C-phenyl glycitol compound for treating diabetes

FIELD: chemistry.

SUBSTANCE: invention relates to a novel C-phenyl glycitol compound which serves as a preventive or therapeutic agent for sugar diabetes by inhibiting SGLT1 activity, as well as SGLT2 activity; demonstrating inhibiting effect on glucose absorption, and also acts on release of glucose with urine. The C-phenyl glycitol compound has formula (I) given below, or pharmaceutically acceptable salt or hydrate thereof, where R1 and R2 are identical or different and denote a hydrogen atom, a hydroxyl group, a C1-6 alkyl group, a C1-6 alkoxy group or a halogen atom, R3 is a hydrogen atom, a C1-6 alkyl group or a C1-6 alkoxy group, Y is a C1-6 alkylene group, -O-(CH2)n- (n is a whole number which assumes values from 1 to 4), provided that when Z denotes -NHC(= NH)NH2 or -NHCON(RB)Rc, n not equal to 1, Z is -CONHRA, -NHC(=NH)NH2 or -NHCON(RB)Rc, or The invention also relates to a pharmaceutical composition based on compounds of formula I.

EFFECT: high efficiency of the compounds.

19 cl, 8 tbl

 

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to a connection C-phenylglycinol possessing inhibitory activity against retrieveimage superelastic 1 glucose (SGLT1) and retrieveimage superelastic 2 glucose (SGLT2).

The prior art INVENTIONS

When people have diabetes, the level of fasting blood glucose is 126 mg/DL or more. Even if the content of the fasting blood glucose falls within the norm, there are people who after a meal demonstrate the level of glucose in the blood, such as 140-200 mg/DL. Such a person is diagnosed impaired glucose tolerance (hereinafter referred to as “IGT”). Believed that the risk of cardiovascular disorders can be reduced by slowing the occurrence of diabetes from IGT state. In confirmation of this was received some data. For example, in the study Da Qing IGT and diabetes in China, held in 1997, reported that the progressive development of IGT to diabetes type II significantly inhibit diet and physical activity (see, Pan XR, et al., Diabets Care, vol 20, p. 534, 1997). Drug treatment is effective when administered inhibitor of α-glucosidase, acarbose, which inhibits the hydrolysis of the oligosaccharide, slowing down the absorption of CH the goats from the small intestine and inhibits the development of IGT to diabetes type II and in addition, significantly suppresses the occurrence of hypertension. This message is contained in document J.-L. Chiasson, et al., Lancent, vol. 359, p. 2072, 2002.

From the above it follows that essential to suppress the occurrence of diabetes is to control IGT through diet, exercise and by medical treatment.

However, when a patient suffers from diabetes, continuous monitoring of glucose level in the blood becomes necessary. Diabetes cure, basically, diet nutrition and physical activity; however, when using such therapies do not achieve an adequate effect, it is necessary to apply the medication.

Metrizability superelastic 1 glucose (SGLT1) with a high frequency is expressed on the epithelium of the small intestine of the mammal. It is known that SGLT1 functions dependent on sodium and plays a role in the active transport of glucose or galactose in the small intestine. Therefore, if it is possible to suppress the consumption of glucose from food, IGT can be prevented or treated. Based on this concept, reported a derivative of pyrazole, the inhibitory activity of SGLT1 (see, WO2002/098893, 2004/014932, 2004/018491, 2004/019958, 2005/121161 and 2004/050122).

Moreover, metrizability superelastic 2 glucose (SGLT2) with a high frequency is expressed in the kidney. Glucose, being filtered renal glomerulus, the setting different absorbed with SGLT2 (see, E. M. Wright, Am. J. Physiol. Renal. Physiol., vol. 280, p. F10, 2001). When the SGLT2 inhibitor is administered a diabetic rat, the excretion of glucose in urine is facilitated by stimulating the hypoglycemic effect. On this basis, a specific inhibitor of SGLT2 considered as a molecule-target, which serves as a therapeutic tool for the treatment of diabetes (see, G. Toggenburger, et al. Biochem. Biophys. Acta., vol. 688, p. 557, 1982). In these circumstances, research has focused on the SGLT2 inhibitor, and have been proposed various types of derivatives of O-arylpyrazole (see, publication EP patent application No. 0850948A1 and the publication of the international application WO2001/068660).

Accordingly, if the simultaneous inhibition of the activity of SGLT1 and SGLT2, you may be offered a new type of therapeutic agent for treating diabetes, which has not only high depressing effect on glucose levels after a meal, attributed to inhibition of SGLT1, but also increasing hypoglycemic effect, attributed to inhibition of SGLT2.

To date reported a derived C-phenylglycine with selective inhibitory activity against SGLT2 (see, a publication of the international application WO 2001/027128), but did not report the derived C-phenylglycine, much as inhibiting SGLT1 and SGLT2.

DISCLOSURE of INVENTIONS

The purpose of this izaberete the Oia is to obtain compound C-phenylglycinol, which presumably is considered as a new type of pharmaceutical agent for the treatment of diabetes, is capable of inhibiting activity and SGLT1 and SGLT2, possessing not only an overwhelming impact on the absorption of glucose from the digestive tract, but also the influence on the excretion of glucose in the urine.

To achieve the above objective, the authors of the present invention conducted a series of intensive research. As a result, they found that the compound C-phenylglycinol, which is formed by the introduction of a specific side chain in the tail part of the aglycone, has excellent inhibitory effect on the activity of SGLT1 and SGLT2 activity. Based on this discovery was made the present invention.

Connection C-phenylglycinol of the present invention (hereinafter referred to as “compound of the invention”) will be discussed below.

On the basis of the present invention has been possible to offer a new connection C-phenylglycinol able to inhibit both the activity of SGLT1 and activity SGLT 2.

The first variant of implementation of the present invention (variant implementation of the invention 1) refers to the connection C-phenylglycinol following formula or its pharmaceutically acceptable salt, or hydrate:

where R1and R2odinakovije different, and represent a hydrogen atom, a hydroxyl group, a C1-6alkyl group, a C1-6alkoxygroup or halogen atom,

R3is a hydrogen atom, a C1-6alkyl group, a C1-6alkoxygroup or a halogen atom,

Y is C1-6alkalinous group, -O-(CH2)n- (n is an integer taking values from 1 to 4) or C2-6alkynylamino group, provided that when Z is-NHC(=NH)NH2or -- NHCON(RBRCn not equal to 1,

Z is-CONHRA, -NHC(=NH)NH2or -- NHCON(RBRC,

or

where RAis

C1-6alkyl group substituted by 1-3 substituents selected from the group consisting of hydroxyl group, amino group and carbamoyl group,

RBis

(1) a hydrogen atom,

(2) C1-6alkyl group which may be substituted by 1-3 substituents selected from group A,

(3) C3-12cycloalkyl group which may be substituted by 1-3 substituents chosen from hydroxyl groups and C1-6hydroxyalkyl group,

(4) (3-12) - membered geteroseksualnoe group or (5-13)-membered heteroaryl group which may be partially saturated; each of which contains from one to three, ciclopaseos atoms, SEL is selected from the group consisting of O, N, S, SO2, CO and NR10(R10is a hydrogen atom, a C1-6alkyl group, a phenyl-C1-6alkyl group or a C2-6alkoxycarbonyl group), and may be substituted by 1-3 substituents selected from the group consisting of hydroxyl group and C1-6hydroxyalkyl group, or

(5) C6-13aryl group, which may be partially saturated and may be substituted by 1 or 2 substituents selected from a hydroxyl group and C1-6alkyl groups, phenyl-C1-6alkyl group, and C1-6alkylsulfonyl group, each of which may be substituted by hydroxyl(s) group(s)

where group A consists of

of halogen atom, hydroxyl group, C1-6alkoxygroup, which may be substituted by hydroxyl(s) group(s), a carboxyl group, a C2-6alkoxycarbonyl group, carbamoyl group, amino group, C1-6alkylaminocarbonyl, dis1-6alkylaminocarbonyl, C2-6allmineral, C1-6alkylthiol, which may be substituted by hydroxyl(s) group(s);

fenoxaprop,

phenyl group which may be substituted by 1-3 substituents selected from group B (Group B consists of hydroxy group, halogen atom, a C1-6alkoxygroup, C1-6alkyl group, to ora may be substituted by hydroxyl(s) group(s), C1-6alkylthiol, thienyl group, phenylthiourea, which may be substituted by hydroxyl(s) group(s) or C1-6hydroxyalkyl(s) group(s), and piperidinium, which may be substituted by hydroxyl(s) group(s) or C1-6hydroxyalkyl(s) group(s)),

C3-12cycloalkyl group which may be substituted by 1-3 substituents selected from the group consisting of hydroxyl group and C1-6hydroxyalkyl group,

(3-12)-membered geteroseksualnoe group or (5-13)-membered heteroaryl group, which may be partially saturated; each of which contains from one to three ciclopaseos atoms selected from the group consisting of O, N, S, SO2, CO and NR10(R10is a hydrogen atom, a C1-6alkyl group, a phenyl-C1-6alkyl group or a C2-6alkoxycarbonyl group), and may be substituted by 1 to 3) substituents selected from the group consisting of hydroxyl group and C1-6hydroxyalkyl group, and

-CONRB1RB2where RB1and RB2together with the nitrogen atom to which they are attached, form a 5 to 6-membered geterotsyklicescoe group, which may contain as another collabrasuite atom, oxygen atom, nitrogen atom or sulfur atom and may be substituted by 1 is 2 substituents, selected from the group consisting of C1-6alkyl group which may be substituted by hydroxyl(s) group(s), C2-6alkoxycarbonyl group and phenyl C1-6alkyl group,

RCis

an atom of hydrogen, C1-6alkyl group which may be substituted by 1 or 2 substituents selected from the group consisting of hydroxyl group, ISD1-6alkylamino, C2-6alkoxycarbonyl group and C1-6alkoxygroup, or C3-12cycloalkyl group which may be substituted by hydroxyl(s) group(s), and

RBand RCtogether with the nitrogen atom to which they are attached, may form (3-12)-membered geterotsyklicescoe group or (5-13)-membered heteroaryl group which may be partially saturated; each of which may contain 1 or 2 ciclopaseos atom selected from O, N, NR11, S, SO2and CO., and which may be substituted by 1 or 2 substituents selected from the group consisting of a hydroxyl group, a C2-6alkoxycarbonyl group, carbamoyl group, C2-6acyl(C1-6alkyl)amino, di-C1-6alkylaminocarbonyl group, pyrrolidinyl group, morpholinopropan, pyrrolidin-1-yl-carbonyl group, a C1-6alkyl group which may be substituted by 1-3 substituents, which imiramine from the group consisting of a hydroxyl group, pyrrolidin-1-ilen group, phenyl group, C2-6alkoxycarbonyl group, and phenyl group which may be substituted by 1-3 substituents selected from the group consisting of C1-6alkyl group, a C1-6alkoxygroup and halogen atom,

where R11is a hydrogen atom, a C2-6acyl group, phenyl group which may be substituted by hydroxyl(s) group(s), peredelnoj group, fuelleborni group, exelononline group, C2-6alkoxycarbonyl group or a C1-6alkyl group which may be substituted by 1 or 2 substituents selected from the group consisting of hydroxyl group, phenyl group, ISD1-6alkylamino, morpholinopropan and pyrrolidin-1-ylcarbonyl group, and

RDis a hydrogen or C1-6alkyl group which may be substituted by 1 or 2 substituents from the group consisting of a hydroxyl group, a C3-12cycloalkyl group, phenyl group which may be substituted by hydroxyl(s) group(s), peredelnoj group, C2-6alkoxycarbonyl group, imidazoline group and 1-benzylimidazole group, and RDAis a hydrogen or C1-6alkyl group.

BEST mode for carrying out IMAGE IS ETENIA

In the present invention offer the following other embodiments of the invention 2-19:

2. Connection C-phenylglycinol that is the conjunction of C-phenylglycine represented by the formula (II)below, or its pharmaceutically acceptable salt, or hydrate,

where R1, R2, R3, Y and Z are defined in formula (I).

3. Connection C-phenylglycinol or its pharmaceutically acceptable salt, or hydrate according to the formula (II), where R1is a hydrogen atom, a hydroxyl group, a C1-4alkyl group or a C1-4alkoxygroup, and R2is C1-4alkyl group or a halogen atom.

4. Connection C-phenylglycinol according to the variant of the invention, the 2 or 3 or its pharmaceutically acceptable salt, or hydrate, where R3is a hydrogen atom.

5. Connection C-phenylglycinol or its pharmaceutically acceptable salt, or hydrate according to the variant embodiment of the invention 3 or 4; where Y is C1-6alkalinous group or-O-(CH2)n- (n is an integer from 2 to 4), and Z is-NHCON(RBRCwhere RBand RCdefined for formula (I).

6. Connection C-phenylglycinol or its pharmaceutically acceptable salt, or hydrate according to the variant embodiment of the invention 3 or 4, where

Y is C1-6alkalinous group or-O-(CH2)n- (n is an integer from 2 to 4), and Z is-NHCON(RBRC,

where RBis

(1) C1-6alkyl group which may be substituted by 1-3 substituents selected from group A,

(2) C3-12cycloalkyl group which may be substituted by 1-3 substituents chosen from hydroxyl groups and C1-6hydroxyalkyl group,

(3) (3-12)-membered geteroseksualnoe group or (5-13)-membered heteroaryl group which may be partially saturated; each of which contains from one to three ciclopaseos atoms selected from the group consisting of O, N, S, and NR10(R10is a hydrogen atom, a C1-6alkyl group, a phenyl-C1-6alkyl group or a C2-6alkoxycarbonyl group) and may be substituted by 1-3 substituents selected from the group consisting of hydroxyl group and C1-6hydroxyalkyl group, or

(4) C6-13aryl group, which may be partially saturated and may be substituted by 1 or 2 substituents selected from a hydroxyl group, and C1-6alkyl groups, phenyl-C1-6the alkyl groups of C1-6alkylsulfonyl groups, each of which may be substituted by hydroxyl(s) group(s)

in which

group A consists of:

of halogen atom, hydroxyl group, C1-6alkoxygroup, which may be substituted by hydroxyl(s) group(s), C2-6alkoxycarbonyl group, carbamoyl group, ISD1-6alkylaminocarbonyl, C1-6alkylthiol, which may be substituted by hydroxyl(s) group(s)

fenoxaprop, thienyl group, benzothiazole group, shriley group,

phenyl group which may be substituted by 1-3 substituents selected from the group consisting of hydroxyl group, halogen atom, a C1-6alkoxygroup, C1-6alkyl group which may be substituted by hydroxyl(s) group(s), C1-6alkylthiol, phenylthiourea, which may be substituted by hydroxyl(s) group(s), or C1-6hydroxyalkyl(s) group(s) and piperidinium, which may be substituted by hydroxyl(s) group(s) or C1-6hydroxyalkyl(s) group(s)

C3-12cycloalkyl group which may be substituted by 1-3 substituents selected from the group consisting of hydroxyl group and C1-6hydroxyalkyl group,

(3-12)-membered geteroseksualnoe group that contains from one to three ciclopaseos atoms selected from the group consisting of O, N, S, and NR10(R10assetstotal hydrogen, C1-6alkyl group, a phenyl-C1-6alkyl group or a C2-6alkoxycarbonyl group); and which may be substituted by 1-3 substituents selected from the group consisting of hydroxyl group and C1-6hydroxyalkyl group; and

4-C1-6alkylpiperazine-1-ylcarbonyl group,

RCis a hydrogen atom, and

RBand RCtogether with the nitrogen atom to which they are attached, form piperidinyl group which may be substituted pyrrolidinyl group or a C1-6alkyl group which is substituted dis1-6alkylaminocarbonyl or pyrrolidin-1-ilen group or group thiomorpholine or group of decahydroquinoline.

7. Connection C-phenylglycinol or its pharmaceutically acceptable salt or hydrate according to any one of the embodiments of the invention 2-4,

where Y is C1-6alkalinous group,

Z is-CONHRA,

where RAis C1-6alkyl group substituted by 1 to 3 substituents selected from the group consisting of hydroxyl group and carbamoyl group.

8. Connection C-phenylglycinol or its pharmaceutically acceptable salt or hydrate according to any one of the embodiments of the invention 2-4, where

Y is C1-6alkalinous group, and

Z is-NHC(=NH)NH2.

9. Soedinenie-phenylglycinol or its pharmaceutically acceptable salt or hydrate according to any one of the embodiments of the invention 2-4, where

Y is C1-6alkalinous group, and

Z is

RDis C1-6alkyl group which is substituted C3-12cycloalkyl group or phenyl group; and RDAis a hydrogen or C1-6alkyl group.

10. Connection C-phenylglycinol according to the variant embodiment of the invention 1, which is compound C-phenylalaninol represented by the formula (III)below, or its pharmaceutically acceptable salt, or hydrate,

where Y is C1-6alkalinous group, and

Z is-CONHRA,

where RAis C1-6alkyl group substituted by 1-3 substituents selected from the group consisting of a hydroxyl group carbamoyl group.

11. Connection C-phenylglycinol according to the variant embodiment of the invention 1, which is compound C-phenylglycine represented by the formula (IV)below, or its pharmaceutically acceptable salt or hydrate

where Y is C1-6alkalinous group, and

Z is-CONHRA1, -NHC(=NH)NH2or-NHCORB1,

where RA1is C1-6alkyl group substituted by 1-3 substituents selected from the group consisting of hydroxyl group, is aminogruppy and carbamoyl group, and

RB1is

C1-6alkylaminocarbonyl, which may be substituted by 1-3 hydroxyl groups, or 4-C1-6alkylpiperazine-1-ylcarbonyl group, or 4-C1-6alkylpiperazine-1-ilen group.

12. Connection C-phenylglycinol according to the variant embodiment of the invention 11 or its pharmaceutically acceptable salt or hydrate, in which

Y is C1-6alkalinous group,

Z is-CONHRA1or-NHC(=NH)NH2or

where RA1is C1-6alkyl group substituted by 1-3 substituents selected from the group consisting of hydroxyl group, amino group and carbamoyl group.

13. Connection C-phenylglycinol according to the variant embodiment of the invention 11 or its pharmaceutically acceptable salt or hydrate, in which

Y is C1-6alkalinous group, and

Z is-CONHRA1

where RA1is C1-6alkyl group substituted by 1-3 substituents selected from the group consisting of hydroxyl group, amino group and carbamoyl group.

14. Connection C-phenylglycinol according to the variant embodiment of the invention 11 or its pharmaceutically acceptable salt or hydrate, in which

Y is C1-6alkalinous group, and

Z is-NHC(=NH)NH2.

15. Connection C-Fanelli is Itala according to the variant embodiment of the invention 11 or its pharmaceutically acceptable salt or hydrate, in which

Y is C1-6alkalinous group, and

Z is-NHCORB1(where RB1is C1-6alkylaminocarbonyl, substituted by 1-3 hydroxyl groups, or 4-C1-6alkylpiperazine-1-ylcarbonyl group, or 4-C1-6alkylpiperazine-1-ilen group).

16. Connection C-phenylglycinol according to the variant embodiment of the invention 11 or its pharmaceutically acceptable salt or hydrate, in which

Y is C1-6alkalinous group, and

Z is represented by the formula

17. Pharmaceutical drug as the active ingredient contains a join C-phenylglycinol according to any one of the embodiments of the invention 1-16 or its pharmaceutically acceptable salt or its hydrate.

18. The pharmaceutical preparation according to the variant embodiment of the invention 17, which is an inhibitor of the activity retrieveimage of superelastic glucose 1 (SGLT1) and inhibitor activity retrieveimage of superelastic glucose 2 (SGLT2).

19. The pharmaceutical preparation according to the variant embodiment of the invention 17, which is a prophylactic or therapeutic agent for the treatment or prevention of diabetes.

DETAILED DESCRIPTION of PREFERRED embodiments of the INVENTION

Terms used in this izobreteny is, will be determined in the following way.

The term “C1-6alkyl group” denotes a linear or branched alkyl group having from 1 to 6 carbon atoms. Examples may include methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, tert-boutelou group, sec-boutelou group, n-pentelow group, tert-pentelow group, n-hexoloy group and isohexyl group.

The term “C1-6alkoxygroup” denotes a linear or branched alkoxygroup having from 1 to 6 carbon atoms. Of them, C1-4alkoxygroup is preferred. Examples of C1-4alkoxygroup may include a methoxy group, ethoxypropan, propoxylate, isopropoxy, n-butoxypropyl, isobutoxy and tert-butoxypropan.

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

The term “C1-6Allenova group” means a divalent group derived by removing a hydrogen atom from the carbon atom C1-6alkyl groups. Examples of linear alkalinous group may include methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group and hexamethylene group.

The term “C2-6alkenylamine group” means vocalistul group, formed by removing a hydrogen atom from the carbon atom C2-6alkenylphenol group. Examples of linear Alcanena may include vanilinovoi (ethenylene group), propenylidene group, butenylamine group, pentesilea group and hexadecanoyl group.

The term “C1-6alkyl group substituted by 1-3 substituents selected from the group consisting of hydroxyl group, amino group and carbamoyl group” denotes a linear or branched C1-6alkyl group in which 1 to 3 hydrogen atoms of C1-6alkyl group substituted by at least one member of the group consisting of hydroxyl group, amino group and carbamoyl group. Examples can include hydroxymethylene group, hydroxyethylene group, 2-hydroxy-1,1-dimethylethylene group, 1,3-dihydroxy-2-methylpropan-2-ilen group, 1,3-dihydroxy-2-hydroxymethylpropane-2-ilen group, carbamoylmethyl group and 2-carbamoylethyl group.

The term “C3-12cycloalkyl group” means a cyclic alkyl group having 3 to 12 carbon atoms, and includes monocyclic-, bicyclic - and spirolateral. Examples of the monocyclic hydrocarbon may include cyclopropyl group, cyclobutyl group, cyclopentyl group, tsiklogeksilnogo group, cycloheptyl group and qi is lactilol group. Examples of bicyclic hydrocarbon may include adamantly group, bicyclo[2.2.1]heptylene group and bicyclo[2.2.2]heptylene group. Examples of spirolaterals may include Spiro[3.4]octillo group, and Spiro[4.5]deganello group.

The term(3-12)-membered heterocytolysine group that contains from one to three ciclopaseos atoms selected from the group consisting of O, N, NR10, S, SO2and CO” refers to a particular higher C3-12cycloalkyl group in which from 1 to 3 methylene groups or marinovich groups substituted atom(s)selected(s) from the group consisting of O, N, NR10, S, SO2and CO. Examples can include ossanlou group, 2-oxohexyl group, 1,3-dioxolo group, pyrrolidinyl group, piperidino, 2-piperidino group, 4-piperidino group, piperazinilnom group, morpholinopropan, thiomorpholine, hinkleyville group, decahydroquinoline group, decahydroquinoline group,

The term “(5-13)-membered heteroaryl group which may be partially saturated, and which contains from one to three ciclopaseos atoms selected from the group consisting of O, N, NR10, S, SO2and CO”means (5-13)-membered unsaturated monocyclic, disilicate or tricyclic hetero is ikl; and may include follow group, imidazolidinyl group, thienyl group, pyridyloxy group, benzothiazoline group, 2,3-dihydrobenzofuranyl group, 2,3-dihydro-1H-benzo[de]athinodorou group, 2,3-dihydro-1H-indolering group, 2,3-dihydro-1H-isoindolyl group and 2,3,4,9-tetrahydro-1H-b-karbonilnuyu group.

The term “C6-13aryl group, which may be partially saturated” refers to unsaturated monocyclic, bicyclic or tricyclic hydrocarbon cycle having 6 to 13 carbon atoms. Examples can include phenyl group, naftalina group, fluorenyl group, 1,2,3,4-tetrahydronaphthalene group, indenolol group.

The term “5 to 6-membered heterocytolysine group, which form an RB1and RB2together with the nitrogen atom to which they are attached, and which may contain oxygen atom, nitrogen atom or sulfur atom as another collabrasuite atom” may include piperidino, piperazinone, morpholinopropan, thiomorpholine.

The term “phenyl C1-6alkyl group” denotes a linear or branched C1-6alkyl group which is substituted by phenyl group. Examples can include benzyl group phenylethylene group.

The term “C2-6alkoxycarbonyl group” defines the structure, asteasu from linear or branched C 1-5alkoxygroup and carbonyl groups, preferred is a C2-5alkoxycarbonyl group. Examples can include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group and tert-butoxycarbonyl group.

The term “C1-6allylthiourea” defines the structure consisting of linear or branched C1-6alkyl groups and one diography (-S-). Preferred is C1-4allylthiourea. Examples of C1-6ancilliary include metalcorp, ethylthiourea and PropertyGroup.

The term “C1-6alkylamino” defines the structure consisting of linear or branched C1-6alkyl groups and amino groups. Examples can include methylaminopropyl and ethylamino.

The term “dis1-6alkylamino” defines the structure consisting of two linear or branched C1-6alkyl groups and amino groups. Examples can include dimethylaminopropyl and diethylaminopropyl.

The term “C2-6acyl group” means a linear or branched aliphatic acyl group that contains from 2 to 6 carbon atoms. Examples include acetyl group, propionyl group, pivaloyloxy group, butyryloxy group from butyryloxy group and valerino group.

The term “C2-6alluminare” defines the structure consisting of C2-6acyl group and an amino group; and preferred is acetaminophe.

The term “C2-6acyl(C1-6alkyl)amino group” defines the structure consisting of C2-6acyl group, a C1-6alkyl groups and amino groups.

The term “dis1-6alkylaminocarbonyl group” defines the structure, consisting of dis1-6alkylamino and carbonyl group.

The term “C1-6hydroxyalkyl group” refers to C1-6alkyl group which is substituted by at least one hydroxyl group. Examples include hydroxymethylene group, 1-hydroxyethylene group, 2-hydroxyethyloxy group, 3-hydroxypentanal group and 2-hydroxy-2-methylbutyl group.

The term(3-12)-membered heterocytolysine group or (5-13)-membered heteroaryl group, which may form RBand RCtogether with the nitrogen atom to which they are attached; and each of which may contain 1 or 2 ciclopaseos atom selected from O, N, NR11, S, SO2and CO” means (3-12)-membered geterotsyklicescoe group or (5-13)-membered heteroaryl group that is defined above.

The term “pharmaceutically acceptable salt” means a salt of an alkali metal, alkaline earth metal,ammonium, alkylamine, or salt of a mineral acid or organic acid. Examples can include sodium salt, potassium salt, calcium salt, ammonium salt, aluminum salt, salt of triethylamine, acetate, propionate, butyrate, formate, triptorelin, maleate, tartrate, citrate, stearate, succinate, ethylsuccinate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, aconsultant, 2-hydroxyethanesulfonic, bansilalpet, p-toluensulfonate, lauryl, malate, aspartate, glutamate, adipat, salt cysteine, salt of N-acetylcysteine, hydrochloride, Hydrobromic, phosphate, sulfate, hydroiodic, nicotinate, oxalate, picrate, thiocyanate, undecanoate, salt polyacrylate and salt carboxyvinyl polymer.

The term “hydrate” refers to pharmaceutically acceptable hydrate compounds according to the invention or its salt. The connection according to the invention or its salt is exposed to air or recrystallization, absorbs moisture, as a result, it is not necessarily contain hygroscopic water or applies to hydrate. Such a hydrate may be included in the "hydrate" of the present invention.

Some compounds according to the invention and their intermediate compounds, which have a chiral center may exist in the form of a diastereoisomer or enantiomer. Moreover, some compounds according to the invention and the intermediate compounds which deposits may be present in the form of keto-enol tautomer. Moreover, some compounds according to the invention and their intermediate compounds can be present as geometric isomers (E, Z form). Therefore, all isomers and their mixtures mentioned above are included in the connection according to the invention and its intermediate connection.

In particular, in the compound represented by formula (I), the steric configuration of the hydroxyl group in 4-position of the glucose part is a or R-form or S-form, which indicate a wavy line.

Preferred examples of compounds according to the invention will be given below.

In the formula (I), preferred positions substituted with R1and R2are the positions shown in the formula (II).

R1preferably is a hydrogen atom, a hydroxyl group, a C1-4alkyl group, and C1-4alkoxygroup, more preferred hydroxyl group and C1-4alkoxygroup, and more preferably a hydroxyl group and a methoxy group.

R2preferably, a is a hydroxyl group, a C1-6alkyl group, a halogen atom, more preferably C1-4alkyl group and a halogen atom; more preferably a methyl group and a chlorine atom.

In the formula (I) or (II), R3preferably is a hydrogen atom, a C1-4alkyl group and a halogen atom, valueproposition a hydrogen atom, methyl group and a fluorine atom, and most preferably a hydrogen atom. When R3is not a hydrogen atom, preferably a substitution in the ortho-position of the benzyl of the formula (I) or (II).

In the formula (I) or (II), Y, preferably, may be C1-4alkalinous group, -O-(CH2)2or C2-4alkynylamino group, more preferably a C1-3alkalinous group, or-O-(CH2)2-, and more preferably C1-3alkalinous group. When Z is-NHCON(RBRCY, most preferably, a is -(CH2)2-.

In the formula (I) or (II)where Z is-NHCON(RBRC, RBand RCpreferred are the following (i)to(v) options for implementing the invention.

(i) RCis a hydrogen atom, and RBis C1-6alkyl group which may be substituted by 1, 2 or 3 substituents selected from group A.

Group A here is a

halogen atom, a hydroxyl group, a C1-6alkoxygroup, which may be substituted by hydroxyl(s) group(s), C2-6alkoxycarbonyl group, carbamoyl group, ISD1-6alkylaminocarbonyl, C2-6allmineral, C1-6alkylthiol, which may be substituted by hydroxyl(s) group(s), fenoxaprop, shriley g is uppoi, thienyl group, benzothiazole group, 2,3-dihydrobenzofuranyl group, phenyl group which may be substituted by 1-3 substituents selected from group B (group B consists of hydroxy group, halogen atom, a C1-6alkoxygroup, C1-6alkyl group which may be substituted by hydroxyl(s) group(s), C1-6alkylthiol, phenylthiourea which may be substituted by hydroxyl(s) group(s) or C1-6hydroxyalkyl(s) group(s), piperidinium, which may be substituted by hydroxyl(s) group(s) or C1-6hydroxyalkyl(s) group(s)),

C3-12cycloalkyl group which may be substituted by 1-3 substituents selected from the group consisting of hydroxyl group and C1-6hydroxyalkyl group,

(3-12)-membered geterotsyklicescoe group that contains from one to three ciclopaseos atoms selected from the group consisting of O, N, S, and NR10(R10is a hydrogen atom, a C1-6alkyl group, a phenyl-C1-6alkyl group or a C2-6alkoxycarbonyl group), and may be substituted by 1-3 substituents selected from the group consisting of hydroxyl group and C1-6hydroxyalkyl group; and

4-C1-6alkylpiperazine-1-ylcarbonyl group.

Valueproposition examples of the group include A hydroxyl group, a methoxy group, ethoxypropan, C3-6cycloalkyl group (cyclopropyl group, cyclobutyl group, cyclopentyl group, tsiklogeksilnogo group), which may be substituted by 1-3 substituents selected from the group consisting of hydroxyl group and C1-6hydroxyalkyl group, methoxycarbonyl group, carbamoyl group, dimethylaminopropyl, acetylamino, methylthiourea, phenyl group, 4-hydroxyproline group, 4-methylthiophenyl group, 3-metoksifenilny group, 3,4-dimethoxyphenyl group, fenoxaprop, 2-(hydroxymethylamino)phenyl group, thienyl group, shriley group, benzothiazole group, 2,3-dihydrobenzofuranyl group, 4-methylpiperazin-1-ylcarbonyl group, 1-pyrrolidinyloxy group, 1,3-dioxane-2-ilen group, 2-oxanilide group and piperidino.

(ii) RCis a hydrogen atom and RBis C3-12cycloalkyl group which may be substituted by 1, 2 or 3 substituents selected from a hydroxyl group and C1-6hydroxyalkyl group.

C3-12Cycloalkyl group there is preferably cyclopropane group, cyclobutyl group, cyclopentyloxy group, tsiklogeksilnogo group, cycloheptyl, cyclooctyl group, adamantly group, bicyclo[2.2.1]heptyl the Noah group, bicyclo[2.2.2]heptylene group, more preferably, cyclopentyloxy group, tsiklogeksilnogo group, bicyclo[2.2.1]heptylene group or Adamantine group.

(iii) RCis a hydrogen atom. RBis “(3-12)-membered geteroseksualnoe group or (5-13)-membered heteroaryl group which may be partially saturated; and each of which contains from one to three ciclopaseos atoms selected from the group consisting of O, N, S, and NR10(R10is a hydrogen atom, a C1-6alkyl group, a phenyl-C1-6alkyl group or a C2-6alkoxycarbonyl group); preferably pyrrolidinyl group, piperidino group and hinkleyville group, more preferably pyrrolidinyl group, 4-piperidino group in which the nitrogen atom substituted phenyl-C1-6alkyl group or a C2-6alkoxycarbonyl group, and more preferably 3-(1-benzyl)pyrrolidinyloxy group, 4-(1-benzyl)piperidino group, or 4-(1-etoxycarbonyl)piperidino group.

(iv) RCis a hydrogen atom. RBis (6-13)-membered aryl group, (C6-13aryl group)which may be substituted by 1 or 2 substituents selected from a hydroxyl group and C1-6alkyl groups, phenyl-C1-6alkyl groups and C1-6alkylsulfonyl group, each of which may be substituted by hydroxyl(s) group(s) or (6-13)-membered aryl group, which is partially saturated, which may be substituted by 1 or 2 hydroxyl groups. Here, the term “(6-13)-membered aryl group includes phenyl group or naftalina group; and the term “(6-13)-membered aryl group, which is partially saturated” includes fluorenyl group, 1,2,3,4-tetrahydronaphthalene group or indenolol group.

Preferred of them is RBwhich is a phenyl group, substituted phenyl-C1-6alkyl group or fluorenyl group, 1,2,3,4-tetrahydronaphthalene group or indenolol group, each of which may be substituted by 1 or 2 hydroxyl groups.

(v) as another preferred example

RBand RCtogether with the nitrogen atom to which they are attached, form a (3-12)-membered geterotsyklicescoe group which may contain 1 or 2 collabrasuite atom selected from O, N, S, and NR11(R11is C1-6alkyl group which may be substituted dis1-6alkylaminocarbonyl) and which may be substituted by 1 or 2 substituents selected from pyrrolidinyl group and C1-6alkyl group which may be substituted by the Deputy selected from the group consisting the th of the hydroxyl group and pyrrolidin-1-ilen group.

Examples (v) variant implementation of the invention include piperidino, 4-methylpiperidino, 2-decahydroquinoline group, thiomorpholine, 4-[2-(pyrrolidin-1-yl)ethyl]piperidine, 4-(pyrrolidin-1-yl)piperidino, 3-decahydroquinoline group, 4-[2-(N,N-dimethylamino)ethyl]piperazine-1-ilen group and 3-hydroxyethylpiperazine.

In the formula (I) or (II)where Z is-CONHRA, RApreferably is C1-6alkyl group substituted by 1-3 substituents selected from the group consisting of hydroxyl group and carbamoyl group.

Methods of obtaining the compound (I) according to the invention will be described below.

The METHOD of OBTAINING 1

The compound (I) according to the invention where Y is C2-6alkalinous group or a C2-6alkynylamino group, and Z represents a-CONHRAcan be synthesized by the following method.

Note that in the formula, R11and R12may be the same or different and represent a hydrogen atom, benzyloxy, methoxyethoxy, (C1-6alkyl)3SiO-, C1-6alkyl group, a C1-6alkoxygroup or halogen atom, Y1represents a single bond or C1-4alkylenes group; the other symbols are defined above.

(1)Stage (Reaction Hake)

The compound (IA) and refinancung acid (IB) in the presence of a palladium catalyst, a phosphine ligand and a corresponding base is subjected to interaction in the Heck reaction, to synthesize the compound (IC). The examples used here, the palladium catalyst may include palladium acetate, tetrakis(triphenylphosphine)palladium, dibenzylideneacetone, bis(triphenylphosphine)allodiploid and palladium/activated carbon. Examples of the phosphine ligand may include triphenylphosphine and Tris(2-were)phosphine. Examples of the base include triethylamine, N,N-diisopropylethylamine, potassium carbonate, calcium carbonate, cesium carbonate and tert-butyl potassium. Examples of the solvent used in this reaction may include acetonitrile, toluene, and tetrahydrofuran. The reaction temperature is from 0°C to the boiling point of the solvent. However, the use of microwave is optional.

(2) stage 2. Conversion to the amide group

The compound (IC) is subjected to the condensation reaction with the amine (RANH2with the removal of water and obtaining the compound (ID). Preferred examples of the solvent used for the reaction include chloroform, dichloromethane and N,N-dimethylformamide. Preferred examples of the condensing agent in the condensation reaction with elimination of water N,N'-dicyclohexylcarbodiimide (DCC), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC), 1,1'-carbonyldiimidazole (CDI) and WSC/1-hydroxybenzotriazole monohydrate. The reaction temperature is 0°C-60°C.

(3) stage 3. Restoration and unprotect

Catalytic hydrogenation of compound (ID), obtained above, is carried out in a hydrogen atmosphere using a catalyst like palladium on charcoal, palladium hydroxide, or platinum-palladium on charcoal. In this way, to obtain the compound (I) according to the invention, the recovery of olefin and dibenzylamine can be performed simultaneously. Of the above catalysts are palladium on charcoal or palladium hydroxide are preferred. The examples used in this reaction, a solvent may include methanol, ethanol, 2-propanol, ethyl acetate, acetic acid and the solvent from mixtures thereof. The reaction temperature ranges from room temperature to the boiling temperature of the solvent; however, room temperature is preferred.

Alternative when dibenzylamine you can use a Lewis acid, such as BF3·Et2O, BCl3, BCl3·Me2S, BBr3, AlCl3, CF3COOH or TfOH. Examples of the solvent used in this reaction may include chloroform, dichloromethane, acetonitrile, IER is silt ether, tetrahydrofuran, dimethyl sulfide and anisole. Of them it is preferable to use CF3COOH, TfOH or acondition in dimethyl sulfide. The reaction temperature preferably is in the range from -78°C to 40°C.

The METHOD of OBTAINING 2

The compound (I) according to the invention where Y is C2-6alkalinous group or a C2-6alkynylamino group, and Z is-NHC(=NH)NH2or -- NHCON(RBRCcan be synthesized in the following way. Note that in the formula, Z1is guanidinium protected benzyloxycarbonyl group or -- NHCON(RBRCand other designations used similarly defined above.

(4) stage 4. The reaction Hake

The compound (IA) and allylamine (IE) on the Heck reaction, as described in stage 1, can be converted to the compound (IF).

(5)Stage 5. Restoration and unprotect

In the compound (IF)obtained above, remove the protection by catalytic hydrogenation or Lewis acid, as described in stage 3, to obtain the compounds (I) according to the invention, where Z represents guanidinium or raidgroup.

The METHOD of OBTAINING 3

The compound (I) according to the invention where Y is a single bond or C1-6alkalinous group and Z is-NHCON(RBRCcan also be synthesized following the method.

Note that R13and R14the formula may be the same or different and represent a hydrogen atom, benzyloxy, C1-6alkyl group, a C1-6alkoxygroup or halogen atom. P1represents methoxymethyl group, tetrahydropyranyloxy group, or (C1-6alkyl)3Si, and other designations used similarly defined above. The intermediate compound (IIB) or of the intermediate compound (IIF), where Y represents a single bond or C1-6alkylenes group can also be synthesized in a manner analogous to that described for stages 34-36 below.

(6) stage 6

Abilitiy reagent can be obtained from the intermediate compound (IIA) which can be synthesized as described in WO06/073197) through the use of ORGANOMETALLIC reagent, such as n-utility, second-utility or tert-utility. It is subjected to the condensation reaction with δ-lactone (X) to obtain the compound (IIB). Examples of the solvent used in this reaction may include tetrahydrofuran, diethyl ether and toluene. The reaction temperature is in the range from -80°C to room temperature, and preferably from -78°C to -25°C.

(7) stage 7. Recovery hydroxyl group

Soy is inania (IIB) and Et 3SiH, (i-Pr3SiH, t-BuMe2SiH or Ph2SiHCl is subjected to interaction in the presence of Lewis acid to restore the hydroxyl group. Examples of the Lewis acid used in this reaction may include BF3·Et2O, CF3COOH, InCl3, TiCl4, TMSOTf, p-toluensulfonate and methansulfonate acid. Examples of the solvent include chloroform, dichloromethane, toluene, tetrahydrofuran, acetonitrile and the solvent, which represent mixtures thereof. The preferred solvent is a mixture containing acetonitrile, such as a mixture of acetonitrile/chloroform, the mixture of acetonitrile/dichloromethane, a mixture of acetonitrile/tetrahydrofuran and a mixture of acetonitrile/tetrahydrofuran/toluene. The reaction temperature is in the range from -60°C to 25°C and preferably from -30°C to 25°C.

In the above reaction, depending on the reaction temperature, the protective group P1optional delete. In this case, not necessarily obtain the compound (IIC), from which P1removed.

(8) stage 8. Hydrolysis

After stage 7 of the protective group P1can be removed using hydrochloric acid, sulfuric acid, monohydrate p-toluenesulfonic acid, pyridine-p-toluenesulfonic acid, pyridine-hydrogen fluoride, n-Bu4NF and the like. Examples of the solvent used in this is the reaction, may include methanol, ethanol, 2-propanol, chloroform, dichloromethane, toluene, tetrahydrofuran, acetonitrile, diisopropyl ether, water and a solvent, which represent mixtures thereof. When P1is methoxymethyl group, the preferred acid is hydrochloric acid and the preferred solvent is methanol, diisopropyl ether, toluene or tetrahydrofuran. And more preferred is a solvent which is a mixture containing methanol, such as a mixture of methanol/toluene, a mixture of methanol/diisopropyl ether or a mixture of methanol/toluene/diisopropyl ether. The reaction temperature varies, depending on the solvent or acid, but it is in the range from 0°C to 100°C and preferably from 0°C to 80°C.

(9) step 9. The substitution reaction

The compound (IIC), where Y is C1-6alkalinous group, and the compound (IID) is subjected to condensation in the reaction conditions, Mitsunobu (Org. reactions, Vol. 42, p. 335)using asuragen and phosphine to obtain the compound (IIE).

Examples of the phosphine, which can be used in the reaction of Mitsunobu may include triphenylphosphine, tri-n-butylphosphine, three-tert-butylphosphine, trailerteen and diphenyl-2-pyridyloxy. Of them triphenylphosphine diphenyl-2-pyridyloxy are preferred; and triphenylphosphine t is aetsa more preferable. Examples of atragene include diethylazodicarboxylate, diisopropylsalicylic, decret-utilisationbased, 1,1'-azo-bis(N,N-dimethylformamide) and 1,1'-(azodicarbon)dipiperidino. Of them diethylazodicarboxylate and diisopropylethylamine are preferred. Examples of the solvent include tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, acetonitrile, ethyl acetate, dimethyl sulfoxide and N,N-dimethylformamide and, preferably, tetrahydrofuran and toluene. The reaction temperature preferably ranges from -20°C to room temperature.

(10)Stage 10. Remove phthalimide

The compound (IIE) and hydrazinehydrate or methylhydrazine subjected to interact in an appropriate solvent to obtain the amine (IIF). Preferred examples of the solvent used here include methanol, ethanol, tetrahydrofuran, water and the solvent, which represent mixtures thereof. The reaction temperature ranges from room temperature to 100°C., preferably from room temperature to 60°C.

The obtained amine (IIF) can be purified by formation of salts with a mineral acid or organic acid as mentioned above. Examples of salts are preferably used for cleaning include hydrochloride, methanesulfonate, aconsultant, 2-hydroxyethanesulfonic, b is solarpanel and p-toluensulfonate; and, more preferably, bansilalpet.

(11) stage 11. Urea formation

The compound (IIF) can be synthesized by using a reagent carbonyl and NH(RBRCfor the synthesis of compound (IIG). Examples of the reagent carbonylation include 1,1'-carbonyldiimidazole, p-nitrophenylphosphate and triphosgene. In this reaction, preferably, may be used such basis as triethylamine, pyridine or N-methylmorpholine. The examples used here, the solvent include chloroform, dichloromethane, tetrahydrofuran, N,N-dimethylformamide and dimethylsulfoxide. Can be used a mixed solvent. Preferred examples of the mixed solvent include a mixture of chloroform/N,N-dimethylformamide, a mixture of chloroform/dimethyl sulfoxide and a mixture of tetrahydrofuran/N,N-dimethylformamide. The reaction temperature ranges from room temperature to 80°C. At low speed the reaction temperature can be raised.

(12) stage 12. Unprotect

In the compound (IIG), obtained above, remove the protection by catalytic hydrogenation or Lewis acid, as described for stage 3, to obtain the compound (I) according to the invention where Z is raidgroups.

The METHOD of OBTAINING 4

The compound (I) according to the invention where Z is raidgroups, can be synthesized after protection of the hydroxy who enoy group in the glucose part of the acyl group, such as acetyl group.

(13) stage 13. Protection of the amino group

The amino group of the compound (IIF) protect with protective groups that are resistant to catalytic hydrogenation, for example, tert-BUTYLCARBAMATE (Boc) or 9-fluorenylmethoxycarbonyl (Fmoc). The compound (IIF), (Boc)2O and Fmoc-Cl leave for interaction in a solvent such as chloroform, dichloromethane, tetrahydrofuran or dioxane in the presence of an appropriate base to obtain the compound (IIJ). Preferred examples of the base include sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydroxide, sodium hydride, pyridine and triethylamine.

(14) stage 14. Removal of the benzyl protective group

Removing the protection connection (IIJ), obtained above, carried out by catalytic hydrogenation as described for stage 3, to obtain the compound (IIK).

(15) stage 15. The acylation

Hydroxyl group of the compound (IIK) protect acyl group such as acetyl group to obtain the compound (IIL). The compound (IIK), acetic anhydride, pivaloyloxy, benzoyl chloride and so on leave for interaction in a solvent in the presence of an appropriate base to obtain the compound (IIL). Examples of the solvent used in the reaction include chloroform, dichloromethane, dioxane, these are the acetate, tetrahydrofuran and N,N-dimethylformamide. Preferred examples of the base include triethylamine, kallidin and pyridine. As a catalyst it is possible to use a 4-dimethylaminopyridine. The reaction temperature preferably ranges from 0°C to room temperature.

(16) stage 16. Unprotect

In the connection (IIL), remove the protective group of an amino group to obtain the compound (IIM). When the protective group is Boc, the compound (IIL) leave for interaction with hydrochloric acid or triperoxonane acid in a solvent such as dichloromethane, chloroform or dioxane, or without using a solvent. For the case of the Fmoc group connection (IIL) leave for interaction, preferably, piperidine or morpholine N,N-dimethylformamide.

(17) stage 17. Urea formation

Connection (IIN) can be synthesized from compound (IIM) in a manner analogous to the method used in stage 11, as described above.

(18) stage 18. Unprotect

Acyl group of the compound (IIN) is removed under alkaline conditions to obtain the compound (I) according to the invention. Examples of the alkali may include sodium methylate, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate and triethylamine. Preferred examples of the solvent include methanol, ethanol and aqueous methanol.

WAYS IS GETTING 5

The compound (I) according to the invention where Y is-O-(CH2)n-, and Z is-NHCON(RBRCcan be synthesized in the following way. Note that the diagram Y2is C2-4alkalinous group, and other designations used similarly defined above.

(19) stage 19

Connection (IIP) can be obtained similarly to the method of obtaining 3, stage 6 from compound (II ° series) which can be synthesized in accordance with the description given in WO06/073197) and compound (X).

(20-21) stage 20 and stage 21

In the connection (IIP) restore hydroxyl group and remove a protective group P1in a manner analogous to the method described in production method of 3, stage 7 and 8, to obtain the compound (IIQ).

(22) stage 22

Connection (IIQ) and the reagent (IIR) leave for interaction in the presence of a base to obtain the compound (IIS). Preferred examples of the base used herein may include sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydride, pyridine, triethylamine. The examples used in this reaction, a solvent may include dioxane, acetonitrile, toluene, dimethoxyethane, tetrahydrofuran, N,N-dimethylformamide. The reaction temperature here is preferably in the range from 20°C to 100°C.

(23) stage 23

In the connection (IIS) remove phthalimido group in a manner analogous to the method described in production method of 3, stage 10, to obtain the compound (IIT).

(24) stage 24

Connection (IIU) can be obtained from compound (IIT) in a manner analogous to the method of obtaining 3, stage 11.

(25) stage 25

In the connection (IIU) remove the protection method similar to the method described in production method of 3, stage 12, to obtain the compound (I) according to the invention where Y is-O-(CH2)n-.

The METHOD of OBTAINING 6

The compound (I) according to the invention where Y is-O-(CH2)n- and Z is-CONHRAcan also be synthesized in the following way. Note that the diagram Y3is C1-4alkalinous group, L1represents a leaving group such as halogen atom, MeSO2O and so forth, and other designations used similarly defined above.

(26) stage 26

Connection (IIQ) and the compound (I-IV) leave for interaction in the presence of a base to obtain the compound (IIW). Preferred examples of the bases used herein may include sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate, n-utillity. Preferred examples of the solvent used in this reaction may include those who rehydrator, diethyl ether, N,N-dimethylformamide, acetone, DMSO (DMSO). The reaction temperature is in the range from 0°C to 60°C.

(27) stage 27

In the connection (IIW) remove the protection method similar to the method described in production method of 3, stage 12, to obtain the compound (I) according to the invention where Y is-O-(CH2)n- and Z is-CONHRA.

The METHOD of OBTAINING 7

The compound (I) according to the invention where Z is geteroseksualnoe group, such as 2,4-dioxoimidazolidin, can be synthesized in the following way. Note that the diagram RNis a hydroxyl group, a C1-4alkoxygroup or phenyl group, and other designations used similarly defined above.

(28) stage 28

Connection (IIM) is subjected to condensation with RARBNH, for example, an amine with a carbonyl group in α-position, such as 2-aminoacetophenone or amino acid by a method similar to the method described in method 4, stage 17, to obtain the compound (IIX).

(29) stage 29. Removing protection in basic terms

In the connection (IIX) remove the protecting acetyl group and simultaneously subjected to a side chain of the compound (IIX) intramolecular cyclization to obtain the compound (I) according to the invention where Z is heterocycle McIlroy group, defined above. Used here, the base is preferably sodium methylate, and the solvent is preferably methanol or ethanol.

The WAY to OBTAIN 8

The compound (I) according to the invention where Y is a single bond, methylene group or-O-(CH2)n- , Z is-NHC(=NH)NH2can be synthesized in the following way.

(30) stage 30. Introduction guanidinium

The compound (IIF) or connection (IIT), obtained in stage 38 or stage 23, is subjected to the interaction with the reagent (IIA1)to obtain the compound (IIA2). Preferred examples of the solvent used in this reaction may include tetrahydrofuran, N,N-dimethylformamide, methanol, ethanol, isopropanol, ethyl acetate, toluene. The reaction temperature is in the range from room temperature to the boiling temperature of the solvent.

(31) stage 31

In the connection (IIA2) remove the protection method similar to the method described for stage 12 ways to obtain 3 to obtain compound (I) according to the invention where Y is a single bond, methylene group or-O-(CH2)n - and Z is-NHC(=NH)NH2.

Methods of obtaining intermediates to obtain the compound (I) will be described below.

The method of obtaining the intermediate with the unity (IA)

Way to obtain the intermediate compound (IA)required to obtain the compound (I) according to the invention will be described below. Note that D1represents Li or MgBr (MgBr2). Other designations used the same notation defined above.

(32) stage 32

Reagent argillite can be obtained from the intermediate compound (IIIA) which can be synthesized as described in WO06/073197) when using this ORGANOMETALLIC reagent, such as n-utility, second-utility or tert-utility. Reagent argillite is subjected to condensation with δ-lactone (X)to obtain the compound (IIIB). Examples of the solvent used in this reaction may include tetrahydrofuran, diethyl ether and toluene. The reaction temperature is in the range from -80°C to room temperature, and preferably in the range from -78°C to -25°C.

(33) stage 33. Acid hydrolysis

Acatalog group of the compound (IIIB) is subjected to hydrolysis using hydrochloric acid and monohydrate p-toluenesulfonic acid and so on, to obtain the compound (IIIC). Preferred examples of the solvent used here include tetrahydrofuran, ethanol, methanol, water and mixtures thereof. The reaction temperature is in the range from 4°C to room temperature; to the room temperature is preferred. The reaction time varies depending on the reaction temperature, and ranges from 1 hour to 24 hours.

(34) stage 34

Connection monolitico reagent (IIIE) can be obtained from compound (IIID), using one equivalent of n-utility, sec-utility or tert-utility with respect to the compound (IIID). Examples of the solvent used in this reaction may include tetrahydrofuran, diethyl ether and toluene. The reaction temperature is in the range from -80°C to room temperature, and preferably in the range from -78°C to -25°C. the reaction Time is preferably from 5 minutes to 30 minutes. Moreover, the Grignard reagent (IIIE) can also be obtained using one equivalent of magnesium metal. Examples of the solvent used in this reaction may include tetrahydrofuran, diethyl ether and diglyme. Then reagent (IIIE) are added to the intermediate compound (IIIC), to obtain the compound (IIIF). The reaction temperature is in the range from -80°C to room temperature, and preferably in the range from -78°C to -25°C.

(35) stage 35. The restoration of the hydroxyl group.

The compound (IA) can be synthesized from compound (IIIF) by a method similar to the method stage 7 above.

Way to obtain the intermediate compound (IIB) or (IIF)

The intermediate compound (IIB) or (IIF), op is sliding above it is possible to synthesize by other means, shown below

(36) stage 36

The compound (IVC) or (IVD) can be synthesized from compound (IVA) or (IVB) by a method similar to the method of stage 34, above.

(37) stage 37. Recovery hydroxyl group

The intermediate compound (IIB) can be synthesized from compound (IVC) by a method similar to the method stage 7 above. Moreover, the n intermediate compound (IVE) can be synthesized from compound (IVD).

(38) stage 38

The compound (IVE) is treated with hydrochloric acid or triperoxonane acid in chloroform or dichloromethane to remove trailvoy (Tr) protective group of amino group, so that the result could be synthesized intermediate compound (IIF). The reaction temperature here is preferably in the range from 0°C to room temperature.

The compound of the invention inhibits both the activity of SGLT1 and SGLT2 activity, which are involved in the process of suppressing the absorption of glucose from the digestive tract and in the process of excretion of glucose in urine, respectively. Through inhibition of SGLT1 connection according to the invention is able to treat diabetes and reduce IGT, thus preventing the development of diabetes. Through inhibition of SGLT2 the connection izaberete the Oia can inhibit reabsorption of sugar and to remove excess sugar from the body, in order to treat diabetes mellitus. Thus, the connection of the present invention is able to correct hyperglycemia without depletion of pancreatic β-cells due to the toxicity of glucose and improve insulin resistance.

Therefore, the compound of the present invention can be used as an inhibitor of SGLT1 and as an inhibitor of SGLT2. The present invention provides a pharmaceutical preparation for preventing or treating diseases or conditions that can be alleviated by the inhibition of the activities of SGLT1 and SGLT2, such as diabetes mellitus, diseases associated with diabetes, and complications caused by diabetes.

The term “diabetes”as used here, includes diabetes mellitus type 1 type and diabetes 2 diabetes type and other types of diabetes specific etiology.

Examples of the term “disease associated with diabetes”as used herein may include obesity, hyperinsulinemia, abnormal carbohydrate metabolism, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, abnormal lipid metabolism, hypertension, congestive heart failure, edema, hyperuricemia and gout.

The term “complications of diabetes”, as used here, can be classified as acute complications and chronic Oslo is to be placed.

Examples covered by the term “acute complications can include hyperglycemia (eg, ketoacidosis) and infectious diseases (for example, skin infections, soft tissue infections, infections of the biliary, respiratory infections and urinary tract infections).

Examples covered by the term “chronic complications can include microangiopathy (e.g., nephropathy, retinopathy), arteriosclerosis (e.g., atherosclerosis, myocardial infarction, cerebral infarction, occlusive lesions of the lower extremity arteries), neuropathy (e.g., sensory nerves, motor nerves, autonomic nerves), gangrene of the foot and so on.

Examples of major complications include diabetic retinopathy, diabetic nephropathy and diabetic neuropathy.

Compounds according to the invention can also be used in combination with any of the medicinal product (hereinafter referred to here simply as “concomitant drug”), such as diabetic medicines, drugs against diabetic complications, protivoepidemicheskie drugs, antihypertensive medicines, drugs against obesity, diuretic drugs and medications that reduce blood clotting, to the E. are subject to a different mechanism of action, than the inhibition of the activity of SGLT1 and SGLT2. It can be expected that when combining the compounds of the present invention with other drugs likely to increase the impact and reduce the dose of the compound. In this case, do not limit the time of the introduction of the connection according to the invention and the concomitant drug. They can be administered to the patient simultaneously or at different times. Moreover, the connection according to the invention and a concomitant drug can be entered as two independent drug, each of which contains the active ingredient. Or they can be entered as a single preparation containing as active ingredient of both products. The dose of the concomitant drug can be selected based, respectively, on clinically used dosage. The ratio of components in a mixture of compounds according to the invention and the concomitant drug can be appropriately selected considering the characteristics of the patient, which injected a drug, route of administration, the disease being treated, the disease manifestations and combinations. For example, if a patient who injected a drug, is a man, a concomitant drug may be used in amounts of from 0.01 to 100 mass parts relative to 1 mass part of the connection from which bretania.

Note that examples of diabetic medicines may include insulin preparations (e.g., animal insulin preparations extracted from pancreas of bovine and swine; preparations of human insulin, genetically synthesized using Escherichia coli or a yeast; insulin zinc; a mixture of Protamine/insulin zinc insulin fragment or derivative (e.g., INS-1), oral insulin preparation); modifier of insulin resistance (e.g., pioglitazone or its salt (preferably hydrochloride), rosiglitazone or its salt (preferably maleate), rivoglitazone (CS-011)(R-119702), cipolletta (TAK-654), metaglidasen (MBX-102), naveglitazar (LY-519818), MX-6054, balaglitazone (NN-2344), T-131 (AMG); PPARγ agonist, a PPARγ antagonist, a dual agonist PPARγ/α; α inhibitor-glucosidase (for example, voglibose, acarbose, miglitol, emiglitate); biguanide agent (for example, phenformin, Metformin, buformin or their salts (e.g. hydrochloride, fumarate, succinate)); stimulator of insulin secretion (sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide, hlorpropamid, tolazamide, acetohexamide, glimepiride, glimepiride, glipizide, glybuzole, Repaglinide, sinapinic, nateglinide, mitiglinide or their hydrates of calcium salts); GPR40 agonist, antagonist of GPR40, agonist GLP-1 receptor (e.g., GLP-1, the agent GP-1MR, liraglutide (NN-2211), ecstatic (AC-2993) (Asendin-4), ecstatic LAR, BIM-51077, ib (8, 35) hGLP-1(7, 37)NH2, CJC-1131, AVE0010, GSK-716155); Amylin agonist (e.g., pramlintide); inhibitor phosphoribosyltransferase (for example, sodium Vanadate); inhibitor of dipeptidylpeptidase IV (e.g., compounds described in WO02/038541, NVP-DPP-278, PT-100, P32/98, vildagliptin (LAF-237), P93/01, sitagliptin (MK-431), saxagliptin (BMS-477118), SYR-322, MP-513, T-6666, GRC-8200); β3 agonist (e.g., AJ-9677, AZ40140); inhibitor of gluconeogenesis (e.g., glycogen phosphorylase inhibitor, an inhibitor of glucose-6-phosphatase, a glucagon antagonist, an inhibitor of fructose-1,6-bisphosphatase); SGLT inhibitor (superelastic sodium-glucose) (for example, compounds described in WO04/014931, WO04/089967, WO06/073197, T-1095, sergliflozin (GSK-869682), GSK-189075, KGT-1251, KGT-1681, KGA-2727, BMS-512148, AVE2268, SAR7226); inhibitor of 11β-hydroxysteroid-dehydrogenase (e.g., compounds described in WO06051662, BVT-3498, INCB13739); GPR119 agonist (e.g., PSN-632408, APD-668), adiponectin or agonist; an inhibitor of IKK (e.g., AS-2868), an activator of AMPK; modifier latinoization; receptor agonist somatostatin; glucokinase activator (for example, Ro-28-1675), an inhibitor of pancreatic enzyme lipase (e.g., orlistat, ATL-962), and inhibitor of DGAT-1.

Examples of drugs for the treatment of diabetic complications may include inhibitor alsoreported (for example, tolrestat, epalrestat, zenarestat, zopolrestat, minale the tat, fidarestat, CT-112); neurotrophic factor and its stimulating drug (e.g., NGF, NT-3, BDNF, production of neurotrophin/secretion stimulator); stimulator reactivation of the nervous system (e.g., Y-128), PKC inhibitor (e.g., ruboxistaurin, LY-333531); inhibitor of age-related changes (for example, ALT946, pimagedine, paroxetin, N-phenacylthiazolium (ALT766), ALT-711, EXO-226, pyridorin, pyridoxamine); agent to remove active oxygen (e.g., thioctic acid); cerebral vasodilator agent (for example, tiaprid, meksiletin); agonist somatostatinomas receptor (e.g., BIM 23190) and the inhibitor of a kinase-1(ASK-1), control signal apoptosis.

Examples of lipid-lowering drugs can include compounds such as statins (such as pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin, rosuvastatin, pitavastatin or their salts (e.g. sodium salt, calcium salt)); inhibitor stvalentines (for example, TAK-475); connection fibrates (for example, bezafibrate, clofibrate, simfibrate, clinofibrate); ACAT inhibitor (for example, avasimibe), eflucimibe), anion-exchange resin (eg, cholestyramine); probucol, nicotine drug (for example, nicomol), niceritrol), italiaspeed, Sterol plant origin (for example, soy Sterol), γ-oryzanol); ing the CETP inhibitors (for example, torcetrapib, JTT-705, JTT-302, FM-VP4) and suppressor of cholesterol absorption (e.g., ezetimib).

Examples of antihypertensives may include angiotensin-converting enzyme (for example, captopril, enalapril, delapril); antagonist of angiotensin II (e.g., candesartan, cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, azilsartan (TAK-536)); calcium antagonist (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine), agent, opening potassium channels (for example, levcromakalim, L-27152, A L0 671, NIP-121), and clonidine.

Examples of drugs that prevent obesity, may include drug against obesity Central action (for example, dexfenfluramin, fenfluramine, phentermine, sibutramine, amfepramone, dexamfetamine, mazindol, phenylpropanolamine, clobenzorex); MCH antagonist of the receptor (for example, compounds described in WO06/035967, SB-568849; SNAP-7941, T-226296); neuropeptide Y antagonist (e.g., CP-422935); cannabinoid antagonist of the receptor (for example, rimonabant (SR 141716), SR-147778); ghrelin antagonist; an inhibitor of 11β-hydroxysteroid-dehydrogenase (e.g., BVT-3498, INCB13739)); inhibitor of pancreatic enzyme lipase (e.g., orlistat, ATL-962); inhibitor of DGAT-1; β3 agonist (e.g., AJ-9677, AZ40140), peptidergic drug reduces appetite (for example, leptin CNTF (derived neurotrophic factor ciliary body); agonist cholecystokinin (for example, lintitript, FPL-15849); the agent of oppression supply (e.g., P-57).

Examples of diuretic drugs may include xanthine derivative (for example, theobromine.calcium sodium, theobromine.calcium calcium); thiazide drug (for example, atiase, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, bestellinformationen, panflutes, polythiazide, methyclothiazide); antialdosterone the drug (e.g., spironolactone, triamterene); carbonic anhydrase inhibitor (e.g., acetazolamide, chlorobenzenesulfonamide the drug (e.g., chlorthalidone, mefruside, indapamide, azosemide, isosorbide, etakrinova acid, piretanide, bumetanide and furosemide.

Examples of antithrombotic drugs may include heparin (e.g., heparin sodium, heparin calcium, dalteparin-sodium, AVE-5026), warfarin (e.g., warfarin-potassium); anti-thrombotic agent (e.g., argatroban, ximelagatran, dabigatran, odiparcil, lepirudin, bivalirudin, desirudin, ART-123, idraparinux, SR-123781, AZD-0837, MCC-977, TGN-255, TGN-167, RWJ-58436, LB-30870, MPC-0920, pegmusirudin, Org-426751); thrombolytic agent (e.g., urokinase, isocynate, alteplase, reteplase, monteplase, pamiteplase); inhibitor of platelet aggregation (for example, ticlopidine hydrochloride, Cilostazol, emilyosment, beraprost-soda is th, sarpogrelate hydrochloride); inhibitor of factor Xa (e.g., fondaparinux, BAY 59-7939, DU-176b, YM-150, SR-126517, apixaban, razaxaban, LY-517717, MLN-102, octoberin, otamixaban, EMD-503982, TC-10, CS-3030, AVE-3247, GSK-813893, KFA-1982); an inhibitor of carboxypeptidase B plasma (or known as [TAFIa] the inhibitor of fibrinolysis, activated by the active form thrombin), such as AZD-9684, EF-6265, MN-462.

The pharmaceutical preparation of the present invention can be introduced systemically or locally via oral administration or parenteral administration (for example, through the rectum, subcutaneously, intramuscularly, intravenously, transdermally).

For use as a pharmaceutical compound according to the present invention can be made up in any desired dosage form selected from solid compositions, liquid compositions and other relevant purpose compositions. The pharmaceutical preparation of the present invention can be obtained by mixing the compounds of the present invention with pharmaceutically acceptable(mi) carrier(s). More specifically, the compound of the present invention may be supplemented widely used excipients, diluents, binders, dezinfeciruyuhimi agents, agents for coatings, covering sugar agents, pH regulators, soljubilizatorami, aqueous or nonaqueous the solvents and so on; then, using standard techniques, to form tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions, solutions for injections, and so forth.

In addition, the compounds of the present invention prior to the preparation may be modified with the formation of compounds include, for example, α -, β - or γ-cyclodextrin or methylated-cyclodextrin.

The adult dose of the compounds of the present invention will vary, depending on the disease or symptom being treated, body weight, age, sex, and route of administration. But it falls in the interval from 0.1 to 1000 mg/kg/day, preferably 0.1 to 200 mg/kg/day, and more preferably 0.1 to 10 mg/kg/day. It can be entered at one time or divided into several times a day.

REFERENCE EXAMPLES

The intermediate compounds necessary for obtaining the compounds of the present invention will be shown below with reference to the following reference examples.

REFERENCE EXAMPLE 1

Getting 2-[4-(benzyloxy)-5-bromo-2-were]-1,3-dioxolane

(1) preparation of 1-[4-(benzyloxy)-2-were]ethanone

To a solution of 4'-hydroxy-2'-methylacetophenone (a 3.06 g, 20 mmol) in N,N-dimethylformamide (20 ml) was added potassium carbonate (3,66 g of 26.4 mmol), benzylbromide (2.7 ml, 22,mmol) and n-Bu 4NI (0.75 g, 2.03 mmol), and the mixture was stirred 14 hours at room temperature. To the reaction solution, cooled in ice, was added a saturated solution of ammonium chloride and then water and ethyl acetate to separate an organic layer. The organic layer is washed with 20% aqueous sodium thiosulfate solution and saturated saline, and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 8:1 to 6:1)to obtain the compound indicated in the title (of 5.05 g, quantitative)as a colorless powder.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm by 2.55 (s, 3H) 2.57 m (s, 3H) 5,11 (s, 2H) 6,78-6,86 (m, 2H) 7,30-7,47 (m, 5H) of 7.75 (DD, J=7,93, 1,09 Hz, 1H).

(2) Obtain 4-(benzyloxy)-5-bromo-2-methylbenzoic acid

To a solution in acetone (300 ml) of 1-[4-(benzyloxy)-2-were]ethanone (20,9 g is 87.1 mmol) was added an aqueous solution (100 ml) NaBr (9,86 g, with 95.9 mmol), water (200 ml), and axon (registered trademark, Oxon-acid chloride nadkarni acid (Aldrich) (59.0 g, with 95.9 mmol), and the mixture was stirred 2.5 hours at room temperature. To the reaction solution, cooled in ice, was added an aqueous solution (50 ml) of sodium sulfite (20 g), then water and ethyl acetate to separate an organic layer. The organic layer PR is mawali 20% aqueous solution of sodium sulfite and saturated saline and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure to obtain a mixture of 27.2 g) 1-[4-(benzyloxy)-5-bromo-2-were]ethanone and 1-[4-(benzyloxy)-3-bromo-2-were]ethanone. To the mixture was added a 5% aqueous solution (300 ml, 255 mol) of sodium hypochlorite and aqueous solution (10 ml) of potassium hydroxide (4,80 g, 85,3 mmol), was stirred at 120°C for one hour, cooled to room temperature, and filtered the precipitated insoluble substance. This insoluble substance was added 2 M hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with 2 M hydrochloric acid and saturated saline solution and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure. Thus obtained residue was washed with methanol to obtain the compound indicated in the title (16.6 g, 59%, stage 2), in the form of colorless powder.

1H NMR (300 MHz, DMSO-D6) δ ppm 2,45-to 2.57 (m, 3H) 5,28 (c, 2H) 7.18 in (c, 1H) 7,31-rate of 7.54 (m, 5H) 8,03 (c, 1H) 12,83 (USS, 1H).

ESI (electrospray ionization) m/z=319(M-H), 321(M+2-H).

(3) Obtaining 2-[4-(benzyloxy)-5-bromo-2-were]-1,3-dioxolane

To a suspension of 4-(benzyloxy)-5-bromo-2-methylbenzoic acid (16.6 g, of 51.7 mmol) in chloroform (80 ml) was added oxalicacid (5 ml, 56,9 mmol) and N,N-dimethylformamide (6 drops), and the mixture was stirred about who in the hour at room temperature. Then the reaction solution was concentrated to obtain 4-(benzyloxy)-5-bromo-2-methylbenzoate. Then to the suspension in chloroform (60 ml) and N,O-dimethylhydroxylamine hydrochloride (5,55 g, 56,9 mmol) and triethylamine (15 ml, 103 mmol), cooled in ice, was added dropwise a solution in chloroform (60 ml) of 4-(benzyloxy)-5-bromo-2-methylbenzonitrile, and the mixture was stirred one hour at room temperature. To the reaction solution, cooled in ice, was added water and chloroform to separate the organic layer. The organic layer was washed saturated aqueous sodium bicarbonate and saturated saline and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure to obtain 4-(benzyloxy)-5-bromo-N-methoxy-N-methylbenzamide. To a solution in tetrahydrofuran (150 ml) of 4-(benzyloxy)-5-bromo-N-methoxy-N-methylbenzamide was added at -10°C alumoweld lithium (1,96 g of 51.7 mmol)and the mixture was stirred one hour at the same temperature. To the reaction solution was added 1 M hydrochloric acid and then ethyl acetate to separate an organic layer. The organic layer washed with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline and dried with anhydrous magnesium sulfate. The desiccant was filtered, and dissolve the ü evaporated under reduced pressure, to obtain 4-(benzyloxy)-5-bromo-2-methylbenzaldehyde. To a solution in toluene (120 ml) of 4-(benzyloxy)-5-bromo-2-methylbenzaldehyde was added ethylene glycol (30 ml, 517 mmol) and the monohydrate of p-toluenesulfonic acid (0.50 g, 2.58 mmol) and was heated for 1.5 hours in the office of Dean-stark to the boiling point of the solvent. To the reaction solution were added ethyl acetate to separate an organic layer. The organic layer was washed with water, saturated aqueous sodium bicarbonate and saturated saline and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 5:1). In addition, the residue was further purified column chromatography on NH silica gel (chloroform)to obtain the compound indicated in the title (12.8 g, 71%, stage 3), in the form of colorless powder.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2,34 (c, 3H) 3,92-4,19 (m, 4H) 5,15 (c, 2H) by 5.87 (c, 1H) 6,74 (c, 1H) 7,27-7,51 (m, 5H) 7,72 (c, 1H).

REFERENCE EXAMPLE 1-2

Getting 2-[4-(benzyloxy)-5-bromo-2-were]-1,3-dioxolane

To a suspension in methanol (3.75 ml) of 4-(benzyloxy)-2-methylbenzaldehyde (0.50 g, 2.21 mmol), cooled in ice, was added hydrobromide perbromide (1.06 g, of 3.32 mmol), and the mixture was stirred for 30 minutes. The reaction is th the mixture was stirred 2.5 hours at room temperature. To the reaction solution was added a 20% solution of Na2SO3water and ethyl acetate. The resulting mixture was extracted with ethyl acetate. To the organic layer was added 1 M hydrochloric acid (20 ml)and the mixture was stirred for 5 minutes. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and saturated saline and dried with anhydrous magnesium sulfate. The desiccant was filtered, the solvent evaporated under reduced pressure to obtain of 1.03 g of residue. To a solution of the residue in toluene (7.0 ml) was added ethylene glycol (1.89 ml, to 33.9 mmol) p-toluensulfonate pyridinium (43 mg, 0,170 mmol) and was heated for 14 hours to the boiling temperature of the solvent with the unit Dean-stark. After cooling the reaction solution, the organic layer was washed saturated aqueous sodium bicarbonate and saturated saline and dried with anhydrous magnesium sulfate. The desiccant was filtered, the solvent evaporated under reduced pressure. Thus obtained residue was recrystallized from a mixture of hexane/ethyl acetate (10:1)to obtain the compound indicated in the title (748 mg, 63%).

REFERENCE EXAMPLE 2

Obtain (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-(4-bromobenzyl)-4-were]-D-glucit

(1) preparation of 2,3,4,6-Tetra-O-Ben the Il-1-C-[2-(benzyloxy)-5-(1,3-dioxolane-2-yl)-4-were]-D-glucopyranose

To a solution in tetrahydrofuran (36 ml) of 2-[4-(benzyloxy)-5-bromo-2-were]-1,3-dioxolane (of 5.82 g of 16.6 mmol) in a nitrogen atmosphere at -78°C was added dropwise to 2.67 M solution of n-utility in hexane (6,40 ml of 16.6 mmol)and the mixture was stirred for 30 minutes at the same temperature. Then was added dropwise a solution in tetrahydrofuran (18 ml) 2,3,4,6-Tetra-O-benzyl-D-glucono-1,5-lactone (8,16 g, 15.1 mmol)and the mixture was stirred for 20 minutes at the same temperature. To the reaction solution was added saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and a saturated saline solution and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = from (3:1) up (2:1)) to obtain the compound indicated in the title (10.7 g, 87%)as a yellow oily compound.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.40 a (c, 3H) 3,65-3,86 (m, 3H) 3,89-is 4.21 (m, 8H) 4,45-4,69 (m, 4H) 4,78-to 5.03 (m, 5H) 5,91 (c, 1H) of 6.71 (c, 1H) 6,97 (DD, J=7,31, 2,18 Hz, 2H) 7,10-7,37 (m, 23H) 7,81 (c, 1H).

(2) Obtain 2,3,4,6-Tetra-O-benzyl-1-C-[2-(benzyloxy)-5-formyl-4-were]-D-glucopyranose

To a solution in tetrahydrofuran (80 ml) 2,3,4,6-Tetra-O-benzyl-1-C-[2-(benzyloxy)-5-(1,3-dioxolane-2-is)-4-were]-D-glucopyranose (10.6 g, 13,0 mmol), cooled in ice, was added 6 M hydrochloric acid (80 ml)and the mixture was stirred 14 hours at room temperature. To the reaction solution was added ice water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium bicarbonate and saturated saline and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 2:1)to obtain the compound indicated in the title (10.2 g, quantitative)as a yellow oily compound.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2,66 (c, 3H) 3,60-and 3.72 (m, 2H) 3,74-3,82 (m, 1H) 4,01 (t, J=a 9.09 Hz, 1H) 4,07-4,20 (m, 3H) 4,40-br4.61 (m, 5H) 4,71-of 5.05 (m, 5H) 6,70 (c, 1H) 6.87 in (d, J=6,68 Hz, 2H) 7,06-7,40 (m, 23H) 8,07 (c, 1H) 10,06 (c, 1H).

(3) Obtain 2,3,4,6-Tetra-O-benzyl-1-C-[2-(benzyloxy)-5-[(4-bromophenyl)(hydroxy)methyl]-4-were]-D-glucopyranose

To a solution of 1,4-dibromobenzene with (6.20 g, and 26.1 mmol) in tetrahydrofuran (80 ml) at -78°C under nitrogen atmosphere was added dropwise to 2.67 M solution of n-utility in hexane (10.5 ml) and 26.1 mmol)and the mixture was stirred 15 minutes at the same temperature. Then was added dropwise a solution of 2,3,4,6-Tetra-O-benzyl-1-C-[2-(benzyloxy)-5-formyl-4-were]-D-glucopyranose (10.0 g, 13,0 mmol) in tetrahed is furane (20 ml), and the mixture was stirred for 30 minutes at the same temperature. To the reaction solution was added saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 2:1). In addition, the residue was further purified column chromatography on NH silica gel (hexane:ethyl acetate = 1:1)to obtain yellow oily compound indicated in the title (5.50 g, 46%), in the form of diastereomeric mixture.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2,21 (c, 3H) 3,54-3,82 (m, 3H) 3,98-to 4.23 (m, 4H) 4,36 with 4.64 (m, 4H) 4,75-of 5.06 (m, 5H) of 5.83 and 5.86 (m, 1H) of 6.71 and was 6.73 (each c, 1H) 6.89 in-7,44 (m, 29H) to 7.67 and 7,71 (each c, 1H).

(4)Obtain (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-(4-bromobenzyl)-4-were]-D-glucit

To a solution in acetonitrile (60 ml) of 2,3,4,6-Tetra-O-benzyl-1-C-[2-(benzyloxy)-5-[(4-bromophenyl)(hydroxy)methyl]-4-were]-D-glucopyranose (5.50 g, 5,96 mmol) was added in a nitrogen atmosphere at -10°C Et3SiH (2,90 ml, 17.8 mmol) and BF3·Et2O (1.90 ml, 14.9 mmol)and the mixture was stirred 15 minutes at the same temperature; at room temperature the mixture was stirred for 2.5 hours. To reaction the th solution cooled in ice, was added saturated aqueous sodium bicarbonate solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = from (15:1) to (10:1))to obtain the compound indicated in the title (2.70 g, 51%)as a pale yellow oily compound.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2,17 (c, 3H) 3,53-3,63 (m, 1H) 3,68-3,91 (m, 7H) 4,00 (d, J=11,04 Hz, 1H) 4,39-of 4.95 (m, 8H) 5,01 (c, 2H) 6.75 in (c, 1H) 6,86-6,97 (m, 4H) 7,10-7,35 (m, 24H) of 7.36-7,46 (m, 2H).

REFERENCE EXAMPLE 3

Obtain (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[(1E)-3-carboxypropyl-1-EN-1-yl]benzyl]-4-were]-D-glucit

To a solution in acetonitrile (8,8 ml) of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-(4-bromobenzyl)-4-were]-D-glucit (780 mg, 0,876 mmol) was added vinyl acetate (184 mg, 2.14 mmol), palladium(II) acetate (20 mg, 0,0890 mmol), tri-O-tolylphosphino (54 mg, 0,177 mmol) and triethylamine (0.64 in ml, of 4.38 mmol) and were subjected to interaction at 120°C for 20 minutes using microwave production Biotage. The reaction solution is evaporated under reduced pressure. Thus obtained is the STATCOM was purified column chromatography on silica gel (hexane:ethyl acetate = 5:1; a mixture of chloroform:methanol = 40:1)to obtain the compound indicated in the title (681 mg, 87%)as an orange-yellow amorphous compound.

1H NMR (600 MHz, CHLOROFORM-D) δ ppm 2,17 (c, 3H) 3,25 (d, J=5.50 Hz, 2H) 3,53-a-3.84 (m, 6H) 3,84-3,95 (m, 2H) 4,00 (d, J=10,55 Hz, 1H) 4,43 (d, J=10,55 Hz, 1H) 4,50 (d, J=11,92 Hz, 1H) 4,57 with 4.65 (m, 2H) 4.80 to is 4.93 (m, 4H) 4,99 (c, 2H) 6,12-to 6.22 (m, 1H) 6.42 per (d, J=15,59 Hz, 1H) 6,74 (c, 1H) 6.89 in-7,03 (m, 4H) 7,11-7,47 (m, 26H).

ESI m/z=893(M-H).

REFERENCE EXAMPLE 4

Obtain (1S)-1-[5-[4-(2-amino-ethyl)benzyl]-2-(benzyloxy)-4-were]-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-D-glucit

(1) preparation of 2,3,4,6-Tetra-O-benzyl-1-C-[2-(benzyloxy)-5-[hydroxy[4-[2-(trailmen)ethyl]phenyl]methyl]-4-were]-D-glucopyranose

To a solution of 2-(4-bromophenyl)-N-trailataimera (0,814 g of 1.84 mmol) in tetrahydrofuran (3 ml) in a nitrogen atmosphere at -78°C was added dropwise to 2.66 M solution in hexane n-utility (0,69 ml of 1.84 mmol)and the mixture was stirred for 30 minutes at the same temperature. Then was added dropwise a solution in tetrahydrofuran (3 ml) 2,3,4,6-Tetra-O-benzyl-1-C-[2-(benzyloxy)-5-formyl-4-were]-D-glucopyranose (0,670 g, 0,876 mmol)and the mixture was stirred for 30 minutes at the same temperature. To the reaction solution was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure is I. Thus obtained residue was purified column chromatography on NH silica gel (chloroform)to obtain the compound indicated in the title (0,634 g, 64%)as a yellow oily compound.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2,12-2,22 (m, 3H) 2,30 is 2.43 (m, 2H) 2,65 was 2.76 (m, 2H) 3,64-a-3.84 (m, 3H) 3,99-4,22 (m, 4H) 4,42 with 4.65 (m, 5H) 4,75-5,04 (m, 5H) of 5.83-5,91 (m, 1H) 6,67-6,72 (m, 1H) 6,88-the 7.43 (m, 44H).

(2) Obtain (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-4-methyl-5-[4-[2-(trailmen)ethyl]benzyl]phenyl]-D-glucit

To a solution in acetonitrile (6 ml) 2,3,4,6-Tetra-O-benzyl-1-C-[2-(benzyloxy)-5-[hydroxy[4-[2-(trailmen)ethyl]phenyl]methyl]-4-were]-D-glucopyranose (0,638 g of 0.565 mmol) under nitrogen atmosphere at 0°C was added Et3SiH (0,27 ml, 1,695 mmol) and BF3·Et2O (1,58 ml of 1.24 mmol)and the mixture was stirred for 30 minutes at the same temperature. To the reaction solution, cooled in ice, was added saturated aqueous sodium bicarbonate solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 9:1)to obtain the compound indicated in the title (0,402 g, 59%)as a pale yellow oily compound.

1H NMR (300 MHz, D) δ ppm 2,16 (c, 3H) a 2.36 (t, J=6,84 Hz, 2H) 2,68 (t, J=6,84 Hz, 2H) 3,52-the 3.65 (m, 1H) 3,67-to 3.92 (m, 7H) 4,00 (d, J=10,88 Hz, 1H) 4,37-of 4.67 (m, 5H) 4,78-of 5.06 (m, 5H) 6.73 x (c, 1H) 6,83-7,01 (m, 5H) 7,05 was 7.45 (m, 40H).

(3) Obtain (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[5-[4-(2-amino-ethyl)benzyl]-2-(benzyloxy)-4-were]-D-glucit

To a solution in chloroform (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-4-methyl-5-[4-[2-(trailmen)ethyl]benzyl]phenyl]-D-glucit (0,402 g, 0,336 mmol) at room temperature was added triptorelin (0.5 ml)and the mixture was stirred 3 hours at the same temperature. To the reaction solution was added ethanol, and the solvent is then evaporated under reduced pressure. Thus obtained residue was purified column chromatography on NH silica gel (hexane:ethyl acetate = 4:6; a mixture of chloroform:methanol = 20:1)to obtain the compound indicated in the title (0,296 g, quantitative)as a colorless oily compound.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2,20 (c, 3H) to 2.65 (t, J=6,84 Hz, 2H) 2,89 (t, J=6,84 Hz, 2H) 3,52-3,95 (m, 8H) 4,00 (d, J=of 10.72 Hz, 1H) to 4.38-of 4.67 (m, 5H) 4,81-5,04 (m, 5H) 6,74 (c, 1H) 6,88 was 7.45 (m, 30H).

REFERENCE EXAMPLE 5

Getting dibenzyl[(Z)-(allylamino)metallican]bicarbonate

To a solution in tetrahydrofuran (4.3 ml) allylamine (250 mg, of 4.38 mmol) was added N,N'-bisbenzimidazole-1-guanidinate (1.98 g, a 5.25 mmol)and the mixture was stirred over night at room te is the temperature. The reaction solution was evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 4:1)to obtain the compound indicated in the title (1.45 g, 90%)as colorless powder.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 4,03-4,12 (m, 2H) 5,11 is 5.28 (m, 6H) 5,81-5,96 (m, 1H) 7.23 percent-the 7.43 (m, 10H) 8,35-to 8.45 (m, 1H) 11,76 (c, 1H).

ESI m/z=368(M+H).

REFERENCE EXAMPLE 6

Obtaining N-allyl-4-methylpiperazin-1-carboxamide

To a solution in chloroform (70 ml) allylamine (400 mg, 7,00 mmol) was added triethylamine (1.31 ml of 9.45 mmol) and 4-nitrophenylphosphate (1,62 g of 8.06 mmol)and the mixture was stirred over night at room temperature. To this reaction solution was added 1-methylpiperazine (771 mg, of 7.70 mmol)and the mixture was stirred over night at room temperature. The reaction solution is evaporated under reduced pressure. To the thus obtained residue was added ethyl acetate, and the precipitated insoluble substance was filtered. The filtrate was concentrated, and the thus obtained residue was purified column chromatography on NH silica gel (hexane:ethyl acetate = 5:1; ethyl acetate) and column chromatography on silica gel (ethyl acetate, a mixture of chloroform:methanol = from (20:1) to (5:1))to obtain the compound indicated in the title (1,38 g, alicantino), in the form of colorless powder.

1H NMR (300 MHz, DMSO-D6) δ ppm 2,16 (c, 3H) 2,18-of 2.26 (m, 4H) 3,23-of 3.31 (m, 4H) 3,59-3,68 (m, 2H) 4,95-5,12 (m, 2H) 5,72-by 5.87 (m, 1H) 6,63 (t, J=5,44 Hz, 1H).

ESI m/z=206(M+Na).

REFERENCE EXAMPLE 7

Obtain tert-butyl[3-(buta-3-anolamine)propyl]carbamate

To a solution of vinyl acetate (500 mg, of 5.81 mmol) in chloroform (58 ml) was added tert-butyl N-(3-aminopropyl)carbamate (2,02 g, 11.6 mmol), 1-hydroxybenzotriazole (0,86 g, to 6.39 mmol) and WSC (1.56 g, 8,13 mmol), and the mixture was stirred over night at room temperature. To the reaction solution was added water, and the resulting mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous solution of ammonium chloride and a saturated saline solution and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 1:1; ethyl acetate)to obtain the compound indicated in the title (1,32 g, 94%)as colorless powder.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1,44 (c, 9H) 1,52-1,71 (m, 2H) 3,01 (d, J=6,99 Hz, 2H) 3,09 is 3.23 (m, 2H) 3,30 (kV, J=6,37 Hz, 2H) 4,89 (c, 1H) 5,14-5,31 (m, 2H) of 5.83-the 6.06 (m, 1H) 6,21 (c, 1H).

ESI m/z=265(M+Na).

REFERENCE EXAMPLE 8

Obtaining N-allyl-N'-(2-hydroxy-1,1-dimethylethyl)urea

To a solution of allylamine (1.5 g, of 26.3 mmol) in chloroform (60 ml) was added triethylamine (4.9 ml, 35.5 mmol) and 4°C was added 4-nitrophenylphosphate (6,09 g, 30.2 mmol), and the mixture was stirred for one hour. To the reaction solution were added at the same temperature a solution in chloroform (3 ml) of 2-amino-2-methylpropanol (2.58 g, of 28.9 mmol), and the mixture was stirred over night at room temperature. The reaction solvent is evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (ethyl acetate)to obtain the compound indicated in the title (4.0 g, 88%)as a yellow oily compound.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.26 in (c, 6H) 3,55 (c, 2H) 3,71-of 3.80 (m, 2H) 4,85-5,08 (m, 2H) 5,08-5,24 (m, 2H) 5,77-5,91 (m, 1H).

ESI m/z=195 (M+Na).

REFERENCE EXAMPLE 9

Getting 1-benzyloxy-2-bromo-5-methyl-4-[4-[2-(methoxyethoxy)ethyl]benzyl]benzene

To a solution in tetrahydrofuran (1 l) 1-bromo-4-[2-(methoxyethoxy)ethyl]benzene (50.2 g, 0,205 mol) was added dropwise in a nitrogen atmosphere at -78°C to 2.6 M solution of n-utility in hexane (78.8 ml 0,205 mol); and the mixture was stirred 15 minutes at the same temperature. Then for an hour was added dropwise a solution in tetrahydrofuran (150 ml) of 4-benzyloxy-5-bromo-2-methylbenzaldehyde (56,9 g, of € 0.195 mol)and the mixture was stirred for 30 minutes at the same temperature is. To the reaction solution was added saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and a saturated saline solution and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure to obtain [4-(benzyloxy)-5-bromo-2-were][4-[2-(methoxyethoxy)ethyl]phenyl]methanol.

Then, to the solution in chloroform (1 l) [4-(benzyloxy)-5-bromo-2-were][4-[2-(methoxyethoxy)ethyl]phenyl]methanol (102 g), cooled in ice, was added Et3SiH them (46.7 ml, 0,293 mol) and BF3·Et2O (29,7 ml, 0,243 mol); and the mixture was stirred 15 minutes at the same temperature. To the reaction solution, cooled in ice, was added saturated aqueous sodium bicarbonate solution and was heated to room temperature. The resulting mixture was extracted with ethyl acetate, washed with saturated saline, and then the organic layer was dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure. Thus obtained residue was purified column chromatography on NH silica gel (hexane:ethyl acetate = from (19:1) to (9:1))to obtain the compound indicated in the title (60 g, 68%)as a pale yellow oily compound

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2,16 (c, 3H) 2,87 (t, J=6,99 Hz, 2H) 3,28 (c, 3H) 3,75 (t, J=6,99 Hz, 2H) 3,85 (c, 2H) br4.61 (c, 2H) 5,12 (c, 2H) 6,77 (c, 1H) 7,03 (d, J=8,08 Hz, 2H) 7.15m (d, 2H) 7,26 (d, J=3,57 Hz, 1H) 7,30-was 7.45 (m, 3H) 7,47 (d, 2H).

REFERENCE EXAMPLE 10

Obtain (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-(2-hydroxyethyl)benzyl]-4-were]-D-glucit

To a solution in tetrahydrofuran (150 ml) of 1-benzyloxy-2-bromo-5-methyl-5-[4-[2-(methoxyethoxy)ethyl]benzyl]benzene (13,0 g, 28.5 mmol) in a nitrogen atmosphere at -78°C was added dropwise a 2.6 M solution of n-utility in hexane (11, 0 ml, 28.5 mmol), and the mixture was stirred 15 minutes at the same temperature. Then dropwise added to the solution in tetrahydrofuran (30 ml) 2,3,4,6-Tetra-O-benzyl-D-glucono-1,5-lactone (14.0 g, 26.0 mmol)and the mixture was stirred 15 minutes at the same temperature. To the reaction solution was added saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with toluene. The organic layer was washed with a saturated aqueous solution of ammonium chloride and a saturated saline solution and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure to obtain 26,0 g of residue.

The residue was dissolved in acetonitrile (70 ml) and tetrahydrofuran (70 ml). To this solution, cooled in ice, was added Et3SiH (2,90 ml, 17.8 mmol) and BF3·Et2/sub> O (1.90 ml, 14.9 mmol)and the mixture was stirred one hour at the same temperature. To the reaction solution, cooled in ice, was added saturated aqueous sodium bicarbonate solution and was heated to room temperature. To this solution was added water (70 ml)and the resulting mixture was extracted with toluene. And then the organic layer was washed with saturated saline solution and dried with anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to get to 27.0 g of residue.

The residue was dissolved in isopropyl ether (140 ml). Then to this solution was added 2-propanol (140 ml) and 6 M hydrochloric acid (140 ml); and the reaction mixture is 2 hours and stirred at 80°C. After cooling the mixture to room temperature, to the mixture was added water (70 ml). The resulting mixture was extracted with toluene. Then the organic layer was washed saturated aqueous sodium bicarbonate and saturated saline and dried with anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = from (9:1) to (7:3)to obtain the compound indicated in the title (12.0 g, 54%)as a pale yellow oily compound.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2,20 (c, 3H) 2,78 (t, J=6,53 Hz, 2H) 3,54-to 3.64 (m, 1H) 3,68-3,88 (m, 8H) 3,93 (USS, 2H) 4,00(d, J=of 10.72 Hz, 1H) was 4.42 (d, J=of 10.72 Hz, 1H) 4,50 (d, 1H) 4,56-of 4.66 (m, 2H) 4,81-of 4.95 (m, 3H) 5,00 (c, 2H) 6.75 in (c, 1H) 6,92 (d, J=to 7.77 Hz, 2H) 7,02 (c, 4H) 7,10-7,35 (m, 22H) of 7.36-7,44 (m, 2H).

ESI m/z=873 (M+NH4).

REFERENCE EXAMPLE 11

Obtain (1S)-1-[5-[4-(2-amino-ethyl)benzyl]-2-benzyloxy-4-were]-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-D-glucit

To a solution in tetrahydrofuran (140 ml) of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-(2-hydroxyethyl)benzyl]-4-were]-D-glucit (12.0 g, 14.0 mmol), triphenylphosphine (5,51 g, 21,0 mmol) and phthalimide of 2.27 g of 15.4 mmol) for 3 minutes at 0°C under nitrogen atmosphere was added a 40% solution in toluene of diisopropylcarbodiimide (11,1 ml, 21,0 mmol). This reaction solution was stirred at room temperature for 30 minutes, and then there was added methanol (70 ml). Then was added hydrazine monohydrate (6,79 ml, 140 mmol)and the reaction mixture is 3 hours and stirred at 60°C. After cooling the mixture to room temperature, was added 2 M aqueous sodium hydroxide solution (100 ml)and the resulting mixture was extracted with toluene. The organic layer was washed with 2 M aqueous solution of sodium hydroxide (100 ml) and saturated saline solution and dried with anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain 22.7 g of residue.

The residue was dissolved in methanol (140 ml), there was added a solution of methanol (50 ml) of Manager is that benzosulfimide acid (of 2.51 g, 14.0 mmol); and a mixture of 15 minutes was stirred at room temperature. This mixture was evaporated under reduced pressure to obtain an amorphous compound. To the thus obtained residue amorphous compounds were added 2-propanol (230 ml) and methanol (90 ml), and the mixture was heated to the boiling point of the solvent to dissolve the residue. This mixture was cooled to room temperature and left for 15 hours. Thus obtained crystal was filtered to obtain a colorless compound indicated in the title (of 9.89 g, 70%).

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2,12 (c, 3H) 2,72-to 2.85 (m, 2H) 2,89 was 3.05 (m, 2H) 3,54-3,63 (m, 1H) 3,68-to 3.89 (m, 8H) to 3.99 (d, J=10,57 Hz, 1H) 4,39-a 4.53 (m, 2H) 4,56 with 4.65 (m, 2H) 4,82-4,94 (m, 3H) 4,98 (c, 2H) 6,72 (c, 1H) 6,79-6,85 (m, 2H) 6,87-of 6.96 (m, 4H) 7,06-7,44 (m, 25H) of 7.75-of 7.90 (m, 4H).

REFERENCE EXAMPLE 12

Obtain (1S)-1-[5-[4-(2-amino-ethyl)benzyl]-2-acetoxy-4-were]-1,5-anhydrous-2,3,4,6-Tetra-O-acetyl-D-glucit

(1) preparation of (1S)-1-[5-[4-(2-tert-butoxycarbonylamino)benzyl]-2-acetoxy-4-were]-1,5-anhydrous-2,3,4,6-Tetra-O-acetyl-D-glucit

To a solution in chloroform (100 ml) of (1S)-1-[5-[4-(2-amino-ethyl)benzyl]-2-(benzyloxy)-4-were]-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-D-puritanicalness acid (10.7 g, 10.6 mmol), cooled in ice under nitrogen atmosphere was added triethylamine (2,22 ml, 15.9 mmol) and di-tert-BUTYLCARBAMATE (2,78 g, 12.7 mmol), and the mixture peremeci the Ali for 30 minutes at the same temperature. To the reaction solution was added water, and the mixture was heated to room temperature. Then the resulting mixture was extracted with ethyl acetate. The organic layer washed with 1 M hydrochloric acid and saturated saline solution and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure to obtain 11.8 g of residue.

The residue was dissolved in ethyl acetate (50 ml) and methanol (100 ml). And there was added 20% palladium hydroxide (2.50 g)and the mixture is 2.5 hours was stirred in hydrogen atmosphere at room temperature. The reaction solution was filtered through celite, and the solvent evaporated under reduced pressure to obtain a residue.

This residue was dissolved in pyridine (100 ml). To this solution was added in a nitrogen atmosphere, acetic anhydride (6,01 ml of 63.6 mmol) and N,N-dimethylaminopyridine; and the mixture was stirred over night at room temperature. Then there was additionally added acetic anhydride (4,00 ml, 42,4 mmol)and the mixture was stirred 2 hours at the same temperature. To the reaction solution was added water, the resulting mixture was extracted with ethyl acetate. The organic layer was washed 3 M hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline and dried with anhydrous magnesium sulfate. The desiccant tfilter Yali, and the solvent evaporated under reduced pressure to obtain a residue. Thus obtained residue was dissolved, adding there ethyl acetate, and to get the crystal, was added hexane. Thus obtained crystal was filtered to obtain the compound indicated in the title (to 5.58 g, 74%)as colorless powder.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1,43 (c, 9H) 1.77 in (c, 3H) 2,00 (c, 3H) 2,04 (c, 3H) 2,07 (c, 3H) 2,19 (c, 3H) 2,35 (c, 3H) 2,75 (t, J=6,92 Hz, 2H) 3,28-of 3.42 (m, 2H) 3.75 to a 3.83 (m, 1H) 3,92 (c, 2H) 4,08 (DD, J=12,43, to 2.18 Hz, 1H) 4,30 (DD, J=12,36, 4,74 Hz, 1H) 4,54 (t, 1H) 5,14-5,23 (m, 1H) 5.25-inch lower than the 5.37 (m, 2H) 6.87 in (c, 1H) 7,02 (d, 2H) 7,10 (d, 2H) 7,16 (c, 1H).

ESI m/z=731 (M+NH4).

(2) Obtain (1S)-1-[5-[4-(2-amino-ethyl)benzyl]-2-acetoxy-4-were]-1,5-anhydrous-2,3,4,6-Tetra-O-acetyl-D-glucit

To a solution in chloroform (80 ml) of (1S)-1-[5-[4-(2-tert-butoxycarbonylamino)benzyl]-2-acetoxy-4-were]-1,5-anhydrous-2,3,4,6-Tetra-O-acetyl-D-glucit added triperoxonane acid (23 ml), and the mixture was stirred 1.5 hours at room temperature. The solvent is evaporated under reduced pressure to obtain a residue. Thus obtained residue was diluted with chloroform, washed with saturated aqueous sodium bicarbonate and saturated saline solution. This solution was dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure to obtain the compound of the landscapes in the name of 4.67 g, quantitatively), as a colourless powder.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.77 in (c, 3H) 2,00 (c, 3H) 2,04 (c, 3H) 2,07 (c, 3H) 2,19 (c, 3H) 2,35 (c, 3H) to 2.67 (t, 2H) 2,85-of 3.07 (m, 2H) 3,75-a-3.84 (m, 1H) 3,92 (c, 2H) 4,08 (DD, J=12,36, 2.10 Hz, 1H) 4,30 (DD, J=12,36, 4.59 Hz, 1H) a 4.53 (t, 1H) 5,13-5,23 (m, 1H) 5,24 and 5.36 (m, 2H) 6,86 (c, 1H) 7,02 (d, 2H) 7,11 (d, 2H) 7,17 (c, 1H).

ESI m/z=614 (M+H).

REFERENCE EXAMPLE 13

Obtain (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-(4-hydroxy-2-methylbenzyl)-4-were]-D-glucit

To a solution in tetrahydrofuran (15 ml) of 1-bromo-4-methoxyethoxy-2-methylbenzene (0,80 g, 3.46 mmol) was added dropwise under nitrogen atmosphere at -60°C to 2.6 M solution in hexane n-utility (1,33 ml, 3.46 mmol)and the mixture 15 minutes was stirred at the same temperature. Then was added dropwise a solution in tetrahydrofuran (6 ml) 2,3,4,6-Tetra-O-benzyl-1-C-[2-(benzyloxy)-5-formyl-4-were]-D-glucopyranose (1.10 g, 1.44 mmol)and the mixture was stirred 15 minutes at the same temperature. To the reaction solution was added saturated aqueous solution of ammonium chloride and warmed up to room temperature. Then the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure to obtain 1.7 g of oily substance.

Then oily substance Rast rely in acetonitrile (10 ml) and chloroform (10 ml). To this solution was added at 4°C Et3SiH (0,92 ml, USD 5.76 mmol) and BF3·Et2O (0,46 ml of 3.60 mmol). The reaction solution for 30 minutes was stirred at the same temperature, and the mixture was stirred for 30 minutes at room temperature. To the reaction solution was added saturated aqueous sodium bicarbonate solution. And volatiles evaporated under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 3:1)to obtain the compound indicated in the title (420 mg, 35%)as a pale yellow oily compound.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2,17 (c, 3H) 2,22 (c, 3H) 3,49-3,59 (m, 1H) 3,63-a-3.84 (m, 6H) of 3.97 (d, J=11,04 Hz, 1H) or 4.31-4,50 (m, 3H) to 4.52-and 4.68 (m, 3H) 4,79 to 4.92 (m, 4H) 5,02 (c, 2H) 6,37 (DD, J=8,32, 2,41 Hz, 1H) 6,55 (d, J=2,49 Hz, 1H) 6,66 (d, J=8,24 Hz, 1H) 6,78 (c, 1H) 6,88-6,97 (m, J=to 5.21, 4,43 Hz, 2H) 7,01 (c, 1H) 7,10-to 7.50 (m, 23H).

ESI m/z=858 (M+NH4), 839 (M-H).

REFERENCE EXAMPLE 14

Obtain (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)ethoxy]-2-methylbenzyl]-4-were]-D-glucit

To a solution in N,N-dimethylformamide (5.0 ml) of (1S)-1,5-anhydrous-2,3,46-Tetra-O-benzyl-1-[2-(benzyloxy)-5-(4-hydroxy-2-methylbenzyl)-4-were]-D-glucit (340 mg, 0.40 mmol) and N-(2-bromacil)phthalimide (1,02 g, 4.0 mmol) was added potassium carbonate (553 mg, 4.0 mmol) and n-Bu4NI (14 mg, of 0.038 mmol). The reaction mixture was stirred 3.5 hours at 80°C. After cooling the mixture to room temperature there was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure to obtain a residue. Thus obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 3:1)to obtain the compound indicated in the title (60 mg, 15%), as pale yellow oily compound.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2,17 (c, 3H) 2,18 (c, 3H) 3,49-of 3.60 (m, 1H) 3,63-of 3.85 (m, 6H) 3,89-4,19 (m, 5H) 4,34-to 4.52 (m, 3H) 4,53 with 4.65 (m, 3H) 4,75-is 4.93 (m, 3H) 5,01 (c, 2H) 6,44 (DD, J=8,55, of 2.64 Hz, 1H) 6,60-of 6.71 (m, 2H) 6,77 (c, 1H) 6,88-6,97 (m, 2H) 7,05 (c, 1H) 7,13 was 7.45 (m, 23H) 7,66-7,72 (m, 2H) 7,80-7,88 (m, 2H).

REFERENCE EXAMPLE 15

Obtain (1S)-1-[5-[4-(2-aminoethoxy)-2-methylbenzyl]-2-(benzyloxy)-4-were]-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-D-glucit

To a solution of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)ethoxy]-2-methylbenzyl]-4-were]-D-glucit (60 mg, 0,059 mmol) in tetrahydrofuran (0.8 ml) and methanol (0.2 ml) was added manage the Rath of hydrazine (30 mg, 0.59 mmol)and the reaction mixture for one hour, stirred at 65°C. After cooling the mixture to room temperature there was added 2 M aqueous sodium hydroxide solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried with anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to quantitatively obtain compound indicated in the title.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2,21 (c, 3H) 2,22 (c, 3H) 3,03 (t, J=4,74 Hz, 2H) 3,50-3,62 (m, 1H) 3,65-a 3.83 (m, 6H) 3,88 (t, J=4,74 Hz, 2H) 3,98 (d, J=10,88 Hz, 1H) 4,34-4,51 (m, 3H) 4,55 with 4.65 (m, 3H) 4,77-is 4.93 (m, 3H) 5,02 (c, 2H) to 6.43-6,51 (m, 1H) 6,66-6,72 (m, 2H) 6,78 (c, 1H) 6,91-6,98 (m, 2H) 7,06 (c, 1H) 7,11 was 7.45 (m, 23H).

In addition, compound (I)in which R3represents a methoxy group or a fluorine atom, can be synthesized using as a starting material 1-bromo-2-methoxy-4-methoxyethoxymethyl or 1-bromo-2-fluoro-4-methoxyethoxymethyl by way of reference examples 13-15.

REFERENCE EXAMPLE 16

Obtain 4-(benzyloxy)-5-bromo-2-chlorobenzaldehyde

To a solution in chloroform (300 ml) of 2-chloro-4-hydroxybenzonitrile (14.0 g, and 91.2 mmol) at -50°C under nitrogen atmosphere was added dropwise a 0.95 M solution in hexane of diisobutylaluminium (307 ml, 291 mmol)and the mixture is 1.5 hours was stirred at the same temperature. The temperature of the solution increases is whether to room temperature, and the mixture was additionally stirred for 3 hours. Then the reaction solution was cooled in ice, and there was added dropwise methanol. To the reaction solution was added 3 M hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium bicarbonate and saturated saline and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure to obtain of 7.25 g of residue.

The residue was dissolved in methanol (140 ml). To this solution, cooled in ice under nitrogen atmosphere was added perbromide hydrobromide (16.3 g, of 50.9 mmol)and the mixture was stirred for 4 hours. To the reaction solution was added a 20% solution of Na2SO3and the resulting mixture was extracted with ethyl acetate. The organic layer was washed 3 M hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 3:1)to obtain 6,17 g of colorless powder.

This powder was dissolved in acetone (260 ml). To this solution under nitrogen atmosphere was added benzylbromide (of 3.45 ml,28.8 mmol) and potassium carbonate (4,70 g, to 34.1 mmol)and the mixture is 4.5 hours was stirred at 50°C. the Reaction solution was cooled to room temperature and then filtered through celite. The solvent is evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 10:1)to obtain the compound indicated in the title (2,02 g, 6.9 per cent), in the form of colorless powder.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 5,23 (c, 2H) 6,97 (c, 1H) 7,32-to 7.50 (m, 5H) 8,15 (c, 1H) 10,27 (c, 1H).

ESI m/z=325 (M+H).

REFERENCE EXAMPLE 17

Obtain [4-(benzyloxy)-5-bromo-2-chlorophenyl][4-[2-(methoxyethoxy)ethyl]phenyl]methanol

To a solution in tetrahydrofuran (6 ml) of 1-bromo-4-[2-(methoxyethoxy)ethyl]benzene (1.52 g, of 6.20 mmol) at -78°C under nitrogen atmosphere was added dropwise 2,6 M hexane solution of n-utility (2.38 ml of 6.20 mmol)and the mixture was stirred 10 minutes at the same temperature. Then for 10 minutes was added dropwise a solution in tetrahydrofuran (6 ml) of 4-(benzyloxy)-5-bromo-2-chlorobenzaldehyde (2,02 g of 6.20 mmol)and the mixture was stirred for 30 minutes at the same temperature. To the reaction solution was added saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and a saturated saline solution and dried betw denim magnesium sulfate. The desiccant was filtered, the solvent evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 10:1)to obtain the compound indicated in the title (750 mg, 25%)as a colorless oily compound.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2,24 (d, J=3,57 Hz, 1H) 2,89 (t, J=6,92 Hz, 2H) 3,27 (c, 3H) 3,75 (t, J=6,84 Hz, 2H) 4,60 (c, 2H) 5,12 (c, 2H) 6,09 (d, J=3,57 Hz, 1H) 6,91 (c, 1H) 7,15-7,51 (m, 9H) 7,80 (c, 1H).

ESI m/z=508 (M+NH4).

REFERENCE EXAMPLE 18

Obtaining 1-(benzyloxy)-2-bromo-5-chloro-4-[4-[2-(methoxyethoxy)ethyl]benzyl]benzene

To a solution in chloroform (8 ml) of [4-(benzyloxy)-5-bromo-2-chlorophenyl][4-[2-(methoxyethoxy)ethyl]phenyl]methanol (750 mg, 1.53 mmol), cooled in ice, was added Et3SiH (367 ml of 2.30 mmol) and BF3·Et2O (232 ml and 1.83 mmol), and the mixture was stirred one hour at the same temperature. To this solution, cooled in ice, was added saturated aqueous sodium bicarbonate solution and was heated to room temperature. The resulting mixture was extracted with ethyl acetate, washed with saturated saline solution and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (mixture Huck is an:ethyl acetate = 4:1), to obtain a connection, indicated in the title (290 mg, 40%)as a colorless oily compound.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm is 2.88 (t, J=7,15 Hz, 2H) 3,28 (c, 3H) 3,75 (t, J=6,99 Hz, 2H) 3,97 (c, 2H) br4.61 (c, 2H) 5,12 (c, 2H) of 6.96 (c, 1H) 7,10 (d, 2H) 7,17 (d, 2H) 7,28-to 7.50 (m, 6H).

ESI m/z=492 (M+NH4).

REFERENCE EXAMPLE 19

Obtain 2,3,4,6-Tetra-O-benzyl-1-C-[2-(benzyloxy)-4-chloro-5-[4-[2-(methoxyethoxy)ethyl]benzyl]phenyl]-D-glucopyranose

To a solution in tetrahydrofuran (3 ml) of 1-(benzyloxy)-2-bromo-5-chloro-4-[4-[2-(methoxyethoxy)ethyl]benzyl]benzene (290 mg, 0,609 mmol) in a nitrogen atmosphere at -78°C was added dropwise a 2.6 M solution in hexane n-utility (234 ml, 0,609 mmol)and the mixture was stirred 5 minutes at the same temperature. Then was added dropwise a solution of 2,3,4,6-Tetra-O-benzyl-D-glucono-1,5-lactone (328 mg, 0,609 mmol) in tetrahydrofuran (3 ml)and the mixture was stirred one hour at the same temperature. To the reaction solution was added saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and a saturated saline solution and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (mixture of exan:ethyl acetate = 3:1), to obtain a connection, indicated in the title (124 mg, 22%)as a colorless oily compound.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2,85 (t, J=6,99 Hz, 2H) 3,28 (c, 3H) 3,60 (c, 5H) 3,94-was 4.02 (m, 3H) 4,04-to 4.15 (m, 3H) 4,43-br4.61 (m, 6H) 4,71 is equal to 4.97 (m, 5H) 6,89 (c, 3H) 7,37 (c, 27H) 7,50 (c, 1H).

ESI m/z=952 (M+NH4).

REFERENCE EXAMPLE 20

Obtain (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-4-chloro-5-[4-(2-hydroxyethyl)benzyl]phenyl]-D-glucit

To a solution of 2,3,4,6-Tetra-O-benzyl-1-C-[2-(benzyloxy)-4-chloro-5-[4-[2-(methoxyethoxy)ethyl]benzyl]phenyl]-D-glucopyranose in acetonitrile (0.5 ml) and tetrahydrofuran (0.5 ml) (124 mg, 0.133 mmol), cooled in ice, was added Et3SiH (63,6 μl, 0.400 mmol) and BF3·Et2O (40,4 μl, 0,320 mmol)and the mixture was stirred 1.5 hours at the same temperature. The mixture was stirred for 4.5 hours at room temperature. To the reaction solution, cooled in ice, was added saturated aqueous sodium bicarbonate solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure to obtain 119 mg of the residue.

The residue was dissolved in isopropyl ether (0.7 ml). Then to this solution was added 2-propanol (0.7 ml) and 6 M hydrochloric acid (0.7 ml);and the reaction mixture is 3 hours and stirred at 80°C. After cooling the mixture to room temperature, to the mixture was added water, and the resulting mixture was extracted with ethyl acetate. Then the organic layer was washed saturated aqueous sodium bicarbonate and saturated saline and dried with anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 7:3)to obtain the compound indicated in the title (79,1 mg, 68%)as a colorless oily compound.

1H NMR (600 MHz, CHLOROFORM-D) δ ppm 2,77 (t, J=6.42 per Hz, 2H) 3,52-of 3.60 (m, 1H) 3,64-3,82 (m, 7H) 3,92-3,99 (m, 3H) 4,03 (d, 1H) to 4.41-4,51 (m, 2H) 4,54 with 4.64 (m, 2H) 4,82-4,89 (m, 3H) 4,91 is equal to 4.97 (m, 2H) 6,86 (d, J=7,34 Hz, 2H) 6,90 (c, 1H) 7,02-7,06 (m, 2H) 7,06-7,10 (m, 2H) 7,13 (t, J=7,34 Hz, 2H) 7,15-7,20 (m, 3H) 7,20-7,33 (m, 17H) of 7.36 (d, J=7,79 Hz, 2H).

ESI m/z=892 (M+NH4).

REFERENCE EXAMPLE 21

Obtain (1S)-1-[5-[4-(2-amino-ethyl)benzyl]-2-(benzyloxy)-4-chlorophenyl]-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-D-glucit

To a solution in tetrahydrofuran (2.0 ml) of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-4-chloro-5-[4-(2-hydroxyethyl)benzyl]phenyl]-D-glucit (79,0 mg, 0,090 mmol), triphenylphosphine (53,1 mg, 0,203 mmol), and phthalimide (23.9 mg, rate £ 0.162 mmol), cooled in ice under nitrogen atmosphere was added a 40% solution of diisopropylcarbodiimide in toluene (386 ml, 0,203 mmol). After premesis is of the reaction solution at room temperature for 1.5 hours, was added methanol (1 ml). Then was added hydrazine monohydrate (or hydrazinehydrate) (43,7 ml, 0.90 mmol)and the reaction mixture is 3 hours and stirred at 60°C. After cooling the mixture to room temperature there was added 2 M aqueous sodium hydroxide solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried with anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (mixture of chloroform:methanol = 9:1)to obtain the compound indicated in the title (of 39.2 mg, 50%)as a colorless oily compound.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm in 2.68 (t, 2H) 2,83-2,96 (m, 2H) 3,52-3,61 (m, 1H) 3,62-3,86 (m, 5H) to 3.99 (t, J=10,57 Hz, 3H) to 4.41-of 4.67 (m, 5H) 4,81 to 4.92 (m, 3H) 4,95 (c, 2H) to 6.88 (d, J=ceiling of 5.60 Hz, 3H) 6,97-the 7.43 (m, 28H).

ESI m/z=874 (M+H).

REFERENCE EXAMPLE 22

Getting 5-bromo-2-chlorobenzaldehyde

To a suspension in chloroform (157 ml) of 5-bromo-2-chlorbenzoyl acid (18.5 g, 78.5 per mmol) was added N,N-dimethylformamide (0.5 ml) and down at room temperature was added dropwise oxalicacid (8.1 ml, was 94.2 mmol). This reaction solution was stirred 30 minutes and then concentrated under reduced pressure. Thus obtained residue was dissolved in chloroform (157 ml)and at 0°C dropwise EXT is ulali to a suspension of N,O-dimethylhydroxylamine hydrochloride (9,19 g, a 94.2 mmol) and triethylamine (26,3 ml, 188 mmol) in chloroform. This reaction solution was stirred for 30 minutes at the same temperature and then washed with water, saturated aqueous sodium bicarbonate and saturated saline solution, and the organic layer was dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure to obtain 24,0 g of residue.

Thus obtained residue was dissolved in tetrahydrofuran (157 ml), and there at 0°C was slowly added alumoweld lithium (1.19 g, 29,0 mmol). After that, the reaction solution was cooled to 0°C and there was gradually added 2 M hydrochloric acid, and the mixture 30 minutes was stirred at room temperature. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated saline solution and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure. Thus obtained residue was recrystallized from a mixed solution of ethyl acetate:hexane (1:9)to obtain the compound indicated in the title (11, 3 g, 65%)as colorless crystals.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm to 7.35 (d, J=of 8.47 Hz, 1H) of 7.65 (DD, J=of 8.47, of 2.56 Hz, 1H) 8,04 (d, J=2,56 Hz, 1H) 10,41 (c, 1H).

REFERENCE EXAMPLE 23

Receive (5-bromo-2-chlorophenyl)[4-[2-(methoxyethoxy)ethyl]Fe is Il]methanol

By way of reference example 17, in which 5-bromo-2-chlorobenzaldehyde used instead of 4-(benzyloxy)-5-bromo-2-chlorobenzaldehyde, received the compound indicated in the title (4,55 g, 63%)as a colorless oily compound.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2,89 (t, J=6,99 Hz, 2H) 3,26 (c, 3H) 3,74 (t, J=6,99 Hz, 2H) 4,59 (c, 2H) 6,11 (c, 1H) 7,13-7,39 (m, 6H) 7,82-to 7.84 (m, 1H).

REFERENCE EXAMPLE 24

Getting 5-bromo-2-chloro-4-[4-[2-(methoxyethoxy)ethyl]benzyl]benzene

The triethylamine (105 ml, 0,756 mmol) was added to a solution in chloroform (1.4 ml) (5-bromo-2-chlorophenyl)[4-[2-(methoxyethoxy)ethyl]phenyl]methanol (0,265 g, 0,687 mmol). And at 0°C there was added dropwise methanesulfonanilide (58,5 μl, 0,756 mmol); and a mixture of 2 hours and stirred at the same temperature. To the reaction solution was added water, and the resulting mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline solution, and the organic layer was dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure to obtain a residue.

To a solution in chloroform (3.4 ml) thus obtained residue and Et3SiH (165 μl, of 1.03 mmol) was added BF3·Et2O (104 μl, 0,824 mmol) at 0°C, and the mixture was stirred one hour at the same temperature. E is from the reaction solution was washed with saturated aqueous sodium bicarbonate solution (twice) and then with saturated salt solution; and the organic layer was dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 9:1)to obtain a pale yellow crude product (41 mg).

ESI m/z=386 (M+NH4).

REFERENCE EXAMPLE 25

Obtain 2,3,4,6-Tetra-O-benzyl-1-C-[4-chloro-3-[4-[2-(methoxyethoxy)ethyl]benzyl]phenyl]-D-glucopyranose

The crude product of the compound indicated in the title (1.07 g)was obtained as a colorless oily substance by the method described in reference example 19, in which instead of 1-(benzyloxy)-2-bromo-5-chloro-4-[4-[2-(methoxyethoxy)ethyl]benzyl]benzene used 5-bromo-2-chloro-4-[4-[2-(methoxyethoxy)ethyl]benzyl]benzene.

ESI m/z=846 (M+NH4).

REFERENCE EXAMPLE 26

Obtain (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[4-chloro-3-[4-(2-hydroxyethyl)benzyl]phenyl]-D-glucit

The crude product of the compound indicated in the title (0,262 g)was obtained as a colorless oily substance according to the method of reference example 20, in which instead of 2,3,4,6-Tetra-O-benzyl-1-C-[2-(benzyloxy)-4-chloro-5-[4-[2-(methoxyethoxy)ethyl]benzyl]phenyl]-D-glucopyranose used 2,3,4,6-Tetra-O-benzyl-1-C-[4-chloro-3-[4-[2-(methoxime the hydroxy)ethyl]benzyl]phenyl]-D-glucopyranose

ESI m/z=786 (M+NH4).

REFERENCE EXAMPLE 27

Obtain (1S)-1-[3-[4-(2-amino-ethyl)benzyl]-4-chlorophenyl]-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-D-glucit

The crude product of the compound indicated in the title (0,230 g)was obtained as a pale yellow oily substance by the method of reference example 21 (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[4-chloro-3-[4-(2-hydroxyethyl)benzyl]phenyl]-D-glucit used instead of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-4-chloro-5-[4-(2-hydroxyethyl)benzyl]phenyl]-D-glucit.

REFERENCE EXAMPLE 28

Obtain (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-(4-bromobenzyl)-4-were]-D-galactic

The compound indicated in the title, was synthesized according to the method of reference example 2, in which 2,3,4,6-Tetra-O-benzyl-D-galactono-1,5-lactone was used instead of 2,3,4,6-Tetra-O-benzyl-D-glucono-1,5-lactone.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2,12 (c, 3H) 3,32-3,81 (m, 4H) 3,86 (c, 2H) 4,07 (t, J=of 10.72 Hz, 3H) 4,32-4,47 (m, 2H) 4,49-4,80 (m, 5H) 4,93 is 5.07 (m, 3H) 6,72 (c, 1H) 6,80-7,01 (m, 4H) 7,06-7,46 (m, 26H).

ESI m/z=911 (M+Na). 913 (M+2+Na).

REFERENCE EXAMPLE 29

Obtain (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-(2-(benzyloxy)-5-[4-[(1E)-3-carboxypropyl-1-EN-1-yl]benzyl]-4-were)-D-Galactica

The compound indicated in the title (377 mg, 41%)was obtained as pale yellow amorphous compound of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-(4-bromobenzyl)-4-were]-D-Galactica (918 mg, 1,03 mmol) according to the method of reference example 3.

EXAMPLES

Compounds of the present invention will be hereinafter described in more detail in the following examples and examples of tests that are not intended to limit the scope.

Example 1

Obtain (1S)-1,5-anhydrous-1-[2-hydroxy-5-[4-[4-[(2-hydroxy-1,1-dimethylethyl)amino]-4-oxobutyl]benzyl]-4-were]-D-glucit

(1) preparation of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[(1E)-4-[(2-hydroxy-1,1-dimethylethyl)amino]-4-exabot-1-EN-1-yl]benzyl]-4-were]-D-glucit

To a solution in chloroform (2.2 ml) of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[(1E)-3-carboxypropyl-1-EN-1-yl]benzyl]-4-were]-D-glucit (200 mg, 0,223 mmol) was added 2-amino-2-methyl-1-propanol (40 mg, 0,446 mmol), 1-hydroxybenzotriazole (33 mg, 0,245 mmol) and WSC (60 mg, 0,312 mmol)and the mixture was stirred over night at room temperature. To the reaction solution was added water, and the resulting mixture was extracted with chloroform. The organic layer was washed with saturated saline solution and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = from (5:1) to (1:2))to obtain a connection, the seat is Noah in the name of (120 mg, 56%), in the form of orange-yellow oily compound.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.26 in (c, 6H) 2,19 (c, 3H) 3,11 (d, J=7,46 Hz, 2H) 3,54-3,63 (m, 3H) 3,67-of 3.85 (m, 5H) 3,89-of 4.05 (m, 3H) 4,40-and 4.68 (m, 4H) 4,81-of 4.95 (m, 3H) 5,00 (c, 2H) ceiling of 5.60 (c, 1H) between 6.08-6,21 (m, 1H) 6,45 (d, J=15,54 Hz, 1H) 6.75 in (c, 1H) 6.89 in-6,97 (m, 2H) 7,03 (d, J=to 7.93 Hz, 2H) 7,11 was 7.45 (m, 26H).

ESI m/z=988.5(M+Na).

(2) Obtain (1S)-1,5-anhydrous-1-[2-hydroxy-5-[4-[4-[(2-hydroxy-1,1-dimethylethyl)amino]-4-oxobutyl]benzyl]-4-were]-D-glucit

To a solution in methanol (1.2 ml) of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[(1E)-4-[(2-hydroxy-1,1-dimethylethyl)amino]-4-exabot-1-EN-1-yl]benzyl]-4-were]-D-glucit (120 mg, 0,124 mmol) was added 10% palladium/activated carbon (22 mg), and the mixture was stirred overnight in a hydrogen atmosphere at room temperature. The reaction solution was filtered through celite and evaporated under reduced pressure to obtain a residue. Thus obtained residue was purified column chromatography on silica gel (mixture of chloroform:methanol = from (20:1) to(5:10)to obtain the compound indicated in the title (58 mg, 90%)as colorless powder. Data of NMR and MS data (MS) for compounds shown in table 1.

Example 2

Obtain (1S)-1,5-anhydrous-1-[2-hydroxy-5-[4-[4-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-4-oxobutyl]benzyl]-4-were]-D-glucit

(1) preparation of (1S)-1,5-anhydrous-2,3,4,6-Tetrao-benzyl-1-[2-(benzyloxy)-5-[4-[(1E)-4-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-4-exabot-1-EN-1-yl]benzyl]-4-were]-D-glucit

The compound indicated in the title (91 mg, 44%)was obtained as a colorless oily compound according to the method (1) of example 1, in which instead of 2-amino-2-methyl-1-propanol used 2-amino-2-methyl-1,3-propandiol.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1,19 (c, 3H) 2,20 (c, 3H) 3.15 in (d, J=the 6.06 Hz, 2H) 3,49-a 3.83 (m, 10H) a 3.87-Android 4.04 (m, 3H) 4,37-of 4.67 (m, 4H) 4,80-4,94 (m, 3H) 5,00 (c, 2H) 6,00-6,23 (m, 2H) 6,40-of 6.52 (m, 1H) 6.75 in (c, 1H) 6,93 (DD, J=7,38, 1,94 Hz, 2H) 7,03 (d, J=8,24 Hz, 2H) 7,11-7,35 (m, 24H) 7,35-7,46 (m, 2H).

ESI m/z=1004.5(M+Na).

(2) Obtain (1S)-1,5-anhydrous-1-[2-hydroxy-5-[4-[4-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-4-oxobutyl]benzyl]-4-were]-D-glucit

To a solution in methanol (1 ml) of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[(1E)-4-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-4-exabot-1-EN-1-yl]benzyl]-4-were]-D-glucit (91 mg, 0,0926 mmol) was added 10% palladium/activated carbon (16 mg)and the mixture was stirred overnight in a hydrogen atmosphere at room temperature. The reaction solution was filtered through celite and evaporated under reduced pressure to obtain a residue. Thus obtained residue was dissolved in methanol (1 ml). There was added 20% palladium hydroxide (91 mg)and a mixture of 2 days was stirred in hydrogen atmosphere at room temperature. The reaction solution was filtered through celite and evaporated under reduced pressure to obtain a residue. Thus obtained oktetakakao column chromatography on silica gel (mixture of chloroform:methanol = 5:1), to obtain a connection, indicated in the title (32 mg, 65%)as colorless powder. Data of NMR and MS data for compounds shown in table 1.

Example 3

Obtain (1S)-1,5-anhydrous-1-[2-hydroxy-5-[4-[4-[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino]-4-oxobutyl]benzyl]-4-were]-D-glucit

(1) preparation of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[(1E)-4-[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino]-4-exabot-1-EN-1-yl]benzyl]-4-were]-D-glucit

The compound indicated in the title (151 mg, 55%)was obtained as pale yellow powder by the method (1) of reference example 1, in which instead of 2-amino-2-methyl-1-propanol used Tris(hydroxymethyl)aminomethan.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2,22 (c, 3H) 3,18 (DD, J=7,15, 1,09 Hz, 2H) 3,43-3,81 (m, 12H) a 3.87-was 4.02 (m, 3H) 4,36-of 4.67 (m, 4H) 4,80-is 4.93 (m, 3H) 5,00 (c, 2H) 6,10-to 6.22 (m, 1H) 6,47 (d, J=15,85 Hz, 1H) 6,68 (c, 1H) 6.75 in (c, 1H) 6,93 (d, J=5,91 Hz, 2H) 7,03 (d, J=8,08 Hz, 2H) 7,10-7,35 (m, 24H) of 7.36-7,44 (m, 2H).

ESI m/z=998.5(M+H).

(2) Obtain (1S)-1,5-anhydrous-1-[2-hydroxy-5-[4-[4-[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino]-4-oxobutyl]benzyl]-4-were]-D-glucit

The compound indicated in the title (60 mg, 76%)was obtained as colorless powder by the method of reference example 2 (2). Data of NMR and MS data for compounds shown in table 1.

Example 4

Obtain (1S)-1-[5-[4-[4-[(2-amino-1,1-dimethyl-2-oxoethyl)amino-4-oxobutyl]benzyl]-2-hydroxy-4-were]-1,5-anhydrous-D-glucit

(1) preparation of (1S)-1-[5-[4-[(1E)-4-[(2-amino-1,1-dimethyl-2-oxoethyl)amino]-4-exabot-1-EN-1-yl]benzyl]-2-(benzyloxy)-4-were]-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-D-glucit

The compound indicated in the title, (75 mg, 42%) was obtained as pale yellow powder by the method of reference example 1 (1), in which instead of 2-amino-2-methyl-1-propanol used 2-amino-2-methylpropionamide.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.55V (c, 3H) 1.57 in (c, 3H) 2,19 (c, 3H) 3,12 (DD, J=7,38, 1,17 Hz, 2H) 3,53-a 3.87 (m, 6H) 3,89-of 4.05 (m, 3H) 4,39-of 4.54 (m, 2H) 4,57-of 4.66 (m, 2H) 4,81-4,94 (m, 3H) 5,00 (c, 2H) between 6.08-6,23 (m, 2H) 6,46 (d, J=16,01 Hz, 1H) 6.75 in (c, 1H) 6,93 (DD, J=7,07, 1,79 Hz, 2H) 7,03 (d, J=8,24 Hz, 2H) 7,10-7,35 (m, 24H) of 7.36 was 7.45 (m, 2H).

ESI m/z=1001.5(M+Na).

(2) Obtain (1S)-1-[5-[4-[4-[(2-amino-1,1-dimethyl-2-oxoethyl)amino]-4-oxobutyl]benzyl]-2-hydroxy-4-were]-1,5-anhydrous-D-glucit

To a solution in methanol (1 ml) of (1S)-1-[5-(4-[(1E)-4-[(2-amino-1,1-dimethyl-2-oxoethyl)amino]-4-exabot-1-EN-1-yl]benzyl)-2-(benzyloxy)-4-were]-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-D-glucit (75 mg, 0,0765 mmol) was added 20% palladium hydroxide (15 mg)and the mixture was stirred overnight in a hydrogen atmosphere at room temperature. The reaction solution was filtered through celite and evaporated under reduced pressure to obtain a residue. Thus obtained residue was purified column chromatography on silica gel (mixture of chloroform:methanol = 5:1; a mixture of ethyl acetate:ethanol:water = 0:2:1), to obtain a connection, indicated in the title (32 mg, 79%)as colorless powder. Data of NMR and MS data for compounds shown in table 1.

Example 5

Obtain (1S)-1-[5-[4-[3-[[amino(imino)methyl]amino]propyl]benzyl]-2-hydroxy-4-were]-1,5-anhydrous-D-glucit

(1) preparation of (1S)-1-[5-[4-[(1E)-3-[[benzyloxycarbonylamino(benzyloxycarbonylamino)methyl]amino] prop-1-EN-1-yl]benzyl]-2-(benzyloxy)-4-were]-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-D-glucit

To a solution in acetonitrile (3 ml) of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-(4-bromobenzyl)-4-were]-D-glucit (271 mg, 0,305 mmol) was added dibenzyl[(Z)-(allylamino)metallican]bicarbonate (335 mg, 0,914 mmol), palladium(II) acetate (18 mg, 0,0791 mmol), tri-O-tolylphosphino (61 mg, mmol 0,201) and triethylamine (154 mg, of 1.52 mmol); and at 120°C for 20 minutes was subjected to interaction in a microwave oven production Biotage. The reaction solution is evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 5:1)to obtain the compound indicated in the title (163 mg, 46%)as a pale yellow amorphous compound.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2,18 (c, 3H) 3,53-3,86 (m, 6H) 3,91 (c, 1H) 4,00 (d, J=11,04 Hz, 1H) 4,19 (t, J=5,75 Hz, 2H) to 4.38-4,55 (m, 2H) 4,57-of 4.67 (m, 2H) 4.80 to 4,95 (m, 3H) 5,00 (c, 2H) 5,10-5,20 (m, 4H) 6,03-6,16 (m, 1) 6,41-of 6.52 (m, 1H) 6.75 in (c, 1H) 6,92 (DD, J=7,31, 1,71 Hz, 2H) 7,01 (d, J=8,08 Hz, 2H) 7,07-7,44 (m, 37H) scored 8.38-to 8.45 (m, 1H) 11,77 (c, 1H)

ESI m/z=1176(M+H).

(2) Obtain (1S)-1-[5-[4-[3-[[amino(imino)methyl]amino]propyl]benzyl]-2-hydroxy-4-were]-1,5-anhydrous-D-glucit

To a solution in methanol (2.6 ml)/ ethyl acetate (1.3 ml) of (1S)-1-[5-[4-[(1E)-3-[[benzyloxycarbonylamino(benzyloxycarbonylamino)methyl]amino] prop-1-EN-1-yl]benzyl]-2-(benzyloxy)-4-were]-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-D-glucit (154 mg, 0,131 mmol) was added 20% palladium hydroxide (160 mg), and the mixture was stirred in hydrogen atmosphere at room temperature overnight. The reaction solution was filtered through celite, and evaporated under reduced pressure to obtain a residue. Thus obtained residue was dissolved in methanol (1.5 ml). And there was added 20% palladium hydroxide (63 mg)and a mixture of 2 days was stirred in hydrogen atmosphere at room temperature. The reaction solution was filtered through celite and evaporated under reduced pressure to obtain a residue. Thus obtained residue was purified column chromatography on silica gel (mixture of ethyl acetate:ethanol:water = 10:2:1, then 5:2:1 and then a mixture of ethanol:water = 10:1)to obtain the compound indicated in the title (38 mg, 63%)as colorless powder. Data of NMR and MS data for compounds shown in table 1.

Example 6

Obtain (1S)-1,5-anhydrous-1-[2-guide is hydroxy-4-methyl-5-[4-[3-[[(4-methylpiperazin-1-yl)carbonyl]amino]propyl]benzyl]phenyl]-D-glucit

(1) preparation of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-4-methyl-5-[4-[(1E)-3-[[(4-methylpiperazin-1-yl)carbonyl]amino]prop-1-EN-1-yl]benzyl]phenyl]-D-glucit

The compound indicated in the title (180 mg, 54%)was obtained as a pale yellow oily compound according to the method of reference example 5 (1), where instead of dibenzyl[(Z)-(allylamino)metallican]bicarbonate used N-allyl-4-methylpiperazin-1-carboxamide.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2,18 (c, 3H) 2,23-of 2.64 (m, 5H) 3,31-3,86 (m, 11H) 3,91 (c, 2H) 3.95 to 4,07 (m, 2H) 4,36-4,55 (m, 3H) 4,55-of 4.66 (m, 2H) 4,77-of 4.95 (m, 4H) 5,00 (c, 2H) 6,05-6,23 (m, 1H) 6,38-6,50 (m, 1H) 6,74 (c, 1H) 6,92 (DD, J=8,24, 1,24 Hz, 2H) 7.03 is (t, J=6,99 Hz, 2H) 7,08 and 7.36 (m, 25H) 7,37-7,46 (m, 2H).

ESI m/z=992(M+H).

(2) Obtain (1S)-1,5-anhydrous-1-[2-hydroxy-4-methyl-5-[4-[3-[[(4-methylpiperazin-1-yl)carbonyl]amino]propyl]benzyl]phenyl]-D-glucit

The compound indicated in the title (51 mg, 53%)was obtained as colorless powder by the method of reference example 5 (2). Data of NMR and MS data for compounds shown in table 1.

Example 7

Obtain (1S)-1-[5-[4-[4-[(3-aminopropyl)amino]-4-oxobutyryl]-2-hydroxy-4-were]-1,5-anhydrous-D-glucit

(1) preparation of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[(1E)-4-[[3-[(tert-butoxycarbonyl)amino]propyl]amino]-4-exabot-1-EN-1-yl]benzyl]-4-were)-D-glucit

Connection, the seat is Noah in the name (200 mg, 56%)was obtained as a colorless oily compound according to the method of reference example 5 (1), where instead of dibenzyl[(Z)-(allylamino)metallican]bicarbonate used tert-butyl[3-(but-3-anolamine)propyl]carbamate.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1,40 (c, 9H) 1,49-to 1.67 (m, 2H) 2,18 (c, 3H) 3,05-3,20 (m, 4H) 3,29 (kV, J=6,32 Hz, 2H) 3,50-of 3.85 (m, 6H) 3,91 (c, 2H) 4,00 (d, J=of 10.72 Hz, 1H) 4,37-4,56 (m, 2H) 4,56-of 4.67 (m, 2H) 4,78-of 4.95 (m, 4H) 5,00 (c, 2H) 6,10-6,37 (m, 2H) 6,46 (d, J=15,70 Hz, 1H) 6,74 (c, 1H) 6,88-of 6.96 (m, 2H) 7,02 (d, J=8,24 Hz, 2H) 7,10-7,33 (m, 25H) 7,37-7,44 (m, 2H).

ESI m/z=1073(M+Na).

(2) Obtain (1S)-1-[5-[4-[(1E)-4-[(3-aminopropyl)amino]-4-oxobutyl-1-EN-1-yl]benzyl]-2-(benzyloxy)-4-were]-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-D-glucit

To a solution of ethyl acetate (2 ml) of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[(1E)-4-[[3-[(tert-butoxycarbonyl)amino]propyl]amino]-4-exabot-1-EN-1-yl]benzyl]-4-were]-D-glucit (200 mg, 0,190 mmol)which was cooled in ice, was added 4 M the hydrochloric acid/ ethyl acetate, and a mixture of 2 days was stirred at room temperature. To the reaction solution were added ethyl acetate and saturated aqueous sodium bicarbonate solution to separate the organic layer. The organic layer was washed with water and saturated saline and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure. Thus obtained residue was purified colonoscopy because it allows the Noah chromatography on silica gel (mixture of chloroform:methanol = 5:1, then a mixture of ethyl acetate:ethanol:water = 5:2:1)to obtain the compound indicated in the title (54 mg, 30%)as a pale yellow oily compound.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1,83-to 1.98 (m, 2H) 2,17 (c, 3H) 2,87-3,03 (m, 2H) 3,03-3,20 (m, 2H) 3,26 is 3.40 (m, 2H) 3,51-a 3.83 (m, 6H) 3,89 (c, 2H) 4,00 (d, J=10,57 Hz, 1H) to 4.38-of 4.54 (m, 2H) 4,54-of 4.66 (m, 2H) 4.80 to 4,94 (m, 3H) 4,99 (c, 2H) 6,06-to 6.22 (m, 1H) 6,37-6,62 (m, 2H) 6,74 (c, 1H) 6,91 (DD, J=6,92, 1,63 Hz, 2H) 7,01 (d, J=8,08 Hz, 2H) 7,07-7,35 (m, 25H) 7,35-7,47 (m, 4H).

ESI m/z=951(M+H).

(3) Obtain (1S)-1-[5-[4-[4-[(3-aminopropyl)amino]-4-oxobutyl]benzyl]-2-hydroxy-4-were]-1,5-anhydrous-D-glucit

The compound indicated in the title (1 mg, 3,5%), was obtained as a colorless amorphous compound according to the method of reference example 5 (2). Data of NMR and MS data for compounds shown in table 1.

Example 8

Obtain (1S)-1,5-anhydrous-1-[5-[4-[3-[[(2-hydroxy-1,1-dimethylethyl)aminocarbonyl]amino]propyl]benzyl]-2-hydroxy-4-were)-D-glucit

(1) preparation of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[5-[4-[(1E)-3-[[(2-hydroxy-1,1-dimethylethyl)aminocarbonyl]amino]prop-1-EN-1-yl]benzyl]-2-(benzyloxy)-4-were)-D-glucit

To a solution in acetonitrile (5,4 ml) of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-(4-bromobenzyl)-4-were]-D-glucit (0,48 g, 0,539 mmol) was added N-allyl-N'-(2-hydroxy-1,1-dimethylethyl)urea (223 mg, 1,29 mmol), palladium(II) acetate (24 mg, to 0.108 mmol), tri-O-tolylphosphino (66 mg,0,216 mmol) and triethylamine (273 mg, 2,69 mmol); and a mixture of 20 minutes was stirred at 120°C in a microwave oven production Biotage. The reaction solvent is evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (chloroform and then a mixture of chloroform:methanol = 50:1)to obtain the compound indicated in the title (210 mg, 40%)as a pale yellow amorphous compound.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.26 in (c, 6H) 2,19 (c, 3H) 3,45 is 4.13 (m, 13H) or 4.31-4,69 (m, 6H) 4,77-of 5.06 (m, 5H) 5,98-6,18 (m, 1H) 6,44 (d, J=15,85 Hz, 1H) 6,74 (c, 1H) 6,86-of 7.48 (m, 31H).

ESI m/z=982 (M+H).

(2) Obtain (1S)-1-[2-(acetoxy)-5-[4-[3-[[[[2-(acetoxy)-1,1-dimethylethyl]amino]carbonyl]amino]propyl]benzyl]-4-were]-1,5-anhydrous-2,3,4,6-Tetra-O-acetyl-D-glucit

To a solution in ethanol (3 ml) of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[5-[4-[(1E)-3-[[(2-hydroxy-1,1-dimethylethyl)aminocarbonyl]amino]prop-1-EN-1-yl]benzyl]-2-(benzyloxy)-4-were]-D-glucit (210 mg, 0,214 mmol) was added 20% palladium hydroxide (210 mg)and the mixture was stirred during the night in an atmosphere of hydrogen at room temperature. The reaction solution was filtered through celite, and the solvent evaporated under reduced pressure to obtain a residue. Thus obtained residue was purified column chromatography on silica gel (mixture of chloroform:methanol = 5:1)to obtain colorless powdery substance (83 mg). To a solution of pyridine (1 ml of this substance was added acetic anhydride (0.25 ml), and the mixture was stirred over night at room temperature. To this reaction solution was added saturated aqueous sodium bicarbonate solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = from (2:3) to (1:2))to obtain the compound indicated in the title (70 mg)as a colorless amorphous compound.

(3) Obtain (1S)-1,5-anhydrous-1-[5-[4-[3-[[(2-hydroxy-1,1-dimethylethyl)aminocarbonyl]amino]propyl]benzyl]-2-hydroxy-4-were]-D-glucit

To a solution in methanol (1 ml) of (1S)-1-[2-(acetoxy)-5-[4-[3-[[[[2-(acetoxy)-1,1-dimethylethyl)amino]carbonyl]amino]propyl]benzyl]-4-were]-1,5-anhydrous-2,3,4,6-Tetra-O-acetyl-D-glucit (70 mg) was added sodium methylate (1 M solution in methanol, 0.5 ml, 0.5 mmol)and the mixture was stirred one hour at room temperature. To this reaction solution was added dry ice, and the solvent evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (mixture of chloroform:methanol = 5:1)to obtain the compound indicated in the title (35 mg, 31%, 3 phase), in the de colorless oily compound. Data of NMR and MS data for compounds shown in table 1.

Example 9

Obtain (1S)-1,5-anhydrous-1-[5-[4-[3-[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]aminocarbonyl]amino]propyl]benzyl]-2-hydroxy-4-were]-D-glucit

(1) preparation of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[5-[4-[(1E)-3-[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]aminocarbonyl]amino]prop-1-EN-1-yl]benzyl]-2-(benzyloxy)-4-were]-D-glucit

The compound indicated in the title (322 mg)was obtained as pale yellow amorphous compound according to the method of reference example 8 (1), in which instead of N-allyl-N'-(2-hydroxy-1,1-dimethylethyl)urea used N-allyl-N'-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]urea.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2,19 (c, 3H) 3,48-4,06 (m, 17H) 4,34-5,08 (m, 11H) 5,98-6,11 (m, 1H) 6,44 (d, J=16,32 Hz, 1H) 6,74 (c, 1H) 6,84-7,46 (m, 31H).

ESI/APCl, m/z=1014(M+H).

(2) Obtain (1S)-1,5-anhydrous-1-[5-[4-[2-[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]aminocarbonyl]amino]propyl]benzyl]-2-hydroxy-4-were]-D-glucit

The compound indicated in the title (60 mg)was obtained as colorless powder by the method of example 8 (2), in which instead of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[5-[4-[(1E)-3-[[(2-hydroxy-1,1-dimethylethyl)aminocarbonyl]amino]prop-1-EN-1-yl]benzyl]-2-(benzyloxy)-4-were)-D-glucit used (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[5-[4-[(1E)-3-[[[2-hydroxy-1,1-bis(hydroxymethylene]aminocarbonyl]amino]prop-1-EN-1-yl]benzyl]-2-(benzyloxy)-4-were)-D-glucit. Data of NMR and MS data for compounds shown in table 1.

Example 10

Obtain (1S)-1,5-anhydrous-1-[5-[4-[2-[[(2-hydroxy-1,1-dimethylethyl)aminocarbonyl]amino]ethyl]benzyl]-2-hydroxy-4-were]-D-glucit

(1) preparation of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[2-[[[(2-hydroxy-1,1-dimethylethyl)amino]carbonyl]amino]ethyl]benzyl]-4-were]-D-glucit

To a solution in chloroform (3 ml) of 4-nitrophenylphosphate (0,177 g, 0,879 mmol) and pyridine (0,071 ml, 0.88 mmol)which was cooled in ice, was added dropwise a solution in chloroform (3 ml) of (1S)-1-[5-[4-(2-amino-ethyl)benzyl]-2-(benzyloxy)-4-were]-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-D-glucit (0,250 g, 0,293 mmol)and the mixture was stirred 20 minutes at room temperature. After this there was added a solution in chloroform (3 ml) of 2-amino-2-methyl-1-propanol (0,209 g 2,344 mmol) and dimethyl sulfoxide (3 ml)and the mixture was stirred overnight at the same temperature. To the reaction solution was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution (3 times) and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure to obtain a residue. Thus obtained residue was purified column chromatography on silica gel NH type (x is roform), to obtain a connection designated in the name of (0, 184 g, 65%)as a pale yellow oily compound.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.18 to (c, 6H) 2,21 (c, 3H) 2,68 (t, J=6,68 Hz, 2H) 3,21-3,37 (m, 2H) 3,45-of 3.94 (m, 10H) 4,00 (d, J=10,88 Hz, 1H) 4,37 with 4.65 (m, 5H) 4,81-to 5.03 (m, 5H) 6,75 (c, 1H) 6.87 in-7,05 (m, 7H) 7,07-7,44 (m, 23H).

(2) Obtain (1S)-1,5-anhydrous-1-[5-[4-[2-[[(2-hydroxy-1,1-dimethylethyl)aminocarbonyl]amino]ethyl]benzyl]-2-hydroxy-4-were]-D-glucit

To a solution in methanol (4 ml) of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[2-[[[(2-hydroxy-1,1-dimethylethyl)amino]carbonyl]amino]ethyl]benzyl]-4-were]-D-glucit (0,184 mg, 0,190 mmol) was added 20% palladium hydroxide (0,180 g)and the mixture was stirred in hydrogen atmosphere at room temperature over night. The reaction solution was filtered through celite and evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (mixture of chloroform:methanol = 17:3)to obtain the compound indicated in the title (57 mg, 58%)as colorless powder. Data of NMR and MS data for compounds shown in table 1.

Example 11

Obtain (1S)-1,5-anhydrous-1-[5-[4-[2-[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]aminocarbonyl]amino]ethyl]benzyl]-2-hydroxy-4-were]-D-glucit

(1) preparation of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[2-[[[[2-hydroxy,1-bis(hydroxymethyl)ethyl]amino]carbonyl]amino]ethyl]benzyl]-4-were]-D-glucit

The compound indicated in the title (251 mg)was obtained as pale yellow amorphous compound according to the method of example 10 (1), in which instead of 2-amino-2-methyl-1-propanol used Tris(hydroxymethyl)aminomethan.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2,22 (c, 3H) 2,68 (t, J=6,61 Hz, 2H) 3,24-to 3.35 (m, 2H) 3,41-3,99 (m, 14H) 4,00 (d, J=10,88 Hz, 1H) to 4.38-4,70 (m, 5H) 4,79-to 5.03 (m, 5H) 5,27 (c, 1H) 6,76 (c, 1H) 6.87 in-7,44 (m, 30H).

(2) Obtain (1S)-1,5-anhydrous-1-[5-[4-[2-[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]aminocarbonyl]amino]ethyl]benzyl]-2-hydroxy-4-were]-D-glucit

The compound indicated in the title (85 mg)was obtained as colorless powder by the method of example 10 (2), in which instead of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[2-[[[(2-hydroxy-1,1-dimethylethyl)amino]carbonyl]amino]ethyl]benzyl]-4-were)-D-glucit used (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[2-[[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino]carbonyl]amino]ethyl]benzyl]-4-were]-D-glucit. Data of NMR and MS data for compounds shown in table 1.

Example 12

Obtain (1S)-1,5-anhydrous-1-[5-[4-[2-[[[1-[1-(4-methylpiperazin-1-yl)carbonyl]-1-(methyl)ethyl]aminocarbonyl]amino]ethyl]benzyl]-2-hydroxy-4-were]-D-glucit

(1) preparation of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[2-[[[[1-[1-(4-methylpiperazin-1-yl)carbonyl]-1-(methyl)ethyl]amino]carbonyl]amino]the active compounds]-4-were]-D-glucit

The compound indicated in the title (326 mg)was obtained as pale yellow amorphous compound according to the method of example 10 (1), in which instead of 2-amino-2-methyl-1-propanol used 2-methyl-1-(4-methylpiperazin-1-yl)-1-oxoprop-2-amine.

1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.41 to (c, 6H) 2,20 (c, 3H) 2.26 and (c, 3H) 2,31-is 2.37 (m, 4H) 2,70 (t, J=6,84 Hz, 2H) 3,29-to 3.41 (m, 2H) 3,50-of 3.94 (m, 12H) 4,00 (d, J=10,88 Hz, 1H) 4,37-of 4.67 (m, 5H) 4,81-5,02 (m, 5H) 6,75 (c, 1H) 6,88-7,44 (m, 30H).

Obtain (1S)-1,5-anhydrous-1-[5-[4-[2-[[[1-[1-(4-methylpiperazin-1-yl)carbonyl]-1-(methyl)ethyl]aminocarbonyl]amino]ethyl]benzyl]-2-hydroxy-4-were]-D-glucit

The compound indicated in the title (35 mg)was obtained as colorless powder by the method of example 10 (2), in which instead of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[2-[[[(2-hydroxy-1,1-dimethylethyl)amino]carbonyl]amino]ethyl]benzyl]-4-were]-D-glucit used (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[2-[[[[1-[1-(4-methylpiperazin-1-yl)carbonyl]-1-(methyl)ethyl]amino]carbonyl]amino]ethyl) - benzyl]-4-were]-D-glucit. Data of NMR and MS data for compounds shown in table 1.

Example 13

Obtain (1S)-1,5-anhydrous-1-[5-[4-[2-[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]aminocarbonyl]amino]ethoxy]-2-methylbenzyl]-2-hydroxy-4-were]-D-glucit

To a solution in chloroform (0.5 ml) 1,1'-carbonyldiimidazole (14 mg, 0,089 mmol) was added rest the R in chloroform (1.5 ml) of (1S)-1-[5-[4-(2-aminoethoxy)-2-methylbenzyl]-2-(benzyloxy)-4-were]-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-D-glucit (52 mg, 0,059 mmol) and N-methylmorpholine (9 mg)and the mixture was stirred for 15 minutes at room temperature. Thereafter, this reaction solution was added Tris(hydroxymethyl)aminomethan (21 mg, 0,177 mmol) and N,N-dimethylformamide (2 ml); and this reaction mixture was stirred at 60°C for 1.5 hours. After cooling the reaction mixture to room temperature there was added ethyl acetate. And the mixture was washed with water, 1 M hydrochloric acid and saturated saline solution and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent evaporated under reduced pressure to obtain 60 mg of the residue.

Thus obtained residue was dissolved in methanol (1 ml). And there was added 20% palladium hydroxide (15 mg)and the mixture was stirred in hydrogen atmosphere at room temperature for 2 hours. The reaction solution was filtered through celite and evaporated under reduced pressure to obtain a residue. Thus obtained residue was purified column chromatography on silica gel (mixture of ethyl acetate:ethanol:water = 10:2:1)to obtain the compound indicated in the title (30 mg, 86%)as colorless powder. Data of NMR and MS data for compounds shown in table 1.

Example 14

Obtain (1S)-1,5-anhydrous-1-[4-chloro-5-[4-[2-[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]aminocarbonyl]amino]ethyl]benzyl]-2-hydroxyphenyl]-D-glucit

To a solution in chloroform (1 ml) 1,1'-carbonyldiimidazole (10,8 mg, 0,0669 mmol) was added to the solution in chloroform (1 ml) of (1S)-1-[5-[4-(2-amino-ethyl)benzyl]-2-(benzyloxy)-4-chlorophenyl]-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-D-glucit (39,0 mg, 0,0446 mmol) and N-methylmorpholine (of 7.36 ml)and the mixture was stirred 10 minutes at room temperature. Thereafter, this reaction solution was added Tris(hydroxymethyl)aminomethan (16.2 mg, 0,134 mmol) and N,N-dimethylformamide (1 ml), and this reaction mixture is 2 hours and stirred at 60°C. After cooling the reaction mixture to room temperature there was added ethyl acetate. The mixture was washed with water, 1 M hydrochloric acid and saturated saline solution and dried with anhydrous magnesium sulfate. The desiccant was filtered, the solvent evaporated under reduced pressure to obtain 41,2 mg of residue.

Thus obtained residue (of 22.3 mg of 0.022 mmol) was dissolved in chloroform (250 ml) and ethanthiol (250 μl). And to this solution, cooled in ice, was added BF3·Et2O (50 μl)and the mixture was stirred at the same temperature for 2 hours. The solvent is evaporated, and the thus obtained residue was purified column chromatography on silica gel (mixture of ethyl acetate:ethanol:water = 10:2:1 and then methanol)to obtain the compound indicated in the title (10,8 mg, 86%), as colourless am hego connection. Data of NMR and MS data for compounds shown in table 1.

Example 15

Obtain (1S)-1,5-anhydrous-1-[5-[4-[2-[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]aminocarbonyl]amino]ethyl]benzyl]-2-hydroxyphenyl]-D-glucit

The compound indicated in the title (8.5 mg, 93%)was obtained as a colorless oily compound according to the method of example 13, in which instead of (1S)-1-[5-[4-(2-aminoethoxy)-2-methylbenzyl]-2-(benzyloxy)-4-were]-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-D-glucit used (1S)-1-[5-[4-(2-amino-ethyl)benzyl]-2-(benzyloxy)-4-chlorophenyl]-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-D-glucit. Data of NMR and MS data for compounds shown in table 1.

Example 16

Obtain (1S)-1,5-anhydrous-1-[3-[4-[2-[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]aminocarbonyl]amino]ethyl]benzyl]phenyl]-D-glucit

The crude product of the compound indicated in the title, obtained by the method of example 13, in which instead of (1S)-1-[5-[4-(2-aminoethoxy)-2-methylbenzyl]-2-(benzyloxy)-4-were]-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-D-glucit used (1S)-1-[3-[4-(2-amino-ethyl)benzyl]-4-chlorophenyl]-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-D-glucit. After that, the crude product was purified HPLC (HPLC) (mixture of 0.025% aqueous solution of acetic acid:acetonitrile=3:1, column YMC-Pack ODS-AM 150×10 mm I.D.(inner diameter), 5.0 ml/min, λ=210 nm)to the floor of the IC connection, indicated in the title (13 mg, 15%)as a colorless amorphous compound. Data of NMR and MS data for compounds shown in table 1.

Example 17

Obtain (1S)-1,5-anhydrous-1-[4-chloro-3-[4-[2-[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]aminocarbonyl]amino]ethyl]benzyl]phenyl]-D-glucit

The crude product of the compound indicated in the title, obtained by the method of example 14, in which instead of (1S)-1-[5-[4-(2-amino-ethyl)benzyl]-2-(benzyloxy)-4-chlorophenyl]-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-D-glucit used (1S)-1-[3-[4-(2-amino-ethyl)benzyl]-4-chlorophenyl]-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-D-glucit. After that, the crude product was purified HPLC (mixture of 0.025% aqueous solution of acetic acid: acetonitrile=7:3, column Waters Sunfire Prep C, 150×19 mm I.D. (inner diameter), 8.0 ml/min, λ=210 nm)to obtain the compound indicated in the title (12 mg, 17%)as a colorless amorphous compound.

Data of NMR and MS data for compounds shown in table 1.

Example 18

Obtain (1S)-1,5-anhydrous-1-[2-hydroxy-5-[4-[4-[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino]-4-oxobutyl]benzyl]-4-were]-D-Galactica

The compound indicated in the title (37 mg, 47%)was obtained as colorless powder from (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[(1E)-3-carboxypropyl-1-EN-1-yl]benzyl]-4-methyl who enyl]-D-Galactica (199 mg, 0,222 mmol) by the method of example 3. Data of NMR and MS data for compounds shown in table 1.

Moreover, the connection 19-36 were also synthesized from the corresponding substances, according to reference examples and examples.

Table 1
Connection
No.
StructureNMR (solvent, methanol-d4), MS
11H NMR (600 MHz) δ ppm 1,25 (C, 6N) 1,81-1,89 (m, 2H) 2,09 (s, 3H) 2,12-to 2.18 (m, 2H) 2,54 at 2.59 (m, 2H) 3,38-to 3.50 (m, 3H) 3,53 is 3.57 (m, 3H) 3,70 (DD, J=12,15, at 5.27 Hz, 1H) 3,84-to 3.89 (m, 3H) 4,51 (d, J=9,63 Hz, 1H) 6,63 (s, 1H) 6,99-was 7.08 (m, 4H) for 7.12 (s, 1H), ESI m/z=518(m+H)
21H NMR (600 MHz) δ ppm 1,22 (s, 3H) 1,80 is 1.91 (m, 2H) 2,09 (s, 3H) 2,15-of 2.23 (m, 2H) of 2.58 (t, J=EUR 7.57 Hz, 2H) 3,37-to 3.50 (m, 3H) 3,51-to 3.73 (m, 6N) 3,83-3,90 (m, 3H) 4,51 (d, J=9,63 Hz, 1H) 6,63 (s, 1H) 6,99-to 7.09 (m, 4H) for 7.12 (s, 1H), ESI m/z=556(m+Na)
31H NMR (600 MHz) δ ppm 1,84-of 1.93 (m, 2H) 2,10 (s, 3H) 2.21 are of 2.27 (m, 2H) 2,59 (t, J=EUR 7.57 Hz, 2H) 3,37-3,44 (m, 2H) 3,48 (t, J=8,48 Hz, 1H) 3,53-3,59 (m, 1H) 3,70 (s, 7H) 3,83-3,90 (m, 3H) 4,51 (d, J=9,63 Hz, 1H) 6,63 (s, 1H) 6,99-7,10 (m, 4H) 7,11 (s, 1H),ESI m/z=572(m+Na)

41H NMR (600 MHz) δ ppm of 1.44 (s, 6N) 1,82-1,90 (m, 2H) 2,09 (s, 3H) 2,19 (t, J=EUR 7.57 Hz, 2H) to 2.57 (t, J=EUR 7.57 Hz, 2H) 3,37-to 3.52 (m, 2H) to 3.56 (t, J=9,17 Hz, 2H) 3,70 (DD, J=11,92, 5,04 Hz, 1H) 3,82-3,90 (m, 3H) 4,51 (d, J=9,63 Hz, 1H) 6,63 (s, 1H) 6,98-was 7.08 (m, 4H) 7,11 (s, 1H), ESI m/z=553(m+Na)
51H NMR (600 MHz) δ ppm 1,82 is 1.91 (m, 2H) 2,10 (s, 3H) 2,61-to 2.67 (m, 2H) 3.15 in (t, J=7,11 Hz, 2H) 3,37-3,44 (m, 2H) 3,48 (t, J=8,71 Hz, 1H) 3,55 (t, J=9,17 Hz, 1H) 3,70 (DD, J=11,92, 5,04 Hz, 1H) 3,83-3,91 (m, 3H) 4,51 (d, J=9,63 Hz, 1H) 6,63 (s, 1H) 7,01-7,13 (m, 5H), ESI m/z=460(m+H)
61H NMR (600 MHz) δ ppm 1,74-to 1.82 (m, 2H) 2,10 (s, 3H) to 2.29 (s, 3H) 2,37-to 2.42 (m, 4H) 2,54-2,60 (m, 2H) 3.15 in (t, J=7,11 Hz, 2H) 3,33-3,44 (m, 6H) of 3.48 (t, J=8,94 Hz, 1H) 3,53-to 3.58 (m, 1H) 3,70 (DD, J=12,15, at 5.27 Hz, 1H) 3,83-to 3.89 (m, 3H) 4,51 (d, J=9,63 Hz, 1H) 6,63 (s, 1H) 6,99-to 7.09 (m, 4H) for 7.12 (s, 1H), ESI m/z=544(m+H)

71H NMR (600 MHz) δ ppm 1.77 in-of 1.84 (m, 2H) 1,85-of 1.93 (m, 2H) 2,10 (s, 3H) 2,17-of 2.23 (m, 2H) of 2.58 (t, J=EUR 7.57 Hz, 2H) 2,87-only 2.91 (m, 2H) 3,24 (t, J=6,65 Hz, 2H) 3,37-3,51 (m, 3H) 3,53-to 3.58 (m, 1H) 3,70 (DD, J=12,15, at 5.27 Hz, 1H) 3,84-3,88 (m, 3H) 4,51 (d, J=9,63 Hz, 1H) 6,63 (s, 1H) 7,01-7,08 m, 4H) 7,11 (s, 1H), ESI m/z=503(m+H)
81H NMR (600 MHz) δ ppm 1,23 (C, 6N) by 1.68 to 1.76 (m, 2H) 2,09 (s, 3H) 2,54-2,60 (m, 2H) 3,05 (t, J=6,88 Hz, 2H) 3,37-3,44 (m, 2H) 3,45-to 3.58 (m, 4H) 3,70 (DD, J=11,92, 5,04 Hz, 1H) 3,83-3,90 (m, 3H) 4,51 (d, J=9,63 Hz, 1H) 6,63 (s, 1H) 6,98-7,03 (m, 2H) 7.03 is-was 7.08 (m, 2H) for 7.12 (s, 1H), ESI m/z=533 (m+H), 531 (m-H)
91H NMR (600 MHz) δ ppm 1.70 to 1.77 in (m, 2H) 2,09 (s, 3H) 2,54-2,62 (m, 2H) 3,07 (t, J=6,88 Hz, 2H) 3,36-of 3.60 (m, 5H) 3,61-to 3.73 (m, 6N) 3,82-3,91 (m, 3H) 4,51 (d, J=9,63 Hz, 1H) 6,63 (s, 1H) 6,99-was 7.08 (m, 4H) 7,08-to 7.15 (m, 1H), ESI m/z=587(m+Na)

101H NMR (300 MHz) δ ppm 1,25 (C, 6N) to 2.13 (s, 3H) 2,72 (t, J=7,07 Hz, 2H) 3.25 to 3,37 (m, 3H) 3,38-of 3.80 (m, 6N) 3,86-of 3.96 (m, 3H) 4,56 (d, J=was 9.33 Hz, 1H) of 6.68 (s, 1H) 7.03 is-7,19 (m, 5H), ESI m/z=519 (m+H), 541 (m+Na)
111H NMR (600 MHz) δ ppm of 2.09 (s, 3H) 2,68 (t, J=7,34 Hz, 2H) 3,24-of 3.32 (m, 3H) 3,36-3,66 (m, N) 3,68-3,74 (m, 1H) 3,81-3,90 (m, 3H) to 4.52 (d, J=9,63 Hz, 1H) 6,64 (s, 1H) 7,00-7,14 (m, 5H), ESI m/z=552 (m+H), 574 (m+Na)
121H NMR (600 MHz) δ ppm 1.39 in (C, 6N) of 2.10 (s, 3H) of 2.23 (s, 3H) 2,70 (who, J=7,11 Hz, 2H) 3,26-3,91 (m, N) to 4.52 (d, J=9,63 Hz, 1H) 6,63 (s, 1H) 7,02-7,14 (m, 5H), ESI m/z=616 (m+H), 637 (m+Na)
131H NMR (300 MHz) δ ppm 2,12 (s, 3H) to 2.25 (s, 3H) 3,34 is 3.57 (m, 6N) 3,66 (C, 6N) 3,67-3,71 (m, 1H) of 3.77 (s, 2H) 3,79-to 3.89 (m, 1H) 3,96 (t, J=5,28 Hz, 2H) 4,45 (d, J=9,48 Hz, 1H) 6,58-of 6.65 (m, 1H) to 6.67 (s, 1H) 6,69-for 6.81 (m, 2H) make 6.90 (s, 1H), ESI m/z=581 (m+H), 603 (m+Na)

141H NMR (600 MHz) δ ppm 2,69 (t, J=7,11 Hz, 2H) 3,24 of 3.28 (m, 2H) 3,34-to 3.41 (m, 2H) 3,42-to 3.50 (m, 2H) 3,60 (C, 6N) to 3.67 (DD, J=12,15, at 5.27 Hz, 1H) a 3.83 (DD, J=11,92 and 1.83 Hz, 1H) 3,89-4,01 (m, 2H) 4,51 (d, J=9,17 Hz, 1H) for 6.81 (s, 1H) was 7.08 (s, 4H) 7,24 (s, 1H), ESI m/z=571 (m+H), 593 (m+Na)
151H NMR (600 MHz) δ ppm 2,69 (t, J=7,11 Hz, 2H) 3,24 of 3.28 (m, 2H) 3,34-of 3.43 (m, 2H) of 3.46 (t, J=8,48 Hz, 1H) 3,52 (t, J=9,17 Hz, 1H) 3,60 (C, 6N) 3,68 (DD, J=11,92, 5,04 Hz, 1H) of 3.77-to 3.89 (m, 3H) to 4.52 (d, J=9,63 Hz, 1H) 6,70 (d, J=of 8.25 Hz, 1H) 6,92 (DD, J=8,25 and 1.83 Hz, 1H) to 7.09 (s, 4H) to 7.18 (d, J=to 2.29 Hz, 1H), ESI m/z=537 (m+H), 559 (m+Na)
161H NMR (300 MHz) δ ppm a 2.71 (t, J=7,07 Hz, 2H) of 3.25 to 3.49 (m, 6N) 3,62 (C, 6N) 3,64-to 3.73 (m, 1H) 3,84-3,95 (m, 3H) 4.09 to (d, J=9,17 Hz, 1H) 7,08-7,17 (m, 5H) 7,21-7,31 (m, 3H), ESI m/z=521 (m+NH4)
171H NMR (300 MHz) δ ppm a 2.71 (t, J=7,07 Hz, 2H) 3,21-of 3.48 (m, 6N) 3,61 (s, 6N) 3,64-to 3.73 (m, J=of $ 11.97, 5,13 Hz, 1H) 3,83-3,91 (m, 1H) 3,99-to 4.14 (m, 3H) for 7.12 (s, 4H) 7.24 to 7,38 (m, 3H), ESI m/z=555 (m+H), 577 (m+Na)

181H NMR (600 MHz) δ ppm 1.85 to 1,95 (m, 2H) 2,10 (s, 3H) of 2.38 (t, J=7,34 Hz, 2H) 2,60 (t, J=7,34 Hz, 2H) 3,56-3,61 (m, 6N) 3,61-3,68 (m, 1H) 3,68-3,74 (m, 1H) 3,74-of 3.80 (m, 1H) 3,85-3,91 (m, 2H) 3,96 (d, J=3,21 Hz, 1H) 4,14 (s, 2H) was 4.42 (d, J=9,63 Hz, 1H) 6,63 (s, 1H) 7,00-to 7.09 (m, 4H) 7,13-7,20 (m, 1H), ESI m/z=550 (m+H), 548 (m-H)
191H NMR (300 MHz) δ ppm of 2.09 (s, 3H) 3,37-3,51 (m, 6N) 3,52-of 3.60 (m, 1H) 3,65 (C, 6N) 3,68 is 3.76 (m, 1H) 3,80-3,91 (m, 3H) 3,95 (t, J=5,13 Hz, 2H) 4,51 (d, J=was 9.33 Hz, 1H) 6,63 (s, 1H) 6,80 (d, J=8,24 Hz, 2H) 7,01 (d, J=8,24 Hz, 2H) 7,10 (s, 1H)
201H NMR (300 MHz) δ ppm of 2.08 (s, 3H) 3,38-3,61 (m, 4H) 3,65 (C, 6N) 3,67-to 3.73 (m, 1H) 3,81-of 3.94 (m, 3H) 4,22 (s, 2H) 4,51 (d, J=9,48 Hz, 1H) 6,63 (s, 1H) 7.03 is-to 7.09 (m, 2H) 7,11-7,19 (m, 3H), ESI m/z=537 (m+H)
211H NMR (300 MHz) δ ppm 2,10 (s, 3H) 2,72 (t, J=7,07 Hz, 2H) 3,29-3,37 (m, 2H) 3,38-of 3.46 (m, 3H) 3,49 (t, 1H) to 3.56 (t, J=8,32 Hz, 1H) 3,0 (, 3H) 3,81-3,91 (m, 5H) 4,51 (d, J=for 9.64 Hz, 1H) 6,63 (s, 1H) 7,00-to 7.15 (m, 5H), ESI m/z=541 (m+Na)

221H NMR (300 MHz) δ ppm of 2.09 (s, 3H) 2,66 (t, J=7,31 Hz, 2H) 2,93 (DD, 1H) a 3.06 (DD, 1H) 3,21 of 3.28 (m, 2H) 3,39 is-3.45 (m, 2H) 3,47 (t, 1H) 3,57 (t, J=8,86 Hz, 1H) 3,62 of 3.75 (m, 4H) a 3.87 (t, J=5,44 Hz, 3H) 4,47-4,59 (m, 2H) 6,63 (, 1H) 6,98-was 7.08 (m, 4H) 7,10-7,19 (m, 3H) 7,18-7,30 (m, 3H), ESI m/z=631 (m+Na)
231H NMR (600 MHz) δ ppm 1,54-to 1.77 (m, 8H) 2,07 (s, 3H) to 2.67 (t, J=7,11 Hz, 2H) 3,24-of 3.27 (m, 2H) 3,36-of 3.42 (m, 2H) of 3.46 (t, J=8,71 Hz, 1H) 3,53 (d, J=9,63 Hz, 1H) to 3.56 (s, 2H) 3,68 (DD, J=11,92, 5.50 Hz, 1H) 3,81-a 3.87 (m, 3H) 4,50 (d, J=9,63 Hz, 1H) of 6.61 (s, 1H) 7,02 (d, 2H) 7,06 (d, 2H) 7,10 (s, 1H), ESI m/z=567 (m+Na), 543(M-H)
241H NMR (600 MHz, METHANOL-d3) δ ppm 0,87-to 0.96 (m, 6N) 1,40-of 1.55 (m, 2H) 1,61 is 1.70 (m, 1H) 2,08 (s, 3H) 2,69 (t, J=7,11 Hz, 2H) 3,30-to 3.34 (m, 2H) 3,35-of 3.42 (m, 2H) of 3.46 (t, J=of 8.25 Hz, 1H) 3,54 (t, J=9,17 Hz, 1H) 3,68 (DD, J=11,92, 5,04 Hz, 1H) 3,80-a 3.87 (m, 3H) 4,18 (DD, J=10,32, to 4.81 Hz, 1H) 4,50 (d, J=9,63 Hz, 1H) of 6.61 (s, 1H) 6,97-7,11 (m, 5H), ESI m/z=582 (m+Na), 558(M-H)

251H NMR (600 MHz, METHANOL-d3) δ ppm 0,6 (kV, 2H) 0,44 (kV, J=5,96 Hz, 2H) 0,83 (t, J=7,34 Hz, 3H) 0,86-to 0.96 (m, 1H) 1,45-and 1.54 (m, 2H) to 2.06 (s, 3H) 2,72 (t, J=7,34 Hz, 2H) is 3.08 (d, J=6.42 per Hz, 2H) 3,17 (t, 2H) of 3.32 (m, 2H) 3,36-of 3.43 (m, 2H) of 3.46 (t, J=8,71 Hz, 1H) 3,54 (t, 1H) 3,69 (DD, J=11,92, 5,04 Hz, 1H) 3,81-a 3.87 (m, 3H) 4,50 (d, J=9,63 Hz, 1H) 6,60 (s, 1H) 7,01 (d, J=of 8.25 Hz, 2H) 7,06 (d, 2H) 7,11 (s, 1H), ESI m/z=565 (m+Na), 541(M-H)
261H NMR (600 MHz) δ ppm 2,07 (s, 3H) 2,69 (t, J=7,11 Hz, 2H) 3,29-to 3.33 (m, 2H) 3,36-of 3.42 (m, 2H) of 3.46 (t, J=8,71 Hz, 1H) 3,54 (t, J=9,40 Hz, 1H) 3,68 (DD, J=11,92, 5.50 Hz, 1H) 3,81-a 3.87 (m, 3H) was 4.42 (s, 2H) of 4.49 (d, J=9,63 Hz, 1H) of 6.61 (s, 1H) 6.87 in-6,91 (m, 2H) 7,01 (d, 2H) 7,05 (d, 2H) 7,10 (s, 1H) 7,22 (DD, J=4,36, to 2.06 Hz, 1H), ESI m/z=565 (m+Na), 541(M-H)
271H NMR (600 MHz) δ ppm 2,07 (s, 3H) 2,70 (t, J=6,88 Hz, 2H) 3,30-to 3.34 (m, 2H) 3,36-of 3.42 (m, 2H) of 3.46 (t, J=8,71 Hz, 1H) 3,53 (t, 1H) 3,68 (DD, J=11,92, 5,04 Hz, 1H) 3,81-3,88 (m, 3H) to 4.23 (s, 2H) of 4.49 (d, J=9,63 Hz, 1H) of 6.61 (s, 1H) 7,02 (d, 2H) 7,06 (d, 2H) 7,10 (s, 1H) 7,21 (d, 2H) 7,27 (d, 1H), ESI m/z=605 (m+H), 603(M-H)
281H NMR (600 MHz) δ ppm 0,82-to 0.96 (m, 2H) 1,13-of 1.30 (m, 3H) of 1.31-1.42 (m, 1H) 1.60-to 1.77 in (m, 5H) 2,07 (s, 3H) 2,68 (t, J=7,11 Hz, 2H) 2,89 (d, J=6,88 Hz, 2H) 3,23-of 3.32 (m, 2H) 3,35-to 3.41 (m, 2H) of 3.46 (t, J=8,71 Hz, 1H) 3,54 (t, J=9,17 Hz, 1H) 3,68 (DD, J=11,92, 5,04 Hz, 1H) 3,80-a 3.87 (m, 3H) of 4.49 (d, J=9,63 Hz, 1H) of 6.61 (s, 1H) 7,01 (d, 2H) 7,06 (d, 2H) 7,10 (s, 1H), ESI m/z=543 (m+H), 541(M-H)
29/td> 1H NMR (600 MHz) δ ppm 2,03-2,11 (m, 6N) 2,52 (t, J=6,88 Hz, 2H) 2,69 (t, J=7,11 Hz, 2H) 3,24-of 3.27 (m, 2H) 3,28-of 3.31 (m, 2H) 3,35-of 3.42 (m, 2H) 3,47 (t, 1H) 3,53 (t, 1H) 3,68 (DD, J=11,92, 5,04 Hz, 1H) 3,81-a 3.87 (m, 3H) 4,50 (d, J=9,63 Hz, 1H) of 6.61 (s, 1H) 7,01 (d, 2H) 7,06 (d, 2H) 7,10 (s, 1H), ESI m/z=543 (m+Na), 519(M-H)
301H NMR (600 MHz) δ ppm 1.77 in (DDD, J=6,76, 3,32, 3,21 Hz, 4H) 2,08 (s, 3H) of 2.51-2.57 m (m, 6N) 2,69 (t, J=7,11 Hz, 2H) 3,22 (t, J=6,65 Hz, 2H) 3,29-to 3.33 (m, 2H) 3,35-of 3.42 (m, 2H) of 3.46 (t, J=8,71 Hz, 1H) 3,53 (t, J=9,17 Hz, 1H) 3,68 (DD, J=12,15, at 5.27 Hz, 1H) 3,82-a 3.87 (m, 3H) of 4.49 (d, J=9,63 Hz, 1H) of 6.61 (s, 1H) 7,02 (d, 2H) 7,06 (d, 2N) to 7.09 (s, 1H), ESI m/z=544 (m+H), 542(M-H)

311H NMR (600 MHz)δ ppm of 2.08 (s, 3H) 2,68 (t, J=7,11 Hz, 2H) 3,23 (t, J=5.50 Hz, 2H) 3,24-to 3.33 (m, 5H) 3,35-of 3.43 (m, 4H) of 3.46 (t, J=8,71 Hz, 1H) 3,54 (t, J=9,17 Hz, 1H) 3,68 (DD, 1H) 3,80-3,88 (m, 3H) of 4.49 (d, J=9,63 Hz, 1H) of 6.61 (s, 1H) 7,02 (d, 2H) 7,06 (d, 2H) 7,10 (s, 1H), ESI m/z=527 (m+Na), 503(M-H)
321H NMR (600 MHz) δ ppm 2,07 (s, 3H) 2,45 (t, J=6.42 per Hz, 2H) to 2.67 (t, J=7,11 Hz, 2H) 3,21 (t, J=6,88 Hz, 2H) 3,30-to 3.35 (m, 2H) 3,35-of 3.42 (m, 2H) 3.46 in (t, 1H) 3,54 (DD, 1H) to 3.64 (s, 3H) 3,68 (DD, J=11,92, 5,04 Hz, 1H) 3,80-3,90 (m, 3H) of 4.49 (d, J=9,63 Hz, 1H) of 6.61 (s, 1H) 7,01 (d, 2H) 7,05 (d, 2H) 710 (, 1H), ESI m/z=555 (m+Na), 531(M-H)
331H NMR (600 MHz) δ ppm 1,37 of 1.50 (m, 2H) 1,80-1,89 (m, 2H) 2,08 (s, 3H) 2,31 (ush. s, 2H) to 2.67 (t, J=6,88 Hz, 2H) 2,88 (ush. s, 2H) 3.25 to to 3.34 (m, 2H) 3,35-of 3.43 (m, 2H) 3,43-to 3.52 (m, 2H) 3,54 (t, 1H) 3,59-3,71 (m, 3H) 3,79-a 3.87 (m, 3H) of 4.49 (d, J=9,63 Hz, 1H) of 6.61 (s, 1H) 7,01 (d, 2H) 7,05 (d, 2H) 7,10 (s, 1H) 7,25-7,37 (m, 5H), ESI m/z=620 (m+H), 618(M-H)

341H NMR (600 MHz) δ ppm of 1.40 and 1.80 (m, 4H) 2,08 (s, 3H) 2,35-to 2.42 (m, 1H) 2,66-2,82 (m, 5H) 3,14-is 3.21 (m, 1H) 3,29-to 3.35 (m, 4H) 3,35-of 3.43 (m, 2H) of 3.46 (t, J=8,94 Hz, 1H) 3,53 (t, 1H) 3,66-3,71 (m, 2H) 3,81-3,88 (m, 3H) of 4.49 (d, J=9,63 Hz, 1H) of 6.61 (s, 1H) 7,02 (d, 2H) 7,06 (d, 2H) 7,11 (s, 1H), ESI m/z=556 (m+H), 554(M-H)
351H NMR (600 MHz) δ ppm 1,72 (m, 1H) 1,73 and 1.80 (m, 1H) 1,80-of 1.88 (m, 1H) 1,90-of 1.97 (m, 1H) 2,07 (s, 3H) 2,65-of 2.81 (m, 4H) 3,24-of 3.27 (m, 2H) 3,31-of 3.42 (m, 3H) of 3.46 (t, J=8,71 Hz, 1H) 3,54 (t, J=9,17 Hz, 1H) 3,68 (DD, J=11,92, 5,04 Hz, 1H) 3,80-a 3.87 (m, 3H) of 4.49 (d, J=9,63 Hz, 1H) 6,60 (s, 1H) 7,02 (d, J=8,25 Hz, 3H) 7,05 for 7.12 (m, 6N), ESI m/z=599 (m+Na),575(M-H)
361H NMR (600 MHz) δ ppm of 0.91 (d, J=6.42 per Hz, 3H) 0,96-of 1.05 (m, 2H) 1,47-of 1.56 (m, 1H) 1,58 (d, J=15,13 Hz, 2H) to 2.06 (s, 3H) 2,65-by 2.73 (m, 4H) 3,27-of 3.31 (m, 2H) 3,35-of 3.43 (m, 2H) of 3.46 (t, J=8,71 Hz, 1H) ,54 (t, J=9,40 Hz, 1H) 3,68 (DD, J=11,92, 5.50 Hz, 1H) 3,81-3,86 (m, 3H) to 3.89 (d, J=12,84 Hz, 2H) 4,50 (d, J=9,63 Hz, 1H) 6,60 (s, 1H) 7,00 (d, 2H) 7,05 (d, 2H) 7,10 (s, 1H), ESI m/z=551 (m+Na), 527(M-H)

Example 11-1 (another way of obtaining compounds of example 11)

Obtain (1S)-1,5-anhydrous-1-[5-[4-[2-[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]aminocarbonyl]amino]ethyl]benzyl]-2-hydroxy-4-were]-D-glucit

(1) preparation of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-acetyl-1-[2-acetoxy-5-[4-[2-[[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino]carbonyl]amino]ethyl]benzyl]-4-were]-D-glucit

To a solution in chloroform (300 ml) 1,1'-carbonyldiimidazole (7,30 mg, 0.045 mmol) was added to the solution in chloroform (150 ml) of (1S)-1-[5-[4-(2-amino-ethyl)benzyl]-2-acetoxy-4-were]-1,5-anhydrous-2,3,4,6-Tetra-O-acetyl-D-glucit (18,4 mg 0,030 mmol) and N-methylmorpholine (4,95 μl, 0.045 mmol)and the mixture was stirred for 30 minutes at room temperature. Thereafter, this reaction solution was added Tris(hydroxymethyl)aminomethan (10,9 mg, 0.09 mmol) and N,N-dimethylformamide (150 ml)and the reaction mixture was stirred at 60°C over night. After cooling the reaction mixture to room temperature, there was added ethyl acetate. The mixture was washed with water, 1 M hydrochloric acid and saturated saline solution and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the solvent is evaporated at below the nom pressure. Thus obtained residue was purified column chromatography on silica gel (mixture of chloroform:methanol = 95:5)to obtain the compound indicated in the title (7.9 mg, 35%)as a colorless amorphous compound.

(2) Obtain (1S)-1,5-anhydrous-1-[5-[4-[2-[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]aminocarbonyl]amino]ethyl]benzyl]-2-hydroxy-4-were]-D-glucit

To a solution in methanol (600 ml) of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-acetyl-1-[2-acetoxy-5-[4-[2-[[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino]carbonyl]amino]ethyl]benzyl]-4-were]-D-glucit (7.9 mg, 0,0104 mmol) was added to 2.5 % wt. a solution in methanol of sodium methylate (34 μl, 0.015 mmol) and the mixture was stirred one hour at room temperature. The solvent is evaporated under reduced pressure. Thus obtained residue was purified column chromatography on silica gel (methanol)to obtain the compound indicated in the title (3.0 mg, 52%)as a colorless amorphous compound.

Connection 37-188 synthesized using the corresponding amines by the method of example 11-1.

Table 2
Connection
No.
FormulaExact MSMS(M+H) or (M+Na) MS(M-H)Ionization
37C23H30N2O7446,21484460ESI
38C28H40N2O9548,27571547ESI
39C27H38N2O7502,27525501ESI
40C32H39N3O8593,27616592ESI

41C37H42N2O8642,29665641ESI
42C28H34N2O8526,23527525ESI
43C28H40N2O8532,28555531ESI
44C29H43N3O7545,31546544ESI
45C27H38N2O9534,26557533ESI
46C29H42N2O8546,29569545ESI
47C2H40N2O8S 564,25587563ESI
48C32H40N2O8580,28603579ESI
49C33H42N2O9S642,26665641ESI

50C27H38N2O8518,26541517ESI
51C32H40N2O8580,28603579ESI
52C31H37FN2O7568,26591 567ESI
53C37H42N2O7626,3649625ESI
54C30H42N2O9574,29597573ESI
55C33H42N2O9610,29633609ESI
56C26H36N2O7488,25511487ESI
57C34H44N2O9624,3625623ESI
58 C27H39N3O7517,28518516ESI

59C31H46N2O7558,33581557ESI
60C32H39N3O8593,27616NDESI
61C32H36N2O7S592,22615591ESI
62C33H42N2O7578,3601577ESI
63C31H38N2O8566,26 589565ESI

64C27H36N2O9532,24555531ESI
65C28H38N2O8530,26553529ESI
66C32H40N2O9596,27619595ESI
67C30H43N3O7557,31558556ESI
68C30H36N2O7536,25559535 ESI

69C31H38N2O8566,26589565ESI
70C32H40N2O9596,27619595ESI
71C31H38N2O7550,27551549ESI
72C27H38N2O8518,26541517ESI

74
73C29H43N3O7545,31546544ESI
C29H42N2O8546,29569545ESI
75C37H42N2O8S674,27676673APCI
76C26H36N2O8504,25527503ESI
77C28H40N2O8532,28555531ESI

78C27H38N2O8S550,23573549ESI
79 C26H36N2O8504,25527503ESI
80C30H45N3O7559,33560558ESI
81C26H36N2O9520,24543519ESI
82C26H36N2O8504,25527503ESI
83C33H50N2O7586,36609585ESI

84C34H38N2O7S618,24641 617ESI
85C35H52N4O10688,37689687ESI
86C33H42N2O7578,3601577ESI
87C32H46N2O8586,33587585ESI
88C32H38N2O8578,26579577ESI

90
89C36H47N3O8649,34672648ESI
C30H37N3O7551,26574550ESI
91C32H40N2O7564,28565563ESI
92C29H36N2O8540,25563539ESI
93C29H35N3O7537,25560536ESI

94C27H38N2O7502,27503501ESI
95 C28H41N3O7531,29532530ESI
96C25H34N2O8490,23513489ESI
97C28H38N4O8558,27559557ESI
98C32H40N2O7564,28587563ESI

Moreover, the compound (III)in which RBrepresents an alkyl group, substituted amino group, can be synthesized using Ethylenediamine or N-methyl-1,3-propandiamine by way of example 11-1.

Example 19

Obtain (1S)-1,5-anhydrous-1-[5-[4-[2-[(4S)-4-(cyclohexylmethyl)-2,5-dioxoimidazolidin-1-yl]ethyl]benzyl]-2-hydroxy-4-were]-D-glucit

The connection is indicated in the name (5 mg, 29%)was obtained as an oily compound according to the method of example 11-1, in which instead of Tris(hydroxymethyl)aminomethane used methyl ether 3-cyclohexyl-L-alanine hydrochloride.

1H NMR (600 MHz, METHANOL-D4) δ ppm 0,81 of 1.00 (m, 2H) 1,31 (ush. s, 3H) to 1.38 to 1.47 (m, 1H) 1,48-of 1.55 (m, 1H) 1,56-of 1.78 (m, 4H) was 2.05 (s, 3H) and 2.83 (t, J=7,34 Hz, 2H) 3,28-to 3.33 (m, 2H) 3,35-of 3.43 (m, 2H) of 3.46 (t, J=8,71 Hz, 1H) 3,54 (t, J=9,17 Hz, 1H) 3,57-3,71 (m, 3H) 3,81-3,88 (m, 3H) 3,96 (DD, J=9,40, 4,36 Hz, 1H) 4,50 (d, J=to 10.09 Hz, 1H) 6,60 (s, 1H) 7,00 (d, 2H)? 7.04 baby mortality (d, 2H) was 7.08 (d, J=5,96 Hz, 1H).

ESI m/z=605(M+Na). 581(M-H).

Connection 190-202 synthesized using the corresponding amino acids by the method of example 19.

EXAMPLE DRUG

Table 4
The composition of the tablets containing 100 mg of the drug:
The content of one tablet:
Medication108,35 mg
Lactose-monohydrate38,65 mg
Crystalline cellulose22,00 mg
Calcium carboxymethylcellulose20,00 mg
Hydroxypropylcellulose10,00 mg
Magnesium stearate1.00 mg
200,00 mg

The WAY to OBTAIN

Drug (compound of the present invention) is mixed with lactose monohydrate, crystalline cellulose, calcium carboxymethyl cellulose, and hydroxypropylcellulose. This mixture is ground in a mill fine grinding. Powdered mixture of 1 minute stir in the granulator-mixer and then for 4-8 minutes is subjected to granulation using water. Thus obtained granulated products dried for 40 minutes at 70°C. the Dry granular powder is sifted through a sieve with a mesh size of 500 μm Sifted dry granular powder and magnesium stearate and mix for 3 minutes in the mixer, V-type, when the rotation speed of 30 rpm For the formation of tablets thus obtained granules are subjected to compression molding in a rotary teletrauma machine for the production of tablets.

Table 5
Mass of tablets:200 mg
Tablet size:8 mm, round

The TEST EXAMPLE 1

(1) Cloning of human SGLT1 and SGLT2 and their introduction into the expression vector

SGLT1 sequence (NM_000343) was obtained by reverse transcription from mRNA of the small intestine of man; then amplified and then introduced into pCMV-tag5A, (Stratagene Corporation). SGLT2 sequence (NM_003041) received a manner described above with renal mRNA person and then introduced into pcDNA3.1+hygro (Invitrogen Corporation). It was confirmed that each cloned sequence is identical to the reported sequence.

(2) the RECEIPT of CHO-K1 CELLS STABLY EXPRESSING HUMAN SGLT1 AND SGLT2 PERSON

Vectors for the expression of human SGLT1 and SGLT2 people were transliterowany in CHO-k1 cells using lipofectamine 2000 (Invitrogen Corporation). Cells expressing SGLT, incubated in the presence of geneticin (SGLT1) or hygromycin B (SGLT2) at a concentration of 500 mg/ml, for sample sustainable stammo is; the indicator was the specific activity of sugar absorption following system.

(3) TEST FOR INHIBITION of RETRIEVEIMAGE ABSORPTION of SUGAR INTO the CELLS

To test for inhibition of retrieveimage absorption of glucose used cells, stably expressing human SGLT1 and SGLT2 person.

Cells 20 minutes, incubated in buffer pre-treatment A (200 ál for SGLT1 and 2 ml for SGLT2). Buffer pre-treatment was removed and added to the buffer absorption B (75 μl for SGLT1, and 200 μl for SGLT2)containing the test compound, so that at 37°C for 30 minutes to conduct the reaction of absorption (SGLT1) or one hour (SGLT2). After the reaction, the cells were twice washed in washing buffer C (200 ál for SGLT1 and 2 ml for SGLT2) and then was dissolved in 0.2 M NaOH solution (75 μl for SGLT1, and 400 µl for SGLT2). After adding back the liquid scintillator and thorough mixing was measured radioactivity apparatus microBETA (SGLT1) or counter liquid scintillation Beckman Coulter, Inc. (SGLT2). The control group received buffer absorption, does not contain the test compound. In addition, as the primary buffer to absorb the received buffer absorption of B, instead of containing choline chloride NaCl.

* Buffer pre-treatment A represents: 140 mm holdingarea, 2 mm KCl, 1 mm CaCl2, 1 mm MgCl2the mixture of 10 mm HEPES/5 mm Tris, pH ,4.

* Buffer absorption of B is: 1 mm methyl-α-D-glucopyranoside, containing [14C]methyl-α-D-glucopyranosid, 140 mm NaCl, 2 mm KCl, 1 mm CaCl2, 1 mm MgCl2,a mixture of 10 mm HEPES/5 mm Tris, pH 7,4.

* Wash buffer C is a: 10 mm methyl-α-D-glucopyranoside, 140 mm holdingarea, 2 mm KCl, 1 mm CaCl2, 1 mm MgCl2,10 mm mixture of HEPES/5 mm Tris, pH 7,4.

To get the value of the IC50used tested compounds having 6 adequate concentrations, and calculated concentrations of the test compounds (value IC50), in which the absorption of sugar inhibited by 50% compared with the absorption of sugar the control group (100%). The results are shown in table 6.

29
[Table 6]
Connection # SGLT1 (nm)SGLT2 (nm)
11117
23218
33565
45131
865
917529
105123
115934
1211348
144921
177925
19302101
20382164
217534
223712
231919
243725
256420
265215
275415
286418
297517
3011113
3114839
3224544
331211
344910
358334
369434

In addition, the percent inhibition of sugar absorption, when the concentration of the test compounds at 100 nm, when compared with the control group, shown in table 7.

70
Table 7
Connection # SGLT1
% inhibition at 100 nm
SGLT2
% inhibition at 10 nm
388983
398083
407989
417886
427887
437786
457580
467491
477389
487387
497381
507177
517184
527184
5374
547973
556969
566877
576851
596786
606691
616595
626579
636381
646276
656276
666283
676182
686083
696083
705983
715986
1237887
1247179
1256890
1329090
1377179
1386584
1436680

The TEST EXAMPLE 2

VALIDATION STUDIES TO confirm the INHIBITORY EFFECT ON the INCREASE of GLUCOSE LEVEL IN BLOOD at STREPTOZOTOCIN MODEL of DIABETES IN RATS

(1) OBTAINING DIABETIC RAT MODELS

A seven-SD/IGS male rats (CHARLES RIVER LABORATORIES JAPAN, INC.) fasted for about 16 hours. Then these rats under ether anesthesia was administered 50 mg/kg is streptozotocin (STZ) through the tail vein, to get a diabetic model rats. Similarly, under ether anesthesia, rats were injected via tail vein with 1 ml/kg saline containing 1.25 mmol/l of citric acid, to obtain the normal control rats. One week after the injection of STZ or saline containing 1.25 mmol/l of citric acid, (8-week-old) rats were tested for tolerance to oral glucose.

(2) TEST TOLERANCE GALLOWEEN GLUCOSE

After the rats were fasted for approximately 16 hours, the drug (1 mg/kg)suspended in 0.5% aqueous solution of carboxymethyl cellulose (CMC), was orally administered to rats in the group that was subjected to treatment with the medicinal product; and the rats of the control group was administered orally only 0.5% aqueous CMC solution. 5 minutes after injection, each rat was administered orally glucose solution (2 g/kg) and took the test a total of 5 points: before the introduction of the (time "0"), at 0.25, 0.5, 1 and 2 hours after oral administration.

Each rat under ether anesthesia took the blood from the orbital venous sinus in a test tube for blood collection, coated with heparin, and centrifuged; and then separating the blood plasma. Using test Glucose CII Test Wako (Wako Pure Chemical Industries, Ltd.) was determined by the glucose concentration in the blood plasma. As for the intensity ingibiruyah the impact on improving the level of glucose in the blood, the area under the curve that describes the level of glucose in blood (AUC)was calculated by the trapezoid method, based on the levels of glucose in the blood in the group of rats subjected to treatment drug, in the time interval from time 0 to time 1 hour. And from the values of the curve AUC subtract the reference value, to describe the intensity as the area under the curve increment of glucose in the blood (ΔAUC) and to describe the intensity as a percentage reduction from ΔAUC control group. The results are shown in table 8.

Table 8
Connection # STZ rats - OGTT (2 g/kg)
% inhibition ΔAUC0-1 h (MGC/DL) at 1 mg/kg
141,7
251,6
363,9
451,0
845,1
1169,3
950,1
1067,8
12 48,8

On the basis of the present invention intend to provide a preventive or therapeutic agent for the treatment of diabetes, comprising as active ingredient the compound C-phenylglycinol, which has not only a depressing effect on the absorption of glucose from the digestive tract, but it also affects the secretion of glucose in urine by inhibiting metrizability superelastic glucose 1 (SGLT1), expressed in the epithelium of the small intestine, and metrizability superelastic glucose 2 (SGLT2), expressed in the kidney.

1. Connection-phenylglycinol represented by the formula (I)below, or its pharmaceutically acceptable salt or hydrate

where R1and R2are the same or different and represent a hydrogen atom, a hydroxyl group, a C1-6alkyl group, a C1-6alkoxygroup or halogen atom,
R3is a hydrogen atom, a C1-6alkyl group,
Y is C1-6alkalinous group, -O-(CH2)n- (n is an integer taking values from 1 to 4, provided that when Z is-NHC(=NH)NH2or -- NHCON(RBRCn not equal to 1,
Z is-CONHRA, -NHC(=NH)NH2or -- NHCON(RBRC,
or
the de R Ais
C1-6alkyl group substituted by 1-3 substituents selected from the group consisting of hydroxyl group, amino group and carbamoyl group,
RBis
(1) a hydrogen atom,
(2)1-6alkyl group which may be substituted by 1-3 substituents selected from group a,
(3) (C3-12cycloalkyl group which may be substituted by 1-3 substituents chosen from hydroxyl groups and C1-6hydroxyalkyl group,
(4) (3-12)-membered geteroseksualnoe group or (5-13)-membered heteroaryl group which may be partially saturated; each of which contains from one to three ciclopaseos atoms selected from the group consisting of N, S, and NR10(R10is phenyl-C1-6alkyl group), or
(5)6-13aryl group, which may be partially saturated and may be substituted by 1 or 2 substituents selected from a hydroxyl group and C1-6alkyl groups, phenyl-C1-6alkyl groups and C1-6alkylsulfonyl groups, each of which may be substituted by hydroxyl(s) group(s),
where group a consists of
of halogen atom, hydroxyl group, C1-6alkoxygroup, which may be substituted by hydroxyl(s) group(s), a carboxyl group, a C2-6alkoxycarbonyl the Oh group, carbamoyl group, amino group, C1-6alkylaminocarbonyl, dis1-6alkylaminocarbonyl,2-6allmineral, C1-6alkylthiol, which may be substituted by hydroxyl(s) group(s);
fenoxaprop,
phenyl group which may be substituted by 1-3 substituents selected from group b (group b consists of hydroxy group, halogen atom, a C1-6alkoxygroup, C1-6alkyl group which may be substituted by hydroxyl(s) group(s), C1-6alkylthiol, thienyl group, phenylthiourea, which may be substituted by hydroxyl(s) group(s) or (C1-6hydroxyalkyl(s) group(s) and piperidinium, which may be substituted by hydroxyl(s) group(s) or (C1-6hydroxyalkyl(s) group(s);
With3-12cycloalkyl group which may be substituted by 1-3 substituents selected from the group consisting of a hydroxyl group; (3-12)-membered geteroseksualnoe group or (5-13)-membered heteroaryl group, which may be partially saturated; each of which contains from one to three ciclopaseos atoms selected from the group consisting of O, N and S,
RCis
an atom of hydrogen, C1-6alkyl group which may be substituted by 1 or 2 substituents selected from the group of the s, consisting of a hydroxyl group or3-12cycloalkyl group which may be substituted by hydroxyl(s) group(s); and
RBand RCtogether with the nitrogen atom to which they are attached, may form a 3-12 membered geterotsyklicescoe group or a 5-13 membered heteroaryl group, which may be partially saturated; each of which may contain 1 or 2 ciclopaseos atom selected from N, NR11, S and CO, and which may be substituted by 1 or 2 substituents selected from the group consisting of a hydroxyl group, a C2-6alkoxycarbonyl group, carbamoyl group2-6acyl(C1-6alkyl)amino group, ISD1-6alkylaminocarbonyl group, pyrrolidinyl group, morpholinopropan, pyrrolidin-1-yl-carbonyl group, a C1-6alkyl group which may be substituted by 1-3 substituents selected from the group consisting of hydroxyl group, pyrrolidin-1-ilen group, phenyl group and2-6alkoxycarbonyl group, and phenyl group which may be substituted by 1-3 substituents selected from the group consisting of C1-6alkyl group, a C1-6alkoxygroup and halogen atom,
where R11is a hydrogen atom, phenyl group which may be substituted by hydroxyl(s) group(s), peredelnoj group fuelleborni group, C2-6alkoxycarbonyl group or a C1-6alkyl group which may be substituted by 1 or 2 substituents selected from the group consisting of phenyl group, ISD1-6alkylamino, morpholinopropan and pyrrolidin-1-yl-carbonyl group, and
RDis a hydrogen or C1-6alkyl group which may be substituted by 1 or 2 substituents from the group consisting of hydroxyl group, With3-12cycloalkyl group, phenyl group which may be substituted by hydroxyl(s) group(s), peredelnoj group2-6alkoxycarbonyl group, imidazoline group and 1-benzylimidazole group, and RDAis a hydrogen or C1-6alkyl group.

2. Connection-phenylglycinol according to claim 1, which is a connection-phenylglycine represented by the formula (II)below, or its pharmaceutically acceptable salt or its hydrate,

where R1, R2, R3, Y and Z are the same as defined in claim 1.

3. Connection-phenylglycinol, or its pharmaceutically acceptable salt, or hydrate according to claim 2, in which R1is a hydrogen atom, a hydroxyl group, With1-4alkyl group or a C1-4alkoxygroup, and R2is1-4alkyl group or as the Ohm halogen.

4. Connection-phenylglycinol according to claim 2 or 3, or its pharmaceutically acceptable salt, or hydrate, where R3is a hydrogen atom.

5. Connection-phenylglycinol, or its pharmaceutically acceptable salt, or hydrate according to claim 3, in which Y is C1-6alkalinous group or-O-(CH2)n- (n is an integer from 2 to 4), and Z is-NHCON(RBRCwhere RBand RCdefined in claim 1.

6. Connection-phenylglycinol, or its pharmaceutically acceptable salt, or hydrate according to claim 3, in which
Y is C1-6alkalinous group or-O-(CH2)n- (n is an integer having a value of from 2 to 4), and Z is-NHCON(RBRC,
where RBis
(1) C1-6alkyl group which may be substituted by 1-3 substituents selected from group a,
(2)3-12cycloalkyl group which may be substituted by 1-3 substituents chosen from hydroxyl groups and C1-6hydroxyalkyl group,
(3) (3-12)-membered geteroseksualnoe group or (5-13)-membered heteroaryl group which may be partially saturated; each of which contains from one to three ciclopaseos atoms selected from the group consisting of N, S and NR10(R10is phenyl-C1-6alkyl group), or
(4)6-13aryl g is uppoi, which may be partially saturated and may be substituted by 1 or 2 substituents selected from a hydroxyl group and1-6alkyl groups, phenyl-C1-6alkyl groups and C1-6alkylsulfonyl groups, each of which may be substituted by hydroxyl(s) group(s)
in which
group a consists of
of halogen atom, hydroxyl group, C1-6alkoxygroup, which may be substituted by hydroxyl(s) group(s), With a2-6alkoxycarbonyl group, carbamoyl group, ISD1-6alkylaminocarbonyl, C1-6alkylthiol, which may be substituted by hydroxyl(s) group(s),
fenoxaprop, thienyl group, benzothiazole group, shriley group,
phenyl group which may be substituted by 1-3 substituents selected from the group consisting of hydroxyl group, halogen atom, With1-6alkoxygroup, C1-6alkyl group which may be substituted by hydroxyl(s) group(s), C1-6alkylthiol, phenylthiourea, which may be substituted by hydroxyl(s) group(s), or C1-6hydroxyalkyl(s) group(s) and piperidinium, which may be substituted by hydroxyl(s) group(s), or C1-6hydroxyalkyl(s)group(s),
With3-12cycloalkyl group, which can be C Medina 1-3 substituents, selected from the group consisting of a hydroxyl group; (3-12)-membered geteroseksualnoe group that contains from one to three ciclopaseos atoms selected from the group consisting of O, N and S;
RCis a hydrogen atom, and
RBand RCtogether with the nitrogen atom to which they are attached can form piperidino group which may be substituted pyrrolidinyl group or1-6alkyl group which is substituted dis1-6alkylaminocarbonyl or pyrrolidin-1-ilen group, or thiomorpholine group, or decahydroquinoline group.

7. Connection-phenylglycinol, or its pharmaceutically acceptable salt, or hydrate according to claim 2 or 3,
in which
Y is C1-6alkalinous group,
Z is-CONHRA,
where RAis C1-6alkyl group substituted by 1-3 substituents selected from the group consisting of hydroxyl group and carbamoyl group.

8. Connection-phenylglycinol or its pharmaceutically acceptable salt or hydrate according to claim 2 or 3, where
Y is C1-6alkalinous group and
Z is-NHC(=NH)NH2.

9. Connection-phenylglycinol or its pharmaceutically acceptable salt or hydrate according to claim 2 or 3, in which
Y is C1-6alkalinous group, and Z is

RDis C1-6alkyl group which is substituted With3-12cycloalkyl group or phenyl group; and RDAis a hydrogen or C1-6alkyl group.

10. Connection-phenylglycinol according to claim 1, which is a connection-phenylalaninol represented by the formula (III)below, or its pharmaceutically acceptable salt or hydrate

where Y is C1-6alkalinous group, and
Z is-CONHRA,
where RArepresents a C1-6alkyl group substituted by 1-3 substituents selected from the group consisting of hydroxyl group and carbamoyl group.

11. Connection-phenylglycinol according to claim 1, which is a connection-phenylglycine represented by the formula (IV)below, or its pharmaceutically acceptable salt or its hydrate,

where Y is C1-6alkalinous group, and
Z is-CONHRA1, -NHC(=NH)NH2or-NHCORB1,
where RA1is C1-6alkyl group substituted by 1-3 substituents selected from the group consisting of hydroxyl group, amino group, carbamoyl group, and
RB1is
C1-6alkylaminocarbonyl, which may be substituted by 1-3 hydroxy groups or 4-C1-6alcippe the Zin-1-ylcarbonyl group, or 4-C1-6alkylpiperazine-1-ilen group.

12. Connection-phenylglycinol according to claim 11 or its pharmaceutically acceptable salt or its hydrate, which,
Y is C1-6alkalinous group,
Z is-CONHRA1or-NHC(=NH)NH2or

where RA1represents a C1-6alkyl group substituted by 1-3 substituents selected from the group consisting of hydroxyl group, amino group and carbamoyl group.

13. Connection-phenylglycinol according to claim 11 or its pharmaceutically acceptable salt or its hydrate, which
Y is C1-6alkalinous group, and
Z is-CONHRA1
where RA1is C1-6alkyl group substituted by 1-3 substituents selected from the group consisting of hydroxyl group, amino group and carbamoyl group.

14. Connection-phenylglycinol according to claim 11 or its pharmaceutically acceptable salt or its hydrate, which
Y is C1-6alkalinous group, and
Z is-NHC(=NH)NH2.

15. Connection-phenylglycinol according to claim 11 or its pharmaceutically acceptable salt or its hydrate, which
Y is C1-6alkalinous group, and
Z is-NHCORB1(where RB1is C1-6alkylaminocarbonyl, substituted by 1-3 hydroxyl groups, or 4-C1-6alkylpiperazine-1-ylcarbonyl the Noah group, or 4-C1-6alkylpiperazine-1-ilen group).

16. Connection-phenylglycinol according to claim 11 or its pharmaceutically acceptable salt or its hydrate, which
Y is C1-6alkalinous group, and
Z are formula
.

17. Pharmaceutical composition having inhibitory activity against sodium-dependent superelastic 1 glucose (SGLT1) and the sodium-dependent superelastic 2 glucose (SGLT2), which contains the connection-phenylglycinol according to claim 1 or its pharmaceutically acceptable salt or its hydrate as an active ingredient.

18. The pharmaceutical composition according to 17, which is an inhibitor of the activity of sodium-dependent of superelastic 1 glucose (SGLT1) and the activity of sodium-dependent of superelastic 2 glucose (SGLT2).

19. The pharmaceutical composition according to 17, which is a prophylactic or therapeutic agent against diabetes.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 ex

7FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a combination of a co-drug (an auxiliary) and a compound o formula (IV) in which radicals and symbols have the values defined in cl. 1 of the patent claim, or salts, or tautomers, or N-oxides, or solvates of this compound; where the specified auxiliary is specified from a monoclonal antibody, an alkylating agent, a malignant growth agent, other cycline-dependent kinase (CDK) inhibitor and a hormone, a hormone agonist, a hormone antagonist or a hormone-modulating agent specified in cl. 1 of the patent claim. The offered combination is used for tumour cell growth inhibition.

EFFECT: invention also refers to a pharmaceutical composition based on the offered combination, application of the combination and its separate ingredients and methods of treating, preventing and relieving the cancer symptoms in a patient.

77 cl, 2 dwg, 8 tbl, 257 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of azabicyclo{3,1,0}hexane of general formula (I) or pharmaceutically acceptable salts thereof (values of radicals are given in the claim), synthesis method thereof, intermediate compounds, a pharmaceutical composition and use of the novel compounds in therapy as dopamine receptor D3 modulators, for example, for treating drug dependence or as antipsychotic agents.

EFFECT: improved properties of the derivatives.

34 cl, 122 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and salts thereof (I), where T is a tetrazolyl group which is not substituted or substituted with [C1-C8]alkyl; L1 denotes (CR1R2)n-, where n equals 1, 2, 3 or 4; R1 and R2 denote hydrogen; L2 denotes a direct bond; A is selected from a group comprising A2, A8 and A20 , where Z1, Z2, Z3 and Z4 are independently selected from a group comprising hydrogen, -NR5R6, -N(R5)C(=O)R6, -N(R5)C(=O)OR6, -N(R5)C(=O)NR6R7, -N(R5)C(=S)NR6R7; Q is selected from a group comprising , where X1, X2 and X3 are independently selected from a group comprising hydrogen, halogen, [C1-C8]alkyl, phenyl or phenyl which is substituted by 1-5 halogen atoms; R5-R7 are independently selected from a group comprising hydrogen, [C1-C8]alkyl, [C1-C8]halogenalkyl, [C2-C8]alkenyl, [C3-C6]cycloalkyl, phenyl and phenyl [C1-C8]alkyl.

EFFECT: invention also relates to a fungicide composition containing an active ingredient in form of an effective amount of the disclosed compound, use of the disclosed compound or fungicide composition thereof for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops and a method for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops.

14 cl, 3 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel pyrimidine derivatives or their pharmaceutically acceptable salts, possessing inhibiting activity with respect to glycogensintase kinase-3 (GSK3). In compound of formula I: R1 is selected from hydrogen, cyano, C1-3alogenoalkinyl, SO2NRbRc, C0-2alkyl(O)NRbRc, C1-4alkylNBbRc, SO2Ri, C(O)ORa, CH(OH)Rj and C(O)Rj; R2 and R4 are independently selected from hydrogen, halogeno, cyano, NO2, C1-4alkyl, C1-3ahalogenoalkyl, ORa, C(O)NRbRc, SO2Ri, and C(O)ORa; or R1 and R2 together with atoms, to which they are bound, are bound with formation of 5- or 6-member heterocyclic ring, which contains one S, any of the hydrogen atoms of group CH2 in said heterocyclic ring can be substituted by oxo, hydroxy, and sulphur atom in said heterocyclic ring is probably oxydised to -SO2-; R3 and R5 represent hydrogen; R6 represents tetrahydropyran; R7 is selected from hydrogen, C1-3alkyl, cyano and C1-3halogenoalkyl; R8 represents hydrogen; Ra is selected from C1-3alkyl and C1-3halogenoakryl. Other radicals are given in formula of invention.

EFFECT: compounds can be applied in manufacturing medication for prevention and/or treatment of predemential states, moderate cognitive failure and type II diabetes, Alzheimer's disease and Parkinson disease, as well as bone-associated malfunctions.

40 cl, 3 dwg, 1 tbl, 122 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (11) given below and pharmaceutically acceptable salts thereof: chemical formula 1

in which: each of G1, G2, G3 and G8 independently denotes -N=, -CR1= or -C(-G9-X)=; one of G1, G2, G3 and G8 is-C(-G9-X)=; X is C1-6 alkyl (where C1-6 can be optionally substituted with a group selected from a halogen atom, hydroxy, cyano and -NR56R57), aryl, heterocycle (where the heterocycle denotes a 5-9-member saturated or unsaturated cyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulphur atoms, and can be a monocycle or condensed ring, and can be optionally substituted with a halogen atom, C1-6 alkyl; C1-6 alkoxy, R33R34NCS-, R3R4NCO-); G9 denotes a single bond, an oxygen atom, a sulphur atom, ring G6 denotes a divalent aryl group or divalent pyridyl group (where the divalent pyridyl group can be optionally substituted with a halogen atom); A is a group of formula (2) given below, or a group of formula (3) given below. Chemical formula 2

, chemical formula 3 , G4 is an oxygen atom or sulphur atom; G5 is an oxygen atom or sulphur atom; G7 is an oxygen atom, -CR42R43-, -CONR44-, -NR44CO, -NR45-, CR42R43NR45-, -S-, -NR44S(=O)2-; R1 is a hydrogen atom, a halogen atom, cyano, C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a halogen atom), carbamoyl or C2-7 alkynyl (where C2-7 alkynyl can be optionally substituted with C1-4 acyl); when G2 or G3 denotes -CR1=, then G8 is -C(-G9-X)=, and X is R3R4NCO-, R33R34NCS-; when G8 is -CR1=, then G3 denotes -C(-G9-X)=, and X is R3R4NCO, or R33R34NCS-; when G1 or G8 denotes -CR4 then G2 is -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; or when G2 is -CR1=, then G1 denotes -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; R1 can form a single bond or -CH2- with R4 or R34; R2 denotes hydroxy or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from a halogen atom, hydroxy, C1-6 alkoxy, formyl and -CO2R50); R3, R4, R9 and R10 each independently denotes a hydrogen atom, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, a halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R6 and R7 each independently denotes a hydrogen atom, C1-6 alkoxy, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R33 and R34 each independently denotes a hydrogen atom, C1-6 alkyl, the combination of R3 and R4 together with a nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom or C1-6 alkyl; the combination of R6 and R7 together with the nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom, C1-6 alkyl or an oxo group; R45 is a hydrogen atom, R13 and R14 each independently denotes a hydrogen atom, C1-6 alkyl or COR32; R56 and R57 each independently denotes a hydrogen atom or C1-6 alkyl, and R5, R8, R28, R29, R32, R42, R43, R44, and R50 each independently denotes a hydrogen atom or C1-6 alkyl. The invention also relates to a pharmaceutical composition, as well as to a medicinal agent for treating cell proliferative disorder.

EFFECT: obtaining novel biologically active compounds having inhibitory effect on cell proliferation.

15 cl, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 5-nitrofuran derivatives of formula I: where R=piperidino, pyrrolidineo, diethylamino, morpholino.

EFFECT: presented preparation of new biologically active compounds which exhibit antimicrobial activity.

1 cl, 4 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of general formula ii-d and to their pharmaceutically acceptable salts. In formula ii-d: , R2 represents C1-3-alkyl or cyclopropyl; R5 represents CH2CH3, CH2CF3, CH2CH2CF3, or Ry represents or Jl represents hydrogen atom or CH3J2 represents C1-4-alkyl; and Cy represents C3-5-cycloalkyl.

EFFECT: production of new compounds of general formula ii-d and their pharmaceutically acceptable salts which exhibit properties of an Aurora-protein kinase activity inhibitor and can be used in treating proliferative disorders.

12 cl, 8 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 3-(1,3-oxazol-4-yl)pyridin-2(1H)-one derivatives of general formula 1, , where 1a R=Br, R'=CH2OCH3, R"=CH3; 1b R=H, R'=CH2, R"=CH3; 1c R=H, R1=CH2OCH3, R"=Ph; 1d R=H, R'=CH3, R"=Ph; 1e R=Br, R=CH3, R" - fur-2-yl, which can be used as potential biologically active substances and intermediate products for synthesis of novel heterocyclic systems. The method of producing 3 -(2-substituted-1,3 -oxazol-4-yl)pyridin-2( 1 H)-ones of general formula I involves formation of a heterocyclic system of 3-(1,3-oxazol-4-yl)pyridin-2(1H)-one as a result of base-catalysed regrouping of 3-acylamino-2-furfurylfuro[2,3-b]pyridines while boiling said compounds in ethanol for 4-20 hours with addition of 6-7 mmol of potassium hydroxide per 1 mol of the initial 3-acylamino-2-furfurylfuro[2,3-b]pyridine.

EFFECT: high yield.

1 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I) and pharmaceutically acceptable salt thereof, where m denotes a direct bond; n equals 0, 1, 2, 3 or 4 and n equals zero indicates a direct bond; p equals 1; s denotes a direct bond; t denotes a direct bond; R1 and R2 each independently denotes hydrogen; A denotes a radical selected from , where R4 and R5 are each independently selected from hydrogen or C1-6alkyloxy; Z denotes a radical (b-2), where R6 and R7 each independently denotes hydrogen. The invention also describes a pharmaceutical composition for treating cancer and preparation method thereof, based on compounds of formula I, use of these compounds to obtain a medicinal agent, as well as a method of producing said compounds.

EFFECT: novel compounds which can be used as p53-MDM2 interaction inhibitors are obtained and described.

10 cl, ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: pharmaceutical compositions containing at least one compound of formula (IIIa) or (IIIb) or (IVa) or (IVb), where -X- and Y are described in the claims, or pharmaceutically acceptable salts, esters or amides thereof and a pharmaceutically acceptable carrier, which can be used in processes with modulation or E- and P-selectin expression.

EFFECT: obtaining low-molecular non-glycoside and non-peptide compounds, capable of creating antagonism to selectin-mediated processes.

11 cl, 38 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , isomer thereof of formula IA , mixture of isomers thereof IA/C , synthesis method thereof, as well as methods of producing compounds of formula IVA from compounds of formula IA, involving reduction and removal of protection from compounds of formula IA via hydrogenolysis using H2 and a catalytic amount of Pd/C, in the presence of trifluoroacetic acid to obtain a compound of formula VA; further reaction of this compound with Cbz-t-leu-OH, EDC and HOBt to obtain a compound of formula VIA; reaction of compound VIA with H2 and a catalytic amount of Pd/C in the presence of citric acid to obtain an amine and reaction of said amine and 4-amino-3-chlorobenzoic acid in the presence of CDMT and NMM to obtain a compound of formula IVA.

EFFECT: fewer synthesis steps and high output while using dynamic crystallisation.

13 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel carbamoyl benzotriazole derivatives of general formula , (values of radicals are given in the description), tautomers thereof and pharmaceutically acceptable salts and use thereof as endothelial lipase inhibitors.

EFFECT: improved properties of the derivatives.

11 cl, 148 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), which have protein kinase inhibiting properties and can be used in treating diseases which are dependent on any one or more protein kinases from FGFR1, FGFR2, FRF3 and/or FGFR4, KDR, HER1, HER2, Bcr-Abl, Tie2 and/or Ret Such diseases can be proliferative diseases, for example bladder cancer, breast cancer and multiple myeloma. In formula

the left-side ring , right-side ring , there are the following fragments, denoted "left-side ring" and "right-side ring", respectively: where X denotes C-R5, and Y and Z both denote N. The left-side ring corresponds to fragment (A):

n equals 0, 1, 2, 3, 4 or 5, X1 denotes hydrogen, where R1 denotes a group of formula Rz-NRa-, where Ra denotes hydrogen and Rz is selected from (1) a straight or branched C1-C4alkyl or (2) a group of formula , where ring A denotes phenyl, cyclohexenyl, cyclohexyl or pyridyl, m equals 0, 1 or 2, one or each of Rb is independently selected from a group -L2-NRcRd; -L2-RING, where RING denotes a 5- or 6-member saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen and oxygen, optionally substituted, as indicated below, halogen; hydroxy; amino; cyano, and a straight or branched C1-C4alkyl optionally substituted with one or more halogens and/or one or two hydroxy groups, wherein the hydroxy and amino groups are in turn optionally substituted on at least one heteroatom with one or, if necessary, more C1-C7aliphatic groups, where L2 denotes a direct bond, a link selected from a group comprising -O-, -S-, -C(O)-, -OC(O)-, -NRaC(O)-, -C(O)-NRa -OC(O)-NRa, -NRa-; or denotes a straight C1-C4alkyl which is optionally interrupted and/or ends in one terminal fragment or in two terminal fragments with the said link, and where Rc and Rd are each independently selected from a group comprising hydrogen and straight or branched C1-C4alkyl, or Rc and Rd together with a neighbouring nitrogen atom form a 5- or 6-member heterocyclic ring which optionally contains an additional heteroatom selected from nitrogen and oxygen, and optionally substituted as indicated below, said optionally substituted rings are independently substituted with 0, 1, 2, 3, 4 or 5 C1-C7aliphatic substitutes which are optionally substituted with one or more halogen atoms; R2 denotes hydrogen or C1-C4alkyl; R3 denotes hydrogen or straight or branched C1-C4alkyl or straight C1-C4alkyl substituted with a 5- or 6-member saturated or unsaturated heterocyclic ring containing 1 or 2 heteroatoms in the ring, selected from nitrogen, oxygen and sulphur; R4 is selected from hydroxy, protected hydroxy group, alkoxy, alkyl, trifluoromethyl and halogen, where the alkyl or alkyl part of the alkoxy is straight or branched and contains 1, 2, 3 or 4 carbon atoms; or R5 denotes hydrogen or C1-C4alkyl; or pharmaceutically acceptable salts, hydrates, solvates, ethers, N-oxides thereof, optionally in form of trans-isomers thereof.

EFFECT: improved properties of the compound.

38 cl, 1 tbl, 231 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (11) given below and pharmaceutically acceptable salts thereof: chemical formula 1

in which: each of G1, G2, G3 and G8 independently denotes -N=, -CR1= or -C(-G9-X)=; one of G1, G2, G3 and G8 is-C(-G9-X)=; X is C1-6 alkyl (where C1-6 can be optionally substituted with a group selected from a halogen atom, hydroxy, cyano and -NR56R57), aryl, heterocycle (where the heterocycle denotes a 5-9-member saturated or unsaturated cyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulphur atoms, and can be a monocycle or condensed ring, and can be optionally substituted with a halogen atom, C1-6 alkyl; C1-6 alkoxy, R33R34NCS-, R3R4NCO-); G9 denotes a single bond, an oxygen atom, a sulphur atom, ring G6 denotes a divalent aryl group or divalent pyridyl group (where the divalent pyridyl group can be optionally substituted with a halogen atom); A is a group of formula (2) given below, or a group of formula (3) given below. Chemical formula 2

, chemical formula 3 , G4 is an oxygen atom or sulphur atom; G5 is an oxygen atom or sulphur atom; G7 is an oxygen atom, -CR42R43-, -CONR44-, -NR44CO, -NR45-, CR42R43NR45-, -S-, -NR44S(=O)2-; R1 is a hydrogen atom, a halogen atom, cyano, C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a halogen atom), carbamoyl or C2-7 alkynyl (where C2-7 alkynyl can be optionally substituted with C1-4 acyl); when G2 or G3 denotes -CR1=, then G8 is -C(-G9-X)=, and X is R3R4NCO-, R33R34NCS-; when G8 is -CR1=, then G3 denotes -C(-G9-X)=, and X is R3R4NCO, or R33R34NCS-; when G1 or G8 denotes -CR4 then G2 is -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; or when G2 is -CR1=, then G1 denotes -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; R1 can form a single bond or -CH2- with R4 or R34; R2 denotes hydroxy or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from a halogen atom, hydroxy, C1-6 alkoxy, formyl and -CO2R50); R3, R4, R9 and R10 each independently denotes a hydrogen atom, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, a halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R6 and R7 each independently denotes a hydrogen atom, C1-6 alkoxy, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R33 and R34 each independently denotes a hydrogen atom, C1-6 alkyl, the combination of R3 and R4 together with a nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom or C1-6 alkyl; the combination of R6 and R7 together with the nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom, C1-6 alkyl or an oxo group; R45 is a hydrogen atom, R13 and R14 each independently denotes a hydrogen atom, C1-6 alkyl or COR32; R56 and R57 each independently denotes a hydrogen atom or C1-6 alkyl, and R5, R8, R28, R29, R32, R42, R43, R44, and R50 each independently denotes a hydrogen atom or C1-6 alkyl. The invention also relates to a pharmaceutical composition, as well as to a medicinal agent for treating cell proliferative disorder.

EFFECT: obtaining novel biologically active compounds having inhibitory effect on cell proliferation.

15 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound selected from N-((1S)-1-{4-[2-fluoro-1-(fluoromethyl)ethoxy]phenyl}ethyl)-2-(7-nitro-1H-benzimidazol-1-yl)acetamide, 2-(7-nitro-1H-benzimidazol-1-yl)-N-{1-[6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl]ethyl}acetamide, N-[1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamde and N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide. The invention also relates to use of said compounds in preparing a medicinal agent.

EFFECT: novel compounds which are useful in treating VR1 mediated disorders or acute and chronic algesic disorders are obtained.

6 cl, 5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of general formula I and pharmaceutically acceptable salts thereof, where R1 is selected from a group comprising aryl and alkyl, optionally substituted hydroxy; R2 is selected from a group comprising hydrogen and alkyl; R3 is selected from a group comprising hydrogen and -X-A, where X is selected from a group comprising -C(O)- and -S(O)2-; and A is selected from a group comprising hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle and optionally substituted cycloalkyl, where the optionally substituted groups are substituted with 1-2 substitutes selected from a group comprising alkyl, substituted alkyl, alkoxy, substituted amine which is a -NRR group, substituted aryloxy, heteroaryl, heterocycle, halogen, hydroxy and -S(O)2-R9, where R9 is an alkyl; or R1 and R3 together with a carbon atom bonded to R1 and a nitrogen atom bonded to R3 form a heterocyclic or substituted heterocyclic group; R4 is selected from a group comprising hydrogen, linear alkyl, -alkylene-aminoacyl-, -alkylene-hydroxy-, -[alkylene]p-nitrogen-containing heterocycle, -[alkylene]p-nitrogen-containing substituted heterocycle, -[alkylene]p-nitrogen-containing heteroaryl, -[alkylene]p-nitrogen-containing substituted heteroaryl and -[alkylene]p-NR10R11, where p equals 0 or 1, the alkylene contains 1-5 carbon atoms and can have 1 or 2 substitutes selected from a group comprising amine, hydroxy and halogen, aminoacyl relates to a group -C(O)NRR, where each R is independently selected from a group comprising hydrogen and alkyl, R10 and R11 are independently selected from a group comprising hydrogen, alkyl, substituted alkyl, -S(O)2-alkyl, substituted aryl, substituted heteroaryl, cycloalkyl, or when R10 is hydrogen, R11 is hydroxy, alkoxy or substituted alkoxy; or when R1 and R3 together with carbon and nitrogen atoms respectively bonded to them do not form a heterocyclic or a substituted heterocyclic group, R3 and R4 together with a nitrogen atom to which they are bonded form a spiro-condensed heterocyclic group; R5 is selected from a group comprising L-A1, where L is selected from a group comprising C1-C5alkylene, where the alkylene is defined above; and A1 is selected from a group comprising aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle; and one of R6 or R7 is selected from a group comprising aryl and heteroaryl, each of which can optionally be substituted with -(R8)m, where m equals a whole number from 1 to 2, and the other of R6 or R7 is selected from a group comprising hydrogen, halogen and alkyl; or R6 as well as R7 denotes hydrogen; R8 is selected from a group comprising cyano, alkyl, -CF3, alkoxy, halogen, where alkyl, aryl, aryloxy, cycloalkyl, heterocycle, heteraryl and substituted alkyl, aryl, aryloxy, cycloalkyl, heterocycle and heteroaryl are described in claim 1. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula I, a method of inhibiting KSP and use of the composition to prepare a medicinal agent.

EFFECT: novel imidazole derivatives are useful as kinesin spindle protein inhibitors for treating cancer.

25 cl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel phenyl methanone derivatives of the formula I: where R1 denote -OR1, heterocycle such as morpholinyl, pyrrolidinyl, tetrahydropyranyl, phenyl, heteoaryl such as pyrazolyl, which are not substituted or substituted with C1-6alkyl, halogen; R1 denote C1-6alkyl, C1-6alkyl substituted with halogen, or denotes a -(CH2)0-saturated C3-6cycloalkyl; R2 denotes -S(O)2-C1-6alkyl, -S(O)2NH-C1-6alkyl, NO2 or CN; R3 denotes pyridinyl, substituted with C1-6alkyl, substituted with halogen, or phenyl which is not substituted or substituted with one to three substitutes selected from a group consisting of C1-6alkyl, C1-6alkoxy, CN, NO2, halogen, C1-6alkyl, substituted with halogen, C1-6alkoxy, substituted with halogen, phenyl, sulphonamide; X denotes -CH2-, -NH-, -CH2O- or -OCH2-; n denotes 1, 2; m denotes 1, 2; o denotes 1 or 1; and pharmaceutically acceptable acid addition salt thereof.

EFFECT: compounds have glycine reuptake inhibition which enables their use to prepare a pharmaceutical composition.

9 cl, 2 tbl, 40 ex

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