ES2351444T3 - DERIVATIVES OF BENCIL.BENZENE SUBSTITUTED WITH GLUCOPIRANOSIL, MEDICINES CONTAINING COMPOUNDS, ITS EMPLOYMENT AND ITS PREPARATION PROCESS. - Google Patents

Abstract

Benzyl benzene derivatives substituted with glucopyranosyl, of general formula I ** (See formula) ** where R1 means hydrogen, fluorine, chlorine, bromine, iodine, C1-4 alkyl, C2-6 alkynyl, C1-4 alkoxy, alkenyl C2-4 C1-4alkoxy, C2-4 alkynyl C1-4 alkoxy, methyl substituted with 1 to 3 fluorine atoms, ethyl substituted with 1 to 5 fluorine atoms, methoxy substituted with 1 to 3 fluorine atoms, ethoxy substituted with 1 to 5 fluorine atoms, C1-4 alkyl substituted with a hydroxyl group or C1-3 alkoxy, C2-4 alkoxy substituted with a hydroxyl group or C1-3 alkoxy, C2-8 alkenyl, C3-7 cycloalkyl, C3- cycloalkyl 7-C 1-3 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl, C 3-7 alkoxy, C 5-7 cycloalkenyl, hydroxy, amino, nitro or cyano, and at the C 5-6 cycloalkyl groups a methylene group it can be substituted by O; R2 means hydrogen, fluorine, chlorine, bromine, hydroxyl, C1-4 alkyl, C1-4 alkoxy, cyano or nitro, and the alkyl or alkoxy group may be mono- or polysubstituted with fluorine, and R3 means C3-7 cycloalkyl, tetrahydrofuranyl or tetrahydropyranyl, substituted with one to four L2 substituents, or R3 means C5-7 cycloalkanonyl, which may be substituted with one to four L2 substituents; and R4, R5, independently of each other, represent hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C1-3 alkyl, C1-3 alkoxy or a methyl or methoxy group substituted with 1 to 3 fluorine atoms, L1, independently of each other, they are chosen from fluorine, chlorine, bromine, iodine, hydroxyl, cyano, C1-3 alkyl, difluoromethyl, trifluoromethyl, C1-3 alkoxy, difluoromethoxy, trifluoromethoxy, amino, C1-3-amino alkyl and di (C1 alkyl -3) -amino; and L2, independently of each other, are selected from fluorine, chlorine, hydroxyl, hydroxy C1-4 alkyl, C1-4 alkoxy, trifluoromethoxy, C1-4 alkoxy-C1-4 alkyl, cyano, hydroxycarbonyl, (C1-4 alkyl) oxycarbonyl, aminocarbonyl, C1-4 alkyl, trifluoromethyl, amino, (C1-4 alkyl) -carbonylamino, C1-3-alkyl and C1-3-dialkyl; and R6, R7a, R7b, R7c, independently of one another, have a meaning chosen from hydrogen, (C1-18 alkyl) carbonyl, (C1-18 alkyl) oxycarbonyl, arylcarbonyl and aryl- (C1-3 alkyl) -carbonyl, and aryl groups may be mono- or disubstituted, independently of one another, with the same or different L1 groups; while the aryl groups mentioned in the definition of the above groups mean phenyl or naphthyl groups that may be substituted in the defined manner; and, if not indicated otherwise, the above-mentioned alkyl groups may be straight or branched chain, their tautomers, stereoisomers, mixtures and salts.

Description

The present invention relates to glucopyranosyl substituted benzylbenzene derivatives, of general formula I

image 1

10 where the groups R1 to R6 and R7a, R7b, R7c are the most defined forward, including its tautomers, stereoisomers, mixtures and you go out The present invention also relates to pharmaceutical compositions containing a compound of the formula general I in accordance with the present invention, as well as the use

15 of a compound according to the present invention to prepare a Pharmaceutical composition for the treatment of metabolic disorders. The present invention also relates to processes to prepare a pharmaceutical composition, as well as a compound according to the present invention.

20 In the literature, compounds that inhibit SGLT2 sodium dependent glucose cotransporter for Treatment of diseases, especially diabetes.

The aromatic groups substituted with glucopyranosyloxy and glucopyranosyl and its preparation and possible activity as 25 SGLT2 inhibitors are known for the publications of International Patent Application WO 98/31697, WO 01/27128,

WO 02/083066, WO 03/099836, WO 2004/063209, WO 2004/080990, WO 2004/013118, WO 2004/052902, WO 2004/052903 and WO 2005 / 092877 and patent application US 2003/0114390.

Purpose of the present invention

The present invention aims to find new benzene derivatives substituted with pyranosyl, especially those who have activity with respect to the co-transporter of SGLT sodium dependent glucose, specifically SGLT2. The The present invention also aims to find derivatives benzene substituted with pyranosyl having an effect good inhibitor until very good about the cotransporter of SGLT2 sodium dependent glucose in vitro and / or in vivo and / or that possess good until very good pharmacological properties and / or pharmacokinetic and / or physicochemical.

Another object of the present invention is to provide new pharmaceutical compositions that serve to prevent and / or treat metabolic disorders, in particular diabetes.

The present invention also has the purpose of providing a process for preparing the compounds according to the same.

Other purposes of the present invention will be obvious. for the specialist, based directly on the preceding and subsequent observations.

Object of the present invention

In a first aspect, the present invention relates to benzyl benzene derivatives substituted with glucopyranosyl, of general formula I

image2

where

R1 means hydrogen, fluorine, chlorine, bromine, iodine, alkyl C1-4, C2-6 alkynyl, C1-4 alkoxy, C2-4 alkenyl-C1-4 alkoxy, C2-4 alkynyl-C1-4 alkoxy, methyl substituted with 1 to 3 fluorine atoms, ethyl substituted with 1 to 5 atoms of fluorine, methoxy substituted with 1 to 3 fluorine atoms, ethoxy substituted with 1 to 5 fluorine atoms, C1-4 alkyl substituted with a hydroxyl group or C13 alkoxy, C2-4 alkoxy substituted with a hydroxyl group or C1-3 alkoxy, C2-6 alkenyl, C3-7 cycloalkyl, cycloalkyl C3-7-C1-3 alkyl, C3-7-cycloalkyl, C3-7 cycloalkyl C1-3, C5-7-oxycycloalkenyl, hydroxyl, amino, nitro or cyano, and in the C5-6 cycloalkyl groups a group methylene may be substituted by O;

R2 means hydrogen, fluorine, chlorine, bromine, hydroxyl, C1-4 alkyl, C1-4 alkoxy, cyano or nitro, and the group alkyl or alkoxy may be mono- or polysubstituted with fluorine, and

R3 means C3-7 cycloalkyl, tetrahydrofuranyl or tetrahydropyranyl, substituted with one to four L2 substituents, or R3 means C5-7 cycloalkanoyl, which can be substituted with one to four L2 substituents; Y

R4, R5, independently of each other, mean hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C1-3 alkyl, C1-3 alkoxy or a methyl or methoxy group substituted with

1 to 3 fluorine atoms,

L1 independently of each other, are chosen from fluorine, chlorine, bromine, iodine, hydroxyl, cyano, C1-3 alkyl, difluoromethyl, trifluoromethyl, C1-3 alkoxy, difluoromethoxy, trifluoromethoxy, amino, C1-3-alkyl alkyl and di (C1-3alkyl) -amino; Y

L2 independently of each other, are chosen from fluorine, chloro, hydroxy, hydroxy C1-4 alkyl, C1-4 alkoxy, trifluoromethoxy, C1-4 alkoxy-C1-4 alkyl, cyano, hydroxycarbonyl, (C1-4 alkyl) oxycarbonyl, aminocarbonyl, C1-4 alkyl, trifluoromethyl, amino, (C1-4 alkyl) carbonylamino, C1-3-alkyl and C1-3-dialkyl; Y

R6, R7a, R7b, R7c, independently of each other, have a meaning chosen from hydrogen, (C1-18 alkyl) carbonyl, (C1-18 alkyl) oxycarbonyl, arylcarbonyl and aryl- (C1-3 alkyl) -carbonyl, and aryl groups can go mono-or disubstituted, independently of each other, with the same or different L1 groups;

while the aryl groups mentioned in the definition of

the above groups mean phenyl or naphthyl groups that

they may be substituted as defined; Y,

if not indicated otherwise, the above-mentioned alkyl groups

they can be straight or branched chain,

to its tautomers, stereoisomers, mixtures and salts. The compounds of general formula I according to the present

invention and its physiologically acceptable salts have pro

valuable pharmacological pieties, particularly an effect

sodium dependent glucose cotransporter inhibitor

SGLT, specifically SGLT2. In addition, the compounds according to

The present invention may have an inhibitory effect on the sodium dependent glucose cotransporter SGLT1. In Compared to a possible SGLT1 inhibitory effect, compounds according to the present invention inhibit preferably selective the SGLT2.

The present invention also relates to salts Physiologically acceptable of the compounds herein invention with inorganic or organic acids.

The present invention also relates to compositions pharmaceuticals containing at least one compound according to the present invention or a physiologically acceptable salt according to the present invention, optionally together with one or more inert supports and / or diluents.

The present invention also relates to the use of, less, a compound according to the present invention or one of its physiologically acceptable salts, in order to prepare a pharmaceutical composition suitable for treating or preventing diseases or conditions sensitive to the inhibition of the SGLT sodium dependent glucose cotransporter, in particular of the SGLT2.

The present invention also relates to the use of, less, a compound according to the present invention or one of its physiologically acceptable salts, in order to prepare a pharmaceutical composition suitable for treating disorders metabolic

The present invention also relates to the use of, less, a compound according to the present invention or one of its physiologically acceptable salts, in order to prepare a pharmaceutical composition to inhibit the cotransporter of

SGLT sodium dependent glucose, in particular SGLT2.

The present invention also relates to a process to prepare a pharmaceutical composition according to the present invention, characterized in that a compound according to the present

The invention or one of its physiologically acceptable salts is incorporated into one or more inert supports and / or diluents by A non-chemical method.

The present invention also relates to a process to prepare the compounds of the general formula I according to the

10 present invention, characterized in that a) to prepare the compounds of the general formula I defined as above and below, a compound of the general formula II

image 1

15 where R ’means H, C1-4 alkyl, (C1-18 alkyl) carbonyl, (C1-18 alkyl) oxycarbonyl, arylcarbonyl and aryl (C1-3 alkyl) carbonyl, in which the alkyl groups or aryl can be mono- or polysubstituted with

20 halogen; R8a, R8b, R8c, R8d, independently of each other, have one of the meanings indicated before or later for the groups R6, R7a, R7b, R7c, or mean a benzyl group or a RaRbRcSi group or a group

Ketal or acetal, in particular an alkylidene group

or arylalkylidene-ketal or acetal, while in

each case two adjacent groups R8a, R8b, R8c, R8d they can form a silyl-ketal, ketal or cyclic group acetal or a 1,2-di (C1-3 alkoxy) -1,2-di (alkyl bridge) C1-3) -ethylene, while said ethylene bridge, along with two oxygen atoms and the two atoms of associated carbon of the pyranose ring, forms a substituted dioxane ring, specifically a ring of 2,3-dimethyl-2,3-di (C1-3 alkoxy) -1,4-dioxane, and while the alkyl, aryl and / or benzyl groups they can be mono- or polysubstituted with halogen or C1-3 alkoxy and benzyl groups can also go substituted with a di (C1-3 alkyl) amino group; Y

Ra Rb, Rc, independently of one another, are alkyl C1-4, aryl or aryl-C1-3 alkyl, in which the groups aryl or alkyl can be mono- or polysubstituted with halogen;

while the aryl groups mentioned in the definition

tion of the above groups means phenyl groups or

naphthyl, preferably phenyl groups;

and while groups R1 to R5 and R6, R7a, R7b, R7c are

defined as before and later;

is reacted with a reducing agent in the presence

of a Lewis or Brønsted acid, separating any

protective group simultaneously or later; or

b) to prepare compounds of the general formula I in

that R6, R7a, R7b and R7c mean hydrogen, a compound

of the general formula III

image2

where R8a, R8b, R8c, R8d and R1 through R5 are defined as before and later, but at least one of the groups R8a, R8b, R8c, R8d does not represent hydrogen, it is hydrolyzed and,

5 if desired, a compound of the general formula I thus obtained, in which R6 means a hydrogen atom, it converts by acylation into a corresponding compound acyl of general formula I, and / or if necessary, any protective group uti is separated

10 in the reactions described above and / or, if desires, a compound of the general formula I thus obtained it is resolved in its stereoisomers and / or, if desired, a compound of the general formula I thus obtained becomes its salts, in particular its

15 physiologically acceptable salts for pharmaceutical use. The present invention also relates to a process to prepare compounds of general formula II

image 1

where

20 R ’means H, C1-4 alkyl, (C1-18 alkyl) carbonyl, (C1-18 alkyl) oxycarbonyl, arylcarbonyl and aryl- (alkyl C1-3) carbonyl, in which the alkyl or aryl groups can be mono- or polysubstituted with halogen;

R8a, R8b, R8c, R8d, independently of each other, have one of the meanings indicated for the groups R6, R7a, R7b, R7c or represent a benzyl group or a RaRbRcSi group or a ketal or acetal group, and in each case two groups with

5 R8a, R8b, R8c, R8d can form a cyclic group silyl-ketal, ketal or acetal or, with two oxygen atoms of the pyranose ring, a substituted 2,3-oxydioxane ring, in particular a 2,3-dimethyl-2,3-di (alkoxy) ring C1-3) -1,4-dioxane, while alkyl, aryl groups

10 and / or benzyl may be mono- or polysubstituted with halogen or C1-3 alkoxy and the benzyl groups may also be substituted with a di (C1-3 alkyl) -amino group; Y Ra, Rb, Rc, independently of each other, means alkyl C1-4, aryl or aryl-C1-3 alkyl, and alkyl groups or

Aryl may be mono- or polysubstituted with halogen; while the aryl groups mentioned in the definition of the above groups mean phenyl or naphthyl groups, preferably phenyl groups; and R1 to R5, R6, R7a, R7b, R7c are defined as before and more

20 forward, in which an organometallic compound (V), which can be obtained by halogen-metal exchange or by insertion of a metal in the carbon-halogen bond of a halogen benzyl benzene compound of the general formula IV

image 1

where Hal means Cl, Br and I and R1 to R5 are defined as before and

later, optionally followed by transmetalation, add to a gluconolactone of general formula VI

image 1

where R8a, R8b, R8c, R8d are defined as before and later,

5y then the resulting adduct is reacted, preferably in situ, with water or with an R’-OH alcohol, in which R ’ means optionally substituted C1-4 alkyl, in the presence of an acid such as methanesulfonic acid, sulfuric acid,

10 hydrochloric, acetic or ammonium chloride, and optionally the product resulting from the reaction with water, in which R ’ means H, in a subsequent reaction with an agent of acylation, such as the corresponding acid chloride or anhydride, becomes the product of formula II

In which R ’means (C1-18 alkyl) -carbonyl, (C1-18 alkyl) oxycarbonyl, arylcarbonyl or aryl- (C1-3 alkyl) -carbonyl, which may be substituted as described.

Related intermediate products, in particular those of formulas IV ’, II and III, are also subject to the 20 present invention.

Detailed description of the present invention

If not indicated otherwise, the groups, radicals and substituents, in particular R1 to R5, L1, L2, R6, R7a, R7b, R7c, R8a, R8b, R8c, R8d are defined as before and later. The radicals, substituents or groups that appear more

once in a compound, such as L1 and L2, can have the same or different meanings.

Some of the preferred meanings of the groups and

individual substituents of the compounds according to the

present invention are indicated below.

The group -O-R3 is preferably in the position

goal or stop of the phenyl ring with respect to the bridge -CH2-, and

therefore the compounds according to the formulas are preferred

I.1 and I.2, in particular those of the formula I.2:

image2

The group R1 preferably means hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, C1-4 alkoxy, methyl substituted with 1 to 3 fluorine atoms, methoxy substituted with 1 to 3

15 fluorine atoms, C3-7-oxycycloalkyl or C3-7-alkoxycycloalkyl C1-3, and in the C5-6 cycloalkyl groups a methylene group can be replaced by O.

Basically preferred meanings of R1 are hydrogen, fluorine, chlorine, methyl, methoxy, ethoxy, cyclopentyloxy, 20 cyclohexyloxy, tetrahydrofuran-3-yloxy and tetrahydropyran-4

il-oxy; in particular methyl and chlorine. Preferred meanings of the R2 group are hydrogen, fluorine, chlorine, methyl, methoxy, ethoxy and methyl substituted with 1

Up to 3 fluorine atoms.

The mainly preferred meanings of the R2 group they are hydrogen, fluorine, methoxy, ethoxy and methyl, in particular hydrogen.

Preferred meanings of the R3 group are cycloalkyl C3-7, tetrahydrofuranyl or tetrahydropyranyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4yl, which are substituted with one or two L2 substituents; in particular cyclopentyl and cyclohexyl substituted with an L2 substituent. Other preferred meanings of the R3 group are cyclopentanonyl or cyclohexanonyl, which may be substituted with one or two L2 substituents.

As especially preferred examples of R3 it is possible to mention 2-hydroxycyclopropyl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-hydroxycyclopentyl, 3-hydroxycyclopentyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, 2-methoxycyclopropyl, 2-methoxycyclobutyl, 3-methoxycyclopentyl, 3-methoxycyclopentyl, methoxycyclopentyl 2-methoxycyclohexyl, 3-methoxycyclohexyl, 4-methoxycyclohexyl, 1-hydroxymethylcyclopentyl, 1-hydroxymethylcyclohexyl, 1-methoxymethylcyclopentyl, 1-methoxymethylcyclohexyl, 4-hydroxytetrahydrofuran-3-yl, 4-methoxytetrahydrofuran-3-yl, 3-hydroxytetrahydropyran-4-yl and 4-hydroxytetra substituted with 2 additional.

In case the group R3 means a tetrahydrofuranyl or tetrahydropyranyl ring with an equal L2 substituent

to hydroxyl, amino, C 1-3 alkyl-amino or di (C 1-3 alkyl) -amino,

this substituent L2 is preferably not attached to the atom of carbon adjacent to the oxygen atom of the ring.

Preferred meanings of the L1 group, independently of each other, are chosen from fluorine, chlorine, bromine, cyano, hydroxyl, C1-3 alkyl, difluoromethyl, trifluoromethyl, C1-3 alkoxy, difluoromethoxy, trifluoromethoxy and di (C1-3 alkyl) amino.

Especially preferred meanings of the L1 group they are chosen from fluorine, chlorine, hydroxyl, trifluoromethyl, ethyl, methoxy, ethoxy and dimethylamino, in particular methyl, ethyl, methoxy, ethoxy and dimethylamino.

Especially preferred meanings of the L2 group are chosen from fluorine, hydroxyl, hydroxy C1-4 alkyl, alkoxy C1-4, C1-4 alkoxy-C1-4 alkyl, C1-4 alkyl, trifluoromethyl, C1-4 alkylcarbonylamino, hydroxycarbonyl and C1-4 alkoxycarbonyl.

Especially preferred meanings of the L2 group are chosen from fluorine, hydroxyl, hydroxy C1-4 alkyl, alkoxy C1-4, C1-4 alkoxy-C1-4 alkyl, C1-4 alkyl, hydroxycarbonyl and C1-4 alkoxycarbonyl, in particular hydroxyl, hydroxymethyl, methoxymethyl, methoxy, methyl, hydroxycarbonyl, methoxycarbonyl and ethoxycarbonyl.

Especially preferred meanings of the R4 group they are hydrogen and fluorine, in particular hydrogen.

Especially preferred meanings of the R5 group they are hydrogen and fluorine, in particular hydrogen.

The group R6 preferably means according to the present invention hydrogen, (C1-8 alkyl) oxycarbonyl, C1-8 alkyl

carbonyl or benzoyl, in particular hydrogen or (C1-6 alkyl)

oxycarbonyl or C1-6 alkylcarbonyl, with particular preference hydrogen, methylcarbonyl, methoxycarbonyl or ethoxycarbonyl, especially hydrogen.

Regardless of each other, the substituents R7a, R7b, R7c

5 represent hydrogen, (C1-8 alkyl) oxycarbonyl, alkyl C1-18-carbonyl or benzoyl, in particular hydrogen, (alkyl C1-6) -oxycarbonyl or (C1-8 alkyl) carbonyl, especially preferably hydrogen, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl or ethylcarbonyl. R7a, R7b and R7c mean above all

10 hydrogen The compounds of the formula I in which R6, R7a, R7b and R7c according to the present invention have a meaning other than hydrogen, for example C1-8 alkylcarbonyl, are preferably suitable as intermediates for synthesizing

The compounds of formula I in which R6, R7a, R7b and R7c represent hydrogen. Especially preferred compounds of formula I are choose between formulas I.2a to I.2d, in particular I.2c:

image2

image2

where the groups R1 to R6 and R7a, R7b, R7c have one of the meanings indicated above, in particular one of the 5 specified as preferred; and in particular

R1 represents hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, C1-4 alkoxy, methyl substituted with 1 to 3 atoms of fluorine, methoxy substituted with 1 to 3 fluorine atoms, C3-7-oxycycloalkyl or C3-7-cycloalkylC1-3alkoxy, and in

10 C5-6 cycloalkyl groups a methylene group can be substituted by O; R1 especially means hydrogen, fluorine, chlorine, methyl, methoxy, ethoxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuran-3-yloxy or tetrahydropyran-4-yloxy; Y

R2 means hydrogen, fluorine, methoxy, ethoxy or methyl, in particular hydrogen; Y R3 means C3-7 cycloalkyl, tetrahydrofuranyl or tetrahydropyranyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran-3-yl, tetra

Hydropyran-3-yl or tetrahydropyran-4-yl, which are substituted with one to four L2 substituents; or R3 means cyclopentanonyl or cyclohexanonyl, which can be substituted with one or two L2 substituents; Y R4 means hydrogen or fluorine, in particular hydrogen; Y

R5

means hydrogen or fluorine, in particular hydrogen; Y

L1

independently of each other, they are chosen from fluorine,

chlorine, bromine, iodine, cyano, hydroxyl, C1-3 alkyl,

difluoromethyl, trifluoromethyl, C1-3 alkoxy, difluoro

methoxy, trifluoromethoxy and di (C1-3 alkyl) -amino; in pair

ticular between fluorine, chlorine, hydroxyl, methyl, trifluo

rometyl, ethyl, methoxy, ethoxy and dimethylamino; on

all between methyl, ethyl, methoxy, ethoxy and dimethylamino;

Y

L2

independently of each other, they are chosen from fluorine,

hydroxyl, hydroxy C1-4 alkyl, C1-4 alkoxy, C1-4 alkoxy

C1-4 alkyl, C1-4 alkyl, trifluoromethyl, C1-4 alkyl

carbonylamino, hydroxycarbonyl and C1-4-oxy alkyl

carbonyl; in particular hydroxyl, hydroxymethyl,

methoxymethyl, methoxy, methyl, hydroxycarbonyl, methoxy

carbonyl and ethoxycarbonyl; Y

R6

means hydrogen, (C1-6 alkyl) oxycarbonyl, (alkyl

C1-6) carbonyl or benzoyl, in particular hydrogen,

methylcarbonyl, methoxycarbonyl or ethoxycarbonyl, with

special preference hydrogen; Y

R7a, R7b, R7c, independently of each other, represent hydrogen, (C1-6 alkyl) oxycarbonyl, (C1-8 alkyl) carbonyl or benzoyl, in particular hydrogen, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl or ethylcarbonyl, with special preference hydrogen;

including its tautomers, stereoisomers, mixtures and salts.

According to a variant of the indicated forms of execution previously those compounds in the which phenyl group bearing the substituent -O-R3 has

at least one other substituent R4 and / or R5 different from hydrogen. According to this variant, those compounds with an R4 substituent representing fluorine are especially preferred.

The compounds of the general formula I described in the

5 next experimental section and its derivatives, in which R6 It has a different meaning according to the present invention than hydrogen, in particular acetyl, ethoxycarbonyl or methoxycarbonyl, including its tautomers, stereoisomers, mixtures and salts, are preferred according to another variant of the present

10 invention. In the process according to the present invention the R1 groups, R2, R3, R4 and R5 preferably have the meanings indicated above as preferred. In addition R ’preferably means H, C1-3 alkyl or benzyl, in particular H, ethyl

R8b R8c

15 or methyl. The R8a,, and R8d groups, independently each other, preferably means H, C1-4alkylcarbonyl

or benzyl, in particular H, methylcarbonyl, ethylcarbonyl or benzyl

The present invention also relates to compounds of 20 the general formula IV ’

image 1

where Hal means chlorine, bromine or iodine and the groups R1, R2, R3, R4 and R5 are defined according to the description above. as intermediate products or starting materials in the sin

25 theses of the compounds according to the present invention. Groups R1, R2, R3, R4 and R5 have special preference for meanings indicated for formulas I.2a to I.2d.

The present invention also relates to compounds of general formula II, in particular of general formula II ’

image2

where R ’, R8a, R8b, R8c, R8d, R1, R2, R3, R4 and R5 are defined as

5 before and later, and in particular R ’means H, alkyl C1-3 or benzyl, and the groups R8a, R8b, R8c and R8d, independently of one another, mean H, C1-4alkylcarbonyl or benzyl, in particular H, methylcarbonyl, ethylcarbonyl or benzyl, and the groups R1, R2, R3, R4 and R5 are as defined

10 above. These compounds can serve as products intermediates or starting materials in the synthesis of compounds according to the present invention. The groups R1, R2, R3, R4 and R5 have special preference for the meanings indicated for formulas I.2a to I.2d.

15 Some terms are defined further below employed above and later to describe the compounds according to the present invention. The term halogen means an atom chosen from the group formed by F, Cl, Br and I, in particular F, Cl and Br.

20 The term C1-n alkyl, where n can have a value of 1 to 18, represents a saturated, linear or linear hydrocarbon group branched, with 1 to n C atoms. Examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl,

Neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc. The term C2-n alkynyl, where n can have a value

from 3 to 6, represents a linear or branched hydrocarbon group with 2 to n C atoms and a C≡C triple bond. Examples of such groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentinyl, 2-pentinyl, 3-pentinyl, 4-pentinyl, 1-hexinyl, 2-hexinyl , 3-hexinyl, 4-hexinyl, 5-hexinyl, etc. If not indicated otherwise, the alkynyl groups are attached to the rest of the molecule through the C-atom in position 1. Therefore terms such as 1-propynyl, 2-propynyl, 1-butynyl, etc. equivalent to the terms 1-propin-1-yl, 2-propin-1-yl, 1-butin-1-yl, etc. This is also applicable by analogy to C2-n alkenyl groups.

The term C1-n alkoxy means a C1-n-O alkyl group in which C1-n alkyl is defined as above. Examples of such groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert-pentoxy, n-hexoxy, iso-hexoxy, etc.

The term C1-n-carbonyl alkyl denotes an alkyl group C1-n-C (= O) in which C1-n alkyl is defined as above. Examples of such groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, iso-pentylcarbonyl, neopentylcarbonyl, tert-pentylcarbonyl, n-hexylcarbonyl, isohexylcarbonyl, isohexylcarbonyl, etc.

The term C3-n cycloalkyl means a saturated group mono-, bi-, tri- or spirocarbocyclic of 3 to n C atoms.

Examples of such groups include cyclopropyl, cycle

butyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, decalinyl, bicyclo [3.2.1.] octyl, spiro [4.5] decyl, norpinyl, norbornyl, norcaryl, adamantyl, etc. The term C3-7 cycloalkyl preferably means saturated monocyclic groups.

The term C5-n cycloalkenyl means a cyclo- group C5-n alkyl defined as before, which additionally has, at less, a double bond C = C unsaturated.

The term C3-n-carbonyl cycloalkyl means a group C3-n-C cycloalkyl (= O) in which C3-n cycloalkyl is defined as above.

The term tri- (C1-4 alkyl) silyl encompasses silyl groups carrying equal alkyl groups or two or three alkyl groups different.

The term di- (C1-3 alkyl) amino comprises amino groups which carry two identical or different alkyl groups.

The term aryl preferably represents naphthyl or phenyl, more preferably phenyl.

In the nomenclature of the structural formulas used above and below, when a bond of a substituent of a cyclic group, such as a phenolic ring, is represents towards the center of the cyclic group, unless it indicate otherwise means that this substituent may be united in any free position of the cyclic group that carries an atom of H.

The compounds according to the present invention can be obtained using synthesis methods known in principle. Preferably the compounds are obtained by the following

methods, according to the present invention, described more

Go ahead in greater detail.

The glucose derivatives of formula II according to the present invention can be synthesized from D-gluconolactone or a derivative thereof, by adding the compound of desired benzylbenzene in the form of an organometallic compound (scheme 1).

Scheme 1: adding an organometallic compound to a gluconolactone

halogen-metal exchange comp .. organometallic V

The reaction according to scheme 1 is preferably carried out starting from a halogenated benzylbenzene compound of general formula IV in which Hal means chlorine, bromine or iodine. The corresponding organometallic compound (V) can be prepared from haloaromatic compound IV by means of a

15 reaction known as halogen-metal exchange or inserting the metal in the carbon-halogen bond. The halogen-metal exchange with aromatic groups substituted with bromine or iodine can be carried out for example with a compound of organo-lithium such as eg n-, sec-o tert-butyllithium, for

20 give the respective lithiated aromatic group. The magnesium analog compound can also be generated by exchange halogen-metal with an appropriate Grignard reagent, e.g. isopropylmagnesium bromide or diisopropylmagnesium. The reactions are preferably carried out between 0 and 100 ° C, with special

Cial preference between -10 and -80 ° C, in an inert solvent or in mixtures thereof, such as diethyl ether, tetrahydrofuran, toluene, hexane or methylene chloride. The compounds magnesium or lithium thus obtained can be transmetalized optionally with metal salts, such as trichloride cerium, to form other organometallic compounds (V) suitable for addition. Optionally the organometallic compound (V) can also be prepared by inserting a metal into the carbon-halogen bond of haloaromatic compound IV. For metals such as lithium or magnesium are suitable. The addition of organometallic compound V to gluconolactone or derivatives thereof of formula VI are preferably carried out at temperatures between 0 and -100 ° C, especially preferably between -30 and -80 ° C, in an inert solvent or in mixtures of them, to obtain the compound of formula II. The lithiation and / or coupling reaction can also lead to out in microreactors and / or in micromixers, in order to avoid low temperatures; for example, analogously to the processes described in WO 2004/076470. Suitable solvents for adding the metallized phenyl group to the Properly protected gluconolactone are eg diethyl ether, toluene, methylene chloride, hexane, tetrahydrofuran or mixtures thereof. Addition reactions can be performed without any other adjuvant or, in case of reactants of slow coupling, in the presence of Lewis acids as eg BF3 · OEt2 or Me3SiCl (see M. Schlosser, Organometallics in Synthesis, John Wiley & Sons, Chichester / New York / Brisbane / Toronto / Singapore, 1994). The preferred meanings of

R8b R8c

R8a,, and R8d groups are benzyl, substituted benzyl,

trialkylsilyl, with special preference for trimethylsilyl, triisopropylsilyl, 4-methoxybenzyl and benzyl. If two groups contiguous of the group formed by R8a, R8b, R8c and R8d are linked together, these two groups are preferably part of a benzylidenacetal, 4-methoxybenzylidenacetal, isopropyl acetal, diisopropylsilyl residencetal, or constitute a 2,3-dimethoxy-butylene group that is attached to the adjacent oxygen atoms of the pyranose ring through positions 2 and 3 Butane The group R ’preferably represents hydrogen

or C1-4 alkyl, especially preferably hydrogen, methyl or ethyl. The R ’group is inserted after the compound is added organometallic V or a derivative thereof to gluconolactone VI. For this purpose the reactive solution is treated with a alcohol, eg with methanol or ethanol or water in the presence of a acid such as methanesulfonic, toluenesulfonic, sulfuric or hydrochloric.

The synthesis of the haloaromatic compound of formula IV is can perform using standard chemical transformations organic or at least known methods of literature specialized in organic synthesis (see among others J. March, Advanced Organic Reactions, Reactions, Mechanisms, and Structure, 4th edition, John Wiley & Sons, Chichester / New York / Brisbane / Toronto / Singapore, 1992 and literature cited there). He use of transition metals and organometallic compounds to synthesize aromatic compounds has been detailed so more concrete in several monographs (see e.g. L. Brandsma,

S.F. Vasilevsky, H.D. Verkruijsse, Application of Transition Metal Catalysts in Organic Synthesis

transition metal workers in organic synthesis], editorial

Springer, Berlin / Heidelberg, 1998; M. Schlosser, Organometallics in Synthesis, John Wiley & Sons, Chichester / New York / Brisbane / Toronto / Singapore, 1994; P.J. Stang, F. Diederich, Metal-Catalyzed Cross-Coupling Reactions [Aco reactions

5 cross plating catalyzed by metals], Wiley-VCH, Weinheim, 1997 and references cited therein). The strategies of synthesis described below are demonstrative examples of it.

10

Scheme 2: synthesis of diaryl ketones

image3

Scheme 2 shows the preparation of a pre compound

15 cursor that can be used to synthesize the compounds of formulas IV and IVa, respectively, from a chloride of benzoyl and a second aromatic group, applying Friedel-Crafts acylation conditions or variations thereof. The second aromatic compound carries a substituent U sele

20 between halogen, such as fluorine, chlorine, bromine and iodine, O-C1-4alkyl or O-R3, so that incompatible radicals can be protected or masked. This classic reaction has a wide field of substrates and is usually done in the presence of a catalyst that is used in catalytic proportions

25 or stoichiometric, eg AlCl3, FeCl3, iodine, iron, ZnCl2, sulfuric acid or trifluoromethanesulfonic acid. Instead of

benzoyl chloride can also be used the respective acid

carboxylic, anhydride, ester or benzonitrile. The reactions they are preferably carried out in chlorinated hydrocarbons, such as eg dichloromethane and 1,2-dichloroethane, at temperatures from -30 to 120 ° C, preferably from 30 to 100 ° C. Without However, reactions without solvents or In a microwave oven.

Example 3: synthesis of diarylmethanes and their possible precursor compounds

image4

In scheme 3 the term "Alk" means C1-3 alkyl and each substituent R is chosen, independently of the others,

from the group consisting of H, C1-3 alkyl and C1-3 alkoxy, while that the remaining groups R1 through R5 are defined as above. Scheme 3 describes the synthesis of diarylmethanes and their possible precursor compounds, starting from a phenyl group metalado that carries a radical U chosen from the group formed by fluorine, chlorine, bromine, iodine, a pseudohalogen group such as e.g. trifluoromethanesulfonate, O-C1-4 alkyl or O-R3, and groups Incompatible may be protected or masked. The aromatic compounds substituted with lithium or magnesium are can synthesize from chlorinated, brominated or aromatic aromatics iodine, by a halogen-metal exchange reaction with, eg, butyl lithium, isopropylmagnesium or halide diisopropyl magnesium or by insertion of the metallic element into the halogen-carbon bond. The corresponding boron substituted compound, eg boronic acid, boronic acid ester or dialkylarylborane, can be obtained from these metalated phenyl groups, by reaction with a compound boron electrophile, such as a boronic acid ester or a derivative thereof. The aromatic compound borado also it can be prepared from the corresponding halogenated or pseudohalogenated precursor and a diboro or borane compound by a reaction catalyzed by a transition metal, such as palladium (see eg Tetrahedron Lett. 2003, p. 4895-4898 and references cited there). The compounds of Lithium or magnesium substituted phenyl are added to benzaldehydes (step 3) and to benzoic acids or derivatives thereof (step 4) as its esters, benzamides such as those of type Weinreb, benzonitriles or benzoyl chlorides. You are reacting

They can be done basically without the need for a catalyst

transition metal zador or from a transmetalation to another metal such as cerium or zinc; sometimes it is advantageous to use One of these last alternatives. Acids can be added arylboronic to benzaldehydes by means of a catalyst of rhodium, to give the respective diaryl methanol (see eg Adv. Synth Catal. 2001, p. 343-350 and references cited there). In addition, arylboronic acids, esters of the same, dialkylarylborane or aryltrifluoroborates with benzoyl chlorides by means of a transition metal, such as e.g. palladium, a complex or salt thereof, to give diaryl ketones. Metalated phenyl groups can be reacted with electrophilic benzyl compounds such as chlorides, bromides or benzyl iodides, to give diarylmethanes. Derivatives of phenyl compounds with lithium or magnesium are made react favorably but not always necessary, in presence of a transition metal such as copper, iron

or palladium (see eg Org. Lett. 2001, 3, 2871-2874 and references cited therein). Transmetalation of lithium or magnesium eg boron, tin, silicon or zinc gives, for example, the corresponding aromatic boronic acids, stannates, silanes or zinc compounds, respectively, that can be coupled with electrophilic benzyl compounds, such as halides, benzyl phosphates, sulphonates or carboxylates. The reaction it is carried out in the presence of a transition metal, e.g. palladium, nickel, rhodium, copper or iron (see Tetrahedron Lett. 2004, p. 8225-8228 and references cited there).

Scheme 4: reduction of diaryl ketones and diaryl methanoles to diarylmethanes

image5

In scheme 4 the substituent R means C1-3 alkyl

5 or aryl and the other substituents R1 to R5 are defined as before. Starting from diaryl ketone or diaryl methanol, you can obtain diarylmethane in one or two reaction stages. U know select from a group consisting of fluorine, chlorine, bromine, iodine, pseudohalogen groups such as trifluoromethanesulfonate,

O-C 1-4 alkyl or O-R3, and the incompatible groups may be protected or masked. The diaryl ketone can be reduced to two-stage diarylmethane, passing through the corresponding diphenylmethanol, or in one stage. In the two stage variant the ketone is reduced with a reducing agent, for example with

15 a metal hydride such as NaBH4, LiAlH4 or iBu2AlH, to form the alcohol. The resulting alcohol can be converted into the desired diphenylmethane with a reducing agent such as Et3SiH, NaBH4 or Ph2SiClH, in the presence of a Lewis acid as per example BF3 · OEt2, trifluoroacetic acid, InCl3 or AlCl3. He

20 process in one stage from the ketone to obtain the diphenylmethane can be carried out, for example, with a silane such as Et3SiH or with a boron hydride such as NaBH4 or aluminum as

LiAlH4, in the presence of a Lewis acid such as, for example, BF3 · OEt2, tris (pentafluorophenyl) borane, trifluoroacetic acid, aluminum chloride or InCl3. The reactions are preferably carried out in solvents such as eg halogenated hydrocarbons, for example dichloromethane, toluene or acetonitrile at temperatures from -30 to 150 ° C, preferably from 20 to 100 ° C. Reductions with hydrogen in the presence of a transition metal catalyst, such as Pd on activated carbon, are another possible synthesis method. Too Wolff-Kishner reductions or variants of the same. First the ketone is transformed with hydrazine or with a derivative thereof, such as 1,2-bis (tert-butyldimethylsilyl) hydrazine, in the hydrazone, which, under conditions of strong and hot basic reaction, decomposes forming diphenylmethane and nitrogen. The reaction can be done. perform in one stage or in two separate stages, if it is isolated the hydrazone or a derivative thereof. As suitable bases can be used eg KOH, NaOH or KOtBu, in solvents such as eg ethylene glycol, toluene, DMSO, 2- (2-butoxyethoxy) ethanol or t-butanol; Solvent-free reactions are also possible. The reactions can be carried out at temperatures between 20 and 250 ° C, preferably between 80 and 200 ° C. An alternative to the basic conditions of Wolff-Kishner reduction is Clemmensen reduction, which takes place in conditions acidic and here it can also be used. The alcohol function of diaryl methanol can also be transformed first into a leaving group such as chloride, bromide, iodide, acetate, phosphate or sulfate; the subsequent reduction stage for form diarylmethane is widely described in lite

Organic chemistry race. The reduction of the carbonyl group

or from a leaving benzyl group, such as hydroxyl, for form the respective diarylmethane can also be performed with hydrogen as a reducing agent, in the presence of a tasting

5 transition metal lizer such as palladium, nickel, rhodium or platinum.

To prepare compounds of general formula I in process a) according to the present invention, a compound of formula general II

image6

where R ’and R1 to R5 are defined as before and R8a, R8b, R8c, R8d are defined as above and independently they represent, for example, acetyl, pivaloyl, benzoyl, tert-butoxycarbonyl, benzyloxycarbonyl, trialkylsi

15 lilo, benzyl or substituted benzyl, or in each case two groups R8a, R8b, R8c, R8d adjacent are combined forming a benzylidenacetal, diisopropylsilyl residencetal or isopropyl residence

or a 2,3-dimethoxy-butylene group that is linked by positions 2 and 3 of the butylene group with oxygen atoms

20 of the pyranose ring, forming with them a substituted dioxane, which can be obtained as described above, is done react with a reducing agent in the presence of an acid of Lewis or Brønsted.

25 Suitable reducing agents for the reaction are for example silanes such as triethyl-, tripropil-, triisopropyl

or diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane, lithium aluminum hydride, diisobutylaluminum hydride or samarium iodide. The reductions are made without or in the presence of a Brønsted acid appropriate, such as hydrochloric acid, toluenesulfonic acid, trifluoroacetic or acetic acid, or of a Lewis acid such as e.g. boron-etherate trifluoride, trimethylsilyltriflate, titanium tetrachloride, tin tetrachloride, scandium triflate

or zinc iodide. Depending on the reducing agent and acid employees the reaction can be carried out in a solvent such as, for example, methylene chloride, chloroform, acetonitrile, toluene, hexane, diethyl ether, tetrahydrofuran, dioxane, ethanol, water or mixtures thereof, at temperatures between -60 ° C and 120 ° C. A particularly suitable combination of reagents it consists, for example, of triethylsilane and boroeterate trifluoride, which is conveniently used in acetonitrile or dichloromethane at temperatures between -60 ° C and 60 ° C. You can also hydrogen used in the presence of a metal catalyst of transition, such as palladium on activated carbon or nickel Raney, in solvents such as tetrahydrofuran, acetate ethyl, methanol, ethanol, water or acetic acid, for that transformation.

Alternatively, to prepare compounds of the formula general I according to process b), in a compound of the formula general III

image 1

where R1 to R5 are defined as before and R8a

to R8d means one of the defined protecting groups above, such as acyl, arylmethyl, acetal, ketal or silyl, which can be obtained, for example, by reducing the compound of formula II as described above, the protective groups dissociate.

Any acyl protecting group employed is dissociated, by for example, hydrolytically in an aqueous solvent, eg in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic, hydrochloric or sulfuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium or potassium, or aprotically, eg in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C. A trifluoroacetyl group is preferably dissociates by treatment with an acid such as hydrochloric, optionally in the presence of a solvent such as acetic acid, at temperatures between 50 and 120 ° C, or by treatment with sodium hydroxide solution, optionally in presence of a solvent such as tetrahydrofuran or methanol, a temperatures between 0 and 50 ° C.

Any protective group employed of acetal type or Cethalic is dissociated, for example hydrolytically in an aqueous solvent, eg in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic, hydrochloric or sulfuric

or aprotically, eg in the presence of iodotrimethylsilane, to temperatures between 0 and 120 ° C, preferably at temperatures

between 10 and 100ºC.

A trimethylsilyl group dissociates for example in water, in an aqueous solvent mixture or in a lower alcohol such as methanol or ethanol, in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium carbonate or sodium methoxide.

Also suitable in aqueous or alcoholic solvents are acids such as hydrochloric, trifluoroacetic or acetic. For dissociation in organic solvents such as for example diethyl ether, tetrahydrofuran or dichloromethane, the use of fluoride reagents such as e.g. tetrabutylammonium fluoride.

A benzyl, methoxybenzyl or benzyloxycarbonyl group is effectively dissociates by hydrogenolysis, eg with hydrogen in the presence of a catalyst such as palladium / charcoal, in an appropriate solvent such as methanol, ethanol, acetate ethyl or glacial acetic acid, with the optional addition of a acid such as hydrochloric, at temperatures between 0 and 100 ° C, but preferably at ambient temperatures between 20 and 60 ° C and at a hydrogen pressure of 1 to 7 bar, preferably of 3 to 5 bar. However a 2,4-dimethoxybenzyl group separates preferably in trifluoroacetic acid and in the presence of anisole

A tert-butyl or tert-butyloxycarbonyl group dissociates preferably by treatment with an acid such as trifluoroacetic or hydrochloric, or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene, dioxane, methanol or diethyl ether.

In the reactions described above any reactive group present, such as, for example, ethynyl, hydroxyl, amino,

alkylamino or imino, can be protected during the reaction with

protective groups that dissociate after the reaction.

For example, a protecting group of an ethynyl group can being a trialkylsilyl such as trimethylsilyl and triisopropylsilyl or a dialkylhydroxymethyl such as 2-hydroxyisopropyl-2-yl.

For example, a protecting group of a hydroxyl group it can be a trimethylsilyl, acetyl, trityl, benzyl group

or tetrahydropyranyl. Protective groups for an amino group, alkylamino

or imino can be, for example, formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl.

In addition, the compounds of the general formula I obtained they can be resolved in their enantiomers and / or diastereoisomers, as stated above. Thus, for example, mixtures cis / trans can be resolved in their cis and trans isomers and compounds with at least one optically carbon atom active can be separated into their enantiomers.

Thus, for example, cis / trans mixtures can be resolved by chromatography on their cis and trans isomers; the compounds of general formula I obtained in the form of racemates can be separated by methods known per se (see Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", vol. 6, Wiley Interscience, 1971) in their optical antipodes and the compounds of the general formula I with at least 2 atoms of asymmetric carbon can be resolved in their diastereoisomers by their physical-chemical differences, using methods known per se, eg by chromatography and / or crystal

fractional lization, and, if these compounds are obtained in

racemic form, then they can be resolved in the enantiomers, as mentioned above.

The enantiomers are preferably separated into columns. of chiral phases, by recrystallization from an optically active solvent or by reaction with an optically active substance that forms salts or derivatives such as e.g. esters or amides with the racemic compound, in particular with activated acids and derivatives or alcohols thereof, and separating the resulting diastereoisomeric mixture of salts or derivatives, eg based on their different solubilities, while that free antipodes can be released from pure diastereoisomeric salts or derivatives by the action of agents adequate. The optically active acids commonly used are eg forms D and L of tartaric or dibenzoyltartaric, di-o-tolyltartaric, malic, mandelic, camphorsulfonic, glutamic, aspartic or quinic acids. An optically active alcohol can be for example (+) or (-) - menthol and a group optically active acyl in amides, for example, may be a (+) - or (-) - Methyloxycarbonyl.

Also the compounds of formula I can be converted in its salts, in particular in its physiologically acceptable salts with inorganic or organic acids for pharmaceutical use. The acids that can be used for this purpose are by example hydrochloric, hydrobromic, sulfuric, methanesulfonic, phosphoric, fumaric, succinic, lactic, citric, tartaric or maleic.

In addition, the compounds obtained can be converted into mixtures, for example in a 1: 1 or 1: 2 ratio with amino acids,

specifically with alpha-amino acids such as proline or phenyl

Alanine, which can have especially favorable characteristics such as great crystallinity.

The compounds according to the present invention are also they can be obtained advantageously using the methods described in the following examples, which for this purpose can also be combined with known methods of the specialist through the literature, such as the methods described in WO 98/31697, WO 01/27128, WO 02/083066, WO 03/099836 and WO 2004/063209.

As already said, the compounds of general formula I according to the present invention and its salts physiologically acceptable possess valuable pharmacological properties, mainly an inhibitor effect of glucose cotransporter SGLT-dependent sodium, preferably SGLT2.

The biological properties of the new compounds are

You can investigate as follows: The ability of substances to inhibit activity of the SGLT-2 can be demonstrated in a test system with a CHO-K1 cell line (ATCC No. CCL 61) or alternatively a HEK293 cell line (ATCC No. CRL-1573), which stably transfected with an expression vector pZeoSV (Invitrogen, EMBL identification number L36849) which contains the cDNA to encode the sequence of the human sodium glucose 2 cotransporter (genetic bank, Accession No. NM_003041) (CHO-hSGLT2 or HEK-hSGLT2). These cell lines carry alpha-methyl-glucopyranoside marked with C14 (14C-AMG, Amersham) inland from the cell, in a sodium dependent manner.

The SGLT-2 test is carried out as follows:

CHO-hSGLT2 cells are cultured in Ham F-12 medium (Bio-Whittaker) with 10% fetal bovine serum and 250 µg / ml zeocin (Invitrogen), and HEK293-hSGLT2 cells are cultured in DMEM medium with fetal bovine serum 10% and 250 µg / ml zeocin (Invitrogen). The cells are detached from the culture flasks by washing twice with PBS and then treating with trypsin / EDTA. After adding cell culture medium the cells are centrifuged, resuspended in culture medium and counted in a Casy cell counter. Then 40,000 cells are seeded per well in a 96-well white plate coated with poly-D-lysine and incubated overnight at 37 ° C and 5% CO2. The cells are washed twice with 250 µl of assay buffer (Hank's balanced saline solution, 137 mM NaCl, 5.4 mM KCI, 2.8 mM CaCl2, 1.2 mM MgSO4 and 10 mM HEPES (pH 7.4 ), 50 µg / ml gentamicin). Then 250 µl of assay buffer and 5 µl of the investigated compound are added to each well and the plate is incubated for an additional 15 minutes in the incubator. As a negative control, 5 µl of 10% DMSO is used. The reaction is started by adding 5 µl of AMG-C14 (0.05 µCi) to each well. After 2 hours of incubation at 37 ° C and 5% CO2 the cells are washed again with 250 µl of PBS (20 ° C) and then lysed by adding 25 µl of 0.1 N NaOH (5 min. At 37 ° C). 200 µl of MicroScint20 (Packard) is added to each well and incubation is continued for 20 min. more at 37 ° C. Once this incubation is over, the absorbed radioactivity of AMG-C14 is measured in a “Topcount” (Packard) with a C14 scintillation program.

To determine selectivity with respect to human SGLT1

an analogous assay is established according to which in the cells CHO-K1 or HEK293 expresses the cDNA for SGLT1 (genetic bank, accession number NM_000343) instead of the cDNA for SGLT2.

The compounds of the general formula I according to the present invention may have, for example, EC50 values below 1000 nM, in particular below 200 nM, especially below 50 nM.

Considering its ability to inhibit the activity of SGLT, the compounds of general formula I according to the present invention and their respective pharmaceutically acceptable salts are suitable in theory for the treatment and / or prevention of all those states or diseases sensitive to inhibition of the activity of the SGLT, especially the activity of the SGLT2. Therefore the compounds according to the present invention are especially useful for the prevention or treatment of diseases, specifically metabolic disorders, or states such as diabetes mellitus type 1 and 2, complications of diabetes (eg retinopathy, nephropathy or neuropathies, diabetic foot, ulcers, macroangiopathies), acidosis or metabolic ketosis, reactive hypoglycemia, hyperinsulinemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidemias of different origin, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, edema and hyperuricemia. These substances also serve to prevent the degeneration of beta cells, eg apoptosis or necrosis of pancreatic beta cells They are also appropriate for improve or restore pancreatic cell functionality and also to increase the number and size of cells

pancreatic beta The compounds according to the present invention they can also be used as diuretics or antihypertensives and They are suitable for prevention and treatment of failure acute renal

In particular the compounds according to the present invention, including their physiologically acceptable salts, are suitable for the prevention or treatment of diabetes, especially diabetes mellitus type 1 and 2, and / or diabetic complications

The dosage needed to get the activity corresponding to the treatment or prevention normally depends on the compound to be administered, of the patient, of the nature and severity of the disease or condition and of the method and frequency of administration, and should be decided by the Patient's doctor For convenience the dosage can be from 1 to 100 mg, preferably from 1 to 30 mg, per intravenously, and 1 to 1000 mg, preferably 1 up to 100 mg, orally, administered in each case 1 to 4 times per day For this, the compounds of formula I prepared according to the present invention can be optionally formulated mind together with other active substances, one or more supports and / or inert diluents, eg with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat, or suitable mixtures of such materials, to produce galenic preparations

conventional such as simple or coated tablets,

capsules, powders, suspensions or suppositories.

The compounds according to the present invention are also they can use together with other active substances, in particular for the treatment and / or prevention of the diseases and conditions mentioned above. Other appropriate active substances for such combinations include, for example, those that enhance the therapeutic effect of an SGLT antagonist according to the present invention with respect to one of the aforementioned indications and / or which allow reducing its dosage. The appropriate therapeutic agents for a combination of this type include, for example, antidiabetic agents such as metformin, sulfonylureas (eg glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (eg rosiglitazone, pioglitazone), PPAR-gamma agonists (eg GI 262570) and antagonists, modulators of PPAR-gamma / alpha (e.g. KRP 297), alpha-glucosidase inhibitors (e.g. acarbose, voglibose), DPPIV inhibitors (eg LAF237, MK431), alpha 2-antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogs (eg exendin-4) or amylin. The list also includes protein tyrosine phosphatase 1 inhibitors, substances that affect irregular production of glucose in the liver, such as eg inhibitors of glucose-6-phosphatase or fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and phosphoenol pyruvate carboxykinase inhibitors, glycogen synthase kinase or pyruvate dehydrogenase, lipid reducing agents such as, for example, HMG-CoA reductase inhibitors (eg simvastatin, atorvastatin), fibrates (eg bezafi

brato, fenofibrate), nicotinic acid and its derivatives, ago

PPAR-alpha lists, PPAR-delta agonists, ACAT inhibitors (eg avasimibe) or cholesterol absorption inhibitors, such as ezetimibe, bile acid fixing substances, such as cholestyramine, acid transport inhibitors ileal bile, HDL elevating compounds such as CETP inhibitors or ABC1 regulators or active substances for the treatment of obesity such as sibutramine or tetrahydrolipostatin, dexfenfluramine, axokin, cannabinoid 1 receptor antagonists, MCH-1 receptor antagonists, MC4 receptor agonists , NPY5 or NPY2 antagonists or β3 agonists such as SB-418790 or AD-9677 and 5HT2c receptor agonists.

Also suitable are combinations with drugs to treat high blood pressure, chronic heart failure or atherosclerosis such as A-II antagonists or ACE inhibitors, ECE inhibitors, diuretics, β blockers, calcium antagonists , centrally acting antihypertensives, alpha-2 adrenergic receptor antagonists, neutral endopeptidase inhibitors, thrombocyte aggregation inhibitors and others or combinations thereof. Examples of angiotensin II receptor antagonists include candesartan cilexetil, losartan potassium, eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan, medoxomil, tasosartan, KT-3671 GA-0113, RU-84276, EMD-90423, BR-9701, etc. Angiotensin II receptor antagonists are preferably used to treat or prevent high blood pressure and diabetic complications, often combined with a diuretic such as hydrochlorothiazide.

A combination with acid synthesis inhibitors Uric is used to treat gout.

A combination with GABA receptor antagonists, Na channel blockers, topiramate, inhibitors of Protein kinase C, inhibitors of advanced glycation end products or aldose reductase inhibitors can be used to treat or prevent diabetic complications.

The dosage of the combination components above cited ranges by utility between 1/5 of the lowest dose Normally recommended and 1/1 of the normally recommended dose.

Therefore, in another aspect, the present invention is refers to the use of a compound according to the present invention or of a physiologically acceptable salt of said compound, in combination with at least one of the active substances above described as mixing components, to prepare a pharmaceutical composition that is suitable for treating or preventing diseases or conditions sensitive to the inhibition of the SGLT sodium dependent glucose cotransporter. These states they are preferably metabolic diseases, especially a of the diseases or conditions listed above and more specifically diabetes or its complications.

The use of a compound according to the present invention or of a physiologically acceptable salt thereof in combination with another active substance it can take place simultaneously or in a staggered way, but especially in a short space of weather. If administered simultaneously, the two substances active are supplied together to the patient and, when used

in a staggered manner, they are supplied to the patient within a

period less than or equal to 12 hours, in particular less than or equal to 6 hours.

Therefore, in another aspect, the present invention refers to a pharmaceutical composition that includes a compound according to the present invention or a physiologically salt acceptable thereof and at least one of the active substances described above as combination components, optional- mind together with one or more inert supports and / or diluents.

Thus, for example, a pharmaceutical composition according to the The present invention comprises a combination of a compound of formula I according to the present invention, or of a salt physiologically acceptable thereof, and at least one angiotensin II receptor antagonist, optionally together with one or more inert supports and / or diluents.

The compound according to the present invention, or a salt physiologically acceptable thereof, and the active substance additional to combine with that one can be together in a formulation, for example in a tablet or capsule, or separated into two identical or different formulations, for example In a so-called component kit.

In the previous and following text the atoms of H of the Hydroxyl groups are not always explicitly represented in structural formulas. The term "temperature ambient ”means temperatures in the range between 20 and 25ºC. The following examples serve to illustrate the present invention without limiting it:

Preparation of starting compounds:

Example I

image2

(5-Bromo-2-chloro-phenyl) - (4-methoxy-phenyl) -methanone 38.3 ml of oxalyl chloride and 0.8 ml of dimethylformamide are added to a solution of 100 g of 5-bromo-2 acid

5 chlorobenzoic acid in 500 ml of dichloromethane. The reactive mixture stir for 14 h, then filter and separate from all volatile components in a rotary evaporator. The residue is dissolved in 150 ml of dichloromethane, the solution is cooled to -5 ° C and 46.5 g of anisole are added. Then they are added

10 51.5 g of aluminum trichloride, in portions, so that the temperature does not exceed 5ºC. The solution is stirred 1 h more at 1-5 ° C and then poured on ice. Phase is separated organic and the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed with solution

15M aqueous hydrochloric acid 1M, twice with solution of 1M sodium hydroxide and with brine. Then the phase is dried organic, the solvent is removed and the residue crystallizes from ethanol. Yield: 86.3 g (64% of theory)

20 Mass spectrum (ESI +): m / z = 325/327/329 (Br + Cl) [M + H] + The following compound can be obtained analogously to example I:

(1) (5-Bromo-2-methyl) - (4-methoxy-phenyl) -methanone

image2

25 Mass spectrum (ESI +): m / z = 305/307 (Br) [M + H] +

Example II

image2

4-Bromo-1-chloro-2- (4-methoxy-benzyl) -benzene A solution of 86.2 g of (5-bromo-2-chloro-phenyl) - (4

5 methoxy-phenyl) -methanone and 101.5 ml of triethylsilane in 75 ml of dichloromethane and 150 ml of acetonitrile is cooled to 10 ° C. Then, stirring, 50.8 ml of boroeterate trifluoride are added, so that the temperature does not exceed 20 ° C. The solution is stirred 14 h at room temperature before adding

10 9 ml of triethylsilane and 4.4 ml of boron-etherate trifluoride plus. The solution is stirred an additional 3 h at 45-50 ° C and then cooled at room temperature. A solution of 28 g of potassium hydroxide in 70 ml of water and the resulting mixture is stir 2 h. Then the organic phase and the aqueous phase are separated

15 is extracted three times with diisopropylether. Organic phases together they are washed twice with 2M potassium hydroxide solution and once with brine and then dried over sodium sulfate. After removing the solvent the residue is Stir in ethanol, separate again and dry at 60 ° C.

20 Yield: 50.0 g (61% of theory) Mass spectrum (ESI +): m / z = 310/312/314 (Br + Cl) [M + H] + The following compound can be obtained analogously to example II:

(1) (5-Bromo-2-methyl) - (4-methoxy-phenyl) -methane

image2

Mass spectrum (EI): m / z = 290/292 (Br) [M] + Example III

image2

4- (5-Bromo-2-chloro-benzyl) -phenol

A solution of 14.8 g of 4-bromo-1-chloro-2- (4-methoxybenzyl) -benzene in 150 ml of dichloromethane is cooled in a ice bath Then 50 ml of a 1 M solution of boron tribromide in dichloromethane and the solution is stirred 2 h at room temperature. Then the solution is cooled by

10 again in an ice bath and saturated potassium carbonate solution is added dropwise. At room temperature The mixture is adjusted to pH 1 with 1 M aqueous hydrochloric acid solution, the organic phase is separated and the aqueous phase is separated. extract three times with ethyl acetate. Organic phases

15 combined are dried over sodium sulfate and the solvent is completely removed. Yield: 13.9 g (98% of theory) Mass spectrum (ESI-): m / z = 295/297/299 (Br + Cl) [M-H] The following compound can be obtained analogously

20 to example III:

(1) 4- (5-Bromo-2-methyl-benzyl) -phenol

image2

Mass spectrum (ESI-): m / z = 275/277 (Br) [M-H] Example IV

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[4- (5-Bromo-2-chloro-benzyl) -phenoxy] -terc-butyl-dimethylsilane A solution of 13.9 g of 4- (5-bromo-2-chloro-benzyl)

5 phenol in 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 4-dimethylaminopyridine. The solution is stirred 16 h at room temperature and then diluted with 100 ml of

10 dichloromethane. The organic phase is washed twice with 1 M aqueous hydrochloric acid solution and once with solution aqueous sodium bicarbonate and then dried over sulfate sodium Once the solvent is removed the residue is filtered with silica gel (cyclohexane / ethyl acetate 100: 1).

15 Yield: 16.8 g (87% of theory) Mass spectrum (EI): m / z = 410/412/414 (Br + Cl) [M] + The following compound can be obtained analogously to example IV:

(1) [4- (5-Bromo-2-methyl-benzyl) -phenoxy] -terc-butyl20 dimethyl-silane

image2

Mass spectrum (EI): m / z = 390/392 (Br) [M] + Example V

image2

2,3,4,6-Tetrakis-O- (trimethylsilyl) -D-glucopiranone A solution of 20 g of D-glucono-1,5-lactone and 98.5 ml of N-methylmorpholine in 200 ml of tetrahydrofuran is cooled to

5 -5 ° C. Then 85 ml of trimethylsilyl chloride drop are added dropwise, so that the temperature does not exceed 5 ° C. Later stir the solution 1 h at room temperature and 5 h at 35 ° C and 14 h more at room temperature. After adding 300 ml of toluene the solution is cooled in an ice bath and added

10 500 ml of water, so that the temperature does not rise from 10ºC. Then the organic phase is separated and washed once, respectively, with aqueous dihydrogen phosphate solution sodium, water and brine. The solvent is removed and the residue is dried azeotropically with toluene.

15 Yield: 52.5 g (90% purity) Mass spectrum (ESI +): m / z = 467 [M + H] + Example VI

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1-Chloro-4- (β-D-glucopyranos-1-yl) -2- (4-hydroxybenzyl)

20 benzene A solution of 4.0 g of [4- (5-bromo-2-chloro-benzyl) phenoxy] -terc-butyl-dimethyl-silane in 42 ml of dry diethyl ether it is cooled to -80 ° C under an argon atmosphere. They are added slowly 11.6 ml of a 1.7 M solution of tert-butyllithium drop by drop

in pentane to the cooled solution and it is then stirred 30 minutes at -80 ° C. This solution is then slowly added dropwise, by means of an ice-cooled transfer needle, to a solution of 4.78 g of 2,3,4,6-tetrakis-O- (trimethylsilyl) -D-glucopyranosone in 38 ml. of diethyl ether cooled to -80 ° C. The resulting solution is stirred 3 h at -78 ° C. Then 1.1 ml of a solution of methanesulfonic acid in 35 ml of methanol are added and the solution is stirred 16 h at room temperature. The solution is then neutralized with solid sodium bicarbonate, ethyl acetate is added and the methanol is removed along with the ether. Aqueous sodium bicarbonate solution is added to the remaining solution and the resulting mixture is extracted four times with ethyl acetate. The organic phases are dried over sodium sulfate and evaporated. The residue is dissolved in 30 ml of acetonitrile and 30 ml of dichloromethane and the resulting solution is cooled to -10 ° C. After the addition of 4.4 ml of triethylsilane, 2.6 ml of boron-etherate trifluoride are added dropwise, so that the temperature does not rise to -5 ° C. Once the addition is finished, the solution is stirred an additional 5 h between -5 and -10 ° C and then neutralized by adding aqueous sodium bicarbonate solution. The organic phase is separated and the aqueous phase is extracted four times with ethyl acetate. The combined organic phases are dried over sodium sulfate, the solvent is removed and the residue is purified with silica gel. The product obtained is a mixture of approximately 6: 1 β / α, which can be converted into the pure β anomer by global acetylation of the hydroxyl groups with acetic anhydride and pyridine in dichloromethane, and recrystallization of the product from ethanol. The pure acetylated β anomer and

crystallized, it becomes the title compound by global deprotection with 4M potassium hydroxide solution in methanol Yield: 1.6 g (46% of theory)

5 Mass spectrum (ESI +): m / z = 398/400 (CI) [M + H] + The following compounds can be obtained in a manner analogous to example VI:

(1) 1-Methyl-4- (β-D-glucopyranos-1-yl) -2- (4-hydroxybenzyl) -benzene

10 After adding the lithiated aromatic compound to the silylated gluconolactone, this reaction is best extinguished by 1% acetic acid in water than with methanesulfonic acid in methanol The crude product obtained from the aqueous treatment is then balance towards the more stable anomer (with the group

15 methoxy in axial position and the aryl radical in equatorial position), using a catalytic amount of methanesulfonic acid in methanol.

image2

Mass spectrum (ESI +): m / z = 660 [M + NH4] + Example VII

image2

1- (2,3,4,6-Tetra-O-benzyl-1-hydroxy-D-glucopyranoses-1

il) -3- [4- (tert-butyl-dimethyl-silyloxy) -benzyl] -4-methylbenzene A solution of 0.34 g of [4- (5-bromo-2-methyl-benzyl) phenoxy] -terc-butyl-dimethyl-silane in 3 ml of tetrahydrofuran

5 is cooled to -80 under argon atmosphere. At dissolution cooled 0.54 ml of a solution of dropwise are added 1.6M n-butyllithium in hexane and the resulting solution is stir 1.5 h at -78 ° C. To this solution is added drop to drop with a transfer needle a solution of 0.43 g of

10 2,3,4,6-tetra-O-benzyl-D-glucopyranone in 2.5 ml of tetrahydrofuran cooled to -80 ° C. The resulting solution is stirred 5 h at -78 ° C. The reaction is terminated with a 0.1 ml solution. of acetic acid in 1 ml of tetrahydrofuran and heated to room temperature. Then aqueous solution of

15 sodium bicarbonate and the resulting mixture is extracted four times with ethyl acetate. The combined organic phases are Dry over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by chromatography on silica gel (cyclohexane / ethyl acetate 15: 1-> 4: 1).

20 Yield: 0.48 g (approximately 88% purity) Mass spectrum (ESI +): m / z = 868 [M + H] + Example VIII

image2

1- (2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl) -3- (425 hydroxy-benzyl) -4-methyl-benzene

A solution of 0.48 g (approx. 88% purity) of 1- (2,3,4,6-tetra-O-benzyl-1-hydroxy-D-glucopyranosyl) -3- [4 (tert-butyldimethyl-silyloxy) -benzyl] -4-methylbenzene in 3.5 ml of dried acetonitrile is cooled to -40 ° C under an argon atmosphere.

5 0.13 ml of triisopropylsilane and 0.08 ml are added dropwise of boron-etherate trifluoride to the cooled solution and it stir 3 h at -35 ° C before adding 0.02 ml of triisopropylsilane and 0.01 ml of boron-etherate trifluoride. After 2 h more at -40 ° C, aqueous potassium bicarbonate solution is added

10 and the resulting solution is stirred 1 h at room temperature. It is then diluted with water and extracted four times with acetate of ethyl. The organic phase is dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (cyclohexane / ethyl acetate 10: 1-> 4: 1).

15 Yield: 0.24 g (68% of theory) Mass spectrum (ESI +): m / z = 738 [M + NH4] + Example IX

image2

1-Chloro-4- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-120 yl) -2- [4- (1-hydroxycarbonyl-cyclopent-1-yloxy) -benzyl] benzene

To a solution of 1-chloro-4- (β-D-glucopyranos-1-yl) -2

[4- (1-Hydroxycarbonyl-cyclopent-1-yloxy) -benzyl] -benzene

(6.50 g; see preparation in example 4) in dichloromethane

25 (50 ml) is added successively pyridine (9 ml), anhydride

acetic (10 ml) and 4-dimethylamino pyridine (0.5 g). The reaction solution is stirred at room temperature for 16 h and then diluted with dichloromethane (50 ml). The resulting solution is washed with aqueous hydrochloric acid solution. (1 mol / l) and aqueous NaHCO3 solution, and dried (Na2SO4). The product is obtained after removing the solvent. Yield: 6.46 g (74% of theory) Mass spectrum (ESI +): m / z = 678/680 (CI) [M + NH4] +

Example X

image2

10

1-Chloro-4- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranoses-1

il) -2- [4- (1-hydroxymethyl-cyclopent-1-yloxy) -benzyl] -benzene To a solution of 1-chloro-4- (2,3,4,6-tetra-O-acetyl-β -D

glucopyranos-1-yl) -2- [4- (1-hydroxycarbonylcyclopent-1-yloxy)

Benzyl] -benzene (1.50 g) in dichloromethane (7 ml) cooled in an ice bath is added oxalyl chloride (1 ml). The solution is stirred at room temperature for 4 h and then It is concentrated under reduced pressure. The residue dissolves in Dry tetrahydrofuran (4 ml), cooled in an ice bath and

20 is treated with sodium borohydride (86 mg). The resulting mixture stir at room temperature for 16 h. Water is added and The resulting mixture is extracted with ethyl acetate. They dry the combined extracts (Na2SO4), the solvent is removed by vacuum and the residue is purified by gel chromatography of

25 silica (cyclohexane / ethyl acetate 1: 0-> 2: 1).

Yield: 1.15 g (78% of theory)

Mass spectrum (ESI +): m / z = 664/666 (CI) [M + NH4] + Example XI

image2

1-Chloro-4- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-15 yl) -2- [4- (1-methoxymethyl-cyclopent-1-yloxy) -benzyl] -benzene

To a solution of 1-chloro-4- (2,3,4,6-tetra-O-acetyl-βD-glucopyranos-1-yl) -2- [4- (1-hydroxymethyl-cyclopent-1-yloxy) benzyl] -benzene (0.56 g) in dichloromethane (4 ml) cooled in an ice bath, tetrafluoroboric acid (0.12 ml) is added and

10 trimethylsilyldiazomethane (0.45 ml). The solution is stirred at room temperature for 1 h and then deactivated with Water. The resulting mixture is extracted with dichloromethane, the Combined extracts are dried (Na2SO4), the solvent is removed and the residue is purified by gel chromatography.

15 silica (cyclohexane / ethyl acetate 1: 0-> 2: 1). Yield: 0.38 g (67% of theory) Mass spectrum (ESI +): m / z = 678/680 (CI) [M + NH4] +

Preparation of the final compounds

Example 1

image2

1-Chloro-4- (β-D-glucopyranos-1-yl) -2- [4- (trans-2-hydroxy

cyclopent-1-yloxy) -benzyl] -benzene

A mixture of 1-chloro-4- (β-D-glucopyranos-1-yl) -2- (4-hi

droxibenzyl) benzene (0.50 g), cyclopentene oxide (1.50 g) and potassium carbonate (0.45 g) in ethanol (1.5 ml) is stirred 75 minutes at 100 ° C in a microwave oven. After cooling to room temperature water is added and the resulting mixture is

5 extracted with ethyl acetate. After drying the organic phases collected on sodium sulfate the solvent and the residue is purified by chromatography on silica gel (dichloromethane / methanol 9: 1-> 1: 1). Yield: 300 mg (49% of theory)

10 Mass spectrum (ESI +): m / z = 465/467 (CI) [M + H] + Diastereomers, 1-chloro-4- (β-D-glucopyranos-1-yl) -2 [4- ( (1R, 2R) -2-hydroxy-cyclopent-1-yloxy) -benzyl] -benzene and 1-chloro-4- (β-D-glucopyranos-1-yl) -2- [4 - ((1S, 2S) - 2-hydroxycyclopent-1-yloxy) -benzyl] -benzene, can be separated by HPLC

15 on chiral phase (DAICEL AD-H, 250 x 4, 6 mm, 5 mm; hexane + aminocyclohexane / ethanol 70:30, 1 ml / min), to obtain the diastereoisomerically pure compounds. Example 2

image2

20 1-Chloro-4- (β-D-glucopyranos-1-yl) -2- [4- (3-hydroxy

cyclopent-1-yloxy) -benzyl] -benzene

A mixture of 1-chloro-4- (β-D-glucopyranos-1-yl) -2- (4-hydroxybenzyl) -benzene (0.25 g), 3-hydroxycyclopent-1-yl p-tolylsulfonate (0 , 19 g) and cesium carbonate (0.33 g) in di25 methylformamide (1.5 ml) is stirred at 70 ° C for 16 h. After cooling to room temperature, water and mixture are added.

The resulting is extracted with ethyl acetate. The phases are dried

organic compounds (Na2SO4), the solvent and the residue is purified by chromatography on silica gel (dichloromethane / methanol 1: 0-> 4: 1). Yield: 90 mg (29% of theory) Mass spectrum (ESI +): m / z = 482/484 (CI) [M + NH4] +

The following compound can be obtained analogously to example 2:

(3) 1-Chloro-4- (β-D-glucopyranos-1-yl) -2- [4- (2-oxo-cyclopent-1-yloxy) -benzyl] -benzene

image2

10

The compound is prepared using 1-chloro-cycle oxide

pentene (prepared from 1-chloro-cyclopentene and acid

m-chloroperoxybenzoic in dichloromethane) as electrophile.

(4) 1-Chloro-4- (β-D-glucopyranos-1-yl) -2- [4- (trans-215 hydroxy-cyclohex-1-yloxy) -benzyl] -benzene

image2

Mass spectrum (ESI): m / z = 496/498 (CI) [M] +

The reaction is carried out with cyclohexene oxide at 100 ° C. Example 5

image2

1-Chloro-4- (β-D-glucopyranos-1-yl) -2- [4- (1-methoxy

carbonyl-cyclopent-1-yloxy) -benzyl] -benzene

A mixture of 1-chloro-4- (β-D-glucopyranos-1-yl) -2- (4-hydroxybenzyl) -benzene (0.46 g), 1-bromo-1-methoxycarbonylcyclopentane (0.87 g), iodide potassium (0.1 g) and carbonate

Potassium (0.5 g) in methanol (5 ml) is stirred at reflux for 16 h. After cooling to room temperature it is added water and the resulting mixture is extracted with ethyl acetate. The combined organic phases are dried (Na2SO4), the solvent and the residue is purified by chromatography on

10 silica gel (dichloromethane / methanol 1: 0-> 4: 1). Yield: 180 mg (30% of theory) Mass spectrum (ESI +): m / z = 524/526 (CI) [M + NH4] + Example 6

image2

1-Chloro-4- (β-D-glucopyranos-1-yl) -2- [4- (1-hydroxycarbonyl-cyclopent-1-yloxy) -benzyl] -benzene A solution of 1-chloro-4- ( β-D-glucopyranos-1-yl) -2- [4 (1-methoxycarbonyl-cyclopent-1-yloxy) -benzyl] -benzene (0.20 g) in aqueous potassium hydroxide solution (4 mol / l, 5 ml) and

20 methanol (5 ml) is stirred at room temperature for 4 h. After neutralizing with aqueous hydrochloric acid solution (1 mol / l) the mixture is concentrated under reduced pressure, Dilute with aqueous NaHCO3 solution and extract with ethyl acetate. The combined organic phases are dried

25 (Na2SO4), the solvent is removed and the residue is purified by chromatography on silica gel (dichloromethane / methanol

1: 0-> 4: 1).

Yield: 31 mg (16% of theory)

Mass spectrum (ESI +): m / z = 510/512 (CI) [M + NH4] + Example 7

image2

5

1-Chloro-4- (β-D-glucopyranos-1-yl) -2- [4- (cis-2-hydroxycyclopent-1-yloxy) -benzyl] -benzene To a solution of 1-chloro-4- ( β-D-glucopyranos-1-yl) -2

10 [4- (2-Oxocyclopent-1-yloxy) benzyl] -benzene (0.10 g) in dry tetrahydrofuran (3 ml) cooled to -78 ° C is added L-selectride (1 mol / l in tetrahydrofuran, 0, 33 ml) Dissolution The resulting mixture is stirred at -78 ° C for 2 h, then diluted with dichloromethane and neutralized with aqueous acid solution

15 hydrochloric (1 mol / l). The organic layer and the layer are separated Aqueous is extracted with dichloromethane. The combined organic phases are dried (Na2SO4), the solvent is removed in vacuo and The residue is purified by chromatography on silica gel (dichloromethane / methanol 1: 0-> 4: 1).

20 Yield: 40 mg (42% of theory) Mass spectrum (ESI +): m / z = 482/484 (CI) [M + NH4] + Example 8

image2

1-Chloro-4- (β-D-glucopyranos-1-yl) -2- [4 - (- hydroxymethyl

cyclopent-1-yloxy) -benzyl] -benzene

To a solution of 1-chloro-4- (β-D-glucopyranos-1-yl) -2 [4- (1-methoxycarbonylcyclopent-1-yloxy) benzyl] benzene (0.15 g) in dry tetrahydrofuran (3 ml ) oil bath cooled it

5 adds lithium borohydride (8 mg). The reaction is stirred at the room temperature for 16 h. Solution is added aqueous NaHCO3 and the resulting mixture is extracted with acetate of ethyl. The combined organic phases are dried (Na2SO4), removes the solvent and the residue is purified by chromate

10 spelling on silica gel (dichloromethane / methanol 1: 0-> 4: 1). Yield: 128 mg (90% of theory) Mass spectrum (ESI +): m / z = 496/498 (CI) [M + NH4] + Example 9

image2

1-Chloro-4- (β-D-glucopyranos-1-yl) -2- [4- (1-methoxymethylcyclopent-1-yloxy) -benzyl] -benzene To a solution of 1-chloro-4- (2 , 3,4,6-tetra-O-acetyl-βD-glucopyranos-1-yl) -2- [4- (1-methoxymethyl-cyclopent-1-yloxy) benzyl] -benzene (0.39 g) in tetrahydrofuran (3 ml) is added

20 pyrrolidine (0.22 ml). The solution is stirred at temperature ambient for 16 h. The resulting solution after dilute with ethyl acetate is washed with aqueous solution of hydrochloric acid (1 mol / l), dried (Na2SO4) and solvent It is removed under reduced pressure. The residue is purified by

25 HPLC in reverse phase (YMC C18; water / acetonitrile 95: 5-> 2:98). Yield: 116 mg (40% of theory)

60 Mass spectrum (ESI +): m / z = 510/512 (CI) [M + NH4] + The following compounds are also prepared in a manner analogous to the previous examples and other known methods of literature:

image7

image8

image9

image10

image11

image12

The following describes some examples of formulations in which the term "active substance" means one or more compounds according to the present invention, including Your salts In case of combination with one or more substances additional assets, as described above, The term "active substance" also includes substances additional assets

Example A Tablets containing 100 mg of active substance

Composition:

1 tablet contains:

active substance

100.0 mg

lactose

80.0 mg

cornstarch

34.0 mg

polyvinylpyrrolidone

4.0 mg

magnesium stearate

2.0 mg

220.0 mg

Preparation method:

The active substance is mixed with lactose and starch and moistened evenly with an aqueous solution of polyvinylpyrrolidone After sifting the composition wet (mesh size 2.0 mm) and dry it at 50 ° C in a rack dryer, sieve again (mesh size 1.5 mm) and the lubricant is added. The finished mixture is compressed in tablet form Tablet weight: 220 mg Diameter: 10 mm, biplane, with facet on both sides and notched on one side.

Example B

Tablets containing 150 mg of active substance Composition: 1 tablet contains:

active substance 150.0 mg lactose powder 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg 1.0 mg magnesium stearate

300.0 mg preparation: The active substance mixed with lactose, starch

of corn and silica is moistened with an aqueous solution of 20% polyvinylpyrrolidone and passed through a 1.5 mm sieve mesh size. The granulate, dried at 45 ° C, is passed another once through the same sieve and mixed with the specified amount of magnesium stearate. The finished mixture is compressed in the form of tablets. Tablet weight: 300 mg Wedge: 10 mm, flat

Example C Hard gelatin capsules containing 150 mg of their

active tance

Composition:

1 capsule contains:

active substance

150.0 mg

cornstarch (dried)

approx. 180.0 mg

lactose (powder)

approx. 87.0 mg

magnesium stearate

3.0 mg

approx. 420.0 mg preparation: The active substance is mixed with the excipients, it is

it passes through a screen of 0.75 mm mesh size and is homogenized by means of a suitable apparatus. With the finished mixture it fill size 1 hard gelatin capsules. Capsule filling: approx. 420 mg Capsule wrap: hard gelatin capsule size 1.

Example D Suppositories containing 150 mg of active substance

Composition:

1 suppository contains:

active substance

150.0 mg

1500 polyethylene glycol

550.0 mg

6000 polyethylene glycol

460.0 mg

polyoxyethylene sorbitan monostearate

840.0 mg

2,000.0 mg

preparation:

The mass of the melted suppository is incorporated homogeneous way the active substance and the molten mixture is Poured into cooled molds.

Example E Ampoules containing 10 mg of active substance Composition:

active substance 10.0 mg 0.01 N hydrochloric acid, c.s. doubly distilled water, up to 2.0 ml

preparation:

The active substance dissolves in the necessary amount

of 0.01 N HCl, is made isotonic with common salt, filtered is

thermally and transferred to 2 ml ampoules.

5 Example F Ampoules containing 50 mg of active substance Composition:

active substance 50.0 mg 0.01 N hydrochloric acid, c.s.

10 doubly distilled water, up to 10.0 ml preparation: The active substance dissolves in the necessary amount of 0.01 N HCl, isotonic with common salt, sterile filtered and transferred to 10 ml ampoules.

fifteen

Claims (14)

 Claims   1. Benzylbenzene derivatives substituted with glucopyranosyl, of general formula I image 1 5 where R1 means hydrogen, fluorine, chlorine, bromine, iodine, C1-4 alkyl, C2-6 alkynyl, C1-4 alkoxy, C2-4 alkenyl C1-4 alkynyl, C2-4 alkynyl-C1-4 alkoxy, substituted methyl with 1 to 3 fluorine atoms, ethyl substituted with 1 10 to 5 fluorine atoms, methoxy substituted with 1 to 3 fluorine atoms, ethoxy substituted with 1 to 5 atoms of fluorine, C1-4 alkyl substituted with a hydroxyl group or C1-3 alkoxy, C2-4 alkoxy substituted with a group hydroxy or C1-3 alkoxy, C2-8 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-3alkyl, C3-7-oxycycloalkyl, C3-7 -cycloalkyl-C1-3alkoxy, C5-7 -oxycycloalkenyl, hydroxyl, amino, nitro or cyano, and in the C5-6 cycloalkyl groups a methylene group may be substituted by O; 20 R2 means hydrogen, fluorine, chlorine, bromine, hydroxyl, C1-4 alkyl, C1-4 alkoxy, cyano or nitro, and the group alkyl or alkoxy may be mono- or polysubstituted with fluorine, and R3 means C3-7 cycloalkyl, tetrahydrofuranyl or 25 tetrahydropyranyl, substituted with one to four L2 substituents, or R3 means C5-7 cycloalkanyl, which may be substituted with one to four L2 substituents; Y R4, R5, independently of each other, represent hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, alkyl C1-3, C1-3 alkoxy or a substituted methyl or methoxy group with 1 to 3 fluorine atoms, L1, independently of each other, is chosen from fluorine, chlorine, bromine, iodine, hydroxyl, cyano, C1-3 alkyl, difluoromethyl, trifluoromethyl, C1-3 alkoxy, difluoromethoxy, trifluoromethoxy, amino, C1-3-alkyl alkyl and di (C1-3alkyl) -amino; and L2, independently of each other, they are chosen from fluorine, chlorine, hydroxyl, hydroxyalkyl C1-4, C1-4 alkoxy, trifluoromethoxy, C1-4 alkoxy C1-4, cyano, hydroxycarbonyl, (C1-4 alkyl) oxycarbonyl, aminocarbonyl, C1-4 alkyl, trifluoromethyl, amino, (C1-4 alkyl) -carbonylamino, C1-3-alkyl and dialkyl C1-3-amino; Y R6, R7a, R7b, R7c, independently of each other, have a meaning chosen from hydrogen, (C1-18 alkyl) carbonyl, (C1-18 alkyl) oxycarbonyl, arylcarbonyl and aryl- (C1-3 alkyl) -carbonyl, and aryl groups can be mono-or disubstituted, regardless of yes, with the same or different L1 groups; while the aryl groups mentioned in the definition of the above groups mean phenyl or naphthyl groups that they may be substituted as defined; Y, if not indicated otherwise, the above-mentioned alkyl groups they can be straight or branched chain, its tautomers, stereoisomers, mixtures and salts. 2. Benzylbenzene derivatives substituted with glucopyranosyl, of general formula I.2 image 1 where the groups R1 to R6 and R7a, R7b and R7c are defined as in the 5 claim 1. 3. Benzylbenzene derivatives substituted with glucopyranosyl according to claim 1 or 2, characterized in that the R3 group represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl or 10 tetrahydropyran-4-yl, which are substituted with one or two L2 substituents; or R3 represents cyclopentanonyl or cyclohexanonyl, which may be substituted with one or two L2 substituents; wherein L2 is defined as in claim 1. 4. Benzylbenzene derivatives substituted with glucopyrran Silo according to one or more of claims 1 to 3, characterized in that the group R1 means hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, C1-4 alkoxy, methyl substituted with 1 to 3 fluorine atoms, methoxy substituted with 1 to 3 atoms of fluorine, C3-7-oxycycloalkyl or C3-7-cycloalkyl-C1-3alkoxy, and in 20 C5-6 cycloalkyl groups a methylene group may be replaced by O. 5. Pharmaceutical composition containing a compound according to one or more of claims 1 to 4 or a physiologically acceptable salt thereof, optionally together with one or 25 more supports and / or inert diluents.

6.

Use of at least one compound according to one or more of the rei

vindications 1 to 4 or of a physiologically acceptable salt thereof to prepare a suitable pharmaceutical composition to treat or prevent metabolic disorders.

7.

Use according to claim 6, characterized in that the metabolic disorder is selected from the group consisting of type 1 and 2 diabetes mellitus, diabetic complications, Acidosis or metabolic ketosis, reactive hypoglycemia, hyperinsulinemia, glucose metabolic disorder, resistance to insulin, metabolic syndrome, different dyslipidemias origin, atherosclerosis and related diseases, obesity, arterial hypertension, chronic heart failure, edema and hyperuricemia.

8.

Use of at least one compound according to at least one of the claims 1 to 4 or a physiologically acceptable salt thereof to prepare a pharmaceutical composition whose Application is to inhibit the sodium dependent glucose cotransporter SGLT2.

9.

Use of at least one compound according to at least one of the claims 1 to 4 or a physiologically acceptable salt thereof to prepare a pharmaceutical composition whose application is to prevent degeneration of beta pancreatic cells and / or improve and / or restore the functionality of beta pancreatic cells.

10.

Process for preparing a compound according to one or more of claims 1 to 4, characterized in that a compound of general formula II

image 1 where R ’means H, C1-4 alkyl, (C1-18 alkyl) carbonyl, (C1-18 alkyl) oxycarbonyl, arylcarbonyl and aryl- (alkyl C1-3) carbonyl, in which the alkyl or aryl groups can be mono- or polysubstituted with halogen; R8a, R8b, R8c, R8d, independently of each other, have one of the meanings indicated for the R6 groups, R7a, R7b, R7c or mean a benzyl group or a group RaRbRcSi or a ketal or acetal group, while in each case two contiguous groups R8a, R8b, R8c, R8d can form a silyl-ketal, ketal or acetal cyclic group or a bridge 1,2-di (C1-3 alkoxy) -1,2-di (C1-3 alkyl) -ethylene, while that said ethylene bridge, along with two atoms of oxygen and the two associated carbon atoms of the ring of pyranose, forms a substituted dioxane ring and while the alkyl, aryl and / or benzyl groups may be mono- or polysubstituted with halogen or alkoxy C1-3 and the benzyl groups may also be substituted with a di (C1-3 alkyl) amino group; Y Ra Rb, Rc, independently of each other, represent C1-4 alkyl, aryl or aryl-C1-3 alkyl, in which the groups aryl or alkyl may be mono- or polysubstituted with halogen; while the aryl groups mentioned in the definition of the above groups mean phenyl or naphthyl groups, preferably phenyl groups; and R1 to R5 and R6, R7a, R7b, R7c have the indicated meanings in claims 1 to 4; it is reacted with a reducing agent in the presence of a 5 Lewis or Brønsted acid, separating any protective group simultaneously or subsequently; if desired, a compound of general formula I thus obtained, where R6 means a hydrogen atom, it is converted by acylation in a corresponding acyl compound of formula 10 general I, and / or if necessary, any protective group used is separated in the reactions described above and / or if desired, a compound of general formula I thus obtained it is resolved in its stereoisomers and / or, 15 if desired, a compound of general formula I thus obtained it becomes its salts, especially its physiologically acceptable salts for pharmaceutical use. 11. Process according to claim 10, characterized in that the compound of the general formula II is obtained by 20 process described in claim 12. 12. Process for preparing compounds of general formula II image 1 where R ’means H, C1-4 alkyl, (C1-18 alkyl) carbonyl, (C1-18 alkyl) oxycarbonyl, arylcarbonyl and aryl- (alkyl C1-3) carbonyl, in which the alkyl or aryl groups can be mono- or polysubstituted with halogen; R8a, R8b, R8c, R8d, independently of each other, have one of the meanings indicated for the R6 groups, R7a, R7b, R7c or represent a benzyl group or a group RaRbRcSi or a ketal or acetal group, and in each case two contiguous groups R8a, R8b, R8c, R8d can form a group cyclic silyl-ketal, ketal or acetal or a 1,2-di (C1-3 alkoxy) -1,2-di (C1-3 alkyl) -ethylene bridge, while said ethylene bridge, together with two oxygen atoms and the two associated carbon atoms of the ring of pyranose, forms a substituted dioxane ring, while alkyl, aryl and / or benzyl groups can be mono- or polysubstituted with halogen or C1-3 alkoxy and benzyl groups can also be substituted with a di (C1-3 alkyl) -amino group; Y Ra, Rb, Rc, independently of each other, represent C1-4 alkyl, aryl or aryl-C1-3 alkyl, where the groups alkyl or aryl may be mono- or polysubstituted with halogen; while the aryl groups mentioned in the definition of the above groups mean phenyl or naphthyl groups, preferably phenyl groups; and R1 to R5 and R6, R7a, R7b, R7c have the indicated meanings in one or more of claims 1 to 4, in which an organometallic compound (V), which can be obtained nerse by halogen-metal exchange or by insertion of a metal in the carbon-halogen bond of a halogen compound benzyl benzene of the general formula IV image 1 where Hal means Cl, Br and I and R1 through R5 are defined as above, optionally followed by transmetalation, is added to a gluconolactone of general formula VI image2 5 where R8a, R8b, R8c, R8d are defined as before, and then the resulting adduct is reacted with water or with an alcohol R’-OH, where R ’means optionally substituted C1-4 alkyl, in the presence of an acid and optionally 10 the product resulting from the reaction with water, in which R ’ means H, is converted by a subsequent reaction with an acylating agent in the product of formula II, in which R ’means (C1-18 alkyl) -carbonyl, (C1-18 alkyl) oxycarbonyl, arylcarbonyl or aryl- (C1-3 alkyl) -carbonyl, 15 which may be substituted as described. 13. Compound of general formula IV ’ image 1 where Hal means chlorine, bromine or iodine and the groups R1, R2, R3, R4 and R5 are defined as in one or more of claims 20 nes1a4. 14. Compound of general formula II image 1 where R ’means H, C1-4 alkyl, (C1-18 alkyl) carbonyl, (C1-18 alkyl) oxycarbonyl, arylcarbonyl and aryl (C1-3 alkyl) carbonyl, in which the alkyl groups or aryl may be mono- or polysubstituted with halogen; R8a, R8b, R8c, R8d, independently of each other, have one of the meanings indicated for the R6 groups, R7a, R7b, R7c, or means a benzyl group or a group RaRbRcSi or a ketal or acetal group, while in each case two adjacent groups R8a, R8b, R8c, R8d can form a silyl-ketal, ketal or acetal cyclic group or a 1,2-di (C1-3 alkoxy) -1,2-di (alkyl) bridge C1-3) -ethylene, while said ethylene bridge, along with two oxygen atoms and the two atoms of associated carbon of the pyranose ring, forms a substituted dioxane ring and while the alkyl, aryl and / or benzyl groups may be mono- or polysubstituted with halogen or C1-3 alkoxy and the benzyl groups can also be substituted with a di (C1-3 alkyl) amino group; Y Ra Rb, Rc, independently of each other, represent C1-4 alkyl, aryl or aryl-C1-3 alkyl, in which the aryl or alkyl groups may be mono- or polysubstituted with halogen; 80 while the aryl groups mentioned in the definition of the above groups mean phenyl groups or naphthyl, preferably phenyl groups; and groups R1 to R5 are defined as in one or more of the claims 1 to 4.