The othera6or-NRa7Ra7(where each of Ra3, Ra6and Ra7represents a C1-6is an alkyl group, Rc1represents a C1-6is an alkyl group, and
Re1represents a C1-6is an alkyl group)},
(vi) -O-(CH2)'-Q' {where m' denotes an integer from 1 to 4, and Q' represents a hydroxyl group, -CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12(where each of Ra8, Ra10and Ra12represents a C1-6is an alkyl group)},
(vii) -ORf{where Rfrepresents a C3-7-cycloalkyl group)},
(viii) morpholinopropan, and
RE, RFand RGthe same or different, and each represents a
(i) a hydrogen atom,
(ii) a halogen atom,
(iii) a hydroxyl group,
(iv) C1-8is an alkyl group, optionally substituted hydroxyl(us) group(the groups),
(v) -(CH2)m-Q {where m denotes an integer from 0 to 4, and
Q represents-CO2H, -ORc1, -CO2Ra3, -SRe1-The othera6or-NRa7Ra7
(where each of Ra3, Ra6and Ra7represents a C1-6is an alkyl group, Rc1represents a C1-6is an alkyl group, and Re1represents a C1-6is an alkyl group)},
(vi) -O-(CH2)m'-Q' {where m' denotes an integer from 1 to 4, and Q' represents a hydroxyl group, -CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12(where each of Ra8, Ra10and Ra12represents a C1-6is an alkyl group)},
(vii) -ORf{where Rfrepresents a C3-7-cycloalkyl group or tetrahydrofur niloy group)},
(viii) morpholinopropan.

8. Connection 1-thio-D-glucitol, or its pharmaceutically acceptable salt, or hydrate of the compound or salt according to claim 7, where
each of RAand RCrepresents a hydrogen atom,
RBrepresents a hydrogen atom, halogen atom, hydroxyl group, C1-8is an alkyl group,
-O-(CH2)m'-Q' {where m' denotes an integer from 1 to 4, and Q' represents a hydroxyl group, -CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12(where each of Ra8, Ra10and Ra12represents a C1-6is an alkyl group)}, or
-ORf1(where Rf1represents a C1-6is an alkyl group),
RDrepresents a hydrogen atom, halogen atom, hydroxyl group, C1-8is an alkyl group or-ORf2(where Rf2represents a C1-6is an alkyl group),
REand RFthe same or different, and each represents a hydrogen atom, a halogen atom, a C1-8is an alkyl group or-ORc3(where Rc3represents a C1-6is an alkyl group), and
RGrepresents a
(i) a hydrogen atom,
(ii) a halogen atom,
(iii) a hydroxyl group,
(iv) C1-8is an alkyl group, optionally substituted hydroxyl(reference) group(the groups),
(v) -(CH2)m-Q {where m denotes an integer from 0 to 4, the Q represents-CO 2H, -ORc1, - CO2Ra3, -SRe1-The othera6or-NRa7Ra7(where each of Ra3, Ra6and Ra7represents a C1-6is an alkyl group, Rc1represents a C1-6is an alkyl group, and Re1represents a C1-6is an alkyl group)},
(vi) -O-(CH2)m'-Q' {where m' denotes an integer from 1 to 4, and Q' represents a hydroxyl group, -CO2H, -CO2Ra8,
-CONRa10Ra10or-NRa12Ra12(where each of Ra8, Ra10and Ra12represents a C1-6is an alkyl group)},
(vii) -ORf{where Rfrepresents a C3-7-cycloalkyl group or tetrahydropyranyloxy group)},
(viii) morpholinopropan.

9. Connection 1-thio-D-glucitol, or its pharmaceutically acceptable salt, or hydrate of the compound or salt of claim 8, where
RBrepresents a hydrogen atom, a C1-6is an alkyl group,
-ORf1(where Rf1represents a C1-6is an alkyl group) or a halogen atom, and
RDrepresents a hydrogen atom, a hydroxyl group or-ORf1
{where Rf1represents a C1-6is an alkyl group}.

10. Connection 1-thio-D-glucitol, or its pharmaceutically acceptable salt, or hydrate of the compound or salt PP or 9,
where RGrepresents a
(i) atom odor is Yes,
(ii) a halogen atom,
(iii) a hydroxyl group,
(iv) C1-8is an alkyl group, optionally substituted hydroxyl(s) group(AMI),
(v) CO2N
(vi) -ORc1,
(vii) -CO2Ra3,
(viii) -SRe1,
(ix) -othera6,
(x) -NRa7Ra7(where each of Ra3, Ra6and Ra7represents a C1-6is an alkyl group, Rc1represents a C1-6is an alkyl group, and Re1represents a C1-6is an alkyl group),
(xi) -O-(CH2)m'-Q' {where m' denotes an integer from 1 to 4, and Q' represents a hydroxyl group, -CO2H, -CO2Ra8, -CONRa10Ra10or-NRa12Ra12(where each of Ra8, Ra10and Ra12represents a C1-6is an alkyl group)},
(xii) -ORf{where Rfrepresents a C3-7-cycloalkyl group or tetrahydropyranyloxy group)},
(xiii) morpholinopropan.

11. Connection 1-thio-D-glucitol the following formula III, or pharmaceutically acceptable salt, or hydrate of the compound or the salt:

where R1, R2, R3and R4the same or different, and each represents a hydrogen atom, a C1-6is an alkyl group,
RHand R1the same or different, and each represents a hydrogen atom, a halogen atom or ORf1{where Rf1predstavljaet a C 1-6is an alkyl group},
Ar3represents a thienyl group, a benzo[b]tiffaniejoy group, thieno[2,3-b]tiffaniejoy group, benzofuranyl group, benzothiazolyl group, indolenine group, pyrrolidino group, imidazolidinyl group, pyrazolidine group, pyridyloxy group, pyrimidinyl group, personilnya group or isoxazolyl group,
R8aand R9athe same or different, and each represents a hydrogen atom, a C1-8is an alkyl group, and
R10arepresents a hydrogen atom, phenyl group or pyridyloxy group].

12. Connection 1-thio-D-glucitol, or its pharmaceutically acceptable salt, or hydrate of the compound or salt according to claim 1 or 2, where Ar1represents heteroarenes group.

13. Connection 1-thio-D-glucitol, or its pharmaceutically acceptable salt, or hydrate of the compound or salt according to item 12, where a represents -(CH2)n- (where n denotes an integer from 0 to 3).

14. Connection 1-thio-D-glucitol the following formula IV, or its pharmaceutically acceptable salt, or hydrate of the compound or the salt:

where R1, R2, R3and R4the same or different, and each represents a hydrogen atom, a C1-6is an alkyl group,
Ar4represents thienylene group, benzo[b]thiophenyl the new group or piridinovy group,
R20aand R21athe same or different, and each represents a hydrogen atom or halogen atom, and
RJand RKthe same or different, and each represents a hydrogen atom, a halogen atom, a C1-8is an alkyl group or-ORc3(where Rc3represents a C1-6is an alkyl group), and
RLrepresents a
(i) a hydrogen atom,
(ii) C1-8is an alkyl group,
(iii) -ORc1(where Rc1represents a C1-6is an alkyl group),
(iv) -NRa7Ra7(where each of Ra7represents a C1-6is an alkyl group),
(v) -O-(CH2)m'-Q' {where m' denotes an integer from 1 to 4, and Q' represents a hydroxyl group, -CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12(where each of Ra8, Ra10and Ra12represents a C1-6is an alkyl group)},
(vi) -ORf2{where Rf2represents a C3-7-cycloalkyl group, tetrahydropyranyloxy group].

15. Connection 1-thio-D-glucitol, or its pharmaceutically acceptable salt, or hydrate of the compound or salt according to 14, in which RLrepresents a hydrogen atom, a C1-8is an alkyl group or-ORc3(where Rc3represents a C1-6is an alkyl group).

16. Connection 1-thio-D-glucitol, or its pharmaceutically acceptable salt, or GI is Rath compound or salt according to claim 1, where the compound is selected from the group consisting of
(1S)-1,5-anhydrous-1-[3-(4-ethoxybenzyl)-6-methoxy-4-were]-1-thio-D-glucitol;
(1S)-1,5-anhydrous-1-[4-chloro-3-(4-methylbenzyl)phenyl]-1-thio-D-glucitol;
(1S)-1,5-anhydrous-1-[4-chloro-3-(4-methylthiophenyl)phenyl]-1-thio-D-glucitol;
(1S)-1,5-anhydrous-1-[4-chloro-3-(4-active compounds)phenyl]-1-thio-D-glucitol.

17. Connection 1-thio-D-glucitol, or its pharmaceutically acceptable salt, or hydrate of the compound or salt according to claim 1, where the compound is selected from the group consisting of




18. Connection 1-thio-D-glucitol, or its pharmaceutically acceptable salt, or hydrate of the compound or salt according to claim 1, where the compound is selected from the group consisting from the group consisting of


19. Pharmaceutical agent that is an inhibitor of the activity of sodium-dependent co-Transporter-2 glucose containing compound 1-thio-D-glucitol, its pharmaceutically acceptable salt or hydrate of the compound or salt according to any one of claims 1 to 18.

20. Pharmaceutical product according to claim 19, which is a pharmaceutical agent for the prophylaxis or treatment of diabetes, is associated with diabetes, diseases or donkey is inania, caused by diabetes.

21. The method of obtaining compounds of 1-thio-D-glucitol following formula I, or its pharmaceutically acceptable salt, or hydrate of the compound or salt

where Ar1, Ar2And R1-R10defined in claim 1,
includes the following stages:
adding thiolactone following formula VIII to more than one equivalent of Grignard reagent following formula IX, to obtain the compound V;
reconnection V; and
if you unprotect the resulting compounds in accordance with the following scheme:

where R11, R12, R13and R14the same or different, and each represents a C1-6is an alkyl group, -SiRa13, -CH2CH=CH2or7-12-aracelio group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, -NO2and OMe (where Ra1represents a C1-6is an alkyl group), X represents a halogen atom, and Ar1Ar2, R5, R6, R7, R8, R9and R10represent values that are defined in claim 1.

22. The method according to item 21, in which up to the stage of adding the Grignard reagent of the formula IX to thiolactone formula VIII to obtain the value V, add approximately from 0.8 to 1.2 equivalents of R30MgX (R30represents a C1-8is an alkyl group or a C3-7-cycloalkyl group, and X represents a halogen atom) to thiolactone formula VIII.

23. The method of obtaining compounds of 1-thio-D-glucitol the following formula I, or its pharmaceutically acceptable salt, or hydrate of the compound or the salt:

where Ar1, Ar2And R1-R10defined in claim 1, comprising the following stages:
(1) adding to the compound of formula X reagent of formula XI, to obtain the compounds XII; and
(2) additional reconnection XII, if Y is a hydroxyl group, to obtain β-stereoselective compounds in which Y represents hydrogen, and
if necessary, further removing protection from the compounds obtained in stage (1) or (2)according to the following scheme:

where Y represents a hydrogen atom or a hydroxyl group (provided that when Y represents a hydrogen atom, the 1-position is S-configuration),
where R11, R12, R13and R14the same or different, and each represents a C1-6is an alkyl group, -SiRa13, -CH2CH=CH2or7-12-aracelio group, optionally substituted one ilible substituents, selected from the group consisting of a halogen atom, -NO2and OMe (where Ra1represents a C1-6is an alkyl group), Ar2, R8, R9and R10have the same meaning as in claim 1, and RARB, RCand RDhave the same meaning as in claim 7,
AA represents-CH(W)(CH2)n'-, -CONH(CH2)n - or-CH=CH- (where W represents a hydrogen atom or hydroxyl group, n means an integer from 0 to 3, and n' denotes an integer from 0 to 2),
EA represents-Cho, -CO2H or-CH2X, and
Da represents -(CH2)n Li, -(CH2)'n MgX, -CH2PPh3+X-, -CH2PO (ORa23), -(CH2)nNH2or SnBu4(where X represents a halogen atom, Ra23represents a C1-6is an alkyl group, n denotes an integer from 0 to 3, and n' denotes an integer from 0 to 2),
provided that if EA represents-Cho, compound X interacts with the reagent XI, where Da represents -(CH2)n Li, -(CH2)'n MgX, -CH2PPh3+X-or-CH2PO(ORa23), with compound XII in which AA represents-CH(W)(CH2)n - or-CH=CH-,
if EA represents-CO2H, then compound X condensed with reagent XI, where Da represents -(CH2)nNH2with obtaining compounds XII, in which the om AA represents-CONH(CH 2)n-, or if EA represents-CH2X, the compound X condensed with reagent XI, where Da represents-SnBu4with obtaining compounds XII, in which AA represents-CH2.

24. The compound of the following formula XIII or its salt:

where Y represents a hydrogen atom or a hydroxyl group (provided that when Y represents a hydrogen atom, then the position 1 is in S-configuration), and
R21, R22, R23and R24the same or different and each represents a C1-6is an alkyl group, -CH2CH=CH2, -SiRa13, benzyl group, where Ra1represents a C1-6is an alkyl group,
R5, R6, R7, R8, R9and R10the same or different, and each represents a
(i) a hydrogen atom,
(ii) a halogen atom,
(iii) a hydroxyl group,
(iv) C1-8is an alkyl group, optionally substituted hydroxyl group(s),
(v) -(CH2)m-Q {where m denotes an integer from 0 to 4, and
Q represents-CO2H, -ORc1, -CO2Ra3, -SRe1-The othera6or-NRa7Ra7(where each of Ra3, Ra6and Ra7represents a C1-6is an alkyl group, Rc1represents a C1-6is an alkyl group, and Re1is the battle With 1-6is an alkyl group)},
(vi) -O-(CH2)m'-Q' {where m' denotes an integer from 1 to 4, and Q' represents a hydroxyl group, -CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12(where each of Ra8, Ra10and Ra12represents a C1-6is an alkyl group)},
(vii) -ORf{where Rfrepresents a C3-7-cycloalkyl group or tetrahydropyranyloxy group or benzyl group)},
(viii) morpholinopropan,
(ix) phenyl group,
(x) pyridyloxy group, and
the other designations correspond to the designations given in claim 1.

25. The compound of the following formula XIV or its salt:

where Y represents a hydrogen atom or a hydroxyl group (provided that when Y represents a hydrogen atom, then the position 1 is in S-configuration), and
E represents-Cho, -CO2H, -CO2Ra24(where Ra24represents a C1-6is an alkyl group), -CH2Ma(where Marepresents a hydroxyl group or a halogen atom), 1,3-dioxolane-2-ilen group or 1,3-dioxane-2-ilen group,
R21, R22, R23and R24have the same meaning as in paragraph 24, and
at least one of RARB, RCand RDrepresents a hydrogen atom, and the other of RARB, RCand Dthe same or different, and each represents a
(i) a hydrogen atom,
(ii) a halogen atom,
(iii) a hydroxyl group,
(iv) C1-8is an alkyl group,
(v) -(CH2)m-QA{where m denotes an integer from 0 to 4, and QArepresents-CO2H, -ORc1, -CO2Ra3, -SRe1-The othera6or-NRa7Ra7(where each of Ra3, Ra6and Ra7represents a C1-6is an alkyl group, Rc1represents a C1-6is an alkyl group, and Re1represents a C1-6is an alkyl group)},
(vi) -O-(CH2)m'-Q' {where m' denotes an integer from 1 to 4, and Q' represents a hydroxyl group, -CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12(where each of Ra8, Ra10and Ra12represents a C1-6is an alkyl group)},
(vii) -ORf{where Rfrepresents a C3-7-cycloalkyl group or benzyl group)},
(viii) morpholinopropan.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel therapeutically suitable derivatives of pyridazin-3(2H)-one of formula and pharmaceutical compositions containing the said derivatives. These compounds are used for treating, preventing or inhibiting corresponding pathological conditions, diseases or disorders, mainly asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, atopic dermatitis, psoriasis or irritable colon syndrome.

EFFECT: obtaining compounds which are active and selective phosphodiesterase 4 (PDE4) inhibitors.

11 cl, 1 tbl, 182 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), their N-oxide forms, pharmaceutically acceptable additive salts and stereochemically isomeric forms as 11-HSD1 inhibitors, to their use, a pharmaceutical composition based on the said compounds and method of obtaining the said compounds. In general formula (I) , X is C or N; Y is C or N; L is methyl or a single bond; Z1 is a single bond, C1-2alkyl or a radical of formula -CH=; Z2 is a single bond, C1-2alkyl; R1 is hydrogen, halogen, hydroxy; R2 is hydrogen, halogen or C1-4alkyloxy; A is phenyl or a monocyclic heterocycle selected from a group consisting of thiophenyl or pyrridinyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by 11-HSD1.

9 cl, 7 dwg, 2 tbl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of purifying thiopenes of formula (I) which are liquid at room temperature and can be used in organic synthesis to produce an electroconductive polymer or an organic semiconductor. The proposed method involves precipitation of thiophene of formula (I) , where R1 and R2 represent hydrogen, optionally broken by 1-5 O and/or S atoms C1-20alkyl, C1-20alkoxy, or R1 and R2 together represent optionally substituted C1-20dioxyalkylene or C6-20dioxyarylene group, where the thiophene is precipitated from a solution in isobutyl-methylketone, chloroform, methylene chloride, toluene, methanol, propanol, ethanol, acetone, isopropanol, n-butanol, fluorobutanol, dimethylformamide, methyl-tertbutyl ether, tetrahydrofuran, diethyl ether, hexane, pentane or mixtures thereof in ratio solvent : thiophene ranging from 0.01:1 to 10:1, cooled to temperature at least 10°C below melting point of the thiophene being purified in pure form, with subsequent separation of thiophene by filtration at low temperature.

EFFECT: design of a new efficient method of purifying low-melting thiophenes.

14 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclic amine compounds of formula (1) or pharmaceutically acceptable salts thereof: . In formula (1), X is O, S, NR2 (where R2 is H, C1-C12 alkyl); when X is O, S, then R1 is H, CN, COOH, C2-C13 alkoxycarbonyl, carbamoyl group; and when X is NR2 (where R2 assumes values given above), R1 is CN; Ar1 and Ar2 are identical or different and each represents an aryl which can be substituted with 1-3 halogens; or Ar1 and Ar2 together with neighbouring carbon atoms to which they are bonded form a group with formula (b): (where ring S and ring T are identical and each is a benzene ring; Y is O); ring B is a benzene ring which can be substituted with 1-3 substitutes independently selected from a group comprising halogen, C1-C12 alkyl, C1-C8 halogenalkyl, C1-C12 alkoxy, C1-C8 halogenalkoxy group; n is an integer from 1 to 10; p, q are identical or different and each is an integer equal to 1 or 2. Formula (1) compounds are bonding inhibitors of the α2C-adrenoreceptor.

EFFECT: possibility of using compounds in pharmaceutical compositions.

7 cl, 1 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: in formula (1), R1 is di-C1-6alkoxyphenyl group; A is one of the following groups (i)-(vi); (i) -CO-B-, where B is C1-6alkylene group; (ii) -CO-Ba-, where Ba is C2-6alkenylene group; (iii) -CH(OH)-B-; (iv) -COCH((C)OOR3)-Bb-, where R3 is C1-6alkyl group and Bb is C1-6alkylene group. Values of the other radicals are specified in the patent claim. Invention also concerns the pharmaceutical composition exhibiting properties of a phosphodiesterase PDE4 inhibitor containing the compound under the invention; the phosphodiesterase 4 inhibitor containing as an active component the compound of the invention; preventive or therapeutic preparation for atopic dermatitis containing as an active component the compound of the invention.

EFFECT: higher effectiveness of application of the compound.

8 cl, 24 tbl, 262 ex

FIELD: medicine.

SUBSTANCE: new compounds of thienopyrazole are described with formula (1) , where R1 means non-substituted C3-C8-cycloalkyl group or tetrahydropyranyl, R2 means non-substituted C1-C3alkyl group, R3 means atom of hydrogen, R4 means various groups mentioned in invention formula. Compounds inhibit PDE 7 and, accordingly, increase cell level of cyclic adenosine monophosphate. Pharmaceutical composition is also described, as well as method for inhibition of PDE, methods for production of compound with formula (1), where R4 means CO2R7, and intermediate compounds.

EFFECT: possibility to use for treatment of various types of such diseases as allergic diseases, inflammatory diseases or immunological diseases.

20 cl, 138 tbl, 440 ex

FIELD: medicine.

SUBSTANCE: invention is related to compound of formula (I), (values of radicals are described in formula of invention) or its pharmaceutically acceptable salts, to methods of its production, pharmaceutical composition, which contains it. Application of invention is described for manufacturing of medicinal agent intended for provision of inhibiting action in respect to HDAC in warm-blooded animal, in production of agent used for treatment of malignant tumor. Method is also described for provision of inhibiting action in warm-blooded animal.

EFFECT: compounds have inhibiting activity in respect to HDAC.

15 cl, 17 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I)

, where R is selected from ethyl, n-propyl, iso-propyl, n-butyl and allyl; R' is selected from hydrogen, straight, branched or cyclic C1-C4alkyl; straight, branched or cyclic C1-C3alkoxy; fluorine, chlorine, bromine, trifluoromethyl and OCHxFy, where x=0, 1, 2, y=1, 2, 3 under the condition that, x+y=3; R" is selected from hydrogen, fluorine and chlorine, with the condition that, R" is selected from fluorine and chlorine only when R' is selected from fluorine and chlorine; R3 is selected from hydrogen and straight, branched or cyclic C1-C5alkyl; R4 is selected from hydrogen, CH2OCOC(CH3)3, pharmaceutically acceptable inorganic or organic cations, and COR4', where R' is straight, branched or cyclic C1-C5alkyl, phenyl, benzyl or phenethyl; R7 is selected from methyl and ethyl; one of A and B is sulphur, and the other is C-R2; when A is S, R2 is selected from hydrogen and methyl, with the condition that R2 is methyl only when R3 is not hydrogen; and when B is S, R2 is hydrogen; and to any tautomer thereof, as well as to a pharmaceutical composition which contains formula (I) compound, to a method of producing said compounds and to a method of treating diseases which are a result of autoimmune response or pathologic inflammation.

EFFECT: new compounds are disclosed, which can be used in treating diseases which are a result of autoimmune response or pathologic inflammation.

35 cl, 2 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: in formula compounds, each of R1, R2, R3, R4 is a substitute for a cyclic system, chosen from hydrogen, halogen, C1-C6-alkyl; C1-C6-alkoxy group; X is a heteroatom, chosen from oxygen or sulphur; R5 and R6 independently represent amino group substitutes, chosen from hydrogen, possibly substituted C1-C6-alkyl; possibly substituted C3-C6-cycloalkyl, which can be annealed with a benzene ring; possibly substituted phenyl, which can be annealed with dioxole, dioxine, -(CH2)n group, where n=4 to 6, or with a 5 or 6-member possibly substituted and possibly condensed azaheterocyclyl; possibly substituted saturated or unsaturated 5-6-member heterocyclyl, containing 1-2 heteroatoms, chosen form nitrogen, oxygen, sulphur and possibly condensed with a benzene ring, or R5 and R6 together with the nitrogen atom to which they are bonded, form an optionally substituted 5 or 6-member azahetero ring, possibly containing an additional heteroatom, chosen from nitrogen, and possibly annealed with a benzene ring or spiro-condensed with dioxole, where substitutes in the said alkyl, cycloalkyl, phenyl and heterocyclyl are chosen from halogen atoms, possibly substituted C1-C6-alkyl, CF3, possibly substituted C3-C6-cycloalkyl, possibly substituted phenyl, 5 or 6-member heterocyclyl, nitro group, substituted amino group, alkyloxycarbonyl, substituted carbonyl, aminocarbonyl, alkylsulphanyl.

EFFECT: design of an efficient method of producing new substituted furo[2,3-b]quinoline-2-carboxamides and substituted thieno[2,3-b]quinoline-2-carboxamides or their racemates, or their optical isomers, as well as their pharmaceutically acceptable salts and/or hydrates of general formula (I), which have antituberculous activity.

9 cl, 1 dwg, 7 tbl, 5 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns indazol derivatives of general formulae (I) or (II) , where radicals and groups are defined as shown in cl. 1 of invention claim, and their pharmaceutically acceptable salts. Also invention claims medicine, method of medicine obtainment and application of claimed compounds in treatment and/or prevention of fatty acid metabolism derangement and glucose assimilation disorders.

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

FIELD: medicine.

SUBSTANCE: in formula (1), R1 is di-C1-6alkoxyphenyl group; A is one of the following groups (i)-(vi); (i) -CO-B-, where B is C1-6alkylene group; (ii) -CO-Ba-, where Ba is C2-6alkenylene group; (iii) -CH(OH)-B-; (iv) -COCH((C)OOR3)-Bb-, where R3 is C1-6alkyl group and Bb is C1-6alkylene group. Values of the other radicals are specified in the patent claim. Invention also concerns the pharmaceutical composition exhibiting properties of a phosphodiesterase PDE4 inhibitor containing the compound under the invention; the phosphodiesterase 4 inhibitor containing as an active component the compound of the invention; preventive or therapeutic preparation for atopic dermatitis containing as an active component the compound of the invention.

EFFECT: higher effectiveness of application of the compound.

8 cl, 24 tbl, 262 ex

FIELD: pharmacology.

SUBSTANCE: invention deals with formula I compounds and their sals pharmaceutically relevant in the capacity of phosphatidylinositol 3-kinase inhibitors, their preparation method as well as their application for production of a pharmaceutical preparation, a pharmaceutical compounds based thereon and a therapy method envisaging their application. In a formula compound R1 is represented by aminocarbonyl, non-obligatorily displaced with nitrile, or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with hydroxi, carboxi, C1-C8-alcoxicarbonyl, nitrile, phenyl, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkyl aminocarbonyl alkylcarbonyl that is non-obligatorily displaced with halogen, hydroxi, C1-C8-alkylanimo, di(C1-C8-alkyl)amino, carboxi, C1-C8-alcoxicarbonyl, nitrile, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, non-obligatorily displaced with C1-C8-cycloalkyl or R1 is represented by C1-C8-alkylcarbonyl or C1-C8-alkylaminocarbonyl, each of them non-obligatorily displaced with C1-C8-alcoxi, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, displaced with phenyl, additionally displaced with hydroxi or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-4 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with C1-C8-alkyl on condition that the 6-membered heterocyclic ring is no 1-piperidyl or R1 is represented by C1-C8-alkylaminocarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring is non-obligatorily displaced with C1-C8-alkyl or R1 is represented by -(C=O)-(NH)a-Het, where a stands to denote 0 or 1 and Het stands to denote a 4-, 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with hydroxi, C1-C8-alkyl, C1-C8-alcoxi or a 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 0 or 1 and T stands to denote C3-C8-cycloalkyl that is non-obligatorily displaced with hydroxi or C1-C8-alkyl displaced with hydroxi or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 1 and T stands to denote phenyl that is non-obligatorily displaced with C1-C8-alkyl or C1-C8-alkyl displaced with hydroxi, R2 is represented by C1-C3-alkyl; one of R3 and R4 is represented by R6 while the other is represented by R7; R5 is represented by hydrogen or a halogen; R6 is represented by hydrogen, hydroxi, amino, -SOR8, -SO2R8, -SO2NH2, -SO2NR9R10, -COR8, -CONHR8, -NHSO2R8, nitrile, carboxi, -OR8 or C1-C8-halogenalkyl; R7 is represented by hydrogen, R11, -OR11, halogen, -SO2R8, ciano or C1-C8-halogenalkyl or, when R4 is represented by R7, R7 may equally be represented by -NR12R13; R8 and R11 are independently represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, nitrile, amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino; any R9 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, C1-C8-alcoxi, nitrile, amino, C1-C8-akrylamino, di(C1-C8-alkyl)amino or 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring where the ring is non-obligatorily displaced with C1-C8-alkyl, and R10 is represented by hydrogen or C1-C8-alkyl or R9 and R10 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl; any R12 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino and R13 is represented by halogen or C1-C8-alkyl or R12 and R13 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl.

EFFECT: proposed compounds are to be utilised for treatment of diseases mediated by phosphatidilinozitol 3-kinase such as allergy, psoriasis, diabetes, atherosclerosis, diabetes, cancer.

19 cl, 3 tbl, 181 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns novel compounds of formula (1a), formula (1b), formula (1c) and formula (1d), as well as pharmaceutical composition based on them and their application in medicine obtainment. R1-R4, G, W, X, X1, U, V, a, b are defined in the invention claim.

EFFECT: compound with antagonistic effect on vasopressin V1A receptor.

73 cl, 133 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

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: chemistry.

SUBSTANCE: there are disclosed 1-(2-aminobenzol)piperazine derivatives of formula (I) and pharmaceutically acceptable acid-additive salts with radical values specified in patent claim. The compounds are characterised with inhibiting effect on glycine I carrier. There is also disclosed medical product based on the compounds of formula (I).

EFFECT: compound can be used for treatment of the diseases associated with glycine uptake inhibition.

12 cl, 5 tbl, 396 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound of the formula (I): wherein R1 represents azido, -OR4, -NHR4 wherein R4 represents hydrogen atom or unsubstituted groups chosen from acyl, thioacyl, (C1-C6)-alkoxycarbonyl, (C3-C6)-cycloalkoxythiocarbonyl, (C2-C6)-alkenyloxycarbonyl, (C2-C6)-alkenylcarbonyl, (C1-C6)-alkoxythiocarbonyl, (C2-C6)-alkenyloxythiocarbonyl, -C(=O)-C(=O)-(C1-C6)-alkoxy, -C(C=S)-S-(C1-C6)-alkyl, -(C=S)-NH2, -(C=S)-NH-(C1-C6)-alkyl, -C(=S)-N-((C1-C6)-alkyl)2, -C(=S)-NH-(C2-C6)-alkenyl, -C(C=S)-(C=O)-(C1-C6)-alkoxy, thiomorpholinylthiocarbonyl; R2 and R3 can be similar or different and represent independently hydrogen atom, halogen atom, (C1-C6)-alkyl group, halogen-(C1-C6)-alkyl; heterocyclic moiety represents 5-membered heterocycle wherein Z represents sulfur (S), oxygen (O) atom or -NRb wherein Rb represents hydrogen atom or unsubstituted (C1-C6)-alkyl, (C3-C6)-cycloalkyl, aryl or aryl-(C1-C6)-alkyl; Y1 represents group =O or =S ; Y2 and Y3 represent independently hydrogen atom, and if Y2 and Y3 present in common on adjacent carbon atoms then they form 6-membered aromatic cyclic structure substituted if necessary with (C1-C6)-alkyl, or to its pharmaceutically acceptable salt. Also invention relates to a pharmaceutical composition possessing antibacterial activity and containing as an active compound the compound of the formula (I) taken in the effective dose and a pharmaceutically acceptable carrier, diluting agent, excipient. Also, invention relates to method for synthesis of compound of the formula (I). Method for synthesis of compound of the formula (I) wherein R1 represents group -NHR4 wherein R4 means acyl, (C1-C6)-alkoxycarbonyl, (C2-C6)-alkenyloxycarbonyl, (C2-C6)-alkenylcarbonyl, -C(=O)-C(=O)-(C1-C6)-alkoxy and -(C=S)-S-(C1-C6)-alkyl involves acetylation of compound of the formula (I) wherein R1 represents -NHR4 group wherein R4 represents hydrogen atom and all symbols are given above and using halide. Method for synthesis of compound of the formula (I) wherein R1 represents -NHR4 group wherein R4 means thioacyl, (C3-C6)-cycloalkoxythiocarbonyl, (C1-C6)-alkoxythiocarbonyl, (C2-C6)-alkenyloxythiocarbonyl involves the following steps: (i) conversion of compound of the formula (I) wherein R1 represents -NHR4 wherein R4 represents hydrogen atom, and all symbols are given above to compound of the formula (I) wherein R1 represents isothiocyanate group by reaction with thiophosgene, and (ii) conversion of compound of the formula (I) wherein R1 represents isothiocyanate group to compound of the formula (I) wherein R1 represents -NHR4 wherein R4 represents -C(=S)-OR4d wherein R4d represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C2-C6)-alkenyl, and all symbols are given above, in reaction with alcohol. Compounds of the formula (I) are used in treatment of bacterial infection that involves administration of compound of the formula (I) in a patient needing in this treatment. Invention provides synthesis of oxazolidinone compounds possessing antibacterial activity.

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

7 cl, 1 tbl, 144 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 novel substituted derivatives of 4-phenyltetrahydroisoquinoline of the general formula (I): wherein R1, R2, R3 and R4 mean independently of one another hydrogen (H), fluorine (F), chloride (Cl), bromine (Br) atoms, CaH2a+1 wherein one or more atoms H are substituted with F, -NR11R12 or -SOj-R15 wherein a = 1-8; R11 and R12 mean independently of one another H, CeH2e+1 or CrrH2rr-1 wherein e = 1-4; rr = 3, 4, or in common with nitrogen atom to which they are bound form a cycle chosen from group consisting of pyrrolidinyl, piperidinyl, N-methylpiperazinyl, piperazinyl or morpholine; j = 1 or 2; R15 means CkH2k+1 wherein k = 1-8; R5 means CpH2p+1 or CssH2ss-1; p = 1-8; ss = 3-8; R6 means H; R7, R8 and R9 mean independently of one another mean -SOwR23, -NR32COR30, NR32CSR30, -NR32SObbR30, H, F, Cl, Br, -OH, -NH2, CeeH2ee+1, -NR40R41, -CONR40R41 or -COOR42 wherein w = 0, 1 or 2; bb = 2 or 3; R23 means NR25R26 wherein R25 and R26 mean independently of one another H or CzH2z+1, CzzH2zz-1 wherein z = 1-8; zz = 3-8 wherein in CzH2z+1 and CzzH2zz-1 one or more H atoms are substituted with fluorine atom and one or more CH2-groups are substituted with -C(=O) or NR27 wherein R27 means H or CaaH2aa+1 wherein aa = 1-4; or R25 and R26 in common with nitrogen atom to which they are bound form 5-, 6- or 7-membered cycle; R30 means H, CccH2cc+1, CyyH2yy-1, pyrrolydinyl, piperidinyl wherein in their cycles CH2-group can be substituted with oxygen atom (O) or -NR33; R32 and R33 mean independently of one another H or ChH2h+1 wherein cc = 1-8; yy = 3-8; h = 1-8 wherein in the group ChH2h+1 one or more hydrogen atoms are substituted with fluorine atom, and in the groups CccH2cc+1 and CyyH2yy-1 one or more hydrogen atoms can be substituted with fluorine atom, and CH2-group can be substituted with O or -NR31 wherein NR31 means H, methyl, ethyl, acetyl or -SO2CH3; or R30 means 6-membered heteroaryl with 1-4 nitrogen atoms, 0 or 1, S-atoms or 0, or 1 O-atom that represents unsubstituted or substituted with up to three substitutes chosen from group consisting of F, Cl, Br, J, CooH2oo+1 wherein one or more hydrogen atoms can be substituted with fluorine atom, -NO2 or -NR70R71 wherein oo = 1-8; R70 and R71 mean independently of one another H, CuuH2uu+1 or -COR72 wherein uu = 1-8; R72 means H, CvvH2vv+1 wherein vv = 1-8; ee = 1-8; R40 and R41 mean independently of one another H, CttH2tt+1 or -C(NH)NH2 wherein tt = 1-8 and wherein in the group CttH2tt+1 one or more CH2-groups can be substituted with NR44 wherein R44 means CggH2gg+1 wherein gg = 1-8; R42 means H or ChhH2hh+1 wherein hh = 1-8 being, however, two substitutes from group R7, R8 and R9 can't mean -OH simultaneously, and at least one residue from R7, R8 and R9 must be chosen from group consisting of -CONR40R41, -OvSOwR23, -NR32COR30, -NR32CSR30 and -NR32SObbR30. Also, invention relates to using above given compounds for preparing a medicinal agent. Also, invention considers a medicinal agent representing inhibitor of sodium-proton exchange of subtype III (NHE3) based on proposed compounds. Invention provides synthesis of novel compounds, a medicinal agent based on thereof for aims of treatment of such diseases as nervous system ischemia, insult and brain edema, in treatment of snore, shock, impaired respiratory impulse, as purgative agents, as agents against extoparasites, for prophylaxis of gall stones formation, as anti-atherosclerotic agents, agents against diabetes mellitus later complications, cancer diseases, fibrous diseases, endothelial dysfunction, hypertrophies and hyperplasia of organs and others.

EFFECT: valuable medicinal properties of compounds and medicinal agents.

21 cl, 15 tbl, 221 ex

FIELD: organic chemistry, medicine, pharmacy.

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

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula Ia: and its pharmaceutically acceptable salt, where: p equals 0 or 1; n assumes values from 1 to 3, q equals 1; R5 is selected from hydrogen, -XNR7R8, pyrimidine-C0-4alkyl, pyridine-C0-4alkyl, phenyl, C3-10cycloalkyl-C0-4alkyl and C3-6heterocycloalkyl-C0-4alkyl, where C3-6heterocycloalkyl is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is hydrogen or C1-4alkyl; R7 and R8 represent C1-4alkyl; R6 denotes hydrogen; or R5 and R6 together with a nitrogen atom to which they are both bonded form morpholine or piperidine; where any piperdine-C0-4alkyl, piperidine-C0-4alkyl or C3-10cycloalkyl-C0-4alkyl of substitute R5 or a combination of radicals R5 and R6 can be optionally substituted with 1-2 radicals which are independently selected from -XNR7R8 and -XOR7, the said phenyl of substitute R5 is substituted with a -XR9 group, the said C3-6heterocycloalkyl-C0-4alkyl of substitute R5 is optionally substituted with a -XOR7 group, where X is a single bond or C1-4alkylene; R7 and R8 are independently selected from hydrogen and C1-4alkyl; R9 is selected from C3-10heterocycloalkyl which is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is as given above; R10 denotes hydrogen; R15 is selected from halogen, C1-6alkyl and C1-6alkoxy; and R16 is selected from halogen, methoxy, nitro, -NR12C(O)R13, -C(O)NR12R12, -NR12R12, -C(O)OR12 and -C(O)NR12R13; each R12 is selected from hydrogen and C1-6alkyl; R13 is selected from phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl, where any phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl of substitute R13 can be optionally substituted with 1-2 radicals which are independently selected from halogen, C1-6alkyl, halogen-substituted C1-6alkyl, imidazole-C0-4alkyl, C3-10cycloalkyl, C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl; where the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl each represent a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R assumes values given above; and the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl can each be optionally substituted with 1 radical independently selected from C1-6alkyl, hydroxyl-substituted C1-6alkyl and NR7R8, where R7 and R8 assume values given above. The invention also relates to pharmaceutical compositions containing the said compounds.

EFFECT: obtaining novel compounds and compositions based on the said compounds which can be used in medicine for treating and preventing diseases or disorders associated with abnormal or uncontrolled kinase activity, particularly diseases or disorders associated with abnormal activity of kinase c-Src, FGFR3, KDR and/or Lck.

12 cl, 1 tbl, 2 ex

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