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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D277/24—Radicals substituted by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

• Hyperinsulinemia can be present as a result of insulin resistance, such as is in obese and/or diabetic (NIDDM) subjects and/or glucose intolerant subjects, or in IDDM subjects, as a consequence of over injection of insulin compared with normal physiological release of the hormone by the endocrine pancreas.
• NIDDM diabetic diabetic
• IDDM glucose intolerant subjects
• Atherosclerosis has been well established by numerous experimental, clinical and epidemiological studies (summarized by Stout, Metabolism 1985, 34, 1, and in more detail by Pyorala et al, Diabetes/Metabolism Reviews 1987, 3, 463). Statistically significant plasma insulin elevations at 1 and 2 hours after oral glucose load correlates with an increased risk of coronary heart disease.
• the independent risk factors obesity and hypertension for atherosclerotic diseases are also associated with insulin resistance.
• insulin resistance is located in peripheral tissues (principally muscle) and correlates directly with the severity of hypertension (DeFronzo and Ferrannini, Diabetes Care 1991, 14, 173).
• insulin resistance generates hyperinsulinemia, which is recruited as a mechanism to limit further weight gain via thermogenesis, but insulin also increases renal sodium reabsorption and stimulates the sympathetic nervous system in kidneys, heart, and vasculature, creating hypertension.
• PTPases Protein-tyrosine phosphatases play an important role in the regulation of phosphorylation of proteins.
• the interaction of insulin with its receptor leads to phosphorylation of certain tyrosine molecules within the receptor protein, thus activating the receptor kinase.
• PTPases dephosphorylate 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.
• the enzymes that appear most likely to closely associate with the insulin receptor and therefore, most likely to regulate the insulin receptor kinase activity include PTP1B, LAR, PTP ⁇ and SH-PTP2 (B.
• the compounds of this invention have been shown to inhibit PTPases derived from rat liver microsomes and human-derived recombinant PTPase- IB (hPTP-lB) in vitro. They are useful in the treatment of insulin resistance associated with obesity, glucose intolerance, diabetes mellitus, hypertension and ischemic diseases of the large and small blood vessels.
• This invention provides a compound of formula I having the structure
• R 2 is hydrogen, alkyl of 1-6 carbon atoms, or aryl of 6 to 10 carbon atoms;
• R 3 and R 4 are independently halogen, hydrogen, alkyl of 1-12 carbon atoms , aryl of 6 to 10 carbon atoms; halogen, trifluoromethylof 1-6 carbon atoms, alkoxyaryl of
• R 5 is hydrogen, alkyl of 1-6 carbon atoms, -CH(R 8 )R 9 , -C(CH 2 ) n CO 2 R 10 ,
• R 6 is hydrogen, alkyl of 1-6 carbon atoms, halogen, alkyoxy of 1-6 carbon atoms, trifluoroalkyl of 1-6 carbon atoms or trifluoroalkoxy of 1-6 carbon atoms;
• R 7 is hydrogen or alkyl of 1 to 6 carbon atoms
• R 8 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, arylalkyl of 7-15 carbon atoms, cycloalkyl of 3-8 carbon atoms, phthalic acid,
• R 9 is CO 2 R 12 , CONHR 12 , tetrazole, PO 3 R 12 ;
• R 10 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-12 carbon atoms, aralkyl of 7-15 carbon atoms;
• R 1 is alkylene of 1 to 3 carbon atoms
• R 12 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-12 carbon atoms, aralkyl of 7-15 carbon atoms;
• X is O, or S
• Z is C, or N
• Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids when a compound of this invention contains a basic moiety.
• organic and inorganic acids for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulf
• Alkyl includes both straight chain as well as branched moieties.
• Halogen means bromine, chlorine, fluorine, and iodine.
• the aryl portion of the aryl or aralkyl substituent is a phenyl, naphthyl or l,4-benzodioxan-5-yl group; with phenyl being most preferred.
• 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 may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formula I, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
• R 2 is alkyl of 1-6 carbon atoms
• Biphenyls (5) converted to phenols (6) by treatment with boron tribromide in dichloromethane [ref. J. Org. Chem. 1974, 39, 1427-1429].
• Phenols (6) were alkylated with bromo or chloro-alkylcarboxylates [(Br or Cl)(CH 2 ) n CO 2 R 12 ] in the presence of sodium hydride or potassium carbonate, using dimethylformamide or acetonitrile as the solvent. Subsequent saponification with sodium hydroxide in methyl alcohol and tetrahydrofuran produced biphenyls (7).
• thiazoles (10) were brominated with bromine in the presence of sodium acetate.
• the 4-bromo-thiazoles (11) were coupled with 4, 4'-methoxy biphenyl boronic acid using the Suzuki protocol [ref. Syn. Comm. 1981, 11, 513-519] to give biphenyls (12).
• Biphenyls (12) were further converted to the desired products in substantially the same manner as described in Scheme I.
• the biphenyl compounds (13 ) can be monobrominated or dibrominated using bromine, potassium acetate and acetic acid.
• the Suzuki coupling protocol [ref. Syn. Comm. 1981, 11, 513-519] was used to generate the terphenyls 15 and 16.
• heterocyclic boronic acids for example thiophene, furan, oxazole, thiazole, pyridine.
• oxazoles (3) were coupled with aryl boronic acids of general structure (4; R 3 , R 4 are alkyl, aryl, trifluoromethyl, substituted aryl, nitro, carbocyclic 5 to 7 carbon atoms rings or heterocyclic rings 5 to 7 atom rings with from 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur) using the Suzuki protocol [ref. Syn. Comm. 1981, 11, 513-519] to produce biphenyls (17).
• Biphenyls (17) were converted to oximes (18) with hydroxylamine in the presence of sodium acetate.
• Oximes (18) were reduced with sodium cyanoborohydride under acidic conditions to produce to hydroxylamines (19).
• hydroxylamines (19) were treated with N- (chlorocarbonyl)isocyanate to produce oxadiazolidinediones (20).
• Thiazolidinediones were prepared from benzaldehydes (17) using known methodology [ref. J. Med. Chem., 1992, 35, 1853-1864].
• the compounds of this invention are useful in treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance.
• the compounds of this invention are therefore, particularly useful in the treatment or inhibition of type II diabetes.
• the compounds of this invention are also useful in modulating glucose levels in disorders such as type I diabetes.
• Rats (Male Sprague-Dawley rats (Charles River, Springfield, NY) weighing 100-150 g, maintained on standard rodent chow (Purina)) are sacrificed by asphyxiation with CO2 and bilateral thoracotomy. The liver is removed and washed in cold 0.85% (w/v) saline and weighed. The tissue is homogenized on ice in 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 non-insulin-dependent diabetes mellitus.
• the pellet, microsomes and small vesicles is resuspended and lightly 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 mM TLCK, 0.1 mM TPCK, 0.5 mM benzamidine, 25 ug/ml leupeptin, 5 ug/ml pepstatin A, 5 ug/ml;H5B antipain, 5 ug/ml chymostatin, 10 ug/ml aprotinin (Buffer A), to a final concentration of approximately 850 ug protein/ml. Protein concentration is determined by the Pierce Coomassie Plus Protein Assay using crystalline bovine serum albumin as a standard (Pierce Chemical Co., Rockford, IL).
• the preincubated microsomal preparation (39.5 ul) with or without drug is added to initiate the dephosphorylation reaction, which proceeds at 37deg.C for 30 min.
• the reaction is terminated by the addition of 200 ul of the malachite green- ammonium molybdate-Tween 20 stopping reagent (MG/AM/Tw).
• the stopping reagent consists of 3 parts 0.45% malachite green hydrochloride, 1 part 4.2% ammonium molybdate tetrahydrate in 4 N HCI and 0.5% Tween 20.
• Sample blanks are prepared by the addition of 200 ul MG/AM/Tw to substrate and followed by 39.5 ul of the preincubated membrane with or without drug.
• sample absorbances are determined at 650 nm using a platereader (Molecular Devices). Samples and blanks are prepared in quadruplicates. Screening activity of 50 uM (final) drug is accessed for inhibition of microsomal PTPases.
• PTPase activities based on a potassium phosphate standard curve, are expressed as nmoles of phosphate released/min/mg protein. Test compound PTPase inhibition is calculated as percent of control. A four parameter non-linear logistic regression of PTPase activities using SAS release 6.08, PROC NLIN, is used for determining IC50 values of test compounds. All compounds were administered at a concentration of 50 uM. The following results were obtained using representative compounds of this invention.
• This standard pharmacological test procedure assess the inhibition of recombinant rat protein tyrosine phosphatase, PTP1B, activity using, as substrate, the phosphotyrosyl dodecapeptide corresponding to the 1142-1153 insulin receptor kinase domain, phosphorylated on the 1146, 1150 and 1151 tyrosine residues.
• the procedure used and 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 preparation used was in microtubes containing 500-700 ⁇ g/ml protein in 33 mM Tris-HCl, 2 mM EDTA, 10% glycerol and 10 mM 2-mercaptoethanol.
• the reaction is terminated by the addition of 200 mL of the malachite green-ammonium molybdate-Tween 20 stopping reagent (MG/AM/Tw).
• the stopping reagent consists of 3 parts 0.45% malachite green hydrochloride, 1 part 4.2% ammonium molybdate tetrahydrate in 4 N HCI and 0.5% Tween 20.
• Sample blanks are prepared by the addition of 200 mL MG/AM/Tw to substrate and followed by 39.5 ml of the preincubated recombinant enzyme with or without drug. The color is allowed to develop at room temperature for 30 min. and the sample absorbances are determined at 650 nm using a platereader (Molecular Devices). Sample and blanks are prepared in quadruplicates.
• mice [Male or female ob/ob (C57 B1/6J) and their lean litermates (ob/+ or +/+, Jackson Laboratories) ages 2 to 5 months (10 to 65 g)] of a similar age were randomized according to body weight into 4 groups of 10 mice. The mice were housed 5 per cage and are maintained on normal rodent chow with water ad libitum. Mice received test compound daily by gavage (suspended in 0.5 ml of 0.5% methyl cellulose); dissolved in the drinking water; or admixed in the diet. The dose of compounds given ranges from 2.5 to 200 mg/kg body weight/day. The dose is calculated based on the fed weekly body weight and is expressed as active moiety.
• Effective administration of these compounds may be given at a daily dosage of from about 1 mg kg to about 250 mg/kg, and may given in a single dose or in two or more divided doses. Such doses may be administered in any manner useful in directing the active compounds herein to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally.
• transdermal administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues.
• Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
• Oral formulations containing the active compounds of this invention may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions.
• Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc.
• Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethyl- cellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar.
• pharmaceutically acceptable diluents including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, micro
• Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s).
• Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin.
• Water soluble suppository bases such as polyethylene glycols of various molecular weights, may also be used.
• the dosage, regimen and mode of administration of these compounds will vary according to the malady and the individual being treated and will be subject to the judgment of the medical practitioner involved. It is preferred that the administration of one or more of the compounds herein begin at a low dose and be increased until the desired effects are achieved.
• Step b) 4-(4-Bromo-phenyl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole
• the title compound was prepared from 4-(4-bromo-phenyl)-5-methyl-2-(4- trifluoromethyl-phenyl)-oxazole, and 4-methoxy-benzeneboronic acid in substantially the same manner, as described in Example 1 step c, and was obtained as a white solid, mp 93-94 °C; MS m/e 409 (M + );
• the title compound was prepared from 4-(4'-methoxy-biphenyl-3-yl)-5-methyl- 2-(4-trifluoromethyl-phenyl)-oxazole, in substantially the same manner, as described in Example 3, and was obtained as a white solid, mp 133-135 °C; MS m/e 395 (M + );
• Example 7 and was obtained as a white solid, mp 148-149 °C; MS m/e 543 (M + ); Analysis for: C 32 H 24 F 3 NO 4 Calc'd: C, 70.71; H, 4.45; N, 2.58 Found: C, 70.72; H ,
• This compound was prepared from 4-(4-bromo-phenyl)-5-methyl-2-(4- trifluoromethyl-phenyl)-oxazole, and 4-formylbenzeneboronic acid in substantially the same manner, as described in Example 1 step c, and was obtained as an off-white solid;
• This compound was prepared from 4'-[5-methyl-2-(4-trifluoromethyl-phenyl)- oxazol-4-yl]-biphenyl-4-carbaldehyde, and hydroxylamine in substantially the same manner, as described in Example 1 step a, and was obtained as an off-white solid; MS m/e 422 (M + );
• N-(Chlorocarbonyl)isocyanate (0.2 mL, 2.6 mmol) was added dropwise into a cold (-5 °Q mixture of N- ⁇ 4'-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]- biphenyl-4-ylmethyl ⁇ -hydroxylamine (1.1, 2.6 mmol), and tetrahydrofuran (20.0 mL).
• reaction mixture was stirred for 30 minutes, poured into water, acidified with HCI
• This compound was prepared from 3-(4-bromo-phenyl)-5-methyl-2-(4- trifluoromethyl-phenyl)-oxazole in substantially the same manner, as described in
• Example 1 steps a-d, and was obtained as a white solid, mp 216-218; MS m/e 493 (M + );
• This compound was prepared from l-(6-methoxy-naphthalen-2-yl)propanone oxime, and 4-trifluoromethyl-phenyl acetyl chloride in substantially the same manner, as described in Example 1 steps b, and was obtained as a white solid, mp 138-139; MS m/e 383 (M + ); Analysis for: C 22 H 19 F 3 NO 2 Calc'd: C, 68.93; H, 4.21; N, 3.65 Found: C, 68.83; H,
• This compound was prepared from 4'-(6-methoxy-naphthalen-2-yl)-5-methyl- 2-(4-trifluoromethyl-phenyl)-oxazole and boron tribromide in substantially the same manner, as described in Example 3, and was obtained as a white solid, mp 188-191; MS m/e 370 (M+H) + ;
• This compound was prepared from 4'-(6-hydroxy-naphthalen-2-yl)-5-methyl-2- (4-trifluoromethyl-phenyl)-oxazole and bromine in substantially the same manner, as described in Example 9, and was obtained as an off-white solid; MS m/e 447 (M + ); Analysis for: C 21 H 13 BrF 3 NO 2 Calc'd: C, 56.27; H, 2.92; N, 3.12 Found: C, 56.20; H, 2.66; N, 3.15
• This compound was prepared from 4'-(5-bromo-6-hydroxy-naphthalen-2-yl)-5- methyl-2-(4-trifluoromethyl-phenyl)-oxazole and methyl bromoacetate in substantially the same manner, as described in Example 5, and was obtained as white solid, mp 212- 214 °C; MS m/e 506 (M+H) + ; Analysis for: C 23 H 15 BrF 3 NO 4 Calc'd: C, 54.57; H, 2.99; N, 2.77 Found: C, 54.17; H, 2.69; N, 2.76
• This compound was prepared from 4'-(5-bromo-6-hydroxy-naphthalen-2-yl)-5- methyl-2-(4-trifluoromethyl-phenyl)-oxazole and methyl bromoacetate in substantially the same manner, as described in Example 7, and was obtained as an off-white solid, mp 195-197 °C; MS m/e 596 (M+H) + ; Analysis for: C 30 H 21 BrF 3 NO 4 Calc'd: C, 60.42; H, 3.55; N, 2.35 Found: C, 60.31; H,

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