WO2012041898A1

WO2012041898A1 - Combination of sglt2 inhibitor and a sugar compound for the treatment of diabetes

Info

Publication number: WO2012041898A1
Application number: PCT/EP2011/066848
Authority: WO
Inventors: Mateusz Mach; Piotr Guzenda; Maciej Wieczorek; Monika Lamparska-Przybysz
Original assignee: Celon Pharma Sp. Z O.O.
Priority date: 2010-09-29
Filing date: 2011-09-28
Publication date: 2012-04-05

Abstract

The combination of anti-diabetic compound - SGLT2 inhibitor and a sugar compound exhibiting affinity to bacterial lectins. The combination finds the use as a medicament for treating type 2 diabetes with concurrent prevention or treatment of urinary tract or genital organs infections.

Description

Combination of SGLT2 inhibitor and a sugar compound for the treatment of diabetes

The field of the invention

The invention relates to the combination of SGLT2 inhibitor compound useful in the treatment of type 2 diabetes and a sugar compound. The combination can be used in the treatment of type 2 diabetes for preventing or treating infections of urinary tract or genital organs.

Background art

Type 2 diabetes represents most diabetes cases in the world. It is characterized by insulin-independence and destruction of pancreatic beta-cells responsible for insulin secretion. Constant growth of morbidity and its prevalence indicate worldwide epidemy of type 2 diabetes. The necessity of life- long treatment and occurrence of many serious complications such as cardiovascular complications that often lead to limbs amputation and exclusion of patients from job market, in combination with its prevalence cause that type 2 diabetes is a serious economic and social problem. Additional problem which must be combated by diabetic patients are infections. Bacterial, fungal and viral infections occur more often in diabetes patients than in the general population. As a rule, the course of these infections in diabetes patients is more severe and complications are more often. The most often affected by complications in diabetes patients are skin and appendages, periodontium, urinary system (urinary tract and kidneys), respiratory system, microvascular system (diabetic foot). Important clinical problem are urinary tract infections, which occur 14-times more often in women than in men. The factors that influence the increase of risk of complications are the value of HbA1c rate, duration of diabetes, glycosuria and pyuria. Although etiology of urinary tract infections (UTI) in diabetic patients does not differ essentially from etiology of this disease in healthy persons, higher recurrence rate is observed in diabetic patients despite longer antibiotic therapy.

Current therapies of type 2 diabetes are based in the first phase on life-style changes, then using oral anti-diabetic medicaments, and administration of insulin at the advanced stage of the disease. Mechanism of action of all medicaments in current clinical practice is based on increasing insulin secretion or increasing the sensitivity of cells to insulin. Despite many years of research currently used medicaments cause many undesirable reactions and side effects. These include among others gastrointestinal problems (nausea, diarrhea, lactic acidosis), hypoglycemia and increased weight. Metformin causes diarrheas and general gastrointestinal problems. In long-term therapy it does not fulfill the basic aim of decrease of HbA1c level, which in metformin-taking patients recurs after several years to the initial level. The main disadvantage of insulin is increase of body weight as a result of appearance of high levels of insulin in the blood after injection and its influence on adipocytes. Serious problem during use of insulin injections are cases of hypoglycemia. Disadvantage of this therapy are also injections themselves. Similarly, use of sulphonylurea derivatives leads to increase of body weight and occurrence of hypoglycemia. The use of PPAR agonists from the group of thiazolidinediones compounds causes increase of the risk of cardiologic complications, increase of body weight, bone fragility and retention of body fluids. The use of newest medicaments potentiating the GLP-1 action (GLP-1 analogs and DPP- IV inhibitors) also causes reactions of gastrointestinal tract and pancreatitis. In the case of GLP-1 analogs there is a risk of immune response and their use requires injections, similarly as insulin.

For these reasons extensive research of new anti-diabetic medicaments is still continued. The most recent approach in the therapy of type 2 diabetes is reduction of glucose level in blood by inhibition of renal SGLT2 transporters, thereby toxic action of insulin is blocked, especially on pancreatic beta cells. The kidney are responsible for the whole glucose re-absorption from urine, returning back to the body approximately 180 g of glucose per day. Two types of glucose transporters are present in the kidney, SGLT1 and SGLT2. The latter is located in the convoluted segment of the proximal tubule (S1 cells) and is responsible for 90% of glucose re-absorption. SGLT1 is located in the distal straight segment of the proximal tubule (S2, S3 cells) and is responsible for re- absorption of remaining part of sugars. It has been shown that inhibition of SGLT2 contributes directly to lowering glucose level and occurrence of glycosuria. Inhibition of SGLT2 activity appears to be the strategy safe and effective from the point of view of correct functioning of the body, as confirmed by the fact of the existence in the population of hereditary mutation within the gene encoding SGLT2 protein. This mutation leads to the production of nonfunctional protein and disease called familial renal glycosuria. Despite of persistent isolated glycosuria (10-130 g/day) in the face of normal fasting serum glucose and correct response to the glucose tolerance test, no increase of urinary tract infections rate has been observed in these individuals.

There are known in the art compounds exhibiting the ability to inhibit SGLT2 transporter (SGLT2 inhibitors) that potentially can find use in the treatment of type 2 diabetes, and which belong to the class of C-arylglycosides, in particular glucopyranosylsubstituted benzenes. Unlike O-arylglycosides, C-arylglycosides are chemically stable and after oral administration there is no hydrolysis of glycosidic bond by beta-glycosidases present in the intestinum. C-Arylglycosidic SGLT2 inhibitors are disclosed inter alia in WO01 /027128, WO04/013118, WO04/080990, EP1852439A1 , WO01 /27128, WO03/099836, WO2005/092877, WO2006/034489, WO2006/064033, WO2006/117359, WO2006/117360, WO2007/025943, WO2007/028814, WO2007/031548, WO2007/093610, WO2007/ 128749, WO2008/049923, WO2008/055870, and WO2008/055940. The search of new SGLT2 inhibitors is also carried out. Several SGLT2 inhibitors are currently at different stages of clinical trials in diabetes treatment.

In clinical tests of SGLT2 inhibitors genito-urinary tract infections are mentioned as a group of potential undesired reactions. However, expected rate of incidence of such infections has been estimated at the low level, comparable with placebo or slightly higher.

An inherent and expected effect of the SGLT2 inhibitors action is glycosuria, i.e. glucose excretion with urine. This effect is dependent on a mechanism of action and thus is specific for the whole class of SGLT2 inhibitors, irrespective of the chemical structure of a given compound. The inventors have found that therapy of diabetes with SGLT2 inhibitors generally may cause increased risk of infections of urinary tract and genital organ as undesired reactions. The increased risk of these undesired reactions is believed to be a class effect associated with glycosuria and serious problem in therapy based on SGLT2 inhibition that should require attention, the more that therapy of type 2 diabetes is a life-long one, and glycosuria will be present during the whole duration of the treatment with SGLT2 inhibitors.

Currently, the most advanced SGLT2 inhibitor under development is dapagliflozin (1 ,5-anhydro-1 -C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]- (IS)-D-glucitol). In all clinical trials carried out with dapagliflozin urinary tract infections occurred in 4.2 - 12.5% of patients compared with values of 0,0 - 6,0% in placebo patients (see List, J. F., V. Woo, et al. (2009). "Sodium-Glucose Cotransport Inhibition With Dapagliflozin in Type 2 Diabetes." Diabetes Care 32(4): 650-657; Wilding, J. P. H., P. Norwood, et al. (2009). "A Study of Dapagliflozin in Patients With Type 2 Diabetes Receiving High Doses of Insulin Plus Insulin Sensitizers: Applicability of a novel insulin-independent treatment." Diabetes Care 32(9): 1656-1662; Bailey, C. J., J. L. Gross, et al. (2010). "Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial." The Lancet 375(9733): 2223-2233, and Ferrannini, E., S. Jimenez Ramos, et al. (2010). "Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo- controlled, phase III trial." Diabetes Care).

Antibacterial treatment of urinary-genital infections in diabetic patients is additionally complicated by the possibility of occurrence of diabetic nephropathy and necessity of simultaneous diabetes control. The use of antibiotics, especially nephrotoxic ones, can be dangerous. The necessity of controlling diabetes in urinary-genital infections once present often requires withdrawal of oral medicaments and introduction of insulin therapy. Although antibiotic treatment can be used in single cases of infections, it will be impossible to treat with antibiotics an infection associated with constant glycosuria, i.e. a chronic one, during the use of SGLT2 inhibitors.

Therefore, there remains an unsolved problem of the risk of bacterial infections of urinary tract during treatment of diabetes with very promising therapy using SGLT2 inhibitors, antidiabetic medicaments which induce glycosuria, i.e. lower serum glucose level via excretion of the excess of glucose with urine.

Disclosure of the invention

In accordance with the invention, said problem is solved by a combination of SGLT2 inhibitor and a sugar compound exhibiting affinity to bacterial lectins.

Accordingly, this invention relates to a combination which comprises

a) anti-diabetic SGLT2 inhibitor compound or its prodrug, and

b) a sugar compound exhibiting affinity to bacterial lectins.

The combination finds its use as a medicament, in particular for the treatment of type 2 diabetes.

Accordingly, the invention relates also to a combination of anti-diabetic SGLT2 inhibitor compound and a sugar compound exhibiting affinity to bacterial lectins for use as a medicament for mammals, in particular for humans.

The invention relates also to the use of anti -diabetic SGLT2 inhibitor compound in combination with a sugar compound exhibiting affinity to bacterial lectins for treating diabetes, especially type 2 diabetes, in mammals, especially in humans.

The invention relates also to a method for treating type 2 diabetes which comprises administration to a patient in need thereof of an effective amount of SGLT2 inhibitor and a sugar compound exhibiting the affinity to bacterial lectins, in particular oral administration.

Detailed description of the invention

Lectins, also called agglutinins, are receptors binding simple carbohydrates present on the surfaces of microorganisms. These receptors are specific for each simple sugar.

All bacteria can possess on their surface several types of lectins specific for various carbohydrates, mainly in bacterial fimbriae. Occurrence of lectins on these structures allow bacteria to adhere to the epithelium of infected tissue by strong binding to sugar residues on the surface of epithelial cells, and then multiply and initiate the infection. This ability of bacteria to adhere to epithelium is very important infection-enabling factor. Sufficiently strong adherence of bacteria to epithelium protects them from being swept away from the body in the normal process of cleansing mucosal surfaces. This enables multiplication of bacterial colonies and infection, among others gastrointestinal tract, urinary tract or genital organs.

It has been found that inhibition of the possibility of binding bacteria to urinary tract epithelium, mainly in the bladder, can lead to substantial reduction of occurrence of urinary tract infections during the use of SGLT2 inhibitors medicaments. Using anti-diabetic medicaments - SGLT2 inhibitors together with sugar compounds, the present inventors obtained reduction of the occurrence rate of urinary tract and genital organs infections. In the tests on rats decrease of the number of urinary tract and genital organs infections has been obtained, and development of the ascending bladder infection and spreading the infection into animal's kidney have been blocked.

Therefore, the combination of the invention can be used in diabetic patients both for the prevention of the appearance of urinary tract and genital organs infections and for alleviation and treatment of already existing infection.

In a specific and preferred embodiment, the combination of the invention can be used in the treatment of type 2 diabetes in diabetic patients wherein urinary tract infection has not appeared yet. The administration of SGLT2 inhibitor as a component of the combination of the invention can prevent such infection to occur.

In another embodiment, the combination of the invention can be used in the treatment of type 2 diabetes in diabetic patients wherein said infection has already appeared and is present at the moment of beginning of the treatment. The combination of the invention can cure such infection or assist therapy of such infection.

Especially preferred is the use of the combination of the invention since the beginning of the therapy of type 2 diabetes with SGLT2 inhibitor.

Also especially advantageous is the use of the combination of the invention in the therapy of type 2 diabetes in patients with diabetic nephropathy. Any compound exhibiting SGLT2 inhibition can be used in the combination of the invention.

In accordance with the invention, the SGLT2 inhibitor can be a selective SGLT2 inhibitor or a non-selective SGLT2 inhibitor.

In a special embodiment, the compound - SGLT2 inhibitor is a C-arylglycosidic SGLT2 inhibitor or its prodrug. In accordance with the invention, SGLT2 inhibitor can be in particular selected from the group of compounds represented by general Formula (I)

or its prodrug, wherein:

X represents -0- or -S-;

A represents -0-, -S- or (CH₂-)_n, where n is an integer from 0 to 4;

C represents 5- or 6-membered aromatic or heteroaromatic ring comprising heteroatom selected from 0 and S;

R³ and R⁴ independently are selected from the group consisting of: hydrogen atom; chlorine or fluorine atom; -OH; -CN; -CrC₄-alkyl, wherein one or more hydrogen atoms can be replaced with -OH or fluorine atom; -C₂-C₄-alkenyl;

-C₂-C₄-alkynyl; -C C₄-alkyl substituted with -CrC₄-alkoxy, wherein one or more hydrogen atoms can be replaced with fluorine atom, -0-d-C₄-alkenyl, or

-0-CrC₄-alkynyl; -C C₄-alkoxy, wherein one or more hydrogen atoms can be replaced with -OH or fluorine atom; -C C₄-alkoxy substituted with -CrC₄- alkoxy, wherein one or more hydrogen atoms can be replaced with fluorine atom, -0-CrC₄-alkenyl, or -0-Ci-C₄-alkynyl;

R^4a represents hydrogen atom,

or R⁴ and R^4a are attached to neighboring carbon atoms and together form -CH=CH-CH=CH-, -0-(CH₂)-0-, -0-(CH₂)₂-0-, -0-(CH₂)₂- or -0-(CH₂)₃- group;

R⁵ and R⁶ independently are selected from the group consisting of: hydrogen atom; chlorine or fluorine atom; -OH; -CN; -COOH; -CrC₄-alkyl, wherein one or more hydrogen atoms can be replaced with -OH or fluorine atom; -CrC₄-alkyl substituted with -d-C₄-alkoxy, wherein one or more hydrogen atoms can be replaced with fluorine atom; -CrC₄-alkyl substituted with -0-C₃-C6-cycloalkyl; -C₂-C₄-alkenyl; -C₂-C₄-alkynyl; -C₂-C₄-alkynyl substituted with -Ci-C₄-alkoxy; -C₃-C₆-cycloalkyl; -CrC₄-alkylphenyl, wherein phenyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from -CrC₄-alkyl, -F and -CN; phenyl unsubstituted or substituted with 1 , 2 or 3 substituents selected from - CrC₄-alkyl, -F and -CN; -CrC₄-alkoxy, wherein one or more hydrogen atoms can be replaced with fluorine atom; -CrC₄-alkoxy substituted with -0-C₂-C₄-alkynyl, -0-C3-C6-cycloalkyl, -0-C3-C6-cycloalkenyl, -0-C2-C₄-alkenyl-C3-C6-cycloalkenyl or -0-C2-C₄-alkynyl-C3-C6-cycloalkenyl; -0-Cs-C6-cycloalkyl, wherein one of the carbon atoms in the ring can be replaced with -0-; -0-CrC₄-alkynyl, substituted with -C C₄-alkoxy, -C3-C₆-cycloalkyl or -0-C3-C₆-cycloalkyl; -O-C0-C4- alkylphenyl, wherein phenyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from -CrC₄-alkyl, -F and -CN; -S-(0)_mCi -C₄-alkyl, wherein m is 0, 1 or 2; -S-(0)_m phenyl, wherein phenyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from -C C₄-alkyl, -F and -CN and m is 0, 1 or 2; -NH-S(0)m-C C₄-alkyl, wherein m is 0, 1 or 2; -NH-S(0)_m phenyl, wherein phenyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from -Ci -C₄-alkyl, -F and -CN and m is 0, 1 or 2; -C(0)-C_rC₄-alkyl; -C(0)-0-C_rC₄- alkyl; -NHC(0)-Ci -C₄-alkyl; 5- or 6-membered saturated or unsaturated heterocyclic group comprising heteroatom selected from O and S;

or R⁵ and R⁶ are attached to neighboring carbon atoms and together form a 5-, 6- or 7-membered aromatic or heterocyclic group comprising heteroatom selected from O and S, wherein heterocyclic group can be saturated, unsaturated or aromatic;

wherein said alkyl, alkenyl, alkynyl, alkadienyl and alkatrienyl groups can be straight or branched.

Specific embodiments of SGLT2 inhibitors embraced with Formula (I) are represented by Formulae ( IA) to (IG) shown below.

Formula (IA) Formula (IB)

Formula (IC) Formula (ID)

Formula (IG)

Also in accordance with the invention, C-arylglucosidic SGLT2 inhibitor can be especially selected from the group 1 ) do 11 ) presented below.

1 ) 1 ,5-Anhydro-1 -C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-(1S)-D-glucitol of Formula 1 , known under INN name dapagliflozin, lUPAC chemical name (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)- tetrahydro-2H-pyran-3,4,5-triol, or a prodrug of this compound.

Formula 1

Dapagliflozin is disclosed inter alia in WO03/099836 and WO2008/002824.

2) (1 S)-1 ,5-Anhydro-1 -C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl- phenyl]-D-glucitol of Formula 2, known under INN name canagliflozin, disclosed in WO2005/012326 and WO2008/069327 (lUPAC chemical name (2S,3R,4R,5S,6R)-2-{3-[5-[4-fluorophenyl)tiophen-2-ylmethyl]-4-methylphenyl}-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol), or a prodrug of this compound.

3) 1 -Chloro-4-([beta]-D-glucopyranos-1 -yl)-2- [4-((S)-tetrahydrofuran-3-yloxy)- benzyl] benzene of the following Formula 3, disclosed in WO2006/1 17360 (lUPAC name (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((S)-tetrahydrofuran-3-yloxy)benzyl)- phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol) , or a prodrug of this compound:

Formula 3

3a) the compound of Formula 3a ((2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((R)- tetrahydrofuran-3-yloxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran- 3,4,5-triol), disclosed in WO2006/1 17360, or a prodrug of this compound:

Formula 3a

3b) the compound of Formula 3b ((2S,3R,4R,5S,6R)-2-(4-chloro-3-(3-((S)- tetrahydrofuran-3-yloxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran- 3,4,5-triol) or its prodrug

4) the compound of Formula 4:

Formula 4 wherein R¹ represents CI, methyl or cyano; R² represents H, methyl, methoxy or hydroxy; R³ represents ethyl, cyclopropyl, ethynyl lub ethoxy, or a prodrug of this compound; 4a) (2S,3R,4R,5S,6S)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-methoxytetra- hydro-2H-pyran-3,4,5-triol of the following Formula 4a or its prodrug

Formula 4a

5) spiroketalic compound of the following Formula 5, disclosed in WO2006/080421 A1 (lUPAC name 1 S, 3'R,4'S,5'S,6'R)-6-(4-etylobenzyl)-6'-(hydroxy- methyl)-3',4', 5',6'-tetrahydro-3H-spiro[izobenzofuran-1 ,2'-pyran]-3',4',5'-triol), or a prodrug of this compound;

6) spiroketalic compound of the following Formula 6

Formula 6

wherein R represents ethyl, iso-propyl, tert-butyl, methoxy or trifluoromethoxy, disclosed in WO2007/140191 and WO2008/013280, or a prodrug of this compound;

7) (1 S)-1 , 5-Anhydro-1 -[5-(azulen-2-ylmethyl)-2-hydroxyphenyl] -D-glucitol of the following Formula 7, disclosed in WO2004/0131 18 and WO2006/006496, and its choline salt, described in W02007/ 007628, or a prodrug of this compound;

Formula 7

8) (1 S)-1 , 5-Anhydro- 1 -[3-(1 -benzothien-2-ylmethyl)-4-fluorophenyl]-D-glucitol of the following Formula 8, disclosed in WO2004/080990 i WO2005/012326, and its co-crystal with L-proline, disclosed in WO2007/1 14475, or a prodrug of this compound;

Formula 8

9) (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethynylbenzyl)phenyl)-6-(hydroxymethyl)- tetrahydro-2H-pyran-3,4, 5-triol of the following Formula 9, disclosed in WO 2007/028814, or its prodrug

10) (2S,3R,4R, 5S,6R)-2-(5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl)-6- (hydroxymethyl)tetrahydro-2H-thiopyran-3,4, 5-triol of the following Formula 10 or its prodrug

1 1 ) (1 S,2S,3S,4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1 -(hydroxymethyl)- 6,8-dioxabicyclo[3.2.1 ]octane-2,3,4-triol of the following Formula 1 1 , disclosed in WO 2010/023594, or its prodrug

As indicated above, component a) of the combination according to the invention may be the prodrug of SGLT2 inhibitor. Particular compounds selected from the following group and their mixtures can be mentioned sugar compounds exhibiting the affinity to bacterial lectins:

- mannose,

- fructose,

- galactose,

- N-acetylglucosamine,

- N -acetylgalactosamine,

- a-D-galactopyranosyl-(1→4)- -D-galactopyranose,

- 4-0- -galactopyranosyl-D-glucopyranose,

- 2-acetamido-2-deoxy- -D-glucopyranosyl-(1→3)-D-galactopyranose,

- -D-galactopyranosyl-(1→4)-2-acetamido-2-deoxy-D-glucopyranose,

- N-acetylo-a-neuraminyl-(2→3)- -D-galactopyranosyl-(1→3)-2-acetamido-2- deoxy-D-galactopyranose, and

- N-glycolyl-a-neuraminyl-(2→3)- -D-galactopyranosyl-(1→4)-D-glucopyranose. In particular, oligosaccharides containing 2 to 10 of sugar units and built from mannose, fructose and/or galactose units can be mentioned as sugar compounds exhibiting the affinity to bacterial lectins.

Particular examples of oligosaccharides are mannooligosaccharides, fructooligosaccharides, galactomannooligosaccharides and galactooligo- saccharides.

In particular, oligosaccharides that include 4-0- -galactopyranosyl-D-gluco- pyranosyl, 2-acetamido-2-deoxy- -D-glucopyranosyl-(1→3)-D-galactopyranosyl, -D-galactopyranosyl-(1→4)-2-acetamido-2-deoxy-D-glucopyranosyl, N-acetyl-a- neuraminyl-(2→3)- -D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-D- galactopyranosyl or N-glycolyl-a-neuraminyl-(2→3)- -D-galactopyranosyl-(1→4)- D-glucopyranosyl as a oligosaccharide fragment, for example and without such limitation as a terminal oligosaccharide fragment, can be mentioned as sugar compounds exhibiting affinity to bacterial lectins.

Conveniently, the combination of the invention includes the SGLT2 inhibitor in the amount of 2,5 to 1000, in particular 2.5 to 100 mg per unit dosage, and the sugar compound in the amount of from 100 mg to 10 g per unit dose, in particular 100 to 400 mg per unit dosage.

The examples of advantageous combination are the combinations of 2.5 mg of SGLT2 inhibitor and 100 mg of mannose, 5 mg of SGLT2 inhibitor and 100 mg of mannose, 10 mg SGLT2 inhibitor and 100 mg of mannose, 25 mg of SGLT2 inhibitor and 100 mg of mannose, or 50 mg of SGLT2 inhibitor and 100 mg of mannose.

Another examples of advantageous combination are the combinations of 2.5 mg of SGLT2 inhibitor and 400 mg of mannose, 5 mg of SGLT2 inhibitor and 400 mg of mannose, 10 mg of SGLT2 inhibitor and 400 mg of mannose, 25 mg of SGLT2 inhibitor and 400 mg of mannose or 50 mg of SGLT2 inhibitor and 400 mg of mannose, and 100 mg of SGLT2 inhibitor and 400 mg of mannose.

Advantageously, the sugar compound is selected from the group consisting of mannose, galactose and their mixtures. Especially advantageous sugar compound is mannose.

In one of the embodiments, the SGLT2 inhibitor is dapagliflozin of Formula 1 , and the sugar compound is selected from the group consisting of mannose, galactose and their mixtures.

Preferably, SGLT2 inhibitor is dapagliflozin, and the sugar compound is mannose. In another embodiment of the invention, the SGLT2 inhibitor is canagliflozin of Formula 2, and the sugar compound is selected from the group consisting of mannose, galactose and their mixtures, especially mannose.

In accordance with one variant of the invention, the SGLT2 inhibitor and the sugar compound are administered to a patient in distinct pharmaceutical formulations/compositions, preferably in two distinct pharmaceutical formulations/compositions for oral administration.

When administered in distinct formulations/compositions, the SGLT2 inhibitor and the sugar compound can be administered orally simultaneously, consecutively (concurrently) one after another in any order, or separately with each other with time intervals.

Distinct compositions for oral administration can be, independently for both components, selected from among tablets, coated tablets, capsules, powders and granulates, syrups and suspensions. In one embodiments, tablets, powders and granulates are effervescent.

In a preferred embodiment of this variant of the invention, for administration simultaneously, consecutively one after another or separately, SGLT2 inhibitor and the sugar compound can be incorporated in distinct pharmaceutical compositions or formulations for oral administration and can be packed in two distinct packagings or in a single common packaging, including both the formulation of SGLT2 inhibitor and the formulation of the sugar compound. For example, said distinct compositions/formulations of the SGLT2 inhibitor and the sugar compound can be tablets and/or capsules placed in separate and specifically marked compartments of a blister containing such tablets and/or capsules. For example, one from the SGLT2 inhibitor and the sugar compound can be in the form of a tablet and the second of them in the form of a capsule, both can be in the form of a tablet or both can be in the form of a capsule.

In another embodiment of this variant, the SGLT2 inhibitor can have the form of a tablet, and the sugar compound the form of a powder, a granulate or a tablet, optionally effervescent, for dissolution in water before ingestion.

Pharmaceutical compositions of SGLT2 inhibitors in a solid form for oral administration, including the form of capsules and tablets, are known for example from W010/092123.

In accordance with the second and advantageous variant of the invention, the SGLT2 inhibitor and the sugar compound are administered to a patient in the same pharmaceutical composition for oral administration common for both components.

Accordingly, another aspect of the invention is a pharmaceutical composition, comprising a combination as defined above, together with pharmaceutically acceptable carriers and/or excipients.

Common compositions for oral administration can be selected from among solid oral formulations. Exemplary solid oral formulations are formulations in the form of distinct units, each containing specified amount of active components a) and b) of the compositions, such as tablets, tablets coated with a non-functional coating, soft and hard capsules, effervescent tablets, quick-dissolving tablets, orodispersible tablets. Other examples of solid oral formulations are powders and granulates, in particular powders and granulates for the preparation of suspensions for oral administration of a liquid. Powders and granulates for the preparation of suspensions can be effervescent.

In accordance with the second variant, the preferred sugar compound is mannose or galactose.

In a particularly preferred embodiment of this second variant, the sugar compound is mannose or galactose and the common composition is capsule or tablet, optionally coated. In this preferred embodiment, apart of its role as a second active ingredient, mannose or galactose can have simultaneously the function of a filler and/or a binder.

In one embodiment, the sugar compound is mannose, SGLT2 inhibitor is dapagliflozin of Formula 1 or canagliflozin of Formula 2 or the compound of Formulae 3, 3a or 3b, and common composition has the form of a tablet, which tablet can be coated with a coating. Besides mannose or galactose, the tablet can additionally include any other conventional filler/binder, such as for example starches, pregelatinised starches, cellulose and cellulose derivatives, such as ethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, microcrystalline cellulose, carboxymethylcellulose; polymers such as polyvinylpyrrolidone, polyethylene glycols, polyvinyl alcohol; gelatine, and their mixtures. Advantageous filler/binder is microcrystalline cellulose.

Tablet can contain typical disintegrant, such as for example starch, crosslinked polyvinylpyrrolidone, croscarmelose sodium, sodium starch glycolate, preferably croscarmelose sodium.

Tablet can contain typical lubricant, such as for example magnesium stearate, stearic acid, polyethylene glycol, talc, sodium stearylfumarate, and typical glidant, such as for example anhydrous colloidal silica.

Tablet for oral administration of the combination according to the invention may generally contain, with respect to the total weight of the tablet, a binder in a total amount of 1 -20% by weight, a disintegrant in a total amount of 0,5-15% by weight, a lubricant in a total amount of 0,2-5% by weight, a glidant in a total amount of 0,2-10% by weight, a filler in a total amount of 0-80% by weight.

Typical excipients and methods for the preparation of tablets are taught extensively in the literature in the field of invention, for example in ..Handbook of Pharmaceutical Excipients", 3 Ed., Arthur H. Kibbe ed. , American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London. A skilled person can select in routine experiments and employ to obtain desired properties of a tablet one or more from among excipients mentioned above. Typically, tablets containing combination of the invention and suitable excipients will be manufactured by direct compression of the a mixture of formulation ingredients.

Moreover, dry mixture of formulation ingredients, after optional compacting, can be also used as the filling for capsules, especially hard gelatine capsules. Alternatively, a granulate containing the sugar compound, especially mannose or galactose, can be obtained, for example by fluid bed granulation, and subsequently the granulate mixed with component a) of the combination and excipients and compressed to form tablets.

For production effervescent tablets, powders and granulates mixtures of an organic acid and a carbonate can be used as disintegrants.

Depending on the needs, formulations for oral administration can include flavoring and/or coloring substances. The invention will be exemplified in details in the Examples, specific embodiments and drawing presented below, which are not limiting for the scope of the invention.

On the drawing, Fig. 1 presents the progress of the infection in dapagliflozin treated rats in comparison with the treatment using dapagliflozin-mannose combination.

Example 1 . Influence of administration of SGLT2 inhibitor in combination with a sugar compound

Administration of SGLT2 inhibitors in combination with mannose or galactose. The experiment was performed on female C57BL/6 mice aged 6-10 weeks with induced acute bladder infection.

Six days before inoculation, mice were given only 5% aqueous glucose solution to drink. At one day before of the beginning of the experiment (before inoculation), the animals were given first a dose of SGLT2 inhibitor and a sugar compound - mannose or galactose. After aspiration of urine from the bladder, 10⁸ of Escherichia coli in 0.05 ml of a physiological saline were introduced directly to the bladder. The animals were administered with daily dosages of SGLT2 inhibitor and a sugar compound once daily by means of stomach probe for 9 consecutive days, before each administration being starved for 6h with unlimited access to 5% glucose. The compounds were administered in the hydroxypropylmethylcellulose solution. The inhibitors were administered in a dose of 1 mg/kg of body weight, and the sugar compound in a dose of 80 mg/kg of body weight.

On days 1 , 3, 5, and 7 urine was collected directly from the bladder and seeding was performed by plating urine on agar plates to determine the number of colonies after 24 h of incubation. On the day 9, the mice were sacrificed, kidney and bladder were collected, then homogenized and seeding of homogenates was performed.

The results are presented Table 1 and in Fig. 1 as a progress of the infection in the group treated with combination of SGLT2 inhibitor and a sugar compound compared to the group treated with SGLT2 inhibitor alone. Table 1 and Fig. 1 show that at day 9 the reduction of the number of CFU in the group receiving dapagliflozin and mannose to the level of 9% with respect to the value in the group receiving dapagliflozin alone was observed. Reduction of the infection progress was also observed in the case of other SGLT2 inhibitors tested. After dissection and analysis of the presence of bacteria in the kidney no ascending kidney infection was found in any animal. The results show that using the combination of the invention allows to achieve inhibition of the progress of the infection induced by direct injection of the bacterial suspension.

Table 1. Inhibition of infection progress in the rat bladder. Showed as percent of infection at day 9 vs. group receiving only SGLT2 inhibitor.

Example 2. The effect of long-term administration of an SGLT2 inhibitor in combination with a sugar compound

The tests were performed on female Wistar rats. To induce diabetes, 6-days animals were given intraperitoneal^ streptozotocin (60 mg/kg in 50 mmol/l citrate pH 4,5) (diabetic animals). After weaning, the rats were given standard food. 6-Weeks rats were qualified for experiment and divided into groups (n=6) which were administered SGLT2 inhibitors and groups which were administered SGLT2 inhibitors together with a sugar compound. SGLT2 inhibitors were administered by means of a stomach probe in a dose of 0.1 mg/kg m.c./day, as a suspension in 1% hydroxypropylmethylcellulose. Additionally, the animals in the groups wherein the influence of a sugar compound was analyzed were administered for 6 weeks mannose or galactose p.o. in a dose of 2 mg/kg m.c./day. Every 7 day before administration of the compound blood was collected (starvation for 18 h) from incision of the tail vein for determination of glucose level. Also every 7 day, twenty-four-hour collection of urine was performed for determination of glucose level and seeding. At the end of the experiment kidney and bladder were collected, also for seeding.

The results are presented in the following Table 2 as a percentage of inhibition of the progress of the infection in the group treated with the combination of SGLT2 inhibitor and a sugar compound in comparison with the group receiving SGLT2 inhibitor alone. It can be seen that the influence of a sugar compound on inhibition of the progress of the infection is enhanced in long-term administration. Table 2. Inhibition of infection progress in the rat bladder. Showed as percent of infection at the end of the study vs. group receiving only a SGLT2 inhibitor.

Example 3. Compositions of an SGLT2 inhibitor in combination with a sugar compound

Tablet containing 100 m¾ of mannose (composition per unit dose)

Tablet containing 400 mg of mannose (composition per unit dose)

Contents

Ingredient mg % of the mass of a tablet

SGLT2 inhibitor - dapagliflozin 100 mg 12.5%

Mannose 400 mg 50%

Colloidal silica, anhydrous 8 mg 1%

Microcrystalline cellulose 204 mg 25.5%

Hydroxypropylmethylcellulose 56 mg 7%

Croscarmelose sodium 24 mg 3%

Magnesium stearylfumarate 8 mg 1%

Total 800 mg 100% The above compositions were formulated into tablets by direct compression. To prepare the tabletting mass, suitable weighed amounts of dapagliflozin, mannose and anhydrous colloidal silica were blended together for 2 minutes. Then, microcrystalline cellulose and croscarmelose sodium were consecutively added to the mixer. After stirring the whole mixture for 30 minutes, magnesium stearylfumarate was added and stirring was continued for 5 minutes. The blend was tabletted using oval punches. Then tablets were coated with a standard coating. Before tabletting tablets were heated to about 30-45 °C, and the whole process of coating was performed at that temperature.

Tablets containing another SGLT2 inhibitor and tablets containing galactose in place of mannose can be prepared analogously.

A solution for oral administration

The solution for the dose of 2.5 mg of SGLT2 inhibitor + 100 mg of a sugar compound can be prepared from the following ingredients.

Glycol methylparaben and propylparaben were added to about 50% of the total amount of propylene glycol and stirred until dissolution. Mannose was added to 95% of the total amount of purified water and stirred until dissolution. To the mixture sorbitol and active substance dissolved in ethyl alcohol were added and stirred to obtain intimate mixture. Then remaining amount of propylene glycol, flavor, sodium saccharinate, sodium citrate, and citric acid were added and stirred until dissolution. pH was measured and adjusted to pH 7-7.5, if needed. Water was added to bring to the required volume, and the solution was filtered. Suspension for oral administration

Due to the solubility of SGLT2 inhibitors, advantageous variant of pharmaceutical formulation for higher doses is a powder for the preparation of a suspension, which contains 100 mg of SGLT2 inhibitor, for example dapagliflozin, and 400 mg of mannose per 5 ml of a suspension after reconstitution, and pharmaceutically acceptable excipients suitable for the preparation of a powder for reconstitution. The powder for the preparation of the suspension can comprise in particular dispersing and viscosity-enhancing agent, for example selected from the group of polysaccharides such as guar gum, starch, xanthan gum; natural cellulose derivatives, such as croscarmelose sodium, hypromellose, hydroxyethylocellulose, synthetic polymers, for example polyvinylalcohol, polyvinylpyrrolidone or inorganic substances, such as colloidal silica, aluminium magnesium, or their mixtures. Especially advantageous for the preparation of suspension is a powder containing xanthan gum and colloidal silica.

SGLT2 inhibitor, mannose, sodium citrate and mannitol were micronized in jet mill to obtain median particle size < 10 μιη. Weighed substances were placed in a mixer and stirred for 20 minutes to obtain homogenous suspension. The mixture was poured into 100 ml bottles, 40 g per each bottle.

Claims

1. A combination, which comprises

a) anti -diabetic SGLT2 inhibitor compound or its prodrug, and

b) a sugar compound exhibiting affinity to bacterial lectins.

2. The combination according to claim 1 , wherein component a) is a C-aryl- glycosidic SGLT2 inhibitor or its prodrug.

3. The combination according to claim 2, wherein component a) is selected from the group consisting of the compounds of Formula (I)

or its prodrug, wherein:

X represents -0- or -S-;

A represents -0-, -S- or (CH₂- )_n, where n is an integer from 0 to 4;

R³ and R⁴ independently are selected from the group consisting of: hydrogen atom; chlorine or fluorine atom; -OH; -CN; -CrC₄-alkyl, wherein one or more hydrogen atoms can be replaced with -OH or fluorine atom; -C2-C₄-alkenyl; -C2-C₄-alkynyl; -C C₄-alkyl substituted with -CrC₄-alkoxy, wherein one or more hydrogen atoms can be replaced with fluorine atom, -0-d-C₄-alkenyl, or -0-CrC₄-alkynyl; -C C₄-alkoxy, wherein one or more hydrogen atoms can be replaced with -OH or fluorine atom; -C C₄-alkoxy substituted with -CrC₄- alkoxy, wherein one or more hydrogen atoms can be replaced with fluorine atom, -0-CrC₄-alkenyl, or -0-Ci -C₄-alkynyl;

R^4a represents hydrogen atom,

or R⁴ and R^4a are attached to neighboring carbon atoms and together form -CH=CH-CH=CH-, -0-(CH₂)-0-, -0-(CH₂)₂-0-, -0-(CH₂)₂- or -0- (CH₂)₃- group;

R⁵ and R⁶ independently are selected from the group consisting of: hydrogen atom; chlorine or fluorine atom; -OH; -CN; -COOH; -CrC₄-alkyl, wherein one or more hydrogen atoms can be replaced with -OH or fluorine atom; -CrC₄-alkyl substituted with -d-C₄-alkoxy, wherein one or more hydrogen atoms can be replaced with fluorine atom; -CrC₄-alkyl substituted with -0-C3-C6-cycloalkyl; -C₂-C₄-alkenyl; -C₂-C₄-alkynyl; -C₂-C₄-alkynyl substituted with -Ci-C₄-alkoxy; -C3-C₆-cycloalkyl; -CrC₄-alkylphenyl, wherein phenyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from -CrC₄-alkyl, -F and -CN; phenyl unsubstituted or substituted with 1 , 2 or 3 substituents selected from - CrC₄-alkyl, -F and -CN; -CrC₄-alkoxy, wherein one or more hydrogen atoms can be replaced with fluorine atom; -CrC₄-alkoxy substituted with -0-C₂-C₄-alkynyl, -0-C3-C₆-cycloalkyl, -0-C3-C₆-cycloalkenyl, -0-C₂-C₄-alkenyl-C3-C₆-cycloalkenyl or -0-C₂-C₄-alkynyl-C3-C₆-cycloalkenyl; -0-C5-C₆-cycloalkyl, wherein one of the carbon atoms in the ring can be replaced with -0-; -0-Ci -C₄-alkynyl, substituted with -C C₄-alkoxy, -C3-C₆-cycloalkyl or -0-C3-C₆-cycloalkyl; -0-Co-C₄- alkylphenyl, wherein phenyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from -CrC₄-alkyl, -F and -CN; -S-(0)_mCrC₄-alkyl, wherein m is 0, 1 or 2; -S-(0)_m phenyl, wherein phenyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from -C C₄-alkyl, -F and -CN and m is 0, 1 or 2; -NH-S(0)m-C C₄-alkyl, wherein m is 0, 1 or 2; -NH-S(0)_m phenyl, wherein phenyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from -Ci-C₄-alkyl, -F and -CN and m is 0, 1 or 2; -C(0)-C_rC₄-alkyl; -C(0)-0-C_rC₄- alkyl; -NHC(0)-d-C₄-alkyl; 5- or 6-membered saturated or unsaturated heterocyclic group comprising heteroatom selected from O and S;

4. The combination according to claim 2, wherein component a) is selected from the group consisting of the following compounds or its prodrugs: the compound of Formula 1

Formula 1 the compound of Formula 2

the compound of Formula 3

Formula 3 the compound of Formula 3a

Formula 3a

(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((R)-tetrahydrofuran-3-yloxy)benzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

the compound of Formula 3b

Formula 3b

(2S,3R,4R,5S,6R)-2-(4-chloro-3-(3-((S)-tetrahydrofuran-3-yloxy)benzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol the compound of Formula 4

Formula 4 wherein R¹ represents CI, methyl or cyano group; R² represents H, methyl, methoxy or hydroxy; R³ represents ethyl, cyclopropyl, ethynyl or ethoxy;

the compound of Formula 4a:

the compound of Formula 6

Formula 6

wherein R represents ethyl, isopropyl, tert-butyl, methoxy or trifluoromethoxy, the compound of Formula 7

Formula 7

the compound of Formula 9

the compound of Formula 1 1

5. The combination according to any one of claims 1 to 4, wherein component b) is selected from the group consisting of mannose, fructose, galactose, N-acetylglucosamine, N-acetylgalactosamine, a-D-galactopyranosyl- (1→4)-p-D-galactopyranose, 4-O-p-galactopyranosyl-D-glucopyranose, 2-acetamido-2-deoxy-p-D-glucopyranosyl-(1→3)-D-galactopyranose,

p-D-galactopyranosyl-(1→4)-2-acetamido-2-deoxy-D-glucopyranose, N-acetyl-a- neuraminyl-(2→3)-p-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-D- galactopyranose, N-glycolyl-a-neuraminyl-(2→3)-p-D-galactopyranosyl-(1→4)-D- glucopyranose, and their mixtures.

6. The combination according to any one of claims 1 to 5, wherein component b) is mannose or galactose.

7. The combination according to any one of claims 1 to 6, wherein component a) is the compound of Formula 1.

8. The combination according to any one of claims 1 to 7, wherein the amount of the component a) is from 2,5 to 1000 mg per unit dose and the amount of the component b) is from 100 mg to 10 g per unit dose.

9. The combination according any one of claims 1 to 8, wherein components a) and b) are comprised in distinct pharmaceutical compositions.

10. The combination according to any one of claims 1 to 8, wherein components a) and b) are comprised in the same single pharmaceutical composition.

11. The combination according to claim 10 in the form of a capsule or a tablet for oral administration.

12. The combination according to any one of claims 1 to 11 for use as a medicament.

13. The combination according to any one of claims 1 to 12 for the treatment of type 2 diabetes.

14. A pharmaceutical composition, comprising a combination as claimed in any one of claims 1 to 8 together with pharmaceutically acceptable carriers and/or excipients.

15. A method for treating type 2 diabetes, which comprises administering to a patient in need of such treatment a combination as defined in any one of claims 1 to 8, said combination including effective amounts of component a) and component b), wherein simultaneously infection of urinary tract or genital organs is prevented or treated.

16. The method according to claim 15, wherein the combination is administered to the patient as distinct pharmaceutical compositions of component a) and component b) simultaneously, consecutively one after another in any order or in time intervals.

17. The method according to claim 15, wherein components a) and b) of the composition are administered to the patient in the same single pharmaceutical composition.

18. The method according to claim 16 or 17, wherein the pharmaceutical composition has the form of a capsule or a tablet.

19. The method according to any one of claims 15 to 18, wherein administered amount of the component a) is from 2.5 to 1000 mg per unit dose, and administered amount of the component b) is from 100 mg to 10 g per unit dose.