ES2360763T3 - PIRIDINE DERIVATIVES FOR THE TREATMENT OF METABOLIC DISORDERS RELATED TO RESISTANCE TO INSULIN OR HYPERGLUCEMIA. - Google Patents

Abstract

A compound of general formula (I): wherein Ar is a phenyl group substituted with heterocyclyl or heteroaryl; wherein the heterocyclyl or heteroaryl group may be unsubstituted or substituted; B is -O-, -S-, or -NH-; R1 is hydrogen; R2 is S (O) 2R4 or C (O) (CH2) n-C (O) OR5; R3 is halogen, cyano, (CO) OR6, or C (O) NR7R8; R4 is unsubstituted or substituted aryl; R5 is hydrogen, (C1-C6) alkyl, or unsubstituted or substituted aryl; R6 is hydrogen or (C1-C4) alkyl; R7 and R8 are independently hydrogen or (C1-C6) alkyl; n is an integer of 1-3; and a pharmaceutically acceptable stereoisomer, solvate or salt thereof.

Description

FIELD OF THE INVENTION

The present invention relates to compounds that are useful in the treatment of metabolic disorders related to insulin resistance or hyperglycemia.

BACKGROUND OF THE INVENTION

Excessive weight, and in extreme cases obesity, is a widespread medical problem. This may be due in part to sedentary lifestyles and a poor diet (high in fat and carbohydrates), as well as a genetic predisposition in many cases. Obesity is a well known risk factor for hypertension, Type 2 diabetes and cardiovascular disease.

Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated plasma glucose levels or fasting hyperglycemia or after glucose administration during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often, abnormal glucose homeostasis is associated both directly and indirectly with alterations in lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic diseases. Therefore patients with Type 2 diabetes mellitus have an especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, the therapeutic control of glucose homeostasis, lipid metabolism and hypertension are extremely important in the clinical management and treatment of diabetes mellitus. There are two generally recognized forms of diabetes. In Type 1 diabetes, insulin dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone that regulates glucose utilization. In Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), patients often have plasma insulin levels that are the same or even elevated compared to non-diabetic subjects; however, these patients have developed a resistance to the stimulating effect of insulin on glucose and lipid metabolism in major insulin-sensitive tissues, which are muscles, liver and adipose tissues, and plasma insulin levels, Although high, they are insufficient to overcome pronounced insulin resistance. Both obesity and Type 2 diabetes are characterized by insulin resistance of peripheral tissue.

The prevalence of insulin resistance in glucose intolerant subjects has been recognized. Reaven et al. (American Journal of Medicine, 60, 80, 1976) used a continuous infusion of glucose and insulin (insulin / glucose clamp technique) and oral glucose tolerance tests to demonstrate that insulin resistance existed in a diverse group of non-obese, non-cesotic subjects. These subjects varied from the glucose tolerance limit to an obvious fasting hyperglycemia. Diabetic groups in these studies included both insulin-dependent (Type 1) and non-insulin-dependent (Type 2) subjects.

Coinciding with sustained insulin resistance is the most easily determined hyperinsulinemia, which can be measured by accurate determination of the concentration of insulin circulating in plasma in the subjects' plasma. Hyperinsulinemia may be present as a result of insulin resistance, as in the case of obese subjects and / or with diabetes (Type 2) and / or glucose intolerant subjects, or in Type 1 subjects, as a result of an overdose of injected insulin compared to the physiological administration of the hormone by the endocrine pancreas.

Independent risk factors such as obesity and hypertension for atherosclerotic diseases are also associated with insulin resistance. Using a combination of insulin / glucose clamps, tracer glucose infusions and indirect calorimetry, it has been shown that insulin resistance of essential hypertension is located in the peripheral tissues (mainly muscle) and correlates directly with the severity of the hypertension (Diabetes Care, 14, 173, 1991). In hypertension of the obese, insulin resistance generates hyperinsulinemia, which is incorporated as a mechanism to limit more weight gain by thermogenesis, but insulin also increases the reabsorption of renal sodium and stimulates the sympathetic nervous system in kidneys, heart , and vasculature, creating hypertension.

It is now appreciated that insulin resistance is usually the result of a defect in the insulin receptor signaling system, at a site of insulin binding to the receptor. The accumulated scientific evidence demonstrating insulin resistance in the main tissues that respond to insulin (muscle, liver, adipose) strongly suggests that in a first stage of this cascade lies a defect in the transduction of the insulin signal, specifically in insulin receptor kinase activity, which seems to be diminished (Diabetologia, 34 (12), 848-861, 1991).

In the recent past a new class of drugs have been developed, which act by reducing peripheral insulin resistance. These drugs are ligands for nuclear receptors, peroxisome proliferation activated gamma receptor isoform (PPAR gamma), expressed primarily in adipose tissue. These drugs act as insulin sensitizers reducing blood sugar and hyperinsulinemia. The most common side effects of these PPAR range activators are weight gain, edema, increased risk of stroke and heart attack.

Obesity is a disorder characterized by the accumulation of excess fat in the body. The increased incidence of obesity leads to complications such as hypertension, Type 2 diabetes, atherosclerosis, dyslipidemia, osteoarthritis and certain forms of cancer.

Obesity is commonly identified by an increase in body weight and body mass index (BMI). People with excess body weight are characterized by insulin resistance of peripheral tissue. The term "insulin resistance" refers to a decreased biological response to insulin. In obese individuals, insulin resistance is often compensated by an increased secretion of insulin from the pancreas. Obese subjects show hyperinsulinemia, as an indirect test of peripheral insulin resistance. However, the body can increase insulin secretion only to a certain level. Therefore, if insulin resistance continues to worsen in an obese person, eventually the body will no longer be able to compensate for insulin secretion by stimulation. At this time, plasma insulin levels tend to fall which in turn leads to an increase in glucose levels thus causing Type 2 diabetes. Naturally, this gradual decrease in secretion and insulin caused by resistance to Insulin, initiated by an excess of fat accumulation, is undesirable for an individual.

Therefore, drugs that prevent excess fat accumulation and obesity are desirable. Therefore the methods and procedure to identify compounds that stop the development of insulin resistance are useful in the treatment of obese individuals. These individuals by virtue of having pharmacological control in insulin resistance will benefit from the aforementioned treatments by having fewer incidences of heart disease such as high blood pressure, abnormal lipid profiles and atherosclerosis.

US 6583157 discloses chyloniol and benzothiaolyl compounds as PPAR modulators. US 6403607 discloses sulfonamide derivatives that show effects in the treatment of peptic ulcer and a drug comprising the derivative as an active ingredient.

US 6262112 and US 6573278 reveal aryl sulfonamides and the like and their use in the treatment of neurodegenerative diseases.

There is a need for improved and alternative medications for the treatment of metabolic disorders related to insulin resistance or hyperglycemia.

SUMMARY OF THE INVENTION

The present invention provides compounds represented by the general formula (I):

image 1

where: Ar is a phenyl group substituted with heterocyclyl or heteroaryl; B is –O-, -S-, or –NH-; R1 is hydrogen;

R2 is S (O) 2R4 or C (O) (CH2) n-C (O) OR5;

R3 is halogen, cyano, (CO) OR6, or C (O) NR7R8; R4 is aryl;  R5 is hydrogen, (C1-C6) alkyl, or aryl; R6 is hydrogen or (C1-C4) alkyl; R7 and R8 are independently hydrogen or (C1-C6) alkyl; n is an integer of 1-3; Y

its pharmaceutically acceptable stereoisomers, salts and solvates. The present invention also relates to a process for the preparation of compounds of general formula (I), their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them. The present invention relates to compounds of general formula (I) that are useful in the treatment of metabolic disorders related to insulin resistance or hyperglycemia, methods employing said compounds, and the use of such compounds. According to another aspect of the present invention, methods for the manufacture of medicaments are provided including compounds of general formula (I), which are useful for the treatment of metabolic disorders related to insulin resistance or hyperglycemia.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Effect of compounds on food intake in skinny mice.

The effect of the standard (Sibutramine), Compound 1 and Compound 11 on food intake in C57B16 / J thin mice at 2, 4, 6 and 24 hours after food introductions. Figure 2: Effect of Compound 1 on cumulative food intake of obese mice

Diet induced

Mice with diet-induced obesity (DIO) were treated with the standard (Sibutramine) or Compound 1 for 10 days. Figure 3: Effect of Compound 1 on body weight of mice with diet-induced obesity. The cumulative body weight increase of mice with diet-induced obesity (DIO) is indicated

treated with the standard (Sibutramine) or Compound 1 for 10 days.

DETAILED DESCRIPTION OF THE INVENTION Definitions:

Definitions are listed below, which apply to the terms as they are used throughout the specification and the claims added (unless otherwise limited in specific examples), either individually or as part of a larger group.

The term "alkyl" means, unless otherwise indicated, a straight or branched chain hydrocarbon radical, which may be completely saturated, mono- or polysaturated, having one to eight carbon atoms. Examples of saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, and the like. An unsaturated alkyl group is one that has one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 1,4-pentadienyl, ethynyl, 1- and 3-propynyl, 3-butynyl, and the like.

Unless otherwise indicated, alkyl groups may be unsubstituted or substituted by one or more identical or different substituents. Any type of substituent present in the substituted alkyl residues may be present in any desired position as long as the substitution does not lead to an unstable molecule. A substituted alkyl refers to an alkyl residue in which one or more, for example, 1, 2, 3, 4 or 5 hydrogen atoms are replaced with substituents, for example alkyl, halogen, hydroxyl, acyl, carboxyl, alkoxy, ester, amino, amido, acetamido, fluoralkyl, aralkyl, acyloxy, heteroaryl, heterocyclyl, and the like.

As used herein, the term "alkoxy" or "alkoxy" refers to an alkyl group having an oxygen radical attached thereto, where the alkyl is as defined above. The terms include, therefore, alkoxy or alkoxy groups that are substituted by one or more identical or different groups. Representative alkoxy groups include methoxy, trifluoromethoxy, ethoxy, propoxy, tert-butoxy group.

As used herein, the term "acyl" refers to any organic group or radical such as alkyl (which may also be substituted with an alkyl, alkoxy, cycloalkylamino, hydroxy or halo) attached to the carbonyl group, where the alkyl is as defined above.

The term "heteroatom" refers to nitrogen, oxygen and sulfur. It should be noted that any heteroatom with unsatisfied valences is assumed to have a hydrogen atom to satisfy the valences.

As used herein, the term "aryl" refers to a monocyclic or bicyclic aromatic ring having up to 10 carbon ring atoms. Examples of aryl include phenyl, naphthyl, biphenyl and the like. Unless otherwise indicated, aryl residues, for example phenyl or amphiphile, may be unsubstituted or optionally substituted by one or more substituents, for example, up to five identical or similar substituents selected from the group consisting of halogen, alkyl, fluoralkyl, hydroxy, alkoxy, trifluoromethoxy, cyano, amide, acyl, carboxyl, sulfonyl, aryl, heteroaryl and a heterocyclyl group.

The aryl residues can be linked by any desired position, and in substituted aryl residues, the substituents can be located at any desired position. For example, in monosubstituted phenyl residues the substituent can be located at position 2, position 3, position 4 or position

5. If the phenyl group has two substituents, they may be located at position 2.3, position 2.4, position 2.5, position 2.6, position 3.4 or position 3.5.

The term "heteroaryl" means, unless otherwise indicated, aryl groups containing one to four heteroatoms selected from N, O and S. Ring heteroatoms may be present at any desired number and at any position relative to each one provided the resulting heteroaryl system is stable.

Non-limiting examples of heteroaryl groups include, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzimidazolyl, benzooxazolyl, quinolyl, isoquinolyl, quinoxalinyl.

The terms "heterocyclyl", "heterocyclic" and "heterocycle" refer to saturated or partially unsaturated monocyclic or bicyclic ring systems containing 3, 4, 5, 6, 7, 8, 9, 10 or 11, 12, 13 or 14 ring atoms of which 1, 2, 3 or 4 are identical or different heteroatoms selected from: nitrogen, oxygen and sulfur. The heterocyclyl group may, for example, have 1 or 2 oxygen atoms and / or 1 or 2 sulfide atoms and / or 1 to 4 nitrogen atoms in the ring. Monocyclic heterocyclyl groups include 3-link rings, 4 links, 5 links, 6 links and 7 links. Suitable examples of the aforementioned heterocyclyl groups are piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, azepanyl, and the like.

Bicyclic heterocyclyl groups may include two fused rings, one of which is a 5, 6 or 7 link heterocyclic ring and the other is a 5 or 6 link heterocyclic or carbocyclic ring. Exemplary bicyclic heterocyclic groups include tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroindolyl and the like.

Unless otherwise indicated, the heteroaryl and heterocyclyl groups may be substituted or unsubstituted with one or more (eg, up to 5) identical or different substituents. Examples of substituents for the carbon ring and nitrogen ring atoms are: alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl, fluoroalkyl, aryloxy, amino, cyano, amide, carboxyl, acyl, aryl, heterocyclyl and the like. Substituents may be present in one or more positions whenever a stable molecule results.

The term "arylalkyl" is understood to include those radicals in which an aryl or heteroaryl group is attached to an alkyl group (eg, benzyl, phenethyl, and the like).

The term "halogen" means, unless otherwise indicated, an atom of fluorine, chlorine, bromine

or iodine.

The term "amino" refers to the group -NH2 which may be optionally substituted with alkyl, acyl, cycloalkyl, aryl, or heterocyclyl where the terms alkyl, acyl, aryl, or heterocyclyl are as defined hereinbefore.

It will be understood that "substitution" or "substituted with" includes the implicit condition that such substitution is in accordance with the permitted valence of the substituted atom and the substituent, as well as occurs in a stable compound, which does not readily undergo a transformation as by reorganization, cycling, elimination, etc.

The term "pharmaceutically acceptable salts" is understood to include salts of the active compounds that are prepared with relatively non-toxic acids or bases, depending on the particular substituents found in the compounds described herein. When the compounds of the present invention contain relatively acidic functionalities, the basic addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable basic addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When the compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of said compounds with a sufficient amount of the desired acid, either pure or in suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogenocarbonic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, sulfuric, monohydrogeonsulfuric, hydroiodic, or phosphorous salts and the like, as well as acid derived salts. relatively non-toxic organic substances such as acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, medelic, phthalic, benzenesulfonic, p-tolisulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids such as glucoronic or galacturonic acid and the like. Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into both acidic and basic addition salts.

The neutral form of the compounds can be regenerated by contacting the son with a base or acid and isolating the main compound in the conventional manner. The main form of the compound may differ from the various salt forms in certain physical properties, such as the solubility in polar solvents.

Certain compounds of the present invention may exist in non-solvated forms as well as in solvated forms, including hydrated forms. In general, solvated and non-solvated forms are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in various crystalline or amorphous forms. In general, all physical forms are within the scope of the present invention.

Compounds are also revealed, which are in the form of prodrugs. The prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted into the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted into the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

Those skilled in the art will recognize that there are stereogenic in the compounds of formula (I). Therefore, the present invention includes all possible stereoisomers and geometric isomers of formula (I) and includes not only racemic compounds but also optically active isomers. When a compound of formula (I) is desired as a single enantiomer, it can be obtained either by resolution of the final product or by stereospecific synthesis of any isomerically pure starting material or any convenient intermediate material. The resolution of the final product, a starting or intermediate material can be carried out by conventional techniques. Additionally, in situations where the tautomers of the compounds of formula (I) are possible, it is intended that the present invention include all the tatomeric forms of the compounds.

Realizations:

Embodiments of the Invention

The present invention provides compounds represented by the general formula (I):

image 1

wherein: Ar is a phenyl group substituted with heterocyclyl or heteroaryl; B is –O-, or –NH-; R1 is hydrogen; R2 is S (O) 2R4 or C (O) (CH2) n-C (O) OR5; R3 is halogen, cyano, (CO) OR6, or C (O) NR7R8; R4 is aryl; R5 is hydrogen, (C1-C6) alkyl, or aryl; R6 is hydrogen or (C1-C4) alkyl; R7 and R8 are independently hydrogen or (C1-C6) alkyl; n is an integer of 1-3; Y

its pharmaceutically acceptable stereoisomers, salts and solvates.

In one embodiment, the present invention provides compounds of formula (I), wherein: Ar is a phenyl group substituted with heterocyclyl; B is –O-, or NH-; R1 is hydrogen; R2 is S (O) 2R4 or C (O) (CH2) n-C (O) OR5; R3 is halogen, cyano, (CO) OR6, or C (O) NR7R8; R4 is aryl; R5 is hydrogen, (C1-C6) alkyl, or aryl; R6 is hydrogen or (C1-C4) alkyl; R7 and R8 are independently hydrogen or (C1-C6) alkyl; n is an integer of 1-3; Y

its pharmaceutically acceptable stereoisomers, salts and solvates.

One embodiment, the present invention provides compounds of formula (I), wherein, Ar is a phenyl group substituted with heterocyclyl; B is oxygen; R1 is hydrogen;

R2 is S (O) 2R4;

R3 is halogen; R4 is aryl; Y its pharmaceutically acceptable stereoisomers, salts and solvates.

In one embodiment, the present invention provides compounds of formula (I), wherein, Ar is a phenyl group substituted with heterocyclyl; as piperazinyl phenyl substituted with the phenyl part coupled to B; B is oxygen; R1 is hydrogen;

R2 is S (O) 2R4; R3 is halogen, preferably chlorine; R4 is substituted or unsubstituted phenyl; such as phenyl substituted with alkoxy, halogen, cyano, substituted alkyl, or

unsubstituted alkyl; how:

methyl or substituted methyl substituted phenyl (for example, 4-methylphenyl, 2-chloro-4-trifluoromethylphenyl, or 3-chloro-4methylphenyl); mono or substituted di-methoxy phenyl (for example, 3,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 4-methoxyphenyl, or 4

trifluoromethoxyphenyl); halogen substituted phenyl, such as substituted phenyl fluorine (for example, 4-fluorophenyl, or 2,4-difluorophenyl), chlorine

substituted phenyl (for example, 2,4-dichlorophenyl, 2-chloro-4-trifluoromethylphenyl, 3-chloro-4-methylphenyl), or chlorine and substituted phenyl fluorine (for example, 2fluor-4-chlorophenyl); or 4-cyanophenyl; Y

its pharmaceutically acceptable stereoisomers, salts and solvates.

In one embodiment, the present invention provides a compound of formula (I), wherein, Ar is 4- (piperazinyl-1-yl) phenyl with the phenyl part coupled to B; B is oxygen; R1 is hydrogen;

R2 is S (O) 2R4;

R3 is chlorine; R4 is substituted or unsubstituted phenyl, such as alkoxy, halogen, cyano, substituted alkyl, or alkyl substituted phenyl

not substituted; as: methyl substituted phenyl (for example, 4-methylphenyl,); mono or di-net-substituted phenyl (for example, 3,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 4-methoxyphenyl, or 4

trifluoromethoxyphenyl); halogen substituted phenyl, such as substituted phenyl fluorine (for example, 4-fluorophenyl or 2,4-difluorophenyl), substituted phenyl chlorine (for example, 2,4-dichlorophenyl, 3,4-dichlorophenyl, or 2-chloro-4-trifluoromethylphenyl ); and its pharmaceutically acceptable stereoisomers, salts and solvates.

In one embodiment, the present invention provides compounds of formula (I), wherein, AR is 3- (4-methyl-piperazinyl-1-yl) phenyl with the phenyl part coupled to B; B is oxygen R1 is hydrogen;

R2 is S (O) 2R4;

R3 is halogen; R4 is 4-methoxyphenyl or 2,4-difluorophenyl; Y its pharmaceutically acceptable stereoisomers, salts and solvates.

In one embodiment, the present invention provides compounds of formula (I), wherein: Ar is a phenyl group substituted with heteroaryl; B is -O-, -S-, or NH-; R1 is hydrogen; R2 is S (O) 2R4, or C (O) (CH2) n-C (O) OR5;

R3 is halogen; cyano, (CO) OR6, or C (O) NR7R8 R4 is aryl; R5 is hydrogen, (C1-C6) alkyl, or aryl; R6 is hydrogen or (C1-C4) alkyl; R7 and R8 are independently hydrogen or (C1-C6) alkyl; N is an integer of 1-3; Y

its pharmaceutically acceptable stereoisomers, salts and solvates.

In one embodiment, the present invention provides compounds of formula (I), wherein; Ar is a phenyl group substituted with heteroaryl; B is oxygen; R1 is hydrogen;

R2 is S (O) 2R4; R3 is halogen, preferably chlorine; R4 is aryl; Y

Its pharmaceutically acceptable stereoisomers, salts and solvates.

In one embodiment, the present invention provides compounds of formula (I), in done: Ar is 6- (2benzo [d] thiazol-2yl) phenyl with the phenyl part coupled to B; B is oxygen; R1 is hydrogen;

R2 is S (O) 2R4; R3 is halogen, preferably chlorine; R4 is substituted or unsubstituted phenyl; as phenyl substituted with alkoxy, halogen, cyano, substituted alkyl or

unsubstituted alkyl; as: Methyl or substituted methyl substituted phenyl (eg, 4-methylphenyl); Mono or substituted di-methoxy phenyl (for example, 3,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 4-methoxyphenyl, or 4

trifluoromethoxyphenyl); Halogen substituted phenyl, such as substituted phenyl fluorine (for example, 4-flurophenyl or 2,4-difluorophenyl) or substituted chloro phenyl (for example, 2,4-dichlorophenyl, 3,4-dichlorophenyl, or 2-chloro-4- trifluoromethylphenyl) and its pharmaceutically acceptable stereoisomers, salts and solvates. In one embodiment, the present invention provides compounds of formula (I), in done:

Ar is 6- (2benzo [d] thiazol-2yl) phenyl with the phenyl part coupled to B; B is oxygen; R1 is hydrogen;

R2 is S (O) 2R4;

R3 is chlorine; R4 is substituted or unsubstituted phenyl; as phenyl substituted with alkoxy, halogen, cyano, substituted alkyl or

unsubstituted alkyl; as: substituted monomethoxy phenyl (for example, 4 methoxyphenyl); or substituted chloro phenyl (for example), 2,4-dichlorophenyl, 3,4-dichlorophenyl, or 2-chloro-4-trifluoromethylphenyl); Y

its pharmaceutically acceptable stereoisomers, salts and solvates.

In one embodiment, the present invention provides compounds of formula (I), wherein, Ar is a phenyl group substituted with heterocyclyl; B is oxygen; R1 is hydrogen;

R2 is C (O) (CH2) n-C (O) OR5; R3 represents halogen, cyano, (CO) OR6, or C (O) NR7R8; R5 is hydrogen, (C1-C6) alkyl, or aryl; R6 is hydrogen or (C1-C4) alkyl; R7 and R8 are independently hydrogen or (C1-C6) alkyl; N is an integer of 1-3; Y its pharmaceutically acceptable stereoisomers, salts and solvates.

In one embodiment, the present invention provides a compound of formula (I), wherein, AR is 4- (4-acetyl-piperazinyl-1-yl) phenyl with the phenyl part coupled to B; B is oxygen; R1 is hydrogen; R2 is C (O) (CH2) 2-C (O) OR5;

R3 is chlorine; R5 is hydrogen; Y a pharmaceutically acceptable sterosiomer, salt and solvate.

Compounds of the present invention are selected but not limited to; N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -2,4-dichlorobenzenesulfonamide, N- (6- (4- (4-Acetylpiperazinyl-1- yl) phenoxy) -5-chloropyridin-3-yl) -4-methoxybenzenesulfonamide, N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -3.4 -dimethoxy-benzene sulfonamide, N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -2,5-dimethoxy-benzene sulfonamide, N- (6- ( 4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -2-chloro-4- (trifluoromethyl) benzenesulfonamide, N- (6- (4- (4-Acetylpiperazinyl-1-yl) ) phenoxy) -5-chloropyridin-3-yl) -3,4-dichlorobenzenesulfonamide, N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -4- (trifluoromethoxy) benzene sulfonamide, N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -4-methylbenzenesulfonamide,

N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -2,4-difluorobenzenesulfonamide,

N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -4-fluorobenzenesulfonamide,

2,4-Dichloro-N- (5-chloro-6- (4- (piperazin-1-yl) phenoxy) pyridin-3-yl) benzenesulfonamide,

N- (5-Chloro-6- (3- (4-methylopiperazin-1-yl) phenoxy) pyridin-3-yl) -2,4-difluorobenzene sulfonamide,

N- (5-Chloro-6- (3- (4-methylopiperazin-1-yl) phenoxy) pyridin-3-yl) -4-methoxybenzenesulfonamide,

4- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yloamino) -4-oxobutanoic acid,

N- (6- (2- (Benzo [d] thiazol-2-yl) phenoxy) -5-chloropyridin-3-yl) -2,4-dichlorobenzenesulfonamide,

N- (6- (2- (Benzo [d] thiazol-2-yl) phenoxy) -5-chloropyridin-3-yl) -4-methoxybenzenesulfonamide,

N- (6- (2- (Benzo [d] thiazol-2-yl) phenoxy) -5-chloropyridin-3-yl) -3,4-dichlorobenzenesulfonamide,

N- (6- (2- (Benzo [d] thiazol-2-yl) phenoxy) -5-chloropyridin-3-yl) -2-chloro-4- (trifluoromethyl) benzenesulfonamide; Y

its pharmaceutically acceptable salts and solvates.

Suitable compounds of the present invention are selected but not limited to:

N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -2,4-dichlorobenzenesulfonamide,

2,4-Dichloro-N- (5-chloro-6- (4- (piperazin-1-yl) phenoxy) pyridin-3-yl) benzenesulfonamide,

4- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yloamino) -4-oxobutanoic acid; Y

its pharmaceutically acceptable salts and solvates.

As used herein, the term "treatment" and "therapy" and the like refer to alleviating, slowing the progression, prophylaxis, attenuation or cure of existing disease (eg, type 2 diabetes, obesity or dyslipidemia).

The term "therapeutically effective amount" as used herein is understood to describe an amount of a compound of the present invention effective in producing the desired therapeutic response in a particular patient suffering from metabolic disorders related to resistance to insulin or hyperglycemia.

According to another aspect of the present invention, methods for the manufacture of medicaments including compounds of general formula (I) are provided, which are useful for the treatment of metabolic disorders related to insulin resistance or hyperglycemia.

According to another aspect of the present invention there are provided methods for the manufacture of a medicament including compounds of general formula (I), which are useful for the treatment of metabolic disorders related to insulin resistance or hyperglycemia in a mammal, that Medication is manufactured to be administered, either sequentially or simultaneously, with at least one other pharmaceutically active compound.

Although it is possible that the compounds of the present invention can be therapeutically administered as a crude chemical, it is preferable to present the active ingredient as a pharmaceutical formulation. Therefore, the present invention further provides a pharmaceutical formulation including a compound of formula (I) or a pharmaceutically acceptable salt or solvate or a prodrug thereof, for example, together with one or more pharmaceutically acceptable carriers thereof and, optionally, other therapeutic and / or prophylactic ingredients.

The pharmaceutical composition may be in the forms normally employed, such as pills, tablets, capsules, powders, syrups, solutions, suspensions and the like specially formulated for oral, oral, parenteral, transdermal, inhalation, intranasal, transmucosal, implant administration, or rectal, however oral administration is preferred. For oral administration, the formulation may take the form of conventionally formulated tablets or tablets. The tablets and capsules for oral administration may contain conventional excipients as binding agents, (e.g., syrup, acacia, gelatin, sorbitol, tragacanth, starch mucilage or polyvinylpyrrolidone), fillers (e.g., lactose, sugar, microcrystalline cellulose, starch of corn, calcium phosphate or sorbitol), lubricants (for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycolate) or wetting agent, as sodium lauryl sulfate. The tablets may be covered according to methods well known in the art.

Alternatively, the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, for example. On the other hand, formulations containing these compounds may be presented as a dry product for constitution with water or other acceptable vehicle before use. Said liquid preparations may contain conventional additives as suspending agents such as sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid. Such preparations may also be formulated as suppositories, for example, containing conventional suppository bases such as coconut butter or other glycerides. Additionally, the formulations of the present invention can be formulated for parenteral administration by continuous injection or infusion. Formulations for injection may take forms such as suspensions, solutions, or emulsions in aqueous or oily vehicles, and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle (eg, sterile, pyrogen-free water) before use.

The formulations according to the invention can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Therefore, the compounds of the invention can be formulated with suitable polymeric or hydrophobic materials (as an emulsion in an acceptable oil, for example), ion exchange resins or as sparingly soluble derivatives such as a sparingly soluble salt, for example.

It will be appreciated by those skilled in the art that the reference herein to treatment extends to prophylaxis as well as to the treatment of established diseases or symptoms. On the other hand, it will be appreciated that the amount of a compound of the invention required for use in the treatment will vary with the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the physician or assistant veterinarian In general, however, the doses used for the treatment of adult humans will typically be in the range of 0.02-5000 mg per day or 1-1500 mg per day. The desired dose may be conveniently presented in a single dose or as divided doses administered at appropriate intervals, for example two, three, four or more sub-doses per day.

The formulations according to the invention may contain between 0.1-99% of the active ingredient, conveniently 30-95% for pills and capsules and 3-50% for liquid preparations.

In addition, in addition to at least one compound of general formula (I), as active ingredient, the pharmaceutical compositions may also contain one or more other therapeutically active ingredients.

A method is also disclosed for the treatment of metabolic disorders related to insulin resistance or hyperglycemia, including administration to a mammal in need of a therapeutically effective amount of a compound of formula (I).

A method is also revealed for the treatment of metabolic disorders related to insulin resistance or hyperglycemia, including type 2 diabetes, obesity, glucose intolerance, dyslipidemia, hyperinsulinemia, atherosclerotic disease, polycystic ovary syndrome, artery disease coronary, hypertension, aging, non-alcoholic fatty liver disease, infections, cancer and stroke, including administration to a mammal in need of a therapeutically effective amount of a compound of formula (I).

A method for the treatment of type 2 diabetes and related disorders is also disclosed, including administration to a mammal in need of a therapeutically effective amount of a compound of formula (I).

A method for the treatment of obesity and related disorders is also disclosed, including administration to a mammal in need of a therapeutically effective amount of a compound of formula (I). A method for the treatment of dyslipidemia and related disorders is also disclosed, including administration to a mammal in need of a therapeutically effective amount of a compound of formula (I).

The compounds of the present invention are useful for the treatment of metabolic disorders related to insulin resistance or hyperglycemia.

The compounds of the present invention are useful for the treatment of metabolic disorders related to insulin resistance or hyperglycemia, including type 2 diabetes, glucose intolerance, dyslipidemia, hyperinsulinemia, atherosclerotic disease, polycystic ovary syndrome, disease of the coronary arteries, hypertension, aging, non-alcoholic fatty liver disease, infections, cancer and stroke.

The compounds of the present invention are useful for the treatment of type 2 diabetes. The compounds of the present invention are useful for the treatment of obesity and disorders

related. The compounds of the present invention are useful for the treatment of dyslipidemia. Representative compounds useful in the treatment of metabolic disorders related to

Insulin resistance or hyperglycemia, according to the present invention are selected, but not limited, from the following: N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3 -yl) -2,4-dichlorobenzenesulfonamide, N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -4-methoxybenzenesulfonamide, N- (6- (4 - (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -3,4-dimethoxy-benzene sulfonamide, N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -2,5-dimethoxy-benzene sulfonamide, N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -2- Chloro-4- (trifluoromethyl) benzenesulfonamide, N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -3,4-dichlorobenzenesulfonamide, N- (6- ( 4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -4- (trifluoromethoxy) benzene sulfonamide, N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -4-methylbenzenesulfonamide, N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -2,4-difluorobenzenesulfonamide, N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -4-fluorobenzenesulfonamide, 2,4-Dichloro-N- (5 -chloro-6- (4- (piperazin-1-yl) phenoxy) pyridin-3-yl) benzenesulfonamide, N- (5-Chloro-6- (3- (4-methylpiperazin-1-yl) phenoxy) pyridine- 3-yl) -2,4-difluorobenzene sulfonamide, N- (5-Chloro-6- (3- (4-methylpiperazin-1-yl) phenoxy) pyridin-3-yl) -4-methoxybenzenesulfonamide, 4- ( 6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yloamino) -4-oxobutanoic, N- (6- (2- (Benzo [d] thiazol-2-yl) phenoxy ) -5-chloropyridin-3-yl) -2,4-dichlorobenzenesulfonamide, N- (6- (2- (Benzo [d] thiazol-2-yl) phenoxy) -5-chloropyridin-3-yl) -4- methoxybenzenesulfonamide, N- (6- (2- (Benzo [d] thiazol-2-yl) phenoxy) -5-chloropyridin-3-yl) -3,4-dichloro-benzene sulfonamide, N- (6- (2- (Benzo [d] thiazol-2-yl) phenoxy) -5-chloropyridin-3-yl) -2-chloro-4- (trifluoromethyl) benzenesulfonamide; and its pharmaceutically acceptable salts and solvates.

Suitable compounds useful in the treatment of metabolic disorders related to insulin resistance or hyperglycemia, according to the present invention are selected from, but not limited to, the following:

N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -2,4-dichlorobenzenesulfonamide, 2,4-Dichloro-N- (5-chloro-6- (4- (piperazinyl-1-yl) phenoxy) pyridin-3-yl) benzenesulfonamide, 4- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yloamino) -4-oxobutanoic acid;

and its pharmaceutically acceptable salts and solvates.

Compound Preparation

According to a further aspect of the invention, a process is provided for the preparation of compounds of general formula (I),

image 1

where: Ar is a phenyl group substituted with heterocyclic or heteroaryl; B is –O-, -S-, or –NH-;  R1 is hydrogen;

R2 is S (O) 2R4 or C (O) (CH2) n-C (O) OR5;

R3 is halogen, cyano, (CO) OR6, or C (O) NR7R8; R4 is aryl;  R5 is hydrogen, (C1-C6) alkyl, or aryl; R6 is hydrogen or (C1-C4) alkyl;

R7 and R8 are independently hydrogen or (C1-C6) alkyl; n is an integer of 1-3; and its pharmaceutically acceptable stereoisomers, salts and solvates. The compounds of general formula (I), according to the invention can be prepared by, or in analogy with, standard synthetic methods, and especially according to, or in analogy with, Scheme 1.

image2

fifteen

presence of a solvent such as dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, or acetonitrile, optionally in the presence of a base such as cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, or potassium fluoride to provide the compound of formula (IV) wherein Ar, B, and R3 are as defined above. The nitro group of the compound of formula (IV) is reduced to the corresponding amino group to obtain the compound of formula (V) wherein Ar, B, and R3 are as defined above. The nitro group reduction can be performed using SnCl2 in a solvent such as acetate

ethyl; or using Fe / HCl; or in the presence of a hydrogen gas and a catalyst such as Pd-C, Rh-C, Pt-C; or any suitable method known in the art.

The compound of formula (V) is further converted to the desired compound of formula (I) wherein R2 is - SO2R4 and AR, B, R1, R3 and R4 are as defined above, by reaction with Hal-SO2R4 where Hal is represented by fluorine, chlorine, bromine or iodine and R4 is as defined above, in the presence of pyridine or triethyl amine as a base and a solvent selected from acetonitrile, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, or dioxane.

The compound of formula (V) can also be converted to the desired compound of formula (I) wherein R2 is -C (O) (CH2) nC (O) OH and Ar, B, n, R1, and R3 are as defined above, by refluxing with an anhydride [(CH2) n (CO) 2], in the presence of a solvent selected from benzene, toluene, tetrahydrofuran, or dioxane, The acid of formula (I) can be converted to the ester where R2 is –C (O) (CH2) nC (O) OR5 wherein Ar, B, n, R1, and R3 are as defined above and R5 is (C1-C4) alkyl or aryl, by known standard esterification reactions In the bibliography.

The compounds of general formula (I), wherein AR, B, R1, R2, and R3 are as defined above, can be converted into a pharmaceutically acceptable salt by standard processes known in the literature.

The compounds of this invention can be prepared as illustrated in the accompanying functional examples. The following examples are set forth to illustrate the synthesis of some particular compounds of the present invention and to exemplify the general processes. Therefore, the following Examples section is in no way intended to limit the scope of the invention contemplated herein.

EXAMPLES List of abbreviations

HCl: hydrochloric acid; POCl3: Cs2CO3 phosphorus oxychloride: Cesium carbonate DCM: Dichloromethane DMF: Dimethylformamide DMSO: Dimethyl sulfoxide CPM: Bills per minute Mpk: mg per Kg. Od: once daily Bid: Twice a day HEPES: N- acid (2) -hydroxyethyl) -piperazine-N'-2-ethanesulfonic MP (DSC): melting point (Differential Scanning Calorimetry) CMC: Carboxymethylcellulose

Preparation 1: 2,3-Dichloro-5-nitro pyridine Step i. 2-Hydroxy-3-chloro-5-nitro pyridine

2-Hydroxy-5 nitro pyridine (1g, 7.4 mmol) was added as a portion to 4.5 mL of concentrated HCl under constant stirring and then heated to 50 ° C. To this was slowly added a chlorate solution. sodium (266 mg, 2.5 mmol) in water (4 mL). The reaction was maintained at the same temperature for an additional hour, and then cooled to 0 ° C. The precipitate obtained was filtered, washed thoroughly with water and dried to obtain 2-hydroxy-3-chlor-5-nitro pyridine.

Yield: 850 mg, (68.2%); 1H NMR (DMSO-d6) δ: 8.36 (d, 1H); 8.65 (d, 1 H).

Step ii. 2,3-Dichloro-5-nitro pyridine

Quinoline (0.3 mL, 2.34 mmol) was added to POCl3 (0.5 mL 4.68 mmol) at 0 ° C under nitrogen. To this stirred mixture was added 2-hydroxy-3-chloro-5-nitro pyridine (816 mg, 4.68 mmol) obtained in step i above. The reaction mixture was heated at 120 ° C for 2 hours, cooled to 0 ° C followed by the addition of ice water. The precipitate obtained was filtered, washed thoroughly with water and dried to obtain 2,3-dichloro-5-nitro pyridine.

Yield: 630 mg, (70.3%); 1H NMR (DMSO-d6) δ: 8.94 (d, 1H); 9.16 (d, 1 H).

Preparation 2: 1- {4- [4 - ((5-Amino-3-chloro-pyridine-2-yloxy) -phenyl] -piperazinyl-1-yl-ethanone

Step i. Preparation of 1- {4- [4 - ((3-Chloro-5-nitro-pyridine-2-yloxy) -phenyl] -piperazinyl-1-yl-ethanone

Dry dimethylformamide (10 mL) was added to 1- [4 - (- hydroxy-phenyl-piperazine-1-yl] -ethanone (696 mg, 3.16 mmol) with stirring and cesium carbonate (1.03 g, 3.16 mmol) at room temperature (25 ° C.) After 30 minutes 2,3-dichloro-5-nitro-pyridine (610mg, 3.16 mmol) was added (as obtained in preparation 1), and stirring was continued for a further 18 hours The solvent was removed in vacuo and to the resulting mass water (20 mL) was added, extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo to obtain the crude product that was also purified by column chromatography (silica gel - ~ 200 mesh, 30% ethyl acetate in petroleum ether) to obtain the title compound.

Yield 1.09 g (92.9%);

1H NMR (CDCl3) δ: 2.01 (s, 3H), 2.99 (t, 2H), 3.05 (t, 2H), 3.54 (s, 4H), 5.30 (s, 2H ), 6.85 (d, 1H), 6.93 (d, 1H), 7.17 (s, 1H), 7.43 (s, 1H).

Step ii. 1- {4- [4 - ((5-Amino-3-chloro-pyridine-2-yloxy) -phenyl] -piperazinyl-1-yl-ethanone

The compound of step i (3.15g, 8.34 mmol) was dissolved in ethyl acetate (50 mL). Tin chloride dihydrate (7.52 g, 33.36 mmol) was added at room temperature (25 ° C) and stirring was maintained for 18 hours. The solvent was removed in vacuo and chloroform (50 mL) was added. A 1 N sodium hydroxide solution was added until a clear solution was obtained. Separated the organic layer was separated and extracted with chloroform. The chloroform layer was washed with brine & water successively, dried over sodium sulfate and concentrated in vacuo to obtain the crude product which was further purified by column chromatography (silica gel - ~ 200 mesh, 1% methanol in chloroform) to Get the title compound.

Yield: 1.77 g (61.52%); 1H NMR (CDCl3) δ: 2.04 (s, 3H), 3.10 (m, 2H), 3.18 (m, 2H), 3.59 (brs, 4H), 5.32 (s, 2H ), 7.05 (d, J = 9Hz, 2H), 7.14 (d, J = 9Hz, 2H), 8.86 (d, J = 2.4 Hz, 1H), 8.95 (d, J = 2.4 Hz, 1H); MS: 347 (M + 1).

Preparation 3: 5-Chloro-6- (3- (4-methylpiperazinyl-1-yl) phenoxy) pyridine-3-amino

3- (4-Methylpiperazinyl-1-yl) phenol was reacted with 2,3-dichloro-5-nitro pyridine (as obtained in preparation 1), to obtain 1- (3- (3-chloro-5-nitropyridine) -2-yloxy) phenyl) -3-methylpiperazinyl which was further converted to the title compound according to the process described in preparation 2.

1H NMR (CDCl3) δ: 3.09 (t, J = 4.5 Hz, 4H), 3.22 (t, J = 4.5 Hz, 4H), 3.70 (s, 3H), 5, 17 (s, 2H), 6.36 (dd, J = 2.5, 8.0 Hz, 1H), 6.46 (s, 1H), 6.55 (dd, J = 1.5, 8.0 Hz , 1H), 7.06 (d, J = 2.5 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H ); MS (ES): 319.01 (M + 1).

Preparation 4: 6- (2-Benzo [d] thiazol-2-yl) phenoxy) -5-chloropyridine-3-amino

2- (Benzo [d] thiazol-2-yl) phenol was reacted with 2,3-dichloro-5-nitro pyridine to obtain 2- (2- (3-chloro-5-nitropyridine-2-yloxy) phenyl) venzo [d] thiazole which was further converted to 6- (2-Benzo [d] thiazol-2-yl) phenoxy) -5-chloropyridine-3amino according to the process described in preparation 2.

1H NMR (DMSO-d6) δ: 5.48 (s, 2H), 6.99 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 2.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.47 (d, J = 2.5 Hz, 1H), 7, 54 (m, 2H), 8.07 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.46 (d, J = 7.0 Hz, 1H); MS: 354.11 (M + 1).

General procedure for the preparation of compounds of formula (I)

To a stirred solution of amino [obtained by preparations 1-4] (1 mmol) in DCM, pyridine (1-3 mmol) was added which was followed by the addition of substituted benzenesulfonyl chloride (1 mmol) substituted. The reaction mixture was stirred at room temperature (25 ° C). The reaction mixture was diluted using DMC, washed with water, dried over sodium anhydride sulfate and concentrated. The crude product was purified using column chromatography (silica gel) to obtain the desired compound.

The compounds of examples 1-10, 12, 13, and 5-18 were prepared with this procedure.

General procedure for salt formation

Procedure A: The compound of formula (I) was dissolved in 1: 1 ethyl acetate and DCM solvent mixture. To the clear solution was added 1 equivalent of the corresponding acid (such as toluene sulfonic acid or methane sulfonic acid, benzene sulfonic acid) and stirred for 30-45 minutes at room temperature (25 ° C). The precipitate was filtered and characterized by 1H NMR and MP (DSC).

Procedure B: The said compound of formula (I) was dissolved in ethanol (a large excess was required to obtain a clear solution in heating). To the clear solution was added 1 equivalent of the corresponding acid (such as toluene sulfonic acid or methane sulfonic acid, benzene sulfonic acid). After reflux for 3 hours, the solvent was removed and the solid obtained was characterized by 1H NMR and MP (DSC).

Example 1

N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridine-3-yl) -2,4-dichlorobenzenesulfonamide (Compound 1)

The title compound was obtained by reacting 1- (4- (4- (5-Amino-3-chloropyridine-2-yloxy) -phenyl) -piperazinyl-1-yl ethanone (obtained according to the procedure described in preparation 2) and 2,4 chloride -dichlorobenzene-1-sulfonyl.

mp: 215 ° C-216 ° C; 1H NMR (DMSO-d6) δ: 2.02 (s, 3H), 3.02 (d, 4H), 3.55 (s, 4H), 6.94 (s, 4H), 7.57 (dd , 1H), 7.64 (d, 1H), 7.70 (d, 1H), 7.87 (d, 1H), 7.96 (d, 1H) 10.98 (s, 1H); MS (ES): 555.03 (M + 1).

Sodium Salt:

The compound of example 1 (250 mg) was dissolved in excess amount (40-50 mL) of methanol and the reaction mixture was heated to 60 ° C to achieve a clear solution. To the stirred solution, 1.0 equivalents of sodium hydroxide was added as a solution in methanol. The solution was refluxed for 2-3 hours. After completion of the reaction, the solvent was removed and dried.

mp: 130 ° C -133 ° C; 1HNMR (DMSO-d6): δ 7.88 (d, 1H), 7.60 (d, 1H), 7.46 (d, 1H), 7.43 (d, 1H), 7.40 (dd, 1H), 6.89-6.80 (m, 4H), 3.50 (brs, 4H), 3.04 (t, 2H), 2.97 (t, 2H), 1.97 (s, 3H ); MS (ES): 577 [(M-1) + Na].

Example 2

N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridine-3-yl) -4-methoxybenzenesulfonamide (Compound 2)

The title compound was obtained by reacting 1- (4- (4- (5-Amino-3-chloropyridine-2-yloxy) -phenyl) -piperazinyl-1-yl ethanone (obtained according to the procedure described in preparation 2) and 4-methoxybenzene chloride -1-sulfonyl.

1H NMR (DMSO-d6) δ: 1.97 (s, 3H), 3.02 (d, 4H), 3.55 (s, 4H), 3.79 (s, 3H), 6.94 (s , 4H), 7.05-7.08 (m, 2H), 7.63-7.66 (m, 4H), 10.30 (s, 1H); MS (ES): 517.12 (M + 1).

Example 3

N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridine-3-yl) -3,4-dimethoxybenzene sulfonamide (Compound 3)

The title compound was obtained by reacting 1- (4- (4- (5-Amino-3-chloropyridine-2-yloxy) -phenyl) -piperazinyl-1-yl ethanone (obtained according to the procedure described in preparation 2) and chloride 3,4 -dimethoxybenzene-1sulfonyl.

1H NMR (DMSO-d6) δ: 2.06 (s, 3H), 3.02 (d, 4H), 3.55 (s, 4H), 3.74 (d, 6H), 6.94 (s , 4H), 7.05 (d, 1H), 7.19 (s, 1H), 7.25 (d, 1H), 7.64 (s, 2H) 10.26 (s, 1H); MS (ES): 545.16 (M-1).

Example 4

N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridine-3-yl) -2,5-dimethoxybenzenesulfonamide (Compound 4)

The title compound was obtained by reacting 1- (4- (4- (5-Amino-3-chloropyridine-2-yloxy) -phenyl) -piperazinyl-1-yl ethanone (obtained according to the procedure described in preparation 2) and 2.5 chloride -dimethoxybenzene-1sulfonyl.

1H NMR (DMSO-d6) δ: 2.02 (s, 3H), 3.02 (s, 2H), 3.09 (s, 2H) 3.54 (d, 4H), 3.70 (s, 3H), 3.78 (s, 3H) 6.93 (s, 4H), 7.14-7.20 (m, 3H)) 7.64 (d, 1H) 7.68 (d, 1H), 10.20 (s, 1 H);

MS (ES): 545.16 (M-1).

Example 5

N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridine-3-yl) -2-chloro-4- (trifluoromethyl) benzenesulfonamide (Compound 5)

The title compound was obtained by reacting 1- (4- (4- (5-Amino-3-chloropyridine-2-yloxy) -phenyl) -piperazinyl-1-yl ethanone (obtained according to the procedure described in preparation 2) and 2-chloro chloride -4 (trifluoromethyl) benzene-1-sulfonyl.

1H NMR (DMSO-d6) δ: 2.01 (s, 3H), 3.02 (d, 4H), 3.54 (s, 4H), 6.93 (s, 4H), 7.69 (s , 2H), 7.8 (d, 1H), 8.138.2 (m, 2H), 11.08 (s, 1H); MS (ES): 589.06 (M + 1). Example 6 N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridine-3-yl) -3,4-dichlorobenzenesulfonamide (Compound 6)

The title compound was obtained by reacting 1- (4- (4- (5-Amino-3-chloropyridine-2-yloxy) phenyl) -piperazinyl-1-yl ethanone (obtained according to the procedure described in preparation 2) and chloride 3,4- dichlorobenzene-1-sulfonyl.

1H NMR (DMSO-d6) δ: 2.02 (s, 3H), 3.03 (s, 2H), 3.1 (s, 2H), 3.55 (s, 4H), 6.92 (s , 4H), 7.62-7.69 (m, 3H)), 7.83 (d, 1H) 7.91 (d, 1H), 10.61 (s, 1H); MS (ES): 554.8 (M-1).

Example 7

N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridine-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (Compound 7)

The title compound was obtained by reacting 1- (4- (4- (5-Amino-3-chloropyridine-2-yloxy) -phenyl) -piperazinyl-1-yl ethanone (obtained according to the procedure described in preparation 2) and chloride 4- ( trifluoromethoxy) benzene-1sulfonyl.

1H NMR (DMSO-d6) δ: 2.02 (s, 3H), 3.02 (s, 2H), 3.09 (s, 2H), 3.55 (s, 4H), 6.95 (s, 4H ), 7.55 (d, 2H) 7.637.67 (m, 2H), 7.83 (d, 2H), 10.58 (s, 1H); MS (ES): 571.03 (M + 1). Example 8 N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridine-3-yl) -4-methylbenzenesulfonamide (Compound 8)

The title compound was obtained by reacting 1- (4- (4- (5-Amino-3-chloropyridine-2-yloxy) -phenyl) -piperazinyl-1-yl ethanone (obtained according to the procedure described in preparation 2) and 4-methylbenzene chloride -1-sulfonyl.

1H NMR (DMSO-d6) δ: 2.02 (s, 3H), 2.33 (s, 3H), 3.02 (s, 2H), 3.09 (s, 2H), 3.55 (s , 4H), 6.94 (s, 4H), 7.34 (d, 2H), 7.58-7.63 (m, 4H)), 10.4 (s, 1H); MS (ES): 501.01 (M + 1).) Example 9 N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridine-3-yl) -2,4- Difluoro benzenesulfonamide (Compound 9)

The title compound was obtained by reacting 1- (4- (4- (5-Amino-3-chloropyridine-2-yloxy) -phenyl) -piperazinyl-1-yl ethanone (obtained according to the procedure described in preparation 2) and 2,4 chloride -difluorobenzene-1sulfonyl.

1H NMR (DMSO-d6) δ: 2.02 (s, 3H), 3.01 (t, 2H), 3.08 (t, 2H), 3.55 (s, 4H), 6.95 (s , 4H), 7.22 (t, 1H), 7.517.59 (dt, 1H), 7.67 (d, 1H), 7.70 (d, 1H), 7.82-7.9 (m, 1H), 10.86 (s, 1H);

MS (ES): 523.09 (M + 1). Example 10 N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridine-3-yl) -4-fluorobenzenesulfonamide (Compound 10)

The title compound was obtained by reacting 1- (4- (4- (5-Amino-3-chloropyridine-2-yloxy) -phenyl) -piperazinyl-1-yl ethanone (obtained according to the procedure described in preparation 2) and 4-fluorobenzene chloride -1-sulfonyl.

1H NMR (DMSO-d6) δ: 2.02 (s, 3H), 3.01 (t, 2H), 3.08 (t, 2H), 3.55 (s, 4H), 6.95 (s , 4H), 7.37 (t, 2H), 7.64 (s, 2H), 7.75-7.80 (m, 2H), 10.48 (s, 1H); MS (ES): 505.1 (M + 1).

Example 11 2,4-Dichloro-N- (5-chloro-6- (4- (piperazinyl-1-yl) phenoxy) pyridine-2-yl) benzene sulfonamide (Compound 11)

The title compound was prepared by deacetylation of N- (6- (4- (4-acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridine-3-yl) -2,4-dichlorobenzenesulfonamide (obtained according to the procedure described in the example 1) using HCl concentrated in methanol-water. N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridine-3-yl) -2,4-dichloro-benzene sulfonamide (500 mg) was dissolved in methanol (100 mL). The mixture was heated at 50 ° C under stirring.

To the stirred solution, 2 mL of concentrated HCl and 1 mL of water were added. The resulting solution was stirred for 6-7 hours at 45-50 ° C. The solvent was removed and water was added to the residue. The reaction mixture was made alkaline using 1N sodium hydroxide solution. The title compound was precipitated, filtered and dried in vacuo at 60 ° C.

Yield: 320 mg (69.3%); 1H NMR (DMSO-d6) δ: 3.17 (brs, 4H), 3.19 (brs, 4H), 3.38 (m, 1H), 6.846.94 (m, 4H), 7.37 (d , 1H), 7.40-7.45 (m, 2H), 7.58 (d, 1H), 7.91 (d, 1H), 9.95 (s, 1H); MS: 513.1 (M-1).

Example 12

N- (5-Chloro-6- (3- (4-methylpiperazinyl-1-yl) phenoxy) pyridine-3-yl) -2,4-difluorobenzene sulfonamide (Compound 12)

The title compound was obtained by reacting 5-chloro-6- (3- (4-methylpiperazinyl-1-yl) phenoxy) pyridine-3amino (obtained according to the process described in preparation 3) and 2,3-difluorobenzene-1 chloride -sulfonyl.

1H NMR (DMSO-d6) δ: 3.21-3.33 (m, 8H), 3.69 (s, 3H), 6.34 (dd, 1H), 6.46 (d, 1H), 6 , 50 (d, 1H), 7.06 (t, 1H), 7.25 (dt, 1H), 7.50 (d, 1H), 7.64 (dt, 1H), 7.86 (d, 1H), 7.94 (d, 1H), 10.76 (s, 1H); MS (ES): 493.1 (M-1). Example 13 N- (5-Chloro-6- (3- (4-methylpiperazinyl-1-yl) phenoxy) pyridine-3-yl) -4-methoxybenzenesulfonamide (Compound 13)

The title compound was obtained by reacting 5-chloro-6- (3- (4-methylpiperazinyl-1-yl) phenoxy) pyridine-3amino (obtained according to the process described in preparation 3) and 4-methoxybenzene-1-sulfonyl chloride .

1H NMR (DMSO-d6) δ: 3.22 (t, 4H), 3.33 (s, 4H), 3.69 (s, 3H), 3.78 (s, 3H), 6.34 (dd , 1H), 6.46 (s, 1H), 6.51 (d, 1H), 7.05-7.12 (m, 3H), 7.45 (d, 1H), 7.64 (d, 2H), 7.88 (d, 1H), 10.26 (s, 1H); MS (ES): 489.1 (M + 1). Example 14 4- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridine-3-yloamino) -4-oxubotanoic acid (Compound 14)

The title compound was obtained by reacting 1- (4- (4- (5-Amino-3-chloropyridine-2-yloxy) -phenyl) -piperazinyl-1-yl ethanone (obtained according to the procedure described in preparation 2) and dihydrofuran-2, 5-dione in toluene at reflux temperature The reaction mixture was concentrated and the crude product was purified by column chromatography (silica gel).

1H NMR (DMSO-d6) δ: 2.02 (s, 3H), 2.48 (t, 4H), 3.04 (d, 4H), 3.56 (s, 4H), 6.97 (s , 4H), 8.10 (s, 1H), 8.28 (s, 1H), 10.26 (s, 1H), 12.17 (s, 1H); MS (ES): 447.1 (M + 1). Example 15 N- (6- (2-Benzo [d] thiazol-2-yl) phenoxy) -5-chloropyridine-3-yl) -2,4-dichlorobenzenesulfonamide (Compound 15)

The title compound was prepared by reacting 6- (2-benzo [d] thiazol-2-yl) phenoxy) -5-chloropyridine-3-amino (obtained according to the procedure described in preparation 4) and 2,4-dichlorobenzene chloride -1-sulfonyl.

1H NMR (DMSO-d6) δ: 7.26 (d, 1H), 7.39-7.46 (m, 2H), 7.49-7.54 (m, 3H), 7.68 (d, 2H), 7.76 (d, 1H), 7.80 (d, 1H), 7.95-7.98 (m, 2H), 8.06 (d, 1H), 8.39 (dd, 1H ); MS (ES): 561.85 (M + 1). Example 16 N- (6- (2-Benzo [d] thiazol-2-yl) phenoxy) -5-chloropyridine-3-yl) -4-methoxybenzenesulfonamide (Compound 16)

The title compound was prepared by reacting 6- (2-benzo [d] thiazol-2-yl) phenoxy) -5-chloropyridine-3-amino (obtained according to the procedure described in preparation 4) and 4-methoxybenzene-1 chloride -sulfonyl.

1H NMR (DMSO-d6) δ: 3.73 (s, 3H), 6.95 (d, 2H), 7.23 (d, 1H), 7.39-7.45 (m, 2H), 7 , 49-7.62 (m, 5H), 7.73 (d, 1H), 8.00 (d, 1H), 8.08 (d, 1H), 8.40 (d, 1H); MS (ES): 522.05 (M-1). Example 17 N- (6- (2-Benzo [d] thiazol-2-yl) phenoxy) -5-chloropyridine-3-yl) -3,4-dichloro-benzenesulfonamide (Compound 17)

The title compound was prepared by reacting 6- (2-benzo [d] thiazol-2-yl) phenoxy) -5-chloropyridine-3-amino (obtained according to the procedure described in preparation 4) and 3,4-dichlorobenzene chloride -1-sulfonyl.

1H NMR (DMSO-d6) δ: 7.28 (d, 1H), 7.40-7.60 (m, 6H), 7.67 (d, 1H), 7.82 (m, 2H), 7 , 96 (m, 1H), 8.05 (m, 1H), 8.36 (dd, 1H), 10.65 (s, 1H); MS (ES): 561.90 (M + 1).

Example 18

N- (6- (2-Benzo [d] thiazol-2-yl) phenoxy) -5-chloropyridine-3-yl) -2-chloro-4- (trifluoromethyl) benzenesulfonamide (Compound 18)

The title compound was prepared by reacting 6- (2-benzo [d] thiazol-2-yl) phenoxy) -5-chloropyridine-3-amino (obtained according to the procedure described in preparation 4) and 2-chloro-4 chloride - (trifluoromethyl) benzene-1-sulfonyl.

1H NMR (DMSO-d6) δ: 5.74 (s, 1H), 7.28 (d, 1H), 7.38-7.57 (m, 4H), 7.70 (s, 1H), 7 , 83 (d, 2H), 7.98 (d, 1H), 8.06 (d, 1H), 8.18 (d, 1H), 8.38 (d, 1H), 11.15 (s, 1 HOUR); MS (ES): 593.93 (M-1).

PHARMACOLOGY

Example 19

In vitro model exhibiting insulin resistance

The essay was designed as in the reference, British Journal of Pharmacology, 130, 351-58, 2000, the disclosure of it is incorporated by reference for teaching it.

The test compound solution (10 μM / mL) was prepared in DMSO.

Rosiglatizona (0.1 μM in DMSO) was used as standard.

Adipocyte differentiation was induced by known methods as described below. (J. Biol. Chem., 260, 2646-2652, 1985), the disclosure of which is incorporated by reference for the teaching of adipocyte differentiation.

A culture medium containing 0.5 nM 1-methyl isobutyl oxanthin (IBMX), 0.25 µM sexametosan, 5 µg / ml insulin (bovine / human), 10mM HEPES buffer and fetal bovine serum (FBS) was used for differentiation 10% by volume in a medium of Eagle modified by Dulbecco (DMEM).

3T3 L1 fibroblasts were seeded in 24- or 6-well multiwell plates at a density of 0.5-2x104 cells / wells and allowed to reach maximum confluence.

The confluent fibroblasts were exposed to the culture medium for 2 days. After this period, a new culture medium (DMEM) containing only insulin was used, 10% FBS was added and cultured for 45 days with a change of medium every 2 days. After 7 days the cultures received DMEM containing 10% FBS without insulin exposure. At the end of 8-10 days, more than 95% of the cells had become differentiated into adipocytes.

Mature adipocytes were exposed to dexamethasone, 100 nM added in ethanol, in the culture medium and incubated for 2 days. On the third day, the test compound solution was added together with 100 nM dexamethasone containing medium for 4 days with a change in the medium after every 2 days. The vehicle control contained 1% v / v DMSO. Rosiglitazone was used as a standard and was added at a concentration of 0.1 μM in DMSO, together with 100 nM dexamethasone containing medium for 4 days with a change in the medium after every 2 days. After a period of 6 days, the cells were processed for glucose uptake as follows.

Insulin resistant adipocytes were exposed to serum free DMEM containing 0.1% bovine serum albumin for 3-4 hours at 37 ° C in a CO2 atmosphere. The test compound was also present during this period. After 3-4 hours, the medium was aspirated and replaced with Kreb’s Ringer phosphate buffer (KRP) at a pH of 7.4 and with human / porcine insulin, 200 nM. The cells were incubated for 30 minutes at 37 ° C. At the end of 30 minutes, 0.05 or 0.1 μCi of 14C-2-deoxyglucose was added to each well of the 24- or 6- multiwell plates respectively and was incubated for exactly 5 minutes. After exactly 5 minutes, the plates were transferred to frozen trays and the medium was quickly aspirated. The cell layer was washed twice with ice phosphate buffered saline, (PBS), pH 7.4. Finally, the cell layer was lysed with 150 µl of 0.1% sodium dodecyl sulfate (SDS) and the radioactivity of the cell lysate was determined in a liquid scintillation counter. Non-specific glucose uptake was tested in wells exposed to cytochalasin B, glucose transport inhibitor. Compounds that showed a statistically significant increase in glucose transport / uptake expressed as CPM / well above the level in cells exposed to the insulin vehicle are considered active in this assay. The cut-off limit per activity in this IR test was defined as the 1.50 fold increase of the vehicle, the test value of 1.0 for the vehicle. The activity was also expressed as a% of Rosiglitazone, which is used as A standard for comparison. Statistical analysis was performed using a mismatched t-test.

The results are summarized in Table 1.

5

10

fifteen

twenty

25

30

35

Table 1: Activity of compounds in the insulin resistant model

Mr. Nº

Compound No. Vehicle Times * Rosiglitazone% **

Std

Rosiglitazone 2.6 ± 0.10 100

01

one 2.10 ± 0.05 61.4

02

4 1.55 ± 0.03 41.33

03

5 1.85 ± 0.04 63.94

04

6 1.93 ± 0.06 69.76

05

14 1.49 ± 0.05 27.5

06

fifteen 2.0 ± 0.13 36.7

* times of activity on the vehicle

Conclusion: Representative compounds of the present invention showed insulin synthesizing activity in increasing insulin uptake in the insulin resistance model.

Example 20

(a) Human PPARγ transactivation assay

The test was designed as in the reference, Biochem. Biophys Res. Comm. 175: 865-871, 1991, the disclosure thereof is incorporated by reference for the teaching of the essay.

Human activity was assessed by transactivation using a luciferase reporter gene. The AOX-3X PPRE-TK-LUC indicator plasmid of pBL-TK-luciferase contains three copies of PPRE rat acyl CoA oxidase cloned up from the thymidine kinase (TK) promoter of the minimal herpes simplex virus. The full length human PPARγcDNA was cloned into an expression vector pSG5 (Stratagen, Lo Jolla, CA).

HEK293 cells were seeded in 24 multiwell plates and cultured in DMEM supplemented with 10% (v / v) FCS. After 24 hours, they were transfected with 100ng of hPPARγ receptor and 300ng of AOX3X PPRE-LUC indicator constructed per well using Fugen 6 transfection reagent (Roche, Indianapolis, IN). Test compounds or Rosiglitazone (dissolved in DMSO) were added 24 hours after transfection. The control was 0.1% DMSO. After 48 hours, the transactivation activity was determined by luciferase assay using the Steady Glow reagent (Promega, Madison, WI). The results are summarized in Table 2

Table 2: Activity of Compound 1 in human PPARγ transactivation assay

PPARγ activity (5 of Rosiglitazone)

100

6.4

(b) PPARγ assay in mouse

The essay was designed as in the reference, Blood, 104 (5), 1361-8, 2004, its disclosure is incorporated by reference for the teaching of the essay.

3T3-L1 fibroblasts were seeded in multiwell plates of 6 at a density of 4 x 104 cells / well and cultured in DMEM containing 10% calf serum. After 4-5 days, when the cells became confluent, Compound 1 was added (from a stock of 20mM in DMSO) to the final concentration of 50 µM in DMEM supplemented with 10% FCS. Rosiglitazone was added (from a stock of 10mM) to the final concentration of 10μM. The plates were incubated for 72 hours at 37 ° C in a CO2 incubator with fresh medium containing test substances added after 48 hours. After 72 hours, the medium was removed; The cell layer was washed and processed for the PPARγ assay according to the manufacturer's instructions (Active Motif, North America, California, USA). PPARγ activation was determined using a 96-well ELISA assay according to the instruction manual (TransAM PPARγ. Active Motif, Cat. 40196). The test reading was the absorbance output of a spectophotometer for the PPARγ assay in mice. The luminescence data reading was recorded for the human PPARγ assay.

5

10

fifteen

twenty

25

30

35

The activity of a compound was expressed as relative activity compared to Rosiglitazone, the reference compound used as a positive control. The results are summarized in Table 3

Table 3: Activity of compound 1 in PPARγ assay in mice

Compound No.

PPARγ activity (% of Rosiglitazone)

Rosiglitazone

 100

one

5.1

Conclusion: In the selective assays for human and mouse PPARγ, the compounds of the present invention showed no PPARγ activation.

Live biological experiments

Note: All experimental procedures on animals were approved by the Animal Ethics Committee.

Example 21

Screening in db / db BL / 6J mice

The protocol was designed as in the references

one.

 Metabolism, 53 (12), 1532-1537, 2004.

2.

 Americal Journal of Hypertension, 17 (5), Supplement 1, S32, 2004.

The disclosures of these two references are incorporated by reference for the teaching of the protocol.

Compound screening was based on their ability to reduce plasma glucose levels in genetically diabetic db / db BL / 6J mice.

 Male db / db mice (obtained from the Animal House of Nicholas Piramal Researcxh Center, Goregaon, Mumbai, India) were used for this study (body weight in the 30-40 g range and the age is 6-8 weeks) and were saved eight per box in individually ventilated boxes at controlled temperature (22 ± 1º C) and humidity (45 ± 5%). Food and water were provided ad libitum during your laboratory stay, except for four hours of fasting before the collection of blood samples. A 12-hour cycle of light and darkness was followed throughout the study period.

After 4 hours of fasting blood samples were collected from the mice. Mice that showed plasma glucose levels between 300 and 500 mg / dL were divided into groups (8-10 per group) such that the mean plasma glucose levels and the variation within the group, for each group, It was almost the same. After grouping, the mice in the respective groups were treated with a 0.5% CMC vehicle, standard compound or test compounds for 10 days. Rosiglitazone was used as standard.

After 4 hours of fasting, the mice were anesthetized using isoflurane (inhalation anesthetic), and blood samples were collected through the retro orbital plexus. The collected blood samples were centrifuged at 7000 rpm for 10 minutes at 4 ° C; Separate plasma was used for plasma glucose estimation using diagnostic equipment (Diasys, Germany). The plasma glucose levels of the treated groups were normalized with the control group using the following formula, which represented the changes in the control group.

The formula used for normalization was

*: {1- (Proportion of mean plasma glucose levels of the control group from day 10 to day 0) / (Proportion of plasma glucose levels of the treated group from day 10 to day 0)} x100.

The results are summarized in Table 4.

Table 4: Reduction in plasma glucose levels in genetically diabetic db / db BL / 6J mice. Formula used for normalization:

Mr. Nº

Compounds tested on db / db mice Rosiglitazone tested in db / db mice

 Compound No.

Dose (10 days) Normalization with control * Dose (10 days) Normalization with control *

01

one 100 mpk twice a day 46.07 ± 4.55 5 mpk twice a day 55.73 ± 4.46

02

14 100 mpk twice a day Inactive 5 mpk twice a day 53.35 ± 4.11

*: {1- (Proportion of mean plasma glucose levels of the control group from day 10 to day 0) / (Proportion of plasma glucose levels of the treated group from day 10 to day 0)} x100.

Conclusion: A representative Compound of the present invention showed a significant decrease

In glucose activity in the animal model of diabetes.

Example 22

Antiobesity Evaluation

The essay was designed as in the reference, PCT publication WO 2003086306, the disclosure thereof is incorporated by reference for the teaching of the trial.

(a) Acute study

Male C57B16 / J mice, weighing 20-25 g, were housed individually in the animal facility. Water and food (Amrut Laboratory Animal feed, Sangli, Maharashtra, India) were available ad libitum. One day before the study, the animals were weighed and separated into treatment groups that had similar average body weight. For the experiment, the animals were deprived of food overnight for 16 hours. They were dosed intraperitonially with test compounds (100 mg / kg) or with a comparator standard (Sibutramine, 3 mg / kg) in a saline vehicle (10 mL / kg). An hour and a half after drug administration the animals were offered a pre-weighed amount of food in the food cup. The food left in the cup was measured at various time points. The effect of standard and test compounds on food intake in fasting skinny C57B16 / J mice at 2, 4, 6 and 24 hours after the introduction of the food was evaluated. The results are as indicated in Figure 1.

Conclusion: Compound 1 and Compound 11 are effective in inhibiting food intake of C57B16 / J mice for 2 hours after food introduction. (*** p <0.001 vs controls treated with the vehicle).

(b) Chronic study

The essay was designed as in the reference, British Journal of Pharmacology, 132, 1898-1904, 2001, its disclosure is incorporated by reference for the teaching of the trial. Male C57B16 / J mice (3-4 weeks old) were housed in groups of 10 animals per box in the animal facility. They were given ad libitum a high-fat diet (D12451 Research Diets Inc., New Brunswick, NJ 08901, USA), 45% Kcal fat) and water for 14 weeks. After this period, the animals were housed individually in boxes. The animals were weighed and separated into groups with similar body weight. They were acclimatized to the experimental procedures for 2 days. They were dosed intraperitoneally with the test compound (200 mg / kg) or with the standard (Sibutramine, 3 mg / kg) in 10 ml / kg of a 0.5% CMC vehicle between 10:00 h - 12: 00 h. After the administration of the drugs, the animals were offered a pre-weighed amount of food in the food cup. The weight of the remaining food in the cup and body weight were recorded daily just before dosing. The change in weight and cumulative food intake was calculated. The results are indicated in Figure 2 and in Figure 3.

Conclusions:

one.

 Compound 1 was effective in reducing the cumulative food intake of mice with diet-induced obesity (DIO) during the 10 days of treatment. (*** p <0.001, ** p <0.01, * p <0.05 vs controls treated with the vehicle).

2.

 Compound 1 was effective in reducing the cumulative body weight gain of mice with diet-induced obesity (DIO) during the 10 days of treatment. (*** p <0.001, ** p <0.01, * p <0.05 vs controls treated with the vehicle).

It should be noted that, as used in this specification and the appended claims, the singular forms "a", "one" and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a composition containing "a compound" includes the mixture of two or more compounds. It should also be noted that the term "or" is generally used in its sense including "and / or" unless the content clearly dictates otherwise.

All publications and patent applications in this specification are indicative of the level of experience in the common field to which this invention pertains.

Claims (14)

1. A compound of general formula (I): image 1 Where Ar is a phenyl group substituted with heterocyclyl or heteroaryl; wherein the heterocyclyl or heteroaryl group can be not substituted or substituted; B is –O-, -S-, or –NH-; R1 is hydrogen; R2 is S (O) 2R4 or C (O) (CH2) n-C (O) OR5; R3 is halogen, cyano, (CO) OR6, or C (O) NR7R8; R4 is unsubstituted or substituted aryl; R5 is hydrogen, (C1-C6) alkyl, or unsubstituted or substituted aryl; R6 is hydrogen or (C1-C4) alkyl; R7 and R8 are independently hydrogen or (C1-C6) alkyl; n is an integer of 1-3; Y a pharmaceutically acceptable stereoisomer, solvate or salt thereof. 2. A compound according to claim 1, wherein

(to)

 Ar is a phenyl group substituted with heterocyclyl; wherein the heterocyclyl group can be unsubstituted or replaced; and a pharmaceutically acceptable stereoisomer, salt or solvate thereof; or

(b)

 Ar is a phenyl group substituted with heterocyclyl; wherein the heterocyclyl group can be unsubstituted or replaced; B is oxygen;

R2 is S (O) 2R4; R3 is halogen; and a pharmaceutically acceptable stereoisomer, salt or solvate thereof; or

(C)

 Ar is a group substituted with pierazinyl with the phenyl part coupled to B; wherein the piperazinyl group may be unsubstituted or substituted;

B is oxygen; R2 is S (O) 2R4; R3 is chlorine; R4 is 4-methylphenyl, 2-chloro-4-trifluoromethylphenyl, 3-chloro-4-methylphenyl, 3,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-fluorine-4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2-chloro-4-trifluoromethylphenyl, or 4-cyanophenyl; and a pharmaceutically acceptable stereoisomer, salt or solvate thereof; or

(d)

 Ar is 4- (piperazinyl-1-yl) phenyl with the phenyl part coupled to B; B is oxygen; R2 is S (O) 2R4;

R3 is chlorine; R4 is 2,4-dichlorophenyl; Y a pharmaceutically acceptable stereoisomer, salt or solvate thereof; or

(and)

 Ar is 4- (4-acetyl-piperazinyl-1-yl) phenyl with the phenyl part coupled to B; B is oxygen; R2 is S (O) 2R4;

R3 is chlorine; R4 is 4-methylphenyl, 3,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, or 2 -chloro-4-trifluoromethylphenyl, and a pharmaceutically acceptable stereoisomer, salt or solvate thereof; or (f) Ar is 3 - (- 4-methyl-piperazinyl-silyl) phenyl with the phenyl part coupled to B; B is oxygen; R2 is S (O) 2R4; R3 is chlorine; R4 is 4-methoxyphenyl or 2,4-difluorophenyl; and a pharmaceutically acceptable stereoisomer, salt or solvate thereof. 3. A compound according to claim 1, wherein

(to)

 Ar is a phenyl group substituted with heteroaryl; wherein the heteroaryl group may be unsubstituted or substituted; Y

a pharmaceutically acceptable stereoisomer, salt or solvate thereof; or

(b)

 Ar is a phenyl group substituted with heteroaryl; wherein the heteroaryl group may be unsubstituted or substituted;

B is oxygen; R2 is S (O) 2R4; R3 is chlorine; Y a pharmaceutically acceptable stereoisomer, salt or solvate thereof; or (c) Ar is 6- (2-benzo [d] thiazol-2-yl) phenyl with the phenyl part coupled to B; B is oxygen; R2 is S (O) 2R4; R3 is chlorine; R4 is 4-methylphenyl ,, 3,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2 -chloro-4-trifluoromethylphenyl, or 4-cyanophenyl; and a pharmaceutically acceptable stereoisomer, salt or solvate thereof; or (d) Ar is 6- (2-benzo [d] thiazol-2-yl) phenyl with the phenyl part coupled to B; B is oxygen; R2 is S (O) 2R4; R3 is chlorine; R4 is 4-methoxyphenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, or 2-chloro-4-trifluoromethylphenyl; and a stereoisomer, salt or pharmaceutically acceptable solvate thereof. 4. A compound according to claim 1 or claim 2, wherein

(to)

 Ar is a phenyl group substituted with heterocyclyl with the phenyl part coupled to B; wherein the heterocyclyl group can be unsubstituted or substituted; B is oxygen

R2 is C (O) (CH2) n-C (O) OR5; Y a pharmaceutically acceptable stereoisomer, salt or solvate thereof; or

(b)

 Ar is 4- (4-acetyl-piperazinyl-1-yl) phenyl with the phenyl part coupled to B; B is oxygen R2 is C (O) (CH2) n-C (O) OR5; R3 is chlorine; R5 is hydrogen; Y a pharmaceutically acceptable stereoisomer, salt or solvate thereof.

5.

 A compound according to any one of the preceding claims 1 to 4, wherein the compound is: N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -2 , 4-dichlorobenzenesulfonamide, N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -4-methoxybenzenesulfonamide, N- (6- (4- (4-Acetylpiperazinyl) -1-yl) phenoxy) -5-chloropyridin-3-yl) -3,4-dimethoxy-benzene sulfonamide, N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridine- 3-yl) -2,5-dimethoxybenzene sulfonamide, N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -2-chloro-4- ( trifluoromethyl) benzenesulfonamide, N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -3,4-dichlorobenzenesulfonamide, N- (6- (4- (4- (4- (4- (4- Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -4- (trifluoromethoxy) benzene sulfonamide, N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin- 3-yl) -4-methylbenzenesulfonamide, N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -2,4-difluorobenzenesulfonamide, N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -4-fluorobenzenesulfonamide, 2,4-Dichloro-N- (5-chloro-6- (4- (piperazin-1 -yl) phenoxy) pyridin-3-1) benzenesulfonamide, N- (5-Chloro-6- (3- (4-methylpiperazin-1-yl) phenoxy) pyridin-3-yl) -2,4-difluorobenzene sulfonamide, N- (5-Chloro-6- (3- (4-methylpiperazin-1-yl) phenoxy) pyridin-3-yl) -4-methoxybenzenesulfonamide, 4- (6- (4- (4-Acetylpiperazinyl-1-) yl) phenoxy) -5-chloropyridin-3-yloamino) -4-oxobutanoic, N- (6- (2- (Benzo [d] thiazol-2-yl) phenoxy) -5-chloropyridin-3-yl) -2 , 4-dichlorobenzenesulfonamide, N- (6- (2- (Benzo [d] thiazol-2-yl) phenoxy) -5-chloropyridin-3-yl) -4-methoxybenzenesulfonamide, N- (6- (2- (Benzo [d] thiazol-2-yl) phenoxy) -5-chloropyridin-3-yl) -3,4-dichloro-benzene sulfonamide, N- (6- (2- (Benzo [d] thiazol-2-yl) phenoxy ) -5-chloropyridin-3-yl) -2-chloro-4- (trifluoromethyl) benzenesulfonamide; Y

a pharmaceutically acceptable stereoisomer, salt or solvate thereof.

6.

 A compound according to any one of claims 1 to 4, wherein the compound is: N- (6- (4- (4-Acetylpiperazinyl-1-yl) phenoxy) -5-chloropyridin-3-yl) -2, 4-dichlorobenzenesulfonamide,

2,4-Dichloro-N- (5-chloro-6- (4- (piperazinyl-1-yl) phenoxy) pyridin-3-yl) benzenesulfonamide, 4- (6- (4- (4-Acetylpiperazinyl-1) -yl) phenoxy) -5-chloropyridin-3-yloamino) -4-oxobutanoic; and a pharmaceutically acceptable stereoisomer, salt or solvate thereof.

7.

A process for the preparation of a compound of general formula (I):

image 1 5 where Ar is a phenyl group substituted with heterocyclyl or heteroaryl; wherein the hetercyclyl or heteroaryl group can be not substituted or substituted; B is –O-, -S-, or –NH-; R3 is halogen, cyano, (CO) OR6, or C (O) NR7R8; R6 is hydrogen or (C1-C4) alkyl; R7 and R8 are independently hydrogen or (C1-C6) alkyl; R1 is H, R2 is SO2R4, and R4 is unsubstituted or substituted aryl, which comprises a) reacting a compound of general formula (II): image 1 wherein Hal is fluorine, chlorine, bromine or iodine and R3 is as defined above, with a compound of formula (III): Ar-BH wherein Ar and B are as defined above, in the presence of a base such as cesium carbonate, to obtain a compound of general formula (IV); image 1  Formula (IV) wherein Ar, B and R3 are as defined above; (b) subject the nitro compound of formula (IV) above to reduction to obtain a corresponding amino compound of formula (V) image 1 wherein Ar, B and R3 are as defined above; c) reacting the amino compound of general formula (V) with Hal-SO2R4 wherein Hal is fluorine, chlorine, bromine, or iodine and R4 is as defined above in the presence of a base to obtain the compound of formula (I) ; Y, d) optionally, convert the resulting compound into a pharmaceutically acceptable salt. 8. A process for the preparation of a compound of general formula (I): image 1 where 10 Ar is a phenyl group substituted with heterocyclyl or heteroaryl; wherein the heterocyclyl or heteroaryl group can be not substituted or substituted; B is –O-, -S-, or –NH-; R3 is halogen, cyano, (CO) OR6, or C (O) NR7R8; R6 is hydrogen or (C1-C4) alkyl; R7 and R8 are independently hydrogen or (C1-C6) alkyl; R1 is H, R2 is C (O) (CH2) n-C (O) OR5, n is an integer of 1-3, and R5 is hydrogen, (C1-C6) alkyl, or unsubstituted aryl or substituted, which comprises a) reacting a compound of general formula (II): image 1 wherein Hal is fluorine, chlorine, bromine or iodine and R3 is as defined above, with a compound of formula (III): Ar-BH wherein Ar and B are as defined above, in the presence of a base such as cesium carbonate, to obtain a compound of general formula (IV); image 1 wherein AR, B and R3 are as defined above; b) subjecting the nitro compound of formula (IV) above to reduction to obtain a corresponding amino compound of general formula (V); image 1 10 Where Ar, B and R3 are as defined above; c) refluxing the amino compound of general formula (V) above with an anhydride [(CH2) n (CO) 2] to obtain an acid of formula (I) wherein R2 is -C (O) (CH2) nC (O ) OH and n is an integer of 1-3; d) optionally, convert the acid of formula (I) to an ester of formula (I) wherein R2 is -C (O) (CH2) n C (O) OR5; n is an integer of 1-3, and R5 is (C1-C4) alkyl or aryl; and, e) optionally, converting the resulting acid or ester into a pharmaceutically acceptable salt.

9.

 A pharmaceutical composition, comprising a pharmaceutically effective amount of a compound of general formula (I) according to any one of the preceding claims 1 to 6, or a stereoisomer, salt

pharmaceutically acceptable or pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier or diluent.

10.

A pharmaceutical composition, comprising a pharmaceutically effective amount of a compound of general formula (I) according to any one of the preceding claims 1 to 6, or a stereoisomer, salt

5 pharmaceutically acceptable or pharmaceutically acceptable solvate thereof, and at least one additional pharmaceutically active compound, together with a pharmaceutically acceptable carrier or diluent. 11. The use of a compound of formula (I) according to any of the preceding claims 1 to 6, or a stereoisomer, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of a disorder metabolic related to resistance to 10 insulin or hyperglycemia in a mammal. 12. The use according to claim 11, wherein the metabolic disorder related to insulin resistance or hyperglycemia comprises: type 2 diabetes, obesity, glucose intolerance, dyslipidemia, hyperinsulinemia, atherosclerosis, polycystic ovary syndrome, disease of coronary arteries, hypertension, aging, non-alcoholic fatty liver disease, infections, cancer or stroke. 13. The use according to claim 11 or claim 12, wherein the metabolic disorder related to insulin resistance or hyperglycemia is type 2 diabetes.

14.

The use according to claim 11 or claim 12, wherein the metabolic disorder related to insulin resistance or hyperglycemia is obesity.

fifteen.

The use of a compound of formula (I) according to any of the preceding claims 1 to 6, or a

20 stereoisomer, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of metabolic disorders related to insulin resistance or hyperglycemia in a mammal, said medicament is manufactured for administration either sequentially or simultaneously. , with at least one other pharmaceutically active compound.