MXPA00011083A - Phenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia - Google Patents

Abstract

This invention provides compounds of structural Formula (I) wherein A is O, S, or N;B is -(CH2)m-, -CH(OH)-, or carbonyl;R1 is hydrogen, halogen, alkyl of 1-6 carbon atoms, alcoxy of 1-6 carbon atoms, or trifluoromethyl;R2 is alkyl of 1-18 carbon atoms, aryl of 6-10 carbon atoms, arylalkyl of 7-15 carbon atoms, Het-alkyl wherein the alkyl moiety is 1-6 carbon atoms;Het is (a) or (b);R2a is alkylene of 1-3 carbon atoms;G is oxygen, sulfur, or nitrogen;R3, R4 are each, independently, hydrogen, halogen, alkyl of 1-3 carbon atoms, aryl of 6-10 carbon atoms or a heterocyclic ring of 5 to 7 ring atom containing 1 to 3 heteroatoms selected from oxygen, nitrogen, sulfur;R5 is hydrogen, alkyl of 1-6 carbon atoms, -CH(R7)R8, -C(CH2)nCO2R9, -C(CH3)2CO2R9, -CH(R7)(CH2)nCO2R9, or CH(R7)C6H4CO2R9;R6 is hydrogen, halogen, alkyl of 1-6 carbon atoms, or -OR5;m=1-6;n=1-6;R7 is hydrogen, alkyl of 1-6 carbons atoms, aryl of 6-10 carbon atoms, or arylalkyl of 7-15 carbon atoms;R8 is -CO2R10, -CONHR10, tetrazole, or -PO3;R9 and R10 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, or arylalkyl of 7-15 carbon atoms;or a pharmaceutically acceptable salt thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia.

Description

USEFUL GENIOXOACOTIC ACIDS IN BL TREATMENT OF INSULIN B RESISTANCE HIPBRGLICKMIA BACKGROUND DB THE INVENTION The prevalence of insulin resistance in glucose-tolerant subjects has been recognized for a long time. Reaven et al (American Journal of Medicine 1976, 60, 80), used a continuous infusion of glucose and insulin (insulin / glucose fixation technique) and oral glucose tolerance tests to demonstrate that there is resistance to insulin in a diverse group of non-cetdnicos and non-obese subjects. These subjects varied from the limit of tolerant to glucose until they showed hyperglycemia in evident fasting. The diabetic groups in these studies included subjects both insulin dependent (IDDM) and non-insulin dependent (NIDDM). Coincident with sustained insulin resistance is the more easily determined hyperinsulinemia, which can be measured by precise determination of circulating plasma insulin concentration in the subjects' plasma. Hyperinsulinemia may be present as a result of insulin resistance, such as in obese and / or diabetic subjects (NIDDM) or in glucose-intolerant subjects, or both, or in IDDM subjects, as a result of a Ref: 12382 insulin overinjection compared to the physiological release of the hormone by the endocrine pancreas. The association of hyperinsulinemia with obesity and ischemic diseases of large blood vessels (for example atherosclerosis) has been well established by numerous experimental, clinical and epidemiological studies (summarized by Stout, Metabolism 1985, 34, 7, and in more detail by Pyorala et al. al, Diabetes / Metabolism Reviews 1987, 3, 63). Statistically significant plasma insulin elevations 1 and 2 hours after oral glucose loading correlate with an increased risk of coronary heart disease. Since most of these studies actually exclude diabetic subjects, the data regarding risk of atherosclerotic diseases to the diabetic condition are not as numerous, but point in the same direction as in non-diabetic subjects (Pyorala et al) . However, the incidence of atherosclerotic diseases in the morbidity and mortality statistics in the diabetic population exceeds that of the non-diabetic population (Pyorala et al., Jarrett Diabetes / Metabolism Reviews 1989, 5, 5 7; Harris et al, Mortality from diabetes, in Diabetes in America 1985).

Risk factors independent of obesity and hypertension for atherosclerotic diseases are also associated with insulin resistance. Using a combination of insulin / glucose loads, tracer glucose infusion and indirect calorimetry, it has been shown that insulin resistance of essential hypertension is localized in peripheral tissues (mainly muscles) and correlates directly with the severity of hypertension (DeFronzo and Ferrannini, Diabetes Care 1991, 14, 173). In hypertension of obese insulin resistance generates hyperinsulinemia, which is recruited as a mechanism to limit the additional weight gain via thermogenesis, but insulin also increases the renal reabsorption of sodium and stimulates the sympathetic nervous system in the kidneys, heart and vasculature, which generates hypertension. It has now been appreciated that insulin resistance is usually the result of a defect in the insulin receptor signaling system, at the site subsequent to the binding of insulin to the recipient. Accumulated scientific evidence demonstrates insulin resistance in the major tissues which respond to insulin (muscle, liver, adipose tissue), strongly suggesting that the defect in transduction of the insulin signal is at an early stage in this cascade , specifically in the activity of the insulin receptor kinase, which appears to be diminished (reviewed by Haring, Diabetalogia 1991, 34, 8 8).

Proteins-tyrosine phosphatases (PTPases play a very important role in the regulation of phosphorylation of - i -protein. The interaction of insulin with its receptor leads to the phosphorylation of certain tyrosine molecules within the receptor protein, thereby activating the receptor kinase. PTPases disform the activated insulin receptor, attenuating the tyrosine kinase activity. PTPases can also modulate post-receptor signaling by catalyzing the dephosphorylation of cellular substrates of the insulin receptor kinase. Enzymes that appear most likely to be closely associated with the insulin receptor, and therefore, are more likely to regulate insulin receptor kinase activity include PTP1B, LAR, PTPa and SH-PTP2 (BJ Goldstein, J. Cellular Biochemistry 1992, 48, 33, BJ Goldstein, Receptor 1993, 3, 1-15, F. Ahitad and BJ Goldstein Biochim, Biophys Acta 1995, 1248, 57-69). McGuire et al. (Diabetes 1991, 40, 939), demonstrated that non-diabetic glucose intolerant subjects possess significantly higher levels of PTPase activity in muscle tissue versus normal subjects, and that insulin infusion did not suppress PTPase activity as it did in sensitive subjects to insulin. Meyerovitch et al., (J. Clinical Invest., 1989, 84, 976) observed significantly increased PTPase activity in the livers of two IDDM rodent models, the genetically diabetic BB rat and the diabetic rat induced by STZ. Sredy et al (? Tetabolisin,, 107, 1995) observed increased PTPase activity similar in the livers of obese ob / ob obese mice, a genetic rodent model of NIDDM. The compounds of this invention have been shown to inhibit PTPases derived from rat liver microsomes and recombinant human-derived PTPase-1B (hPTP-1B) in vi tro. They are useful in the treatment of insulin resistance associated with obesity, glucose intolerance, diabetes mellitus, hypertension and ischemic diseases of large and small blood vessels. European patent application 5359 Al describes the preparation of 3-benzoylbenzofuran derivatives as intermediates of the cardiovascular drug. Czech patent 265559 Bl describes a process for preparing 2-ethyl-3- (3,5-dibromo- -hydroxybenzoyl) coumarona as an uricosuric agent. Fodor describes 2-ethyl-3- (3,5-dibromo- -hydroxybenzoyl) benzofuran [HU 18236 (1980)].

DESCRIPTION OF THE INVENTION This invention provides a compound of formula I that has the structure where: A is 0, S or N; B is - (CH2) "-, -CH (OH) -, or carbonyl; R1 is hydrogen, nitro, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms or trifluoromethyl; R2 is alkyl of 1-18 carbon atoms, aryl of 6-10 carbon atoms, arylalkyl of 7-15 carbon atoms, Het-alkyl wherein the alkyl portion is 1-6 carbon atoms; it is alkylene of 1-3 carbon atoms,; G is oxygen, sulfur or nitrogen; R3 and R4 each independently are hydrogen, halogen, alkyl of 1-3 carbon atoms, aryl of 6-10 carbon atoms or a heterocyclic ring of 5 to 7 ring atoms containing 1 to 3 heteroatoms which are selected of oxygen, nitrogen, sulfur; R5 is hydrogen, alkyl of 1-6 carbon atoms, -CH (R7) RC (CH2) nC02R9, C- (CH3) 2C02R9, -CH (R7) (CH2) nC02R9 or CH (R7) C6H4C02R9; R6 is hydrogen, halogen, alkyl of 1-6 carbon atoms or -OR5; m = 1-6; n = 1-6; R7 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms or arylalkyl of 7-15 carbon atoms; R8 is -C02R10, -COONHR10, tetrazole, or -P03H2; R9 and R10 are each independently hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms or arylalkyl of 7-15 carbon atoms; or a pharmaceutically acceptable salt thereof, which are useful in the treatment of metabolic disorders related to insulin resistance or hyperglycemia.

The pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, maldonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfadic, naphthalenesulfonic, benzenesulfdane, toluenesulfonic, camphorsulfonic and acceptable acids similarly known when a The compound of this invention contains a basic portion. The salts may also be formed from organic and inorganic bases, preferably alkali metal salts, for example sodium, lithium or potassium, when a compound of this invention contains a carboxylate or phenolic portion, or similar portion capable of forming addition salts of base. Alkyl includes portions of both straight and branched chain, halogen means bromine, chlorine, fluorine and iodine. It is preferred that the aryl portion of the aryl or aralkyl substituent be a phenyl, naphthyl or 1,4-benzodioxan-5-yl group; the phenyl being preferred. The aryl portion may optionally be mono-, di- or tri-substituted with a substituent selected from the group consisting of alkyl of 1-6 carbon atoms, alkoxy of carbon atoms, trifluoromethyl, halogen, 2-7 alkoxycarbonyl. carbon atoms, alkylamino of 1-6 carbon atoms and dialkylamino, in which each of the alkyl groups is 1-6 carbon atoms, nitro, cyano, -C02H, alkylcarbonyloxy of 2-7 carbon atoms and alkylcarbonyl of -7 carbon atoms.

The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and thus give rise to optical isomers and diastereomers. Although shown to be without respect to the stereochemistry in formula I, the present invention includes such optical isomers and diastereomers, as well as the enantiomerically pure, racemic and R-S separated stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. Preferred compounds of this invention are those compounds of formula I, wherein: R 1 is hydrogen or halogen; R2 is alkyl of 1-6 carbon atoms or aralkyl of 7-15 carbon atoms; R3 and R4 are halogen; and m = 1; or a pharmaceutically acceptable salt thereof. The most preferred compounds of the present invention are set forth below: Example 1. (2-Ethyl-benzofuran-3-yl) - (3,5-dibromo-4-hydroxyphenyl) methanone Example 2. [2, 6-dibromo-4 - (2-et-il-benzofuran-3-carbonyl) -phenoxy] -acetic acid Example 3. 2, 6-dibromo-4- (2-ethyl-benzofuran-3-yl-methyl) -phenol Example 4. (3, 5-dibromo-2,4-dihydroxy-phenyl) - (2-ethyl- benzofuran-3-yl) -metanone. Example 5. [2,6-dibromo-4- (2-butyl-benzofuran-3-carbonyl) -phenoxy] -acetic acid Example 6. (2-Butyl-benzofuran-3-yl) - (3, 5-dibromo) 4-dihydroxy-phenyl) -methanone Example 7. (2,6-dibromo-4- (2-butyl-benzofuran-3-ylmethyl) -phenoxy] -acetic acid Example 8. (2-yl-benzofuran) 3-yl) - (2,4,6-tribromo-3-hydroxy-phenyl) -methanone Example 9. (2-benzyl-benzofuran-3-yl) - (4-hydroxy-3,5-diiodo-phenyl) -metanone- Example 10. [4- (2-Benzyl-benzofuran-3-carbonyl) -2,6-dibromo-phenoxy] -acetic acid Example 11. (2-benzyl-benzo [b] thiophen-3-yl] ) - (3,5-dibromo-hydroxy-phenyl) -methanone Example 12. [4- (2-Benzyl-benzo [b] thiophen-3-carbonyl) -2,6-dibromo-phenoxy] -acetic acid Example 13. (5-Chloro-2-ethyl-benzofuran-3-yl) - (3,5-dibromo-4-hydroxy-phenyl) methanone Example 14. (2-benzyl-benzofuran-3-yl) - (3 , 5-dibromo-4-hydroxy-phenyl) -metanone Example 15. (3,5-dibromo-4-hydroxy-phenyl) - (2-phenethyl-benzofuran-3-yl) -methanone Example 16. (2-Butyl-benzofuran-3-yl) - (4-hydroxy) 3, 5-diiodo-phenyl) -metanone 5 Example 17. [4- (2-Benzyl-benzofuran-3-carbonyl) -2,6-diiodo-phenoxy] -acetic acid Example 18. (2-ethyl-benzofuran- 3-yl) - (4-hydroxy-3), 5-diiodo-phenyl) -methanone Example 19. [2,6-dibromo-4- (2-phenethyl-10-benzofuran-3-carbonyl) -phenoxy [-acetic acid] Example 20. [2,6-dibromo-] acid 4- (5-Chloro-2-ethyl-1-benzofuran-3-carbonyl) -phenoxy] -acetic Example 21. [4- (2-Benzyl-benzo [b] thiophen-3-carbonyl) -2-6 acid dibromo-phenoxy-methyl] -phosphdomic acid Example 22. (R) -2- [2,6-dibromo-4- (2-butyl-benzofuran-3-carbonyl) -phenoxy] -3-phenyl-propionic acid Example 23 (R) -2- [2,6-dibromo-4- (2-butyl-benzofuran-3-ylmethyl) -phenoxy] -3-phenyl-propionic acid The compounds of this invention are prepared in accordance with the following scheme from commercially available starting materials or initial materials which can be prepared using literature procedures. Reaction Scheme I shows the preparation of the representative compounds of this invention. ~ 25 Reaction scheme "*" '' * n-BuULi ¡^ "CF.CP.H ¡^ x-o.s 1 In reaction scheme I, commercially available benzofurans and benzothiophenes (1) can be cleaned in position 2 with alkyl lithium reagents which, by treatment with aldehydes R2-CHO, produce the alcohols (2) [see Org, React . 1979, volume 26]. The reduction of alcohols (2) with sodium borohydride and trifluoroacetic acid [see Syn. Comm. 1990. 20, 487-493] provide the compounds (3). Compounds (3) can be treated with acyl chlorides using the Friedel-Crafts protocol [Friedel-Crafts and Related Reactions. Wiley Interscience, New York, 1963-1965] to produce ketones (4). Ketones can be reduced to compounds (6) using the Wolff-Kishner protocol [see, Org. Reactions, 1948, volume 4]. The compounds (4) and (6) can be demethylated with BBr3 [see J. Org. Chem. 1974, 39, 1427-1429] to produce the phenols (5) and (7). The phenols (5) and (7) can be brominated with bromine and potassium acetate in acetic acid or can be iodinated with iodine in the presence of sodium hydroxide to produce the brominated or iodinated compounds (9). The compounds (9) can be coupled with aromatic or heteroaromatic boronic acids in the presence of palladium catalysts [Suzuki protocol; see Syn. Comm. 1981, 11, 513-519] to produce terphenyls (10). The compounds (5), (7), (9) and (10) can be used to produce the desired products (11-13). First, the compounds (5). (7) and (9) they can be alkylated with methyl bromoacetate in the presence of sodium hydride to produce methyl esters of oxoacetic acids which can be saponified with sodium hydroxide to produce the oxoacetic acids (11). Secondly, the compounds (5), (7) and (9) can be alkylated with bromoacetonitrile to produce oxo-acetonitrile which, under treatment with sodium azide and ammonium chloride, produces tetrazoles (12). Third, compounds (5), (7) and (9) can be treated with 2-hydroxycarboxylates (for example 3-phenyl-lactic acid), using the Mitsunobu protocol [see Synthesis 1981, 1-27] to produce oxoacetates, which can be saponified with sodium hydroxide to provide oxoacetic acids (13). The compounds of this invention are useful for treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. Therefore, the compounds of this invention are particularly useful in the treatment of type II diabetes inhibition. The compounds of this invention are also useful in modulating glucose levels in disorders such as diabetes I. The ability of the compounds of this invention to treat or inhibit disorders related to insulin resistance or hyperglycemia was established with representative compounds of this invention in the following two standard pharmacological test procedures which measure the inhibition of PTPase.

Inhibition of dephosphorylation of the triphosphorylated insulin receptor dodecaphospeptide by rat hepatic protein tyrosine phosphatases (PTPases).

This standard pharmacological test procedure determines the inhibition of rat hepatic microsomal PTPase activity using, as a substrate, the phosphotyrosyl dodecapeptide which corresponds to the insulin receptor kinase domain 1142-1153, phosphorylated at the tyrosine residues 1146, 1150 and 1151. procedure used and the results obtained are briefly indicated in the following.

Preparation of the microsomal fraction: Rats (male Sprague-Dawley rats (Charles River, Kingston, NY) weighing 100-150 g, maintained with standard rodent feed (Purina)) are sacrificed by asphyxiation with C02 and bilateral thoracotomy. The liver is removed and washed in cold 0.85% (w / v) saline, and weighed. The tissue is homogenized on ice and 10 volumes of buffer A and the microsomes are isolated essentially as described by Meyerovitch J, Rothenberg P, Shechter Y. Bonner-Weir S, Kahn CR. Vanadate normalizes hyperglycemia in two mouse models of diabetes mellitus not insulin dependent. J Clin Ipvest 1991; 87: 1286-1294 and Alberts B. Bray D. Lewis J. Raff M, Roberts K. Watson JD, editors. Molecular biology of the cell. New York; Garland Publishing, Inc., 1989 with minor modifications. The liver homogenate is filtered through silk to remove any remnant of remaining tissue and then centrifuged at 10,000 xg for 20 minutes at 40 ° C. The supernatant is decanted and centrifuged at 100,000 xg for 60 minutes at 40 ° C. The sediment, microsomes and small vesicles are resuspended and slightly homogenized in: 20 mM TRIS-HC1 (pH 7.4), 50 mM 2-mercaptoethanol, 250 mM sucrose, 2 mM EDTA, 10 mM EGTA, 2 mM AEBSF, 0.1 TLCK mM, 0.1 mM TPCK, 0.5 mM benzamidine, 5 μg / ml leupeptin, 5 μg / ml pepstatin A, 5 μg / ml antialpan H5B, 5 μg / ml chymostatin, 10 μ / ml aprotinin (buffer A) , to a final concentration of approximately 850 μg protein / ml. The protein concentration is determined by the Pierce Coomassie Plus protein assay using crystalline bovine serum albumin as a standard (Pierce Chemical Co., Rockford, ID.

Measurement of PTPase activity: The malachite-molybdate ammonium green method was used, as described by Lanzetta PA, Alvarez LJ, Reinach PS, Candia OA. An improved assay is used for nanomolar quantities of inorganic phosphate, Anal Biochem. 1979; 100: 95-97, and it adapts to plate reader for the nanomolar detection of phosphate released by rat hepatic microsomal PTPases. The test procedure uses as substrate a dodecaphospeptide adapted, synthesized by AnaSpec, Inc. (San José, CA). The peptide, TRDIYETDYYRK, which corresponds to the catalytic domain 1142-1153 of the insulin receptor, is phosphorylated in tyrosine, in the tyrosine residues 1146, 1150 and 1151. 83.25 μl of the microsomal fraction is preincubated for 10 min at 37 ° C with or without 6.25 μl of the test compound and 305.5 μl of a HEPES 81.83 mM reaction buffer, pH 7.4. The peptide substrate, 10.5 μl at a final concentration of 50 μM, is equilibrated at 37 ° C in a LABLINE Multi-Blok heater equipped with a titration plate adapter. 39.5 μl of the pre-incubated microsomal preparation is added with or without medication to initiate the dephosphorylation reaction, which is carried out at 37 ° C for 30 min. The reaction is terminated by the addition of 200 μl of a malachite-ammonium molybdate green reagent-Tween 20 reagent (MG / AM / Tw). The detection reagent consists of 3 parts malachite green hydrochloride 0.45%, one part ammonium molybdate tetrahydrate in 4 N HCl and 0.5% Tween 20. The sample blanks are prepared by the addition of 200 μl of MG / AM / Tw to the substrate and followed by 39.5 μl of the pre-incubated membrane with or without drug. The color is allowed to develop at room temperature for 30 min and the Absorbances of the sample at 650 nm using a plate reader (Molecular Devices). Samples and targets are prepared in quadruplicate. The activity of 50 μM drug analysis (final) is determined by inhibition of the microsomal PTPases.

Calculations: PTPase activities, based on a standard potassium phosphate curve, are expressed as phosphate nmoles released / min / mg protein. The inhibition of PTPase of the test compound is calculated as percent of the control. A fourth non-linear logistic regression parameter of PTPase activities using SAS version 6.08, PROC NLIN is used to determine the IC50 values of the test compounds. All compounds were administered at a concentration of 50 μM. The following results were obtained using representative compounds of this invention.

Inhibition of the dephosphorylation of the triphosphorylated insulin receptor dodecaphospeptide. by hPTPIB This standard pharmacological test procedure determines the inhibition of recombinant rat tyrosine phosphatase protein, PTP1B, using activity as a substrate, in phosphotyrosyl dodecapeptide corresponding to the insulin receptor kinase domain 1142-1153, phosphorylated at tyrosine residues 1146-1150 and 1151. The procedure used and the results obtained are discussed briefly in the following. Human recombinant PTP1B is prepared as described by Goldstein (see Goldstein et al., Mol, Cell, Biochem, 109, 107, 1992). The enzyme preparation used is in microtubes containing 500-700 μg / ml of protein in Tris-Hcl, 2 mM EDTA, 10% glycerol and 2-mM 10-mercaptoethanol.

Measurement of PTPase activity. The malachite-ammonium molybdate green method was used as described (Lanzetta et al, Anal Biochem., 100, 95, 1979) and adapted for a plate reader, for the nanomolar detection of phosphate released by recombinant PTP1B. The test procedure uses as substrate a dodecaphospeptide adapted synthesized by AnaSpec, Inc. (San José, CA). The TRDIYETDYYRK peptide, which corresponds to the catalytic domain 1142-1153 of the insulin receptor, is phosphorylated on tyrosine, on the tyrosine residues 1146, 1150 and 1151. The recombinant rPTPIB is diluted with buffer (pH 7.4 containing 33 mM Tris-HCl, 2 mM EDTA and 50 mM b-mercaptoethanol) to obtain an activity of approximately 1000-2000 nmoles / min / mg of protein. 83.25 ml of enzyme diluted for 10 min at 37 ° C are preincubated with or without 6.25 ml of the test compound and 305.5 ml of HEPES 81.83 mM reaction buffer, pH 7.4 of peptide substrate, 10.5 ml at a final concentration of 50 mM, and equilibrated at 37 ° C in a LABLINE Multi-Blok heater equipped with a titration plate adapter. 39.5 ml of recombinant enzyme preparation pre-incubated with or without medication is added to initiate the dephosphorylation reaction, which is carried out at 37 ° C for 30 minutes. The reaction is terminated by the addition of 200 ml of malachite-ammonium molybdate-green detection reagent Tween 20 (MG / AM / Tw). The detection reagent consists of 3 parts of hydrochloride malachite green 0.45%, one part ammonium molybdate tetrahydrate 4.2% in 4 N HCl and 0.5% Tween 20. The sample blanks are prepared by the addition of 200 ml of MG / AM / Tw to the substrate and followed by 39.5 ml of the pre-incubated recombinant enzyme, with or without medication. Heat is allowed to develop at room temperature for 30 min and the absorbances of the sample at 650 nm are determined using a plate reader (Molecular Devices). The sample and the targets are prepared in quadruplicate.

Calculations: PTPase activities, based on a standard potassium phosphate curve, are expressed as phosphate nmoles released / min / mg protein. Inhibition of recombinant PTP1B by test compounds is calculated as percent phosphatase control. A nonlinear logistic regression of four parameters of PTPase activities using SAS version 6.8, PROC NLIN, is used to determine the CIS0 values of the test compounds. The following results were obtained.

The blood glucose lowering activity of the representative compounds of this invention was demonstrated in a standard in vivo procedure using diabetic mice (ob / ob). The procedures used and the results obtained are briefly described in the following.

The non-insulin-dependent diabetic syndrome (NIDDM) is typically characterized by obesity, hyperglycemia, Abnormal insulin secretion, hyperinsulinemia and insulin resistance. Genetically obese-hyperglycemic ob / ob mice show many of these metabolic abnormalities and are considered to be a useful model for the investigation of hypoglycemic agents to treat NIDDM [Coleman, D.; Diabetology 14: 141-148, 1978]. In each procedure, mice [male or female ob / ob (C57 B1 / 6J) and their thin counterparts (ob / + or + / +, Jackson Laboratories) aged 2 to 5 months (10 to 65 g) were randomized. ] of a similar age, according to body weight, in 4 groups of 10 mice. Five mice were housed per cage and maintained with normal rodent feed and water ad libitum. Mice received the test compound daily by tube feeding (suspended in 0.5 ml of 0.5% methylcellulose); dissolved in water to drink, or mixed in the diet. The dose of the compounds provides ranges of 2.5 to 200 mg / kg body weight / day. The dose is calculated based on the weekly body weight fed and expressed as active portion. The positive control, ciglitazone (5- (4- (1-methylcyclohexylmethoxy) benzyl) -2,4-dione, see Chang, A., Wyse, B., Gilchrist, B., Peterson, T. and Diani. Diabetes 32: 830-838, 1983) is administered at a dose of 100 mg / kg / day, which produces a significant decrease in plasma glucose. Control mice received only vehicle.

On the morning of day 4, 7 or 14, two drops of blood (approximately 50 μl) are collected in tubes containing sodium fluoride, either from the tail vein or after decapitation. For those studies in which the compound was administered daily by tube feeding, blood samples were collected two hours after administration of the compound. The plasma was isolated by centrifugation and the glucose concentration was measured enzymatically in an Abbot V.P analyzer. For each mouse, the percentage change in plasma glucose was calculated on days 4, 7 or 14, relative to the mean plasma glucose of the vehicle-treated mice. The analysis of variance followed by the Dunnett's comparison test (one-tailed) was used to estimate the significant difference between the plasma glucose values of the control group and the groups treated with the individual compound (CMS SAS version 5.18). The results shown in the table below show that the compounds of this invention are antihyperglycemic agents since they have lower blood glucose levels in diabetic mice.

Ciglitazopa (standard 100 -43 -39 reference) a - without significant activity (p> 0.05) at this dose Based on the results obtained in standard pharmacological test procedures, compounds representative of this inhibition have been shown to inhibit PTPase activity and decrease blood glucose levels in diabetic mice, and are therefore useful for treating metabolic disorders. related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. More particularly, the compounds of this invention useful in the treatment of type II diabetes inhibition and for modulating glucose levels in disorders such as type I diabetes. As used herein, the term "modular" means maintaining glucose levels within of clinically normal intervals. The effective administration of these compounds can be delivered at a daily dosage of about 1 mg / kg to about 250 mg / kg, and can be administered in a single dose or in two or more divided doses. Such doses may be administered in any manner useful for targeting the active compounds herein to the bloodstream of the patient. receptor, including oral, by means of implants, parenteral (including intravenous, intraperitoneal and subcutaneous injections), rectal, vaginal and transdermal. For purposes of this description, transdermal administrations are understood to include all administrations through the body surface and the inner linings of the body passages that include epithelial and mucosal tissues. Such administrations can be carried out using the present compounds, or pharmaceutically acceptable salts thereof in lotions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal), The oral formulations containing the active compounds of this invention they can comprise any conventionally used oral form, including tablets, capsules, mouth forms, troches, dragees and oral fluids, suspensions or solutions. The capsules may contain mixtures of the active compound or compounds with inert fillers or diluents, or arabos, such as pharmaceutically acceptable starches, for example corn starch, potato or tapioca), sugars, artificial sweetening agents, powdered celluloses such as cellulose crystalline and microcrystalline, flours, jellies, gums, etc. Useful tablet formulations can be made by conventional compression, granulation in number or methods of Dry granulation and use diluents, binding agents, lubricants, agents that improve the suspension or stabilizers pharmaceutically acceptable, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, calcium carboxymethyl cellulose, polyvinyl pyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, carbonate calcium, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dried starches and powdered sugar. Oral formulations herein may use standard formulations of delayed or delayed release in time to alter the absorption of the active compound or compounds. The suppository formulations can be made from traditional materials including cocoa butter with or without the addition of wax to alter the suppository melting point, and glycerin. Water-soluble suppository bases such as polyethylene glycols of various molecular weights can also be used. It is understood that the doses and their fixation, regimen and mode of administration of these compounds will vary according to the disease and the individual being treated and will be submitted to the judgment of the practicing physician involved. It is preferred that the administration of one or more compounds in the present start at a low dose and increase until the desired effects are obtained. The following procedures describe the preparation of representative examples of this invention.

Example 1 (2-ethyl-benzofuran-3-yl) - (3,5-dibromo-4-hydroxy-phenyl) -metanone This compound is obtained from Sigma Chemicals.

Example 2 Acid [2,6-dibromo-4- (2-ethyl-benzofuran-3-carbonyl) -phenoxyl-acetic acid Tertbutyl bromoacetate (0.57 ml, 3.54 mmol) in a mixture of (2-ethyl-benzofuran-3-yl) - (3,5-dibromo-4-hydroxy-phenyl) -methanone (1.0 g, 2.36 g) is added dropwise. mmoles), potassium carbonate (0.98 g, 7.08 mmol) and 10 ml of N, N-dimethylformamide. The mixture is stirred at 80 ° C for 3 hours, poured into water and extracted with ethyl acetate. The organic extracts are dried over MgSO4. Evaporation gives 1.4 g of a yellow oil which is taken up in 50 ml of dichloromethane and treated with 5 ml of acid trifluoroacetic for 10 hours. The volatile fractions are removed in vacuo and the residue is purified by flash chromatography on acid silica gel ((hexane / EtOAc 1: 1) to give a white solid (0.82 g, 42% yield): mp 135-137; m / e 480 M *; Analysis for: C19H14Br205 calculated: C, 47.33; H, 2.93 Found: C, 47.25; H, 2.91.

Example 3 2,6-dibromo-4- (2-ethyl-benzofuran-3-yl-methyl) -phenol Tert-butyldimethylsilyl chloride is added to a mixture of (2-ethyl-benzofuran-3-yl) - (3, 5-dibromo-4-hydroxy-phenyl) -methanone (10.0 g, 23.58 mmol), imidazole (1.6 g, 23. 58 mmoles) 100 mg of 4-dimethylaminopyridine and 100 mg of N, N-dimethylformamide. The mixture is stirred at room temperature for 10 hours, poured into water and extracted with ethyl acetate. The organic extracts are dried over MgSO4. Evaporation provides 11.5 g of an oil which is taken in 100 ml of MeOH and treated with sodium borohydride (0.96 g, • 25.65 mmoles). The mixture is stirred at room temperature for 3 hours, poured into water and extracted with ethyl ether. The organic extracts are dried over MgSO4. Evaporation provides 10.5 g of a residue which is taken in 100 ml of dichloromethane and treated at 0 ° C with triethylsilane (6.21 ml, 38.9 mmoles) and 10 ml of trifluoroacetic acid. After stirring for 30 minutes, the volatile fractions are removed in vacuo and the residue is treated with 5.0 ml of hydrofluoric acid in 50 ml of acetonitrile at 80 ° C for 5 hours. The volatile fractions are removed ip vacuo and the residue is purified by flash chromatography (hexane / ethyl acetate, 10: 1) to give a white solid (6.5 g, 37% yield: mp 87-88; MS m / e 408 M *; Example 4 (3,5-dibromo-2,4-dihydroxy-phenyl) - (2-ethyl-benzofuran-3-yl) -metanone A solution of bromine (0.73 ml, 14.2 mmol) in 3 ml of acetic acid is added to a solution of the known compound (2,4-dehydroxy-phenyl) - (2-ethyl-benzofuran-3-yl) -methanone (CA Reg.No.90908-66-0) (2.0 g, 7.08 mmol) in acetic acid: water 6: 1 (14 mL). The reaction mixture is added to 200 ml of water and filtered to provide the title compound as a tan solid (2.7 g, 87%); p.f. 150-151; MS m / e 438 M *; Analysis for: C17H12Br204 calculated: C, 46.39; H, 2.75 Found: C, 45.95; H, 2.66 Example 5 Acid \ 2 .6-dibromo-4- (2-butyl ^ benzofuran-3-carbonyl) -phenoxyl-acetic acid This compound is prepared from (2-butyl-benzofuran-3-yl) - (3, 5-dibromo-4-hydroxy-phenyl) -methanone and tert-butyl bromoacetate in substantially the same manner as described in Example 2 , and it is obtained as a whitish solid, mp 92-94 ° C; MS m / e 508 M *; Analysis for: C21HlβBr205 Calculated for C, 49.44; H. 3.56 Found: C, 47.24; H, 3.59 Example 6 (-butyl-benzofuran-3-yl) - (3,5-dibromo-4-dihydroxy-phenyl) -metanone 3-49 ml of bromine are added dropwise to a mixture of 2-n-butyl-3 - (hydroxy-benzoyl) benzo [b] furan (10.0 g, 34.0 mmol), 50 ml of acetic acid and 10 ml of H20. The mixture is stirred for 12 hours and poured into water. The precipitated solid is filtered and dried to give a white solid (11.2 g, 71% yield): m.p. 95-97; MS m / e 450 M *; Analysis for: C19H16Br203 x 0.8 H20 Calculated: C, 48.89; H, 3.80 Found: C, 48.83; H, 3.37.

Example 7 2,6-dibromo-4- (2-butyl-benzofuran-3-ylmethyl) -phenoxyl-acetic acid This compound is prepared from 2,6-dibromo-4- (2-ethyl-benzofuran-3-yl-methyl) -phenol and tert-butylbromoacetate in substantially the same manner as described in example 2, and as a whitish solid, mp 118-119 ° C; MS m / e 494 (M) *; Analysis for: C21H20Br2O4 Calculated: C, 50.83; H, 4.06 Found: C, 50.46; H, 3.94.

Example 8 (2-ethyl-benzof uran-3-yl) - (2,4,6-tribromo-3-hydroxy-phenyl) -metanone This compound is prepared from (2-ethyl-benzofuran-3-yl) - (3-hydroxy-f-enyl) -metanone and bromine in substantially the same manner as described in the example 6, and is obtained as a white solid, m.p. 153-154 ° C; MS m / e 517 (M-H) *; Analysis for: C17H11Br303 Calculated: C, 40.52; H, 2.20 Found: C, 40.12; H, 2.07.

Example 9 (2-benzyl-benzofuran-3-yl) - (4-hydroxy-3,5-diiodo-phenyl) -metanone A solution of (2-benzyl-benzofuran-3-yl) - (4-hydroxy-phenyl) -methanone (2.48 g, 7.55 mmol) in 1.2 g of sodium hydroxide and 113 ml of water is added dropwise in a mixture. 4.22 g of iodine, 2.75 g of sodium iodide and 113 ml of water. The new mixture is stirred at 65 ° C for 3 hours. The mixture is poured into water and extracted with ethyl acetate. The organic extracts are dried over MgSO4. Evaporation and purification by flash chromatography (petroleum ether / ethyl acetate, 6: 4) gives a tan solid (1.92 g, 4% yield): m.p. 153-154 ° C; MS m / e 580 (M) *; Analysis for: C22H14I203 Calculated: C, 45.55; H, 2.43 Found: C, 46.23; H, 2.36.

Example 10 Í4- (2-benzyl-benzofuran-3-carbonyl) -2,6-dibromo-phenoxy] -acetic acid This compound is prepared from (2-benzyl-benzofuran-3-yl) - (4-hydroxy-phenyl) -methanone and methyl bromoacetate in substantially the same manner as described in Example 20, and is obtained as a solid white, mp 165-167 ° C; MS m / e 544 (M) *; Analysis for: C24H16Br205 Calculated: C, 59.97; H, 2.96 Found: C, 52.74; H, 2.94 Example 11 (2-benzyl-benzo Tbl thiophen-3-yl) - (3,5-dibromo-4-hydroxy-phenyl) -metanone The known compound 2-benzyl-benzo [b] thiophene (CA, reg, No. 3407-15-6) is acylated with one equivalent of anisoyl chloride using one equivalent of a tin (IV) chloride promoter in a solvent of carbon disulfide to provide (2-benzyl-benzo [b] thiophen-3-yl) - (4-methoxy-phenyl) -methanone (85% yield). This compound is demethylated using six equivalents of pyridinium hydrochloride a 228 ° C to provide (2-benzyl-benzo [b] thiophen-3-yl) - (4-hydroxy-phenyl) -methanone (90% yield). This compound is brominated according to the procedure in Example 4 to provide the title compound as a white solid (95% yield): m.p. 155.5-156.5; MS m / e 500 (M) *; Analysis for: C22H14Br202S Calculated: C, 52.61; H, 2.80 Found: C, 52.43; H, 2.71 Example 12 Acid (4- (2-benzyl-benzo fbl thiophen-3-carbonyl) - .6-dibromo-phenoxy-acetic acid This compound is prepared from (2-benzyl-benzo [b] thiophen-3-yl) - (3, 5-dibromo-4-hydroxy-phenyl) -methanone and methyl bromoacetate in substantially the same manner, as described in Example 20, and obtains as a whitish solid, mp 162-163 ° C; MS m / e 588 (M) *; Analysis for: C24H16Br204S Calculated: C, 51.45; H, 2.88 Found: C, 51.15; H, 2.71 Example 13 (5-chloro-2-ethyl-benzofuran-3-yl) - (3,5-dibromo-4-hydroxy-phenyl) methanone The compound is prepared from (5-chloro-2-ethyl-benzofuran-3-yl) - (4-hydroxy-phenyl) -methanone and bromine in substantially the same manner as described in the example 6, and is obtained as a white solid, m.p. 126-128 ° C; MS m / e 454.9 (M-H) *; Analysis for: C17H11Br2C103 Calculated: C, 44.52; H, 2.42 Found: C, 44.35; H, 2.13 Example 14 (2-benzyl-benzofuran-3-yl) - (3,5-dibromo-4-hydroxy-phenyl) -metanone This compound is prepared from (2-benzyl-benzofuran-3-yl) - (4-hydroxy-phenyl) -methanone and bromine in substantially the same manner as described in the example 6, and is obtained as a white solid, m.p. 156-158 ° C; MS m / e 484 (M) *; Analysis for: C22Hl4Br203 Calculated: C, 53.43; H, 2.74 Found: C, 53.73; H, 2.75 Example 15 (3,5-dibromo-4-hydroxy-phenyl) - (2-phenethyl-benzofuran-3-yl) -metanone This compound is prepared from (2-phenethyl-benzofuran-3-yl) - (4-hydroxy-phenyl) -methanone and bromine, in substantially the same manner, as described in Example 6, and is obtained as a solid yellow, mp 153-154 ° C; MS m / e 502 (M-H) *; Analysis for: C23H16Br203 x 0.057 C2H402; Calculated: C, 55.12 H, 3.25 Found: C, 54.72; H, 2.99 Example 16 (2-Butyl-benzofuran-3-yl) - (4-hydroxy-3,5-divodo-phenyl) -metanone It is a known compound (CA Reg. No. 1951-26-4): p.f. 141.5-1425 ° C; MS m / e 545 (M + H) *; Analysis for: C19H16I203 Calculated: C, 41.79; H, 2.95 Found: C, 41.97; H, 2.83.

Example 17 Ii - (2-benzyl-benzofuran-3-carbonyl) -2,6-di-odo-phenoxyl-acetic acid This compound is prepared from (2-benzyl-benzofuran-3-yl) - (3, 5-diiodo-4-hydroxy-phenyl) -metanone and tert-butyl bromoacetate in substantially the same manner as described in Example 2. Formic acid is used instead of trifluoroacetic acid. The product is obtained as a whitish solid, m.p. 144-146 ° C; MS m / e 638 (M *); Analysis for: C24H16I205 Calculated: C, 45.17; H, 2.53 Found: C, 44.19; H, 2.42 Example 18 Acid \ i-benzyl-benzo fbl thiophen-3-carbonyl) -2,6-dibromo-phenoxy-acetic It is a known compound (CA Reg. No. 68-90-6).

Example 19 [2,6-dibromo-4- (2-phenethyl-benzofuran-3-carbonyl) -phenoxy [-abético] acid This compound is prepared from (2-phenethyl-benzofuran-3-yl) - (3,5-dibromo-4-hydroxy-phenyl) -methanone in substantially the same manner as described in the example and obtained as white solid, m.p. 163-164 ° C; MS / e 556 (M *); Analysis for: C25H18Br205 Calculated: C, 53.79; H, 3.25 Found: C, 53. 91; H, 3. 14 -.

Example 20 f 2, 6 -dibromo -4 - (5-chloro-2-ethyl-1-benzofuran-3-carbonyl) phenoxy] acetic Step a) [2,6-dibromo-4- (5-chloro-2-ethyl-l-benzofuran-3-carbonyl) -phenoxyl-acetic acid methyl ester Methyl bromoacetate is added dropwise to a mixture of (4-chloro-2-ethyl-benzofuran-3-yl) - (3,5-dibromo-4-hydroxy-phenyl) -methanone (2.81 g, 6.13 mmol), 0.93 g of potassium carbonate and 28 ml of N, N-dimethylformamide. Mix it is stirred for 15 hours, poured into water and extracted with ethyl acetate. The organic extracts are dried over MgSO4. Evaporation and purification by flash chromatography (petroleum ether / ethyl acetate, 9: 1) gives a white solid (2.89 g, 89% yield): m.p. 108-109 ° C; MS m / e 528 (M *); Analysis for: C20H51Br2ClO5 Calculated: C, 45.27; H, 2.89 Found: C, 45.08; H, 2.61 Stage b) f2.6-dibromo-4- (5-chloro-2-ethyl-l-benzofuran-3-carbonyl) -phenoxyl-acetic Potassium hydroxide (15.9 ml, 0.5 N) is added to a solution of the methyl ester of [2,6-dibromo-4- (5-15-chloro-2-ethyl-l-benzofuran-3-carbonyl) -phenoxy]] -acetic (2.8 g, 5.3 mmol) in 20 ml of tetrahydrofuran and 20 ral of methyl alcohol. The mixture is stirred for 30 minutes, poured into water, acidified with HCl and cooled to 0 ° C. The precipitated solid is filtered and dried. The crude product recrystallizes from acetic acid and water to give a white solid (2.01 g, 74% yield); p.f. 175-177 ° C; MS / E 514 (M *); Analysis for: C19H13Br2C105 Calculated: C, 44.18; H, 2.54 Found: C, 44.16; H, 2.46. '25 Example 21 f4- (2-benzyl-benzo fbl thiophen-3-carbonyl) -2 .6-dibromo-phenoxy-methyl-phosphonic acid Sodium hydride (0.09 g, 80% in mineral oil) is added in a cold (0 ° C) mixture of (2-benzyl-benzo [b] thiophen-3-yl) - (3,5-dibromo-4-) hydroxy-phenyl) -methanone (0.96 mg, 1.91 mmol) and 20 ml of tetrahydrofuran. The mixture is stirred for 1 hour and then 0.63 g of diethyl trifluoromethanesulfonoxymethylphosphonate is added dropwise. The new mixture is allowed to reach room temperature, stirred for 4 hours and then heated to 50 ° C and stirred for an additional 2 hours. The mixture is poured into water and extracted with ethyl acetate. The organic extracts are dried over MgSO4. Purification by flash chromatography (dichloromethane / acetonitrile 95: 5) gives a brown oil (0.79 g, 63% yield). The product is taken up in 18 ml of dichloromethane and treated at 0 ° C with 0.45 ml of iodotrimethylsilane for 6 hours. The mixture is poured into water and extracted with ethyl acetate. The organic extracts are dried over MgSO4. Evaporation and purification by flash chromatography (dichloromethane / acetonitrile 85:15) gives a yellow solid (1.1 g, 77% yield): m.p. 210-212 ° C; MS m / e 595 (M + H) *.

Example 22 (R) -2- [2,6-dibromo-4- (2-butyl-l-benzofuran-3-carbonyl) -phenoxy] -3-phenyl-propionic acid 0.13 ml of diethylazodicarboxylate in a solution of (2-butyl-benzofuran-3-yl) - (3,5-dibromo-4-dihydroxy-phenyl) -methanone (0.24 g, 0.54 mmoles), 0.21 g of water are added dropwise. triphenylphosphine, 0.14 g of (S) - (-) - 3-phenyl-lactic acid methyl ester and 2.4 ml of benzene. The mixture is stirred at 80 ° C for 3 hours and at room temperature overnight. The volatile fractions are removed in vacuo and the residue is purified by flash chromatography to provide 0.13 g of an oil. The product is dissolved in 1.7 ml of thydrofuran and 1.7 ml of methyl alcohol, and treated with potassium hydroxide (1.0 N, 0.5 ml). After stirring for 4 hours, the mixture is poured into water, acidified with HCl (1 N) and extracted with ethyl ether. The organic extracts are dried over MgSO4. Evaporation gives a light yellow solid (0.23 g, 84% yield): m.p. 56-58 ° C; MS m / e 597 (M-H) *; Analysis for: C28H24Br205 x 0.8 H20 Calculated: C, 54.69; H, 4.20 Found: C, 54.65; H, 3.88 Example 23 (R) -2- \ 2 .6-Dibromo-4- (2-butyl-benzofuran-3-ylmethyl) -phenoxyl-3-phenyl-propionic acid This compound is prepared from 2,6-dibromo-4- (2-ethyl-benzofuran-3-yl-methyl) -phenol and the methyl ester of (S) - (-) - 3-phenylacetic acid substantially from the Same way as described in Example 21, and obtained as an oil (0.11 g, 91% yield). The product is treated with 0.19 ml of 1 N sodium hydroxide in methyl alcohol for 30 minutes. Evaporation gives a white solid (0.1 g, 84% yield): m.p. 225-226 ° C; MS m / e 583 (M-H) *; Analysis for: C28H25Br204Na x 0.3 H20 Calculated: C, 54.78; H, 4.20 Found: C, 54.60; H, 3.79.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (25)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A compound of formula I, characterized in that it has the structure where: A is O, S or N; B is - (CH2) m-, -CH (OH) -, or carbonyl; R1 is hydrogen, nitro, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms or trifluoromethyl; R2 is alkyl of 1-18 carbon atoms, aplo of 6-10 carbon atoms, arylalkyl of 7-15 carbon atoms, Het-alkyl wherein the alkyl portion is 1-6 carbon atoms; R2 * is alkylene of 1-3 carbon atoms,; G is oxygen, sulfur or nitrogen; R3 and R4 each independently are hydrogen, halogen, alkyl of 1-3 carbon atoms, aryl of 6-10 carbon atoms or a heterocyclic ring of 5 to 7 ring atoms containing 1 to 3 heteroatoms which are selected of oxygen, nitrogen, sulfur; R5 is hydrogen, alkyl of 1-6 carbon atoms, -CH (R7) R8, -C (CH2) nC02R9, C- (CH3) 2C02R9, -CH (R7) (CH2) "C02R9 OR CH (R7) C6H4C02R9; R6 is hydrogen, halogen, alkyl of 1-6 carbon atoms or -OR5; m = 1-6; n = 1-6; R7 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms or arylalkyl of 7-15 carbon atoms; R8 is -C02R ", -COONHR10, tetrazole, or -P03; R9 and R10 are each independently hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms or arylalkyl of 7-15 carbon atoms or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, characterized in that: R1 is hydrogen or halogen; R2 is alkyl of 1-6 carbon atoms or aralkyl of 7-15 carbon atoms; R3 and R4 are halogen; and m = 1; or a pharmaceutically acceptable salt thereof.

3. The compound can be in accordance with claim 1, characterized in that it is [2,6-dibromo-4- (2-ethyl-benzofuran-3-carbonyl) -phenoxy] -acetic acid or a pharmaceutically acceptable salt of the same.

4. The compound according to claim 1, characterized in that it is 2,6-dibromo-4- (2-ethyl-benzofuran-3-yl-methyl) -phenol or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, characterized in that it is (3, 5-dibromo-2,4-dihydroxy-phenyl) - (2-ethyl-benzofuran-3-yl) -methanone or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, characterized in that it is [2,6-dibromo-4- (2-butyl-benzofuran-3-carbonyl) -phenoxy] -acetic acid or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, characterized in that it is (2-butyl-benzofuran-3-yl) - (3, 5-dibromo-4-dihydroxy-phenyl) -methanone or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1, characterized in that it is [2,6-dibromo-4- (2-butyl-benzofuran-3-ylmethyl) -phenoxy] -acetic acid or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1, characterized in that it is (2-ethyl-benzofuran-3-yl) - (2,4,6-tribromo-3-hydroxy-phenyl) -methanone or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, characterized in that it is (2-benzyl-benzofuran-3-yl) - (4-hydroxy-3,5-diiodo-phenyl) -methanone or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1, characterized in that it is [4- (2-benzyl-benzofuran-3-carbonyl) -2,6-dibromo-phenoxy] -acetic acid or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1, characterized in that it is (2-benzyl-benzo [b] thiophen-3-yl) - (3, 5-dibromo-4-hydroxy-phenyl) -methanone or a pharmaceutically acceptable salt thereof .

13. The compound according to claim 1, characterized in that it is [4- (2-benzyl-benzo [b] thiophene-3-carbonyl) -2,6-dibromo-phenoxy] -acetic acid or a pharmaceutically acceptable salt thereof .

I4- The compound according to claim 1, characterized in that it is (5-chloro-2-ethyl-benzofuran-3-yl) - (3,5-dibromo-4-hydroxy-phenyl) methanone or a pharmaceutically acceptable salt of the same.

15. The compound according to claim 1, characterized in that it is (2-benzyl-benzofuran-3-yl) - (3, 5-dibromo-4-hydroxy-phenyl) -methanone or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1, characterized in that it is [4- (2-benzyl-benzofuran-3-carbonyl) -2,6-diiodo-phenoxy] -acetic acid or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1, characterized in that it is [2,6-dibromo-4- (2-phenethyl-benzofuran-3-carbonyl) -phenoxy] -acetic acid or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 1, characterized in that it is [2,6-dibromo-4- (5-chloro-2-ethyl-1,1-benzofuran-3-carbonyl) -phenoxy] acetic acid or a pharmaceutically acceptable salt of the same.

19. The compound according to claim 1, characterized in that it is [4- (2-benzyl-benzo [b] thiophene-3-carbonyl) -2,6-dibromo-phenoxy-methyl] -phosphonic acid or a pharmaceutically acceptable salt of the same.

20. The compound according to claim 1, characterized in that it is (R) -2- [2,6-dibromo-4- (2-butyl-benzofuran-3-carbonyl) -phenoxy] -3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 1, characterized in that it is (R) -2- [2,6-dibromo-4- (2-butyl-benzofuran-3-ylmethyl) -phenoxy] -3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.

22. A method for treating metabolic disorders mediated by insulin resistance or hyperglycemia in a mammal in need thereof, which comprises administering to the mammal, a compound of formula I having the structure: where: A is 0, S or N; B is - (CH2) _-, -CH (OH) -, or carbonyl; R1 is hydrogen, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms or trifluoromethyl; R 2 is alkyl of 1-18 carbon atoms, aryl of 6-10 carbon atoms, arylalkyl of 7-15 carbon atoms, Het-alkyl wherein the alkyl portion is 1-6 carbon atoms; Ra is alkylene of 1-3 carbon atoms,; G is oxygen, sulfur or nitrogen; R3 and R4 each independently are hydrogen, halogen, alkyl of 1-3 carbon atoms, aryl of 6-10 carbon atoms or a heterocyclic ring of 5 to 7 ring atoms containing 1 to 3 heteroatoms which are selected of oxygen, nitrogen, sulfur; R5 is hydrogen, alkyl of 1-6 carbon atoms, -CH (R7) R8, -C (CH2) "C02R9, C- (CH3) 2C02R9, -CH (R ') (CH2) nC02R9 OR CH (R7) C6H1C02R9; R6 is hydrogen, halogen, alkyl of 1-6 carbon atoms or -OR5; m = 1-6; n = 1-6; R7 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms or arylalkyl of 7-15 carbon atoms; R8 is -C02R ", -CONHR10, tetrazole, or -P03; R9 and R10 are each independently hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms or arylalkyl of 7-15 carbon atoms or a pharmaceutically acceptable salt thereof.

23. A method for treating or inhibiting type II diabetes in a mammal in need thereof, characterized in that it comprises administering to the mammal a compound of formula I, having the structure: where: A is O, S or N; B is - (CH2) ", -, -CH (OH) -, or carbonyl; R1 is hydrogen, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms or trifluoromethyl; R 2 is alkyl of 1-18 carbon atoms, aryl of 6-10 carbon atoms, arylalkyl of 7-15 carbon atoms, Het-alkyl wherein the alkyl portion is 1-6 carbon atoms; R2 * is alkylene of 1-3 carbon atoms,; G is oxygen, sulfur or nitrogen; R3 and R4 each independently are hydrogen, halogen, alkyl of 1-3 carbon atoms, aryl of 6-10 carbon atoms or a heterocyclic ring of 5 to 7 ring atoms containing 1 to 3 heteroatoms which are selected of oxygen, nitrogen, sulfur; R5 is hydrogen, alkyl of 1-6 carbon atoms, -CH (R7) Rβ, -C (CH2) nC02R9, C- (CH3) 2C02R9, -CH (R7) (CH2) nC02R9 or CH (R) C6H4C02R9; Rβ is hydrogen, halogen, alkyl of 1-6 carbon atoms or -OR5; m = 1-6; n = 1-6; R7 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms or arylalkyl of 7-15 carbon atoms; R8 is -C02R10, -CONHR ", tetrazole, or -P03; R9 and R10 are each independently hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms or arylalkyl of 7-15 carbon atoms or a pharmaceutically acceptable salt thereof.

24. A method for modulating glucose levels in a mammal in need thereof, characterized in that it comprises administering to the mammal a compound of formula I having the structure: where: A is O, S or N; B is - (CH.) .-, -CH (OH) -, or carbonyl; JS ' R1 is hydrogen, haldgefio, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms or trifluoromethyl; R 2 is alkyl of 1-18 carbon atoms, aryl of 6-10 carbon atoms, arylalkyl of 7-15 carbon atoms, Het-alkyl wherein the alkyl portion is 1-6 carbon atoms; R2 * is alkylene of 1-3 carbon atoms; G is oxygen, sulfur or nitrogen; R3 and R4 each independently are hydrogen, halogen, alkyl of 1-3 carbon atoms, aryl of 6-10 carbon atoms or a heterocyclic ring of 5 to 7 ring atoms containing 1 to 3 heteroatoms which are selected of oxygen, nitrogen, sulfur; R5 is hydrogen, alkyl of 1-6 carbon atoms, -CH (R7) R8, -C (CH2) nC02R9, C- (CH3) 2C02R9, -CH (R7) (CH2) nC02R9 OR CH (R7) C6H4C02R9; R6 is hydrogen, halogen, alkyl of 1-6 carbon atoms or -OR5; m = 1-6; n = 1-6; R7 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms or arylalkyl of 7-15 carbon atoms; R 'is -C02R ", -CONHR", tetrazole, or -P03; R9 and R1 are each independently hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms or arylalkyl of 7-15 carbon atoms; or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition, characterized in that it comprises a compound of formula I, having the structure: where: A is O, S or N; B is - (CH2) "-, -CH (OH) -, or carbonyl; R1 is hydrogen, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms or trifluoromethyl; R 2 is alkyl of 1-18 carbon atoms, aryl of 6-10 carbon atoms, arylalkyl of 7-15 carbon atoms, Het-alkyl wherein the alkyl portion is 1-6 carbon atoms; R2 * is alkylene of 1-3 carbon atoms,; G is oxygen, sulfur or nitrogen; R3 and R4 each independently are hydrogen, halogen, alkyl of 1-3 carbon atoms, aryl of 6-10 carbon atoms or a heterocyclic ring of 5 to 7 ring atoms containing 1 to 3 heteroatoms which are selected of oxygen, nitrogen, sulfur; R5 is hydrogen, alkyl of 1-6 carbon atoms, -CH (R7) R8, -C (CH2) bnC02R9, C- (CH3) 2C02R9, -CH (R7) (CH2) nC02R9 or CH (R7) C6H4C02R9; R6 is hydrogen, halogen, alkyl of 1-6 carbon atoms or -OR5; m = 1-6; n «1-6; R7 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms or arylalkyl of 7-15 carbon atoms; R "is -C02R10, -CONHR10, tetrazole, or -P03; R9 and R10 are each independently hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms or arylalkyl of 7-15 carbon atoms or a pharmaceutically acceptable salt thereof.