Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds

UKRAINE

(19) and A (11) 89040 (13) C2

(51) IPC (2009)

A61K 31/351

007 to 309/10 (2009.01)

MINISTRY OF EDUCATION SCIENCE OF UKRAINE

STATE DEPARTMENT OF INTELLECTUAL PROPERTY

DESCRIPTION

TO THE INVENTORY PATENT

(54) GLYCOPYRANOZIUM SUBSTITUTED GAS DENOMINATIONS, MEDICINAL MEDICINAL PRODUCTS WHICH CONTAINS THE FACILITIES

(21) a200610843

(22) 11.03.2005

(24) 25.12.2009

(86) PCT / ЕР2005 / 002618, 11.03.2005

(31) 05002628.5

(32) Feb 09, 2005

(33) EP

(31) 10 2004 012 676.3

(32) March 16, 2004

(33) YE

(31) 10 2004 040 168.3

(32) Aug 18, 2004

(33) YE

(31) 10 2004 061 145.9

(32) 16.12.2004

(33) YE

(46) Dec 25, 2009, BULL No. 24, 2009

(72) HIMMELSBACH FRANK, YUE, ECHARDT MAT-TIAS, YEA, AYKELMANN PETER, YEA, BARSUMIANANDVARD LEON, υδ / PU, TOMAS LEO, YEA

(73) BOORINGER INGELHAM INTERMEDIARY, YE

(56) from 2003114390 A

SHO 02083066 A

(57) 1. The glucopyranosyl-substituted benzene halides of the general formula I

in which

R¹ selected among the values ​​of group A, and when P³ in addition to the values ​​of Group B, additionally may also be hydrogen, fluoro, chloro, bromo, iodo, C-i-C4 alkyl, C2-C4alkenyl-C-i-C4 alkyl, C2-C4alkynyl-C-i-C4alkyl, C2- C4 alkenyl-SC-

C4-alkoxy, C2-C4alkynyl-C-i-C4alkoxy, C3-C7cycloalkyl-C-i-C4alkyl, C5-C7cycloalkenyl-C-i-C4alkyl substituted by 1 to 3 fluoro methyl groups substituted with 1 to 5 fluorine atoms of the ethyl group ,

2

A C 1 -C 4 alkoxy group substituted with 1 to 3 fluoroether group atoms substituted with 1 to 5 fluorine atoms of the ethoxy group substituted by a hydroxy or C1-C3 alkoxy group of a C1-C4 alkyl group substituted by a hydroxy or C1-C3 alkoxy group of a C2-

C4 alkoxy group, C3-C6cycloalkyl-C-i-

C3 alkoxy or hydroxy, with the above cycloalkyl and cycloalkenyl rings, one or two methylene groups independently of one another may be substituted on O or CO, P² means hydrogen, fluorine, chlorine, bromine, hydroxyurea, C 1 -C 4 alkyl, C 1 -C 4 alkoxy group, cyano group, or nitro group, wherein the alkyl group or alkoxy group may be mono- or polysubstituted by fluoro,

R³ selected among the values ​​of group B, and when P¹ in addition to the values ​​of Group A, may additionally be hydrogen, fluorine, chlorine, bromine, iodine, C1-C6alkyl, C2-C4alkenyl-C1-C4alkyl, C2-

C4alkynyl-C1-C4alkyl, C2-C4alkenyl-C1-

A C 4 alkoxy group, a C 2 -C 4 alkynyl-C 1-4 alkoxy group,

C3-C7cycloalkyl, C5-C7cycloalkenyl, C3-

C7 cycloalkyl-C1-C4alkyl, C5-C7cycloalkenyl-C1-

C4 alkyl, C3-C6 cycloalkylidenemethyl, hydroxy, C1-C6alkoxy, C3-C6cycloalkyl-C1-

C3 alkoxy group, aryl, aryl-C1-C3alkyl, heteroaryl, heteroaryl-C1-C3alkyl, aryloxy, aryl-C3-C3alkyloxy substituted by 1 to 3 fluoromethyl or methoxy groups substituted with 1 to 5 carbon atoms, C2-C4 alkyl or C2- A C1-4 alkoxy group substituted with a cyano group of a C1-C4 alkyl group substituted with a C1-C4 alkyl group, a C1-4 alkyl group, a cyano group, a carboxy group, a C1-C3 alkoxycarbonyl group, an aminocarbonyl group, (C1-

C3alkylamino) carbonyl, di (C1-

C1-4alkyl) aminocarbonyl, pyrrolidine-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4- (C1-C3alkyl) piperazin-1-ylcarbonyl, (C1-C4alkyl) carbonylamino, C1- C4 alkylsulfonylamino group, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, aryl-sulfonylamino group, aryl-C1-

C3 alkylsulfonylamino group or arylsulfonyl,

R⁴, P⁵ independently of each other means

day, fluorine, chlorine, bromine, iodine, cyano group, nitro group

iA (11) 89040 (13) C2

σ>

3

Pu, Ci-Salkyl, Cys-Alkoxy, or substituted by 1 to 3 fluorine atoms of methyl or methoxy,

A is C2 -Balkin-1-yl, C2 -Balken-1-yl, C1-C6 cycloalkyl, C1-C6 cycloalkenyl, aryl, heteroaryl, C-Sdalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, Ci-

1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4- (Ci-C4alkyl) piperazin-1-ylcarbonyl, arylaminocarbonyl , heteroarylaminocarbonyl, Ci-

S-alkoxycarbonyl, aryl-C1-C6alkoxycarbonyl, heteroaryl-C1-C6alkoxycarbonyl, amino, C4-C4 alkylamino, di (C1-C6alkyl) amino, pyrrolidin-i-yl, pyrrolidine-2-on-1-yl, piperidin- yl, piperidine-2-one, and morpholin-4-yl, morpholin-on-4-yl, piperazin-i-yl, 4- (C1-C6alkyl) piperazin-i-yl, CI C4 alkylcarbonylamino group, arylcarbonylamino-

group, heteroarylcarbonylamino group, Cs-

Cycloalkyloxy, C5-

C7 cycloalkenyloxy, aryloxy, heteroaryloxy, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 2 -C 7 cycloalkylsulfanyl, C 5 -C 7 cycloalkylsulfinyl, C 2-4 alkylcycloalkyl,

Cycloalkylsulfonyl, C5-

Cycloalkenylsulfanyl, C5-

Cycloalkenylsulfinyl, C5-

Cycloalkenylsulfonyl, arylsulfanyl, arylsulphinyl, arylsulfonyl, heteroarylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl, cyano or nitro group, with the above alkynyl and alkenyl groups may be mono- or polysubstituted by fluorine or chlorine and may be singly or double-substituted with the same or different residues I_1 , and the above cycloalkyl and cy-cloalkenyl rings independently of one another can be mono- or di-substituted by substituents selected from fluoro and C 1 -soalkyl, and in the above-mentioned cycloalkyl and cyclic alkenyl kiltsyahodna or two methylene groups independently fromone may be replaced by O, C, CO, GO, ZO2abo ΝΡ^ν,

B is (C4-C4alkyl) silyl-C-balkyl, C2 -Balcine-i-il, C2 -Balcene-i-ol, amino, C1-C9alkylamino, di (C1-C6alkyl) amino, pyrrolidine yl-pyrrolidine-2-on-and-yl, piperidin-i-yl, piperidine-2-one-yl, morpholin-4-yl, morpholin-on-4-yl, piperazine yl, 4- (Cysalkyl) piperazin-i-yl, arylcarbonylamino, heteroarylcarbonylamino, nitro, Cs-Ciocycloalkyloxy,

Cg-Ciocycloalkenyloxy group, Cs-

Ciocycloalkylsulfanyl, Cs-

Ciocycloalkylsulfinyl, Cs-

Ciocycloalkylsulfonyl, C5-

Ciocycloalkenylsulfanyl, C5-

Ciocycloalkenylsulfinyl, C5-

Cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, heteroarylsulfonyl or heteroaryl sulfinyl, wherein the alkynyl and alkenyl groups mentioned above may be mono- or poly-substituted with fluorine or chlorine and may be mono- or di-substituted with the same or different residues I_1, as defined above cycloalkyl and cycloalkyl rings independently of one another may be mono- or di-substituted by substituents selected from fluoro and C 1 -C 6 alkyl, and in the above

89040 4

cycloalkyl and cycloalkenyl rings, one or two methylene groups independently of one another can be substituted on O, Z, CO, CO, ZO2 or vρ^ν,

P^ν is H, C 1 -C 4 alkyl, C 1 -C 4 alkylcarbonyl, and C 1 -C 4 alkylsulfonyl,

And in each case is independently selected from the group consisting of a hydroxy group, a cyano group, a nitro group, a C 1 -C 6 cycloalkyl, aryl, heteroaryl, C 1 -C 4 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, C 1 -C 4 alkylaminocarbonyl, ) aminocarbonyl, pyrrolidine-i-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, Ci-C4 alkoxycarbonyl, aryl-C6-alkanoylcarbonyl, heteroarylC1-6alkoxycarbonyl, Ci-

S4alkiloksyhrupu, aryloxy, heteroaryloksy group, C-S4alkilsulfanil, arylsulfanil, Goethe roarylsulfanil, Sea S4alkilsulfinil, arylsul-finil, heteroarylsulfinil, Sea S4alkilsulfonil, arylsulfonyl and heteroarylsulfonil, aI_2 in each case independently selected from the game-pi, which includes fluoro , chlorine, bromine, iodine, cis-alkali, difluoromethyl, trifluoromethyl, cyano-cyano, difluoromethoxy, trifluoromethoxy and cyano-group, and

R⁶, P, P, P independently of one another represent hydrogen, (C1-C2alkyl) carbonyl, (C1-C2alkyl) oxycarbonyl, arylcarbonyl, or aryl- (C1-C6alkyl) carbonyl,

while under the aforementioned in the definition mentioned above, the remaining aryl groups are intended to have a phenyl or naphthyl group independently of one another which may be mono- or di-substituted identically or differently with the residues I_2, in the definition of the above-mentioned residues by heteroaryl groups, is meant pyrrole, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl or tetrazolyl group, or meaning pyrolyl, furanyl, thienyl or pyridyl group in Kyi one or two metynovihrupy replaced by nitrogen atoms, or indolilna, be-nzofuranilna, benzotiofenilna, hinolinilnaabo izohinolinilna group in which one to trohmetynovyh groups replaced by nitrogen atoms,

their tautomers, their stereoisomers, their mixtures and their salts.

2. Benzyl derivatives replaced by glucopyranosyl. 1 general formula I.2

in which the remnants of P^and-R⁶, as well as P^7a, P^uh and R^Us have

indicated in item 1 value.

5

3. Benzyl derivatives replaced by glucopyranosyl. 1 or 2, wherein group A is C2 -Balkin-1-yl, C2 -Salanken-1-yl, C5-C7cycloalkyl, C5-

C7 cycloalkenyl, Ci-Sdalkylcarbonyl, aminocarbonyl, Ci-Sdalkylaminocarbonyl, di (Ci-

Zalkyl) aminocarbonyl, pyrrolidine-1-ylcarbonyl,

piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,

1-ylcarbonyl, piperazin-1-ylcarbonyl, 4- (C1-Sdalkyl) piperazin-1-ylcarbonyl, C1-Sdalkoxycarbonyl, amino, C1-C4alkylamino, di (C1-Salkyl) amino, pyrrolidin-1-yl, pyrrolidin-2-one 1-yl, piperidin-1-yl, piperidine-2-one-1-yl, morpholin-4-yl, morpholin-on-4-yl, piperazin-1-yl, 4- (C1- Zalcil) piperazin-1-yl,

C1-C4alkylcarbonylamino group, Сz-

C7 cycloalkyloxy, C5-

C7 cycloalkenyloxy, C1-Sdalkylsulfinyl, C1-Sdalkylsulfonyl, C3Z-cycloalkylsulfanyl, C6-C7cycloalkylsulfinyl, C2-

C7 cycloalkylsulfonyl, C5-

C7 cycloalkenylsulfanyl, C5-

C7 cycloalkenylsulfinyl, C5-

C7 cycloalkenylsulfonyl, cyano group or nitro-rupe,

the alkynyl and alkenyl groups mentioned above may be mono- or polysubstituted by fluorine or chlorine and may be mono- or di-substituted with the same or different residues I_1, the above cycloalkyl and cycloalkenyl kisels may be one of the independently of each other - or two-substituted with substituents selected from isfluoride and C1-C6alkyl, and in the above cycloalkyl and cycloalkenyl rings, one or two methylene groups independently of one another may be substituted on O, Z, CO, ZO, ZO2 or NR^ν, andІІ and p^ν have the values ​​indicated in clause 1.

4. Substituted glucopyranosyl benzene derivatives forgotten from pp. 1-3, wherein group B is a sulfur atom (C1-Sdalkyl) silyl-C1-Balcil, C2 -Balkin-1-yl, C2 -Salcen-1-yl, amino, C1-C9alkylamino, di (C1-C6alkyl) amino, 1-yl, pyrrolidin-2-one-1-yl, piperidin-1-yl, piperidin-2-one-1-yl, morpholin-4-yl, morpholin-on-4-yl, piperazin- 1-yl, 4- (C1-C6alkyl) piperazin-1-yl, nitro group, C2-

C7 cycloalkyloxy, C5-

C7 cycloalkenyloxy, C2-

C7cycloalkylsulfanyl, Cs-

C7 cycloalkylsulfinyl, Cs-

C7 cycloalkylsulfonyl, C5-

C7 cycloalkenylsulfanyl, C5-

C7 cycloalkenylsulfinyl or C5-

C7 cycloalkenylsulfonyl,

the alkynyl and alkenyl groups mentioned above may be mono- or polysubstituted by fluorine or chlorine and may be mono- or di-substituted with the same or different residues I_1, the above cycloalkyl and cycloalkenyl kisels may be one of the independently of each other - or two-substituted with substituents selected from isofluoro and C1-S zalkyl, and in the above-mentioned cycloalkyl and cycloalkenyl rings, one or two methylene groups independently of one another may

89040 6

be replaced by O, C, CO, CO, ZO2 or NP^ν, and I_1 and Ya¹⁴ have the values ​​indicated in clause 1.

5. Substituted glucopyranosyl benzene derivatives forgotten from pp. 1-4, where is the remainder of me^with selected from the values ​​of group B, indicated in clauses 1 or 4.

6. Benzyl derivatives substituted with glucopyranosyl

any of the paragraphs. 1-5, where is the remainder of me¹ represents a hydrogen, fluorine, chlorine, bromine, iodine, C1-C4alkyl, C2-Balkinyl, -CH2 -Salkoxy, C2-Sdalkenyl-C1-C4-alkoxy, a C2-C4alkynyl-C1-C4-alkoxy group substituted with from 1 to 3 fluorine atoms of methyl substituted with 1-5 fluorine atoms of ethyl substituted with 1 to 3 atoms of a fluorine methoxy group substituted by 1 to 5 fluoroethoxy tooms substituted with a hydroxy or C1-C6 alkoxy group of C1-C4 alkyl substituted by a hydroxy or C1-C6 alkoxy group of a C2-C4 alkoxy group, C2 -Salenkylene, C1-C5cycloalkyl, C1-C6alkyl, C1-C7cycloalkyloxy, C6-

Cycloalkyl, C1-C6alkoxy, C5-

A C7 cycloalkenyloxy group, a hydroxy group, an amino group, a nitro group or a cyano group, while in the C5-Sbcycloalkyl groups, one methylene group can be replaced by O.

7. Substituted glucopyranosyl benzene derivatives forgotten from pp. 1-5, where is the remainder of me¹ selected from the values ​​of Group A indicated in Sections 1 or 3.

8. Benzyl derivatives substituted with glucopyranosyl

any of the paragraphs. 1-4 and 7, where the rest of I am^with represents a water, fluorine, chlorine, bromine, hydroxy group, cyanogrupe, C1-Balcyl, trimethylsilylethyl, C2-Balkenyl, C2-C₆alkynyl, difluoromethyl, trifluoromethyl, C6-C7cycloalkyl, C5-C7cycloalkenyl, C1-

A benzyloxy group, a difluoromethoxy group, a trifluoromethoxy group, a pentafluoroethoxy group, a Cs-

C7 cycloalkyloxy, tetrahydrofuranoyloxy-glycol, tetrahydrofuranoyloxy, C1-balkylsulfanyl, cyclopropylidenemethyl, arylabo-heteroaryl.

9. Substituted glucopyranosyl benzene derivatives forgotten from pp. 1-8, where is the balance of me² represents a hydrogen, fluorine, chlorine, bromine, methyl, hydroxy, methoxy, ethoxy, trifluoromethoxy, cyano, nitro, or substituted with 1 to 3 atoms of a methylfluoride.

10. Substituted glucopyranosyl benzene derivatives of any of the items. 1-9, where the remnants of I am⁴ and / or I⁵ independently of each other are hydrogen or fluorine.

11. Substituted glucopyranosyl benzene derivatives of any of the claims. 1-10, where is the rest of me⁶ represents a hydrogen sulfide, (C1-C6alkyl) oxycarbonyl, C1-C9alkylcarbonyl or benzoyl, preferably hydrogen.

12. Substituted glucopyranosyl benzene derivatives of any of the claims. 1-11, where the remnants of I am^7a, I^7b, I^7sare hydrogen.

13. Substituted glucopyranosyl benzene derivatives of any of the items. 1 -12 in the form of physiologically compatible salts with inorganic and organic acids.

A medicament containing a compound according to any one of the preceding claims. 1-13 and optionally one or more inert carriers and / or diluents.

7

89040

8

The present invention relates to benzene derivatives substituted with glucopyranosyl of general form

are the following values, including their tautomers, their stereoisomers, mixtures thereof and their salts. The invention also utilizes medicaments containing one of the compounds of the invention as claimed in the invention, as well as the use of one of the compounds of the invention for the preparation of a medicament for the treatment of metabolic diseases. The invention also relates to the method of the preparation of the drug as well as the compounds proposed in the invention.

For the treatment of various diseases, in particular, diabetes, in the literature are offered various spores, which have inhibitory effect on the sodium dependent glucose transporter ЗСИ_Т2.

From publications SHO 98/31697, SHO 01/27128, SHO02 / 083066, SHO 03/099836, SHO 2004/063209, SHO2004 / 080990, SHO 2004/013118, SHO 2004/052902, SHO 2004/052903 and applications YZ 2003/0114390 known substituents of glucopyranosyl aromatic compounds, as well as their production and their possible activity, which inhibitors ZSTT2.

The basis of the present invention was to propose new substituted pyranosylbenzene derivatives, in particular those having activity against sodium dependent cotransporter glucose ZSI_T, mainly ZSTT2. It is a further object of the present invention to provide new substituted pyranosylbenzene derivatives which are effective in combination with known compounds of the same structure, which have an increased inhibitory effect on the sodium dependent glucose transporter ZSI-T2 and / or improved phamacological or pharmacokinetic properties.

The object of the present invention was to offer new drugs suitable for the prevention and / or treatment of metabolic diseases, primarily diabetes.

Another object of the present invention was to provide a method for the preparation of the compounds of the invention.

Other objects of the present invention are apparent to the facsimile in the art, proceeding directly from the foreground and the following description.

A first object of the present invention is substituted benzyl derivatives of general formula I with glucopyranosyl

in which

IS¹ selected among the values ​​of group A, and when E³optionally among the values ​​of Group B may also be hydrogen, fluorine, chlorine, bromine, iodine, C1-C4 alkyl, C2-C4alkenyl-C1-C4alkyl, C2-C4alkynyl-C1-C4alkyl, C2-C4alkenyl-C1-

C4alkoxy, C2-C4alkynyl-C1-C4alkoxy, C3-C7cycloalkyl-C1-C4alkyl, C5-C₇cycloalkenyl-C1-C4alkyl substituted by 1 to 3 fluorine atoms of a metal group substituted with 1 to 5 fluorine atoms of the ethyl group, a C1-C4 alkoxy group substituted with 1 to 3 fluoroether group atoms, substituted by 1 to 5 fluorine atoms of the ethoxy group, substituted hydroxy or C1-

A C 1 -C 4 alkoxy group substituted by a hydroxy or C 1 -C 3 alkoxy group of a C 2 -C 4 alkyl group,

C4alkoxy, C3-C6cycloalkyl-C1-

C3 alkoxy or hydroxy, with the above cycloalkyl and cycloalkenyl rings, one or two methylene groups independently of one another can be substituted on O or CO,

IS² means hydrogen, fluorine, chlorine, bromine, hydroxy group, C1-C4 alkyl, C1-C4 alkoxy group, cyano group or nitro group, wherein the alkyl group or alkoxy group may be mono- or polysubstituted by fluorine,

IS³ selected among the values ​​of group B, and when E¹optionally among the values ​​of Group A may also be hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C2-C4alkenyl-C1-C4alkyl, C2-C4alkynyl-C1-C4alkyl, C2-C4alkenyl-C1-

C4 alkoxy, C2-C4alkynyl-C1-C4alkoxy, C3-C7cycloalkyl, C5-C7cycloalkenyl, C3-

C7 cycloalkyl-C1-C4alkyl, C5-C7cycloalkenyl-C1-C4alkyl, C3-C6cycloalkylidenemethyl, hydroxy, C1-C6alkoxy, C3-C6cycloalkyl-C1-

C3 alkoxy, aryl, aryl-C1-C3 alkyl, heteroaryl, heteroaryl-C1-C3 alkyl, aryloxy, aryl-C1-C3 alkyloxy substituted with 1 to 3 fluoromethyl or methoxy groups substituted with 1 to 5 carbon atoms, C2-C4 alkyl or C2-C4 alkoxy groups, substituted with a cyano group, a C1-C4 alkyl group, a substituted hydroxy group, or a C1-C4 alkyl group having a C1-C3 alkyloxy group, a cyano group, a carboxy group, a C1-

C3 alkoxycarbonyl, aminocarbonyl, (C1-

C3alkylamino) carbonyl, di (C1-

C1-4alkyl) aminocarbonyl, pyrrolidine-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4- (C1-C3alkyl) piperazin-1-ylcarbonyl, (C1-C4alkyl) carbonylamino, C1- C4 alkylsulfonylamino group, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, aryl-sulfonylamino group, aryl-C1-

C3 alkylsulfonylamino group or arylsulfonyl,

IS⁴, IS⁵ independently of each other means

hydrogen, fluorine, chlorine, bromine, iodine, cyano group, nitroglycerine,

9

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10

Rupa, Ci-Salkil, Ci-Salkyloxy, or substituted by 1 to 3 fluorine atoms of methyl or methoxy,

A is C2 -Balkin-1-yl, C2 -Salanken-1-yl, C2-C7cycloalkyl, C5-C7cycloalkenyl, aryl, heteroaryl, Ci-Sdalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, Ci-

Salkylaminocarbonyl, di (Ci-

Pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4- (Ci-Sdalkyl) piperazin-1-ylcarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, Ci-Sdalkoxycarbonyl , aryl-Ci-

Sialkoxycarbonyl, heteroaryl-Ci-

Sialkoxycarbonyl, amino group, Ci-

Pyrrolidin-i-yl, pyrrolidine-2-one-yl, piperidin-i-yl, pyridine-2-one-yl, morpholin-4-yl, yl, morpholin-on-4-yl, piperazin-i-yl, 4- (C1-C6alkyl) piperazin-i-yl, C4-C4alkylcarbonylamino, arylcarbonylamino-

group, heteroarylcarbonylamino group, Cs-

C7 cycloalkyloxy, C5-

A C7 cycloalkenyloxy group, an aryloxy group, a heteroaryloxy group, a C 1 -C 4 alkyl sulfinyl group, a C 1 -C 6 -alkoxylsulfonyl group, C 1 -C 7 cycloalkylsulfanyl, C 2 -C 7 cycloalkylsulfinyl group,

C7 cycloalkylsulfonyl, C5-

C7 cycloalkenylsulfanyl, C5-

C7 cycloalkenylsulfinyl, C5-

C7 cycloalkenylsulfonyl, arylsulfanyl, arylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl, cyano or nitro group, wherein the alkenyl and alkenyl groups mentioned above may be mono- or polysubstituted by fluorine or chlorine and may be singly or double substituted with the same or different residues I_1 , and the above cycloalkyl and cy-cloalkenyl rings independently of one another may be mono- or di-substituted by substituents selected from fluoro and C 1 -C 6 alkyl, and in said above cycloalkyl and cyclo alkenyl ring or two methylene groups independently of one can be substituted on O, C, CO, CO, SO2 or NR^ν,

B represents the three (Ci-Sdalkyl) silyl-Ci-Balcal, C2-Balkin-i-il, C2-Balken-i-il, amino-glycine, C1-C6alkylamino, di (Ci-

Pyrrolidine-i-yl, pyrrolidine-2-on-1-yl, piperidin-1-yl, piperidin-2-one-yl, morpholin-4-yl, morpholin-on-one, 4-yl, piperazin-i-yl, 4- (Cysalkyl) piperazin-i-yl, arylcarbonylamino, heteroarylcarbonylamino, nitro, Cs-

Ciocycloalkyloxy, C5-

Ciocycloalkenyloxy group, Cs-

Ciocycloalkylsulfanyl, Cs-

Ciocycloalkylsulfinyl, Cs-

Ciocycloalkylsulfonyl, C5-

Ciocycloalkenylsulfanyl, C5-

Ciocycloalkenylsulfinyl, C5-

Cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, heteroarylsulfonyl or heteroaryl sulfinyl, wherein the alkynyl and alkenyl groups mentioned above may be mono- or poly-substituted with fluorine or chlorine and may be mono- or di-substituted with the same or different residues I_1, as defined above cycloalkyl and cycloalkyl rings independently of one another can be

be mono- or di-substituted by substituents selected from fluoro and C 1 -C 6 -alkyl, and in the above-mentioned cycloalkyl and cycloalkenyl rings, one or two methylene groups independently of one another can be substituted on O, Z, CO, ZO, ZO2 or vρ^ν,

P^Ν is H, C1-C4alkyl, Ci-

C4 alkylcarbonyl or C 1 -C 4 alkylsulfonyl,

In each case, I_1 is independently selected from the group consisting of a hydroxy group, a cyano group, a nitro group, a C7-C7 cycloalkyl group, an aryl group, a heteroaryl group, a C 1 -C 4 alkylcarbonyl group, an arylcarbonyl group, a heteroarylcarbonyl group, an aminocarbonyl group, a C 1 -C 4 alkylaminocarbonyl group, a di (C2 -C6alkyl) aminocarbonyl group, pyrrolidine-and-

ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, arylaminocarbonyl, heteroarylamino carbonyl, C 1 -C 4 alkoxycarbonyl, aryl-C 1 -C 6 alkoxycarbonyl, heteroaryl-Ci-

Sialkoxycarbonyl, C 1 -C 4 -alkyloxy, aryl-group, heteroaryloxy, Ci-

C4 alkylsulfanyl, arylsulfanyl, heteroarylsulfanyl, Ci-C4 alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, Ci-C4alkylsulfonyl, arylsulfonyl and heteroarylsulfonyl, and

And in each case independently selected from the group consisting of fluorine, chlorine, bromine, iodine, C1-C6alkyl, difluoromethyl, trifluoromethyl, C2-C2alkoxy, difluoromethoxy, trifluoromethoxy, and cyano, and

P⁶, P, P^7b, P^7s independently of one another, represent hydrogen, (C1-C2alkyl) carbonyl, (C1-C2alkyl) oxycarbonyl, arylcarbonyl, or aryl- (C1-C6alkyl) carbonyl,

while under the aforementioned definitions in the definition of the above-mentioned residues, aryl groups are intended to have phenyl or naphthyl groups independently of one another being mono- or di-substituted with the same or different moieties of I_2 as defined in the definition of the above-mentioned residues by heteroaryl groups, meaning pyrrole- flax, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, or tetrazolyl group, refers to a pyrrol, furanyl, thienyl or pyridyl group in which one or two of the methine groups are replaced by nitrogen atoms, or indolyl, be-nzofuranyl, benzothiophenyl, quinolinyl, or isoquinolinyl, in which one to three methane groups are replaced by nitrogen atoms,

their tautomers, their stereoisomers, their mixtures and their salts.

The compounds of the general formula I and their physiologically compatible salts, as provided in the invention, have valuable pharmacological properties, primarily inhibiting the sensation of a sodium dependent glucose transport catheter, in particular, ZSI_T2. In addition, the compounds proposed in the invention may have an inhibitory effect on the natrioreceptor glucose transport carrier ZSI_T1. In comparison with the possible inhibitory effect on ZSi_T1, the advantages of the compounds of the invention proposed in the invention,

11

waves in the selective inhibition of their kotransporterZSBT2.

The object of the present invention is also the physiologically compatible salts of the compounds proposed therein with non-organic and organic acids.

A further object of the present invention is pharmaceutical agents containing at least one compound of the invention proposed in the invention, or at least one physiologically acceptable salt thereof, and optionally one or more inert carriers or diluents.

The object of the present invention is the use of at least one compound of the invention or at least one physiologically compatible salt thereof for the preparation of a medicament useful for the treatment or prophylaxis of diseases and pathological conditions that may be influenced by the inhibition of sodium-dependent cotransportergagglucose ZSI-T, in particular ZSBT2.

A further object of the present invention is the use of at least one compound of the invention or at least one physiologically acceptable salt thereof for the preparation of a medicament suitable for the treatment of metabolic diseases.

Another object of the present invention is the use of at least one compound of the invention or at least one physiologically acceptable salt thereof for the manufacture of a medicament for inhibiting sodium-dependent glucose transporter, ZSI-T, in particular, ZSBT2.

It is an object of the present invention to further provide a method for the preparation of a medicament according to the invention, characterized in that at least one of the inventions of the alkene compound, or at least one of the one proposed by the invention, is chemically combined with one or more inert carriers and / or diluents

The object of the present invention is also a method for the preparation of the compounds of general formula I, which is characterized in that

a) for the preparation of compounds of general formula I wherein the substituents have the meanings indicated above and below, a compound of the general formula II

in which

I 'mean H, Si-Salkil, (Ci-

Cisalkyl) carbonyl, (Ci-Cvalkyl) oxycarbonyl, arylcarbonyl, or aryl- (Cysalkyl) carbonyl, wherein the alkyl or aryl groups may be mono- or halogen-substituted by halogen,

R^wah, pp, p^Sun, the genes independently of each other have one of the above and below for the residues I⁶, P^7a, P^7b, P^7s values ​​or denotes the benzyl group, I^andR^ıR^withCI group or ketal or acetyl group, especially alkylidene orarylalkylideneketal or acetal group, with

89040 12

this is every two adjacent remnants from the number i^wah, P^uh, Dvs In you Mr.-

P, P may form a cyclic ketal or acetal group or a 1,2-di (C1-C6alkoxy) -1,2-di (C1-C6alkyl) ethylene bridge, which collectively together with the oxygen atoms and the corresponding two atomic moieties of the pyranose ring forms a substitution the non-dioxane ring, in particular 2,3-dimethyl-2,3-di (C1-S zalkoxy) -i, 4-dioxane ring, and alkyl, aryl and / or benzyl groups may be mono- or polysubstituted by halogen or C 1 -C 8 -alkoxy , and benzyl groups may also be substituted by di (C1-C6alkyl) amino,

R^and, P^ı, P^with independently of one another denote -Si-Sdalkyl, aryl, or aryl-Ci-Salkyl, wherein aryl or alkyl groups may be mono- or halogen-substituted by halogen,

while under the aforementioned residues indicated in the definitions of aryl groups, the phenyl or naphthyl groups, preferably the phenyl groups, and

the remnants of me^--R⁵ and I⁶, P^7a, P^7b, P^7s have the above and below values, are interacting with the recipe in the presence of lyusium or brusted acids, with the simultaneous or subsequent cleavage of possibly present protecting groups, or

b) for the preparation of compounds of general formula I in which I.⁶, P^7a, P^7b and I^7s mean hydrogen, hydrolyzate the compound of general formula III

the above and below values, but provided that at least one of the residues of the I^wah, P^uh, P^Sun, P^you does not denote hydrogen, and if desired, is thus obtained by a compound of general formula I in which I.⁶is a hydrogen atom, is acylated by transferring to the corresponding acyl compound of the general formula I and / or

if necessary, cleaved again, protecting group used during the reaction described above, and / or

if desired, the resulting compound of the general formula I obtained in this way is separated into its stereo-humers and / or

if necessary, obtained in this way by the formula of the general formula I, is converted into its salt, on the one hand, for the pharmaceutical use, it is transferred into its physiologically compatible salts.

A further object of the present invention is to provide compounds of general formula II

Ε '

means

N,

S-i-Salkil

(Si

C6alkyl) carbonyl, (C1-C8alkyl) oxycarbonyl, arylcarbonyl, or aryl- (C1-C6alkyl) carbonyl, wherein the alkenyl or aryl groups may be mono- or halogen-substituted by halogen,

R^wah, pp, p^Sun, pwy independently of one another have one of the residues E as indicated⁶, P^7a, P^7b, P^7s values ​​or meaning the benzyl group, P^andR^ıR^withCI group or ketal or acetal group, with each of two adjacent residues from the number Ε, P^uh, P^Sun, P^you may form a cyclic ketal or an acetal group, or with two oxygen atoms of the pyranose ring, may form a substituted 2,3-oxidioxane ring, in particular 2,3-dimethyl-2,3-di (C1-S zalkoxy) -i, 4-dioxane ring, and alkyl , aryl and / or benzyl groups may be mono- or polysubstituted by halogen or C 1 -C 6 alkoxy, and benzyl groups may also be substituted by di (C 1 -C 6 alkyl) amino,

R^and, P^ı, P^with independently of one another denotes C 1 -C 4 alkyl, aryl, or aryl-C 1 -C 6 -alkyl, wherein the alkyl or aryl groups may be mono- or halogen-substituted by halogen,

while under the aforementioned residues indicated in the definitions of aryl groups, the phenyl or naphthyl groups, preferably the phenyl groups, and

p^and-r⁵, P⁶, P^7a,

R^7b, P^7s have the above and

lower the value, which is the metal-organic compound (V), which is produced by over-mischennya for metal halogen or by vprova-INSTITUTING metal by carbon-halogen compound uhalohenzamischeniy benzylbenzolniy gener-efficient innovation infrastructure formula IV

in which NAI means SI, B or I, and E^and-R⁵ have the above and below values, if necessary, with a significant change, attach to a dog colony of the general formula VI

14

in which E^wah, P^uh, P^Sun, P^you have the above and lower values, and then the resulting adduct is subjected to interactions, preferably with ip 5Ii, with water or an alcohol E'-OH, where E^and is optionally substituted C 1 -C 4 alkyl, in the presence of an acid, such as methanesulfonic acid, sulfuric acid, hydrochloric acid, acetic acid, or ammonium chloride, and obtained as a result of interaction with water, a product in which E^and is a H-beta reaction of the following with an acylating agent, such as, for example, the corresponding acid chloride or acid anhydride, optionally converting the product of the formula II wherein E 'is (Ci-Cvalkyl) carbonyl, (Ci-Sivalkyl ) oxycarbonyl, arylcarbonyl, or aryl- (C1-C6alkyl) carbonyl, which may be substituted by the aforementioned substituent -i.

The above-mentioned intermediate products, above all before Formula IV, Formula II, and also Formula III, are likewise objects of the present invention.

Unless otherwise stated, all groups, remnants and substitutes, first of all, are E.^and-R⁵, A, B, I_1, I_2, E^Ν, P⁶, P^7a, P^7b, P^7s, P^wah, P^uh, P^Sun and have the above mentioned values ​​in the following description.

In the presence of several compounds of the same residues, substituents or groups, they may have identical or different meanings.

According to the invention, preferred benzyl derivatives of general formula I are substituted with glucopyranosyl

in which

R^and is chosen among the values ​​of group A, and when Ε³selected from among the values ​​of Group B, may additionally be hydrogen, fluorine, chlorine, bromine, iodine, Si-Sdalkyl, C2-C4alkenyl-Si-Sdalkyl, C2-C4alkynyl-C1-C4alkyl, C6-C7cycloalkyl-C1-C4alkyl, C5- C7 cycloalkenyl-C 1 -C 4 alkyl substituted by 1-3 atoms of the fluorine methyl group substituted with 1 to 5 fluorine atom ethyl groups, C 1 -C 4 alkoxy group substituted with 1 to 3 fluoro atoms of the methoxy group substituted with 5 fluorine atoms of the ethoxy group substituted hydroxy or C 1 -C 6 alkoxy, a C 1 -C 4 alkyl group substituted by a hydroxy or C 1 -C 6 alkoxy group of C 2 -C 4 alkoxy, C 5 -C 6 cycloalkyl-Ci-

A zalkoxy group or a hydroxy group, with the above cycloalkyl and cycloalkenyl rings, one or two methylene groups independently of one another can be substituted on O or CO,

p² means hydrogen, fluorine, chlorine, bromine, hydroxy group, Ci-Sdalkyl, C 1 -C 6 -alkoxy group, cyano group or nitro group, the alkyl group or alkoxy group may be mono- or polysubstituted by a fluorine,

R³ selected among the values ​​of group B, and when E^and

selected among the values ​​of group A, can additionally

also represent hydrogen, fluorine, chlorine, bromine,

15

89040

16

iodine, Si-Balcil, C2-Sdalkenyl-Si-Sdalkyl, C2-Sdalkinyl-Si-Sdalkyl, C5-C7cycloalkyl, C5-

C7 cycloalkenyl, C6-C7cycloalkyl-C2-Sdalkyl, C5-C7cycloalkenyl-C-Sdalkyl, C2-

Sbcycloalkylidenemethyl, hydroxy, Ci-

C 1 -C 4 alkoxy group, C 1 -C 7 -cycloalkyl-Ci-

Aralkyl, aryl, aryl-C6-alkali, heteroaryl, heteroaryl-C6-alkenyl, aryloxy, aryl-C6-alkenyloxy substituted by 1 to 3 fluoromethyl or methoxy groups substituted with 1 to 5 carbon atoms, C2-Sdalkyl or C2-Sdalkoxy groups, a substituted cyano group, a C 1 -C 6 alkyl group, a substituted hydroxy or C 1 -C 6 alkyloxy group of C 1 -C 6 alkyl group, a cyano group, a carboxy group,

Sialkoxycarbonyl, aminocarbonyl, (Ci-

Zalcylamino) carbonyl, di (Ci-

Zalcil) aminocarbonyl, pyrrolidine-i-ilcarbonyl, piperidin-i-ylcarbonyl, morpholin-d-ilcarbonyl, piperazin-i-ilcarbonyl, 4- (Cysalkyl) piperazin-i-ilcarbonyl, (Ci-Sdalkyl) carbonylamino, Ci- Salkylsulfonylamino group, Ci-Sdalkylsulfanyl, Ci-Sdalkylsulfinyl, Ci-Sdalkylsulfonyl, Arylsulfonylamino group, Aryl-Ci-

Zalkylsulfonylamino group or arylsulfonyl,

R^d, P⁵ independently of one another mean a hydrogen, a fluorine, a chlorine, a bromine, an iodine, a cyano group, a nitrograph, a Cis-alkali, a C 1 -Salkoxy group, or a substituted methyl or methoxy group of fluorine atoms,

A means C2 -Balkin-i-yl, C2 -Salankin-i-il, C2-C7cycloalkyl, C5-C7cycloalkenyl, aryl, heteroaryl, Ci-Sdalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, Ci-

Salkylaminocarbonyl, di (Ci-

Zalcil) aminocarbonyl, pyrrolidine-i-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-d-ilcarbonyl, piperazin-i-ylcarbonyl, 4- (Ci-Sdalkyl) piperazin-i-ylcarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, Ci-Sdalkoxycarbonyl , aryl-Ci-

Sialkoxycarbonyl, heteroaryl-Ci-

Sialkoxycarbonyl, amino group, Ci-

Pyrrolidin-i-yl, pyrrolidine-2-on-1-yl, piperidin-i-yl, pyridin-2-on-1-yl, morpholin-d-pyrrolidinyl, yl, morpholine-on-one-dl, piperazin-i-yl, 4- (Cys-alkali) piperazin-i-yl, Ci-Sdalkylcarbonylamino, arylcarbonylamino-

group, heteroarylcarbonylamino group, Cs-

C7 cycloalkyloxy, C5-

A C7 cycloalkenyloxy group, an aryloxy group, and a heteroaryloxy group, a Ci-Sdalkylsulfinyl group, a Ci-

Sdalkylsulfonyl, Cs-C7cycloalkylsulfanyl, Cs-C7cycloalkylsulfinyl, Cs-

C7 cycloalkylsulfonyl, C5-

C7 cycloalkenylsulfanyl, C5-

C7 cycloalkenylsulfinyl, C5-

C7 cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, arylsulfonyl, heteroarylsulfanyl, heteroarylsulfinyl, heteroarylsulfonyl, cyano or nitro group,

the alkynyl and alkenyl groups mentioned above may be mono- or polysubstituted by fluorine or chlorine and may be mono- or di-substituted with the same or different residues I_1, the above cycloalkyl and cycloalkenyl kisels independently of one another may be one - or two-substituted with substituents selected from isofluorocarbon and cyazalcyl, and in the above-mentioned cycloalkyl-

and cycloalkenyl rings, one or two methylene groups independently of one another may be replaced by O, C, CO, SO, SO2 or NR^Ν,

B stands for the three (Ci-Sdalkyl) silyl-Ci-Balcal, C2-Balkin-i-il, C2-Balkin-i-il, amino group, C1-C6 alkanoylamino group, di (C2-C6) alkynyl amino group, pyrrolidin-i- yl, pyrrolidine-2-on-and-yl, piperidin-i-yl, p-peridin-2-on-yl, morpholin-d-yl, morpholin-on-d-yl, piperazin-i- yl, 4- (Cysalkyl) piperazin-i-il, arylcarbonylamino, heteroarylcarbonylamino, nitro, Cs-C7cycloalkyloxy, C5-

C7 cycloalkenyloxy, C2-

C7cycloalkylsulfanyl, Cs-

C7 cycloalkylsulfinyl, Cs-

C7 cycloalkylsulfonyl, C5-

C7 cycloalkenylsulfanyl, C5-

C7 cycloalkenylsulfinyl, C5-

C7 cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, heteroarylsulfonyl or heteroaryl sulfinyl, with the alkynyl and alkenyl groups mentioned above may be mono- or polysubstituted by fluorine or chlorine and may be mono- or di-substituted with the same or different residues I_1, as defined above the cycloalkyl and cycloalkyl rings independently of one another may be mono- or di-substituted by substituents selected from fluoro and C 1 -C 6 alkyl, and in the above-mentioned cycloalkyl and cycloalkenyl rings, one or two methylene groups independently at one of odnoyimozhut be replaced by O, C, CO, GO, ZO2 aboΝΡ^ν,

P^Ν means H or C-Salkil

In each case, I_1 is independently selected from the group consisting of cyano group, nitro group, aryl, heteroaryl, Ci-Sdalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, Ci-Sdalkylaminocarbonyl, di (Ci-

Zalcyl) aminocarbonyl, pyrrolidine-i-ilcarbonyl, piperidin-1-ylcarbonyl, morpholin-d-ilcarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, Ci-Sdalkoxycarbonyl, aryl-Ci -Salkoxycarbonyl, heteroarylCi -Salkoxycarbonyl, Ci-

An aralkyl group, an aryloxy group, a heteroaryloxy group, a Ci-Sdalkylsulfanyl, arylsulfanyl, a heteroaryl sulfanil, a Ci-Salkylsulfinyl group, an arylsulfinyl group, a heteroarylsulfinyl group, a Ci-Sdalkylsulfonyl group, an arylsulfonyl group, and a heteroarylsulfonyl group

And in each case independently selected from the group consisting of fluorine, chlorine, bromine, iodine, C1-C6alkyl, difluoromethyl, trifluoromethyl, C2-C2alkoxy, difluoromethoxy, trifluoromethoxy, and cyano, and

R^b, P^7a, P^7b, P^7s independently of one another, represent hydrogen, (C1-C2alkyl) carbonyl, (C1-C2alkyl) oxycarbonyl, arylcarbonyl, or aryl- (C1-C6alkyl) carbonyl,

while under the aforementioned residues indicated in the definitions given above, the aryl groups have the meaning of phenyl or naphthyl groups which can be mono- or di-substituted with the same or different residues I_2 independently of one another,

as indicated in the definitions given above

the residues by heteroaryl groups are on

Note pyrrol, furanyl, thienyl, pyridyl-

on, indolyl, benzofuranyl, benzothiophenyl-

on, a quinolinyl or isoquinolinyl group or a pyro-

17

lignyl, furanyl, thienyl or pyridyl group in which one or two methine groups are replaced by nitrogen atoms, or indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl, in which from one to three methine groups are replaced by nitrogen atoms, the above heteroaryl- groups independently of one another may be one or two substituents of the same or different residues I_2 and, unless otherwise indicated, said said alkyl groups may have a straight or branched chain, their tautomers, their stereoisomers, mixtures thereof, and their salts.

Below are the preferred values ​​for individual groups and substituents in the compounds of the invention.

The remnant of E^with is preferably located in the meta- or para-position relative to -CH₂-substance, according to which the preferred compounds of the following formulas 1.1 and 1.2, especially formula 1.2:

The term "aryl", which occurs in the definition of groups B1, E¹, IS^with, A and B, it is preferable to mean phenyl.

The term "heteroaryl", which occurs in the definition of groups BI, E¹, IS³, A and B, preferably refers to pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolilabo and thiadiazolyl.

Preferably, Group A is C2-Balkin-1-yl, C.₂1-ylcarbonyl, pyrrolidine-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-pyrrolidin-1-yl, cis-C7 cycloalkyl, C1-C7 cycloalkyl, C1-Sdalkylcarbonyl, aminocarboxyl, Ci-Sdalkylaminocarbonyl, di (C1-C6alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, ylcarbonyl, piperazin-1-ylcarbonyl, 4- (Ci-C4alkyl) piperazin-1-ylcarbonyl, C1-C4 alkoxycarbonyl, amino, C1-

Pyrrolidine-1-yl, pyrrolidine-2-on-1-yl, piperidin-1-yl, pyridin-2-one-1-yl, morpholin-4-yl, (C1-C4 alkyl) amino, yl, morpholin-3-one-4-yl, piperazin-1-yl, 4- (C1-C3alkyl) piperazin-1-yl,

C1-C4 alkylcarbonylamino group, C3-

Cycloalkyloxy, C5-

C7 cycloalkenyloxy, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C3-C7cycloalkylsulfanyl, C3-C7cycloalkylsulfinyl, C3-

Cycloalkylsulfonyl, C5-

Cycloalkenylsulfanyl, C5-

89040 18

Cycloalkenylsulfinyl, C5-

Cycloalkenylsulfonyl, cyano group or nitro group, with the above alkynyl and alkenyl groups may be mono- or polysubstituted by fluorine or chlorine, preferably fluorine, and may be mono- or bi-substituted with the same or different residues B1, and the cycloalkyl cycloalkenyl rings mentioned above independently of one another may be mono- or di-substituted by substituents selected from fluoro and C1-C3 alkyl, and in said above cycloalkyl and cycloalkenyl ring groups, or two methylene groups, independently of each other, may be substituted Annie at O, C, CO, GO, ZO2abo ΝΕ^ν, preferably on O or CO, is most important on O.

In a more preferred embodiment, Group A is

a C2 -Balkin-1-yl, C2-Salken-1-yl, C2-Cycicloalkyl, C1-Cycloalkenyl, C2-

Cycloalkyloxy, C5-

Cycloalkenyloxy, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C3-cycloalkylsulfanyl, C3-Cycicloalkylsulfinyl, C3-

Cycloalkylsulfonyl, C5-

Cycloalkenylsulfanyl, C5-

Cycloalkenylsulfinyl, C5-

Cycloalkenylsulfonyl, cyano group or nitro group, with the above alkynyl and alkenyl groups may be mono- or polysubstituted by fluorine or chlorine, preferably fluorine, and may be mono- or bi-substituted with the same or different residues B1, and the cycloalkyl cycloalkenyl rings mentioned above independently of one another may be mono- or di-substituted by substituents selected from fluoro and C1-C3 alkyl, and in said above C1-C6 cycloalkyl ring, the methylene group may be substituted on O.

In the most preferred embodiment, the group A is C2 -Balcine-1-yl, C2 -Balcen-1-yl, C6-Cycloalkyl, C3-Cycloalkyloxy or cyano group, while in the C1-C5 cycloalkyl groups, the methylene moiety may be replaced by AT.

Examples of especially preferred values ​​of the group A include ethinyl, prop-1-in-1-yl, but-1-in-1-yl, cyano group, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

Preferably, the group B is a Sobutur (Ci-Sdalkyl) silyl-Ci-Balcal, C2-Balkin-1-yl, C2-Balcen-1-yl, amino group, C6-alkanoylamino group, di (C1-C6alkyl) amino group, pyrrolidine- 1-yl, pyrrolidin-2-one-1-yl, piperidin-1-yl, piperidin-2-one-1-yl, morpholin-4-yl, morpholin-on-4-yl, piperazin- 1-yl,

4- (C1-Salkyl) piperazin-1-yl, nitro group, Cs-

Cycloalkyloxy, C5-

Cycloalkenyloxy, Cs-

Cycloalkylsulfanyl, Cs-

Cycloalkylsulfinyl, Cs-

Cycloalkylsulfonyl, Cg-

Cycloalkenylsulfanyl, Cg-

Cycloalkenylsulfinyl or C5-

Cycloalkenylsulfonyl, with the above alkynyl and alkenyl groups, may be mono- or polysubstituted by fluorine or chlorine, preferably fluorine, and may be mono- or di-substituted identical or different residues B1, and the above are cycloalkyl and cycloalkenyl rings,

19th

independently of one another may be mono- or di-substituted by substituents selected from fluoro and C1-C6alkyl, and in the above cycloalkyl and cycloalkenyl rings, one or two methylene groups, independently of one another, may be substituted on O, C, СО, ЗО, ЗО₂ or ΝΡ^ν, predominantly naO, CO, C, CO₂ or ΝΕ^ν, most preferably on OOE CO.

In a more preferred embodiment, the group B is three (C 1 -C 4 alkyl) silyl-Ci-Balcal, C2-Balkin-

i-yl, C2 -Balken-1-yl, nitro group, Cs-

Cycloalkyloxy, C5-

Cycloalkenyloxy, Cs-

Cycloalkylsulfanyl, Cs-

Cycloalkylsulfinyl, Cs-

Cycloalkylsulfonyl, C5-

Cycloalkenylsulfanyl, C5-

Cycloalkenylsulfinyl or C5-

Cycloalkenylsulfonyl, with the above-mentioned alkynyl and alkenyl groups, may be mono- or polysubstituted by fluorine or chlorine, preferably fluorine, and may be mono- or di-substituted identically or differently with the residues I_1, and the above-mentioned cycloalkyl and cycloalkenyl rings independently of one another may be one or two substituents selected from fluoro and C1-C6alkyl, and in the above cycloalkyl and cycloalkenyl rings, one or two methylene groups, independently of one another, may be substituted on O, C, CO, CO, ZO2, or ΝΕ^ν, preferably Na, CO, C, CO2, or N^ν, most preferably on OOE CO.

In the most preferred embodiment, the group B is three (C 1 -C 4 alkyl) silyl-C-balcal, C2-

Balkin-1-yl, C2-Balken-i-il, Cz-

Cycloalkyloxy, C5-

Cycloalkenyloxy, Cs-

Cycloalkylsulfanyl or C5-

Cycloalkenylsulfanyl, with the above alkynyl and alkenyl groups, may be mono- or polysubstituted by fluorine or monosubstituted chloride or by the residue I_1, and in the above-mentioned cycloalkyl and cycloalkenyl groups, one or two methylene groups may be independently substituted on O, CO, Z, ZO2 or ΝΕ^ν, first of all on О or СО.

Examples of especially preferred values ​​of the B group include trimethylsilylethyl, ethinyl, and propin-i-ol, 1-butyn-i-yl, tert-butylethynyl, 2-hydroxyprop-2-ilethinyl, 2-methoxyprop-2-ilethinyl, 1-propenyl, 1-butenyl, tert-butyl ethyl, cyclopropyloxy, cyclobutyloxy, cyclo-lpentyloxy, cyclohexyloxy, tetra-hydrofuranyloxy, hydroxy-i-propionyl, 3-methoxy-i -propin-i-yl, tetrahydrothiophenyloxy rupture, 1,1-dioxotetrahydrothiophenyloxy group,

tetrahidropiraniloksyhrupu, tetrahidrotiopiranilo-ksyhrupu, 1,1-dioksotetrahidrotiopiraniloksyhrupu, tetrahidrofuranoniloksyhrupu, piperydyniloksyh-rupee, piperydynoniloksyhrupu, pyrrolidine-out iloksyhrupu, pyrrolidinone-out iloksyhrupu, tetrahid-rofuranilsulfanil, tsyklopropilsulfanil, CEC-lobutylsulfanil, tsyklopentylsulfanil and cyclo-heksylsulfanil, while The N-group to the piperidinyl, piperidinonyl, pyrrolidinyl, or pyrrolidinonyl ring may be

89040 20

is replaced by the residue P^Ν, first of all, Cisalcilomabo acetyl.

The most preferred values ​​are trimethylsilylethyl, ethinyl, 2-hydroxyprop-2-ilethinyl, 2-methoxyprop-2-iletinyl,? -Hydroxy-i -propin-i-yl, 3-methoxy-i -propin-i-yl, cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group, tetrahydrofuran-y-yloxy group, tetrahydropyran-4-yloxy group, piperidin-4-yloxy group, N-methylpiperidine-4-yloxy group and N-

acetylpiperidine-4-yloxy group. Among these, particular mention should be made of ethinyl, trimethylsiliethyl, cyclobutyloxy, cyclopentyloxy rupture, cyclohexyloxy, tetrahydrofuran-cyloxy and tetrahydropyran-4-yloxy.

In the presence of residues or groups of A, B, and I^andor N^with cycloalkyl or cycloalkenyl chains in which two methylene groups are replaced by O, Zabo NP^ν or replaced by C, NP^ν, CO, CO2 or ZO2, these methylene groups are preferably not interconnected intermediately with each other. Two are methylene groups, substituted on O and CO or on NR^ν and CO, can be directly linked to each other with the formed-ynym-O-CO-, respectively, -NRN-CO-groups.

In a preferred embodiment, the value of the residue I_1 is selected from the group consisting of hydroxy, cyano, C 2 -C 7 -cycloalkyl, C 1 -C 4 alkylcarbonyl, amino-carbonyl, C 1 -C 4 alkylaminocarbonyl, di (Ci-

Zalcyl) aminocarbonyl, pyrrolidine-i-ilcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, Ci-C4alkoxycarbonyl, Ci-C4alkyloxy, Ci-C4 alkylsulfanyl, Ci-C4 alkylsulfonyl, and C4-C4 alkylsulfonyl.

In a more preferred embodiment, the values ​​of the buffer I_1 are selected from the group consisting of hydroxy, C 1 -C 4 alkoxy and C 1 -C 4 alkyl sulfanil.

When I_1 represents a hydroxy group, it is not directly connected to the C-atom of the double or triple bond.

The compounds of the invention, including their tautomers, their stereoisomers, mixtures thereof and their salts, according to the first embodiment, can be described by the general formula I, most notably by formulas 1.1 and 1.2, most preferably by the formula 1.2, where H^with has one of the above values ​​of group B, and other residues and substituents have the above and below values.

In this embodiment, the invention provides a negligible value for the remainder H^and include hydrogen, fluorine, chlorine, bromine, iodine, C1-C4alkyl, C2-Balcinyl, C4-C4alkoxy, C2-C4alkenyl-Ci-

A C 2 -C 4 alkynyl-C 1 -C 4 alkoxy group substituted with 1 to 3 fluoro methyl atoms, substituted with 5 fluorine atoms of ethyl, substituted with 1 to 3 atoms, a fluoro methoxy group substituted with 1 to 5 fluoroethoxy groups substituted by a hydroxy or C 1 -C 6 alkoxy C 1 -C 4 alkyl, substituted C 1 -C 4 -alkoxy, C 2 -Salkoxy, C 2 -C 4 -alkyl, C 2 -C 4 -alkoxy, C 2 -C 4 -alkoxy, C 2 -C 4 -alkoxy, C 2 -C 4 -alkoxy, C 2 -C 4 -alkoxy,

C1-C6 cycloalkyl-C1-C6alkoxy, C5-

The cocycloalkenyloxy group, hydroxy group, amino

pa, nitro group and cyano group, while in the C5-

In the cycloalkyl groups there is one methylene group

can be replaced by O.

21

The most preferred values ​​are hydrogen, fluorine, chlorine, bromine, cyano group, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, ethinyl, prop-1-in-1-yl, but-1-in-1-yl, hydroxy rupa, methoxy group, ethoxy group, difluoromethoxy rupa, cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group and cyclohexyloxy group, especially methyl and chloro.

The compounds of the invention, including their tautomers, their stereoisomers, mixtures thereof and their salts, according to a second embodiment, can be described by the general formula I, most notably by formulas 1.1 and 1.2, most preferably by formula 1.2, wherein E¹ has the above-mentioned value of A-group, and the remainder and substituents have the above and below values.

In this second embodiment, the invention provides the preferred values ​​of the residue E.³ fluorine, chlorine, bromine, hydroxy group, cyano group, C-i-Balcyl, trimethylsilylethyl, Cg-Balcenyl, Cg-Balkinyl, difluoromethyl, trifluoromethyl, Cs-Cycicloalkyl, Cg-Cocycloalkenyl, C1-

The benzyloxy group, difluoromethoxy group, trifluoromethoxy group, pentafluoroethoxy group, C3-Cycloalkyloxy group, tetrahydrofuranoyloxy rupa, tetrahydrofuranoyloxy group, C1-balkylsulfanyl, cyclopropylidenemethyl, aryl, and heteroaryl.

To more preferable values ​​of the balance of E¹ In this second embodiment, hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, t-butyl, ethinyl, 1-propynyl, trimethylsilylethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutane, cyclopentyl, methoxy, ethoxy, isopropoxy, cyclopentyloxy group, difluoromethoxy group, trifluoromethoxy group, pentafluoroethoxy group, tetrahydrofuran-3-yloxy group, tetrahydrofuran-2-one-3-yloxy group, methylsulfanyl, ethylsulfanyl, isopropylsulfanyl, cyclopropyl-denethyl, phenyl, fluorophenyl, pyridinyl, pyrimidine, pyridazinyl, pi azynil, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl and thiadiazolyl.

To the most preferred values ​​of the balance of E.¹in this second embodiment, hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, t-butyl, ethinyl, 1-propynyl, trimethylsilylethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutane, cyclopentyl, methoxy, ethoxy, isopropoxy , cyclopentyloxy, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, tetrahydrofuran-3-yloxy, tetra-hydrofuran-2-one-3-yloxy, methylsulfanyl, ethylsulfanyl, isopropylsulfanyl, and cyclopropyl-denethyl. Examples of such most important values ​​can be called methyl, ethyl, methoxy, ethoxy, trimethylsilyl-ethyl, ethynyl, cyclopentyloxy, tetrahydrofuran-3-yloxy and tetrahydrofuran-2-on-3-yloxy, in particular trimethylsilylethyl, ethoxy -group, cyclopentyloxy and tetrahydrofuran-3-yloxy.

The following are the values ​​of other residues and residues that, according to the general formula I, formulas 1.1 and 1.2, as well as the above-described variations

89040 22

The implementation of the invention should be regarded as overriding.

To the overriding values ​​of the balance of Е² fluorine, chlorine, bromine, methyl, hydroxy group, methoxy group, ethoxy group, trifluoromethoxy group, cyano group, nitro group, and substituted with 1 to 3 atoms in the methylthiopropylmethoxy group.

To the most preferred values ​​of the balance of E.²Hydrogen, fluorine, hydroxy group, methoxy-rupa, ethoxy group and methyl, in particular, are methylmethyl hydrogen.

To the overriding values ​​of the balance of Е⁴ include water and fluorine, primarily hydrogen.

To the overriding values ​​of the balance of Е⁵ include water and fluorine, primarily hydrogen.

The preponderant value of the residue E¹''¹ is H, methylene, ethyl or acetyl.

Preferably the remainder of E according to the invention^b is hydrogen, (C1-

Zalcyl) oxycarbonyl, C1-C9alkylcarbonyl or benzoyl, especially hydrogen or (C1-

Balcyl) oxycarbonyl or C1-C2alkylcarbonyl, more preferably hydrogen, methylcarbonyl, methoxy-carbonyl or ethoxycarbonyl, most preferably diatom or methoxycarbonyl.

The substitutes are E.^Ua, IS^uh, IS^Us (C1-C6alkyl) oxycarbonyl, (C1-C18alkyl) carbonyl or benzoyl, especially hydrogen or (C1-C5alkyl) oxycarbonyl or (C1-C6alkyl) carbonyl, especially hydrogen, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl or ethylcarbonyl. In the most preferred embodiment, each of the salts E^7a, IS^uh and E^7s means hydrogen.

Compounds of formula I in which E.^b, IS^Ua, IS^uh and E^usin accordance with the invention, is different from hydrogen, for example, denotes C1-

Szalkylcarbonyl can advantageously be used as intermediates in the synthesis of compounds of Formula I in which E^ua, IS^uh and E^us mean hydrogen.

The most preferred compounds of the general Formula I are selected from the group of compounds of formulas 2a and 2b, in particular Formulas I.2c:

23 89040 24

above for them, above all, one of the above-mentioned above as preferred, values ​​and all-in front of P^and means hydrogen, fluorine, chlorine, bromine, iodine, Ci-Sdalkyl, C2-Balkinyl, C2-Sdalkoxy, C2-Sdalkenyl-C2-Sdalkoxy, C2-Sdalkinyl-Ci-

A substituted alkoxy group substituted with 1 to 3 fluoromethyl atoms substituted with 1 to 5 fluorine atoms of ethyl substituted with 1 to 3 fluoro atoms of a methoxy group substituted with 5 fluoro ethoxy groups substituted by a hydroxyl or C 1 -C 6 alkoxy group of C 1 -C 6 -alkyl, substituted hydroxy C1-C6alkoxy group C2-

Sdalkoxy, C2 -Salkenyl, C2-Sbcycloalkyl, C2-Sbcycloalkyl-Si-Salkyl, C2-

C1-C6 cycloalkyl-C1-

A C 1 -C 6 alkyloxy group, a C 1 -C 6 cycloalkenyloxy group, a hydroxyl group, an amino group, a nitro group or a cyano group, while in the C 5 -C 7 Cycloalkyl groups, one methylene group may be substituted on O, most preferably hydrogen, fluoro, chloro, bromo, cyano, methyl , ethyl, isopropyl, difluoromethyl, trifluoromethyl, ethinyl, prop-in-and-il, buty-and-indolyl, hydroxy, methoxy, ethoxy, difluoromethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cycloalkyl -haloxyloxy group

R² means hydrogen, fluorine, hydroxy, methoxy, ethoxy or methyl, especially hydrogen per day or methyl,

R^with selected from among the values ​​of the B group in the range comprising trimethylsilylethyl, ethinyl, 1-propyl-i-yl, 1-butyn-1-yl, tert-butylethynyl, 2-hydroxyprop-2-ilethinyl, 2-methoxyprop-2-iletinyl, 3-methoxy-i -propin-i-yl, 3-methoxy-i-propin-i-yl, ethenyl, 1-propenyl, 1-butylene, tert-butylene, cyclopropyloxy, cyclobutyloxy, cyclo-lpentyloxy, cyclohexyloxy, tetra- hydrofuranyloxy group, tetrahydrothiophenyloxy rupe, 1,1-dioxotetrahydrothiophenyloxy group,

tetrahidropiraniloksyhrupu, tetrahidrotiopiranilo-ksyhrupu 1.1 -dioksotetrahidrotiopiraniloksyhrupu, tetrahidrofuranoniloksyhrupu, piperydyniloksyh-rupee, piperydynoniloksyhrupu, pyrrolidine-out iloksyhrupu, pyrrolidinone-out iloksyhrupu, tetrahid-rofuranilsulfanil, tsyklopropilsulfanil, CEC-lobutylsulfanil, tsyklopentylsulfanil and cyclo-heksylsulfanil, while The N-group is piperidinyl, piperidinonyl, pyrrolidine-

nyl or pyrrolidinonyl ring may be substituted by a P residue^Ν, especially C1-C6alkyl or acetyl, most preferably of a number which includes trimethylsilylethyl, ethinyl, 2-hydroxyprop-2-ilethinyl, 2-methoxyprop-2-ilethinyl, and -hydroxy-i -propin-i-yl, 3-methoxy- and cyclopropyloxy, cyclohexyloxy, tetra-hydrofuran-to-hydroxy, tetrahydropyran-4-yloxy, piperidin-4-yloxy, N-methylpiperidine-4-yloxy and N-

acetylpiperidine-4-yloxy group,

R⁴ means hydrogen or fluorine, especially one day,

R⁵ means hydrogen or fluorine, especially one day,

R⁶ means hydrogen, (Ci-Balcyl) oxycarbonyl, (Ci-Balcyl) carbonyl or benzoyl, especially hydrogen per day, methylcarbonyl, methoxycarbonyl or ethoxy-carbonyl, most preferably hydrogen, and

R^7a, P^7b, P^7s independently of one another are hydrogen, (Ci-Balcyl) oxycarbonyl, (Ci-Salkyl) carbonyl or benzoyl, especially hydrogen, methoxycarbonyl, ethoxycarbonyl, methylcarbonylabo and ethylcarbonyl, most preferably hydrogen,

including their tautomers, their stereoisomers, their mixtures and their salts.

In the above-described embodiments, it is also preferred that those compounds in which the phenyl group is in the group carrying the substituent P^with, has at least one other hydrogen substituent R⁴ and / or R⁵. Inthis case, the most preferred are those compounds inwhich is the substitute of P⁴ is fluorine.

Fennyl residue bearing the substituent R.^with, in the preferred variant is the maximum monofluorocarbon.

Preferred according to the invention are represented in the next experimental portion of the compound of the general formula I, as well as derivatives thereof, wherein R⁶ in accordance with the invention, which is different from hydrogen, means ethoxycarbonyl or methoxycarbonyl, including their tautomers, their ste-reosomers, and mixtures thereof.

The most preferred compounds of the general Formula I are selected from the group consisting of

(1) and -chloro-2- (4-cyclopentyloxybenzyl) -4-f-O-glucopyranos-y-yl) benzene,

(2) and-chloro-4-p-0-glucopyranos-y-yl) -2- [4 - ((P) tetrahydrofuran-cyloxy) benzyl] benzene,

(3) and-chloro-4-p-0-glucopyranos-y-yl) -2- [4 - ((5) -tetrahydrofuran-cyloxy) benzyl] benzene,

(4) and-chloro-4-p-0-glucopyranos-y-yl) -2- [4- (tetrahydrofuran-2-onyloxy) benzyl] benzene,

(5) and-chloro-4-p-0-glucopyranos-i-yl) -2- (4-cyclobutyloxybenzyl) benzene,

(6) and-chloro-4-p-0-glucopyranos-y-yl) -2- (4-cyclohexyloxybenzyl) benzene,

(7) and-chloro-4-p-0-glucopyranos-i-yl) -2- [4- (tetrahydropyran-4-yloxy) benzyl] benzene,

(8) and -chloro-4-p-0-glucopyranos-i -yl) -2- [4- (α-acetylpiperidin-4-yloxy) -benzyl] -benzene,

(10) and -f-0-glucopyranos-i-yl) -4-methyl-5- [4- (tetrahydrofuran-cyloxy) benzyl] benzene,

(11) and -f-0-glucopyranos-i-yl) -4-methyl-5- [4- (2-trimethylsilylethyl) benzyl] benzene,

25

(12) 1-chloro-4-p-0-glucopyranos-1-yl) -2- (4-ethinylbenzyl) benzene,

(13) 1-chloro-4- (P-O-glucopyranos-1-yl) -2- [4- (piperidin-4-yloxy) benzyl] benzene,

(14) 1-Fluoro-4-p-0-glucopyranos-1-yl) -2- (4-ethinylbenzyl) benzene,

(15) 1-β-O-glucopyranos-1-yl) -3- (4-ethinylbenzyl) benzene,

(16) 1-Ethinyl-4- (P-O-glucopyranos-1-yl) -2- (4-ethoxybenzyl) benzene and

(17) 1-methoxy-4-p-0-glucopyranos-1-yl) -2- (4-ethinylbenzyl) benzene, as well as derivatives thereof, in which P⁶in accordance with the invention, which is different from hydrogen, means ethoxycarbonyl or methoxycarbonyl, including their tautomers, their ste-reosomers, and mixtures thereof.

In the implementation of the methods of the invention, the residues R¹, P², P³, P⁴ and R⁵ preferably are as above preferred values. In addition, P 'in this case is preferably H, C1-C6alkyl or benzyl, especially H, ethyl or methyl. Remains of R^8a, P^8b, P^8s and R^{8s |} independently of one are preferably H, C1-

C4 alkylcarbonyl or benzyl, especially H, methylcarbonyl, ethylcarbonyl or benzyl.

The subject matter of the present invention is also useful as intermediates or starting compounds for the synthesis of the compounds of the invention of the compounds of the general formula IV, especially the general formula IV '

in which NaI means chlorine, bromine or iodine, leaving R¹, P², P⁴ and R⁵ have the above values, and the balance of P³ is selected among the values ​​of group B. Particularly preferred is the remainder of P¹, P², P³, P⁴ and R⁵ have the meanings specified for the formulas І.2a-І.2b. The most preferred compounds of general formula IV, in which NaI is chlorine, bromine or iodine, the residues P¹, P², P⁴ and R⁵ the values ​​for the formulas І.2a-І.2b are given, and the balance of Р³is ethynyl or C3-Cb-1-alkyl-1-yl, wherein the ethinyl group may be substituted with a -81R3 hollow, wherein the residues P independently of one another represent C1-C4alkyl, C1-C4alkoxy orарил, and С3- The 1? -Alkyl-1-yl group can be substituted by hydroxy or C 1 -C 3 alkoxy, in general, with a hydroxy or methoxy group.

Another object of the present invention is to be used as intermediates or starting compounds in the synthesis of the compounds of the invention of the compounds of general formula II, especially the general formula II '

in which P ', P^8a, P^8b, P^8s, P^8s,

R¹, P², P³, P⁴ and R⁵

have the above and below values, and in particular, the term P 'means H, C 1 -C 3 alkyl or benzyl, in the first instance H, ethyl or methyl, the residues P^8a, P^8b, P^8s and R^8sindependently of one another denote H, C1-C4alkylcarbonyl or benzyl, especially H, methylcarbonyl, ethylcarbonyl or benzyl, the residues P¹, P², P⁴ and R⁵ have the above values, and the hole-shock R.³ selected among the values ​​of group B. In the most preferred embodiment, the residues P¹, P², P³, P⁴and R⁵ have the same meanings for the formulas b2a-I.2.

The following are more detailed definitions of the terms used above and in the following for the compounds of the invention.

The term "halogen" means an atom selected from the group consisting of P, SI, B and I, in particular P, SI and

Hr

The term "C1-Spalkyl", wherein η may be from 1 to 18, means a saturated branched or unbranched hydrocarbon group containing from 1 to η C atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, and

propylcarbonyl

butylcarbonyl

butylcarbonyl

etc.

The term "C2-Palkkinil", wherein η may have a value of from 3 to 6, means a branched or unbranched-wise hydrocarbon group containing from 2 to η C-atoms and a triple carbon-carbon bond (^ = C) . Examples of such groups include ethinyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc. Unless otherwise indicated, alkynyl groups are bonded via the C atom to the position1 with the other part of the molecule. Accordingly, such designations as 1-propynyl, 2-propynyl, 1-butynyl, etc., are equivalent to 1-propin-1-yl, 2-propin-1-yl, 1-butyn-1-yl, and the like. d. The above is analogous to the C2-Squalene groups.

The term "C1-Salkkoxy group" or "C1-Salkyloxy group" means C._gSpalk-O-group, in which C1-Spalkyl has the above values. Examples of such groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy rup, neopentoxy, t-pentoxy, n-hexoxy, isohexoxy and t .d

The term "C1-Pbalkylcarbonyl" means a C1-

Pklkil-C (= O) - a group in which C1-Spalkyl has a value higher than the value. Examples of such groups include methylcarbonyl, ethylcarbonyl, n-n-

otrn

isopropylcarbonyl

isobutylcarbonyl

t-butylcarbonyl

27 89040 28

pentylkarbonil, izopentylkarbonil, neopentylka rbonil-tert-pentylkarbonil, n-heksylkarbonil, izoheksylkarbonil etc.

The term "Cs-C₁₋₆alkyl" means a saturated, mono-, tri- or spiro-carboxylic group containing from 3 to η C atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo [3.2.1] octyl, spiro [4.5] decyl, norpinyl, norbornyl, nucuryl, adamantyl and t .d In the preferred embodiment, the term "C6-C7cycloalkyl" refers to saturated monocyclic groups.

The term & quot; C1-C6 cycloalkenyl & quot; means the C5 -Pcycloalkyl group as defined above and having at least one unsaturated double carbon-carbon bond (C = C).

The term "Cs-Ci-Cycloalkylcarbonyl" means Cis -Phc-Cycloalkyl-C (= O) -group, wherein Cs-Ccycloalkyl has the above-stated meaning.

The term "tri (Ci-Sdalkyl) silyl" means a silyl group having the same or two or three different alkyl groups.

The term "di (C1-C6alkyl) amino group" means an amino group of the same or two different alkyl groups.

The graphical representation of the structural formulas used in the preceding and subsequent descriptions, in which the substitution of a phenyl group in a phenyl group has been carried out to the center of a phenyl ring, means that this substituent, unless indicated otherwise, can be attached to any free- th position of the phenyl ring bearing the H atom.

The compounds of the invention can be obtained by using, in principle, known synthesis methods. Preferably, such compounds are provided in more detail below by the methods proposed in the invention.

The glucose derivatives of Formula II according to the invention can be obtained from Y-gluconolactone or its derivative by attaching the desired benzylbenzene compound as a metal organ-compound (Scheme 1).

As the starting compound in the reaction according to Scheme 1, it is preferable to use a benzene benzene compound of the general formula IV in which the NaI is chlorine, bromine or iodine. Going from the halogen-substituted aromatic compound of Formula IV, the corresponding organometallic compound (V) can be obtained either by the so-called substitution of halogen on the metal, or by conducting metal by binding of carbon-halogen. For the replacement of a halogen to a metal in bromo- or iodide-containing aromatic compounds, for example, it is possible to interact with a lithium organic compound such as n-, sec- or t-butyllithium, with the corresponding lithiated aromatic compounds. A similar magnesium-containing compound can also be obtained by substituting halide onmetal by reaction with an acceptable Grin-yar compound, such as, for example, isopropylmagnesium bromide or diisopropyl magnesium.

or methylene chloride. The magnesium, respectively, lithium-containing compounds thus obtained can be displaced by metal salts, such as cerium trichloride, to others suitable for use in the methanorphan compounds (V) addition process, when necessary. In another embodiment, meta-organic compounds (V) can also be obtained by introducing the metal by the bonding of carbon monoxide in a halogen-substituted aromatic compound of formula IV. For this purpose, suitable metals such as, for example, lithium or magnesium. The addition of meta-organochlorine compound V to gluconolactone according to its derivative of formula VI is preferably carried out at a temperature in the range of from 0 to -100 ° C., most preferably from -30 ° to -80 ° C., a dielectric solvent or a mixture thereof Preparation of the compounds of formula II.

29 89040 30

As solvents, for example, diethyl ether, toluene, methylene chloride, hexane, tetrahydrofuran or mixtures thereof can be used. Reactions can be carried out without additional auxiliary agents, or in the case of chemically passive reagents that give rise to a coupling, in the presence of a Lyusian kissel, such as, for example, VES-OEI2 or MezVISI [see. M. ZsMoejeg, Oshpoteaeiisie ip Zuppeeiee, View of the Shiyou & Zope, Spišeideig / Meimohök / Vigienepa / Togopio / ZIPdaroge, 1994]. In this case, the predominant values ​​of groups P^8a, P, P^8s and R⁸⁸ benzyl, substituted benzyl, trialkylsilyl, most preferably trimethylsilyl, trisopropylsilyl, 4-methoxybenzyl and benzyl. If two adjacent parts of the group consisting of P^8a, P, P^8s and R⁸⁸, are both bound together, both of these residues are preferably a fragment of benzylidene acetal, 4-methoxybenzylidene acetal or isopropyl ketal, or a 2,3-dimethoxybutylene group, which is bound to adjacent oxygen atoms of the pyranose ring through positions 2 and 3 butane The remainder of P 'is preferably hydrogen or Ci-Sdalkyl,

more preferably hydrogen, methyl or ethyl. Shut-off P 'is introduced after the addition of organometallic compound V or its derivative to the gluconolactone of the Formula VI. For this, the reaction solution is treated with an alcohol, such as, for example, methanol or ethanol, or water in the presence of an acid such as, for example, methanesulfonic acid, toluene sulfonic acid, sulfuric acid or hydrochloric acid.

Halogen-substituted aromatic compounds of formula V may be synthesized using standard-transformed organic chemistry or using at least the methods known in the field of organic synthesis from special literature (see, for example, b. Magsi, Abuapseb Ağdapis Reaciyope, Reasyiope, Mesiyapite, A8 Zigismiego, 4th ed., Shiyou & Zope, SIIiyeye / NedaUohk / VgIyiapa / Togopio / ZIPdarog, 1992, and the literature cited in this publication]. The above-mentioned generalized form is illustrated by the example of the below-mentioned synthesis options.

In the above scheme, which illustrates the 1 st synthesis variation (Scheme 2), it is shown that the halo-substituted aromatic compound of formula II is obtained from benzoylchloride and the second aromatic compound, which is converted by acylation by Friedel-Craft in the biphenylketone derivative. This classical a reaction characterized by a large selection of substrates is carried out in the presence of a catalyst which is used in a catalytic or stoichiometric amount, such as AISI, EeSis, iodine, iron, 2PCC sulfuric acid or trifluoromethanesulfonic acid Lot Instead of carboxylic acid chloride, it is also possible to use carboxylic acid, its anhydride or ester or the corresponding benzonitrile. Such reactions are generally carried out in chlorinated hydrocarbons, such as, for example, dichloromethane and 1,2-dichloroethane, at a temperature in the range of -30 to 120 ° C., preferably from 30 to 100 ° C. However, it is possible as well as chemical transformations carried out after the removal of solvents, or chemical transformations carried out in a microwave oven. At the second stage of the reaction

Diphenylketone is reduced to diphenylmethane. Zureaction can be carried out in two stages through the preparation of the corresponding intermediate diphenylmethanol or in one stage. In carrying out a similar reaction, two stages of the ketone, its interaction with a reducing agent, for example, a metal hydride, such as IMAVND, BIIAD or iso-VsCHAIN, is reduced to alcohol. The obtained alcohol can be transformed in the presence of peanut butyric acid, for example, VEE-OEG, trifluoroacetic acid , IpSiZ or AISI, interacting with a reducing agent such as, for example, EIZZIN, IMAVND or RIGZISIN, in the required diphenylmethane. In the same stage of the process, the ketone can be converted into diphenylmethane, for example, by interaction with a silane such as, for example, EISI , Borohydride such as eg IMaVNd or aluminum hydride such as BIAINd in presence-ness lyuisovoyi acids such as VES-oEih, tris (pentafluorophenyl) borane, trifluoroacetic acid, aluminum chloride or ipSiZ. Such reactions are preferably carried out in solvents, for example halogenated hydrocarbons such as dichloro-

31

methane, toluene or acetonitrile, at temperatures in the range of -30 to 150 ° C., preferably from 20 to 100 ° C. Another possible method of synthesis is also in the reduction of hydrogen in the presence of a catalytic converter on the basis of a transition metal, such as, for example, Pb on coal. Recovery can be done according to the Kizhne-Wolff reaction or its modifications. In this case, the ketone interacting with hydrazin or its derivatives, such as 1,2-bis- (t-butyldimethylsilyl) hydrazine, is initially translated into hydrazone, which then in the strongly alkaline reaction conditions, during distillation, disodium phenylmethane and nitrogen are decomposed. This reaction can be carried out in one stage or in two separate stages after the appearance

89040 32

Hydrazone or its derivative. If the foundations withThis used, for example, KOH, №ONabo-tert-Κθ you in solvents, such as ethylene glycol, toluene, DMSO, 2- (2-butoksietoksy) ethanol or tert-butanol, but sosame chemical transformations may carry ypid time of absence of solvents. Reactions can be further carried out at a temperature in the range of from 20 to 250 ° C., preferably from 80 to 200 ° C. An alternative to the recovery of the Kizner-Wolf reaction, which occurs in alkaline conditions, is the restoration of the Klementsen reagent in acidic conditions, which can also be used in this case.

Scheme 3: 2nd version of the synthesis

In the above scheme, which illustrates the 2 nd version of the synthesis (Scheme 3), another motif of the preparation of a halogen-substituted aromatic compound of formula II is illustrated by the example of the trimethylsilylacetylene diphenylmethane substituted. Extract from an aromatic compound carrying two residues from a group comprising iodine, bromine, chlorine and sulfonate, such as, for example, trifluoromethylsulfonate, by catalyzing a transition metal to a more reactive end of the halogen substituted aromatic compound, i.e. in this case, iodine carbon, an alkynyl residue is added (step 1). As catalysts, in this case, for example, the use of elemental palladium or nickel or their salts or complex compounds are used. Reactions can be made with the use of the most alkin or the metal-cetylidene derived from it.

Sonogashir's reaction). Such reactions are not limited to the use of trimethylsilylacetylene, and before the use of various finitehalhkins. Such a reaction in all its possible modifications is described in detail in the literature [see. Pb ZIAPD, P Ιίθάθίίξ, MIiAi-SAIAiUDEB SOGZZ-SOIRIIPRD REAsIiOpe, KIiyu-UHN, KHEIPYEIT, 1997, andApdem. Stu Ιπί. Eb 42, 2003, p. 1566-1568, cited in these publications of literature]. Both subsequent stages of the preparation of the diphenylmethane derivative include the re-functionalization of the alkynesubstituted aromatic compound to the metalloil (Md, B-containing) aromatic compound, which can be obtained, for example, by substituting halogen into a metal according to the method described above (step 2). This metallated aromatic compound, which can be used in the next reaction, either directly or after further refining, join to the benzaldehyde derivative. In this case, the representation represented by the scheme of diphenylmethanol. In another version, it is possible

33

89040

34

also to use a derivative of benzoic acid, such as, for example, ether, anhydride, chloranhydride, or benzoic acid, or the very acid-base benzonitrile. In this case, instead of alcohol, the corresponding ketone is formed, which can also be squeezed by the Free-worm-Crafting acrylics described above. The next transformation of alcohol and ketone in the biphenyl methane derivative is already described above (stage 3). However, trimethylsily-lyletinylated halogen-substituted aromatic sponge can also be immediately followed by transferring into the desired product (step 4). For this, obtained after replacing the halogen with a lithium or magnesium-containing magnesium metal, the reaction with benzyl electrolyte, such as, for example, benzyl bromide or -chloride, is obtained. The reaction can be carried out without or, more preferably, in the presence of a catalyst on the basis of a transition metal such as, for example,

POB 3, 2001, p. 2871-2874, and the literature cited in this public literature]. However, the lithium- or magnesium-containing aromatic compound can also be re-melted, for example, to the corresponding boronic acids, ethers of boronic acids, stananes, silanes or zinc-containing compounds. Then, with the transition metal, such as, for example, palladium, nickel, rhodium, copper or iron, the benzyl residue is added [see. B. VgapSet, Z.R. Uayeieueku, N.Yu. Ughghiieee, Lririsaiioop οί Tgapiyiopi MIiAiSaIAyuEiye iP AghdPis ZuPiIeziz, see ZgRypdeg-Vehiad, Vegipi / NeiSeIiEgd, 1998]. The substituted alkynamoromatic compounds can be converted into an intermediate of the formula II 'according to steps 2 and 3 or step 4, which in this case are considered in the example of P³ in the sense of ethinyl, respectively, of trimethyl-lsilyletinil, by analogy and with the use of other substituted by other residues of P³ aromatic compounds.

The third variant of synthesis (Scheme 4), which is a variation of the 2nd synthesis option, is also explained by the example of the preparation of trimethylsilylethinilated aromatic compound of formula II, but is not limited to the preparation of such a compound. The synthesis is made up of an aromatic compound that carries the NaII group, which is a halogen atom of chlorine, bromine or iodine, or a pseudohalogen group such as, for example, i-trifluoromethanesulfonate, and also having a meta-left center M, such as B (OH )₂-, Zi (OLK) z- or ZvVis-balance. Both of these "activated-vans" in such a way centers can be sequentially transposed chemosecely. A similar substitution in the 3-sample of the synthesis is illustrated by the example in which initially a halide atom of NaI by a reaction-catalyzed transition metal, for example, by a combination of the so-called Sono-gashir reaction, is replaced by an alkynyl substituent. At the second stage, the metal center M by another catalysed transition metal of the coupling reaction is replaced by a benzyl residue activated, for example, in the form of benzyl halide, from the resulting

for the necessary product [see, for example, TejgaIeSgop Beyb 44, 20θ3, p. 9255-9258, as well as literature cited in this publication]. Both stages can be carried out with the use of transitionmetals such as, for example, palladium, rhodium, niolevel, copper or iron, or their complex compounds. The reactions of both types are described in detail in the literature. Both of the considered reaction stages can be carried out not only in the above sequence, but also in reverse order. In accordance with this approach, initially, you can replace the metal center M with the gasoline residue, and then replace the halogen or the pseudohalogen group on alkin.

For the preparation of compounds of general formula I according to the variant a) of the method of the invention, obtained by the method described above, a compound of general formula II

35

I¹ I²

89040

and, for example, independently of one another, denote acetyl, pivaloyl, benzoyl, t-butoxycarbonyl, benzyloxycarbonyl, trialkylsilyl, benzyl or substituted benzyl, or each of two adjacent residues from the number Y^8a, I^8b, I^8s, I⁸⁸ form a benzylidene acetal or isopropylideneketal or 2,3-dimethoxybutylene group, which through the positions 2 and 3 of the butylene group is attached to the oxygenates of the pyranose ring and forms a substituted dioxane with them, are reacted with a reducing compound in the presence of a lesy or brusted acid.

Examples of suitable compounds for use with reducing agents include silanes such as triethyl, tripropyl, trisopropyl or diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane, lithium aluminum hydride, diisobutylalumohydride or samarium iodide. Similar redox reactions are carried out in the absence or in the presence of suitable brendium tide acid, such as, for example, hydrochloric acid, toluenesulfonic acid, trifluoroacetic acid or acetic acid, or leucic acid, such as, for example, bortifluoroderate, tri- methyl silyl triflate, titanium tetrachloride, tetrachloride tin, triflate of scandium or zinc iodide. Depending on the particular used reducing agent and acid, the reaction can be carried out in a rosin factor such as, for example, methylene chloride, chloroform, acetonitol il, toluene, hexane, diethyl ether-headed, tetrahydrofuran, dioxane, ethanol, water, or a mixture thereof, at a temperature in the range of -60 to 120 ° C. As an example of the most preferred combination of reagents, the combination of triethylsilane and bortifluorodederate, which is expediently used in acetonitrile or dichloromethane at a temperature in the range of -60 to 60 ° C, can be called. In addition, for the above-described transformation, it is also possible to use hydrogen in the use of which the reduction is carried out in the presence of a transition metal catalyst, such as, for example, palladium on charcoal or Raney nickel, in solvents such as tetrahydrofuran, ethyl acetate, methanol, ethanol , water or acetic acid. As an example of the most preferred combination of reagents, the combination of triethylsilane and bortifluorodederate, which is expediently used in acetonitrile or dichloromethane at a temperature in the range of -60 to 60 ° C, can be called. In addition, for the above-described transformation, it is also possible to use hydrogen in the use of which the reduction is carried out in the presence of a transition metal catalyst, such as, for example, palladium on charcoal or Raney nickel, in solvents such as tetrahydrofuran, ethyl acetate, methanol, ethanol , water or acetic acid. As an example of the most preferred combination of reagents, the combination of triethylsilane and bortifluorodederate, which is expediently used in acetonitrile or dichloromethane at a temperature in the range of -60 to 60 ° C, can be called. In addition, for the above-described transformation, it is also possible to use hydrogen in the use of which the reduction is carried out in the presence of a transition metal catalyst, such as, for example, palladium on charcoal or Raney nickel, in solvents such as tetrahydrofuran, ethyl acetate, methanol, ethanol , water or acetic acid.

In a second embodiment, for the preparation of compounds,

of the general formula I according to option b)

a process according to the invention from a compound

general formula III

36

means one of the aforementioned protecting groups, such as, for example, an acyl, arylmethyl, acetal, ketal or silyl group obtained, for example, from a compound of the formula II of the above described recovery, the cleavage of the protecting group.

The acyl protecting group used is split off, for example, by hydrolytic addition of an aqueous solvent, such as water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid, or in the presence of a base metal such as lithium hydroxide, hydroxyditrile or potassium hydroxide, or aprotic gallium, for example in the presence of iodotrimethylsilane, at a temperature of from 0 to 120 ° C., preferably from 10 to 100 ° C. WITH. The trifluoroacetyl group is predominantly cleaved with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid, at a temperature of from 50 to 120 ° C., or by treatment with caustic soda, non-viscous in the presence of a solvent such as tetra-hydrofuran or methanol,

The used acetal or ketal protecting group is cleaved, for example, by hydrolytic means in an aqueous solvent, for example, effluent, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid , hydrochloric acid or sulfuric acid, or in the aprotic way, for example in the presence of iodotrimethylsilane, at a temperature of from 0 to 120 ° C., preferably 10 to 100 ° C.

The trimethylsilyl group is cleaved, for example, in water, an aqueous mixture of solvents, or a lower alcohol such as methanol or ethanol, in the presence of a base such as lithium hydroxide, hydroxide, potassium carbonate, or sodium methoxide. For the cleavage of a trimethylsilyl group in aqueous or alcoholic solvents, acids may also be used, such as, for example, hydrochloric acid, trifluoroacetic acid, or acetic acid. For the cleavage of the trimethylsilyl group in inorganic solvents, such as diethyl ether, tetrahydrofuran or dichloromethane, fluoride reagents are also suitable, for example, tetrabutylammonium fluoride.

The benzyl, methoxybenzyl or benzyl-cis-carbonyl group is preferably cleaved by hydrogenolysis, in particular under the action of hydrogen in the presence of a catalyst, such as vulgar palladium, in an acceptable solvent such as methanol, ethanol, ethyl acetate or acetic acetic acid, optionally with the addition of acid, such

37

as hydrochloric acid, at a temperature of from 0 to 100 ° C., but preferably at room temperatures in the range of from 20 to 60 ° C., and at a hydrogen pressure of 1 to 7 bar, preferably, however, from 3 to 5 bars. The 2,4-dimethoxybenzyl group is preferably, however, isolated from trifluoroacetic acid in the presence of an anisole.

tert-Butyl or tert-butyloxycarbonyl group is preferably cleaved with an acid such as trifluoroacetic acid or hydrochloric acid, or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ester.

In carrying out the reactions described above, under certain conditions, reactive groups, such as baintinin groups, hydroxy, amino, alkylamino or amino groups, can be protected at the time the reaction takes place with ordinary protecting groups and again separated from the reaction upon completion of the reaction, in particular, as described herein. methods.

As an example of a protecting group for the ethinyl group, the trimethylsilyl or trisopropyl group can be mentioned. As a protecting group in this case, the 2-hydroxyisoprop-2-yl group can itself be used.

As an example of a protecting group for a hydroxy group, one can refer to trimethylsilyl, acetyl, tri-tall, benzyl or tetrahydropyranyl group.

As an example of a protecting group for the amino, alkyl-mino- or imino group, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group can be mentioned.

In addition, the resulting compounds of the general Formula I can be separated, as already indicated at the beginning of the description, into their enantiomers and / or diastereomers. Thus, for example, cis- / trans-mixtures can be separated by their separate cis and trans isomers , and compounds at least with one optically active carbon atom can be divided into their enantiomers.

Thus, in particular, the resulting cis / trans mixtures can be separated by chromatography into their separate cis- and trans-isomers; the compounds of the general Formula I, which are formed as racemates, can be separated by known methods [see AIIPEED N.0 and EIIiEi Ex., "Thorris and IseEgegospezii", vol. 6, Miocannon et al., 1971] on their opticalantipodes, and compounds of the general formula I and at least two asymmetric carbon atoms can be based on the differences in their physico-chemical properties by known methods, for example, chromatography and / or fractionated crystal -zation, on their diastereomers, which, when they are formed, a racemic form, can be further separated, as described above, into enantiomers.

The enantiomers are preferably carried out by column separation on chiral phases, or by recrystallization from an optically active solvent, or by interaction with an optically active substance that forms a racemic compound of a salt or derivatives such as complex ethers or amides, in particular with acids and their active derivatives or alcohols, and the separation isobtained as a result of a mixture of diastereomeric

89040 38

salts or derivatives, for example, based on differences in solubility, while pure diastereomeric salts or derivatives can be liberated by effective antipodes by the action suitable for this purpose. As an example, the most commonly used for the above-mentioned purposes, the optically active acids can be called u-and b-forms of wine aldibenzoylvinnic acid, di-O-tolylvinnic acid, malic acid, almond acid, camphorsulfonic acid, glutamic acid, asparagine acid or chic acid. An example of a motivatedly active alcohol is (+) - or (-) - menthol, but as an example of an optically active acyl residue in amides, one can call (+) - or (-) - menthyloxycarbonyl.

In addition, the resulting compounds of formula I can translate into their salts, primarily for pharmacological use - in their physiologically compatible salts with inorganic or organic acids. As an example of suitable for this purpose acids can be called hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

The resulting compounds can then be transferred to a mixture, for example, in a mixture with a ratio of 1: 1 or 1: 2, with amino acids, especially with os-amino acids such as proline or phenylalanine, which may have optimal properties, however, as a high degree of crystallinity .

The compounds of the invention are also preferably prepared in the examples described below in the methods that for this purpose can also be combined with known specialists in the art, for example, from literature methods, especially with the methods described in MO 98/31697, MO 01 / 27128, MO 02/083066, MO 03/099836 and MO 2004/063209.

The compounds of the general formula I and their physiologically compatible salt according to the invention have, as indicated above, at the beginning of the description, valuable phaneramic properties, primarily inhibiting the sensation of a natriess dependent catheter of glucose, preferably 8CST2.

The biological properties of the new compounds can be verified by the method described below.

The ability of the compounds of the invention to inhibit 8CB2 activity can be tested experimentally using the cell line CHO-K1 (ATCC No. OS 61) or in another variant of cells of the HEK293 line (ATCC No. SR-1573), which has been successfully transfected with the expressing vector of the epoxy (firm Hipiyogodep , registration number I_36849 in the EMSB database) containing the cDNA for the cytokine sequence of human natriasis glucose type 2 catheter (registration number in the gene bank, NМ_003041) (CHO-I8CB2, respectively, NEC-I8CB2). The cells of cichlids provide a natriyasljenny transportin them inside¹⁴C-labeled 01-

methylglucopyranoside (¹⁴C-AMG, firmAtegzIyat).

Experiments on suppressing the activity of 8CB2 pro-

drive this way.

CHO-I8ST2 cells are cultured in a medium-

Supreme Hem P12 (firm ViomIiIiAiAkg), supplemented

39

10% of fetal calf serum and zeocin at a concentration of 250 μg / ml (Ipuiyogodep), and cells NEK29z-I86bT2 cultured in a 1EMEM medium (modified by the Dulbecco Eagle environment), supplemented with 10% fetal serum and zeocin at a concentration of 250 μg / ml (Ipuiyogodep )

Cells are separated from the flasks for cultivation by two-time flushing with zabuf-rhenium phosphate by physiological solution (PFR) and subsequent treatment with trypsin / EDTA. After addition of the culture medium, the cells are purified by centrifugation, then resuspended in a culture medium and counted on a cathode-gauge with SA8U technology. After this, the cells were seeded in a white, coated poly-O-lysine 96-well plate in an amount of 40,000 wells and incubated overnight at 37 ° C. and 5% CO2. The cells are then washed twice with 300 μl of Buffer for analysis (balanced Hencex salt solution containing IChCl at a concentration of 110 mM, KCl in a concentration of 5.4 mM, SACl 2 at a concentration of 2.8 mM, Md8Od at a concentration of 1.2 mM and HERO8 M-2-hydroxyethylpiperazine-M-2-ethanesulfonic acid) at a concentration of 10 mM (pH 7.4), as well as gentamycin at a concentration of 50 μg / ml). Next, in each ml, 250 μl of a buffer for analysis and 5 μl of the test compound are added and incubated for the next 15 minutes in the thermostat. 5 μl of 10% DMSO is used as a negative control. Reaction is initiated by adding 5μl in each well¹⁴C-AMG (0.05 mKi). After 2 hours of incubation at 37 ° C and 5% CO2, the cells are washed again with 300 μL PH (20 ° C.), after which they are lysed with addition of 25 μl 0.1 n. ICaON (for 5 minutes at 37 ° C). Then in 200 ml of scintillator Mizgo8spi20 (Rascagf and incubate for the next 20 minutes at 37 ° C. are added to each well). After completing this incubation, then in the detector Torsoipi (firm Raskagb) using the program of measurement of scintillation caused¹⁴C, measure the radioactivity of the absorbed ¹⁴C-AMG

To determine the selectivity with respect to human 861T1, a similar experiment was carried out in which the cDNAs for I86bT1 (register number in the OMN000343 gene bank) are expressed in CHO-K1 cells, respectively, NOK293, instead of the cDNA for Ig86iT2.

The compounds of the general formula I according to the invention may have, for example, EC50 values ​​less than 1000 nM, in particular less than 200 nM, most preferably less than 50 nM.

The compounds of the general formula I and their respective pharmaceutically acceptable salts according to their ability to suppress the activity of 8bTT are essentially suitable for treating and / or preventing all of these pathological conditions or diseases that may be influenced by the inhibition of the activity of 86bT, in particular the activity of 86bT2 . Therefore, the compounds according to the invention are suitable primarily for the prophylaxis or treatment of such diseases, mainly the disease of metabolism, or pathological conditions, such as diabetes mellitus type 1 and type 2, diabetic complications (for example, retinopathy, nephropathy or neuropathy, diabetic foot, ulcer, macroangiopathy,

89040 40

beta), metabolic acidosis or ketosis, reactive hypoglycemia, hyperinsulinemia, glucose metabolism disturbance, insulin resistance, metabolic syndrome, dyslipidemia of various genesis, atherosclerotic related diseases, obesity, hypertension, chronic heart failure, edema and hyperuricemia. In addition to the compounds of the present invention, it is possible to prevent de-neuratation of β-cells, for example, apoptosis or necrospancreatic β-cells. The compounds according to the invention are further suitable for improving or restoring the functional activity of pancreaticcells and, in addition, for increasing the number and size of pancreatic β-cells. The proposed compounds in the same way can be used as diuretic or antihypertensive drugs and are suitable for the prevention and treatment of acute renal insufficiency.

The compounds of the invention, including their physiologically compatible salts, are most suitable for preventing or treating diabetes, in particular diabetes type 1 and type 2, and / or diabetic complications.

Needed to achieve the appropriate action for the treatment or prophylaxis of the foregoing doses of the dosage of the compounds according to the invention, usually depends on the particular compound used, on the peculiarities of the body of the patient, on the type and severity of the disease or pathological condition present, and on the path and the frequency of administration of the active substance in the body and remains at the discretion of the physician. It is advisable to administer the compound according to the invention in an organism from 1 to 4 times daily in a dose that is from 1 to 100 mg, preferably from 1 to 30 mg, for intravenous administration, and is from 1 to 1000 mg per oral, preferably ranging from 1 to 100 mg. For this purpose, the invention provides compounds of the formula I, optionally in conjunction with other active substances, recycled together with one or more conventional inert carriers and / or diluents, for example, with corn starch, lactose, tropical sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol , water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethylcellulose, or fatty substances, such as hard fat, or their acceptable mixtures, strange galenic forms such as a tablet ing, pills, capsules, powders, solutions, suspensions or supozy-thorium.

The compounds of the invention can be used in combination with other active substances, especially for the treatment and / or prophylaxis of the above diseases and pathological conditions. As other such active compounds for use in combination with the compounds of the invention, the compounds are considered, first of all, those which, for example, enhance the therapeutic effect of the inhibitor 86bT proposed in the invention when used in one of the above indications and / or reduce the dosage of the proposed in the invention of an inhibitor

41

Z6BT For such therapeutic agents that may be used in combination with the compounds of the invention, there are, for example, antidiabetic agents such as metformin, sulfonylureas (eg, glibenclamide, tol-butamide, glimepiride), nateglinide, repaglinide, thiazolidindiones (e.g., Rosiglitazone, Pioglitazone), Pyrogenic receptor agonists (e.g., 61 262570) and PTPAγγ receptor antagonists, PTCAγγ / α retseptor modulators (e.g., KAP 297), oz-glucosidase inhibitors (eg, acarbose, hydrolysis) , PIP-IV inhibitors (for example, Ι _Αρ237, MK-431), os2-antagonists, insulin and its analogs, 61P-1 and analogs6RP-1 (eg, eksendin-4) or amilin. In addition to the list of other suitable for use, in combination with the compounds of active substances proposed herein, the inhibitors (protein tyrosine) -phosphatase 1, revo-guys that affect deregulation of glucose-induced liver production, such as glucose-6-phosphatase inhibitors, fructose-1,6-bisphosphatase or glycogen phosphorylase, glucagon receptor antagonists, and phosphoenolpiruvate carboxycinase inhibitors, glycogen synthase kinases (protein kinase) or pyruvate dehydrogenase, such as HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin), fibrates (for example, bezafibrate, phenofibrate), nicotinic acid and its derivatives, ΡΡΑΕζ receptor agonists, reagent agonists Epitope PTPAδδ, ACAT inhibitors (for example, avasimib) or cholesterol absorption inhibitors, such as ezetimibe, bile acid binding agents such as colestiramine, bile acid inhibitor gallium oxide, levels that increase the level of administration lipoproteins of high gastrin in blood,

In addition, in conjunction with the compounds of the invention, medications that affect high blood pressure, chronic heart failure, or atherosclerosis, such as angiotensin II antagonists (A-II) or ACE inhibitors, inhibitors ECE, diuretics, β-blockers, Ca-antagonists, hypotensive agents that have a central effect, antagonistio-2 adrenergic receptor, inhibitors of neutral endopeptidase, platelet aggregation inhibitors, and others, or combinations thereof. Examples of antagonists of the angiotensin II receptor are candesartan, tsilke-netl, potassium losartan, eprosartan mesylate, valsartan, telmisartan, irbesartan, ECR-3174, I_-158809, EXP-3312, olmesartan, medoxomil, tazo-sartan, CT -3-671.6A-0113, EІI-64276, ЕМВ-90423, ВЕ-9701 and others.

For the treatment or prophylaxis of gout, the compounds of the invention may be used according to the invention.

89040 42

administered in combination with inhibitors of the synthesis of uric acid or agents that promote the removal oforganism of uric acid.

For the treatment or prevention of diabetic complications, the compounds of the invention may be used in combination with antagonists of the GABA receptor, N-channel blockers, topiramatum, protein kinase inhibitors, inhibitors of terminal glycosylation products ("ape-bis-eu-ecytopiaepbrobiosis"), or aldosore duttazid inhibitors ( aldehyde reductase).

The above active substances, when used in conjunction with the compounds of the invention, are expediently administered in an amount in an amount ranging from 1/5 of the generally recommended minimum dose to 1/1 of the usual dose of the recombinant.

According to the following object, the present invention is the use of one of the compounds of the invention or of physiologically compatible salts thereof with at least one of the other active ingredients described above for the preparation of a medicament useful for the treatment or prophylaxis of diseases and pathologies that may be affected by inhibition of sodium-dependent glucose transporter ZbtT. In this case, the main thing is the illness of the metabolism, on the one of one of the diseases described above or pathological conditions, most preferably diabetic or diabetic complications.

When using the compound of the invention or a physiologically compatible salt thereof in combination with another active ingredient, the inventive compound can be administered simultaneously or sequentially through a certain time interval, preferably, however, over a short period of time. When simultaneous use of both active substances is introduced into the patient's body jointly, and when consistent in time, the use of both active substances is introduced into the body of the patient consistently with an interval of no more than 12 hours, at all, before no more than 6 hours.

According to the following object, the present invention is a medicinal product which comprises one of the compounds of the invention or a physiologically compatible salt thereof, as well as at least one of the above described, used in combination with the active substances and optionally one or decile of inert carriers and / or diluents.

Так, наприклад, запропонований у винаході лі-карський засіб може містити комбінацію із запро-понованої у винаході сполуки формули І або її фі-зіологічно сумісної солі й принаймні одинантагоніст рецептора ангіотензину II і необов'язко-во один або декілька інертних носіїв і/або розрі-джувачів.

The compound or its physiologically compatible salt according to the invention and the other active ingredient combined with it can be collectively included in a single dosage form, for example, tablets or capsules, or separately to be included in two single or multi-dosage forms, for example, in a form like this. called set.

In the above and below structural forms

The moles of the H-atoms of the hydroxyl groups are not shown in the expression

but in each case. Below is an invention of more pre-

89040

44

43

treacherously considered by examples, which, however, do not limit its scope.

Preparation of starting compounds

Example I: (5-Bromo-2-chlorophenyl) - (4-

methoxyphenyl) methanone

To a mixture of 100 g of 5-bromo-2-chlorobenzoic acid in 500 ml of dichloromethane is added 38.3 ml of oxalic chloride and 0.8 ml of dimethylformamide. Next, the reaction mixture is stirred for 14 hours, after which it is filtered and all volatile components are removed on the rotary evaporator. The residue was dissolved in 150 ml of dichloromethane, the solution was cooled to -5 ° C. and 46.5 g of anisole added. Then, 51.5 g of aluminum trichloride are added in portions, so that the temperature does not rise above 5 ° C. Then the solution is stirred for another 1 hour at 1-5 ° C and thenolve on ice. The organic phase is separated, the anhydrous phase is extracted three times with dichloromethane. The combined organic phases are washed with 1-molar hydrochloric acid, twice with 1 molar solution of sodium hydroxide and saturated solution of chloride of sodium. After this, the organic phase is dried, the solvent is removed and the residue is recrystallized from the vatanols.

Output: 86.3g (64% of the theory).

Mass spectrum (EII +): t / i = s25 / s2U / s29 (Br + CI) [M + H] +.

Analogously to Example I, the followingcompounds are obtained:

(i) (5-bromo-2-iodophenyl) - (4-

ethoxyphenyl) methanone

Mass spectrum (EII +): t / i = 4z / 4zz (Bg) [M + H] +.

(2) (5-bromo-2-chlorophenyl) - (4-iodophenyl) methanone

Example II: 4-Bromo-and-chloro-2- (4-

methoxybenzyl) benzene

A solution of 86.2 g (5-bromo-2-chlorophenyl) - (4-

methoxyphenyl) methanone and 101.5 ml of triethylsilane in 75 ml of dichloromethane and 150 ml of acetonitrile are cooled to 10 ° C. Then, when stirred, give 50.8 ml of boron trifluoride to a temperature such that the temperature does not rise above 20 ° C. Then, the solution is stirred for 14 hours at room temperature, after which 9 ml of triethylsilane and 4.4 ml of borate fluoride are added again. After this solution is stirred for the next 3 h at 45-50 ° C and then cooled to room temperature. Then add a solution of 28 g of hydroxyducial to 70 ml of water and stir for 2 hours. After this, the organic phase is separated, and the water-well phase is extracted three times with diisopropylmefir. The combined organic phases are washed twice with a 2-molar solution of potassium hydroxide and a one-shot solution of sodium chloride and then dried over sodium sulfate.

Output: 50.0 g (61% of the theory).

Mass spectrum (EII +): t / i = zo / s2 / s4 (Br + CI) [M + H]⁺.

Analogously to Example II, the followingcompounds are obtained:

(i) 4-bromo-iodo-2- (4-ethoxybenzyl) benzene

(2) 4-bromo-and-chloro-2- (4-iodobenzyl) benzene

Example III: 4- (5-Bromo-2-chlorobenzyl) phenol

A solution of 14.8 g of 4-bromo-and-chloro-2- (4-

methoxybenzyl) benzene in 150 ml of dichloromethane is cooled in an ice bath. Then add 50 ml-molar solution of boron tribromide in dichloromethane and stir the solution for 2 hours at room temperature. After this, the solution is again cooled in an ice bath and drops of saturated potassium carbonate solution are added. Then in room temperature, the pH value is set 1 by the addition of 1 molar aqueous hydrochloric acid, after which the organic phase is separated, the anhydrous phase is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is completely removed.

45

Output: 13.9 g (98% of the theory).

Mass spectrum (E5G): ιτι / ζ = 295/297/299 (Br + CI) [M-

N]-.

Example IV: [4- (5-Bromo-2-

chlorobenzyl) phenoxy] -t-butyldimethylsilane

A solution of 13.9 g of 4- (5-bromo-2-chlorobenzyl) phenolum 140 ml of dichloromethane is cooled in an ice bath. Then, 7.54 g of tert-butyldimethylsilyl chloride are added in 20 ml of dichloromethane, followed by 9.8 ml of triethylamine and 0.5 g of dimethylaminopyridine. The solution is then stirred for 16 hours at room temperature and then diluted with 100 ml of dichloromethane. The organic phase was washed twice with 1-molar hydrochloric acid and once with aqueous sodium hydrogen carbonate solution, and then dried over sodium sulfate. After removal of the solvent, the residue was filtered through silica gel (cyclohexane / ethyl acetate in a ratio of 100: 1). Output: 16.8g (87% of the theory).

Mass spectrum (EI): π / ζ = 410/412/414 (Br + CI) [M] +.

Example V: 1-Bromo-4-

triisopropylsilylethinylbenzene

To a solution that does not contain oxygen, 15.0 g of 1-bromo-4-iodobenzene in 150 ml of dry tetrahydrofuran in an argon atmosphere is added 11.6 ml of triisopropylacetylene and 14.4 ml of triethylamine and then 0.2 g of copper iodide and 0.73 g dichloride bis (triphenylphosphine) palladium. Then, the solution is stirred for 16 minutes at room temperature, after which it is filtered through celite and concentrated. The oil is chromatographed on silica gel (cyclohexane).

Output: 17.4g (100% of the theory).

Mass spectrum (E5I +): π / ζ = 336/338 (Bg) [M] +.

Analogously to example V, the followingcompounds are obtained:

(1) 4-bromo-1- (triisopropylsilylethinyl) -2- (4-

ethoxybenzyl) benzene

4-bromo-1-iodo-2- (4-ethoxybenzyl) benzene is used as the starting material for the coupling reaction described above.

Mass spectrum (E9 +): π / ζ = 471/473 (Bg) [M + H] +.

(2) [4- (5-Bromo-2-

chlorobenzyl) phenylethynyl] trisopropylsilane

As the starting material, 4-bromo-and-chloro-2- (4-iodobenzyl) benzene is used.

The title compound may also be prepared according to Example X.

Example VI: (5-Bromo-2-fluorophenyl) - {4-

[(trisopropylsilyl) ethynyl] phenyl} methanol

To a solution of 17.4 g of 1-bromo-4-triazopropylsilylethinylbenzene in a 120 ml of dry tetrahydrofuran in an argon atmosphere was added dropwise 33.8 ml of a 1.6 molar solution of n-butyllithium in hexane to a solution of 17.4 g of a solution of 17.4 g. The solution is then stirred at -70 ° C. for 1 hour. After this, for 15 minutes, a solution of 10.8 g of 5-bromo-2-fluorobenzaldehyde in 30 ml of tetrahydrofuran is added dropwise over 15 minutes. The resulting solution is left overnight to warm in a cooling bath to room temperature. Then water is added and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and dissolved solvent. The residue is purified on silica gel (cyclohexane / ethyl acetate in a ratio of 4: 1).

Output: 14,3 g (60% of the theory).

Mass spectrum (E9 +): π / ζ = 461/463 (Bg) [M + H] +.

Analogously to Example VI, the following are obtained

compounds:

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48

(1) (S-bromophenyl) - {4-

[(trisopropylsilyl) ethynyl] phenyl} methanol

Mass spectrum (EZ ^: t ^ = 427/429 (Bg) [M + H] +.

(2) [4- (5-Bromo-2-

methoxybenzyl) phenylethynyl] triazopropylsilane

Mass spectrum (EZG): π / ζ = 487/489 (Bg)

[M + NCO] '.

(2) (5-bromo-2-methoxyphenyl) - {4-

[(trisopropylsilyl) ethynyl] phenyl} methanol

Mass spectrum (EII +): t ^ = 47z / 475 (Bg) [M + H] +. Example VII: [4- (5-Bromo-2-

fluorobenzyl) phenylethynyl] trisopropylsilane

A solution of 5.6 g (5-bromo-2-fluorophenyl) - {4-

[(trisopropylsilyl) ethinyl] phenyl} methanol and 4,1 ml of triethylsilane in 50 ml of dichloromethane are cooled in an ice bath. Then, 4.7 ml of trifluoroacetic acid is slowly added dropwise and the solution is stirred for 4 hours at room temperature. After that, the solution is diluted with dichloromethane and washed with aqueous sodium hydrogen carbonate solution. After drying over sodium sulfate, remove the solvent and purify the residue on silica gel (cyclohexane).

Output: 2,6 g (48% of the theory).

Mass spectrum (EI): π / ζ = 445/447 (Bg) [M] +.

In the same way as Example VII, the following compounds are obtained:

(1) [4- (3-

bromobenzyl) phenylethynyl] trisopropylsilane

In contrast to the method described above in this case, the reaction solution is stirred until the completion of the reaction in an ice bath, and not at room temperature.

Mass spectrum (EZ4: t1 = 457/459 (Bg) [M + H] +.

Example VIII: 4-Bromo-2-bromomethyl-1-

chlorobenzene

To a solution of 5.0 g of 4-bromo-1-chloro-2-hydroxymethylbenzene and 5.9 g of triphenylphosphine in 50 ml of tetrahydrofuran, cooled to 5 ° C., 4.0 g of N-bromosuccinimide are slowly added. After 1 hour stirring at room temperature, the precipitate is filtered off and the solvent removed in vacuo. The zalishch is purified on silica gel (cyclohexane / ethyl acetate in the ratio of 50: 1).

Output: 4.9 g (76% of the theory).

Mass spectrum (EI): t ^ = 282/284/286 (Br + CI) [M] +.

Example IX: (4-

iodophenylethinyl) trisopropylsilane

20.0 g (4-

bromophenylethynyl) trisopropylsilane in an atmosphere of argon is added 18.0 g of sodium iodide (dry), 0.6 g of copper and 0.8 g of N, N'-dimethylcyclohexane-1,2-diamine. After this, the solution is boiled under reflux for 24 hours and then cooled to room temperature. Next, add 1% solution of ammonia (100 ml) and

49

extracted with ethyl acetate. After drying over sodium sulfate, remove the solvent and purify on silica gel (cyclohexane).

Output: 21.0 g (92% of the theory).

Mass spectrum (EI): t / g = 384 [M] +.

EXAMPLE X [4- (5-Bromo-2-

chlorobenzyl) phenylethynyl] trisopropylsilane

A solution of 0.50 g (4-iodophenylethynyl) trisopropylsilane in 2.2 ml of dry tetrahydrofuran in a drop of argon atmosphere is added to 0.65 ml of a 2 molar solution of isopropylmagnesium chloride in tetrahydrofuran until cooled to -25 ° C.. Next, the solution was stirred at -25 ° C. and then mixed with 0.26 ml of a 1 molar solution of SiC2BiCl2 in etherhydrofuran (obtained by dissolving SiCNi and NaCl in a ratio of 1: 2). Shortly thereafter, add 0,35 g of 4-bromo-2-bromomethyl-i-chlorobenzyl the reaction mixture is heated in a cooling well to -5 ° C. After 6 hours of stirring at-5 ° C, the solution is heated to room temperature and left to stir at night. Then add a mixture of a saturated solution of ammonium chloride and 25% solution of ammonia (in the ratio 9: 1) and the resulting mixture is added to water. The organic phase is separated, and the aqueous phase is extracted with ethyl cetate, The combined organic phases are dried over sodium sulfate and the solvent removed. Finish off on silica gel (cyclohexane).

Output: 0,28 g (50% of the theory).

Mass spectrum (EI): t / 2 = 461/463/465 (Br + CI)

[M + H] +.

Example XI: 2,3,4,6-tetrakis-O-

(trimethylsilyl) -O-glucopyranone

A solution of 20 g of 3-glucanone, 5-lactone and 98.5 ml of N-methylmorpholine in 200 ml of tetrahydrofuran is captured to -5 ° C. Then, 85 mltrimethylsilyl chloride is added dropwise in such a way that the temperature does not rise above 5 ° C. After this, the initiation is initially stirred for 1 hour at the temperature of the temperature, then for 5 hours at 35 ° C, and at the end for 14 hours again at room temperature. After adding 300 ml of toluene, the solution is cooled in an ice bath, after which 500 ml of water is added so that the temperature rises above 10 ° C. Organic phase then

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separated and then once washed with an aqueous solution of sodium hydrogen phosphate, water and saturated sodium chloride solution. After this remove the solvent, the residue is dissolved in 250 ml of toluene and again completely removed solvent.

Exit: 52.5 g (approximately 90% purity). Mass spectrum (EII +): t / 2 = 467 [M + H] +.

EXAMPLE XII: 1-Fluoro-4- (1-methoxy-O-

glucopyranose-and-yl) -2- (4-triisopropylsilylethinylbenzyl) benzene

A solution of 4.46 g [4- (5-bromo-2-

fluorobenzyl) phenylethinyl] trisopropylsilane in 30 ml of dry diethyl ether in an argon atmosphere is cooled to -80 ° C. To a cooled solution, 11.8 ml of a 1,7-

molar solution of t-butyllithium in pentane, and then the solution is stirred at -80 ° C. for 45 minutes. Then to this solution, through a double-sided solution, droplets are cooled to -80 ° C with a solution of 5,19 g of 2,3,4,6-tetrakis-O- (trimethylsilyl) -O-glucopyranon in 50 ml of diethyl ether. The resulting solution is stirred for 3 hours at -78 ° C. Then a solution of 1.7 ml of methanesulfonic acid in 50 ml of methanol is added, the cooling bath is removed and the solution is stirred for 16 hours at room temperature. After this solution neutralize with ethyldiisopropylamine and concentrate to dryness. The residue is purified on silica gel (dichloromethane / methanol in the ratio 50: 1 ^ 4: i).

Output: 2,8 g (50% of the theory).

Mass spectrum (EII +): π / ζ = 576 [M + NH4] +.

In the same manner as Example XII, the following compounds are obtained:

(i) i-methoxy-4- (i-methoxy-O-glucopyranos-i-yl) -2- (4-triisopropylsilylethinylbenzyl) benzene

When this compound is obtained, the reaction mixture is obtained

predominantly mixed with only a small excess

com methanesulfonic acid.

Mass spectrum (EZD): π / ζ = 588 [M + NH4] +.

51

(2) and-chloro-4- (i-methoxy-O-glucopyranos-i-yl) -2- (4-triisopropylsilylethinylbenzyl) benzene

Mass spectrum (EII +): π / z = 592/594 (CI) [M + NH4] +. Example XIII: 1-fluoro-4- (2,6,6-tetra-O-

acetyl-O-glucopyranos-i-yl) -2- (4-

trisopropylsilylethinylbenzyl) benzene

A solution of 0.8 g of 1-fluoro-4- (1-methoxy-O-

glucopyranos-i-yl) -2- (4-

triisopropylsilylethinylbenzyl) benzene and 0.5 ml of triethylsilane in 6 ml of dichloromethane and 10 ml of acetonitrile are cooled to -10 ° C. To the cooled solution in droplets add 0,27 ml borotrifluoro-deuterate. The solution is then stirred in the ice bath for the duration of the year. Next, to the solution is added aqueous sodium bicarbonate solution and then treated with ethyl acetate. The organic phase is dried over sodium sulfate, the solvent removed and the residue dissolved in 6 ml of dichloromethane. After this, 1.2 ml of pyridine, 1.3 ml of acetic anhydride and 8 mg of 4-dimethylaminopyridine are added. Then the solution is stirred for 1 hour at room temperature, after which it is mixed with water. The mixtures are extracted with dichloromethane, the organic phase is washed with 1-molar hydrochloric acid and suspended with sodium sulfate.

Output: 0.23 g (23% of the theory).

Mass spectrum (EII +): t / 2 = yi4 [M + NH4 +.

Analogously to Example XIII, nast-

Stumps of the compound:

(i) i-methoxy-4- (2,6,6,4-tetra-O-acetyl-O-

glucopyranos-and-yl) -2- (4-

trisopropylsilylethinylbenzyl) benzene

Mass spectrum (ESI +): t / i = y26 [M + NH4 +.

(2) and-chloro-4- (2, s, 4,6-tetra-O-acetyl-O-

glucopyranos-and-yl) -2- (4-

trisopropylsilylethinylbenzyl) benzene

Mass spectrum (ESI +): t / 7 = u0 / u2 (CI) [M + NH4 +. Example XIV: 1 - (2, 4,6-tetra-O-acetyl-i-

methoxy-O-glucopyranos-i-yl) -z- (4-

trisopropylsilylethinylbenzyl) benzene

A solution of 2.6 g [4- (3-

bromobenzyl) phenylethynyl] trisopropylsilane in 20 ml of dry diethyl ether in an argon atmosphere is cooled to -80 ° C. To the cooled solution in droplets slowly add 7.9 ml of a 1,7-molar solution of t-butyllithium in pentane, and then the solution is stirred at -80 ° C. for 30 minutes. Then to this solution through a two-sided needle, drop-dropwise, a solution of 3.2 g2, s, 4,6-tetrakis-O- (trimethylsilyl) -O-

glucopyranone in 30 ml of diethyl ether. The resulting solution is stirred at -78 ° C. for 2 hours, after which a cooled-to -80 ° C. solution of 1.0 g of 2,3,4,6-tetrakis-O- (trimethylsilyl) -O- glucopyranone in 10 ml of diethyl ether. After this, the mixture is stirred for an hour at -78 ° C., then a solution of 2 ml is added

53

methanesulfonic acid in 20 ml of methanol, the cooled bath is removed and the solution is stirred for 16 hours at room temperature. After this, the solution is neutralized with ethyldiisopropylamine, the solvent is completely removed, and resuspended in 50 ml of toluene. Then, 8.5 ml-diisopropylamine is added and the solution is cooled in an ice-cold bath. Then add 4.3 ml of acetic anhydride to 0.15 g of 4-dimethylaminopyridine. The solution is stirred for 2 hours at room temperature and then mixed with an aqueous solution of hydrocarbonate sodium. After that, they are extracted with ethyl acetate, the organic phases are dried over sodium sulfate and the solvent is removed. The residue is chromatographed on silica gel (cyclohexane / ethyl acetate in a 4: 1 ratio of 1: 3).

Output: 2.0g (46% of the theory).

Mass spectrum (Ε5.1 +): π / ζ = 726 [M + YND]⁺.

Similarly to Example XIV, the nast-foot compound is obtained:

(1) 1- (triisopropylsilyletinyl) -4- (2,3,4,6-tetra-O-acetyl-1-methoxy-O-glucopyranos-1-yl) -2- (4-ethoxybenzyl) benzene

Mass spectrum (E5I +): π / ζ = 770 [M + NH4] +.

Example XV: 1 - (2,3,4,6-Tetra-O-acetyl-O-

glucopyranos-1-yl) -3- (4-

trisopropylsilylethinylbenzyl) benzene

To ice-cooled solution of 1.0 g of 1- (2,3,4,6-tetra-O-acetyl-1-methoxy-O-glucopyranos-1-yl) -3- (4-triisopropylsilylethinylbenzyl) benzolei in 25 ml of water in 10 ml of acetonitrile in drops, give 1.2 ml of triethylsilane and 0.36 ml of borothiferous-rideratetra. After this, the solution is initially stirred for 3 hours in an ice bath and then for 1 hour at room temperature. The solution is further cooled in an ice bath and again added 1.2 ml of triethylsilane and 0.36 ml of borate fluoride-

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a deuterate. After this, the solution is initially for the next 0.5h stirred in an ice bath, and then for 2 hours at room temperature. Further aqueous solution of sodium hydrocarbonate is added to the solution and the resulting solution is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent removed.

Output: 0,78 g (81% of the theory).

Mass spectrum (E5I +): π / ζ = 696 [M + NH4] +.

Similarly to Example XV, the nast-foot compound is obtained:

(1) 1- (triisopropylsilyletinyl) -4- (2,3,4,6-tetra-O-acetyl-O-glucopyranos-1-yl) -2- (4-ethoxybenzyl) benzene

EXAMPLE XVI: 1-Chloro-4-f-O-glucopyranos-1-yl) -2- (4-hydroxybenzyl) benzene

A solution of 4.0 g [4- (5-bromo-2-chlorobenzyl) phenoxy] -t-butyldimethylsilane in 42 ml of dry diethyl ether under argon atmosphere is cooled to -80 ° C. To a cooled solution, 11.6 ml of a 1.7-molar solution of t-butyllithium in pentane are added dropwise, and then the solution is stirred at -80 ° C. for 30 minutes. This solution is then added to a 38 ml diethyl ether solution which is cooled to about -80 ° C. with 4.78 g of 2,3,4,6-tetrakis-O- (trimethylsilyl) -O-glucopyranon in a cooled dry ice. The resulting solution is stirred for 3 hours at -78 ° C. Then a solution of 1.1 ml of methanesulfonic acid in 35 ml of methanol is added and the solution is stirred for 16 hours at room temperature. After this solution is neutralized with solid sodium hydrocarbonate, ethyl acetate and methanol are added together with diethyl ether. To the remaining solution add aqueous hydrochloride solution of sodium bromate and four times extracted with ethyl acetate. The organic phases are dried over sodium trifluoride and concentrated. The residue was dissolved in 30 ml of acetonitrile and 30 ml of dichloromethane and the solution was cooled to -10 ° C. After addition of 4.4 ml of triethylsilane, 2.6 ml of boron trifluoroacetate

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rider therapy so that the temperature does not go above -5 ° C. After the completion of this operation, the addition of the solution for 5 hours is stirred at a temperature in the range of -5 to -10 ° C, and then the reaction is stopped by the addition of an aqueous solution of sodium bicarbonate. The organic phase is separated, and the aqueous phase is extracted four times with ethyl acetate. The combined organic phases are cooled over sodium sulfate, the solvent removed, the residue is purified on silica gel. The resultant product of this product is a mixture of β / α-anomers in a ratio of about 6: 1 which can be converted into a pure β-anomer by full acetylation of hydroxy groups with acetic anhydride and pyridine in dichloromethane and recrystallization of the product in ethanol. The product obtained in this way, in a mode in methanol with a 4 molar solution of potassium salts, is converted to the title compound.

Output: 1.6 g (46% of the theory).

Mass spectrum (E8): π / ζ = 398/400 (CI) [M + H] +. Example XVII: 1-Chloro-4-p-O-glucopyranos-1-

yl) -2- [4-

(trifluoromethylsulfonyloxy) benzyl] benzene

To a solution of 0.38 g of 1-chloro-4-p-O-glucopyranos-1-yl) -2- (4-hydroxybenzyl) benzene, 0.21 ml of triethylamine and 0.39 g of N, N-bis-

(trifluoromethanesulfonyl) aniline in 10 ml of dryhydrochloromethane is added 10 mg of 4-

dimethylaminopyridine. Then the solution is stirred for 4 hours at room temperature, after which it is mixed with an aqueous solution of sodium chloride. Then extracted with ethyl acetate, the organic extracts are dried over sodium sulfate and removed solvent. The residue is chromatographed on silica gel (dichloromethane / methanol in the ratio of 1: 0-> 4: 1).

Output: 0.33 g (64% of the theory).

Mass spectrum (E8I +): π / ζ = 530/532 (CI) [M + NH4] +.

Example XVIII: 2,3,4,6-tetra-O-benzyl-O-glucopyranone

To a solution of 10.0 g of 2,3,4,6-tetra-O-benzyl-O-glucopyranose in 140 ml of dichloromethane is added 4 g of a suspended molecular sieve (4 angstroms) and 3,3 g of N-methylmorpholine N-oxide. Then, the solution is stirred for 20 minutes at room temperature, after which add 0,3 g of tetrapropylammonium poruthenate. After 2nd mixing at room temperature, the solution is diluted with dichloromethane and filtered through celite. The filtrate is washed with an aqueous solution of thiosulphate of sodium and water and then dried over sodium sulfate. The residue obtained after removal of the solvent is chromatographed on silica gel (cyclohexane / ethyl acetate in the ratio of 4: 1).

Output: 8.2 g (82% of the theory).

Mass spectrum (E8I +): π / ζ = 539 [M + H] +.

EXAMPLE XIX 1- (2,3,4,6-Tetra-O-benzyl-1-hydroxy-O-glucopyranos-1-yl) -3- [4- (t-butyldimethylsilyloxy) benzyl] -4-methylbenzene

A solution of 0.34 g of [4- (5-bromo-2-

methylbenzyl) phenoxy] -t-butyldimethylsilylamine 3 ml of dry tetrahydrofuran in an argon atmosphere is cooled to -80 ° C. To a cooled solution, 0.54 ml of a 1.6-molar solution of butyllithium in hexane are added dropwise and the solution is stirred at -78 ° C. for 1.5 hours. To this solution, then through a two-sided needle, droplets are added a solution of 0.44 g of 2,3,4,6-tetra-O-benzyl-O-glucopyranone in 2.5 ml of tetrahydrofuran to -80 ° C.. The resulting solution is stirred at -78 ° C for 5 hours. Then the reaction is stopped by adding a solution of 0.1 ml of acetic acid to 1 ml of tetrahydrofuran and the mixture is heated to room temperature. Then add aqueous solution of hydrocarbonate sodium and four times extracted with ethyl acetate. The organic phases are dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (cyclohexane / ethyl acetate in a ratio of 15: 1 to 4: 1).

Output: 0.44 g (approximately 88% purity).

Mass spectrum (E8I +): π / z = 868 [M + H] +.

Example XX: 1- (2,3,4,6-Tetra-O-benzyl-O-glucopyranos-1-yl) -3- (4-hydroxybenzyl) -4-methylbenzene

57

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58

A solution of 0.44 g of 1- (2,3,4,6-tetra-O-benzyl-1-

O-glucopyranos-1-yl) -3- [4- (t-butyldimethylsilyloxy) benzyl] -4-methylbenzene (approximately 88% purity) in 3.5 ml of dry acetonitrile under argon is cooled to -40 WITH. To the cooled solution, 0.13 ml of trisopropylsilane and 0.08 ml of borothiphydride are added dropwise. The solution is then re-stirred at -35 ° C. over a period of time, after which 0.02 ml of trisopropylsilane and 0.01 ml of borotrifluoride are added again. After 2nd exposure at -40 °, aqueous potassium carbonate is added and the solution is stirred for 1 hour at room temperature. The mixture is diluted with water and extracted with ethyl acetate four times. The organic phase is dried over sodium sulfate, concentrated and chromatographed on silica gel (cyclohexane / ethyl acetate in a co-existence of 10: 1 -> 4: 1).

Output: 0.24 g (68% of the theory).

Mass spectrum (E8): π / ζ = 738 [M + NH4] +.

Example XXI: 1- (2,3,4,6-tetra-O-benzyl-O-glucopyranos-1-yl) -3- [4- (tetrahydrofuran-3-yloxy) benzyl] -4-methylbenzene

To a mixture of 0.24 g of 1- (2,3,4,6-tetra-O-benzyl-0-glucopyranos-1-yl) -3- (4-hydroxybenzyl) -4-methylbenzene and 0.13 g of cesium carbonate in To a solution of 2.5 ml of dimethylformamide is added 0.10 g of toluene-4-sulfonic acid, tetrahydrofuran-3-yl ether. The mixture is stirred for 4 hours at 65 ° C., then water is added. Then, three times extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent removed. The residue is purified on silica gel (cyclohexane / ethyl acetate in a ratio of 10: 1 -> 4: 1).

Output: 0.23 g (78% of the theory).

Mass spectrum (E9 +): π / ζ = 808 [M + H] +.

Example XXII: 1- (2,3,4,6-Tetra-O-benzyl-O-glucopyranos-1-yl) -3- [4- (trifluoromethylsulfonyloxy) benzyl] -4-methylbenzene

A solution of 0.62 g of 1- (2,3,4,6-tetra-O-benzyl-O-

glucopyranos-1-yl) -3- (4-hydroxybenzyl) -4-methylbenzene in 4.5 ml of dry dichloromethane in argon atmosphere is cooled to -10 ° C. To a cooled solution is added 0.14 ml of pyridine and 0.3 g of trifluoromethanesulfonic anhydride in 0.8 ml of dichloromethane. The solution is then stirred at -5 ° to about -10 ° C. at an ambient temperature, after which an aqueous solution of sodium disodium carbonate is added. The following are extracted three times with dichloromethane, the collected organic phases are washed with 1-molar hydrochloric acid and dried over sodium sulfate. The residue obtained after removal of the solvent is chromatographed on strength-gel (cyclohexane / ethyl acetate in the ratio 15: 1-> 7: 1).

Output: 0.62 g (84% of the theory).

Mass spectrum (E8I +): π / ζ = 853 [M + H] +.

Example XXIII: 1- (2,3,4,6-Tetra-O-benzyl-O-glucopyranos-1-yl) -3- [4- (trimethylsilylethinyl) benzyl] -4-methylbenzene

To a solution of 0.60 g of 1- (2,3,4,6-tetra-O-benzyl-O-glucopyranos-1-yl) -3- [4- (trifluoromethylsulfonyloxy) benzyl] -4-methylbenzene in 3 ml of dimethylformamide in the atmosphere -feron argon is added 27 mg copper iodide, 49 mg dichloride bis (triphenylphosphine) palladium, 0.30 ml of triethylamine and, at the end, 0.14 ml

trimethylsilylacetylene. The flask is tightly sealed and its content is stirred for 4 hours at 90 ° C. Then again add 20 mg of bis (triphenylphosphine) palladium dichloride and 0.6 ml of trimethylsily-lacetylene, and the solution is stirred even during the next 4 hours at 90 ° C. After this, add aqueous sodium bicarbonate solution, three times extracted with ethyl acetate and collect the organic phases over sodium sulfate. The residue obtained after removal of the solvent is chromatographed on

59 89040 60

silica gel (cyclohexane / ethyl acetate in a ratio of 40: 1, 10: 1).

Output: 0,45 g (80% of the theory).

Mass spectrum (E5i +): π / ζ = 818 [M + NH4] +.

Preparation of Finite Compounds

Example 1: 1-Chloro-2- (4-

cyclopentyloxybenzyl) -4- (P-O-glucopyranos-1-

yl) benzene

To a mixture of 0.25 g of 1-chloro-4-p-O-glucopyranos-1-yl) -2- (4-hydroxybenzyl) benzene and 0.4 g of carbonate cesium in 2.5 ml of dimethylformamide, 0.16 ml of cyclopentane is added. Then the mixture is stirred for 4 hours at 45 ° C., then again, add cesium tartrate and 0.05 ml of iodo-cyclopentane. After this, the mixture is stirred for 14 hours at 45 ° C., and then an aqueous solution of tri-sodium chloride is added and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, the solution is removed, and the residue is purified on silica gel (dichloromethane / methanol in the ratio 1: 0 5: 1).

Output: 0.23 g (78% of the theory).

Mass spectrum (E5i +): π / ζ = 466/468 (SI) [M + NH4] +.

Similarly to Example 1, the followingcompounds are obtained:

(2) 1-chloro-4-f-O-glucopyranos-1-yl) -2- [4 - ((P) -tetrahydrofuran-3-yloxy) benzyl] benzene

The reaction is carried out using tetrahydrofuran-3-yl ether (5) -toluene-4-sulfonic acid as a reagent which is subjected to the coupling.

Mass spectrum (E5i +): π / ζ = 451/453 (SI) [M + H] +.

(3) 1-chloro-4-p-O-glucopyranos-1-yl) -2- [4 - ((5) -tetrahydrofuran-3-yloxy) benzyl] benzene

The reaction is carried out using tetrahydrofuran-3-yl ether (P) -toluene-4-sulfonic acid as a reagent which is subjected to the coupling.

Mass spectrum (E5i +): t / z = 451/453 (SI) [M + H] +.

(4) 1-Chloro-4-p-O-glucopyranos-1-yl) -2- [4-

(tetrahydrofuran-2-one-3-yloxy) benzyl] benzene

The reaction is carried out using 3-bromo-butyrolactone as a reagent that is subjected to combining.

Mass spectrum (E5i +): t? = 465/467 (CI) [M + H] +.

(5) 1-Chloro-4-f-O-glucopyranos-1-yl) -2- (4-

cyclobutyloxybenzyl) benzene

Mass spectrum (E5i +): m.p. = 452/454 (CI) [M + NH4] +.

(6) 1-chloro-4-f-O-glucopyranos-1-yl) -2- (4-

cyclohexyloxybenzyl) benzene

Mass spectrum (E5i +): t4 = 480/482 (CI) [M + NH4] +. (Y) 1-Chloro-4-p -O-glucopyranos-1-yl) -2- [4-

(tetrahydropyran-4-yloxy) benzyl] benzene

Mass spectrum (E5i +): t ^ = 487/489 (CI) [M + Nα] +.

(8) 1-Chloro-4-p-O-glucopyranos-1-yl) -2- [4- (1-

acetylpiperidin-4-yloxy) benzyl] benzene

61 89040 62

The reaction is carried out using 1-acetyl-4-methylsulfonyloxypiperidine as an electrophile.

Mass spectrum (E9 +): t / 2 = 506/508 (CI) [M + H] +.

(9) 1-Chloro-4-p-O-glucopyranos-1-yl) -2- [4- (1-

tert-butyloxycarbonylpiperidine-4-

hydroxy) benzyl] benzene

The reaction is carried out using 1-t-butyloxycarbonyl-4-

methylsulfonyloxypiperidine as an electrophile. Mass spectrum (EZH): t / 2 = 586/588 (CI) [M + I] 1a]⁺. Example 10: 1-f-O-glucopyranos-1-yl) -4-

methyl-sec- [4- (tetrahydrofuran-to-

hydroxy) benzyl] benzene

A mixture of 0.21 g of 1- (2,6,6-tetra-O-benzyl-O-glucopyranos-1-yl) -is- [4- (tetrahydrofuran-cyloxy) benzyl] -4-methylbenzene and 0.1 g of 10% palladium hydroxide on charcoal in 3 ml of ethyl acetate for 24 hours is shaken at a hydrogen pressure of 1 atm at room temperature. Then again, add the same amount of catalyst and the solution shakes even for the next 24 hours in an atmosphere of hydrogen. After that, the catalyst is filtered off, the filtrate concentrated and the residue is chromatographed on strength-gel (dichloromethane / methanol in the ratio 1: 0-> 5: 1).

Output: 0.06 g (49% of the theory).

Mass spectrum (EII +): t / 2 = 448 [M + YND] +.

Example 11: 1-f-O-glucopyranos-1-yl) -4-

methyl-5- [4- (2-trimethylsilylethyl) benzyl] benzene

A mixture of 0.29 g of 1- (2,6,6-tetra-O-benzyl-O-glucopyranos-1-yl) -4-methyl-5- [4- (trimethylsilylethinyl) benzyl] benzene and 0.25 g 10% palladium hydroxide on charcoal in 3 ml of ethyl acetate for 24 hours is shaken under a pressure of hydrogen at room temperature at room temperature. Then again give-up 0.2 g of the catalyst and the solution is shaken in the next 20 hours in an atmosphere of hydrogen.

After that, the catalyst is filtered off, the filtrate concentrated and the residue is chromatographed on carbon-gel (dichloromethane / methanol in the ratio of 1: 0-> 5: 1).

Output: 0.08 g (51% of the theory).

Mass spectrum (ESI +): t / 7 = 462 [M + YND] +.

Example 12: 1-Chloro-4-f-O-glucopyranos-1-yl) -

2- (4-Ethinylbenzyl) benzene

To a solution of 0.32 g of 1-chloro-4-p-O-glucopyranos-1-yl) -2- [4-

(trifluoromethylsulfonyloxy) benzyl] benzene in 3 ml of dimethylformamide in an argon atmosphere give 25 mg copper iodide, 44 mg bis (triphenylphosphine) palladium, 0.30 ml of triethylamine, at 0.14 ml of trimethylsilylacetylene. . After this, 25 mg of bis (triphenylphosphine) palladium dioxide 0.1 ml of trimethylsilylacetylene are added again and the solution is re-stirred over the next 10 hours at 90 ° C. Then an aqueous solution of sodium hydrogen carbonate is added, three times extracted with ethyl acetate and the organic phases are collected. dried over sodium sulfate. After removal of the solvent, the omithanis are left to the brine in 5 ml of methanol and mixed with potassium 0.12 g of carbonate. The mixture is then re-stirred at room temperature for 1 hour and then neutralized with 1 molar hydrochloric acid. After this, evaporate methanol, The residue is mixed with a solvent of sodium chloride and extracted with ethyl acetate. The collected organic extracts are suspended with sodium sulfate and the solvent removed. The zalishchyne is chromatographed on silica gel (dichloromethane / methanol in the ratio 1: 0 ^ 5: 1).

Output: 0,095 g (40% of the theory).

Mass Spectrum (ESI +): t / 2 = 406/408 (CI) [M + YND] +. The title compound of the compound can also be obtained from

Sprinkle in the same way as Example 14.

Example 13: 1-Chloro-4-f-O-glucopyranos-1-yl) -

2- [4- (piperidin-4-yloxy) benzyl] benzene

To a solution of 0.19 g of 1-chloro-4-p-O-glucopyranos-1-yl) -2- [4- (1-t-butyloxycarbonylpiperidin-4-yloxy) benzyl] benzene in 4 ml of dichloromethane is added 2 ml of trifluoroacetic acid . Then the solution for a period of 1.5 hours is stirred at room temperature, then diluted with ethyl acetate and

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Undersign aqueous solution of potassium carbonate. The organic phase is separated, and the aqueous phase is ex-tragic with ethyl acetate. The combined organic phases dry over sodium sulfate and completely remove the solvent.

Output: 0.060g (38% of the theory).

Example 14: 1-Fluoro-4-p-0-glucopyranos-1-yl) - & lt; RTI ID = 0.0 & gt; (M + H) + & lt; / RTI & gt;

2- (4-Ethinylbenzyl) benzene

To a solution of 0.23 g of 1-fluoro-4- (2,3,4,6-tetra-O-acetyl-O-glucopyranos-1-yl) -2- (triisopropylsilylethinylbenzyl) benzene in 1,5 ml of tetrahydrofuran is added 0,33 ml 1 -molar solution of tetrabutylammonium fluoride in tetrahydrofuran. Then the solution is stirred for 1 hour at room temperature. Then 1 ml of methanol and 1.5 ml of a 4 molar solution of caustic potassium are added and the solution is stirred for the next hour at room temperature. After this, the rose is neutralized with 1 molar hydrochloric acid and then evaporated with methanol. The residue is mixed with anhydrous sodium chloride solution and extracted with ethyl acetate. The collected organic extracts are dried over sodium sulfate and the solvent removed. The zalishchoc is chromatographed on silica gel (dichloromethane / methanol in the ratio 19: 1 -> 2: 1).

Output: 0.060g (49% of the theory).

Mass spectrum (ESI +): π / ζ = 390 [M + IR.

Similarly to Example 14, the following compounds are obtained:

(15) 1-β-O-glucopyranos-1-yl) -3- (4-

ethinylbenzyl) benzene

Mass spectrum (EII +): π / ζ = 372 [M + NH4] +.

(16) 1-Ethinyl-4-f-O-glucopyranos-1-yl) -2- (4-

ethoxybenzyl) benzene

Mass spectrum (ESI +): π / ζ = 416 [M + NH4] +.

(17) 1-methoxy-4-f-O-glucopyranos-1-yl) -2- (4-

ethinylbenzyl) benzene

Mass spectrum (ESI +): π / ζ = 402 [M + NH4] +.

Compound of Example (12), i.e. 1-chloro-4-p-O-

glucopyranos-1-yl) -2- (4-ethinylbenzyl) benzene

can also be synthesized in the same way as for example 14. In this case, the intermediate 1-chloro-4- (2,3,4,6-tetra-O-acetyl-O-glucopyranos-1-yl) -2- (4-ethinylbenzyl) Benzene, which is obtained after the decolouration with tetrabutylammonium fluoride, optionally can be purified by recrystallization in ethanol.

Mass spectrum (EII +): t / 2 = 406/408 (CI) [M + NH4] +.

Analogously to the above examples and other known methods of literature, they receive the following compounds:

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Below are examples of medicalforms in which the "active ingredient" is intended to have one or more of the inventivecompounds, including their salts. In the use of the compounds of the invention in combination with one or more other active substances from the list of the above, the term "active substance" includes, but is not limited to, other active substances.

Example A

Tablets containing active ingredient 100 mg

Composition per 1 tablet:

Magnesium stearate 2.0 mg

220.0 mg

Preparation: The active ingredient is mixed with lacquer and starch and evenly watered with a solution of polyvinylpyrrolidone. After selling the moist mass through a sieve (with a size of about 2.0 mm) and drying in a lattice dryer at 50 ° C, the product is sift again through (with a cell size of 1.5 mm) and mixing the lubricant. Ready-to-press mixture is processed into tablets.

Tablet weight: 220 mg.

Diameter of the tablet: 10mm, two-plane with two-

root face and split knot from one

the sides

Example B

Tablets containing the active substance 150 mg

active substance 100,0 mg

lactose 80.0 mg

corn starch 34,0 mg

polyvinylpyrrolidone 4.0 mg

<tr><td><p>75</p></td><td><p></p></td></tr><tr><td><p>Composition per 1 tablet:</p></td><td><p></p></td></tr><tr><td><p>active substance</p></td><td><p>150.0 mg</p></td></tr><tr><td><p>lactose, powdered</p></td><td><p>89.0 mg</p></td></tr><tr><td><p>cornstarch</p></td><td><p>40.0 mg</p></td></tr><tr><td><p>colloidal silicic acid</p></td><td><p>10.0mg</p></td></tr><tr><td><p>polyvinylpyrrolidone</p></td><td><p>10.0mg</p></td></tr><tr><td><p>magnesium stearate</p></td><td><p>1.0mg</p></td></tr>

300.0 mg

Preparation: A mixture of the active ingredient with lactose, corn starch and siliceous acid is moistened with a 20% aqueous solution of poly-vinylpyrrolidone and pushed through a sieve with a size of 1.5 mm cells. Dried at 45 ° C, the granulate is again wiped out through the same sieve and mixed with the specified amount of magnesium stearate. From this mixture press the tablets.

Weight of the tablet: 300 mg.

The punch: a 10mm dm, with a flat working surface.

Example B

Solid-gelatin capsules containing the active substance 150 mg

Composition per 1 capsule: Active ingredient 150.0 mg

corn starch, is dried at about 180.0 mg

lactose, powdered approximately 87.0 mg

Magnesium stearate 3.0 mg

approximately 420,0 mg Contents: The active ingredient is mixed with auxiliary substances, sifted through a sieve with a cell size of 0,75 mm cells and mixed to homogeneity in the appropriate apparatus. The resulting mixture is molded in hard-gelatin capsules of size 1.

Content of the capsule: approximately 320 mg.

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Capsule shell: hard gelatine capsule size 1.

Example G.

Suppositories containing the active substance 150 mg

Composition per 1 candle: active substance 150,0 mg

polyethylene glycol 1500 550,0 mg

polyethylene glycol 6000 460,0 mg

polyoxyethylene sorbitan monostearate 840.0 mg 2.000.0 mg

Obtaining: After the melting of the mass forsupervisors in it, homogeneously disperse the active substance, and the molten mass is poured into the previously cooled forms.

Example D

Ampoules containing 10 mg of active ingredient

Storage:

active substance 10,0 mg

0.01n. hydrochloric acid c.5.

twice distilled water to 2.0 ml

Preparation: The active substance is dissolved in an inactive amount of 0.01 n. HCl, a solution of adding dichloric acid have isotonicity, after which sterilize by filtration and packaged in 2-milliliter ampoules.

Example Ε

Ampoules containing active ingredient 50 mg

Storage:

active substance 50,0 mg

0.01n. hydrochloric acid c.5.

twice distilled water to 10,0 ml

Preparation: The active substance is dissolved in an inactive amount of 0.01 n. NSI, solution of adding dichloric acid salt isotonic, after which sterilize by filtration and packaged in 10-milliliter ampoules.

Computer layout O. Gaponenko Subscription Circulation 28 copies.

Ministry of Education and Science of Ukraine

State Department of Intellectual Property, st. Uritskogo, 45, Kyiv, SME, 03680, Ukraine

State Enterprise "Ukrainian Institute of Industrial Property", st. Glazunova, 1, Kyiv - 42, 01601