CN1308621A - 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; R<1> is hydrogen, halogen, alkyl of 1-6 carbon atoms, alcoxy 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 moiety is 1-6 carbon atoms; Het is (a) or (b); R<2a> is alkylene of 1-3 carbon atoms; G is oxygen, sulfur, or nitrogen; R<3>, R<4> 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; R<5> is hydrogen, alkyl of 1-6 carbon atoms, -CH(R<7>)R<8>-, -C(CH2)nCO2R<9>, -C(CH3)2CO2R<9>, -CH(R<7>)(CH2)nCO2R<9>, or CH(R<7>)C6H4CO2R<9>; R<6> is hydrogen, halogen, alkyl of 1-6 carbon atoms, or -OR<5>; m=1-6; n=1-6; R<7> is hydrogen, alkyl of 1-6 carbons atoms, aryl of 6-10 carbon atoms, or arylalkyl of 7-15 carbon atoms; R<8> is -CO2R<10>, -CONHR<10>, tetrazole, or -PO3; R<9> and R<10> 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

Phenyloxo-acetic acid for the treatment of insulin resistance and hyperglycemia

Background of the invention

It has long been recognized that insulin resistance is prevalent in patients with glucose intolerance. Reaven et al. (American Journal of Medicine 1976, 60, 80) demonstrated that insulin resistance exists in different groups of non-obese, in non-ketotic patients. These patients range from borderline glucose tolerance to marked fasting hyperglycemia. In these studies, the diabetic group included both insulin-dependent (IDDDM) and non-insulin-dependent (NIDDM) patients.

Consistent with persistent insulin resistance is more readily measurable hyperinsulinemia, as measured by accurate determination of circulating insulin concentrations in the patient's plasma. Hyperinsulinemia can occur as a result of insulin resistance, for example, in patients with obesity and/or diabetes mellitus (NIDDM) and/or glucose intolerance, or in patients with IDDM as a result of interactions with transendocrine pancreatic hormones Normal physiological release compared to the results of over-injection of insulin occurs.

It has been well established through a large number of experimental, clinical and epidemiological studies (summarized by Stout, Metabolism, 1985, 34, 7 and in more detail by Pyorala et al., Diabetes/Metabolism Reviews 1987, 3, 463) Hyperinsulinemia is linked to obesity and to ischemic diseases of large vessels such as atherosclerosis. A statistically significant increase in plasma insulin within 1 to 2 hours after an oral glucose load was associated with an increased risk of coronary heart disease.

Since most of these studies actually excluded diabetic patients, there are not many data on the risk of atherosclerotic disease in relation to diabetic symptoms, but show the same trend as in non-diabetic patients (Pyorala et al.). However, in the diabetic population, the incidence of atherosclerotic disease statistically exceeds that of the non-diabetic population in terms of morbidity and mortality (Pyorala et al., Jarrett Diabetes/Metabolism Reviews 1989, 5, 547; Harris et al., in Diabetes et al. mortality rate, Diabetes in America 1985).

Obesity and hypertension, independent risk factors for atherosclerotic disease, are also associated with insulin resistance. Using a combined insulin/glucose lock approach, tracer glucose infusion, and indirect calorimetry, it has been demonstrated that insulin resistance in essential hypertension is located in the peripheral tissues (mainly muscle) and is directly related to the severity of hypertension ( DeFronzo and Ferrannini, Diabetaes care 1991, 14, 173). In obese individuals with hypertension, insulin resistance produces hyperinsulinaemia, which is restored by mechanisms that limit further weight gain by heat production, but insulin also increases renal sodium reabsorption and stimulates sympathetic responses in the kidneys, heart, and vascular system nervous system, causing high blood pressure.

It is now recognized that insulin resistance is generally the result of defects in the insulin receptor signaling system at the site of insulin binding to the receptor. Scientific evidence demonstrating the accumulation of insulin resistance in the major tissues that respond to insulin (muscle, liver, fat) strongly suggests that there is a role for insulin signaling in the early stages of this cascade, particularly upon activation of the insulin receptor kinase , which appears to be attenuated (review by Haring, Diabetalogia 1991, 34, 848).

Protein-tyrosine phosphatases (PTPases) play an important role in the regulation of the phosphorylation of proteins. The interaction of insulin with its receptor results in the phosphorylation of certain tyrosine molecules in the receptor protein, thereby activating the receptor kinase. PTPases dephosphorylate activated insulin receptors, attenuating tyrosine kinase activity. PTPases can also regulate post-receptor signaling by catalyzing the dephosphorylation of cellular substrates of insulin receptor kinase. Enzymes that seem likely to be closely related to the insulin receptor and thus likely to regulate insulin receptor kinase activity include PTP1B, LAR, PTPα, and SH-PTP2 (B.J. Goldstein, J. Cellular Biochemistry 1992, 48, 33; B.J. Goldstein, Receptor 1993, 3, 1-15; F. Ahmad and B.J. Goldstein, Biochim. Biophys Acta 1995, 1248, 57-69).

McGuire et al. (Diatetes 1991, 40, 939) demonstrated that non-diabetic glucose-impaired patients had significantly elevated levels of PTPase activity in muscle tissue relative to normal patients, and that insulin infusions were not able to suppress it as much as insulin-sensitive patients. PTPase activity.

Meyerovitch et al. (J. Clinical Invest. 1 989, 84, 976) observed significantly increased PTPase activity in the livers of two rodent models of IDDM, BB rats with hereditary diabetes and STZ-induced diabetic rats. Sredy et al. (Metabolism, 44, 1074, 1995) observed similar increased PTPase activity in the liver of obese, diabetic ob/ob mice, a genetic rodent model of NIDDM.

Compounds of the present invention have been shown to inhibit PTPases derived from rat liver microsomes and human derivatized recombinant PTPase-1B (hPTP-1B) in vitro. They are used in the treatment of insulin resistance associated with obesity, glucose intolerance, diabetes, hypertension, and ischemic disease of large and small vessels.

Eur.Pat.Appl.425359 A1 discloses the preparation of 3-benzoylbenzofuran derivatives as intermediates of cardiovascular drugs. Czech. Patent 265559 B1 discloses the method for preparing 2-ethyl-3-(3,5-dibromo-4-hydroxybenzoyl)benzofuran as a uricosuric agent. Fodor disclosed 2-ethyl-3-(3,5-dibromo-4-hydroxybenzoyl)benzofuran [HU 18236(1980)]

Description of the invention

The present invention provides compounds of formula I having the following structure or their pharmaceutically acceptable salts for use in the treatment of metabolic disorders associated with insulin resistance and hyperglycemia,

in:

A is O, S or N;

B is -(CH ₂ ) _m -, -CH(OH)- or carbonyl;

^R is hydrogen, nitro, halogen, alkyl of 1-6 carbon atoms, alkoxyl of 1-6 carbon atoms or trifluoromethyl;

^R is an alkyl group of 1-18 carbon atoms, an aryl group of 6-10 carbon atoms, an aralkyl group of 7-15 carbon atoms, a Het-alkyl group of which the alkyl part is 1-6 carbon atoms ;

或

Het is

or

R ^2a is an alkylene group of 1-3 carbon atoms;

G is oxygen, sulfur or nitrogen;

Each of R ³ and R ⁴ is independently hydrogen, halogen, an alkyl group of 1-3 carbon atoms, an aryl group of 6-10 carbon atoms, or 5 containing 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur Heterocycles of up to 7 ring atoms;

R ⁵ is hydrogen, an alkyl group with 1-6 carbon atoms, -CH(R ⁷ )R ⁸ , -C(CH ₂ ) _n CO ₂ R ⁹ , -C(CH ₃ ) ₂ CO ₂ R ⁹ , -CH (R ⁷ )(CH ₂ ) _n CO ₂ R ⁹ or CH(R ⁷ )C ₆ H ₄ CO ₂ R ⁹ ;

R ⁶ is hydrogen, halogen, alkyl of 1-6 carbon atoms or -OR ⁵ ;

m=1-6;

n=1-6;

R is ^hydrogen , an alkyl group of 1-6 carbon atoms, an aryl group of 6-10 carbon atoms or an aralkyl group of 7-15 carbon atoms;

R ⁸ is -CO ₂ R ¹⁰ , -CONHR ¹⁰ , tetrazole or -PO ₃ H ₂ ;

R ⁹ and R ¹⁰ are each independently hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, or aralkyl of 7-15 carbon atoms.

When the compounds of the present invention contain a basic moiety, they can be synthesized from organic and inorganic acids such as acetic acid, propionic acid, lactic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid , phthalic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, camphorsulfonic acid and similar known acceptable acids forming pharmaceutically acceptable of salt. Salts can also be formed from organic and inorganic bases, preferably alkali metal salts such as sodium, lithium or potassium, when compounds of the present invention contain carboxylate or phenolic moieties or similar moieties capable of forming base addition salts.

Alkyl includes both straight chain as well as branched chain moieties. Halogen refers to bromine, chlorine, fluorine and iodine. It is preferred that the aryl portion of the aryl or aralkyl substituent is phenyl, naphthyl or 1,4-benzodioxan-5-yl, with phenyl being most preferred. The aryl moiety may be optionally mono-, di- or tri-substituted with substituents selected from the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoromethyl, halogen, 2- Alkoxycarbonyl with 7 carbon atoms, alkylamino with 1 to 6 carbon atoms and dialkylamino with each alkyl group with 1 to 6 carbon atoms, nitro, cyano, -CO ₂ H, Alkylcarbonyloxy of 2-7 carbon atoms and alkylcarbonyl of 2-7 carbon atoms.

The compounds of the present invention may contain asymmetric carbon atoms and some of the compounds of the present invention may contain one or more asymmetric centers, and may thus give rise to optical isomers and diastereomers. Although the stereochemistry of Formula I is not indicated, the present invention includes such optical isomers and diastereomers as well as racemic and resolved enantiomerically pure R and S stereoisomers; and other R and S Mixtures of stereoisomers and their pharmaceutically acceptable salts.

Preferred compounds of the present invention are those compounds of formula I or their pharmaceutically acceptable salts, wherein ^R is hydrogen or halogen; ^R is an alkyl group of 1-6 carbon atoms or an aralkyl group of 7-15 carbon atoms ; ^R3 and ^R4 are halogen; and m is 1;

More preferred compounds of the present invention are listed below: Example 1. (2-Ethyl-benzofuran-3-yl)-(3,5-dibromo-4-hydroxyl-phenyl)-methanone Example 2. [2,6-Dibromo-4-(2-ethyl-benzofuran-3-carbonyl)-phenoxy]-acetic acid Example 3.2,6-Dibromo-4-(2-ethyl-benzofuran-3-carbonyl)-phenoxy]-acetic acid Furan-3-yl-methyl)-phenol Example 4. (3,5-dibromo-2,4-dihydroxy-phenyl)-(2-ethyl-benzofuran-3-yl)-methanol Ketone 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- Methyl)-phenoxy]-acetic acid Example 8. (2-Ethyl-benzofuran-3-yl)-(2,4,6-tribromo-3-hydroxyl-phenyl)-methanone Example 9. (2-Benzyl-benzofuran-3-yl)-(4-hydroxy-3,5-diiodo-phenyl)-methanoneExample 10.[4-(2-Benzyl- Benzofuran-3-carbonyl)-2,6-dibromo-phenoxy]-acetic acid Example 11. (2-Benzyl-benzo[b]thiophen-3-yl)-(3,5-di Bromo-4-hydroxy-phenyl)-methanone Example 12. [4-(2-Benzyl-benzo[b]thiophene-3-carbonyl)-2,6-dibromo-phenoxy]-acetic acid Example 13. (5-Chloro-2-ethyl-benzofuran-3-yl)-(3,5-dibromo-4-hydroxy-phenyl)-methanoneExample 14. (2-Benzyl -Benzofuran-3-yl)-(3,5-dibromo-4-hydroxyl-phenyl)-methanone Example 15. (3,5-dibromo-4-hydroxyl-phenyl)-(2 -Phenylethyl-benzofuran-3-yl)-methanone Example 16. (2-Butyl-benzofuran-3-yl)-(4-hydroxy-3,5-diiodo-phenyl) - Methanone Example 17. [4-(2-Benzyl-benzofuran-3-carbonyl)-2,6-diiodo-phenoxy]-acetic acid Example 18. (2-Ethyl-benzofuran-3-carbonyl)-2,6-diiodo-phenoxy]-acetic acid Example 18. (2-Ethyl-benzofuran Furan-3-yl)-(4-hydroxy-3,5-diiodo-phenyl)-methanone Example 19. [2,6-Dibromo-4-(2-phenethyl-benzofuran- 3-Carbonyl)-phenoxy]-acetic acid Example 20.[2,6-Dibromo-4-(5-chloro-2-ethyl-1-benzofuran-3-carbonyl)-phenoxy] - Acetic acid Example 21. [4-(2-Benzyl-benzo[b]thiophene-3-carbonyl)-2,6-dibromo-phenoxy-methyl]-phosphoric 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.

Compounds of the invention were prepared from commercially available starting materials or from materials that could be prepared using literature procedures according to the following schemes. Scheme I shows the preparation of representative compounds of the invention.

Process I

In Scheme 1, commercially available benzofurans and benzothiophenes (1) can be lithiated at the 2-position with alkyllithium reagents, which are treated with the aldehyde ^R2 -CHO to generate alcohols (2) [ref. Org. React .1979, Vol. 26]. Reduction of alcohol (2) with sodium borohydride and trifluoroacetic acid [ref. Syn. Comm. 1990, 20, 487-493] affords compound (3). Compound (3) is treated with an acid chloride to give ketone (4) using the Friedel-Crafts method [Friedel-Crafts and Related Reactions, Wiely Interscience, New York. 1963-1965]. The ketone can be reduced to compound (6) using the Wolf-Kriener method [ref. Org. Reactions. 1948, Vol. 4]. Demethylation of compounds (4) and (6) with _BBr3 [ref. J. Org. Chem. 1974, 39, 1427-1429] leads to phenols (5) and (7). Phenols (5) and (7) can be brominated or iodized with bromine and potassium acetate in acetic acid or with iodine in the presence of sodium hydroxide to give bromo or iodo compounds (9). Compounds (9) can be coupled with aromatic or heteroaromatic boronic acids to give terphenyls (10) in the presence of a palladium catalyst [Suzuki method; ref. Syn. Comm. 1981, 11, 513-519]. Compounds (5), (7), (9) and (10) can be used to generate the desired products (11-13). First, compounds (5), (7) and (9) can be alkylated with methyl bromoacetate in the presence of sodium hydride to form oxo-methyl acetate, which can be saponified with sodium hydroxide to form Oxo-acetic acid (11). Second, compounds (5), (7) and (9) can be alkylated with bromoacetonitrile to give oxo-acetonitrile, which is treated with sodium azide and ammonium chloride to give tetrazole (12). Third, using the Mitsunobu method [ref. Synthesis. Oxo-acetate, which can be saponified with sodium hydroxide to give oxo-acetic acid (13).

The compounds of the invention are useful in the treatment of metabolic disorders associated with insulin resistance or hyperglycemia, generally associated with obesity or glucose intolerance. The compounds of the invention are therefore particularly useful in the treatment or inhibition of type 2 diabetes. The compounds of the invention are also useful for modulating glucose levels in diseases such as type 1 diabetes.

The ability of compounds of the invention to treat or inhibit diseases associated with insulin resistance or hyperglycemia was determined using representative compounds of the invention in the following two standard pharmacological assays which measure inhibition of PTPases. Inhibition of triphosphorylated insulin receptor dodecaphosphopeptide dephosphorylation by rat liver protein-tyrosine phosphatase (PTPase)

This standard pharmacological assay uses phosphotyrosyl dodecapeptide as substrate corresponding to the 1142-1153 insulin receptor kinase domain phosphorylated at 1146, 1150, and 1151 tyrosine residues to evaluate rat liver microparticles Body PTPase activity. The methods used and the results obtained are briefly outlined below. Preparation of microsomal fractions: Rats (male Sprague-Dawley rats (Male Sprague-Dawley rats (Charles River, Kingston, NY) body weight 100-150 g, maintained on standard rodent chow (Purina)) were sacrificed by _CO2 asphyxiation and bilateral thoracotomy. incision. Livers were removed and washed with cold 0.85% saline (w/v) and weighed. Tissue was homogenized with 10 volumes of buffer A on ice and microsomes were essentially isolated as described by Meyerovitch J, Rothenberg P, Shechter Y, Bonner-Weir S, Kahm CR. Normalization of hyperglycemia with vanadate in two mouse models of non-insulin-dependent diabetes. J Clin Invest 1991;87:1286-1294 and edited by Alberts B, Bray D, Lewis J, RaffM, Roberts K, Watson JD Molecular Biology of Cells. New York: Garland Publishing Company, 1989 (with minor modifications). Liver homogenate was filtered through silk to remove any remaining tissue debris and then centrifuged at 10,000 xg for 20 minutes at 40°C. Decant the supernatant and centrifuge at 100,000 x g for 60 min at 40 °C. Precipitate, microsomes and a small amount of carrier in 20mM TRIS-HCl (pH7.4), 50mM 2-mercaptoethanol, 250mM sucrose, 2mM EDTA, 10mM EGTA, 2mM AEBSF, 0.1mM TLCK, 0.1mM TPCK, 0.5mM benzamidine , 25ug/ml leupeptin, 5ug/ml pepstatin A, 5ug/ml H5B antiprotease, 5ug/ml chymotrypsin inhibitor, 10ug/ml aprotinin (buffer A) Mix gently until a final concentration of approximately 850 ug protein/ml is achieved. Protein concentrations were determined by the Pierce Coomassie positive protein assay using crystalline bovine serum albumin as a standard (Pierce Chemical Company, Rockford, IL). Measurement of PTPase activity: Malachite green-ammonium molybdate method as described by Lanzetta PA, Alvarez LJ, Reinach PS, Candia OA. A modified assay adapted for nanomolar determination of inorganic phosphate (Anal Biochem. 1979; 100:95-97) and adapted for a plate reader was used for nanomolar determination of phosphate released by rat liver microsomal PTPases. This assay method uses as a substrate a dodecaphosphopeptide synthesized on commission from AnaSpec Corporation (San Jose, CA). The peptide TRDIYETDYYRK corresponding to the 1142-1153 catalytic domain of the insulin receptor is tyrosine phosphorylated on the 1146, 1150 and 1151 tyrosine residues. Microsomal fractions (83.25ul) with or without test compounds (6.25ul) and 305.5ul of 81.83mM HEPES reaction buffer (pH 7.4) were pre-incubated for 10 minutes at 37°C. Equilibrate 10.5ul of peptide substrate at a final concentration of 5OuM to 37°C on a LABLINE Multi-Blok heater equipped with a titer plate adapter. A pre-incubated microsome preparation (39.5ul) with or without drug was added to initiate the dephosphorylation reaction, which was carried out at 37°C for 30 minutes. The reaction was terminated by adding 200 ul of Malachite Green-Ammonium Molybdate-Tween 20 inhibitor (MG/AM/Tw). The inhibitor contained 3 parts 0.45% malachite green hydrochloride, 1 part 4.2% ammonium molybdate tetrahydrate in 4 N HCl and 0.5% Tween 20. A sample blank was prepared by adding 200ul of MG/AM/Tw to the substrate followed by the addition of 39.5ul of pre-incubated membrane solution with or without drug. The color was developed for 30 minutes at room temperature and the absorbance of the samples was measured at 650 nm using a plate reader (Molecular Devices). The operation of preparing samples and blank groups was repeated four times. Screening for activity of 50uM (final) drug evaluates its inhibitory effect on microsomal PTPases. Calculation: PTPase activity based on the potassium phosphate standard curve is expressed in nanomoles of phosphate released per mg of protein per min. Inhibition of recombinant PTP1B by test compounds was calculated as a percentage of the phosphatase control. _IC50 values for test compounds were determined using a four-parameter nonlinear logistic regression of PTPase activity using SAS release 6.08 PROCNLIN. All compounds were administered at a concentration of 50 μM. Using representative compounds of the present invention, the following results were obtained. Example _IC50 (μM) % change from control at 50 μM 1 70.1 2 -25 3 -34 4 34.3 5 31.2 6 24.2 7 22.7 8 17.5 9 22.7 10 36 11 33.9 12 27.8 13 27.1 14 27.8 15 20.5 16 15.3 17 28.4 18 30.7 19 26.3 20 40.4 twenty one 34.5 twenty two -77 twenty three -85 Phenylarsine oxide (reference substance) -57 Inhibition of dephosphorylation of triphosphorylated insulin receptor dodecaphosphopeptide via hPTP1B

This standard pharmacological assay evaluates the recombinant rat protein using as substrate phosphotyrosyl dodecapeptide corresponding to the 1142-1153 insulin receptor kinase domain phosphorylated at 1146, 1150 and 1151 tyrosine residues Inhibition of the activity of the tyrosine phosphatase PTP1B. The methods used and the results obtained are briefly described below.

Human recombinant PTP1B was prepared as described by Goldstein (see Goldstein et al. Mol. Cell Biochem. 109, 107, 1992). The enzyme preparations used were placed in microtubes containing 500-700 μg/ml protein in 33 mM Tris-HCl, 2 mM EDTA, 10% glycerol and 10 mM 2-mercaptoethanol. Measurement of PTPase activity: Nanomolar detection of phosphate released by recombinant PTP1B was performed using the malachite green-ammonium molybdate method as described by Lanzetta et al. (Anal Biochem. 100:95, 1979) and adapted to a plate reader. The assay method used as a substrate a dodecaphosphopeptide synthesized on commission from AnaSpec Corporation (San Jose, CA). The peptide TRDIYETDYYRK corresponding to the 1142-1153 catalytic domain of the insulin receptor is tyrosine phosphorylated on the 1146, 1150 and 1151 tyrosine residues. Recombinant rPTP1B was diluted with buffer (pH 7.4, containing 33 mM Tris-HCl, 2 mM EDTA and 50 mM b-mercaptoethanol) to give an activity of approximately 1000-2000 nmoles/min/mg protein. At 37°C, pre-incubated the diluted enzyme (83.25ul) with or without the test compound (6.25mL) and 305.5mL of 81.83mM HEPES reaction buffer (pH7.4) for 10 minutes, in a titer plate equipped with 10.5 ml of the peptide substrate at a final concentration of 50 uM was equilibrated to 37°C on the LABLINE Multi-Blok heater of the instrument. Pre-incubated recombinant enzyme preparations (39.5 ml) with or without drug were added to initiate the dephosphorylation reaction, which was carried out at 37°C for 30 minutes. The reaction was terminated by adding 200 mL malachite green-ammonium molybdate-Tween 20 inhibitor (MG/AM/Tw). The inhibitor contained 3 parts 0.45% malachite green hydrochloride, 1 part 4.2% ammonium molybdate tetrahydrate in 4N HCl and 0.5% Tween 20. A sample blank was prepared by adding 200 mL of MG/AM/Tw to the substrate followed by the addition of 39.5 ml of pre-incubated recombinant enzyme with or without drug. The color was developed for 30 minutes at room temperature and the absorbance of the samples was measured at 650 nm using a plate reader (Molecular Devices). Four replicates each of the sample and blank groups were prepared. Calculation: PTPase activity based on the potassium phosphate standard curve is expressed in nanomoles of phosphate released per mg of protein per min. Inhibition of recombinant PTP1B by test compounds was calculated as a percentage of the phosphatase control. _IC50 values for test compounds were determined using a four-parameter nonlinear logistic regression of PTPase activity using SAS release 6.08 PROCNLIN. Get the following result. Example % change from control at 10 μM _IC50 (μM) 1 25.8 (rPTP1B) 2 -30 (rPTP1B) 3 -74 (rPTP1B) 4 -64 (rPTP1B) 5 -78 (rPTP1B) 6 -90 (rPTP1B) 7 -99 (rPTP1B) 7 1.4 (hPTP1B) 8 -61 (rPTP1B) 9 -99 (rPTP1B) 10 -75 (rPTP1B) 11 3.97 (rPTP1B) 11 1.94 (hPTP1B) 12 -88 (rPTP1B) 13 -64 (rPTP1B) 14 -81 (rPTP1B) 15 2.6 (rPTP1B) 16 0.19 (rPTP1B) 16 2.6 (hPTP1B) 17 -97 (rPTP1B) 18 -60 (rPTP1B) 19 -53 (rPTP1B) 20 -34 (rPTP1B) twenty one -35 (rPTP1B) twenty two 1.15 (hPTP1B) twenty three 0.87 (hPTP1B) Phenylarsine oxide (reference substance) 39.7 Sodium orthovanadate (reference substance) 244.8 Ammonium molybdate tetrahydrate (reference substance) 8.7

Using diabetic (ob/ob) mice, the blood glucose-lowering activity of representative compounds of the present invention was confirmed by in vivo standard methods. The methods used and the results obtained are briefly described below.

The syndrome of non-insulin-dependent diabetes mellitus (NIDDM) is generally characterized by obesity, hyperglycemia, abnormal insulin secretion, hyperinsulinemia, and insulin resistance. The genetically obese-hyperglycemic ob/ob mouse exhibits a variety of these metabolic abnormalities and is considered a useful model for studying hypoglycemic drugs for the treatment of NIDDM [Coleman, D.: Diabetologia 14:141-148, 1978] .

In each test method, mice of similar age [male or female ob/ob(C57B1/6J) and their lean litermates (ob/+ or +/+, Jackson Laboratories), aged 2 to 5 months in size (10-65g)] were randomly divided into 4 groups according to body weight, with 10 mice in each group. Five mice were housed per cage, watered ad libitum, and maintained with normal rodent chow. Mice received test compounds dissolved in drinking water or mixed with food by gavage (suspended in 0.5 ml of 0.5% methylcellulose) daily. The dose of compound administered is in the range of 2.5 to 200 mg/kg body weight/day. Doses are calculated based on weekly body weight feeding and expressed as active fraction. The positive control ciglitazone (5-(4-(1-methylcyclohexylmethoxy)benzyl)-2,4-dione) was administered at a dose of 100 mg/kg/day (see Chang, A. Wyse , B., Gilchrist, B., Peterson, T. and Diani, A. Diabetes 32:830-838, 1983.), the drug produced significantly lower plasma glucose. Control mice received vehicle only.

On the morning of day 4, day 7 or day 14, two drops of blood (approximately 50 uL) were collected from the tail vein or post-decapitation into tubes containing sodium fluoride. For those studies in which the compound was administered daily by gavage, blood samples were collected two hours after compound administration. Plasma was separated by centrifugation and glucose concentrations were measured enzymatically on an Abbott V.P. analyzer.

For each mouse, the percent change in plasma glucose at day 4, day 7 or day 14 relative to the mean plasma glucose of vehicle-treated mice was calculated. Analysis of variance according to Dunett's comparison test (one-tailed) was used to evaluate significant differences in plasma glucose levels between the control group and each compound-treated group (CMS SAS release 5.18).

The results shown in the table below demonstrate that the compounds of the present invention are antihyperglycemic agents as they lower blood glucose levels in diabetic mice. Example Dose (mg/Kg) Glucose % change from vehicle Insulin % change from vehicle 1 100 -44.6 -89.5 2 100 -48.1 -78.2 3 100 -6.2a -56.6 4 100 -19.8a -61.8 5 100 -20.1 -54.8 6 100 -40.6 -70.4 7 100 -29.4 -13.1a 8 100 -3.3a -31.2 9 100 -37.1 -73.7 10 100 -17.7a -70.0 11 100 -30.3 -53.2 12 100 -30.7 -60.7 13 100 -12a -74.5 14 100 -36.8 -40.7a 15 100 -32.8 -10.3a 16 100 51.8 -73.7 18 100 39.6 -83.6 Ciglitazone (reference substance) 100 -43 -39

a - No significant activity at this dose (p<0.05).

Based on the results obtained in the standard pharmacological experimental procedures, representative compounds of the present invention have been shown to inhibit PTPase activity and reduce blood glucose levels in diabetic mice, and are thus useful in the treatment of Metabolic dysregulation in patients with obesity, usually associated with obesity or glucose intolerance. More specifically, the compounds of the invention are useful in the treatment or inhibition of type II diabetes, and in the regulation of glucose levels in diseases such as type I diabetes. As used herein, the term regulation means maintaining glucose levels within a clinically normal range.

These compounds are administered at an effective daily dose of about 1-250 mg/kg, and may be administered in a single dose or in two or more divided doses. These doses may be administered in any useful manner to provide the active compounds of this invention directly into the recipient's bloodstream, including oral, implant, parenteral (including intravenous, intraperitoneal and subcutaneous injection), rectal, vaginal and transdermal administration. . The transdermal administration disclosed in the present invention includes all administrations through the surface of the body and the endothelium of the body passages, including epithelial and mucous tissues. Such administration may be carried out in the form of lotions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal) with a compound of this invention, or a pharmaceutically acceptable salt thereof.

Oral formulations containing the active compounds of this invention may include any commonly used oral dosage forms, including tablets, capsules, buccal dosage forms, troches, lozenges and oral liquids, suspensions or solutions. Capsules may contain the active compound together with inert fillers and/or diluents, such as pharmaceutically acceptable starches such as corn, potato or tapioca, sugars, artificial sweeteners, powdered celluloses such as crystals and Mixture of microcrystalline cellulose, flour, gelatin, gums, etc. The tablets used may be prepared by conventional compression, wet granulation or dry granulation methods and may utilize pharmaceutically acceptable diluents, binders, lubricants, disintegrants, suspending agents or stabilizers, including, but Not limited to magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, calcium carboxymethylcellulose, polyvinylpyrrolidone, gelatin, alginic acid, gum arabic, xanthan gum, Sodium citrate, silicate complex, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starch and flour shaped sugar. Oral formulations of the invention may utilize standard delayed or time release dosage forms to modify the absorption of the active compounds. Suppositories may be prepared using traditional materials, including cocoa butter, with or without the addition of beeswax, which changes the suppository's melting point, and glycerin. Water soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used.

It is to be understood that the dosage, dosage regimen and mode of administration of these compounds will vary according to the disease and individual being treated and will be subject to the judgment of the medical practitioner. It is preferred to start administration of one or more compounds of the invention at low dosages and increase the dosage to achieve the desired effect.

The following procedures illustrate the preparation of representative examples of the invention. Example 1 (2-Ethyl-benzofuran-3-yl)-(3,5-dibromo-4-hydroxyl-phenyl)-methanone

This compound was obtained from Sigma Chemicals. Example 2 [2,6-dibromo-4-(2-ethyl-benzofuran-3-carbonyl)-phenoxy]-acetic acid

tert-Butyl bromoacetate (0.57 mL, 3.54 mmol) was added dropwise to (2-ethyl-benzofuran-3-yl)-(3,5-dibromo-4-hydroxy-phenyl)-methanone (1.0g, 2.36mmol), potassium carbonate (0.98g, 7.08mmol) and N,N-dimethylformamide (10mL). The mixture was stirred at 80°C for 3 hours, poured into water and extracted with ethyl acetate. The organic extracts were dried over MgSO ₄ . Evaporation gave a yellow oil (1.4 g), which was dissolved in dichloromethane (50 mL) and treated with trifluoroacetic acid (5 mL) for 10 hours. Volatiles were removed in vacuo. And the residue was 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; MSm/e 480 M ⁺ ; para C _Anal. Calcd. _{for19H14Br2O5} : C, 47.33; _H , 2.93; Found _: C, 47.25; H, 2.91. Example 32, 6-dibromo-4-(2-ethyl-benzofuran-3-yl-methyl)-phenol

tert-Butyldimethylsilyl chloride was added to (2-ethyl-benzofuran-3-yl)-(3,5-dibromo-4-hydroxy-phenyl)-methanone (10.0 g, 23.58mmol), imidazole (1.6g, 23.58mmol), 4-dimethylaminopyridine (100mg) and N,N-dimethylformamide (100mL). The mixture was stirred at room temperature for 10 hours, poured into water, and extracted with ethyl acetate. The organic extracts were dried over MgSO ₄ . Evaporation gave an oil (11.5 g), which was dissolved in methanol (100 mL) and treated with sodium borohydride (0.96 g, 25.65 mmol). The mixture was stirred at room temperature for 3 hours, poured into water, and extracted with ether. The organic extracts were dried over MgSO ₄ . Evaporation gave a residue (10.5 g), which was dissolved in dichloromethane (100 mL) and treated with triethylsilane (6.21 mL, 38.9 mmol) and trifluoroacetic acid (10 mL) at 0°C. After stirring for 30 minutes, the volatiles were removed in vacuo and the residue was treated with hydrofluoric acid (5.0 mL) in acetonitrile (50 mL) for 5 hours at 80°C. The volatiles were removed in vacuo and the residue was purified by flash chromatography (hexane/ethyl acetate 10:1) to give a white solid (6.5 g, 37% yield): mp 87-88; MSm/e 408 M ⁺ ; Example 4 (3,5-dibromo-2,4-dihydroxy-phenyl)-(2-ethyl-benzofuran-3-yl)-methanone

A solution of bromine (0.73 mL, 14.2 mmol) in acetic acid (3 mL) was added to the known compound (2,4-dihydroxy-phenyl)-(2-ethyl-benzofuran-3-yl)- Methanone (CA Registry No. 90908-66-0) (2.0 g, 7.08 mmol) in a solution of 6:1 acetic acid:water (14 mL). The reaction mixture was added to water (200 mL) and filtered to give the title compound (2.7 g, 87% yield) as _a tan solid: mp 150-151; MSm/e 438 M ⁺ ; _p for _C17H12Br2 Anal. Calcd. for _O4 : C, 46.39; H, 2.75; Found: C, 45.95; H, 2.66. Example 5 [2,6-dibromo-4-(2-butyl-benzofuran-3-carbonyl)-phenoxy]-acetic acid

In substantially the same manner as described in Example 2, from (2-butyl-benzofuran-3-yl)-(3,5-dibromo-4-hydroxy-phenyl)-methanone and bromine The compound was prepared by substituting tert-butyl acetate and gave an off-white solid, mp 92-94° _C ; MSm/e 508 (M ⁺ ); Anal. _Calcd . for _C21H18Br2O5 : C, _49.44 ; H, 3.56 ; Found: C, 47.24; H, 3.59. Example 6 (2-butyl-benzofuran 3-yl)-(3,5-dibromo-4-dihydroxy-phenyl)-methanone

Bromine (3.49 mL) was added dropwise to 2-n-butyl-3-(hydroxy-benzoyl)-benzo[b]furan (10.0 g, 34.0 mmol), acetic acid (50 mL) and H ₂ O (10 mL ) in the mixture. The reaction mixture was stirred for 12 hours and poured into water. The precipitated solid was filtered and dried to give a white solid ₍ 11.2 g, 71% yield ₎ : mp 95-97; MS m/e 450 M ⁺ ; Anal. Calc. for _{C19H16Br2O3 x 0.8H2O} Values: C, 48.89; H, 3.80; Found: C, 48.83; H, 3.37. Example 7 [2,6-dibromo-4-(2-butyl-benzofuran-3-ylmethyl)-phenoxy]-acetic acid

Prepared from 2,6-dibromo-4-(2-ethyl-benzofuran-3-yl-methyl)-phenol and tert-butyl bromoacetate in essentially the same manner as described in Example 2 The compound and gave _an off _- white solid, mp 118-119°C; MS m/e 494 (M ⁺ ); Anal. Calcd. for _C21H20Br2O4 : C, _50.83 ; H, 4.06; Found: C , 50.46; H, 3.94. Example 8 (2-Ethyl-benzofuran-3-yl)-(2,4,6-tribromo-3-hydroxyl-phenyl)-methanone

This compound was prepared from (2-ethyl-benzofuran-3-yl)-(3-hydroxy-phenyl)-methanone and bromine in substantially the same manner as described in Example 6, and _{A white solid was obtained, mp 153-154 °C; MS m/e 517 MH)+; Anal. Calcd. for C17H11Br3O3 :} ^C _{, 40.52} ; H, 2.20; Found: C, 40.12; H, 2.07. Example 9 (2-benzyl-benzofuran-3-yl)-(4-hydroxyl-3,5-diiodo-phenyl)-methanone

A solution of (2-benzyl-benzofuran-3-yl)-(4-hydroxy-phenyl)-methanone (2.48 g, 7.55 mmol) in sodium hydroxide (1.2 g) and water (113 mL) Added dropwise to a mixture of iodine (4.22 g), sodium iodide (2.75 g) and water (113 mL). The new mixture was stirred at 65°C for 3 hours. The mixture was poured into water and extracted with ethyl acetate. The organic extracts were dried over MgSO ₄ . Evaporation and purification by flash chromatography (petroleum ether/ethyl acetate 6:4) gave a brown solid (1.92 g, 4% yield): mp 153-154°C; MS m/e 580 (M ⁺ ); _Anal. Calcd. for _C22H14I2O3 : C, 45.55; H, _2.43 ; Found _: C, 46.23; H, 2.36. Example 10 [4-(2-Benzyl-benzofuran-3-carbonyl)-2,6-dibromo-phenoxy]-acetic acid

This compound was prepared in essentially the same manner as described in Example 20 from (2-benzyl-benzofuran-3-yl)-(4-hydroxy-phenyl)-methanone and methyl bromoacetate , and gave an off _- white solid, mp 165-167°C; MS m/e 544 (M) ⁺ ; Anal. _Calcd . for _C24H16Br2O5 : C, _52.97 ; H, 2.96; Found: C, 52.74 ; H, 2.94. Example 11 (2-Benzyl-benzo[b]thiophen-3-yl)-(3,5-dibromo-4-hydroxyl-phenyl)-methanone

The known compound 2-benzyl-benzo[b]thiophene (CA Registry No. 3407-15- 6) to give (2-benzyl-benzo[b]thiophen-3-yl)-(4-methoxy-phenyl)-methanone (85% yield). Demethylation of this compound with 6 equivalents of pyridinium hydrochloride at 228°C afforded (2-benzyl-benzo[b]thiophen-3-yl)-(4-hydroxy-phenyl)- Methanone (90% yield). According to the method of Example 4, this compound was brominated to obtain the title compound (95% yield) as a white solid: mp 155.5-156.5°C; MS m/e 500 (M) ⁺ ; p C ₂₂ H ₁₄ Br ₂ Anal. Calcd. for _O2S : C, 52.61; H, 2.80; Found: C, 52.43; H, 2.71. Example 12 [4-(2-Benzyl-benzo[b]thiophene-3-carbonyl)-2,6-dibromo-phenoxy]-acetic acid

In essentially the same manner as described in Example 20, from (2-benzyl-benzo[b]thiophen-3-yl)-(3,5-dibromo-4-hydroxy-phenyl)-methanol ketone and methyl bromoacetate and gave _an off _- white solid, mp 162-163 °C; MS m/e 558 (M) ⁺ ; Anal. _Calcd . for _C24H16Br2O4S : 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-hydroxyl-phenyl)-methanone

This was prepared from (5-chloro-2-ethyl-benzofuran-3-yl)-(4-hydroxy-phenyl)-methanone and bromine in essentially the same manner as described in Example 6. Compound, and a white solid was obtained, mp 126-128°C; MS m/e 454.9 (MH) ⁺ ; Anal. Calcd. for C ₁₇ H ₁₁ Br ₂ ClO ₃ : C, 44.53; H, 2.42; Found: C, 44.35; H, 2.13. Example 14 (2-Benzyl-benzofuran-3-yl)-(3,5-dibromo-4-hydroxyl-phenyl)-methanone

This compound was prepared from (2-benzyl-benzofuran-3-yl)-(4-hydroxy-phenyl)-methanone and bromine in essentially the same manner as described in Example 6, and gave Off-white solid, mp 156-158°C; MS m/e 484 (M ⁺ ); Anal. _Calcd . for _{C22H14Br2O3 :} C, _53.43 ; H, 2.74; Found: C, 53.73; H, 2.75. Example 15 (3,5-dibromo-4-hydroxyl-phenyl)-(2-phenethyl-benzofuran-3-yl)-methanone

This compound was prepared from (2-phenethyl-benzofuran-3-yl)-(4-hydroxy-phenyl)-methanone and bromine in substantially the same manner as described in Example 6, and _A yellow solid was obtained, mp 153-154 °C; MS m/e ₅₀₂ (M+H) ⁺ ; Anal. Calcd. for _{C23H16Br2O3 x 0.057C2H4O2} : C _{, 55.12} ; H, 3.25; Found: C, 54.72; H, 2.99. Example 16 (2-Butyl-benzofuran 3-yl)-(4-hydroxyl-3,5-diiodo-phenyl)-methanone

Known compound (CA Registry No. 1951-26-4): mp 141.5-142.5°C; MS m/e 545(M+H) ⁺ ; calculated for C ₁₉ H ₁₆ I ₂ O ₃ : C, 41.79; H, 2.95; Found: C, 41.97; H, 2.83. Example 17 [4-(2-Benzyl-benzofuran-3-carbonyl)-2,6-diiodo-phenoxy]-acetic acid

In essentially the same manner as described in Example 2, from (2-benzyl-benzofuran-3-yl)-(3,5-diiodo-4-hydroxy-phenyl)-methanone and bromine Substitute t-butyl acetate to prepare this compound. Formic acid was used instead of trifluoroacetic acid. The product was obtained as _an off-white solid, mp 144-146 °C; MS m/e 638 (M ⁺ ); Anal. _Calcd . for _C24H16I2O5 : C, _45.17 ; H, 2.53; Found: C, 44.19; H, 2.42. Example 18 [4-(2-Benzyl-benzo[b]thiophene-3-carbonyl)-2,6-dibromo-phenoxy]-acetic acid

Known compound (CA Registry No. 68-90-6). Example 19 [2,6-dibromo-4-(2-phenethyl-benzofuran-3-carbonyl)-phenoxy]-acetic acid

Prepared from (2-phenethyl-benzofuran-3-yl)-(3,5-dibromo-4-hydroxy-phenyl)-methanone in essentially the same manner as described in Example 20 _The compound and gave an off-white solid, mp 163-164°C; MS m/e 556 (M ⁺ ); Anal. Calcd. for _C25H18Br2O5 : C, _53.79 ; H, _3.25 ; Found: C , 53.91; H, 3.14. Example 20 [2,6-dibromo-4-(5-chloro-2-ethyl-1-benzofuran 3-carbonyl)-phenoxy]-acetic acid step a)[2,6-dibromo- 4-(5-Chloro-2-ethyl-1-benzofuran-3-carbonyl)-phenoxy]-acetic acid methyl ester

Methyl bromoacetate was added dropwise to (4-chloro-2-ethyl-benzofuran-3-yl)-(3,5-dibromo-4-hydroxyl-phenyl)-methanone (2.81g, 6.13mmol), potassium carbonate (0.93g) and N,N-dimethylformamide (28mL). The mixture was stirred for 15 hours, poured into water and extracted with ethyl acetate. The organic extracts were dried over MgSO ₄ . Evaporation and purification by flash chromatography (petroleum ether/ethyl acetate 9:1) afforded a white solid (2.89 g, 89% yield): mp 108-109°C; MS m/e 528 (M ⁺ ); _Anal. Calcd _{. for C20H51Br2ClO5} : C, 45.27; H, 2.89; Found: C, 45.08; H, 2.61. Step b) [2,6-Dibromo-4-(5-chloro-2-ethyl-1-benzofuran-3-carbonyl)-phenoxy]-acetic acid

Add potassium hydroxide (15.9 mL, 0.5 N) to [2,6-dibromo-4-(5-chloro-2-ethyl-1-benzofuran-3-carbonyl)-phenoxy]-acetic acid A solution of the methyl ester (2.8 g, 5.3 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL). The mixture was stirred for 30 minutes, poured into water, acidified with HCl and cooled to 0 °C. The precipitated solid was filtered and dried. The crude product was recrystallized from acetic acid and water to give a white solid (2.01 g, 74% yield): mp 175-177°C; MS m/e 514 (M ⁺ ). _Anal . _{Calcd .} for _{C19H13Br2ClO5} : C, 44.18; H, 2.54; Found: C, 44.16; H, 2.46. Example 21 [4-(2-Benzyl-benzo[b]thiophene-3-carbonyl)-2,6-dibromo-phenoxymethyl]-phosphoric acid

Sodium hydride (0.09 g, 80% in mineral oil) was added to cold (0 °C) (2-benzyl-benzo[b]thiophen-3-yl)-(3,5-dibromo-4- In a mixture of hydroxy-phenyl)-methanone (0.96g, 1.91mmol) and tetrahydrofuran (20mL). The mixture was stirred for 1 hour and then diethyl trifluoromethanesulfonyloxymethylphosphate (0.63 g) was added dropwise. The new mixture was allowed to warm to room temperature, stirred for 4 hours, and then warmed to 50 °C and stirred for an additional 2 hours. The mixture was poured into water and extracted with ethyl acetate. The organic extracts were dried over MgSO ₄ . Purification by flash chromatography (dichloromethane/acetonitrile 95:5) afforded a brown oil (0.79 g, 63% yield). This product was dissolved in dichloromethane (18 mL) and treated with iodotrimethylsilane (0.45 mL) at 0 °C for 6 hours. The mixture was poured into water and extracted with ethyl acetate. The organic extracts were dried over MgSO ₄ . Evaporation and purification by flash chromatography (dichloromethane/acetonitrile 85:15) gave a yellow solid (1.1 g, 77% yield): mp 210-212 °C; MS m/e 595 (M+H) ⁺ ; Example 22 (R)-2-[2,6-dibromo-4-(2-butyl-benzofuran-3-carbonyl)-phenoxy]-3-phenyl-propionic acid

Diethyl azodicarboxylate (0.13 mL) was added dropwise to (2-butyl-benzofuran-3-yl)-(3,5-dibromo-4-hydroxy-phenyl)-methanone ( 0.24g, 0.54mmol), triphenylphosphine (0.21g), (S)-(-)-3-phenyllactate methyl ester (0.14g) and benzene (2.4mL). The mixture was stirred at 80°C for 3 hours and at room temperature overnight. The volatiles were removed in vacuo and the residue was purified by flash chromatography to give an oil (0.13g). This product was dissolved in tetrahydrofuran (1.7 mL) and methanol (1.7 mL) and treated with potassium hydroxide (1.0 N, 0.5 mL). After stirring for 4 hours, the mixture was poured into water, acidified with HCl (1N) and extracted with ether. The organic extracts were dried over MgSO ₄ . Evaporation gave a pale yellow solid (0.23 g, 84% yield): mp 56-58°C; MS m/e 597 (MH) ⁺ . Anal. Calcd. for _{C28H24Br2O5 x 0.8H2O} : 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)-phenoxy]-3-phenyl-propionic acid

In essentially the same manner as described in Example 21, from 2,6-dibromo-4-(2-ethyl-benzofuran-3-yl-methyl)-phenol and (S)-(- )-3-Phenyl lactate methyl ester to prepare this compound and give an oil (0.11 g, 91 yield). The product was treated with 1 N sodium hydroxide in methanol (0.19 mL) for 30 minutes. Evaporation gave a white solid (0.1 g, 84% _yield ), mp _225-226 °C; MS m/e 583 (MH) ⁺ ; Anal. Calcd _. for _{C28H25Br2O4Na} x _0.3H2O : C, 54.78; H, 4.20; Found: C, 54.60; H, 3.79.

Claims (25)

1. have the formula I compound of following structure or their pharmacy acceptable salt,

Wherein:

A is O, S or N;

B is-(CH ₂) _m-,-CH (OH)-or carbonyl;

R ¹Be the alkyl of hydrogen, nitro, halogen, a 1-6 carbon atom, the alkoxyl group or the trifluoromethyl of a 1-6 carbon atom;

R ²For the aralkyl of the aryl of the alkyl of 1-18 carbon atom, a 6-10 carbon atom, a 7-15 carbon atom, wherein moieties is the Het-alkyl of 1-6 carbon atom;

Het is Or

R ^2aAlkylidene group for 1-3 carbon atom;

G is oxygen, sulphur or nitrogen;

R ³, R ⁴Each is independently for the aryl of the alkyl of hydrogen, halogen, a 1-3 carbon atom, a 6-10 carbon atom or contain 1 to 3 heterocycle that is selected from heteroatomic 5 to 7 annular atomses of oxygen, nitrogen, sulphur;

R ⁵For the alkyl of hydrogen, a 1-6 carbon atom ,-CH (R ⁷) R ⁸,-C (CH ₂) _nCO ₂R ⁹,-C (CH ₃) ₂CO ₂R ⁹,-CH (R ⁷) (CH ₂) _nCO ₂R ⁹Or CH (R ⁷) C ₆H ₄CO ₂R ⁹

R ⁶For the alkyl of hydrogen, halogen, a 1-6 carbon atom or-OR ⁵

m＝1-6；

n＝1-6；

R ⁷Be the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom;

R ⁸For-CO ₂R ¹⁰,-CONHR ¹⁰, tetrazolium or-PO ₃

R ⁹And R ¹⁰Each independently is the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom.

2. the compound of claim 1 or their pharmacy acceptable salt, wherein

R ¹Be hydrogen or halogen;

R ²Be the alkyl of 1-6 carbon atom or the aralkyl of 7-15 carbon atom;

R ³And R ⁴Be halogen; With

m＝1。

4. the compound of claim 1, it is [2,6-two bromo-4-(2-ethyl-cumarone-3-carbonyl)-phenoxy group]-acetate or its pharmacy acceptable salt.

5. the compound of claim 1, it is 2,6-two bromo-4-(2-ethyl-cumarone-3-base-methyl)-phenol or its pharmacy acceptable salt.

6. the compound of claim 1, it is (3,5-two bromo-2,4-dihydroxyl-phenyl)-(2-ethyl-cumarone-3-yl)-ketone or its pharmacy acceptable salt.

7. the compound of claim 1, it is [2,6-two bromo-4-(2-butyl-cumarone-3-carbonyl)-phenoxy group]-acetate or its pharmacy acceptable salt.

8. the compound of claim 1, it is (2-butyl-cumarone-3-yl)-(3,5-two bromo-4-dihydroxyl-phenyl)-ketone or its pharmacy acceptable salt.

9. the compound of claim 1, it is [2,6-two bromo-4-(2-butyl-cumarone-3-ylmethyl)-phenoxy group]-acetate or its pharmacy acceptable salt.

10. the compound of claim 1, it is (2-ethyl-cumarone-3-yl)-(2,4,6-three bromo-3-hydroxyl-phenyl)-ketone or its pharmacy acceptable salt.

11. the compound of claim 1, it is (2-benzyl-cumarone-3-yl)-(4-hydroxyl-3,5-two iodo-phenyl)-ketone or its pharmacy acceptable salt.

12. the compound of claim 1, it is [4-(2-benzyl-cumarone-3-carbonyl)-2,6-two bromo-phenoxy groups]-acetate or its pharmacy acceptable salt.

13. the compound of claim 1, it is (2-benzyl-benzo [b] thiene-3-yl-)-(3,5-two bromo-4-hydroxyl-phenyl)-ketone or its pharmacy acceptable salt.

14. the compound of claim 1, it is [4-(2-benzyl-benzo [b] thiophene-3-carbonyl)-2,6-two bromo-phenoxy groups]-acetate or its pharmacy acceptable salt.

15. the compound of claim 1, it is (5-chloro-2-ethyl-cumarone-3-yl)-(3,5-two bromo-4-hydroxyl-phenyl)-ketone or its pharmacy acceptable salt.

16. the compound of claim 1, it is (2-benzyl-cumarone-3-yl)-(3,5-two bromo-4-hydroxyl-phenyl)-ketone or its pharmacy acceptable salt.

17. the compound of claim 1, it is [4-(2-benzyl-cumarone-3-carbonyl)-2,6-two iodo-phenoxy groups]-acetate or its pharmacy acceptable salt.

18. the compound of claim 1, it is [2,6-two bromo-4-(2-styroyl-cumarone-3-carbonyl)-phenoxy group]-acetate or its pharmacy acceptable salt.

19. the compound of claim 1, it is [2,6-two bromo-4-(5-chloro-2-ethyl-1-cumarone-3-carbonyl)-phenoxy group]-acetate or its pharmacy acceptable salt.

20. the compound of claim 1, it is [4-(2-benzyl-benzo [b] thiophene-3-carbonyl)-2,6-two bromo-phenoxymethyls]-phosphoric acid or its pharmacy acceptable salt.

21. the compound of claim 1, it is (R)-2-[2,6-two bromo-4-(2-butyl-cumarone-3-carbonyl)-phenoxy group]-3-phenyl-propionic acid or its pharmacy acceptable salt.

22. the compound of claim 1, it is (R)-2-[2,6-two bromo-4-(2-butyl-cumarone-3-ylmethyl)-phenoxy group]-3-phenyl-propionic acid or its pharmacy acceptable salt.

23. treatment is by the method for the Metabolic disorder of insulin resistance or hyperglycemia mediation in the Mammals that needs is arranged, this method comprises and gives formula I compound that described Mammals has following structure or their pharmacy acceptable salt,

Wherein:

A is O, S or N;

B is-(CH ₂) _m-,-CH (OH)-or carbonyl;

R ¹Be the alkyl of hydrogen, halogen, a 1-6 carbon atom, the alkoxyl group or the trifluoromethyl of a 1-6 carbon atom;

R ²For the aralkyl of the aryl of the alkyl of 1-18 carbon atom, a 6-10 carbon atom, a 7-15 carbon atom, wherein moieties is the Het-alkyl of 1-6 carbon atom;

Het is

Or

R ^2aAlkylidene group for 1-3 carbon atom;

G is oxygen, sulphur or nitrogen;

R ³, R ⁴Each is independently for the aryl of the alkyl of hydrogen, halogen, a 1-3 carbon atom, a 6-10 carbon atom or contain 1 to 3 heterocycle that is selected from heteroatomic 5 to 7 annular atomses of oxygen, nitrogen, sulphur;

R ⁵For the alkyl of hydrogen, a 1-6 carbon atom ,-CH (R ⁷) R ⁸,-C (CH ₂) _nCO ₂R ⁹,-C (CH ₃) ₂CO ₂R ⁹,-CH (R ⁷) (CH ₂) _nCO ₂R ⁹Or CH (R ⁷) C ₆H ₄CO ₂R ⁹

R ⁶For the alkyl of hydrogen, halogen, a 1-6 carbon atom or-OR ⁵

m＝1-6；

n＝1-6；

R ⁷Be the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom;

R ⁸For-CO ₂R ¹⁰,-CONHR ¹⁰, tetrazolium or-PO ₃

R ⁹And R ¹⁰Each independently is the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom.

24. comprising, treatment or suppress the method for type ii diabetes in the Mammals that needs is arranged, this method give formula I compound that described Mammals has following structure or their pharmacy acceptable salt,

Wherein:

A is O, S or N;

B is-(CH ₂) _m-,-CH (OH)-or carbonyl;

R ¹Be the alkyl of hydrogen, halogen, a 1-6 carbon atom, the alkoxyl group or the trifluoromethyl of a 1-6 carbon atom;

R ²For the aralkyl of the aryl of the alkyl of 1-18 carbon atom, a 6-10 carbon atom, a 7-15 carbon atom, wherein moieties is the Het-alkyl of 1-6 carbon atom;

Het is

Or

R ^2aAlkylidene group for 1-3 carbon atom;

G is oxygen, sulphur or nitrogen;

R ³, R ⁴Each is independently for the aryl of the alkyl of hydrogen, halogen, a 1-3 carbon atom, a 6-10 carbon atom or contain 1 to 3 heterocycle that is selected from heteroatomic 5 to 7 annular atomses of oxygen, nitrogen, sulphur;

R ⁵For the alkyl of hydrogen, a 1-6 carbon atom ,-CH (R ⁷) R ⁸,-C (CH ₂) _nCO ₂R ⁹,-C (CH ₃) ₂CO ₂R ⁹,-CH (R ⁷) (CH ₂) _nCO ₂R ⁹Or CH (R ⁷) C ₆H ₄CO ₂R ⁹

R ⁶For the alkyl of hydrogen, halogen, a 1-6 carbon atom or-OR ⁵

m＝1-6；

n＝1-6；

R ⁷Be the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom;

R ⁸For-CO ₂R ¹⁰,-CONHR ¹⁰, tetrazolium or-PO ₃

R ⁹And R ¹⁰Each independently is the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom.

25. regulate the method for glucose level in the Mammals that needs is arranged, this method comprises and gives formula I compound that described Mammals has following structure or their pharmacy acceptable salt, Wherein:

A is O, S or N;

B is-(CH ₂) _m-,-CH (OH)-or carbonyl;

R ¹Be the alkyl of hydrogen, halogen, a 1-6 carbon atom, the alkoxyl group or the trifluoromethyl of a 1-6 carbon atom;

R ²For the aralkyl of the aryl of the alkyl of 1-18 carbon atom, a 6-10 carbon atom, a 7-15 carbon atom, wherein moieties is the Het-alkyl of 1-6 carbon atom;

Het is

Or

R ^2aAlkylidene group for 1-3 carbon atom;

G is oxygen, sulphur or nitrogen;

R ³, R ⁴Each is independently for the aryl of the alkyl of hydrogen, halogen, a 1-3 carbon atom, a 6-10 carbon atom or contain 1 to 3 heterocycle that is selected from heteroatomic 5 to 7 annular atomses of oxygen, nitrogen, sulphur;

R ⁵For the alkyl of hydrogen, a 1-6 carbon atom ,-CH (R ⁷) R ⁸,-C (CH ₂) _nCO ₂R ⁹,-C (CH ₃) ₂CO ₂R ⁹,-CH (R ⁷) (CH ₂) _nCO ₂R ⁹Or CH (R ⁷) C ₆H ₄CO ₂R ⁹

R ⁶For the alkyl of hydrogen, halogen, a 1-6 carbon atom or-OR ⁵

m＝1-6；

n＝1-6；

R ⁷Be the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom;

R ⁸For-CO ₂R ¹⁰,-CONHR ¹⁰, tetrazolium or-PO ₃

R ⁹And R ¹⁰Each independently is the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom.

26. medicinal compositions, it comprises formula I compound or their pharmacy acceptable salt and the pharmaceutical carrier with following structure, Wherein:

A is O, S or N;

B is-(CH ₂) _m-,-CH (OH)-or carbonyl;

R ¹Be the alkyl of hydrogen, halogen, a 1-6 carbon atom, the alkoxyl group or the trifluoromethyl of a 1-6 carbon atom;

R ²For the aralkyl of the aryl of the alkyl of 1-18 carbon atom, a 6-10 carbon atom, a 7-15 carbon atom, wherein moieties is the Het-alkyl of 1-6 carbon atom;

Het

Or

R ^2aAlkylidene group for 1-3 carbon atom;

G is oxygen, sulphur or nitrogen;

R ³, R ⁴Each is independently for the aryl of the alkyl of hydrogen, halogen, a 1-3 carbon atom, a 6-10 carbon atom or contain 1 to 3 heterocycle that is selected from heteroatomic 5 to 7 annular atomses of oxygen, nitrogen, sulphur;

R ⁵For the alkyl of hydrogen, a 1-6 carbon atom ,-CH (R ⁷) R ⁸-,-C (CH ₂) _nCO ₂R ⁹,-C (CH ₃) ₂CO ₂R ⁹,-CH (R ⁷) (CH ₂) _nCO ₂R ⁹Or CH (R ⁷) C ₆H ₄CO ₂R ⁹

R ⁶For the alkyl of hydrogen, halogen, a 1-6 carbon atom or-OR ⁵

m＝1-6；

n＝1-6；

R ⁷Be the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom;

R ⁸For-CO ₂R ¹⁰,-CONHR ¹⁰, tetrazolium or-PO ₃

R ⁹And R ¹⁰Each independently is the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom.