HK1143951A - Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivative - Google Patents

Description

Pharmaceutical compositions comprising glucopyranosyl-substituted benzene derivatives

Technical Field

The present invention relates to pharmaceutical compositions comprising a glucopyranosyl-substituted benzene derivative of formula (I) as described below in combination with a DPP IV inhibitor as specified below, which are suitable for the treatment or prevention of a condition selected from one or more of type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose and hyperglycemia.

Furthermore, the present invention relates to the following method in a patient in need thereof:

-preventing, slowing the progression, delaying or treating a metabolic disease;

-improving glycemic control and/or lowering fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbAlc;

-preventing, slowing, delaying or reversing the progression from impaired glucose tolerance, impaired fasting glucose, insulin resistance and/or from metabolic syndrome to type II diabetes;

-preventing, slowing the progression, delaying or treating a condition or disorder selected from diabetic complications;

-reducing body weight or preventing body weight gain or promoting body weight loss;

-preventing or treating pancreatic beta cell degeneration and/or improving and/or restoring pancreatic beta cell function and/or restoring pancreatic insulin secretion function;

-preventing, slowing, delaying or treating a disease or condition caused by abnormal accumulation of liver fat;

maintaining and/or improving insulin sensitivity and/or treating or preventing hyperinsulinemia and/or insulin resistance,

characterized in that a glucopyranosyl-substituted benzene derivative of the formula (I) as defined below is administered in combination or alternation with a DPP IV inhibitor as defined below.

In addition, the present invention relates to the use of a glucopyranosyl-substituted benzene derivative of formula (I) as defined below for the preparation of a medicament for use in the methods described above and below.

In addition, the present invention relates to the use of a DPP IV inhibitor as defined below for the manufacture of a medicament for use in the methods described above and below.

The invention also relates to the use of a pharmaceutical composition of the invention in the manufacture of a medicament for use in the methods described above and below.

Background

Glucopyranosyl-substituted benzene derivatives are described in the prior art, for example in WO01/27128, WO 03/099836, WO2005/092877, WO 2006/034489, WO 2006/064033, WO 2006/117359, WO 2006/117360, WO 2007/025943, WO 2007/028814, WO 2007/031548, WO 2007/093610, WO 2007/128749, WO 2008/049923, WO 2008/055870, WO 2008/055940. Glucopyranosyl-substituted benzene derivatives are proposed as inducers of urinary glucose excretion and therapeutic agents for diabetes.

Among other mechanisms, renal filtration and reuptake of glucose contributes to steady state plasma glucose concentrations and thus can be used as a target for anti-diabetes. The reuptake of glucose filtered by renal epithelial cells proceeds along a sodium gradient via sodium-dependent glucose cotransporters (SGLT) located in brush-border membranes (brush-border membranes) of the renal tubules⁽¹⁾. There are at least 3 SGLT subtypes which differ in their mode of expression and physicochemical properties⁽²⁾. SGLT2 is expressed only in the kidney⁽³⁾SGLT1 is additionally expressed in other tissues such as the intestine, colon, skeletal muscle and cardiac muscle^(4，5). SGLT3 has been found to be a glucose receptor in intestinal stromal cells without any transport function⁽⁶⁾. Possibly, other related but not characteristic genes may also contribute to renal glucose reuptake^(7，8，9). At normal blood glucose levels, glucose is completely reabsorbed by SGLT in the kidney, whereas the kidney has a reuptake capacity of greater than 10mMGlucose concentrations are saturated, leading to diabetes ("diabetes"). This critical concentration can be lowered by SGLT2 inhibition. In experiments using the SGLT inhibitor phlorizin, it has been shown that SGLT inhibition will partially inhibit the reuptake of glucose from glomerular filtrate into the blood, thereby causing a decrease in blood glucose concentration and causing diabetes^(10，11)。

(1)Wright，E.M.(2001)Am.J.Renal Physiol.280，F10-F18；

(2) Wright, e.m. et al, (2004) Pflugers arch.447 (5): 510-8;

(3) you, G, et al, (1995) J.biol.chem.270(49) 29365-;

(4)Pajor AM，Wright E M(1992)J.Biol.Chem.267(6)：3557-3560；

(5) zhou, l. et al, (2003) j.cell.biochem.90: 339 and 346;

(6) Diez-Sampedro, A. et al, (2003) Proc. Natl. Acad. Sci. USA 100(20), 11753-11758;

(7)Tabatabai，N.M.(2003)Kidney Int.64，1320-1330；

(8)Curtis，R.A.J.(2003)US Patent Appl.2003/0054453；

(9) bruss, M. and Bonisch, H. (2001) Cloning and functional characterization of an angle human sugar transporter in kidney (Genbank Acc.No. AJ305237);

(10) rossetti, L. et al, (987) J.Clin.invest.79, 1510-1515;

(11)Gouvea，W.L.(1989)Kidney Int.35(4)：1041-1048。

DPP IV inhibitors represent a new class of drugs that are being developed for the treatment or improvement of glycemic control in type II diabetes patients.

For example, DPP IV inhibitors and uses thereof are disclosed in WO 2002/068420, WO2004/018467, WO 2004/018468, WO 2004/018469, WO 2004/041820, WO2004/046148, WO 2005/051950, WO 2005/082906, WO 2005/063750, WO2005/085246, WO 2006/027204, WO 2006/029769, WO 2007/014886; WO2004/050658, WO 2004/111051, WO 2005/058901, WO 2005/097798; WO2006/068163, WO 2007/071738, WO 2008/017670; WO 2007/054201 or WO 2007/128761.

As further DPP IV inhibitors, the following compounds may be mentioned:

sitagliptin (Sitagliptin) (MK-0431) having the following structural formula a, (3R) -3-amino-1- [3- (trifluoromethyl) -5, 6, 7, 8-tetrahydro-5H- [1, 2, 4] triazolo [4, 3-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) butan-1-one, also known as (2R) -4-oxo-4- [3- (trifluoromethyl) -5, 6-dihydro [1, 2, 4] triazolo [4, 3-a ] pyrazin-7 (8H) -yl ] -1- (2, 4, 5-trifluorophenyl) butan-2-amine,

in one embodiment, sitagliptin is in the form of its dihydrogen phosphate salt, i.e. sitagliptin phosphate. In another embodiment, sitagliptin phosphate is in the form of a crystalline anhydrate or monohydrate. One class of such embodiments involves sitagliptin phosphate monohydrate. Sitagliptin free base and its pharmaceutically acceptable salts are disclosed in U.S. Pat. No. 6,699,871 and example 7 of WO 03/004498. Crystalline sitagliptin phosphate monohydrate is disclosed in WO 2005/003135 and WO 2007/050485. For details, e.g., regarding methods of making or configuring the compounds or salts thereof, reference is made to these documents. Tablet formulations of sitagliptin are under the trade name sitagliptinIt is commercially available.

Vildagliptin (LAF-237), having the following structural formula B, (2S) - { [ (3-hydroxyadamantan-1-yl) amino ] acetyl } pyrrolidine-2-carbonitrile, also known as (S) -1- [ (3-hydroxy-1-adamantyl) -amino ] acetyl-2-cyano-pyrrolidine,

vildagliptin is specifically disclosed in us patent 6,166,063 and example 1 of WO 00/34241. Specific salts of vildagliptin are disclosed in WO 2007/019255. Crystalline forms of vildagliptin and vildagliptin tablet formulations are disclosed in WO 2006/078593. Vildagliptin may be formulated as described in WO00/34241 or WO 2005/067976. Modified release vildagliptin formulations are described in WO 2006/135723. For details, e.g., regarding methods of preparing or formulating the compounds or salts thereof, reference is made to these documents. Tablet formulations of vildagliptin are contemplated under the trade name VildagliptinIt is commercially available.

Saxagliptin (Saxagliptin) (BMS-477118), having the following structural formula C, (1S, 3S, 5S) -2- { (2S) -2-amino-2- (3-hydroxyadamantan-1-yl) acetyl } -2-azabicyclo [3.1.0] hexane-3-carbonitrile, also known as (S) -3-hydroxyadamantylglycine-L-cis-4, 5-methanoprolinecarbonitrile (methanstenotrophoritile),

saxagliptin is specifically disclosed in example 60 of U.S. patent No. 6,395,767 and WO 01/68603. In one embodiment, saxagliptin is its HCl salt or its monobenzoate salt form (as disclosed in WO 2004/052850). In another embodiment, saxagliptin is in its free base form. In another embodiment, saxagliptin is in the form of the monohydrate of the free base as disclosed in WO 2004/052850. Methods for preparing saxagliptin are also disclosed in WO2005/106011 and WO 2005/115982. Saxagliptin can be formulated as tablets as described in WO 2005/117841. For details, e.g., regarding methods of making, formulating, or using the compounds or salts thereof, reference is made to these documents.

-denalogliptin (GSK-823093), having the following structural formula D, (2S, 4S) -1- [ (2S) -2-amino-3, 3-bis (4-fluorophenyl) propionyl ] -4-fluoropyrrolidine-2-carbonitrile, also known as (2S, 4S) -4-fluoro-1- [ 4-fluoro- β - (4-fluorophenyl) -L-phenylalanyl ] -2-pyrrolidinecarbonitrile

Desalaliptin is specifically disclosed in U.S. Pat. No. 7,132,443 and WO 03/002531. In one embodiment, dinagliptin is in the hydrochloride form as disclosed in example 2 of WO03/002531 or in the tosylate form as disclosed in WO 2005/009956. One class of this embodiment relates to the dinagliptin tosylate. Crystalline anhydrous dexliptin tosylate is disclosed in WO 2005/009956. For details on the process for preparing the compound or its salt, reference is made to these documents.

-Alogliptin (SYR-322), having the following structural formula E, is 2- ({6- [ (3R) -3-aminopiperidin-1-yl ] -3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidin-1-yl } methyl) benzonitrile

Alogliptin is specifically disclosed in US 2005/261271, EP 1586571 and WO 2005/095381. In one embodiment, alogliptin is in the form of its benzoate salt, its hydrochloride salt, or its tosylate salt, each as disclosed in WO 2007/035629. One class of this embodiment relates to alogliptin benzoate. Polymorphs of alogliptin benzoate are disclosed in WO 2007/035372. A process for the preparation of alogliptin is disclosed in WO 2007/112368 and in particular in WO 2007/035629. Alogliptin (i.e. its benzoate salt) can be formulated into tablets and administered as described in WO 2007/033266. For details, e.g., regarding methods of making, formulating, or using the compounds or salts thereof, reference is made to these documents.

- (2S) -1- { [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethylamino ] -acetyl } -pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof, preferably a mesylate salt, or (2S) -1- { [1, 1-dimethyl-3- (4-pyridin-3-yl-imidazol-1-yl) -propylamino ] -acetyl } -pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof.

These compounds and their preparation are disclosed in WO 03/037327. The mesylate salt of the former compound and its crystalline polymorph are disclosed in WO 2006/100181. The fumarate salt of the latter compound and its crystalline polymorphs are disclosed in WO 2007/071576. These compounds may be formulated as pharmaceutical compositions as described in WO 2007/017423. For details, e.g., regarding methods of making, formulating, or using these compounds or their salts, reference is made to these documents.

- (S) -1- ((2S, 3S, 11bS) -2-amino-9, 10-dimethoxy-1, 3, 4, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-3-yl) -4-fluoromethyl-pyrrolidin-2-one or a pharmaceutically acceptable salt thereof.

This compound and its preparation are disclosed in WO 2005/000848. Methods for preparing the compounds, in particular their dihydrochloride salts, are also disclosed in WO 2008/031749, WO 2008/031750 and WO 2008/055814. The compounds may be formulated as pharmaceutical compositions as described in WO 2007/017423. For details, e.g., regarding methods of making, formulating, or using the compounds or salts thereof, reference is made to these documents.

- (3, 3-difluoropyrrolidin-1-yl) - ((2S, 4S) -4- (4- (pyrimidin-2-yl) piperazin-1-yl) pyrrolidin-2-yl) methanone or a pharmaceutically acceptable salt thereof.

Such compounds and their preparation are disclosed in WO 2005/116014 and US 7291618. For details, e.g., regarding methods of making, formulating, or using the compounds or salts thereof, reference is made to these documents.

- (1((3S, 4S) -4-amino-1- (4- (3, 3-difluoropyrrolidin-1-yl) -1, 3, 5-triazin-2-yl) pyrrolidin-3-yl) -5, 5-difluoropiperidin-2-one or a pharmaceutically acceptable salt thereof.

Such compounds and their preparation are disclosed in WO 2007/148185 and US 20070299076. For details, e.g., regarding methods of making, formulating, or using the compounds or salts thereof, reference is made to these documents.

- (2S, 4S) -1- {2- [ (3S, 1R) -3- (1H-1, 2, 4-triazol-1-ylmethyl) cyclopentylamino ] -acetyl } -4-fluoropyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof.

Such compounds and their preparation are disclosed in WO 2006/040625 and WO 2008/001195. Specifically claimed salts include the mesylate and the p-toluenesulfonate salts. For details, e.g., regarding methods of making, formulating, or using the compounds or salts thereof, reference is made to these documents.

- (R) -2- [6- (3-amino-piperidin-1-yl) -3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidin-1-ylmethyl ] -4-fluoro-benzonitrile or a pharmaceutically acceptable salt thereof.

The compound and the preparation method and the application thereof are disclosed in WO 2005/095381, US 2007060530, WO 2007/035629, WO 2007/074884, WO 2007/112368 and WO 2008/033851. Specifically claimed salts include succinate, benzoate, benzenesulfonate, p-toluenesulfonate, (R) -mandelate and hydrochloride salts. For details, e.g., regarding methods of making, formulating, or using the compounds or salts thereof, reference is made to these documents.

For the avoidance of any doubt, the disclosures of each of the foregoing documents cited above, as well as the specific DPP IV inhibitors, are incorporated herein by reference in their entirety.

Type II diabetes is an increasing disease that results in a significant reduction in life expectancy due to a high frequency of complications. Type II diabetes is currently the most common cause of adult-onset vision loss, renal failure, and amputation in the industrialized world, due to microvascular complications associated with diabetes. Furthermore, the presence of type II diabetes is accompanied by a 2 to 5 fold increase in the risk of cardiovascular disease.

After a long duration of disease, most type II diabetics will eventually fail to treat by oral administration and become insulin dependent, requiring daily injections of insulin and multiple daily measurements of glucose.

Ukpds (united Kingdom reactive Diabetes study) demonstrated only limited improvement in glycemic control with either metformin, sulfonylureas, or insulin (a difference of about 0.9% in HbAlc). Furthermore, arm glycemic control deteriorates significantly over time even in patients within the intensive treatment group due to deterioration of beta cell function. Importantly, intensive therapy is not associated with a significant reduction in macrovascular complications (i.e., cardiovascular events).

Thus, there remains an unmet medical need for methods, medicaments and pharmaceutical compositions with good efficacy in glycemic control, disease regulation properties and reduction of cardiovascular morbidity and mortality while showing improved safety.

Object of the Invention

It is an object of the present invention to provide pharmaceutical compositions and methods for preventing, slowing down (slowing) progression, delaying (delaying) or treating metabolic disorders, especially type II diabetes.

It is another object of the present invention to provide pharmaceutical compositions and methods for improving glycemic control in a patient in need thereof.

It is another object of the present invention to provide pharmaceutical compositions and methods for preventing, slowing or delaying the progression from Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), insulin resistance (insulin resistance) and/or metabolic syndrome to type II diabetes.

It is another object of the present invention to provide pharmaceutical compositions and methods for preventing, slowing the progression of, delaying or treating a condition or disorder selected from diabetic complications.

It is another object of the present invention to provide pharmaceutical compositions and methods for reducing body weight or preventing weight gain in a patient in need thereof.

It is another object of the present invention to provide novel pharmaceutical compositions having high efficacy for the treatment of metabolic diseases, in particular diabetes, Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG) and/or hyperglycemia, and having good to very good pharmacological and/or pharmacokinetic and/or physicochemical properties.

Other objects of the present invention will be apparent to those skilled in the art from the above and the following description and by way of examples.

Summary of The Invention

Within the scope of the present invention, it has now surprisingly been found that pharmaceutical compositions comprising glucopyranosyl-substituted benzene derivatives of formula (I) as defined below can be advantageously used in combination with DPP IV inhibitors as specified below for the prevention, slowing of progression, delaying or treatment of metabolic diseases, in particular for improving glycemic control, in a patient. This opens up new therapeutic possibilities in the treatment and prevention of type II diabetes, overweight, obesity, diabetic complications and similar disease states.

Accordingly, in a first aspect the present invention provides a pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivative of formula (I)

Wherein R is¹Represents Cl, methyl or cyano; r²Represents H, methyl, methoxy or hydroxy, and R³Represents ethyl, cyclopropyl, ethynyl, ethoxy, (R) -tetrahydrofuran-3-yloxy or (S) -tetrahydrofuran-3-yloxy.

And in a first embodiment (embodiment a), further comprising a DPP IV inhibitor of the formula:

formula (I)

Or formula (II)

Or formula (III)

Or formula (IV)

Wherein R1 represents ([1, 5] naphthyridin-2-yl) methyl, (quinazolin-2-yl) methyl, (quinoxalin-6-yl) methyl, (4-methyl-quinazolin-2-yl) methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl) methyl, (3-cyano-pyridin-2-yl) methyl, (4-methyl-pyrimidin-2-yl) methyl or (4, 6-dimethyl-pyrimidin-2-yl) methyl, and R2 represents 3- (R) -amino-piperidin-1-yl, (2-amino-2-methyl-propyl) -methylamino or (2- (S) -amino-propyl) -methylamino;

or a pharmaceutically acceptable salt thereof;

alternatively, in a second embodiment (embodiment B), further comprising a DPP IV inhibitor selected from: sitagliptin; vildagliptin; saxagliptin; alogliptin; obtaining nanoliptin;

(2S) -1- { [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethylamino ] -acetyl } -pyrrolidine-2-carbonitrile;

(2S) -1- { [1, 1-dimethyl-3- (4-pyridin-3-yl-imidazol-1-yl) -propylamino ] -acetyl } -pyrrolidine-2-carbonitrile;

(S) -1- ((2S, 3S, 11bS) -2-amino-9, 10-dimethoxy-1, 3, 4, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-3-yl) -4-fluoromethyl-pyrrolidin-2-one;

(3, 3-difluoropyrrolidin-1-yl) - ((2S, 4S) -4- (4- (pyrimidin-2-yl) piperazin-1-yl) pyrrolidin-2-yl) methanone;

(1((3S, 4S) -4-amino-1- (4- (3, 3-difluoropyrrolidin-1-yl) -1, 3, 5-triazin-2-yl) pyrrolidin-3-yl) -5, 5-difluoropiperidin-2-one;

(2S, 4S) -1- {2- [ (3S, 1R) -3- (1H-1, 2, 4-triazol-1-ylmethyl) cyclopentylamino ] -acetyl } -4-fluoropyrrolidine-2-carbonitrile; and

(R) -2- [6- (3-amino-piperidin-1-yl) -3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidin-1-ylmethyl ] -4-fluoro-benzonitrile,

or a pharmaceutically acceptable salt thereof.

According to another aspect of the present invention there is provided a method of preventing, slowing the progression of, delaying or treating a metabolic disorder selected from type I diabetes, type II diabetes, Impaired Glucose Tolerance (IGT), impaired fasting plasma glucose (IFG), hyperglycemia, postprandial hyperglycemia (postprandial plasma aggregation), overweight, obesity and metabolic syndrome in a patient in need thereof, characterized by combined or alternating administration of a glucopyranosyl-substituted benzene derivative as defined above and below and a DPP IV inhibitor as defined above and below.

According to another aspect of the present invention there is provided a method for improving glycemic control and/or lowering fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbAlc in a patient in need thereof, characterized in that a glucopyranosyl-substituted benzene derivative as defined above and below is administered in combination or alternation with a DPP IV inhibitor as defined above and below.

The pharmaceutical compositions of the present invention may also have important disease modifying properties for diseases or conditions associated with Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), insulin resistance and/or metabolic syndrome.

According to another aspect of the present invention there is provided a method for preventing, slowing, delaying or reversing the progression from Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), insulin resistance and/or from metabolic syndrome to type II diabetes in a patient in need thereof, characterized by administering a glucopyranosyl-substituted benzene derivative as defined above and below in combination or alternation with a DPP IV inhibitor as defined above and below.

Since improved glycemic control can be achieved in patients in need thereof by using the pharmaceutical composition of the present invention, it can also treat those conditions and/or diseases associated with or caused by increased blood glucose levels.

According to another aspect of the present invention, there is provided a method of preventing, slowing the progression of, delaying or treating a condition or disorder selected from the group consisting of: diabetic complications, such as cataracts and micro-and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischemia, arteriosclerosis, myocardial infarction, stroke and peripheral arterial occlusive disease, characterized in that a glucopyranosyl-substituted benzene derivative as defined above or below is administered in combination or alternation with a DPP IV inhibitor as defined above or below. The term "tissue ischemia" encompasses, inter alia, diabetic macroangiopathy, diabetic microangiopathy, impaired wound healing (diabetic wound healing) and diabetic ulcers.

By administering the pharmaceutical composition of the present invention and due to SGLT2 inhibitory activity of the glucopyranosyl-substituted benzene derivative, excessive levels of blood glucose are not converted into insoluble storage forms (such as fats) but are excreted through the urine of the patient. Thus, the result is no weight gain or even weight loss.

According to another aspect of the present invention there is provided a method of reducing body weight or preventing weight gain or promoting weight loss in a patient in need thereof, characterized by administering a glucopyranosyl-substituted benzene derivative as defined above or below in combination or alternation with a DPP IV inhibitor as defined above or below.

The pharmacological effect of the glucopyranosyl-substituted benzene derivative in the pharmaceutical composition of the invention is independent of insulin. Thus, it is possible to improve glycemic control without additional stress on pancreatic beta cells. By administering the pharmaceutical composition of the present invention, the degeneration of beta cells and the decline of beta cell function (e.g., pancreatic beta cell apoptosis or necrosis) can be delayed or prevented. But also improve or restore pancreatic cell function and increase the number and size of pancreatic beta cells. It was shown that the differentiation state and hyperproliferation of pancreatic beta cells disturbed by hyperglycemia can be normalized by treatment with the pharmaceutical composition according to the present invention.

According to another aspect of the present invention there is provided a method for preventing, slowing, delaying or treating degeneration of pancreatic beta cells and/or decline of pancreatic beta cell function and/or improving and/or restoring pancreatic beta cell function and/or restoring pancreatic insulin secretion function in a patient in need thereof, characterized by combined or alternating administration of a glucopyranosyl-substituted benzene derivative as defined above and below with a DPP IV inhibitor as defined above and below.

Abnormal accumulation of fat in the liver can be reduced or inhibited by administering the combination or pharmaceutical composition of the present invention. Thus, according to another aspect of the present invention there is provided a method for the prevention, alleviation, delay of progression or treatment of a disease or condition caused by abnormal accumulation of liver fat in a patient in need thereof, characterised by the combined or alternating administration of a glucopyranosyl-substituted benzene derivative as defined above and below and a DPP IV inhibitor as defined above and below. The disease or disorder caused by abnormal accumulation of liver fat is selected from the group consisting of fatty liver in general (NAFL), non-alcoholic fatty liver disease (NAFL), non-alcoholic steatohepatitis (NASH), fatty liver induced by malnutrition, diabetic fatty liver, fatty liver induced by alcohol, and toxic fatty liver.

Accordingly, a further aspect of the present invention provides a method for maintaining and/or improving insulin sensitivity and/or treating or preventing hyperinsulinemia and/or insulin resistance in a patient in need thereof, characterized in that a glucopyranosyl-substituted benzene derivative as defined above and below is administered in combination or alternation with a DPP IV inhibitor as defined above and below.

According to a further aspect of the present invention there is provided the use of a glucopyranosyl-substituted benzene derivative as defined above and below in the manufacture of a medicament for use in:

-preventing, slowing the progression, delaying or treating a metabolic disorder selected from type I diabetes, type II diabetes, Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity and metabolic syndrome; or

-improving glycemic control and/or lowering fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbAlc; or

-preventing, slowing, delaying or reversing the progression from Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), insulin resistance and/or from metabolic syndrome to type II diabetes; or

-preventing, slowing the progression, delaying or treating a condition or disorder selected from: diabetic complications such as cataract and microvascular and macrovascular diseases such as nephropathy, retinopathy, neuropathy, tissue ischemia, arteriosclerosis, myocardial infarction, stroke and peripheral arterial occlusive disease; or

-reducing body weight or preventing body weight gain or promoting body weight loss; or

-preventing, slowing, delaying or treating degeneration of pancreatic beta cells and/or decline of pancreatic beta cell function and/or improving and/or restoring pancreatic beta cell function and/or restoring pancreatic insulin secretion function; or

-preventing, slowing, delaying or treating a disease or condition caused by abnormal accumulation of liver fat; or

-maintaining and/or improving insulin sensitivity and/or treating or preventing hyperinsulinemia and/or insulin resistance;

characterized in that a glucopyranosyl-substituted benzene derivative is administered in combination or alternation with a DPP IV inhibitor as defined above and below.

According to another aspect of the present invention there is provided the use of a DPP IV inhibitor as defined above and below for the manufacture of a medicament for use in:

-preventing, slowing the progression, delaying or treating a metabolic disorder selected from type I diabetes, type II diabetes, Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity and metabolic syndrome; or

-improving glycemic control and/or lowering fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbAlc; or

-preventing, slowing, delaying or reversing the progression from Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), insulin resistance and/or from metabolic syndrome to type II diabetes; or

-preventing, slowing the progression, delaying or treating a condition or disorder selected from: diabetic complications such as cataract and microvascular and macrovascular diseases such as nephropathy, retinopathy, neuropathy, tissue ischemia, arteriosclerosis, myocardial infarction, stroke and peripheral arterial occlusive disease; or

-reducing body weight or preventing body weight gain or promoting body weight loss; or

-preventing, slowing, delaying or treating degeneration of pancreatic beta cells and/or decline of pancreatic beta cell function and/or improving and/or restoring pancreatic beta cell function and/or restoring pancreatic insulin secretion function; or

-preventing, slowing, delaying or treating a disease or condition caused by abnormal accumulation of liver fat; or

-maintaining and/or improving insulin sensitivity and/or treating or preventing hyperinsulinemia and/or insulin resistance;

characterized in that a DPP IV inhibitor is administered in combination or alternation with a glucopyranosyl-substituted benzene derivative as defined above and below.

According to a further aspect of the invention there is provided the use of a pharmaceutical composition of the invention in the manufacture of a medicament for use in a method of treatment or prophylaxis as hereinbefore and hereinafter defined.

Definition of

The term "active ingredient" of the pharmaceutical composition of the present invention refers to the glucopyranosyl-substituted benzene derivative and/or the DPP IV inhibitor of the present invention.

The term "body mass index" or "BMI" of a human patient is defined as the weight in kilograms divided by the square of the height in meters, so that the BMI has the unit kg/m²。

The term "overweight" is defined as where the subject has more than 25kg/m²And less than 30kg/m²A disorder of BMI of (a). The terms "overweight" and "pre-obesity" are used interchangeably.

The term "obesity" is defined as where an individual has 30kg/m or more²A disorder of BMI of (a). According to the WHO definition, the term obesity can be classified as follows: the term "class I obesity" is where the BMI is equal to or greater than 30kg/m²But less than 35kg/m²The disorder of (a); the term "class II obesity" is where the BMI is equal to or greater than 35kg/m²But less than 40kg/m²The disorder of (a); the term "class III obesity" is where the BMI is equal to or greater than 40kg/m²The disorder of (1).

The term "visceral adiposity" is defined as a condition wherein a waist-to-hip ratio (waist-to-hip) of greater than or equal to 1.0 is measured in men and a waist-to-hip ratio of greater than or equal to 0.8 is measured in women. Which defines the risk of insulin resistance and pre-diabetic development.

The term "abdominal obesity" is generally defined as a condition in which the waist is > 40 inches or 102cm in men and > 35 inches or 94cm in women. For Japanese race or Japanese patients, abdominal obesity can be defined as waist circumference of > 85cm in males and > 90cm in females (see, for example, research council for diagnosis of Japanese metabolic syndrome).

The term "euglycemia" is defined as a condition in which a subject has a fasting blood glucose concentration within the normal range, i.e., greater than 70mg/dL (3.89mmol/L) and less than 110mg/dL (6.11 mmol/L). The word "fasting" has its usual meaning as a medical term.

The term "hyperglycemia" is defined as a condition in which a subject has a fasting blood glucose concentration above the normal range, i.e., greater than 110mg/dL (6.11 mmol/L). The word "fasting" has its usual meaning as a medical term.

The term "hypoglycemia" is defined as a condition in which a subject has a blood glucose concentration below the normal range of 60mg/dL to 115mg/dL (3.3mmol/L to 6.3 mmol/L).

The term "postprandial hyperglycemia" is defined as a condition in which a subject has a 2 hour postprandial blood glucose or serum glucose concentration of greater than 200mg/dL (11.11 mmol/L).

The term "impaired fasting glucose" or "IFG" is defined as a condition in which the subject has a fasting glucose concentration or fasting serum glucose concentration in the range of 100mg/dL to 125mg/dL (i.e. 5.6mmol/L to 6.9mmol/L), especially greater than 110mg/dL and less than 126mg/dL (7.00 mmol/L). A subject with "normal fasting glucose" has a fasting glucose concentration of less than 100mg/dL (i.e., less than 5.6 mmol/L).

The term "impaired glucose tolerance" or "IGT" is defined as a condition in which a subject has a 2-hour postprandial blood glucose or serum glucose concentration of greater than 140mg/dL (7.78mmol/L) and less than 200mg/dL (11.11 mmol/L). Abnormal glucose tolerance (i.e., 2 hours post-prandial blood glucose or serum glucose concentration) can be measured as blood glucose concentration in mg glucose/dL plasma 2 hours after intake of 75g glucose after fasting. A subject with "normal glucose tolerance" has a 2-hour postprandial blood glucose or serum glucose concentration of less than 140mg/dL (7.78 mmol/L).

The term "hyperinsulinemia" is defined as a condition in which a subject has insulin resistance and is normoglycemic or abnormal, wherein fasting or postprandial serum or plasma insulin concentrations rise above normal, and a lean individual without insulin resistance has a waist-to-hip ratio < 1.0 (male) or < 0.8 (female).

The terms "insulin sensitivity", "improvement in insulin resistance" or "reduction in insulin resistance" are synonymous and used interchangeably.

The term "insulin resistance" is defined as where circulating insulin levels are required to exceed the normal response to glucose load to maintain euglycemic status (Ford ES et al, JAMA. (2002) 287: 356-9). The method for determining insulin resistance is a euglycemia-hyperinsulinemia clamp test. The ratio of insulin to glucose was determined within the scope of a combined insulin-glucose infusion technique. Insulin resistance was found to be present if glucose uptake was below 25% of the background population studied (WHO definition). A test that is much easier than the jaw test is the so-called minimum model, in which during an intravenous glucose tolerance test, the insulin and glucose concentrations in the blood are measured at fixed time intervals and the insulin resistance is calculated therefrom. Using this method, it is not possible to distinguish between hepatic insulin resistance and peripheral insulin resistance.

In addition, insulin resistance, patient response to treatment with insulin resistance, insulin sensitivity, and hyperinsulinemia can be quantified by assessing a "steady state model insulin resistance index (HOMA-IR)" score, a reliable indicator of insulin resistance (Katsuki A et al, Diabetes Care 2001; 24: 362-5). Reference may also be made to the method for determining the HOMA index for insulin sensitivity (Matthews et al, Diabetes 1985, 28: 412-19) or the ratio of intact proinsulin to insulin (Forst et al, Diabetes 2003, 52 (suppl.1): A459) and to the euglycemic jaw study. In addition, plasma adiponectin levels can be monitored as a potential alternative to insulin sensitivity. The estimate of insulin resistance was calculated from the steady state model index (HOMA) -IR score using the following formula (Galvin P et al, diabetes Med 1992; 9: 921-8):

HOMA-IR ═ fasting serum insulin (μ U/mL) ] × [ fasting plasma glucose (mmol/L)/22.5]

Typically, other parameters are used in daily clinical practice to assess insulin resistance. Preferably, an increase in triglyceride concentration, e.g. triglyceride content, of the subject is used which is significantly correlated with the presence of insulin resistance.

Patients with a predisposition to develop IGT or IFG or type II diabetes are those with hyperinsulinemia and euglycemia and by definition are insulin resistant. Patients with insulin resistance in general are often overweight or obese. If insulin resistance is detectable, this is a particularly strong indicator of the presence of pre-diabetes. Therefore, it is possible that in order to maintain glucose stability, insulin resistant patients require 2-3 times as much insulin as healthy people, and thus do not cause any clinical symptoms.

The method of studying the function of pancreatic beta cells is similar to the above-described method for insulin sensitivity, hyperinsulinemia or insulin resistance: for example, improvements in beta cell function can be measured by determining the HOMA index of beta cell function after an oral glucose tolerance test or a meal tolerance test (Matthews et al, Diabetologia 1985, 28: 412-19), the ratio of intact proinsulin to insulin (Forst et al, Diabetes 2003, 52 (suppl.1): A459), insulin/C peptide secretion, or by using hyperglycemic clamp studies and/or minimal modeling after a frequently sampled intravenous glucose tolerance test (Stumvoll et al, Eur J Clinquest 2001, 31: 380-81).

The term "pre-diabetic" is a condition in which an individual is predisposed to developing type II diabetes. Pre-Diabetes extends the definition of impaired glucose tolerance to include individuals with fasting plasma glucose in the high normal range ≥ 100mg/dL (J.B.Meigs, et al Diabetes 2003; 52: 1475-1484) and fasting hyperinsulinemia (elevated plasma insulin concentrations). The scientific and medical basis for identifying pre-Diabetes as a serious health threat is set forth in The National Institute of Diabetes and Digestive and renal Diseases (National Institute of Diabetes and Digestive and renal Diseases), a Position State publication (Diabetes Care 2002; 25: 742-749) entitled "The Prevement of Diabetes of Type 2", which is jointly issued by The American Diabetes Association.

Individuals who may have insulin resistance are those who have two or more of the following characteristics: 1) overweight or obesity, 2) hypertension, 3) hyperlipidemia, 4) one or more of the degrees 1 associated with diagnosis of IGT or IFG or type II diabetes. Insulin resistance can be determined in these individuals by calculating the HOMA-IR score. For the purposes of the present invention, insulin resistance is defined as a clinical condition in which an individual has a HOMA-IR score of > 4.0 or a HOMA-IR score greater than the upper limit of normal values defined for the laboratory where glucose and insulin tests are conducted.

The term "type II diabetes" is defined as a condition in which a subject has a fasting blood glucose or serum glucose concentration greater than 125mg/dL (6.94 mmol/L). Measurement of blood glucose values is a standard method in conventional medical analysis. If a glucose tolerance test is performed, the blood glucose level of a diabetic patient 2 hours after a 75g glucose intake on an empty stomach will exceed 200mg glucose/dl plasma (11.1 mmol/L). In the glucose tolerance test, 75g of glucose was orally administered to the tested patients after 10-12 hours of fasting, and the blood glucose level was recorded immediately before and 1 and 2 hours after the ingestion of glucose. In healthy subjects, the blood glucose level will be between 60 and 110mg per dL of plasma prior to glucose uptake, less than 200mg/dL 1 hour after glucose uptake and less than 140mg/dL 2 hours after glucose uptake. If after 2 hours the value is between 140 and 200mg, it is considered abnormal glucose tolerance.

The term "advanced type II diabetes" includes patients with secondary drug failure, insulin therapy indications, and the development of microvascular and macrovascular complications, such as diabetic nephropathy or Coronary Heart Disease (CHD).

The term "HbAlc" refers to the non-enzymatic glycation products of the heme B chain. The determination of which is well known to those skilled in the art. HbAlc values are of particular importance in monitoring treatment of diabetes. Since its production depends essentially on blood glucose content and red blood cell life, HbAlc in the sense of "glycemic memory" reflects the average blood glucose content of the previous 4-6 weeks. In which HbAlc values have been significantly better protected against diabetic microangiopathies by diabetic patients who are well-regulated by intensive diabetes therapy (i.e. < 6.5% total hemoglobin in the sample). For example, metformin itself achieves an average improvement in HbAlc values in diabetic patients on the order of 1.0-1.5%. This reduction in HbAlc values is not sufficient to achieve the desired target range of HbAlc of < 6.5% and preferably < 6% in all diabetic patients.

"Metabolic syndrome", also known as "syndrome X" (when used in the context of metabolic disease), also known as "metabolic disease syndrome", is a complex syndrome characterized primarily by insulin resistance (Laaksonen DE et al, Am J Epidemiol 2002; 156: 1070-7). According to the ATP III/NCEP guidelines (Executive Summary of the Third Report of the National Cholesterol reduction Program (NCEP) Expert Panel on Detection, Evaluation, and Evaluation of High Blood Cholesterol in additives (additive Treatment Panel III) JAMA: Journal of the American Medical Association (2001) 285: 2486-:

1. abdominal obesity, defined as waist circumference > 40 inches or 102cm in men and > 35 inches or 94cm in women; or for Japanese race or Japanese patient, defined as waist circumference of > 85cm in men and > 90cm in women;

2. triglyceride: not less than 150 mg/dL;

3. HDL-cholesterol < 40mg/dL in men;

4. the blood pressure is greater than or equal to 130/85mm Hg (SBP is greater than or equal to 130 or DBP is greater than or equal to 85);

5. fasting blood glucose is more than or equal to 110 mg/dL.

The NCEP definition has been validated (Laaksonen DE et al, Am J Epidemiol (2002) 156: 1070-7). Triglycerides and HDL cholesterol in blood can also be determined by standard methods in medical analysis and are disclosed, for example, in Thomas L (editor): "Labor und Diagnose", TH-BooksVerlagsgesellschaft mbH, Frankfurt/Main, 2000.

According to the usual definition, hypertension is diagnosed if the Systolic Blood Pressure (SBP) exceeds a value of 140mm Hg and the Diastolic Blood Pressure (DBP) exceeds a value of 90mm Hg. If the patient has overt diabetes, the systolic pressure is currently recommended to be reduced to a level below 130mm Hg and the diastolic pressure to be reduced to a level below 80mm Hg.

The term "treatment" includes therapeutic treatment of a patient who has developed the disorder, particularly the dominant form of the disorder. Therapeutic treatment may be symptomatic treatment in order to alleviate the symptoms of a particular indication, or causal treatment in order to reverse or partially reverse the pathology of an indication or to halt or slow the progression of a disease. Thus, the compositions and methods of the invention can be used, for example, for therapeutic treatment over a period of time as well as for long-term treatment.

The terms "prophylactic treatment", "prophylactic treatment" and "prevention" are used interchangeably and include treating a patient at risk of developing the above-mentioned condition, thereby reducing that risk.

Detailed Description

Aspects of the invention, especially pharmaceutical compositions, methods and uses, relate to glucopyranosyl-substituted benzene derivatives of formula (I) as defined above and below.

Preferably, R¹Represents chlorine or cyano; especially chlorine.

Preferably, R²Represents H.

Preferably, R³Represents ethyl, cyclopropyl, ethynyl, (R) -tetrahydrofuran-3-yloxy or (S) -tetrahydrofuran-3-yloxy. Even more preferably, R³Represents cyclopropyl, ethynyl, (R) -tetrahydrofuran-3-yloxy or (S) -tetrahydrofuran-3-yloxy.

Preferably, the glucopyranosyl-substituted benzene derivative is selected from the compounds (1) to (10):

(1)6- (4-ethylbenzyl) -4- (beta-D-glucopyranos-1-yl) -2-methoxy-benzonitrile

(2)2- (4-ethylbenzyl) -4- (beta-D-glucopyranos-1-yl) -5-methoxy-benzonitrile

(3) 1-cyano-2- (4-ethylbenzyl) -4- (. beta. -D-glucopyranos-1-yl) -5-methyl-benzene

(4)2- (4-ethylbenzyl) -4- (beta-D-glucopyranos-1-yl) -5-hydroxy-benzonitrile

(5)2- (4-ethyl-benzyl) -4- (beta-D-glucopyranos-1-yl) -benzonitrile

(6)2- (4-cyclopropyl-benzyl) -4- (beta-D-glucopyranos-1-yl) -benzonitrile

(7) 1-chloro-4- (beta-D-glucopyranos-1-yl) -2- (4-ethynyl-benzyl) -benzene

(8) 1-chloro-4- (beta-D-glucopyranos-1-yl) -2- [4- ((R) -tetrahydrofuran-3-yloxy) -benzyl- ] -benzene

(9) 1-chloro-4- (beta-D-glucopyranos-1-yl) -2- [4- ((S) -tetrahydrofuran-3-yloxy) -benzyl ] -benzene

(10) 1-methyl-2- [4- ((R) -tetrahydrofuran-3-yloxy) -benzyl ] -4- (beta-D-glucopyranos-1-yl) -benzene

(11) 1-methyl-2- [4- ((S) -tetrahydrofuran-3-yloxy) -benzyl ] -4- (β -D-glucopyranos-1-yl) -benzene.

Even more preferred glucopyranosyl-substituted benzene derivatives are selected from the group consisting of compounds (6), (7), (8), (9) and (11).

In accordance with the present invention, it is to be understood that the definition of glucopyranosyl-substituted benzene derivatives set forth above also encompasses hydrates, solvates and polymorphs thereof. Advantageous crystal forms for the preferred compound (7) are described in international patent application WO 2007/028814, which is incorporated herein by reference in its entirety. For the preferred compound (8), advantageous crystalline forms are described in international patent application WO 2006/117360, which is incorporated herein by reference in its entirety. Advantageous crystal forms for the preferred compound (9) are described in international patent application WO 2006/117359, which is incorporated herein by reference in its entirety. Advantageous crystal forms for the preferred compound (11) are described in international patent application WO 2008/049923, which is incorporated herein by reference in its entirety. These crystalline forms have good solubility, which provides SGLT2 inhibitors with good bioavailability. Furthermore, the crystalline form is physicochemically stable and thus provides good storage stability.

Aspects of the present invention, especially pharmaceutical compositions, methods and uses, relate to a DPP IV inhibitor or a prodrug thereof or a pharmaceutically acceptable salt thereof as defined above and below.

For the first embodiment (embodiment a), preferred DPP IV inhibitors are any or all of the following compounds and their pharmaceutically acceptable salts:

(A) the method comprises the following steps 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine (cf. WO 2004/018468, example 2 (142)):

(B) the method comprises the following steps 1- [ ([1, 5] naphthyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (cf. WO 2004/018468, example 2 (252)):

(C) the method comprises the following steps 1- [ (quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (cf. WO 2004/018468, example 2 (80)):

(D) the method comprises the following steps 2- ((R) -3-amino-piperidin-1-yl) -3- (but-2-ynyl) -5- (4-methyl-quinazolin-2-ylmethyl) -3, 5-dihydro-imidazo [4, 5-d ] pyridazin-4-one (cf. WO2004/050658, example 136):

(E) the method comprises the following steps 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (2-amino-2-methyl-propyl) -methylamino ] -xanthine (cf. WO 2006/029769, example 2 (1)):

(F) the method comprises the following steps 1- [ (3-cyano-quinolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (cf. WO2005/085246, example 1 (30)):

(G) the method comprises the following steps 1- (2-cyano-benzyl) -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (cf. WO2005/085246, example 1 (39)):

(H) the method comprises the following steps 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (S) - (2-amino-propyl) -methylamino ] -xanthine (cf. WO 2006/029769, example 2 (4)):

(I) the method comprises the following steps 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (cf. WO2005/085246, example 1 (52)):

(J) the method comprises the following steps 1- [ (4-methyl-pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (cf. WO2005/085246, example 1 (81)):

(K) the method comprises the following steps 1- [ (4, 6-dimethyl-pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (cf. WO2005/085246, example 1 (82)):

(L): 1- [ (quinoxalin-6-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (cf. WO2005/085246, example 1 (83)):

these DPP IV inhibitors differ from structurally similar DPP IV inhibitors by having both unexpected potency and sustained action, as well as favorable pharmacological properties, receptor selectivity and favorable side-effect profile, or by producing unexpected therapeutic advantages or improvements when combined with other pharmaceutically active substances. Their preparation is disclosed in the publications mentioned.

For the second embodiment (embodiment B), preferably the DPP IV inhibitor is selected from sitagliptin, vildagliptin, saxagliptin and alogliptin.

According to the present invention, it is understood that the definition of DPP IV inhibitor as listed above also comprises pharmaceutically acceptable salts thereof as well as hydrates, solvates and polymorphs thereof. For the salts, hydrates and polymorphs thereof, reference is made in particular to those mentioned above and below.

The pharmaceutical compositions, methods and uses of the present invention most preferably relate to a combination selected from table 1.

TABLE 1

Serial number	Compound number of SGLT2 inhibitor	DPP IV inhibitors
			1	(1)	(A)
2	(1)	(B)
			3	(1)	(C)
4	(1)	(D)
			5	(1)	(E)
6	(1)	(F)

Serial number	Compound number of SGLT2 inhibitor	DPP IV inhibitors
			7	(1)	(G)
8	(1)	(H)
			9	(1)	(I)
10	(1)	(J)
			11	(1)	(K)
12	(1)	(L)
			13	(2)	(A)
14	(2)	(B)
			15	(2)	(C)
16	(2)	(D)
			17	(2)	(E)
18	(2)	(F)
			19	(2)	(G)
20	(2)	(H)
			21	(2)	(I)
22	(2)	(J)
			23	(2)	(K)
24	(2)	(L)
			25	(3)	(A)
26	(3)	(B)
			27	(3)	(C)
28	(3)	(D)

Serial number	Compound number of SGLT2 inhibitor	DPP IV inhibitors
			29	(3)	(E)
30	(3)	(F)
			31	(3)	(G)
32	(3)	(H)
			33	(3)	(I)
34	(3)	(J)
			35	(3)	(K)
36	(3)	(L)
			37	(4)	(A)
38	(4)	(B)
			39	(4)	(C)
40	(4)	(D)
			41	(4)	(E)
42	(4)	(F)
			43	(4)	(G)
44	(4)	(H)
			45	(4)	(I)
46	(4)	(J)
			47	(4)	(K)
48	(4)	(L)
			49	(5)	(A)
50	(5)	(B)

Serial number	Compound number of SGLT2 inhibitor	DPP IV inhibitors
			51	(5)	(C)
52	(5)	(D)
			53	(5)	(E)
54	(5)	(F)
			55	(5)	(G)
56	(5)	(H)
			57	(5)	(I)
58	(5)	(J)
			59	(5)	(K)
60	(5)	(L)
			61	(6)	(A)
62	(6)	(B)
			63	(6)	(C)
64	(6)	(D)
			65	(6)	(E)
66	(6)	(F)
			67	(6)	(G)
68	(6)	(H)
			69	(6)	(I)
70	(6)	(J)
			71	(6)	(K)
72	(6)	(L)

Serial number	Compound number of SGLT2 inhibitor	DPP IV inhibitors
			73	(7)	(A)
74	(7)	(B)
			75	(7)	(C)
76	(7)	(D)
			77	(7)	(E)
78	(7)	(F)
			79	(7)	(G)
80	(7)	(H)
			81	(7)	(I)
82	(7)	(J)
			83	(7)	(K)
84	(7)	(L)
			85	(8)	(A)
86	(8)	(B)
			87	(8)	(C)
88	(8)	(D)
			89	(8)	(E)
90	(8)	(F)
			91	(8)	(G)
92	(8)	(H)
			93	(8)	(I)
94	(8)	(J)

Serial number	Compound number of SGLT2 inhibitor	DPP IV inhibitors
			95	(8)	(K)
96	(8)	(L)
			97	(9)	(A)
98	(9)	(B)
			99	(9)	(C)
100	(9)	(D)
			101	(9)	(E)
102	(9)	(F)
			103	(9)	(G)
104	(9)	(H)
			105	(9)	(I)
106	(9)	(J)
			107	(9)	(K)
108	(9)	(L)
			109	(10)	(A)
110	(10)	(B)
			111	(10)	(C)
112	(10)	(D)
			113	(10)	(E)
114	(10)	(F)
			115	(10)	(G)
116	(10)	(H)

Serial number	Compound number of SGLT2 inhibitor	DPP IV inhibitors
			117	(10)	(I)
118	(10)	(J)
			119	(10)	(K)
120	(10)	(L)
			121	(11)	(A)
122	(11)	(B)
			123	(11)	(C)
124	(11)	(D)
			125	(11)	(E)
126	(11)	(F)
			127	(11)	(G)
128	(11)	(H)
			129	(11)	(I)
130	(11)	(J)
			131	(11)	(K)
132	(11)	(L)
			133	(1)	Sitagliptin
134	(1)	Vildagliptin
			135	(1)	Saxagliptin
136	(1)	Alogliptin
			137	(2)	Sitagliptin
138	(2)	Vildagliptin

Serial number	Compound number of SGLT2 inhibitor	DPP IV inhibitors
			139	(2)	Saxagliptin
140	(2)	Alogliptin
			141	(3)	Sitagliptin
142	(3)	Vildagliptin
			143	(3)	Saxagliptin
144	(3)	Alogliptin
			145	(4)	Sitagliptin
146	(4)	Vildagliptin
			147	(4)	Saxagliptin
148	(4)	Alogliptin
			149	(5)	Sitagliptin
150	(5)	Vildagliptin
			151	(5)	Saxagliptin
152	(5)	Alogliptin
			153	(6)	Sitagliptin
154	(6)	Vildagliptin
			155	(6)	Saxagliptin
156	(6)	Alogliptin
			157	(7)	Sitagliptin
158	(7)	Vildagliptin
			159	(7)	Saxagliptin
160	(7)	Alogliptin

Serial number	Compound number of SGLT2 inhibitor	DPP IV inhibitors
			161	(8)	Sitagliptin
162	(8)	Vildagliptin
			163	(8)	Saxagliptin
164	(8)	Alogliptin
			165	(9)	Sitagliptin
166	(9)	Vildagliptin
			167	(9)	Saxagliptin
168	(9)	Alogliptin
			169	(10)	Sitagliptin
170	(10)	Vildagliptin
			171	(10)	Saxagliptin
172	(10)	Alogliptin
			173	(11)	Sitagliptin
174	(11)	Vildagliptin
			175	(11)	Saxagliptin
176	(11)	Alogliptin

Among the combinations No. 1 to 176 of the present invention listed in Table 1, the emphasis is on the combinations No. 1, No. 13, No. 25, No. 37, No. 49, No. 61, No. 73, No. 85, No. 97, No. 109, No. 121 and No. 133-.

The combination of a glucopyranosyl-substituted benzene derivative of the invention with a DPP IV inhibitor leads to a significant improvement of glycemic control compared to monotherapy with the glucopyranosyl-substituted benzene derivative or the DPP IV inhibitor, especially in patients as described below. Improved glycemic control was measured as increased reduction in blood glucose and increased reduction in HbAlc. With monotherapy in patients, especially those described below, glycemic control is often not further significantly improved by administering above a certain maximum dose of the above-mentioned drugs. In addition, long-term treatment with the highest dose is inappropriate in view of potential side effects. Therefore, complete glycemic control cannot be achieved in all patients via monotherapy with glucopyranosyl-substituted benzene derivatives or DPP IV inhibitors. In such patients, diabetes continues to develop and diabetic complications, such as macrovascular complications, may occur. The pharmaceutical compositions and methods of the invention reduce the HbAlc values of a larger number of patients to the desired target range, e.g. < 7% and preferably < 6.5%, compared to the corresponding monotherapy.

In addition, the combination of the glucopyranosyl-substituted benzene derivative of the present invention with a DPP IV inhibitor allows the dosage of the glucopyranosyl-substituted benzene derivative or the DPP IV inhibitor or both active ingredients to be reduced. Dose reduction is beneficial to patients who otherwise suffer from potential side effects in monotherapy with higher doses of glucopyranosyl-substituted benzene derivatives or DPP IV inhibitors. Accordingly, the pharmaceutical compositions and methods of the present invention exhibit fewer side effects, thereby making the therapy more tolerable and improving patient compliance with the treatment.

Monotherapy with the DPP IV inhibitors of the present invention is not independent of insulin secretion capacity or insulin sensitivity of the patient. On the other hand, the treatment by administering the glucopyranosyl-substituted benzene derivative of the present invention is independent of the insulin secretion ability or insulin sensitivity of the patient. Thus, any patient independent of the predominant insulin content or insulin resistance and/or hyperinsulinemia may benefit from therapy with the glucopyranosyl-substituted benzene derivative of the invention in combination with a DPP IV inhibitor. These patients, independent of their predominant insulin content or their insulin resistance or hyperinsulinemia, can still be treated with DPP IV inhibitors due to the combined or alternating administration of glucopyranosyl-substituted benzene derivatives.

The DPP IV inhibitors of the present invention are capable of reducing glucagon secretion in a patient by increasing the active GLP-1 content. Thereby limiting hepatic glucose production. Furthermore, the elevated active GLP-1 content produced by DPP IV inhibitors has a beneficial effect on beta-cell regeneration and neogenesis. All these characteristics of DPP IV inhibitors make the combination with glucopyranosyl-substituted benzene derivatives very useful and complementary therapeutically.

While the present invention relates to patients in need of treatment or prevention, it primarily relates to treatment and prevention in humans, but the pharmaceutical composition may also be used accordingly in veterinary medicine in mammals.

As described above, by administering the pharmaceutical composition of the present invention and especially in consideration of the high SGLT2 inhibitory activity of the glucopyranosyl-substituted benzene derivative therein, excessive blood glucose is excreted through urine of a patient, and thus it is impossible to cause weight gain or even cause weight loss. Thus, the treatment or prevention according to the invention is advantageously suitable in those patients in need of such treatment or prevention diagnosed with one or more of the following conditions selected from: overweight, class I obesity, class II obesity, class III obesity, visceral obesity, and abdominal obesity.

The pharmaceutical compositions of the invention and especially the glucopyranosyl-substituted benzene derivatives thereof show very good efficacy in glycemic control, especially for lowering fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin (HbAlc). By administering the pharmaceutical composition of the invention, the reduction in HbAlc is preferably up to equal to or more than preferably 0.5%, even preferably equal to or more than 1.0%, and the reduction is in particular in the range of 1.0% to 1.5%.

Furthermore, the methods and/or uses of the invention are advantageously applicable to those patients who exhibit one, two or more of the following conditions:

(a) fasting or serum glucose concentrations greater than 110mg/dL, particularly greater than 125 mg/dL;

(b) postprandial blood glucose equal to or greater than 140 mg/dL;

(c) HbAlc values are equal to or greater than 6.5%, in particular equal to or greater than 8.0%.

The invention also discloses the use of a pharmaceutical composition for improving glycemic control in a patient suffering from type II diabetes or showing a first sign of pre-diabetes. Thus, the present invention also includes diabetes prevention. Thus, if the pharmaceutical composition of the present invention is used for improving glycemic control as soon as possible in the presence of one of the aforementioned pre-diabetic symptoms, it is apparent that the onset of type II diabetes can be delayed or prevented.

Furthermore, the pharmaceutical composition of the invention is particularly suitable for treating a patient having insulin dependence, i.e. a patient being treated or about to be treated by or in need of treatment with insulin or an insulin derivative or an insulin substitute or a formulation comprising insulin or a derivative or a substitute thereof. These patients include type II diabetes patients and type I diabetes patients.

It has been found that by using the pharmaceutical composition of the invention, an improvement in glycemic control can be achieved even in those patients with insufficient glycemic control, in particular in those patients with insufficient glycemic control despite treatment with an antidiabetic drug, for example despite oral monotherapy treatment with metformin or an SGLT2 inhibitor (in particular an SGLT2 inhibitor of the invention) or a DPP IV inhibitor (in particular a DPP IV inhibitor of the invention) at maximally tolerated doses. The maximum tolerated dose for metformin is, for example, 850mg three times daily or any equivalent thereof. For the SGLT2 inhibitors of the invention, especially for compound (6), (7), (8), (9) or (11), the maximum tolerated dose is, for example, 100mg, preferably 50mg or even 30mg, once daily, or any equivalent dose thereof. For the DPP IV inhibitors of the present invention, especially for compound (a) (1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine), the maximum tolerated dose is e.g. 10mg once daily or any equivalent dose thereof. For the DPP IV inhibitors of the present invention, such as sitagliptin, the maximum tolerated dose is, for example, 100mg, once daily or any equivalent dose thereof. Within the scope of the present invention, the term "insufficient glycemic control" refers to a condition wherein the patient exhibits a HbAlc value of more than 6.5%, in particular more than 8%.

Accordingly, a preferred embodiment of the present invention provides a method for improving glycemic control and/or lowering fasting glucose, postprandial blood glucose and/or glycosylated hemoglobin HbAlc in a patient diagnosed with Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), with insulin resistance, with metabolic syndrome and/or with type 2 or type I diabetes mellitus in need thereof, characterized in that a glucopyranosyl-substituted benzene derivative as defined above and below is administered in combination or alternation with a DPP IV inhibitor as defined above and below.

The lowering of blood glucose concentration by administration of the glucopyranosyl-substituted benzene derivative of the present invention is non-insulin dependent. Accordingly, the pharmaceutical compositions of the present invention are particularly suitable for treating patients diagnosed with one or more of the following conditions:

insulin resistance,

Hyperinsulinemia,

-pre-diabetes,

Type II diabetes, in particular with advanced stages of type II diabetes,

-type I diabetes.

Furthermore, the pharmaceutical compositions of the present invention are particularly suitable for treating patients diagnosed with one or more of the following conditions:

(a) obesity (including I, II and/or class III obesity), visceral obesity and/or abdominal obesity,

(b) the blood content of triglyceride is more than or equal to 150mg/dL,

(c) HDL-cholesterol blood levels are < 40mg/dL in female patients and < 50mg/dL in male patients,

(d) the systolic pressure is more than or equal to 130mm Hg and the diastolic pressure is more than or equal to 85mm Hg,

(e) the fasting blood sugar content is more than or equal to 110 mg/dL.

Patients diagnosed with Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), with insulin resistance and/or with metabolic syndrome are believed to have an increased risk of developing cardiovascular disease (e.g., myocardial infarction, coronary heart disease, cardiac insufficiency, thromboembolic event). The glycemic control of the present invention can result in a reduction in cardiovascular risk.

The pharmaceutical composition of the present invention shows good safety especially due to the glucopyranosyl-substituted benzene derivative therein. Thus, the treatment or prevention of the present invention is advantageously feasible in those patients for whom monotherapy with another antidiabetic agent (such as metformin) is contraindicated and/or intolerant to therapeutic doses of these agents. In particular the treatment or prevention of the present invention is advantageously applicable in those patients exhibiting or suffering from an increased risk of one or more of the following conditions, including: renal insufficiency or kidney disease, heart failure, liver disease, lung disease, metabolic state and/or risk of lactic acidosis.

Furthermore, it has been found that the administration of the pharmaceutical composition of the invention does not have or has a very low risk of hypoglycemia. Thus, the treatment or prevention according to the invention is also advantageously feasible in those patients who show or have a high risk of hypoglycemia.

The pharmaceutical compositions of the invention are particularly suitable for the long-term treatment or prevention of the diseases and/or disorders described above and below, in particular for the long-term glycemic control of patients suffering from type II diabetes.

The term "long-term" as used in this context means treatment or administration in a patient over a period of longer than 12 weeks, preferably longer than 25 weeks, even more preferably longer than 1 year.

Thus, a particularly preferred embodiment of the present invention provides a method for treatment, preferably oral treatment, for improving, in particular long-term improvement of glycemic control in type II diabetic patients, in particular in type II advanced patients, especially in patients otherwise diagnosed with overweight, obesity (including class I, class II and/or class III obesity), visceral obesity and/or abdominal obesity.

This effect is observed both when the glucopyranosyl-substituted benzene derivative is administered in combination (e.g., simultaneously) with a DPP IV inhibitor, and when it is administered alternately (e.g., sequentially) in separate formulations.

It will be appreciated that the amount of the pharmaceutical composition of the invention required to be administered to a patient and used in the treatment or prevention of the invention will vary with the route of administration, the nature and severity of the condition to be treated or prevented, the age, weight and condition of the patient, the concomitant medication, and will ultimately be at the discretion of the attendant physician. However, in general, the glucopyranosyl-substituted benzene derivatives and the DPP IV inhibitor of the present invention are included in a pharmaceutical composition or dosage form by combined or alternating administration thereof in an amount sufficient to improve glycemic control in a patient to be treated.

Preferred ranges for the amounts of glucopyranosyl-substituted benzene derivatives and DPP IV inhibitor used in the pharmaceutical compositions and methods and uses of the invention are set forth below. These ranges refer to the amount administered per day for an adult patient, and may be adjusted accordingly for 2, 3, 4 or more doses per day, as well as for other routes of administration, and for the age of the patient.

Within the scope of the present invention, the pharmaceutical composition is preferably administered orally. Other forms of administration may also be employed and are disclosed hereinafter. Preferably, the dosage form comprising the glucopyranosyl-substituted benzene derivative is administered orally. The route of administration of the DPP IV inhibitor is oral or generally known.

In general, the amount of glucopyranosyl-substituted benzene derivative in the pharmaceutical compositions and methods of the invention is preferably between the amounts 1/5 and 1/1 generally suggested for monotherapy utilizing the glucopyranosyl-substituted benzene derivative. Advantageously, the combination therapies of the present invention use lower doses than the single glucopyranosyl-substituted benzene derivative or the single DPP IV inhibitor in monotherapy or conventional therapy, thereby avoiding the possible toxic and adverse side effects that occur when those drugs are used as monotherapy.

For example, for a human of about 70 kg body weight, the amount of glucopyranosyl-substituted benzene derivative is preferably in the range of 0.5mg to 200mg per day, even more preferably 1mg to 100mg per day, most preferably 5mg to 50mg per day. Oral administration is preferred. Thus, the pharmaceutical composition may comprise the above mentioned amounts for once daily administration and comprise 0.25mg to 100mg, even more preferably 0.5mg to 50mg, most preferably 2.5mg to 25mg for 2 times daily administration. A particular dosage strength (e.g. per tablet or capsule) is e.g. 5mg, 10mg, 15mg, 20mg, 25mg or 50mg of compound (6), (7), (8), (9) or (11), especially compound (9).

Generally, the amount of DPP IV inhibitor in the pharmaceutical compositions and methods of the present invention is preferably between 1/5 and 1/1, which are generally suggested for monotherapy using the DPP IV inhibitor.

For the first embodiment (embodiment a), the dosages required for the DPP IV inhibitors mentioned in embodiment a herein are from 0.1mg to 10mg, preferably from 0.25mg to 5mg, when administered intravenously, and from 0.5mg to 100mg, preferably from 2.5mg to 50mg or from 0.5mg to 10mg, more preferably from 2.5mg to 10mg or from 1mg to 5mg, when administered orally, in each case from 1 to 4 times daily. Thus, the compound (a) (1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine) when administered orally requires a dose of 0.5mg to 10mg per patient per day, preferably 2.5mg to 10mg per patient per day (more preferably 5mg to 10mg per patient per day) or 1mg to 5mg per patient per day.

Dosage forms prepared with pharmaceutical compositions comprising the DPP IV inhibitors mentioned in embodiment a herein contain the active ingredient in a dosage range of 0.1-100mg, especially 0.5-10 mg. Thus, the specific dosage strengths of compound (a) (1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine) were 0.5mg, 1mg, 2.5mg, 5mg and 10mg, more specific dosage strengths thereof were 1mg, 2.5mg and 5 mg.

For the second embodiment (embodiment B), the dose of DPP IV inhibitor mentioned herein in embodiment B to be administered to a mammal (e.g. a human of about 70 kg body weight) may typically be about 0.5mg to about 350mg, e.g. about 10mg to about 250mg, preferably 20-200mg, more preferably 20-100mg of active fraction per human per day, or about 0.5mg to about 20mg, preferably 2.5-10mg per human per day, preferably divided into 1 to 4 single doses, which may for example have the same capacity. Single dose strengths comprise, for example, 10mg, 25mg, 40mg, 50mg, 75mg, 100mg, 150mg, and 200mg of the DPP IV inhibitor active moiety.

The dosage strength of the DPP IV inhibitor sitagliptin is typically between 25mg and 200mg of the active moiety. The recommended dose of sitagliptin is 100mg, calculated for the active fraction (free base anhydrate), once daily. The unit dosage strengths of sitagliptin free base anhydrate (active fraction) were 25mg, 50mg, 75mg, 100mg, 150mg, and 200 mg. Specific unit dose strengths of sitagliptin (e.g. per tablet) are 25mg, 50mg and 100 mg. Equivalent amounts of sitagliptin phosphate monohydrate and sitagliptin free base anhydrate were used in the pharmaceutical composition, namely 32.13mg, 64.25mg, 96.38mg, 128.5mg, 192.75mg and 257mg, respectively. Adjusted doses of 25mg and 50mg sitagliptin were used for patients with renal failure.

The dosage range of the DPP IV inhibitor vildagliptin is typically between 10mg and 150mg daily, especially between 25mg and 150mg, 25mg and 100mg or 25mg and 50mg or 50mg and 100mg daily. Specific examples of daily oral doses are 25mg, 30mg, 35mg, 45mg, 50mg, 55mg, 60mg, 80mg, 100mg or 150 mg. In a more specific aspect, the daily administration of vildagliptin is between 25mg and 150mg or between 50mg and 100 mg. In another more specific aspect, the daily administration of vildagliptin is 50mg or 100 mg. The application of the active ingredient may take place up to three times daily, preferably once or twice daily. A particular dosage form (e.g. tablet) comprises 50mg or 100mg vildagliptin.

Alogliptin may be administered to the patient in a daily dose of alogliptin of between 5 mg/day and 250 mg/day, optionally between 10mg and 200mg, optionally between 10mg and 150mg, and optionally between 10mg and 100mg (in each case calculated as the molecular weight of the free base form of alogliptin). Thus, specific dosages that may be used include, but are not limited to, 10mg, 12.5mg, 20mg, 25mg, 50mg, 75mg and 100mg daily of alogliptin. Alogliptin may be administered in its free base form or as a pharmaceutically acceptable salt.

Saxagliptin may be administered to a patient in a daily dose of between 2.5 mg/day and 100 mg/day, optionally between 2.5mg and 50 mg. Specific dosages that may be used include, but are not limited to, 2.5mg, 5mg, 10mg, 15mg, 20mg, 30mg, 40mg, 50mg and 100mg of saxagliptin per day.

The amounts of glucopyranosyl-substituted benzene derivative and DPP IV inhibitor in the pharmaceutical composition of the invention correspond to the respective dosage ranges as provided above. For example, a pharmaceutical composition comprises compound (6), (7), (8), (9) or (11), especially compound (9), in an amount of 5mg to 50mg and compound (a) (1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine) in an amount of 0.5mg to 10 mg.

Another example of a pharmaceutical composition comprises compound (6), (7), (8), (9) or (11), especially compound (9), in an amount of 5mg to 50mg and sitagliptin in an amount of 1mg to 100mg of the active ingredient.

Another example of a pharmaceutical composition comprises compound (6), (7), (8), (9) or (11), especially compound (9), in an amount of 5mg to 50mg and vildagliptin in an amount of 1mg to 100mg of the active moiety.

Another example of a pharmaceutical composition comprises compound (6), (7), (8), (9) or (11), especially compound (9), in an amount of 5mg to 50mg and alogliptin in an amount of 1mg to 100mg of the active moiety.

Another example of a pharmaceutical composition comprises compound (6), (7), (8), (9) or (11), especially compound (9), in an amount of 5mg to 50mg and saxagliptin in an amount of 1mg to 100mg of the active ingredient.

In the methods and uses of the present invention, the glucopyranosyl-substituted benzene derivative is administered in combination or alternation with a DPP IV inhibitor. The term "administration in combination" means that the two active ingredients are administered at the same time (i.e. simultaneously) or substantially at the same time. The term "administration in alternation" means that the first active ingredient is administered first and the second active ingredient is administered after a period of time, i.e. the two active ingredients are administered sequentially. The time period may be between 30 minutes and 12 hours. The combined or alternating administration may be carried out once, twice, three times or four times a day.

For administration of the glucopyranosyl-substituted benzene derivative in combination with a DPP IV inhibitor, the two active ingredients may be present in a single dosage form (e.g., in a tablet or capsule), or each active ingredient may be present in separate dosage forms (e.g., in two different or the same dosage forms).

For their alternate administration, each active ingredient is present in a separate dosage form (e.g., in two different or the same dosage forms).

Thus, the pharmaceutical compositions of the present invention may be presented as a single dosage form comprising the glucopyranosyl-substituted benzene derivative and the DPP IV inhibitor as well as separate dosage forms wherein one dosage form comprises the glucopyranosyl-substituted benzene derivative and the other dosage form comprises the DPP IV inhibitor.

The following situations may arise: one of the active ingredients has to be administered more often (e.g. twice daily) than the other active ingredient, which for example needs to be administered once daily. The term "combined or alternating administration" thus also includes a dosage regimen in which the two active ingredients are first combined or alternating administered and only one active ingredient is administered again after a period of time, or vice versa.

Thus, the invention also includes pharmaceutical compositions in separate dosage forms, wherein one dosage form comprises the glucopyranosyl-substituted benzene derivative and the DPP IV inhibitor and the other dosage form comprises the glucopyranosyl-substituted benzene derivative or the DPP IV inhibitor.

Pharmaceutical compositions in single or multiple dosage forms, preferably in the form of kits, may be used in combination therapy to flexibly suit the individual therapeutic needs of the patient.

A preferred kit comprises:

(a) a first container containing a dosage form comprising a glucopyranosyl-substituted benzene derivative and at least one pharmaceutically acceptable carrier; and

(b) a second container comprising a dosage form comprising a DPP IV inhibitor and at least one pharmaceutically acceptable carrier.

Another aspect of the invention is an article of manufacture comprising a pharmaceutical composition in the form of individual dosage forms of the invention and a label or package insert containing instructions for the combined or alternating administration of the individual dosage forms.

Another aspect of the invention is an article of manufacture comprising an agent comprising a glucopyranosyl-substituted benzene derivative of the invention and a label or package insert comprising instructions that the agent may be or is to be combined or administered alternatively with an agent comprising a DPP IV inhibitor of the invention.

Another aspect of the invention is an article of manufacture comprising an agent comprising a DPP IV inhibitor of the invention and a label or package insert comprising instructions that the agent may be or is to be combined or administered alternatively with an agent comprising a glucopyranosyl-substituted benzene derivative of the invention.

The desired dosage of the pharmaceutical composition of the invention may conveniently be presented in divided dosage form (e.g. two, three or more doses per day) administered once a day or at suitable intervals.

Pharmaceutical compositions may be formulated for oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration in liquid or solid form or in a form suitable for administration by inhalation or insufflation. Oral administration is preferred. The formulations may conveniently be presented in discrete dosage unit form as appropriate and may be prepared by methods well known in the art of pharmacy. All methods include the steps of bringing into association the active ingredient with one or more pharmaceutically acceptable carriers, such as a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

The pharmaceutical composition can be formulated into the forms of tablet, granule, fine granule, powder, capsule, caplet (caplets), soft capsule, pill, oral solution, syrup, dry syrup, chewable tablet, buccal tablet, effervescent tablet, drop, suspension, instant tablet, oral fast-dispersing tablet, etc.

Pharmaceutical compositions and dosage forms preferably contain one or more pharmaceutically acceptable carriers that must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Pharmaceutical compositions suitable for oral administration may conveniently be presented in the following forms: discrete unit forms, such as capsules, including soft gelatin capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; in powder or granular form; in the form of a solution, suspension or emulsion, for example a syrup, elixir or self-emulsifying delivery system (SEDDS). The active ingredient may also be presented in the form of bolus, electuary or paste. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as an anhydrous product for constitution with water or other suitable vehicle before use. These liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives.

The pharmaceutical compositions of the invention may also be formulated for parenteral administration (e.g., by injection, such as bolus injection or continuous infusion) and may be presented in unit dosage form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use, by sterile isolation of a sterile solid or by lyophilization from solution.

Pharmaceutical compositions suitable for rectal administration in which the carrier is a solid are most preferably in the form of unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art, and suppositories may be conveniently formed by mixing the active compound with the softened or melted carrier followed by cooling and shaping in a mould.

The pharmaceutical compositions and methods of the present invention show advantageous effects in the treatment and prevention of the diseases and disorders described above, compared to pharmaceutical compositions and methods comprising only one of the two active ingredients. Beneficial effects can be seen, for example, in efficacy, dose intensity, dose frequency, pharmacodynamic properties, pharmacokinetic properties, fewer side effects, etc.

Examples of pharmaceutically acceptable carriers are well known to those skilled in the art.

Methods of preparing the glucopyranosyl-substituted benzene derivatives and prodrugs thereof of the present invention are known to those skilled in the art. Advantageously, the compounds of the invention can be prepared using synthetic methods as described in the literature, in particular as described in WO01/27128, WO 03/099836, WO2005/092877, WO 2006/034489, WO 2006/064033, WO 2007/025943 and WO 2007/031548. The compounds (1) to (6) can be preferably prepared according to the synthetic methods described in WO 2007/093610 and WO 2008/055870. Advantageously, compound (7) is prepared as described in WO2005/092877 (see example 12). Advantageous methods for the synthesis of compounds (8) and (9) are described in WO2005/092877 (see examples 2 and 3), WO 2006/117360, WO 2006/117359 and WO 2006/120208. Compounds (10) and (11) are preferably obtained via the synthetic methods described in WO 2006/064033.

For embodiment a, the methods of synthesis of the DPP IV inhibitors of embodiment a of the present invention are known to those skilled in the art. Advantageously, the DPP IV inhibitors of embodiment a of the present invention may be prepared using synthetic methods as described in the literature. Thus, for example, purine derivatives of formula (I) may be obtained as described in the following patents: WO 2002/068420, WO 2004/018468, WO2005/085246, WO 2006/029769 or WO 2006/048427, the disclosures of which are incorporated herein by reference. Purine derivatives of formula (II) may be obtained as described, for example, in WO2004/050658 or WO2005/110999, the disclosures of which are incorporated herein by reference. Purine derivatives of formula (III) and (IV) may be obtained as described in, for example, WO2006/068163, WO 2007/071738 or WO2008/017670, the disclosures of which are incorporated herein by reference. The preparation of those DPP IV inhibitors mentioned specifically above and the documents mentioned in connection therewith are disclosed herein. Polymorphic crystal modifications and formulations of certain DPP IV inhibitors are disclosed in WO 2007/054201 and WO2007/128724, respectively, the disclosures of which are incorporated herein by reference.

For embodiment B, methods of synthesizing the DPP IV inhibitors of embodiment B are described in the scientific literature and/or published patent literature, particularly in those cited in the "background of the invention" section above.

The DPP IV inhibitor may be present in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include, but are not limited to, salts with inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; salts with organic carboxylic acids such as oxalic acid, acetic acid, citric acid, malic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, and glutamic acid; and salts with organic sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid. These salts can be formed by mixing the compound with the acid in the appropriate amounts and proportions in the solvent and decomposer. These salts can also be obtained from other salt forms by cation or anion exchange. The DPP IV inhibitor may be present in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include, for example, salts with inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; salts with organic carboxylic acids such as oxalic acid, acetic acid, citric acid, malic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, and glutamic acid; and salts with organic sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid. These salts can be formed by mixing the compound with the acid in the appropriate amounts and proportions in the solvent and decomposer. These salts can also be obtained from other salt forms by cation or anion exchange.

The glucopyranosyl-substituted benzene derivative and/or the DPP IV inhibitor or a pharmaceutically acceptable salt thereof may be present in the form of a solvate, such as a hydrate or an alcohol adduct.

Any of the above combinations and methods within the scope of the present invention can be tested by animal models known in the art. In vivo experiments suitable for evaluating the pharmacologically relevant properties of the pharmaceutical compositions and methods of the present invention are described below:

the pharmaceutical compositions and methods of the invention can be tested in genetically hyperinsulinemic or Diabetic animals, such as db/db mice, ob/ob mice, Zucker Fatty (fa/fa) rats or Zucker Diabetic Fatty (ZDF) rats. In addition, it can be tested in animals (e.g., HanWistar or Sprague Dawley rats) with experimentally induced diabetes and pre-treated with streptozotocin (streptozotocin).

In an oral glucose tolerance test in the animal models described above, the effect of the combination of the invention on glycemic control can be tested after a single administration of the glucopyranosyl-substituted benzene derivative and the DPP IV inhibitor alone and in combination. The course of blood glucose over time was followed after oral glucose challenge (challenge) in overnight fasted animals. The combination of the invention resulted in a significant improvement in glucose excursion (infusion) as measured by a decrease in peak glucose concentration or a decrease in glucose AUC compared to each monotherapy. In addition, after the glucopyranosyl-substituted benzene derivative and the DPP IV inhibitor are administered singly and in combination several times in the above animal model, the blood glucose control effect can be determined by measuring HbAlc values in blood. The combination of the invention significantly reduces HbAlc compared to each monotherapy.

The possible dose reduction of the glucopyranosyl-substituted benzene derivative or the DPP-IV inhibitor or both active ingredients can be tested by the glycemic control effect by lower doses of the combination and monotherapy in the above mentioned animal models. Lower doses of the combination of the invention significantly improved glycemic control compared to placebo treatment, whereas lower doses of the monotherapy failed.

The treatment of the present invention shows improved independence from insulin after a single administration in the oral glucose tolerance test performed in the animal models described above. The course of plasma insulin changes over time was followed after glucose challenge in overnight fasted animals. The combination of the glucopyranosyl-substituted benzene derivative and the DPP IV inhibitor shows a lower peak concentration of insulin or insulin AUC at lower blood glucose excursions than the DPP IV inhibitor alone.

The increase in the level of active GLP-1 caused by the treatment of the invention after a single or multiple administration can be determined by measuring the level in plasma of the animal models described above in a fasting or postprandial state. Also, the decrease in glucagon content in plasma can be measured under the same conditions. The combination of the glucopyranosyl-substituted benzene derivative with the DPP IV inhibitor shows higher active GLP-1 concentration and lower glucagon concentration compared to the glucopyranosyl-substituted benzene derivative alone.

The superior effect of the combination of a glucopyranosyl-substituted benzene derivative of the invention with a DPP IV inhibitor on beta-cell regeneration and neogenesis compared to the glucopyranosyl-substituted benzene derivative alone can be determined by the following method: after multiple dosing of the animal models described above, the increase in pancreatic insulin content is measured, or the increase in β -cell mass is measured via morphometric analysis after immunohistochemical staining of pancreatic sections, or the increase in glucose-stimulated insulin secretion in isolated islets is measured.

In this context, the H atoms of the hydroxyl groups are not explicitly shown in each case in the structural formulae. The following examples are intended to illustrate the invention without limiting it. The terms "room temperature" and "ambient temperature" are used interchangeably and refer to a temperature of about 20 ℃. The following abbreviations are used:

tBu tert-butyl

dba dibenzylidene acetone

DMF dimethyl formamide

DMSO dimethyl sulfoxide

NMP N-methyl-2-pyrrolidone

THF tetrahydrofuran

Preparation of the starting compound:

example I

2-bromo-5-iodo-4-methyl-benzoic acid

N-iodosuccinimide (19.1g) was added portionwise to 2-bromo-4-methyl-benzoic acid (18.4g) dissolved in sulfuric acid (20mL)In ice-cold solution. The resulting mixture was stirred at 5-10 ℃ for 3 hours, then allowed to warm to room temperature overnight. Then, the mixture was poured onto crushed ice, and the resulting solution was extracted with ethyl acetate. The combined extracts were in turn treated with 10% Na₂S₂O₃Aqueous (2X), water (3X) and brine (1X). Drying (MgSO)₄) After that, the organic solvent was evaporated under reduced pressure. The remaining solid was dissolved in water and the resulting slurry was stirred at 70 ℃ for 5 minutes. The undissolved portion was separated by filtration and dried to give the desired product.

Yield: 27.2g (96% of theory).

Mass spectrometry (ESI)^-)：m/z＝339/341(Br)[M-H]^-。

The following compounds are obtained analogously to example I:

(1) (2-bromo-5-iodo-4-methoxy-phenyl) - (4-ethyl-phenyl) -methanone

Mass spectrum (ESI +): m/z 445/447(Br) [ M + H ]]⁺。

The starting material (2-bromo-4-methoxy-phenyl) - (4-ethyl-phenyl) -methanone was prepared as described in examples II and III below.

Example II

(2-bromo-5-iodo-phenyl) - (4-ethyl-phenyl) -methanone

Oxalyl chloride (9.5mL) was added to a solution of 2-bromo-5-iodo-benzoic acid (25.0g) in dichloromethane (50 mL). A few drops of DMF were added and the mixture was stirred at rt overnight. Then, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (50mL) and ethylbenzene (23 mL). The resulting solution was cooled in an ice bath, and aluminum trichloride (12.5g) was added in portions. Then, the cooling bath was removed and the reaction mixture was stirred at room temperature for 4 hours. After consumption of the intermediate substituted benzoyl chloride, the reaction mixture was poured onto crushed ice and the organic phase was separated. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed successively with 1M hydrochloric acid, 1M potassium hydroxide solution and brine. The organic phase was dried (sodium sulfate) and the solvent was removed under reduced pressure to give the product as an oil which crystallized on standing.

Yield: 30.8g (97% of theory).

Mass spectrometry (ESI)⁺)：m/z＝415/417(Br)[M+H]⁺。

The following compounds can be obtained analogously to example II:

(1) (2-bromo-5-iodo-4-methyl-phenyl) - (4-ethyl-phenyl) -methanone

Mass spectrometry (ESI)⁺)：m/z＝429/431(Br)[M+H]⁺。

(2) (2-bromo-4-fluoro-phenyl) - (4-ethyl-phenyl) -methanone

Mass spectrometry (ESI)⁺)：m/z＝307/309(Br)[M+H]⁺。

Example III

(2-bromo-4-methoxy-phenyl) - (4-ethyl-phenyl) methanone

Sodium methoxide (10.5g) was added portionwise to (2-bromo-4-fluoro-phenyl) - (4-ethyl-phenyl) -methanone (43.0g) dissolved in DMF (200 mL). The solution was stirred overnight, then another portion of sodium methoxide (5.5g) was added. After stirring for a further 3 hours, water was added and the resulting mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate), the solvent was removed and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 20: 1- > 9: 1).

Yield: 33.7g (75% of theory).

Mass spectrometry (ESI)⁺)：m/z＝319/321(Br)[M+H]⁺。

Example IV

4-bromo-3- (4-ethyl-benzyl) -1-iodo-benzene

A solution of (2-bromo-5-iodo-phenyl) - (4-ethyl-phenyl) -methanone (32g) and triethylsilane (50mL) in dichloromethane (30mL) and acetonitrile (100mL) was cooled in an ice bath. Then, boron trifluoride diethyl etherate (20mL) was added dropwise over 5 minutes. The cooling bath was removed and the solution was heated to 45-50 ℃ and stirred at this temperature for 4 hours. After cooling to ambient temperature, 4M aqueous KOH was added and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with 2M potassium hydroxide solution and brine and then dried (sodium sulfate). After evaporation of the solvent, the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1: 0- > 9: 1).

Yield: 21g (68% of theory).

Mass spectrometry(ESI⁺)：m/z＝418/420(Br)[M+NH₄]⁺。

The following compounds are obtained analogously to example IV:

(1) 4-bromo-5- (4-ethyl-benzyl) -1-iodo-2-methyl-benzene

Mass spectrometry (ESI)⁺)：m/z＝432/434(Br)[M+NH₄]⁺。

(2) 4-bromo-5- (4-ethyl-benzyl) -1-iodo-2-methoxy-benzene

Mass spectrometry (ESI)⁺)：m/z＝448/450(Br)[M+NH₄]⁺。

Example V

1-bromo-4-cyano-3-methoxy-5- (4-ethyl-benzyl) -benzene

KOtBu (11.8g) was added to a flask equipped with a stir bar and charged with anhydrous NMP (40mL), and cooled to-10 ℃ under an argon atmosphere. A solution of (4-ethyl-phenyl) -acetic acid ethyl ester (10.1g) and 1-bromo-4-cyano-3, 5-difluoro-benzene (11.5g) in NMP (40mL) was added at a rate that maintained the reaction temperature below 10 ℃. After stirring at room temperature for 1 hour, methanol (50mL) and 1M aqueous sodium hydroxide (39mL) were added, and the resulting mixture was stirred at 100 ℃ overnight. Then, 4M aqueous hydrochloric acid (100mL) was added and mixedThe mixture was stirred at 100 ℃ for a further 1 hour. The methanol fraction was evaporated, water (200mL) was added to the residue, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed 2 times with water, 2 times with brine and dried (MgSO)₄). The solvent was evaporated and the residue was washed with methanol. The insoluble residue was separated by filtration and dried to give a white product.

Yield: 10.0g (58% of theory).

Mass spectrometry (ESI)⁺)：m/z＝330/332(Br)[M+H]⁺。

Example VI

4-bromo-3-chloromethyl-1-iodo-benzene

Thionyl chloride (13mL) was added to a suspension of 4-bromo-3-hydroxymethyl-1-iodo-benzene (47.0g) in dichloromethane (100mL) containing DMF (0.1 mL). The mixture was stirred at ambient temperature for 3 hours. The solvent and excess reagent were then removed under reduced pressure. The residue was triturated with methanol and dried.

Yield: 41.0g (82% of theory).

Example VII

4-bromo-1-iodo-3-phenoxymethyl-benzene

Phenol (13g) dissolved in 4M aqueous KOH (60mL) was added to 4-bromo-3-chloromethyl-1-iodo-benzene (41.0g) dissolved in acetone (50 mL). NaI (0.5g) was added, and the resulting mixture was stirred at 50 ℃ overnight. Then, water was added, and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried (Na)₂SO₄) And the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 19: 1).

Yield: 38.0g (79% of theory).

Example VIII

1-bromo-4- (1-methoxy-D-glucopyranos-1-yl) -2- (phenoxymethyl) -benzene

A THF solution (11mL) of 2M iPrMgCl was added to anhydrous LiCl (0.47g) suspended in THF (11 mL). The mixture was stirred at room temperature until all the LiCl was dissolved. This solution was added dropwise to a solution of 4-bromo-1-iodo-3-phenoxymethyl-benzene (8.0g) in tetrahydrofuran (40mL) cooled to-60 ℃ under argon. The resulting solution was warmed to-40 ℃ and then 2, 3, 4, 6-tetra-O- (trimethylsilyl) -D-glucopyranosone (glucopyranosone) (10.7g, 90% pure) in tetrahydrofuran (5mL) was added. The resulting solution was warmed to-5 ℃ in a cooling bath and stirred at this temperature for a further 30 minutes. Addition of NH₄Aqueous Cl solution, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was dissolved in methanol (80mL) and treated with methanesulfonic acid (0.6 mL). The reaction solution was stirred overnight at 35-40 ℃ and then treated with solid NaHCO₃The solution was neutralized and methanol was removed under reduced pressure. The residue is treated with NaHCO₃The aqueous solution was diluted and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent was evaporated to give the crude product, which was reduced without further purification.

Yield: 7.8g (93% of theory).

The following compounds are obtained analogously to example VIII:

(1) 1-bromo-2- (4-ethylbenzyl) -4- (1-methoxy-D-glucopyranos-1-yl) -benzene

Mass Spectrometry (ESI-): m/z 511/513(Br) [ M + HCOO ]]^-。

(2) 1-bromo-2- (4-ethylbenzyl) -4- (1-methoxy-D-glucopyranos-1-yl) -5-methyl-benzene

Alternatively, the reaction can be carried out with 2, 3, 4, 6-tetra-O-benzyl-D-glucopyranosone instead of 2, 3, 4, 6-tetra-O- (trimethylsilyl) -D-glucopyranosone, giving a similar tetra-O-benzyl protected addition product of this compound. Benzyl can be prepared by using BCl₃The solution of (A) in dichloromethane was reduced and the anomeric center (anomeric center) was removed.

(3) 1-bromo-2- (4-ethylbenzyl) -4- (1-methoxy-D-glucopyranos-1-yl) -5-methoxy-benzene

Example IX

6- (4-ethylbenzyl) -2-methoxy-4- (1-methoxy-D-glucopyranos-1-yl) -benzonitrile 1.7M solution of tBuLi in pentane (18.3mL) cooled to-78 deg.CTo a solution of 1-bromo-4-cyano-5- (4-ethyl-benzyl) -3-methoxy-benzene (5.0g) in hexane (40mL) and THF (20mL) cooled to-78 deg.C was added dropwise. It is also possible to use nBuLi or sBuLi instead of tBuLi. After addition was complete and stirring for a further 15 minutes, a solution of 2, 3, 4, 6-tetra-O- (trimethylsilyl) -D-glucopyranosone (90%, 7.9g) in hexane (30mL) cooled to-78 ℃ was added via a transfer needle. The resulting solution was stirred at-70 ℃ for 2 hours and then slowly warmed to-5 ℃. The reaction was quenched with 1% aqueous acetic acid (100mL) and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried (sodium sulfate). After removal of the solvent, the residue was dissolved in methanol (50mL) and treated with methanesulfonic acid (2.5mL) to give the desired more stable anomeric linkage. The solution was stirred at 50 ℃ overnight and then purified by addition of solid NaHCO₃And (4) neutralizing. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic solution was washed with water and brine and dried (sodium sulfate). After removal of the solvent, the crude product is purified by chromatography on silica gel (dichloromethane/methanol 1: 0- > 2: 1).

Yield: 0.5g (7% of theory).

Alternatively, the reaction can be carried out with 2, 3, 4, 6-tetra-O-benzyl-D-glucopyranosone instead of 2, 3, 4, 6-tetra-O- (trimethylsilyl) -D-glucopyranosone to yield a similar tetra-O-benzyl protected addition product of this compound. Benzyl can be prepared by using BCl₃The solution of dichloromethane is removed after reduction of the anomeric centre.

Example X

1-bromo-4- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranos-1-yl) -2- (phenoxymethyl) -benzene

Boron trichloride etherate (4.9mL) was added to a solution of 1-bromo-4- (1-methoxy-D-glucopyranos-1-yl) -2- (phenoxymethyl) -benzene (8.7g) and triethylsilane (9.1mL) in dichloromethane (35mL) and acetonitrile (50mL) cooled to-20 ℃ at a rate to maintain the temperature below-10 ℃. Over 1.5 hours, the resulting solution was warmed to 0 ℃ and then treated with aqueous sodium bicarbonate. The resulting mixture was stirred for 0.5 hour, the organic solvent was removed, and the residue was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and the solvent was removed. The residue was dissolved in dichloromethane (50mL) and pyridine (9.4mL), and acetic anhydride (9.3mL) and 4-dimethylaminopyridine (0.5g) were added to the solution in this order. The solution was stirred at ambient temperature for 1.5 hours and then diluted with dichloromethane. The solution was washed 2 times with 1M hydrochloric acid and dried over sodium sulfate. After removal of the solvent, the residue was recrystallized from ethanol to give the product as a colorless solid.

Yield: 6.78g (60% of theory).

Mass spectrometry (ESI)⁺)：m/z＝610/612(Br)[M+NH₄]⁺。

The following compounds are obtained analogously to example X:

(1) 1-bromo-2- (4-ethylbenzyl) -4- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranos-1-yl) -benzene

Mass spectrometry (ESI)⁺)：m/z＝622/624[M+NH₄]⁺。

(2) 1-bromo-2- (4-ethylbenzyl) -4- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranos-1-yl) -5-methoxy-benzene

Mass spectrometry (ESI)⁺)：m/z＝652/654(Br)[M+NH₄]⁺。

(3)6- (4-ethylbenzyl) -4- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranos-1-yl) -2-methoxy-benzonitrile

Mass spectrometry (ESI)⁺)：m/z＝599[M+NH₄]⁺。

In analogy to the procedure described above, 6- (4-ethylbenzyl) -4- (1-methoxy-D-glucopyranos-1-yl) -2-methoxy-benzonitrile was reduced.

(4) 1-bromo-2- (4-ethylbenzyl) -4- (beta-D-glucopyranos-1-yl) -5-methyl-benzene

Mass spectrometry (ESI)⁺)：m/z＝468/470(Br)[M+NH₄]⁺。

After completion of the reduction according to the procedure described above, the compound is isolated with free hydroxyl groups.

Example XI

2- (phenoxymethyl) -4- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranos-1-yl) -benzonitrile

The flask was charged with a stir bar, 1-bromo-4- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranos-1-yl) -2-(Phenoxymethyl) -benzene (5.4g), Zinc cyanide (1.0g), Zinc (30mg), Pd₂(dibenzylidene acetone)₃*CHCl₃(141mg) and tri-tert-butylphosphonium tetrafluoroborate (111mg), and the flask was purged with argon. Degassed NMP (12mL) containing 0.1% water was then added (alternatively, the glycoside dissolved in NMP was added) and the resulting mixture was stirred at room temperature for 18 hours. After dilution with ethyl acetate, the mixture was filtered, and the filtrate was washed with an aqueous sodium bicarbonate solution. The organic phase was dried (sodium sulfate) and the solvent was removed. The residue was recrystallized from ethanol.

Yield: 4.10g (84% of theory).

Mass spectrometry (ESI)⁺)：m/z＝557[M+NH₄]⁺。

Alternatively, the compound can also be obtained using the procedures described in examples XII and 3.

Example XII

2- (4-ethylbenzyl) -5-methoxy-4- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranos-1-yl) -benzonitrile

The flask was charged with a stir bar, 1-bromo-2- (4-ethylbenzyl) -5-methoxy-4- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranos-1-yl) -benzene (1.6g), copper (I) cyanide (0.56g), and NMP (10mL), and stirred at 215 ℃ for 3 hours. Subsequently, water was added, and the precipitate was separated by filtration. The precipitate was dissolved in ethyl acetate (50mL) and filtered through celite. Drying (Na)₂SO₄) The filtrate was filtered and concentrated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 2: 1- > 1: 2).

Yield: 1.1g (75% of theory).

Mass spectrometry (ESI)⁺)：m/z＝583[M+NH₄]⁺。

The compound can also be prepared using the procedures described for examples XI and 3.

Example XIII

2-bromomethyl-4- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranos-1-yl) -benzonitrile

A 33% solution of hydrobromic acid in acetic acid (15mL) was added to a solution of 2-phenoxymethyl-4- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranos-1-yl) -benzonitrile (0.71g) and acetic anhydride (0.12mL) in acetic acid (10 mL). The resulting solution was stirred at 55 ℃ for 6 hours and then cooled in an ice bath. The reaction mixture was neutralized with a cooled aqueous potassium carbonate solution, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate/cyclohexane (1: 5) and the precipitate was isolated by filtration and dried at 50 ℃ to give the product.

Yield: 0.52g (75% of theory).

Mass spectrometry (ESI)⁺)：m/z＝543/545(Br)[M+NH₄]⁺。

Example XIV

4-cyclopropyl-phenylboronic acid

A2.5M solution of n-butyllithium in hexane (14.5mL) was added dropwise to a solution of 1-bromo-4-cyclopropyl-benzene (5.92g) in THF (14mL) and toluene (50mL) cooled to-70 ℃. The resulting solution was stirred at-70 ℃ for 30 minutes, after which triisopropyl borate (8.5mL) was added. The solution was warmed to-20 ℃ and treated with 4M aqueous hydrochloric acid (15.5 mL). The reaction mixture was allowed to warm to room temperature again and the organic phase was subsequently separated. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried (sodium sulfate). The solvent was evaporated and the residue triturated with a mixture of diethyl ether and cyclohexane to give the product as a colourless solid.

Yield: 2.92g (60% of theory).

Mass spectrometry (ESI)^-)：m/z＝207(C1)[M+HCOO]^-。

Preparation of the final compound:

example (1): 6- (4-ethylbenzyl) -4- (beta-D-glucopyranos-1-yl) -2-methoxy-benzonitrile

Aqueous sodium hydroxide (1.4mL, 1mol/L) was added to 6- (4-ethylbenzyl) -4- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranos-1-yl) -2-methoxy-benzonitrile (0.16g) dissolved in methanol (1mL) and THF (1 mL). The solution was stirred at room temperature for 1 hour and then neutralized with hydrochloric acid (1 mol/L). After removing the organic solvent, the residue was diluted with aqueous sodium bicarbonate solution, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate) and the solvent was evaporated. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1: 0- > 8: 1).

Yield: 65mg (57% of theory).

Mass spectrometry (ESI)⁺)：m/z＝431[M+NH₄]⁺。

The following compounds were obtained analogously to example 1:

example (2): 2- (4-ethylbenzyl) -4- (beta-D-glucopyranos-1-yl) -5-methoxy-benzonitrile

Mass spectrometry (ESI)⁺)：m/z＝431[M+NH₄]⁺。

Example (3): 1-cyano-2- (4-ethylbenzyl) -4- (. beta. -D-glucopyranos-1-yl) -5-methyl-benzene

To which was added a stir bar, 1-bromo-2- (4-ethylbenzyl) -4- (. beta. -D-glucopyranos-1-yl) -5-methyl-benzene (0.40g), Ni (CN)₂A microwave oven equipped reactor (0.10g) and NMP (4mL) purged with argon was heated for 1 hour. Subsequently, water was added, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate) and the solvent was evaporated. The residue was purified by reverse phase HPLC (YMC C18, acetonitrile/water).

Yield: 0.30g (85% of theory).

Mass spectrometry (ESI)⁺)：m/z＝415[M+NH₄]⁺。

Example (4): 2- (4-ethylbenzyl) -4- (beta-D-glucopyranos-1-yl) -5-hydroxy-benzonitrile

A mixture of 2- (4-ethylbenzyl) -5-methoxy-4- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranos-1-yl) -benzonitrile (0.80g) and pyridinium hydrochloride (9.0g) was heated at 215 ℃ for 1 hour. After cooling to ambient temperature, water is added andthe resulting solution was extracted with ethyl acetate. Drying (MgSO)₄) The combined organic extracts were removed under reduced pressure. The residue was dissolved in methanol (10mL) and treated with 4M NaOH aqueous solution (2.2 mL). The solution was stirred at room temperature for 1 hour and then acidified with hydrochloric acid (4 mol/L). After removal of the organic solvent, the residue was extracted with ethyl acetate, the combined organic extracts were dried (sodium sulfate) and the solvent was evaporated. The residue was purified by reverse phase HPLC (YMC C18, acetonitrile/water).

Yield: 0.25g (46% of theory).

Mass spectrometry (ESI)^-)：m/z＝398[M-H]^-。

Example (5): 2- (4-ethyl-benzyl) -4- (beta-D-glucopyranos-1-yl) -benzonitrile

The flask was charged with a stir bar, zinc (10mg), zinc cyanide (0.12g), Pd₂(dba)₃*CHCl₃(42mg) and tert-butylphosphonium tetrafluoroborate (26mg) under an argon atmosphere. Subsequently, 1-bromo-2- (4-ethylbenzyl) -4- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranos-1-yl) -benzene (1.0g) dissolved in degassed NMP (2mL) containing 0.1% water was added and the mixture was stirred at room temperature for 18 hours. Subsequently, ethyl acetate was added, the resulting mixture was filtered, and NaHCO was used₃The filtrate was washed with an aqueous solution. After drying the organic solution (sodium sulfate), the solvent was removed under reduced pressure and the residue was dissolved in methanol (10 mL). 4M aqueous potassium hydroxide (2mL) was added and the solution was stirred at ambient temperature for 1 hour. The solution was neutralized with 1M hydrochloric acid and methanol was evaporated. The residue was extracted with ethyl acetate, the combined extracts were dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel (dichloromethane/methanol 1: 0- > 4: 1).

Yield: 0.51g (81% of theory).

Mass spectrometry (ESI)⁺)：m/z＝401[M+NH₄]⁺。

Example (6): 2- (4-cyclopropyl-benzyl) -4- (beta-D-glucopyranos-1-yl) -benzonitrile

An argon-filled flask was charged with a stir bar, 2-bromomethyl-4- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranos-1-yl) -benzonitrile (1.78g), 4-cyclopropyl-phenylboronic acid (1.00g), potassium carbonate (1.85g) and degassed 3: 1 mixture of acetone and water (22 mL). The mixture was stirred at room temperature for 5 minutes, after which it was cooled in an ice bath. Subsequently, palladium dichloride (30mg) was added and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was then diluted with brine and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was dissolved in methanol (20mL) and treated with 4M aqueous potassium hydroxide (3.8 mL). The resulting solution was stirred at ambient temperature for 1 hour and then neutralized with 1M hydrochloric acid. The methanol was evaporated and the residue was diluted with brine and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and the solvent was removed. The residue is chromatographed on silica gel (dichloromethane/methanol 1: 0- > 8: 1).

Yield: 0.91g (76% of theory).

Mass spectrometry (ESI)⁺)：m/z＝413[M+NH₄]⁺。

Example (7): 1-chloro-4- (beta-D-glucopyranos-1-yl) -2- (4-ethynyl-benzyl) -benzene

Compound (7) can be advantageously prepared according to example 12 described in WO 2005/092877.

Example (8): 1-chloro-4- (beta-D-glucopyranos-1-yl) -2- [4- ((R) -tetrahydrofuran-3-yloxy) -benzyl ] -benzene

Compound (8) can be advantageously prepared according to example 2 described in WO 2005/092877.

Example (9): 1-chloro-4- (beta-D-glucopyranos-1-yl) -2- [4- ((S) -tetrahydrofuran-3-yloxy) -benzyl ] -benzene

Compound (9) can be advantageously prepared according to example 3 described in WO 2005/092877.

Example (10): 1-methyl-2- [4- ((R) -tetrahydrofuran-3-yloxy) -benzyl ] -4- (beta-D-glucopyranos-1-yl) -benzene

Compound (10) can be advantageously prepared according to example 2 described in WO 2006/064033.

Example (11): 1-methyl-2- [4- ((S) -tetrahydrofuran-3-yloxy) -benzyl ] -4- (β -D-glucopyranos-1-yl) -benzene

Compound (10) can be advantageously prepared according to example 3 described in WO 2006/064033.

Pharmacological examples

The following examples show the beneficial effects of the combination of glucopyranosyl-substituted benzene derivatives of the invention with DPP IV inhibitors on glycemic control compared to the respective monotherapy. All experimental protocols involving the use of laboratory animals were reviewed by the federal Ethics Committee (Ethics Committee) and approved by governmental authorities.

The first embodiment:

according to a first example, overnight fasting 9 week old male Zucker Diabetic Fatty (ZDF) rats (ZDF/Crl-Lepr)^fa) Oral glucose tolerance tests were performed. Pre-dose blood samples were obtained by tail bleeding. Blood glucose was measured with a glucometer and animals were randomly grouped for blood glucose measurements (n ═ 5 per group). Subsequently, each group received a single oral administration of either vehicle alone (0.5% hydroxyethylcellulose in water containing 3mM HCl and 0.015% Polysorbat 80) or a vehicle containing a glucopyranosyl-substituted benzene derivative or a DPPIV inhibitor or a combination of a glucopyranosyl-substituted benzene derivative and a DPP IV inhibitor. 30 minutes after compound administration, animals received an oral glucose load (2 g/kg). Blood glucose in tail blood was measured 30, 60, 90, 120 and 180 minutes after the glucose challenge. Glucose excursions were quantified by calculating the reactive glucose AUC. Data are expressed as mean ± sem. Statistical comparison of control and active groups was performed by a two-sided unpaired Student's t-test.

The results are shown in figure 1 below. "Compound A" is the DPP IV inhibitor 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine and is administered at a dose of 1 mg/kg. Compound B is a glucopyranosyl-substituted benzene derivative (9), i.e., 1-chloro-4- (β -D-glucopyranos-1-yl) -2- [4- ((S) -tetrahydrofuran-3-yloxy) -benzyl ] -benzene, at a dose of 3 mg/kg. The combination a + B is a combination of the DPP IV inhibitor and the glucopyranosyl-substituted benzene derivative at the same dose. The P values relative to the control are indicated by the symbol above the bar. The P-value of the combination relative to monotherapy is shown below the graph (P < 0.05;. P < 0.01;. P < 0.001). DPPIV inhibitors reduced glucose excursions (glucose excersior) by 56%, and glucopyranosyl-substituted benzene derivatives reduced glucose excursions by 51%. This combination reduced glucose excursions by 84% in the oral glucose tolerance test, and this reduction in glucose AUC was statistically significant relative to each monotherapy.

Second embodiment:

according to a second example, an overnight fasting male Sprague Dawley rat (Crl: CD (SD)) weighing about 200g was subjected to an oral glucose tolerance test. Pre-dose blood samples were obtained by tail bleeds. Blood glucose was measured with a glucometer and animals were randomly grouped for blood glucose measurements (n ═ 5 per group). Subsequently, each group received a single oral administration of either vehicle alone (0.5% hydroxyethylcellulose in water containing 0.015% Polysorbat 80) or a vehicle containing a glucopyranosyl-substituted benzene derivative or a DPP IV inhibitor or a combination of a glucopyranosyl-substituted benzene derivative and a DPP IV inhibitor. 30 minutes after compound administration, animals received an oral glucose load (2 g/kg). Blood glucose in tail blood was measured 30, 60, 90 and 120 minutes after the glucose challenge. Glucose excursions were quantified by calculating the reactive glucose AUC. Data are expressed as mean ± s.e.m. Statistical comparisons were made by Student's t-test.

The results are shown in figure 2 below. "Compound A" is a glucopyranosyl-substituted benzene derivative (9), 1-chloro-4- (. beta. -D-glucopyranos-1-yl) -2- [4- ((S) -tetrahydrofuran-3-yloxy) -benzyl ] -benzene, administered at a dose of 3 mg/kg. The DPP IV inhibitor saxagliptin is administered at a dose of 0.3 mg/kg. In the combination, the glucopyranosyl-substituted benzene derivative and saxagliptin are administered together in the same dose as in the respective monotherapy. The P values relative to the control are indicated by the symbol above the column (.: P < 0.05). Glucopyranosyl-substituted benzene derivatives and saxagliptin reduced glucose excursions by 21% and 12%, respectively, although the reduction was not statistically significant in these non-diabetic animals. This combination reduced glucose excursions by 50% in the oral glucose tolerance test, and this reduction in glucose AUC was statistically significant.

The third embodiment:

in the third embodiment, the same experimental settings as in the second embodiment as described above were used. The glucopyranosyl-substituted benzene derivative (9), i.e., 1-chloro-4- (. beta. -D-glucopyranos-1-yl) -2- [4- ((S) -tetrahydrofuran-3-yloxy) -benzyl ] -benzene, was administered at a dose of 3 mg/kg. The DPP IV inhibitor sitagliptin is administered at a dose of 10 mg/kg. In combination, the glucopyranosyl-substituted benzene derivative and sitagliptin are administered together in the same dose as in the respective monotherapy.

The results are shown in FIG. 3 below, in which "Compound A" describes glucopyranosyl-substituted benzene derivatives (9). The P values relative to the control are indicated by the symbol above the column (.: P < 0.05). Glucopyranosyl-substituted benzene derivatives and sitagliptin reduced glucose excursions by 21% and 16%, respectively, although the reduction was not statistically significant in these non-diabetic animals. This combination reduced glucose excursions by 51% in the oral glucose tolerance test, and this reduction in glucose AUC was statistically significant.

Formulation examples

The following examples of formulations obtainable in analogy to the methods known in the art are intended to illustrate the invention more fully and are not to be construed as limiting the invention to the contents of these examples. The term "active substance" denotes one or more compounds of the invention, i.e. denotes a glucopyranosyl-substituted benzene derivative of the invention or a DPP IV inhibitor of the invention or a combination of said glucopyranosyl-substituted benzene derivative and DPP IV inhibitor, e.g. selected from the group listed in Table 1Combinations 1 through 176. Other suitable formulations for the DPP IV inhibitor of embodiment a may be those disclosed in application WO2007/128724, the disclosure of which is incorporated herein by reference in its entirety. Other suitable formulations for the DPP IV inhibitor of embodiment B may be those commercially available, or those described in the patent application in the "background of the invention" paragraph, or those described in the literature (e.g. in the contemporary journal "Rote)"(edition Cantor Verlag Aulendorf, Germany) or" Physician's Desk Reference ".

Example 1: anhydrous ampoules containing 75mg of active substance per 10ml

Consists of the following components:

75.0mg of active substance

Mannitol 50.0mg

Water for injection is added to 10.0ml

Preparation:

the active substance and mannitol were dissolved in water. After encapsulation, the solution was freeze dried. To prepare a ready-to-use solution, the product is dissolved in water for injection.

Example 2: anhydrous ampoules containing 35mg of active substance per 2ml

Consists of the following components:

35.0mg of active substance

Mannitol 100.0mg

The water for injection is added to 2.0ml

Preparation:

the active substance and mannitol were dissolved in water. After encapsulation, the solution was freeze dried. To prepare a ready-to-use solution, the product is dissolved in water for injection.

Example 3: tablet containing 50mg of active substance

Consists of the following components:

(1) active substance 50.0mg

(2) Lactose 98.0mg

(3) Corn starch 50.0mg

(4) Polyvinylpyrrolidone 15.0mg

(5) Magnesium stearate 2.0mg

215.0mg

Preparation:

mixing (1), (2) and (3) together and granulating with the aqueous solution of (4). Adding (5) to the dried particulate matter. This mixture was compressed into tablets having a biplanar face, polished on both faces and having a dividing notch on one face.

Tablet diameter: 9 mm.

Example 4: tablet containing 350mg of active substance

Preparation:

(1) active substance 350.0mg

(2) Lactose 136.0mg

(3) Corn starch 80.0mg

(4) Polyvinylpyrrolidone 30.0mg

(5) Magnesium stearate 4.0mg

600.0mg

Mixing (1), (2) and (3) together and granulating with the aqueous solution of (4). Adding (5) to the dried particulate matter. This mixture was compressed into tablets having a biplanar face, polished on both faces and having a dividing notch on one face.

Tablet diameter: 12 mm.

Example 5: capsule containing 50mg of active substance

Consists of the following components:

(1) active substance 50.0mg

(2) Dried corn starch 58.0mg

(3) Powdered lactose 50.0mg

(4) Magnesium stearate2.0mg

160.0mg

Preparation:

the (1) and the (3) are developed together. This trituration was added to the mixture of (2) and (4) with vigorous mixing. The powder mixture was filled into hard gelatin capsules No. 3 in a capsule filling machine.

Example 6: capsule containing 350mg of active substance

Consists of the following components:

(1) active substance 350.0mg

(2) Dried corn starch 46.0mg

(3) Powdered lactose 30.0mg

(4) Magnesium stearate4.0mg

430.0mg

Preparation:

the (1) and the (3) are developed together. This product was added to the mixture of (2) and (4) with vigorous mixing. The powder mixture was filled into size 0 hard gelatin capsules in a capsule filling machine.

Claims (24)

1. Pharmaceutical compositions comprising glucopyranosyl-substituted benzene derivatives of formula (I)

Wherein R is¹Represents C1, methyl or cyano: r²Represents H, methyl, methoxy or hydroxy, and R³Represents ethyl, cyclopropyl, ethynyl, ethoxy, (R) -tetrahydrofuran-3-yloxy or (S) -tetrahydrofuran(ii) a pyran-3-yloxy group,

and in a first embodiment (embodiment a), further comprising a DPP IV inhibitor selected from the following formulas:

formula (I)

Or formula (II)

Or formula (III)

Or formula (IV)

Wherein R1 represents ([1, 5] naphthyridin-2-yl) methyl, (quinazolin-2-yl) methyl, (quinoxalin-6-yl) methyl, (4-methyl-quinazolin-2-yl) methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl) methyl, (3-cyano-pyridin-2-yl) methyl, (4-methyl-pyrimidin-2-yl) methyl or (4, 6-dimethyl-pyrimidin-2-yl) methyl, and R2 represents 3- (R) -amino-piperidin-1-yl, (2-amino-2-methyl-propyl) -methylamino or (2- (S) -amino-propyl) -methylamino,

or a pharmaceutically acceptable salt thereof;

alternatively, in a second embodiment (embodiment B), further comprising a DPP IV inhibitor selected from: sitagliptin; vildagliptin; saxagliptin; alogliptin; obtaining nanoliptin;

(2S) -1- { [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethylamino ] -acetyl } -pyrrolidine-2-carbonitrile;

(2S) -1- { [1, 1-dimethyl-3- (4-pyridin-3-yl-imidazol-1-yl) -propylamino ] -acetyl } -pyrrolidine-2-carbonitrile;

(S) -1((2S, 3S, 11bS) -2-amino-9, 10-dimethoxy-1, 3, 4, 7, 11 b-hexahydro-2H-pyrido [2, 1-a ] isoquinolin-3-yl) -4-fluoromethyl-pyrrolidin-2-one;

(3, 3-difluoropyrrolidin-1-yl) - ((2S, 4S) -4- (4- (pyrimidin-2-yl) piperazin-1-yl) pyrrolidin-2-yl) methanone;

(1((3S, 4S) -4-amino-1- (4- (3, 3-difluoropyrrolidin-1-yl) -1, 3, 5-triazin-2-yl) pyrrolidin-3-yl) -5, 5-difluoropiperidin-2-one;

(2S, 4S) -1- {2- [ (3S, 1R) -3- (1H-1, 2, 4-triazol-1-ylmethyl) cyclopentylamino ] -acetyl } -4-fluoropyrrolidine-2-carbonitrile; and

(R) -2- [6- (3-amino-piperidin-1-yl) -3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidin-1-ylmethyl ] -4-fluoro-benzonitrile,

or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, wherein the glucopyranosyl-substituted benzene derivative is selected from the group consisting of compounds (1) to (11):

(1)6- (4-ethylbenzyl) -4- (β -D-glucopyranos-1-yl) -2-methoxy-benzonitrile;

(2)2- (4-ethylbenzyl) -4- (β -D-glucopyranos-1-yl) -5-methoxy-benzonitrile;

(3) 1-cyano-2- (4-ethylbenzyl) -4- (β -D-glucopyranos-1-yl) -5-methyl-benzene;

(4)2- (4-ethylbenzyl) -4- (β -D-glucopyranos-1-yl) -5-hydroxy-benzonitrile;

(5)2- (4-ethyl-benzyl) -4- (β -D-glucopyranos-1-yl) -benzonitrile;

(6)2- (4-cyclopropyl-benzyl) -4- (β -D-glucopyranos-1-yl) -benzonitrile;

(7) 1-chloro-4- (β -D-glucopyranos-1-yl) -2- (4-ethynyl-benzyl) -benzene;

(8) 1-chloro-4- (β -D-glucopyranos-1-yl) -2- [4- ((R) -tetrahydrofuran-3-yloxy) -benzyl ] -benzene;

(9) 1-chloro-4- (β -D-glucopyranos-1-yl) -2- [4- ((S) -tetrahydrofuran-3-yloxy ] -benzyl ] -benzene;

(10) 1-methyl-2- [4- ((R) -tetrahydrofuran-3-yloxy) -benzyl ] -4- (β -D-glucopyranos-1-yl) -benzene; and

(11) 1-methyl-2- [4- ((S) -tetrahydrofuran-3-yloxy) -benzyl ] -4- (β -D-glucopyranos-1-yl) -benzene.

3. The pharmaceutical composition according to claim 1 or 2, wherein the DPP IV inhibitor is selected from:

1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine;

1- [ ([1, 5] naphthyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine;

1- [ (quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine;

2- (((R) -3-amino-piperidin-1-yl) -3- (but-2-ynyl) -5- (4-methyl-quinazolin-2-ylmethyl) -3, 5-dihydro-imidazo [4, 5-d ] pyridazin-4-one;

1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (2-amino-2-methyl-propyl) -methylamino ] -xanthine;

1- [ (3-cyano-quinolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (((R) -3-amino-piperidin-1-yl) -xanthine;

1- (2-cyano-benzyl) -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine;

1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (S) - (2-amino-propyl) -methylamino ] -xanthine;

1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine;

1- [ (4-methyl-pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine;

1- [ (4, 6-dimethyl-pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine; and

1- [ (quinoxalin-6-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine;

or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition according to claim 1 or 2, wherein the DPP IV inhibitor is selected from sitagliptin, vildagliptin, saxagliptin and alogliptin, or a pharmaceutically acceptable salt thereof.

5. Pharmaceutical composition according to any of the preceding claims, characterized in that the composition is suitable for combined or simultaneous or sequential use of a glucopyranosyl-substituted benzene derivative and a DPP IV inhibitor.

6. Pharmaceutical composition according to any of the preceding claims, characterized in that the glucopyranosyl-substituted benzene derivative and the DPP IV inhibitor are present in a single dosage form.

7. Pharmaceutical composition according to any of the preceding claims, characterized in that the glucopyranosyl-substituted benzene derivative and the DPP IV inhibitor are each present in separate dosage forms.

8. A method for preventing, slowing down the progression, delaying or treating a metabolic disorder selected from the group consisting of type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity and metabolic syndrome in a patient in need thereof, characterized by combined or alternating administration of a glucopyranosyl-substituted benzene derivative of the formula (I) according to claim 1 or 2 with a DPP IV inhibitor according to claim 1, 3 or 4.

9. A method for improving glycemic control and/or lowering fasting plasma glucose, postprandial blood glucose and/or glycosylated hemoglobin HbA1c in a patient in need thereof, characterized in that a glucopyranosyl-substituted benzene derivative of the formula (I) according to claim 1 or 2 is administered in combination or alternation with a DPP IV inhibitor according to claim 1, 3 or 4.

10. A method for preventing, slowing, delaying or reversing the progression from impaired glucose tolerance, impaired fasting glucose, insulin resistance and/or from metabolic syndrome to type II diabetes in a patient in need thereof, characterized by administering a glucopyranosyl-substituted benzene derivative of the formula (I) according to claim 1 or 2 in combination or alternation with a DPP IV inhibitor according to claim 1, 3 or 4.

11. A method of preventing, slowing the progression of, delaying or treating a condition or disorder selected from the group consisting of: diabetic complications, such as cataracts and micro-and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischemia, arteriosclerosis, myocardial infarction, stroke and peripheral arterial occlusive disease, characterized in that a glucopyranosyl-substituted benzene derivative of the formula (I) according to claim 1 or 2 is administered in combination or alternation with a DPPIV inhibitor according to claim 1, 3 or 4.

12. A method for reducing body weight or preventing body weight gain or promoting body weight loss in a patient in need thereof, characterized in that a glucopyranosyl-substituted benzene derivative of the formula (I) according to claim 1 or 2 is administered in combination or alternation with a DPP IV inhibitor according to claim 1, 3 or 4.

13. A method for preventing, slowing, delaying or treating degeneration of pancreatic beta cells and/or decline of pancreatic beta cell function and/or improving and/or restoring pancreatic beta cell function and/or restoring pancreatic insulin secretion function in a patient in need thereof, characterized in that a glucopyranosyl-substituted benzene derivative of the formula (I) according to claim 1 or 2 is administered in combination or alternation with a DPP IV inhibitor according to claim 1, 3 or 4.

14. A method for preventing, slowing, delaying or treating a disease or condition caused by abnormal accumulation of liver fat in a patient in need thereof, characterized by administering a glucopyranosyl-substituted benzene derivative of formula (I) according to claim 1 in combination or alternation with a DPP IV inhibitor according to claim 1, 3 or 4.

15. A method for maintaining and/or improving insulin sensitivity and/or treating or preventing hyperinsulinemia and/or insulin resistance in a patient in need thereof, characterized in that a glucopyranosyl-substituted benzene derivative of the formula (I) according to claim 1 or 2 is administered in combination or alternation with a DPPIV inhibitor according to claim 1, 3 or 4.

16. Use of a glucopyranosyl-substituted benzene derivative of formula (I) according to claim 1 or 2 for the preparation of a medicament for use in a method according to any of claims 8, 9, 10, 11, 12, 13, 14 or 15.

17. Use of a DPP IV inhibitor according to claim 1 or 3 for the manufacture of a medicament for use in a method according to any one of claims 8, 9, 10, 11, 12, 13, 14 or 15.

18. Use of a pharmaceutical composition according to any one of claims 1 to 7 in the manufacture of a medicament for use in:

-preventing, slowing the progression, delaying or treating a metabolic disorder selected from type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity and metabolic syndrome; or

-improving glycemic control and/or lowering fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbA1 c; or

-preventing, slowing, delaying or reversing the progression from impaired glucose tolerance, insulin resistance and/or from metabolic syndrome to type II diabetes; or

-preventing, slowing the progression, delaying or treating a condition or disorder selected from: diabetic complications such as cataract and microvascular and macrovascular diseases such as nephropathy, retinopathy, neuropathy, tissue ischemia, arteriosclerosis, myocardial infarction, stroke and peripheral arterial occlusive disease; or

-reducing body weight or preventing body weight gain or promoting body weight loss; or

-preventing, slowing, delaying or treating degeneration of pancreatic beta cells and/or decline of pancreatic beta cell function and/or improving and/or restoring pancreatic beta cell function and/or restoring pancreatic insulin secretion function; or

-preventing, slowing, delaying or treating a disease or condition caused by abnormal accumulation of liver fat;

-maintaining and/or improving insulin sensitivity and/or treating or preventing hyperinsulinemia and/or insulin resistance.

19. The method of any one of claims 8 to 15 or the use of any one of claims 16, 17 or 18, wherein the patient is an individual diagnosed with one or more selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity.

20. The method of any one of claims 8 to 15 or the use of any one of claims 16, 17 or 18, wherein the patient is an individual who exhibits one, two or more of the following symptoms:

(a) fasting or serum glucose concentrations greater than 110mg/dL, particularly greater than 125 mg/dL;

(b) postprandial blood glucose equal to or greater than 140 mg/dL;

(c) HbA1c values are equal to or greater than 6.5%, in particular equal to or greater than 8.0%.

21. The method of any one of claims 8 to 15 or the use of any one of claims 16, 17 or 18, wherein the patient is an individual presenting with one, two, three or more of the following symptoms:

(a) obesity, visceral obesity and/or abdominal obesity;

(b) the blood content of triglyceride is more than or equal to 150 mg/dL;

(c) HDL-cholesterol blood levels are < 40mg/dL in female patients and < 50mg/dL in male patients;

(d) systolic blood pressure is more than or equal to 130mmHg and diastolic blood pressure is more than or equal to 85 mmHg;

(e) the fasting blood sugar content is more than or equal to 110 mg/dL.

22. The method of any one of claims 8 to 15 or the use of any one of claims 16, 17 or 18, wherein the patient is an individual contraindicated to metformin monotherapy and/or intolerant to therapeutic doses of metformin.

23. The method according to any one of claims 8 to 15 or the use according to any one of claims 16, 17 or 18, wherein the patient is an individual who has failed to adequately control blood glucose despite monotherapy with an SGLT2 inhibitor, in particular a glucopyranosyl-substituted benzene derivative of formula (I) according to claim 1 or 2.

24. The method according to any one of claims 8 to 15 or the use according to any one of claims 16, 17 or 18, wherein the patient is an individual who has failed to adequately control blood glucose despite monotherapy with a DPP IV inhibitor, in particular a DPP IV inhibitor according to claim 1, 3 or 4.