EP1077970A1 - 11-ARYL-BENZO B]NAPHTO 2,3-D]FURANES ET 11-ARYL-BENZO b]NAPHTO 2,3-d]THIOPHENES UTILES DANS LES TRAITEMENTS DE LA RESISTANCE INSULINIQUE ET DE L'HYPERGLYCEMIE - Google Patents

11-ARYL-BENZO B]NAPHTO 2,3-D]FURANES ET 11-ARYL-BENZO b]NAPHTO 2,3-d]THIOPHENES UTILES DANS LES TRAITEMENTS DE LA RESISTANCE INSULINIQUE ET DE L'HYPERGLYCEMIE

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Publication number
EP1077970A1
EP1077970A1 EP99922897A EP99922897A EP1077970A1 EP 1077970 A1 EP1077970 A1 EP 1077970A1 EP 99922897 A EP99922897 A EP 99922897A EP 99922897 A EP99922897 A EP 99922897A EP 1077970 A1 EP1077970 A1 EP 1077970A1
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European Patent Office
Prior art keywords
benzo
naphtho
carbon atoms
thiophen
bromo
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EP99922897A
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German (de)
English (en)
Inventor
Jay Edward Wrobel
Arlene Joan Dietrich
Zenan Li
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Wyeth
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American Home Products Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/74—Naphthothiophenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur 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
  • hyperinsulinemia with obesity and with ischemic diseases of the large blood vessels (e.g. 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.
  • insulin resistance is usually the result of a defect in the insulin receptor signaling system, at a site post binding of insulin to the receptor.
  • Accumulated scientific evidence demonstrating insulin resistance in the major tissues which respond to insulin strongly suggests that a defect in insulin signal transduction resides at an early step in this cascade, specifically at the insulin receptor kinase activity, which appears to be diminished (reviewed by Haring, Diabetalogia 1991, 34, 848).
  • Protein-tyrosine phosphatases (PTPases) play an important role in the regulation of phosphorylation of proteins.
  • 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, PTPoc and SH-PTP2 (B. J. Goldstein, J. Cellular Biochemistry 1992, 48, 33; B. J.
  • This invention provides a compound of formula I having the structure
  • B and D are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, nitro, amino or OR;
  • R is hydrogen, alkyl of 1-6 carbon atoms, -COR 1 , -CH 2 CO2R 1 , -CH(R la )CO 2 R 1 , or
  • R 1 and R la are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms or aryl; E is S, SO, SO 2 , O;
  • X is hydrogen, halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy of 6-12 carbon atoms, nitro, amino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl, or -OCH 2 CO 2 R lb ;
  • R lb is hydrogen or alkyl of 1-6 carbon atoms
  • Y and Z are each, independently, hydrogen or OR 2
  • R is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or
  • R 3 is hydrogen or alkyl of 1-6 carbon atoms
  • C is hydrogen, halogen or OR 4
  • R 4 is hydrogen, alkyl of 1-6 carbon atoms, -CH(R 5 )W, -C(CH 3 ) 2 CO 2 R 6 ,
  • R 5 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH 2 (lH-imidazol-4-yl), -CH 2 (3- 1 H-indolyl), -CH 2 CH 2 ( 1 ,3-dioxo- 1 ,3-dihydro-isoindol-2-yl),
  • W is -CO 2 R 6 , -CONH 2 , -CONHOH, CN, -CONH(CH 2 ) 2 CN, 5-tetrazole, -PO 3 (R 6 ) 2 , -CH 2 OH, or -CH 2 Br, -CONR 6 CHR 7 CO2R 8 , R 6 is hydrogen, alkyl of 1-6 carbon atoms, aryl or aralkyl;
  • R 7 is hydrogen, alkyl of 1-6 carbon atoms, aryl or aralkyl
  • R 8 is hydrogen, alkyl of 1-6 carbon atoms, aryl or aralkyl; or a pharmaceutically acceptable salt thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia.
  • 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, such as when R 5 is -CH 2 (3-pyridyl) or contains similar basic moieties.
  • 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 moiety.
  • Alkyl includes both straight chain as well as branched moieties.
  • Halogen means bromine, chlorine, fluorine, and iodine. It is preferred that the aryl portion of the aryl or aralkyl substituent is a phenyl or naphthy; with phenyl being most preferred.
  • the aryl moiety may be optionally mono-, di-, or tri- substituted with a substituent selected from the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoromethyl, halogen, alkoxycarbonyl of 2-7 carbon atoms, alkylamino of 1-6 carbon atoms, and dialkylamino in which each of the alkyl groups is of 1-6 carbon atoms, nitro, cyano, -CO 2 H, alkylcarbonyloxy of 2-7 carbon atoms, and alkylcarbonyl of 2-7 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 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.
  • the compounds of this invention may be atropisomers by virtue of possible restricted or slow rotation about the aryl-tetracyclic single bond. This restricted rotation creates additional chirality and leads to enantiomeric forms. If there is an additional chiral center in the molecule, diasteriomers exist and can be seen in the NMR and via other analytical techniques. While shown without respect to atropisomer stereochemistry in Formula I, the present invention includes such atoropisomers (enantiomers and diastereomers; as well as the racemic, resolved, pure diastereomers and mixutures of diasteomers) and pharmaceutically acceptable salts thereof.
  • Preferred compounds of this invention include compounds of formula (I) in which
  • a and B are each, independently, hydrogen, or bromine; C and D are OH; E is S, or O;
  • X is hydrogen, halogen, alkyl of 1-6 carbon atoms, CN, alkoxy of 1-6 carbon atoms, aryloxy of 6-12 carbon atoms; arylalkoxy of 6-12 carbon atoms, arylsulfanyl, or pyridylsulfanyl;
  • Y and Z are H; or a pharmaceutically acceptable salt thereof.
  • A is hydrogen
  • B and D are each, independently, halogen, alkyl of 1-6 carbon atoms, aryl or aralkyl of 6-12 carbon atoms, or alkoxy of 1-6 carbon atoms;
  • E is S, O;
  • X is hydrogen, halogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, CN, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy of 6-12 carbon atoms, arylsulfanyl, pyridylsulfanyl;
  • Y and Z are H
  • R 4 is H, alkyl of 1-6 carbon atoms, -CH(R 5 )W, or 5-thiazolidine-2,4-dione;
  • R 5 is H, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, -CH 2 (3-1H- indolyl) , -CH 2 CH 2 ( 1 ,3-dioxo- 1 ,3-dihydro-isoindol-2-yl), -CH 2 CH 2 ( 1 -oxo- l,3-dihydro-isoindol-2-yl), or -CH 2 (3-pyridyl);
  • W is -CO 2 R 6 , -CONH 2 , -CONHOH, -5-tetrazole, or -PO 3 (R 6 ) 2 ;
  • R 6 is hydrogen or alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof.
  • More preferred compounds of this invention include:
  • the compounds of this invention can be prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using to literature procedures. These schemes show the preparation of representative compounds of this invention.
  • a benzyl halide such as benzyl bromide (PhCH 2 Br)
  • This acylation is accomplished most readily using a one to five molar equivalents of a Lewis acid catalyst such as tin tetrachloride or aluminum chloride in an inert solvent such as dichloromethane, 1, 2- dichloroethane or carbon disulfide, generally at temperatures such as -78°C to room temperature.
  • a Lewis acid catalyst such as tin tetrachloride or aluminum chloride
  • an inert solvent such as dichloromethane, 1, 2- dichloroethane or carbon disulfide
  • the reaction is best performed at - 78°C with warming to room temperature in a halocarbon solvent such as dichloromethane under an inert atmosphere such as nitrogen or argon.
  • This compound can then be demethylated using boron tribromide or boron trichloride to produce the compound of formula (la: A, B, D, Y is H; C, Z is OH; E is S or O).
  • the compounds of formula (la: A is H; B, D is alkyl of 1-6 carbon atoms; C is OH; Y, Z is H; E is S or O) can be prepared starting from the compound of formula (III: Q, Y, Z is H; E is S or O) and the appropriate benzoic acid chloride (IV: A is H; B, D is alkyl of 1-6 carbon atoms; C is OMe).
  • the benzoic acid chloride (IV: A is H; B, D is alkyl of 1-6 carbon atoms; C is OMe) is prepared from the corresponding benzoic acid by standard procedures using reagents such as oxalyl chloride and thionyl chloride.
  • the starting benzoic acid of the benzoic acid chloride (IV: A is H; B, D is alkyl of 1-6 carbon atoms; C is OMe) is commercially available or can be easily prepared by known procedures.
  • the acid starting material for benzoic acid chloride (IV: A is H; B, D is is isopropyl; C is OMe) can be prepared using a modification of the method of Schuster, et al., J. Org.
  • the compounds of formula (la: A, C is F; D is H; B is OH; Y, Z is H; E is S or O) can be prepared starting from the compound of formula (III: Q, Y, Z is H; E is S or O) and the appropriate benzoic acid chloride (IV: A, C is F; D is H; B is OMe).
  • the benzoic acid chloride (IV: A, C is F; D is H; B is OMe) is prepared from the corresponding benzoic acid by standard procedures using reagents such as oxalyl chloride and thionyl chloride.
  • the starting benzoic acid of the benzoic acid chloride (IV: A, C is F; D is H; B is OMe) can be easily prepared from the known, 4-bromo-2, 6-difluoroaniline (L. I. Kruse, et al., Biochemistry 1986, 25, 7271-7278) by reacting the latter compound with n-butyl lithium to effect deprotonation ortho to the bromine and fluorine atoms, reaction of the resultant organolithium species with carbon dioxide to install the carboxy moiety ortho to the bromine and fluorine atoms, and further reaction with n-bultyl lithium to effect lithium-bromine exchange and reaction of the final, resultant organolithium species with a proton source upon aqueous workup to provide 2, 4-difluoro, 3-methoxy benzoic acid.
  • Precedence for the fluorine directed ortholithiation reaction over lithium-bromine exchange reaction is found in the following paper: F. Mongin and M. Schlosser,
  • This acylation is accomplished most readily using a one to five molar equivalents of a Lewis acid catalyst such as tin tetrachloride or aluminum chloride in an inert solvent such as dichloromethane, 1, 2-dichloroethane or carbon disulfide, generally at temperatures such as -78°C to room temperature.
  • a Lewis acid catalyst such as tin tetrachloride or aluminum chloride
  • an inert solvent such as dichloromethane, 1, 2-dichloroethane or carbon disulfide
  • Cyclization of the compounds of formula (X: A, B, C, D is H or OMe; with the A, B, C, D, combination of substituents having at least one OMe group but not more than three OMe groups) is generally best accomplished using one to ten molar equivalents of a strong Lewis acid such as a trihaloborane, most conveniently tribromoborane.
  • a strong Lewis acid such as a trihaloborane, most conveniently tribromoborane.
  • the reaction is best performed at -78°C with warming to room temperature in a halocarbon solvent such as dichloromethane under an inert atmosphere such as nitrogen or argon.
  • the compounds of formula (la': A is H; B, D is alkyl of 1-6 carbon atoms; C is OH) can be prepared starting from the compound of formula (VIII: Q is H 2 ) and the appropriate benzoic acid chloride (IX: A is H; B, D is alkyl of 1-6 carbon atoms; C is OMe).
  • the benzoic acid chloride (IX: A is H; B, D is alkyl of 1-6 carbon atoms; C is OMe). is prepared from the corresponding benzoic acid by standard procedures using reagents such as oxalyl chloride and thionyl chloride.
  • the starting benzoic acid of the benzoic acid chloride (IX is H; B, D is alkyl of 1-6 carbon atoms; C is OMe) is commercially available or can be easily prepared by known procedures.
  • the acid starting material for benzoic acid chloride (IX: A is H; B, D is isopropyl; C is OMe) can be prepared using a modification of the method of Schuster, et al., J. Org. Chem 1988, 53, 5819.
  • the tribromophenol of formula (lb: B, D, X is Br; C is OH; E is S, O) can be methylated to produce the methyl ether of formula (lb: B, D, X is Br; C is OMe; E is S, O) by reacting the phenol moiety with a suitable methylating agent such as one or more molar equivalents of methyl iodide or dimethylsulfate employing a base such an alkali methyl carbonate or hydroxide such as potassium carbonate or sodium hydroxide in a suitable solvent such as THF, DMF or DMSO.
  • a suitable methylating agent such as one or more molar equivalents of methyl iodide or dimethylsulfate
  • a base such an alkali methyl carbonate or hydroxide such as potassium carbonate or sodium hydroxide
  • a suitable solvent such as THF, DMF or DMSO.
  • the methyl ether of formula (lb: B, D, X is Br; C is OMe; E is S, O) can be reacted with three or more molar equivalents of lower tetra-alkyltin in the presence of a palladium catalyst such as 1 to 10 mole % of bis(triphenylphosphine)palladium II chloride in a suitable solvent such as DMF, DMA or l-methyl-2-pyrrolidinone at temperatures ranging from 140°C to 200°C to provide the trialkylmethoxy derivative of formula (lb: B, D, X is alkyl of 1-6 carbon atoms; C is OMe; E is S, O).
  • a palladium catalyst such as 1 to 10 mole % of bis(triphenylphosphine)palladium II chloride
  • a suitable solvent such as DMF, DMA or l-methyl-2-pyrrolidinone
  • This methoxy analog can be converted to the corresponding phenol analog of formula (Ic: B, D, X is alkyl of 1-6 carbon atoms; E is S, O) using standard demethylation procedures including one or more molar equivalents of boron tribromide or boron trichloride in dichloromethane at -78°C to room temperature; excess neat pyridinium hydrochloride at 190 to 280°C; hydrobromic acid in acetic acid at 0°C to 50°C; excess trimethylsilylbromide or trimethylsilyliodide in dichloromethane, carbon tetrachloride or acetonitrile at -78°C to 50°C; lithium iodide in pyridine or quinoline at temperatures from 100° to 250°C and one or more molar equivalents of ethyl, methyl or isopropyl mercaptan in the presence of one or more molar equivalents of a Lewis acid such
  • the phenol of formula (lb: B, D, X is H; C is OH; E is S, O) (Scheme 2) can be conveniently iodinated to the diiodophenol of formula (lb: B, D is I; X is H; C is OH; E is S, O) using at least two molar equivalents of iodine in the presence of two or more molar equivalents of an alkali metal hydroxide such as NaOH in an alcohol solvent such as methanol at -20°C to room temperature.
  • an alkali metal hydroxide such as NaOH
  • the monoiodophenol (lb: B is I; X, D is H; C is OH; E is S, O) can be prepared from the phenol of formula (lb: B, D, X is H; C is OH; E is S, O) (Scheme 2) using one to 1.5 molar equivalents of iodine in the presence of at least one equivalent of an alkali metal hydroxide such as NaOH in an alcohol solvent such as methanol at -20°C to room temperature.
  • an alkali metal hydroxide such as NaOH
  • Either the monoiodophenol (lb: B is I; X, D is H; C is OH; E is S, O) or the diiodophenol (lb: B, D is I; X is H; C is OH; E is S, O) can be converted to the respective methyl ether derivatives of formula (lb: B is I; X, D is H; C is OMe; E is S, O) or (lb: B, D is I; X is H; C is OMe; E is S, O) by reacting the phenol moiety with a suitable methylating agent such as one or more molar equivalents of methyl iodide or dimethylsulfate employing a base such an alkali methyl carbonate or hydroxide such as potassium carbonate or sodium hydroxide in a suitable solvent such as THF, DMF or DMSO.
  • a suitable methylating agent such as one or more molar equivalents of methyl iodide or dimethyl
  • the monoiodo methylether derivative of formula (lb: B is I; X, D is H; C is OMe; E is S, O) or the diiodo methylether of formula (lb: B, D is I; X is H; C is OMe; E is S, O) can be reacted with one or more molar equivalents of copper (I) cyanide for the monoiodo analog or two or more molar equivalents of copper (I) cyanide for the diiodo derivative to produce the monocyanomethyl ether of formula (lb: B is CN; X, D is H; C is OMe; E is S, O) or the dicyanomethyl ether of formula (lb: B, D is CN; X is H; C is OMe; E is S, O).
  • the cyanation reaction is generally performed at temperatures ranging from 100°C to 250°C employing polar aprotic solvents such as DMF, l-methyl-2-pyrrolidinone or HMPA. Quinoline or pyridine can also be used.
  • the mono or dicyano methoxy analogs of formula (lb: B is CN; D is H or CN; X is H; C is OMe; E is S, O) can be converted to the corresponding mono or dicyano phenol analogs of formula (Ic: B is CN; D is H or CN; X is H; E is S, O) (Scheme 2) using standard demethylation procedures including one or more molar equivalents of boron tribromide or boron trichloride in dichloromethane at -78°C to room temperature; excess neat pyridinium hydrochloride at 190 to 280°C; hydrobromic acid in acetic acid at 0°C to 50°C; excess trimethylsilyl
  • the monoiodo methylether derivative of formula (lb: B is I; X, D is H; C is OMe; E is S, O) or the diiodo methylether of formula (lb: B, D is I; X is H; C is OMe; E is S, O) (Scheme 2) can be reacted with one or more molar equivalents of copper (I) bromide for the monoiodo analog or two or more molar equivalents of copper (I) bromide for the diiodo derivative to produce the monobromo methyl ether of formula (lb: B is Br; X, D is H; C is OMe; E is S, O) or the dibromo-methyl ether of formula (lb: B, D is Br; X is H; C is OMe; E is S, O).
  • the bromine/idodine exchange reaction is generally performed at temperatures ranging from 100°C to 250°C employing polar aprotic solvents such as DMF, l-methyl-2-pyrrolidinone or HMPA. Quinoline or pyridine can also be used.
  • the mono or dibromo methoxy analogs of formula (lb: B is Br; D is H or Br; X is H; C is OMe; E is S, O) can be converted to the corresponding mono or dibromo phenol analogs of formula (Ic: B is Br; D is H or Br; X is H; E is S, O) (Scheme 2) using standard demethylation procedures including one or more molar equivalents of boron tribromide or boron trichloride in dichloromethane at -78°C to room temperature; excess neat pyridinium hydrochloride at 190 to 280°C; hydrobromic acid in acetic acid at 0°C to 50°C; excess trimethylsilylbromide or trimethylsilyliodide in dichloromethane, carbon tetrachloride or acetonitrile at -78°C to 50°C; lithium iodide in pyridine or quinoline at temperatures from 100° to 250
  • This reaction is best known as the Suzuki reaction (N. Miyaura, T. Yanagi , A Suzuki, Synthetic Comm. 1981, 11, 513-319) and further involves the use of 0.5 to 10 mol% of a palladium catalyst such as tetakis(triphenylphosphine) palladium or a palladium (II) species such as palladium acetate or [1,1 '- bis(diphenyphosphino)ferrocene]palladium(II).
  • a palladium catalyst such as tetakis(triphenylphosphine) palladium or a palladium (II) species such as palladium acetate or [1,1 '- bis(diphenyphosphino)ferrocene]palladium(II).
  • a palladium catalyst such as tetakis(triphenylphosphine) palladium or a palladium (II) species such as palladium acetate or
  • the reaction can be run in a variety of solvents including benzene, THF, dioxane, DME or DMF.
  • solvents such as THF and benzene
  • water or methanol can be used as a colvent.
  • the reaction is generally run at temperatures ranging from room temperature to 120°C.
  • the mono or dibromo methoxy analogs of formula (lb: B is Br; D is H or Br; X is H; C is OMe; E is S, O) and the mono and diphenyl methoxy analogs of formula (lb: B is Ph; D is H or Ph; X is H; C is OMe; E is S, O) can be converted to the corresponding mono or dibromo phenol analogs of formula (Ic: B is Br; D is H or Br; X is H; E is S, O) or the mono and diphenyl phenol analogs of formula (lb: B is Ph; D is H or Ph; X is H; C is OH; E is S, O) (Scheme 2) using standard demethylation procedures including one or more molar equivalents of boron tribromide or boron trichloride in dichloromethane at -78°C to room temperature; excess neat pyridinium hydrochloride at 190 to 280°C; hydrobro
  • the acylating agent is generally a alkyl of 1-6 carbon atoms or aryl carboxy lie acid anhydride or a alkyl of 1-6 carbon atoms or aryl carboxylic acid chloride.
  • the reaction is run under standard conditions, for example, the use of pyridine as solvent with or without a co-solvent such as dichloromethane at 0°C to room temperature.
  • the acylated phenols of formula (Id: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; E is S, O) can then be brominated in the 6-position of the benzo[b]naphtho[2,3-d]thiophene or benzo[b]naphtho[2,3-d]furan ring to form the acylated bromophenols of formula (le: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is Br; E is S, O) (Scheme 3).
  • This bromination reaction is generally done using 1 to 1.3 molar equivalents of molecular bromine in an inert solvent such as dichloromethane or carbon tetrachloride at temperatures ranging from
  • the phenols of formula (Id: B, D is alkyl of 1-6 carbon atoms, C is OH; E is S, O) can then be brominated in the 6-position of the benzo[b]naphtho[2,3-d]thiophene or benzo[b]naphtho[2,3-d]furan ring to form the bromophenols of formula (le: B, D is alkyl of 1-6 carbon atoms, C is OH; X is Br; E is S, O) (Scheme 3).
  • This bromination reaction is generally done using 1 to 1.3 molar equivalents of molecular bromine in an inert solvent such as dichloromethane or carbon tetrachloride at temperatures ranging from -78 °C to room temperature.
  • the acyl group can then be removed from the acylated bromophenols of formula (le: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is Br; E is S, O) to provide the bromophenols of formula (le: B, C, D is H or OH; with the B, C, D combination having at least one OH group; X is Br; E is S, O) (Scheme 3) using standard conditions.
  • These conditions include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0°C to 40°C.
  • acid conditions may also be employed in which the compound is reacted with one or more molar equivalents of a mineral acid such as HC1 or sulfuric acid in water with or without a co-solvent such as THF at temperatures ranging from room temperature to 80°C.
  • the acylated phenols of formula (Id: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; E is S, O) can be nitrated to provide the nitro compounds of formula (le: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is NO 2 ; E is S, O) (Scheme 3).
  • Dilute nitric acid at temperatures ranging from 0°C to room temperature is suitable to effect this transformation.
  • the nitro compounds of formula (le: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is NO 2 ; E is S, O) can be further reduced to the primary amine of formula (le: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is NH 2 ; E is S, O) using a suitable reducing agent such as catalytic hydrogenation with a palladium or platinum catalyst, tin dichloride in aqueous HC1 or in ethyl acetate.
  • a suitable reducing agent such as catalytic hydrogenation with a palladium or platinum catalyst, tin dichloride in aqueous HC1 or in ethyl acetate.
  • the acyl group of the compounds of formula (le: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is NO 2 or NH 2 ; E is S, O) can be removed by using standard conditions to provide the phenols of formula (le: B, C, D is H or OH; with the B, C, D combination having at least one OH group; R is alkyl of 1-6 carbon atoms, aryl; X is NO 2 or NH 2 ; E is S, O).
  • the acylated bromophenols of formula (le: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is Br; E is S, O) (Scheme 3) can be converted to the acylated cyanophenols of formula (le: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is CN; E is S, O) by reaction with one or more molar equivalents of copper (I) cyanide.
  • the cyanation reaction is generally performed at temperatures ranging from 100°C to 250°C employing polar aprotic solvents such as DMF, l-methyl-2-pyrrolidinone or HMPA. Quinoline or pyridine can also be used.
  • polar aprotic solvents such as DMF, l-methyl-2-pyrrolidinone or HMPA.
  • Quinoline or pyridine can also be used.
  • the acyl group can also be removed from the isolated acylated cyanophenols of formula (le: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is CN; E is S, O) to provide the cyanophenols of formula (le: B, C, D is H or OH; with the B, C, D combination having at least one OH group; X is CN; E is S, O) by using standard conditions.
  • These conditions include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0°C to 40°C.
  • acid conditions may also be employed in which the compound is reacted with one or more molar equivalents of a mineral acid such as HC1 or sulfuric acid in water with or without a co-solvent such as THF at temperatures ranging from room temperature to 80°C.
  • the compounds of formula (Id: B, C, D is H or OH; with the B, C, D combination having at least one OH group; E is S, O) (Scheme 3) can be sulfonylated on the phenolic oxygen using one or more molar equivalents of suitable sulfonylating agent to provide the sulfonic acid esters of formula (Id: B, C, D is H or OSO 2 R; with the B, C, D combination having at least one OSO 2 R group; R is alkyl of 1-6 carbon atoms, aryl; E is S, O).
  • the sulfonylating agent is generally a alkyl of 1-6 carbon atoms or aryl sulfonic acid anhydride or a alkyl of 1-6 carbon atoms or aryl sulfonic acid chloride.
  • the reaction is run under standard conditions such as using pyridine as solvent with or without a co-solvent such as dichloromethane at 0°C to room temperature.
  • the sulfonic acid esters of formula (Id: B, C, D is H or OSO 2 R; with the B, C, D combination having at least one OSO 2 R group; R is alkyl of 1-6 carbon atoms, aryl; E is S, O) can be treated with a chlorinating agent to effect chlorination at the 6- position of the benzo[b]naphtho[2,3-d]thiophene or benzo[b]naphtho[2,3-d]furan ring to afford the chloro-sulfonic acid esters of formula (le: B, C, D is H or OSO 2 R; with the B, C, D combination having at least one OSO 2 R group; R is alkyl of 1-6 carbon atoms, aryl; X is Cl; E is S, O).
  • Suitable chlorinating agents include one or more molar equivalents of sulfuryl chloride, chlorine gas or N-chlorosuccinimide in suitable halocarbon solvents such as dichloromethane or chloroform at temperatures ranging from -78°C to 40 °C.
  • the sulfonic ester group can then be removed from the chloro-sulfonic acid esters of formula (le: B, C, D is H or OSO 2 R; with the B, C, D combination having at least one OSO 2 R group; R is alkyl of 1-6 carbon atoms, aryl; X is Cl; E is S, O) to provide the chlorophenols of formula (le: B, C, D is H or OH; with the B, C, D combination having at least one OH group; X is Cl; E is S, O) (Scheme 3) using standard conditions.
  • These conditions include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from room temperature to l l0°C.
  • a co-solvent such as THF, dioxane or a lower alcohol
  • methanol or mixtures of THF and a lower alcohol at temperatures ranging from room temperature to l l0°C.
  • the sulfonic acid esters of formula (Id: B, C, D is H or OSO 2 R; with the B, C, D combination having at least one OSO 2 R group; R is alkyl of 1-6 carbon atoms, aryl; E is S, O) can also be treated with iodinating reagents to effect iodination at the 6- position of the benzo[b]naphtho[2,3-d]thiophene or benzo[b]naphtho[2,3-d]furan ring to afford the iodo-sulfonic acid esters of formula (le: B, C, D is H or OSO 2 R; with the B, C, D combination having at least one OSO 2 R group; R is alkyl of 1-6 carbon atoms, aryl; X is I; E is S, O).
  • a suitable iodinating reagent includes a mixture of 0.7 or more molar equivalents of molecular iodine and 0.25 or more molar equivalents of iodic acid in a mixture of THF and 80% aqueous acetic acid with a small amount of concentrated sulfuric acid at temperatures ranging from room temperature to 80°C.
  • the sulfonic ester group can then be removed from the iodo-sulfonic acid esters of formula (le: B, C, D is H or OSO 2 R; with the B, C, D combination having at least one OSO 2 R group; R is alkyl of 1-6 carbon atoms, aryl; X is I; E is S, O) to provide the iodophenols of formula (le: B, C, D is H or OH; with the B, C, D combination having at least one OH group; X is I; E is S, O) (Scheme 3) using standard conditions.
  • These conditions include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from room temperature to 110°C.
  • a co-solvent such as THF, dioxane or a lower alcohol
  • THF methanol or mixtures of THF and a lower alcohol
  • the reagent and conditions to effect this exchange include reacting (If) under anhydrous conditions with one to ten molar molar equivalents of a sodium perfluorocarboxylate (RCO 2 Na: R is perfluoroalkyl) and one to five molar molar equivalents of copper (I) iodide in a high boiling inert solvent such as DMF, DMA or l-methyl-2-pyrrolidinone at temperatures ranging from 140°C to 200°C.
  • a sodium perfluorocarboxylate RCO 2 Na: R is perfluoroalkyl
  • copper (I) iodide in a high boiling inert solvent such as DMF, DMA or l-methyl-2-pyrrolidinone at temperatures ranging from 140°C to 200°C.
  • the compound of formula (Ig: C, D is H or OSO 2 R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; X is perfluoroalkyl of 1-6 carbon atoms; E is S, O) can be prepared from the compound of formula (If: C, D is H or OSO 2 R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; E is S, O) by reacting the former with one to ten molar molar equivalents of a perfluoroalkyl iodide and one to five molar molar equivalents of activated Cu° in a high boiling inert solvent such as DMF, DMA or l-methyl-2-pyrrolidinone at temperatures ranging from 140°C to 200°C.
  • a high boiling inert solvent such as DMF, DMA or l-methyl-2-pyrrolidinone
  • the compound of formula (If: C, D is H or OSO 2 R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; E is S, O) can be reacted with 0.5 to two molar equivalents of bis(trifluoromethylmercury) and two to four molar equivalents of activated Cu° in a high boiling inert solvent such as DMF, DMA or l-methyl-2-pyrrolidinone at temperatures ranging from 140°C to 200°C to produce the compound of (Ig: C, D is H or OSO 2 R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; X is CF 3 ; E is S, O).
  • a high boiling inert solvent such as DMF, DMA or l-methyl-2-pyrrolidinone
  • 6- Alkyl of 1-6 carbon atoms derivatives of the compound of formula (Ig: C, D is H or OSO 2 R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; X is alkyl of 1-6 carbon atoms; E is S, O) (Scheme 4) can be prepared by reaction of (If: C, D is H or OSO 2 R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; E is S, O) with three or more molar equivalents of lower tetra-alkyltin in the presence of a palladium catalyst such as 1 to 10 mole % of bis(triphenylphosphine)palladium II chloride in a suitable solvent such as DMF, DMA or l-methyl-2-pyrrolidinone at temperatures ranging from 140°C to 200°C.
  • a palladium catalyst such as 1 to 10 mole % of bis(triphenyl
  • the sulfonic ester group can then be removed from the sulfonic acid esters of formula (Ig: C, D is H or OSO 2 R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; X is alkyl of 1-6 carbon atoms or perfluoroalkyl of 1-6 carbon atoms; E is S, O) to provide the phenols of formula (Ig: C, D is H or OH; C, D cannot both be H; X is alkyl of 1-6 carbon atoms or perfluoroalkyl of 1-6 carbon atoms; E is S, O) using standard conditions.
  • These conditions include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from room temperature to l lO°C.
  • a co-solvent such as THF, dioxane or a lower alcohol
  • methanol or mixtures of THF and a lower alcohol at temperatures ranging from room temperature to l lO°C.
  • 6-Alkoxy derivatives of the compound of formula (Ig: C, D is H, OH; C, D cannot both be H; X is alkoxy of 1-6 carbon atoms; E is S, O) can be prepared by reaction of (If: C, D is H or OSO 2 R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; E is S, O) with three or more molar equivalents of lower alkali metal alkoxide in the presence of a copper (I) or copper (II) catalyst such as 1 to 10 mole % copper (II) chloride in a suitable solvent such as DMF, DMA or l-methyl-2- pyrrolidinone at temperatures ranging from 80°C to 180°C. Under the reaction conditions, the sulfonic acid group of (If: C, D is H or OSO 2 R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; E is S, O) is
  • X is alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl;
  • E is S, O
  • C, D is H or OSO 2 R; C, D cannot both be H;
  • R is alkyl of 1-6 carbon atoms, aryl; E is S, O) with one or more molar equivalents of the appropriate alkyl of 1-6 carbon atomsthiol, arylthiol, thiopyridine or 2-N,N-dimethylaminoethyl- mercaptan, one or more molar equivalents of an alkali metal hydroxide such as sodium hydroxide, one or more molar equivalents of a copper (I) or copper (
  • the dibromo-bisphenols of formula (Ii: A is OH; B, D is Br; X is H; E is S, O) can be further brominated in the 6-position of the benzo[b]naphtho[2,3-d]thiophene ring to form the bisphenols of formula (Ii: A is OH; B, D, X is Br; E is S, O).
  • This bromination reaction is generally done using 1 to 1.3 molar equivalents of molecular bromine in an inert solvent such as dichloromethane or carbon tetrachloride at temperatures ranging from -78 °C to room temperature.
  • the bisphenols of formula (Ij: C, D is OH;
  • X is halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl;
  • E is S, O
  • A is H;
  • B is Br;
  • C, D is OH;
  • X is halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1- 6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, aryl
  • D is OH;
  • X is halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; E is S, O) can be further alkylated with a alkyl of 1-6 carbon atoms halide to provide the dialkylated product of formula (Ik: A is H; B is Br; C is benzyloxy, D is alkoxy of 1-6 carbon atoms; X is halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkyls
  • E is S, O
  • This product may be contaminated with small amounts ( ⁇ 10%) of the regioisomer of formula (Im: C is OCH 2 CO 2 CH 3 ; Y is OH; Z is H; E is S).
  • the regioisomers can be separated by conventional means.
  • the bisphenols of formula (II: Y, C is OH; Z is H; E is S) or (Z, C is OH; Y is H; E is S or O) can be diaklylated with two or more molar equivalents of an alkyl haloacetate of formula (X 2 CH 2 CO 2 R 6 where X 2 is Cl, Br or I and R 6 is alkyl of 1-6 carbon atoms) and with two or more molar equivalents of an alkali metal carbonate such as potassium carbonate in a polar aprotic solvent such as DMF to afford the dialkylated product of formula (Im: Y, C is OCH 2 CO 2 R 6 ; Z is H; E is S; R 6 is alkyl of 1-6 carbon atoms) or (Z, C is OCH 2 CO 2 R 6 ; Y is H; E is S or O; R 6 is alkyl of 1-6 carbon atoms).
  • the monoesters of formula (Im: Y is OCH 2 CO 2 CH 3 ; C is OH; Z is H; E is S) as well as the diesters of formula (Im: Y, C is OCH 2 CO 2 R 6 ; Z is H; E is S; E is S) or (Z, C is OCH 2 CO 2 R 6 ; Y is H; E is S or O) can be transformed into their carboxylic acid analogs using standard conditions to afford the moncarboxylic acids of formula (Im: Y is OCH 2 CO 2 H; C is OH; Z is H; E is S) and the dicarboxylic acids of formula (Im: Y, C is OCH 2 CO 2 H; Z is H; E is S) or (Z, C is OCH 2 CO 2 H; Y is H; E is S or O).
  • the conditions to effect these transformations include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0°C to 40°C.
  • a co-solvent such as THF, dioxane or a lower alcohol
  • methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0°C to 40°C.
  • the bisphenols of formula (In: A, B is H or Br; C, D is OH; X is halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is S, O) can be diaklylated with two or more molar equivalents of an alkyl haloacetate of formula (X 2 CHR 6 CO 2 R 6 where X 2 is Cl, Br or I and R 6 is alkyl of 1-6 carbon atoms, R 6' is H) and with two or more molar equivalents of an alkali metal carbonate such as potassium carbonate in a polar aprotic solvent such as DMF to afford the
  • the other co-reagents necessary to effect the Mitsunobu Reaction include one or more molar equivalents of a alkyl of 1-6 carbon atoms azodicarboxylate diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate and one or more molar equivalents of triarylphosphine such as triphenylphosphine in a suitable solvent such as diethyl ether, THF, benzene or toluene at temperatures ranging from -20°C to 120°C.
  • X is halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; R 6 , R 6 is alkyl of 1-6 carbon atoms, aralkyl, aryl; E is S, O) as well as the diesters of formula (Io: A, B is H or Br; C is OCHR 6 CO 2 R 6 , X is halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6
  • the conditions to effect these transformations include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0°C to 40°C.
  • a co-solvent such as THF, dioxane or a lower alcohol
  • methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0°C to 40°C.
  • A is H or OH
  • B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, alkoxy of 1-6 carbon atoms, nitro
  • Y, Z is H or OCH 2 CO 2 R 6 , but Y and Z are not concurrently OCH 2 CO 2 R 6
  • the other co-reagents necessary to effect the Mitsunobu Reaction include one or more molar equivalents of a alkyl of 1-6 carbon atoms azodicarboxylate diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate and one or more molar equivalents of triarylphosphine such as triphenylphosphine in a suitable solvent such as diethyl ether, THF, benzene or toluene at temperatures ranging from -20°C to 120°C.
  • the 2-hydroxy carboxylic acid ester of formula CH(OH)(R 5 )CO 2 R 6 (R 5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH 2 (lH-imidazol-4-yl), CH 2 (3-1H- indolyl), CH 2 CH 2 ( 1 ,3-dioxo- 1 ,3-dihydro-isoindol-2-yl), CH 2 CH 2 ( 1 -oxo- 1 ,3-dihydro- isoindol-2-yl), CH 2 (3-pyridyl), CH 2 CO 2 R 6 , R 6 is alkyl of 1-6 carbon atoms) are commercially available or can be prepared from commercially available carboxylic acid precursors under standard esterification conditions.
  • (S)-(+)-2-Hydroxy-l-oxo-3- dihydro-2-isoindolinebutyric acid, methyl ester can be prepared from (S)-(+)-2- hydroxy-l,3-dioxo-2-isoindolinebutyric acid, methyl ester via sequential treatment with 1) sodium borohydride in THF- water; 2) trifluoroacetic acid / chloroform; 3) triethylsilane / trifluoroacetic acid and 4) aqueous sodium bicarbonate.
  • 3-(Pyridin-3-yl)-phenyllactic acid, ethyl ester can be prepared according to the two step procedure of B.A. Lefker, W.A. Hada, P.J. McGarry Tetrahedron Lett. 1994, 35, 5205-5208, from commericially available 3-pyridinecarboxaldehyde and ethyl chloroacetate.
  • a strong base such as lithium diisopropyl amide
  • suitable solvent such as THF
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; W is CO 2 R 6 ; R 5 is H, alkyl of 1- 6 carbon atoms, aralkyl, aryl, CH 2 (lH-imidazol-4-yl), CH 2 (3-lH-indolyl), CH 2 CH 2 ( 1 ,3-d
  • the conditions to effect these transformations include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0°C to 40°C.
  • a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0°C to 40°C.
  • acid conditions may also be employed in which the above mentioned carboxylic acid ester of formula (Iq) is reacted with one or more molar equivalents of a mineral acid such as HC1 or sulfuric acid in water with or without a co-solvent such as THF at temperatures ranging from room temperature to 80°C.
  • ester to acid transformation leading to (Iq) include reacting the carboxylic acid ester of formula (Iq) with one or more molar equivalents of boron tribromide or boron trichloride in dichloromethane at -78°C to room temperature; one or more molar equivalents hydrobromic acid in acetic acid at 0°C to 50°C; one or more molar equivalents trimethylsilylbromide or trimethylsilyliodide in dichloromethane, carbon tetrachloride or acetonitrile at -78°C to 50°C; one or more molar equivalents lithium iodide in pyridine or quinoline at temperatures from 100° to 250°C.
  • A is H;
  • B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, alkoxy of 1-6 carbon atoms, nitro;
  • Y, Z is H or OCH 2 CO 2 R 6 , but Y and Z are not concurrently OCH 2 C 2 R 6 ;
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
  • R 6 is alkyl of 1-6 carbon atoms;
  • E is S, O) can be alkylated with one or more molar equivalents of diethyl tri
  • A is H
  • B is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, alkoxy of 1-6 carbon atoms, nitro
  • Y is H or OCH 2 CO 2 R 6 , but Y and Z are not concurrently OCH 2 CO 2 R 6
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridyl- sul
  • A is H or OH
  • B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, alkoxy of 1-6 carbon atoms, nitro
  • Y, Z is H or OCH 2 CO 2 R 6 , but Y and Z are not concurrently OCH 2 CO 2 R 6
  • the other co-reagents necessary to effect the Mitsunobu Reaction include one or more molar equivalents of a alkyl of 1-6 carbon atoms azodicarboxylate diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate and one or more molar equivalents of triarylphosphine such as triphenylphosphine in a suitable solvent such as diethyl ether, THF, benzene or toluene at temperatures ranging from -20°C to 120°C.
  • azodicarboxylate diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate
  • triarylphosphine such as triphenylphosphine in a suitable solvent such as diethyl ether, THF, benzene or toluene at temperatures ranging from -20°C to 120°C.
  • the 2-hydroxy phosphonic acid diester of formula CH(OH)(R 5 )PO 3 R 6 (R 5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, R 6 is alkyl of 1-6 carbon atoms) can be prepared by reacting a dialklylphosphonate of formula HP(O)(OR 6 ) 2 (R 6 is alkyl of 1-6 carbon atoms) with an aldehyde of formula R 5 CHO (R 5 is alkyl of 1-6 carbon atoms, aryl, aralkyl) under standard conditions.
  • A is H or OH
  • B is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, alkoxy of 1-6 carbon atoms, nitro
  • Y, Z is H or OCH 2 CO 2 R 6 , but Y and Z are not concurrently OCH 2 CO 2 R 6
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
  • W is PO 3 (R 6 ) 2
  • R 5 is H, alkyl of 1-6 carbon atoms, aralkyl,
  • A is H or OH
  • Y Z is H
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
  • W is CO 2 R 6 ;
  • R 5 is H, alkyl of 1- 6 carbon atoms, aralkyl, aryl, CH 2 (lH-imidazol-4-yl), CH 2 (3-lH-indolyl), CH 2 CH 2 (
  • This transformation can be accomplished using standard methods to effect carboxylic acid to carboxylic acid amide transformations. These methods include converting the acid to an activated acid and reacting with one or more molar equivalents of the desired amine. Amines in this category include ammonia in the form of ammonium hydroxide, hydroxyl amine and 2-aminopropionitrile. Methods to activate the carboxylic acid include reacting said acid with one or more molar equivalents of oxalyl chloride or thionyl chloride to afford the carboxylic acid chloride in a suitable solvent such as dichloromethane, chloroform or diethyl ether.
  • This reaction is often catalyzed by adding small amounts (0.01 to 0.1 molar equivalents) of dimethylformamide.
  • Other methods to activate the carboxylic acid include reacting said acid with one or more molar equivalents dicyclohexylcarbodiimide with or without one or more molar equivalents of hydroxybenzotriazole in a suitable solvent such as dichloromethane or dimethylformamide at temperatures ranging from 0°C to 60°C.
  • A is H or OH
  • Y Z is H
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N- dimethylamino-ethylsulfanyl;
  • W is CONH 2 ;
  • R 5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH 2 (lH-imidazol-4-yl), CH 2 (3-lH-indolyl), CH
  • One set of conditions to effect this transformation include reacting the said primary carboxylic acid amide with one or more molar equivalents of trifluoroacetic anhydride and two or more molar equivalents of pyridine in a suitable solvent such as dioxane at temperatures ranging from 60°C to 120°C.
  • A is H or OH
  • Y Z is H
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
  • W is CN;
  • R 5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH 2 (lH-imidazol-4-yl), CH 2 (3-1 H-indolyl), CH 2 CH 2 (1,3-
  • the nitrile fuction can be reacted with one or more molar equivalents of ammonium azide in a suitable solvent such as dimethylformamide at temperatures ranging from 60°C to 160°C.
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; W is CO 2 R 6 ; R 5 is H, alkyl of 1- 6 carbon
  • the other co-reagents necessary to effect the Mitsunobu Reaction include one or more molar equivalents of a alkyl of 1-6 carbon atoms azodicarboxylate diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate and one or more molar equivalents of triarylphosphine such as triphenylphosphine in a suitable solvent such as diethyl ether, THF, benzene or toluene at temperatures ranging from -20°C to 120°C at temperatures ranging from -20°C to 120°C.
  • the 2-hydroxy carboxylic acid ester of formula CH(OH)(R la )CO 2 R 1 (R 1 , R la s alkyl of 1-6 carbon atoms, aralkyl, aryl) are commercially available or can be prepared from commercially available carboxylic acid precursors under standard esterification conditions .
  • R 1 is alkyl of 1-6 carbon atoms, aralkyl, aryl
  • R la is H or alkyl of 1-6 carbon atoms, aralkyl, aryl
  • E is S, O
  • the conditions to effect these transformations include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0°C to 40°C.
  • a co-solvent such as THF, dioxane or a lower alcohol
  • methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0°C to 40°C.
  • R 4 is (R, S)-5- thiazolidine-2,4-dione
  • B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, alkoxy of 1-6 carbon atoms, nitro
  • the phenols of formula (It: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, alkoxy of 1-6 carbon atoms, nitro;
  • X is halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridyl- sulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
  • E is S, O) can be reacted with one or more molar equivalents of tetrazole and di-tert-butyl N,N-diethylphosporamidate in THF at room temperature followed by addition of one or more molar equivalents of meta-chlorobenzoic
  • R 4 is P(O)(OtBu) 2
  • B D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, alkoxy of 1-6 carbon atoms, nitro
  • R 4 is P(O)(OH) 2 ;
  • B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
  • the phenols of formula (It: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, alkoxy of 1-6 carbon atoms, nitro;
  • X is halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N- dimethylamino-ethylsulfanyl;
  • E is S, O)
  • R 4 is C(CH 3 ) 2 CO 2 H
  • B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, alkoxy of 1-6 carbon atoms, nitro;
  • the phenols of formula (It: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, alkoxy of 1-6 carbon atoms, nitro;
  • X is halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N- dimethylamino-ethylsulfanyl;
  • E is S, O
  • R 4 is CH 2 CH 2 CO 2 H
  • B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, alkoxy of 1-6 carbon atoms, nitro
  • X is
  • the phenols of formula (It: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, alkoxy of 1-6 carbon atoms, nitro;
  • X is halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2- N,N-dimethylamino-ethylsulfanyl;
  • E is S, O) can be reacted with a 3-hydroxy carboxylic acid ester of formula CH(OH)(R 7 )CH 2 CO 2 R 6 (R 7 is H or alkyl of 1-6 carbon atoms; R 6 is alkyl of 1-6 carbon atoms) to afford the esters of formula
  • the other co-reagents necessary to effect the Mitsunobu Reaction include one or more molar equivalents of a alkyl of 1-6 carbon atoms azodicarboxylate diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate and one or more molar equivalents of triarylphosphine such as triphenylphosphine in a suitable solvent such as diethyl ether, THF, benzene or toluene at temperatures ranging from -20°C to 120°C at temperatures ranging from -20°C to 120°C.
  • the 3-hydroxy carboxylic acid ester of formula CH(OH)(R 7 )CH 2 CO 2 R 6 (R 7 is H or alkyl of 1-6 carbon atoms; R 6 is alkyl of 1-6 carbon atoms) are commercially available or can be prepared from commercially available carboxylic acid precursors under standard esterification conditions.
  • R 4 is (R)-CH(R 7 )CH 2 CO 2 R 6 ;
  • B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, alkoxy of 1-6 carbon atoms, nitro;
  • X is halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
  • R 7 is H or alkyl of 1-6 carbon atoms;
  • R 6 is alkyl of 1-6 carbon atoms;
  • E is S, O
  • esters of formula (Iu) include reacting the esters of formula (Iu) with two or more molar equivalents of boron tribromide or boron trichloride in dichloromethane at -78°C to room temperature; two or more molar equivalents hydrobromic acid in acetic acid at 0°C to 50°C; two or more molar equivalents trimethylsilylbromide or trimethylsilyliodide in dichloromethane, carbon tetrachloride or acetonitrile at -78°C to 50°C; two or more molar equivalents lithium iodide in pyridine or quinoline at temperatures from 60° to 250°C.
  • esters of formula (Iv: B, D is H, halogen, alkyl of 1-6 carbon atoms; R 5 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; R 6 is alkyl of 1-6 carbon atoms; E is S, O)
  • a halocarbon solvent such as dichloromethane at temperatures ranging from -78 to room temperature
  • B, D is H, halogen, alkyl of 1-6 carbon atoms
  • R 5 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl
  • R 6 is alkyl of 1-6 carbon atoms
  • R 8 is H
  • E is S, O
  • the phenols of formula (Iw: B, D is H, halogen, alkyl of 1-6 carbon atoms; R 5 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; R 6 is alkyl of 1-6 carbon atoms; R 8 is H; E is S, O) can be alkylated with one or more molar equivalents of an alkylating agent of formula R 8 X (R 8 is alkyl of 1-6 carbon atoms, lower aralkyl and CH 2 CO 2 CH 3 ; X is halogen; E is S, O) and with one or more molar equivalents of an alkali metal carbonate such as potassium carbonate in a polar aprotic solvent such as DMF to afford the alkylated phenol of formula (Iw: B, D is H, halogen, alkyl of 1-6 carbon atoms; R 5 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; R 6
  • esters of formula (Iw: B, D is H, halogen, alkyl of 1-6 carbon atoms; R 5 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; R 6 is alkyl of 1-6 carbon atoms; R 8 is alkyl of 1-6 carbon atoms, lower aralkyl, CH 2 CO 2 CH 3 ; E is S, O)
  • B, D is H, halogen, alkyl of 1-6 carbon atoms; R 5 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; R 6 is H; R 8 is alkyl of 1-6 carbon atoms, lower aralkyl, CH 2 CO 2 H; E is S, O).
  • the conditions to effect these transformations include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0°C to 40°C.
  • the compounds of formula (Ix: B, D is H, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms; X is halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, R 5 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; R 6 is H, alkyl of 1-6 carbon atoms) can be transformed into their sulfone derivatives of formula (Iy: n is 2; B, D is H, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms; X is halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy, R 5 is H, alkyl of 1-6
  • 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.
  • This standard pharmacological test procedure assess the inhibition of rat hepatic microsomal PTPase 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 outlined below.
  • 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.
  • liver homogenate is filtered through silk to remove any remaining tissue debris and then is centrifuged at 10,000xg for 20 minutes at 40C. The supernatant is decanted and centrifuged at 100,000xgfor 60 minutes at 40C.
  • 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 microsomal fraction (83.25 ul) is preincubated for 10 min at 37deg.C with or without test compound (6.25ul) and 305.5 ul of the 81.83 mM HEPES reaction buffer, pH 7.4.
  • Peptide substrate, 10.5 ul at a final concentration of 50 uM, is equilibrated to 37deg.C in a LABLINE Multi-Blok heater equipped with a titerplate adapter.
  • 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 HC1 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 ⁇ M. 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. Measurement of PTPase activity. The malachite green-ammonium molybdate method, as described (Lanzetta et al. Anal. Biochem. 100, 95, 1979) and adapted for a platereader, is used for the nanomolar detection of liberated phosphate by recombinant PTP1B.
  • the test procedure uses, as substrate, a dodecaphosphopeptide custom synthesized by AnaSpec, Inc. (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.
  • the recombinant rPTPlB is diluted with buffer (pH 7.4, containing 33 mM Tris-HCl, 2 mM EDTA and 50 mM b-mercaptoethanol) to obtain an approximate activity of 1000-2000 nmoles/min/mg protein.
  • the diluted enzyme (83.25 mL) is preincubated for 10 min at 37°C with or without test compound (6.25 mL) and 305.5 mL of the 81.83 mM HEPES reaction buffer, pH 7.4 peptide substrate, 10.5 ml at a final concentration of 50 mM, and is equilibrated to 37°C. in a LABLINE Multi-Blok heater equipped with a titerplate adapter.
  • the preincubated recombinant enzyme preparation (39.5 ml) with or without drug is added to initiate the dephosphorylation reaction, which proceeds at 37°C for 30 min.
  • 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 HC1 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.
  • PTPase activities based on a potassium phosphate standard curve, are expressed as nmoles of phosphate released/min/mg protein. Inhibition of recombinant PTP1B by test compounds is calculated as percent of phosphatase control.
  • the non-insulin dependent diabetic (NIDDM) syndrome can be typically characterizes by obesity, hyperglycemia, abnormal insulin secretion, hyperinsulinemia and insulin resistance.
  • the genetically obese-hyperglycemic ob/ob mouse exhibits many of these metabolic abnormalities and is thought to be a useful model to search for hypoglycemic agents to treat NIDDM [Coleman, D.: Diabetologia 14: 141-148, 1978].
  • 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.
  • mice received vehicle only.
  • representative compounds of this invention have been shown to inhibit PTPase activity and lower blood glucose levels in diabetic mice, and are therefore useful in 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 or inhibition of type II diabetes, and in modulating glucose levels in disorders such as type I diabetes. As used herein, the term modulating means maintaining glucose levels within clinically normal ranges.
  • 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, carboxymethylcellulose 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.
  • Example 1 Benzorblthiophene-2-yl-(phenyl -methanol n-Butyl lithium (35 ml, 2.5 N in hexanes) was added dropwise to a stirred solution of thianaphthene (11.5 g, 85.6 mmol) in THF (300 mL) at -78°C under a dry N2 atmosphere. After 1 h , benzaldehyde (9.6 mL, 94.4 mmol ) was added and the cold bath was removed. After an additional 30 minutes, sat. aq. NH4C1 was added and the reaction mixture was partitioned between water and ether. The ether phase was washed with brine and concentrated.
  • Example 2 (6-Methoxy-benzo [bl thiophene-2-yl-(pheny 1) -methanol n-Butyl lithium (12.5 ml, 2.5 N in hexanes) was added dropwise to a stirred solution of 6-methoxythianaphthene (5.0 g, 30.4 mmol, S. L. Graham, et al., J. Med. Chem. 1989, 32, 2548-2554) in THF (70 mL) at -78°C under a dry N2 atmosphere. After 1 h , benzaldehyde (3.42 mL, 33.4 mmol ) was added. After an additional 45 minutes, sat. aq.
  • Trifluoroacetic acid 105 mL was added dropwise over a 35 minute period to a stirred suspension of benzo[b]thiophene-2-yl-(phenyl)-methanol (17.6 g, 73.2 mmol), sodium borohydride (13.75 g, 364 mmol) and ether (1.3 L). After an additional 5 hours the reaction mixture was added to 10 % aqueous sodium hydroxide (1.3 L) and stirred for 30 minutes. The layers were separated and the ether phase was washed with brine (500 mL) and dried (MgSO4).
  • Tin tetrachloride (9.0 mL, 76.91 mmol) was added dropwise over a 25 minute period to a stirred solution of 2-benzyl-benzo[b]thiophene (14.87 g, 96.79 mmol), p- anisoyl chloride (11.75 g, 68.87 mmol) and carbon disulfide (75 mL) under a dry nitrogen atmosphere. After 6 hours, the reaction mixture was added to water and extracted with dichloromethane. The dichloromethane extract was washed with sat. aq. sodium bicarbonate and brine. The solvent was removed and the resultant solid was triturated with pet.
  • Tin tetrachloride (2.0 mL, 17.09 mmol) was added dropwise over a 10 minute period to a stirred, -78°C solution of 2-benzyl-6-methoxy-benzo[b]thiophene (2.7 lg, 10.65 mmol), anisoyl chloride (1.93 g, 11.29 mmol) and dichloromethane (41 mL) under a dry nitrogen atmosphere. After 1 hours at -78°C, the reaction mixture was slowly warmed to room temperature and stirred for 16 h period. The reaction mixture was added to water and extracted with ether. The ether phase was washed with brine and silica gel was added to it.
  • Tin tetrachloride (3.44 mL, 29.48 mmol) was added dropwise over a 20 minute period. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was added to water and extracted with ether. The ether extract was washed with water and brine. Silica gel was added and the solvent was removed. The adsorbate was flash chromatographed (gradient, petroleum ether to 95:5 petroleum ether : ethyl acetate).
  • Neat boron tribromide (4.3 mL, 45.2 mmol) was added dropwise to a stirrred suspension of (2-benzyl-benzo[b]thiophen-3-yl)-(3,5-diisopropyl-4-methoxy-phenyl)- methanone (3.57 g, 8.07 mmol) in dichloromethane (30 mL) at -78°C under a dry nitrogen atomosphere. The solution was allowed to warm to ambient temperature and was stirred for 1.5 h. The reaction mixture was cooled to 0°C and carefully quenched with water . The reaction mixture was partitioned between water and ether. The ether phase was washed with water and brine.
  • reaction mixture was quenched with water (100 mL), diluted with methylene chloride (50 mL) and the organics were extracted with diethyl ether (1x100 mL, 1x75 mL). The extracts were combined, washed with brine, and combined with silica gel.
  • Example 27 Prepared from 4-(benzo[b]naphtho[2,3-d]thiophen-l l-yl)-2-iodo-phenol (Example 27) according to the procedure on Example 22.
  • White solid mp 274- 275°C: MS (El): [M+], 466 (100%, MI); Anal. Calc. for C23H15IOS: C, 59.24, H, 3.24, N, 0.00. Found: C, 58.53, H, 3.11 , N, 0.11.
  • Example 30 Example 30.
  • Example 29 Prepared from 1 l-(3-iodo-4-methoxy-phenyl)-benzo[b]naphtho[2,3-d]thio- phene (Example 29) according to the procedure on Example 30.
  • White solid mp 230- 232 °C: MS (El): [M+], 365 (100%, MI); Anal. Calc. for C24H15NOS: C, 78.88, H, 4.41, N, 3.83. Found: C, 77.61, H, 4.23, N, 4.10.
  • Example 30 Prepared from 5-benzo[b]naphtho[2,3-d]thiophen-l l-yl-2-methoxy-iso- phthalonitrile (Example 30) according to the procedure on Example 20.
  • White solid mp 274-276 °C: MS (El): [M+], 376 (80%, MI);
  • Example 31 Prepared from 5-(benzo[b]naphtho[2,3-d]thiophen-l l-yl)-2-methoxy-benzo- nitrile (Example 31) according to the procedure on Example 20.
  • White solid mp 231- 232 °C: MS (El): [M+], 351 (100%, MI); Anal. Calc. for C23H13NOS: C, 78.61, H, 3.73, N, 3.99. Found: C, 78.27, H, 3.59, N, 3.89.
  • Acetic anhydride (0.62 mL, 6.57 mmol) was added to a 0°C, stirred solution of 4-benzo[b]naphtho[2,3-d]thiophen-l l-yl-phenol (2.0 g, 6.13 mmol) in pyridine (8 mL).
  • Example 18 according to the procedure of Example 34.
  • White solid mp 179-180°C: MS (El): [M+], 426; Anal. Calc. for C26H18O4S: C, 73.22, H, 4.25, N, 0.00. Found: C, 73.17, H, 4.30, N, 0.12.
  • Example 37
  • Example 35 Prepared from acetic acid 3-benzo[b]naphtho[2,3-d]thiophen-l l-yl)-phenyl ester (Example 35) according to the procedure of Example 37.
  • Example 36 Prepared from acetic acid 2-acetoxy-4-(benzo[b]naphtho[2,3-d]thiophen-l l- yl)-phenyl ester (Example 36) according to the procedure of Example 37.
  • Example 40 Example 40.
  • Methanesulfonic acid 4-Benzo[b]naphthor2,3-d1thiophen-l l-yI-phenyl Ester Methylsulfonyl chloride (0.63 mL, 8.14 mmol) was added dropwise to a cold
  • Methanesulfonic acid 4-(6-Iodo-benzo[b]naphthoF2.3-dlthiophen-l l-yl)-phenyl ester To a solution of methanesulfonic acid 4-benzo[b]naphtho[2,3-d]thiophen-l l- yl-phenyl ester (2.24 g, 5.54 mmole) in tetrahydrofuran (22.4 mL), 80% aqueous acetic acid (11.2 mL) and sulfuric acid (0.6 mL) was added iodine (0.984 g, 3.87 mmol) and iodic acid (0.244 g, 1.39 mmol).
  • Methanesulfonic acid 4-(6-trifluoromethyl-benzo[blnaphtho[2.3-d1thiophen-l 1-ylV phenyl ester
  • Methanesulfonic acid 4-(6-methyl-benzorblnaphtho[2.3-dlthiophen-l 1-vD-phenyl ester A suspension of methanesulfonic acid 4-(6-iodo-benzo[b]naphtho[2,3- d]thiophen-l l-yl)-phenyl ester (1.65g, 3.11 mmole), tetramethyltin (3.58, 25.8 mmole), and bis(triphenyl ⁇ hosphine)palladium II chloride (0.218g, 0.311 mmole 10 mole %) in dry N,N dimethylformamide (16mL) was heated in a sealed vessel under argon at 103°C for 4 hours and left at room temperature overnight.
  • a biphasic mixture of methanesulfonic acid 4-(6-chloro-benzo[b]naphtho[2,3- d]thiophen-l l-yl)-phenyl ester (0.917 g, 2.09 mmol) in dioxane (13 mL) and a solution of sodium hydroxide (2.5 N, 6.7 mL, 16.7 mmol, 8 eq) was heated at reflux overnight. After cooling to room temperature the reaction mixture was combined with water (50 mL), acidified with concentrated hydrochloric acid, and stirred for 15 minutes. The crude white solid product was collected by filtration, redissolved in ether, combined with silica gel, and the solvent was removed.
  • Example 48 Prepared from methanesulfonic acid 4-(6-trifluoromethyl-benzo[b]naphtho- [2,3-d]thiophen-l l-yl)-phenyl ester (Example 48) according to the procedure of Example 51.
  • Example 49 Prepared from methanesulfonic acid 4-(6-methyl-benzo[b]naphtho[2,3-d]thio- phen-l l-yl)-phenyl ester (Example 49) according to the procedure of Example 51.
  • reaction mixture was heated at reflux for approximately 3 hours, cooled to room temperature, diluted with water (400 mL), acidified with 10% hydrochloric acid and extracted with diethyl ether. The extracts were combined, silica gel was added and the solvent removed.
  • Example 58 l l-(3, 5-Dibromo-4-hydroxy-phenylVbenzo[b1naphthor2.3-d]thiophene-6-carbonitriIe
  • acetic acid 3 mL
  • Example 59-66 The compounds in Examples 59-66 were prepared using the procedure in Example 58 and the appropriate starting material. Example 59.
  • the layers were separated and silica gel was added to the ether phase.
  • the ether was removed and the adsorbate was flashed (gradient: 9: 1 to 1: 1 petroleum ethe ⁇ ethyl acetate).
  • Silica gel was added to the fractions containing the desired product and the solvent was removed.
  • the adsorbate was flashed (9: 1 petroleum ethe ⁇ ethyl acetate).
  • Silica gel was added to the fractions containing the desired product and the solvent was removed.
  • reaction mixture was diluted with water and extracted with ether (100 mL).
  • the aqueous phase was acidified with 10% aqueous HCl and filtered.
  • the solid was washed with water and triturated with pet. ether.
  • the solid was dried in vacuo at 70°C to provide a grey solid.
  • Example 76 ri l-(4-Carboxymethoxy-phenyl ' )-benzo[b1naphthor2.3-d1thiophen-8-yloxyl-acetic acid
  • methyl ester 0.268 g, 0.551 mmol
  • tetrahydrofuran 8 mL
  • methanol 5 mL
  • reaction mixture was concentrated, water (2.5 mL) was added and the solid was filtered (101 mg) .
  • the aqeous phase was extracted with ether (25 mL) and the ether phase was evaporated to dryness to provide a second solid (77 mg).
  • the ethyl acetate extract was washed with water, dried with brine and anhydrous MgSO4, and concentrated to provide a white solid.
  • the solid was dissolved in ethyl acetate (60 mL) and silica gel was added. Solvent was removed and the adsorbate was flash chromatographed (eluent 7:3 petroleum ether: ethyl acetate) to provide the methyl ester as a white solid (0.195 g, 42%).
  • Aqueous potassium carbonate (124 mg in 4 mL of water, 0.90 mmol) was added to a stirred solution of this methyl ester (0.190 g, 0.45 mmol) in THF (5 mL) at ambient temperature.
  • Example 84-95 The compounds in Examples 84-95 were prepared using the procedure in Example 83 and the appropriate starting material.
  • Example 84 r4-Benzorb]naphthol2.3-d1thiophen-l 1-yl-phenoxyl -acetic acid From 4-benzo[b]naphtho[2,3-d]thiophen-l 1-yl-phenol (Example 14).
  • Example 86 f 2.6-Dimethyl-4-r6-methyl-(benzo[b]naphthor2.3-dlthiophen-l l-yl 1-phenoxyl- acetic acid From ⁇ 2,6-dimethyl-4-[6-methyl-(benzo[b]naphtho[2,3-d]thiophen- 11-yl)]- phenoxy] -acetic acid methyl ester (Example 25).
  • Example 87 r4-(6-Bromo-benzo[b]naphtho[2.3-dlthiophen-l l-yl)-phenoxyl-acetic acid From [4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-l l-yl)-phenoxy]-acetic acid, methyl ester ester (Example 41).
  • N-t-BOC-L- ⁇ -Imidazolelactic acid, methyl ester Triethylamine (0.878 mL, 6.3 mmol) was added dropwise to a stirred, ambient temperature solution of L- ⁇ -imidazolelactic acid, methyl ester, hydrochloride (0.87 g, 4.2 mmol) in methanol (12 mL) under a dry nitrogen atmosphere. The stirring was continued at ambient temperature for 40 min. After 6 h., the reaction mixture was concentrated to yield an oil and dichloromethane (150 mL) was added. The dichloromethane was washed with water and brine. Silica gel (12 mL) was added.
  • Example 104 3-Pyridin-3-yl-propionic acid, ethyl ester
  • Trifluoroacetic anhydride (1.1 mL, 7.66 mmol) was added dropwise to a stirred suspension of (s)-(+)- ⁇ ,3-dihydroxy-l-oxo-2-isoindolinebutyric acid, methyl ester (0.84 g, 3.19 mmol) in chloroform (10 mL) under a try N2 atmosphere for 2 hours. After the reaction mixture was concentrated to yield an oil, trifluoroacetic acid (3.4 mL) and triethylsilane (1.1 mL, 3.83 mmol) were added at ambient temperature under a dry nitrogen atmosphere. After 6 hours, the reaction mixture was carefully quenched with 10% aqueous sodium bicarbonate.
  • Diethylazodicarboxylate (0.437 mL, 2.74 mmol) was added dropwise to a stirred, room temperature suspension of 2,6-dibromo-4-(6-bromo-benzo[b]naphtho- [2,3-d]thiophen-l l-yl)-phenol ( 1.00 g, 1.83 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.494 g, 2.74 mmol), triphenylphosphine (0.72 g, 2.74 mmol) and benzene (12 mL) under a dry nitrogen atmosphere. Dissolution occurred and the solution was heated in an 80°C oil bath for 3.5 h.
  • Diethylazodicarboxylate (0.839 mL, 5.50 mmol) was added dropwise to a stirred, room temperature suspension of 2,6-dibromo-4-(6-bromo-benzo[b]naphtho- [2,3-d]thiophen-l l-yl)-phenol (2.00 g, 3.55 mmol), (R)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.96 g, 5.50 mmol), triphenylphosphine (1.40 g, 5.50 mmol) and benzene (15 mL) under a dry nitrogen atmosphere. Dissolution occurred and the solution was heated in an 80°C oil bath for 19 h.
  • Diethylazodicarboxylate (DEAD, 0.210 mL, 1.33 mmol) was added to a stirred, room temperature solution of 2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3- d]thiophen-l l-yl)-phenol ( 0.500 g, 0.888 mmol), (S)-2-hydroxy-4-phenyl-butyrate, ethyl ester (0.277 g, 1.33 mmol), triphenylphosphine (0.350 g, 1.33 mmol) and benzene (3.8 mL) under a dry nitrogen atmosphere. Dissolution occurred and the solution was heated in an 80°C oil bath for 2 h.
  • reaction mixture Upon cooling to room temperature, the reaction mixture was diluted with ether and silica gel was added. The reaction mixture was concentrated and the silica adsorbate was flash chromatographed (95 : 5 petroleum ether : ethyl acetate) to provide a white solid (0. 570 g, 85%). Aqueous potassium hydroxide (1 N, 1.4 mL, 1.4 mmol) was added to a stirred solution of this solid (0.562 g, 0.746 mmol) in THF (12 mL)/methanol (5 mL). After 3h the solution was concentrated, diluted with water and acidified with 10% aqueous HCl.
  • Examples 114-144 were prepared using the procedure in Example 113 and the appropriate starting materials.
  • Diethylazodicarboxylate (0.293 mL, 1.86 mmol) was added dropwise to a stirred, ambient temperature suspension of 2,6-dibromo-4-(6-bromo-benzo[b]- naphtho[2,3-d]thiophen-l l-yl)-phenol (0.700 g, 1.24 mmol), (S)-(+)-2-hydroxy-l,3- dioxo-2-isoindolinebutyric acid, methyl ester (0.490 g, 1.86 mmol), triphenylphosphine (0.488 g, 1.86 mmol) and benzene (5.5 mL) under a dry nitrogen atmosphere.
  • reaction mixture was quenched with 10% aqueous sodium bisulfide and further diluted with water (100 mL). Aqueous mixture was extracted with ethyl acetate (150 mL). The ethyl acetate extract was washed with water, dried with brine and anhydrous MgSO4, and concentrated to provide a white solid.
  • Diethylazodicarboxylate (DEAD, 0.133 mL, 0.845 mmol) was added to a stirred, room temperature solution of l l-(4-hydroxy-phenyl)-benzo[b]naphtho[2,3- d]thiophen-3-yloxy]-acetic acid methyl ester ( 0.140 g, 0.338 mmol), L-3-phenyllactic acid, methyl ester (0.133 g, 0.845 mmol), triphenylphosphine (0.222 g, 0.845 mmol) and benzene (1.5 mL) under a dry nitrogen atmosphere. Dissolution occurred and the solution was heated in an 80°C oil bath for 6 h.
  • This solid was recrystalized from acetonitrile containing 0.1% of trifluoroacetic acid to provide a white solid (144 mg).
  • 1.0 M solution of boron tribromide (1.4 mL, 1.4 mmol) in dichloromethane was added to a stirred, -78°C solution of this solid in dichloromethane (3. 0 mL). After 45 min the reaction mixture was warmed to room temperature.
  • Afer 3.5 h the reaction mixture was recooled to -78°C and an additional amount of 1.0N boron tribromide (0.8 mL, 0.8 mmol) was added. The reaction mixture was warmed to room temperature.
  • Example 150 (RV2-[4-(6-Bromo-benzorblnaphthoI2.3-d1thiophen-l l-ylVphenoxy1-4-(l. 3-dioxo-l. 3-dihydro-isoindol-2-ylVbutyric acid
  • Diethylazodicarboxylate (0.254 mL, 1.61 mmol) was added dropwise to a stirred, room temperature suspension of 2,6-dibromo-4-(6-bromo-benzo[b]naphtho- [2,3-d]thiophen-l l-yl)-phenol ( 0.600 g, 1.10 mmol), dimethyl (S)-(-)-malate (0.213 mL, 1.61 mmol) and triphenylphosphine (0.421 g, 1.61 mmol) in benzene (7.5 mL) under a dry nitrogen atmosphere. The solution was heated in an 79°C oil bath for 23 h.
  • Diisopropylamine (distilled over CaH2, 0.169 mL, 1.2 mmol) was added to anhydrous tetrahydrofuran (0.65 mL) and cooled to -74°C under a dry argon atmosphere.
  • n-Butyllithium (2.5M in hexane, 0.516 mL, 1.29 mmole) was added dropwise and the mixture was warmed to 0°C for 10 minutes then recooled to -74°C.
  • Hexamethylphosphoramide (0.83 mL) was added followed 5 minutes later by the slow (0.5 hour) dropwise addition of a solution of (R)-2-[2,6-dibromo-4-(6-bromo- benzo[b]naphtho[2,3-d]thiophen-l l-yl)-phenoxy]-propionic acid, tert-butyl ester (0.715g, 1.06 mmole) in anhydrous tetrahydrofuran (2.8 mL). After stiring one hour at -75°C, 4-fluorobenzylbromide (0.158 mL, 1.29 mmol) was added dropwise.
  • reaction mixture After stirring 1 hour at -80°C the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was quenched with dilute aqueous ammonium chloride and was partitioned between water (100 mL) and a 1 : 1 methylene chloride : ether solution (130 mL). After one more extraction with methylene chloride (50mL) the organic layers were combined, silica gel was added, and the solvents removed.
  • reaction mixture After stirring 0.5 hour at -80°C the reaction mixture was allowed warm to room temperature overnight. The reaction mixture was quenched with dilute aqueous ammonium chloride and was partritioned between water (100 mL) and a 1 : 1 methylene chloride : ether solution (200 mL).
  • Example 159 r4-(Benzo[b1naphtho[2.3-dlthiophen-l l-yl)-phenoxymethy 11 -phosphonic acid diethyl ester
  • a solution of 4-(benzo[b]naphtho[2,3-d]thiophen-l 1-yl-phenol (1.00 g, 3.06 mmol) in THF (5 mL) was added dropwise to a stirred, 0°C solution of 80 % sodium hydride (0.138 g, 4.95 mmol) in THF (10 mL) under a dry nitrogen atmosphere over a period of 15 min.
  • Diethylazodicarboxylate (0.420 mL, 2.67 mmol) was added dropwise to a stirred, ambient temperature suspension of 2,6-dibromo-4-(6-bromo-benzo[b]- naphtho[2,3-d]thiophen-l l-yl)-phenol (1.00 g, 1.78 mmol), 3 -phenyl- 1 -hydro- 1- propylphosphonic acid, diethyl ester (0.730 g, 2.67 mmol), triphenylphosphine (0.700 g, 2.67 mmol) and benzene (9 mL) under a dry nitrogen atmosphere. The solution was heated in an 80°C oil bath for 4 h.
  • the solid was filtered and partitioned in ethyl acetate (100 mL) and 20 % aquous HCl (60 mL) with stirring for 3 h.
  • the solid was filtered ,washed with water and triturated with pet. ether.
  • reaction mixture was added to water and partitioned between water/ethyl acetate and THF.
  • Silica gel was added to the organic phase and the solvent was removed.
  • the adsorbate was flashed (7:3, petroleum:ethyl acetate) to provide an off-white solid (2.23 g). This solid was dissolved in dichloromethane and silica gel was added.
  • Trifluoroacetic anhydride (0.375, 2.65 mmol) was added to a stirred, room temperature suspension of (R)-2-[2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3- d]thiophen-l l-yl)-phenoxy]-3-phenyl-propionamide (1.68 g, 2.37 mmol), pyridine (0.393 mL, 4.74 mmol) and dioxane (5.4 mL). Dissolution occurred and the solution was heated in a 105°C oil bath for 2h. The reaction mixture was cooled to room temperature, diluted with ether, washed with 5% HCl and brine.
  • Trimethylaluminum (2.55 mL, 3.84mmol, 2.0 M solution in toluene) was added to [2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-l l-yl)-phenoxy]- acetonitrile (0.615 g, 1.02 mmol) under a dry nitrogen atmosphere.
  • Trimethylsilyl azide 0.510 mL, 3.84 mmol
  • Trimethylaluminum (7.24 mL, 14.4 mmol, 2.0 M solution in toluene) was added to (R)-2-[2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-l l-yl)- phenoxy]-3-phenyl-propionamide (1.33 g, 1.93 mmol) under a dry nitrogen atmosphere. Trimethylsilyl azide (1.92 mL, 14.4 mmol) was then added and the solution was heated in a 85 °C oil bath. After 7h the reaction mixture was cooled to room temperature and diluted with ether.
  • Lithium (bis)trimethylsilylamide (1.0 M in THF, 5.32 mL, 5.32 mmol) was added dropwise over a 20 min period to a -78°C stirred solution of 2,6-dibromo-4-(6- bromo-benzo[b]naphtho[2,3-d]thiophen-l l-yl)-phenol (1.50 g, 2.66 mmol), 5- bromothiazolidine dione (Zask, et al., J. Med Chem, 1990, 33, 1418-1423, 0.522 g, 2.66 mmol) and THF (20 mL) under a dry nitrogen atmosphere. After 45 min, the reaction mixture was warmed to room temperature.
  • Phosphoric acid Di-tert-Butyl ester 2.6-Dibromo-4-(6-bromo-benzo[b1naphthor2.3- dlthiophen-1 l-yl)-phenyl ester Tetrazole (0.215 g, 3.0 mmol) was added in one portion to a stirred suspension of 2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-l l-yl)-phenol (0.527 g, 1.0 mmol), di-tert-butyl N,N-diethyhlphosporamidate (93%, 0.353 mL, 1.0 mmol) in THF at room temperature under a dry nitrogen atmosphere.
  • Solid sodium hydroxide (0.682 g, 17.05 mmol) was added in three equal portions to a 0°C, stirred suspension of 2,6-dibromo-4-(6-bromo-benzo[b]naphtho- [2,3-d]thiophen-l l-yl)-phenol (0.800 g, 1.421 mmol), l,l,l-trichloro-2-methyl-2- propanol tetrahydrate (1.06 g, 4.263 mmol) in acteone (7.5 mL) over 3 h period.
  • the resulting suspension was warmed to room temperature and stirred for 15 h.
  • the reaction mixture was added to water, acidified with 10% aqueous HCl and extracted with ether.
  • To the ether phase was added acid washed (2% phosphoric acid in methanol) silica gel and the solvent was removed.
  • reaction mixture was added to water, acidified with 10% aqueous HCl and extracted with ethyl acetate. To the ethyl acetate phase was added acid washed (2% phosphoric acid in methanol) silica gel and the solvent was removed.
  • the reaction mixture was added to water and extracted with ethyl acetate.
  • the ethyl acetate layer was washed with aqueous IN Hcl, sat. sodium bicarbaonte and dried *(magnesium sulfate).
  • the ethyl acetate was removed and and the crude product was flash chromatographed (95:5 ethyl acetate: pet. ether) to provide (5'-benzo[b]naphtho[2,3-d]thiophen-l l-yl)-[l,l ';3',l"]- terphenyl-2'-yloxy)-acetic acid, methyl ester as a white solid (0.177 g).
  • Aqueous potassium hydroxide (1 N, 1.61 mL, 1.61 mmol) was added to a stirred solution of this methyl ester in 3:2 THF:methanol (5.0 mL) at ambient temperature. After 2 h the solution was concentrated, diluted with water (75 mL) and acidified with 10% aqueous HCl.
  • Benzyl bromide (0.093 mL, 0.78 mmol) was added dropwise to this mixture over a period of ten minutes. After the mixture was stirred at 0 °C for 6.5 h., the reaction mixture was quenched with aqueous hydrochloric acid to pH 1 and further diluted with water (60 mL) and aqueous mixture was extracted with methylene chloride (2 X 60 mL). The combined organic extracts were washed with water and dried with brine. Silica gel (5 mL) was added.
  • Iodomethane (0.086 mL, 1.38 mmol) was added dropwise to a room temperature, stirred light suspension of a mixture [3-bromo-5-(6-bromo-benzo[b]- naphtho[2,3-d]thiophen-l l-yl)-2-benzyloxy-phenol (87% pure, contaminated with 2-bromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen- 11 -yl)-6-benzyloxy-phenol (13%), 0.271 g, 0.46 mmol), potassium carbonate (0.191 g, 1.38 mmol) in DMF (2 mL) over a period of twenty minutes.
  • reaction mixture was quenched with aqueous hydrochloride to pH 1 and further diluted with water (40 mL) and aqueous mixture was extracted with methylene chloride (80 mL).
  • Iodomethane (0.074 mL, 1.2 mmol) was added dropwise to a rt, stirred light suspension of 3-bromo-5-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-l l-yl)-benzene- 1,2-diol (0.30 g, 0.60 mmol), potassium carbonate (0.083 g, 0.6 mmol) in DMF (1.5 mL) over a period of five minutes.
  • reaction mixture was quenched with aqueous hydrochloric acid to pH 1 and further diluted with water (80 mL) and aqueous mixture was extracted with methylene chloride (120 mL). The organic extract was washed with water and dried with brine. Silica gel (5 mL) was added.
  • Example 201 r3-(6-Bromo-benzo[blnaphthor2.3-d1thiophen- 11 -yl)-2.6-difluoro-phenoxyl-acetic acid
  • 3-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-l l-yl)-2,6 difluoro-phenol (0.200 g, 0.453 mmol) and potassium carbonate (0.085, 0.612 mmol) in N,N-dimethylformamide (2 mL) was added methyl bromoacetate (0.086 mL, 0.906 mmol) dropwise at room temperature under a dry nitrogen atmosphere.

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Abstract

La présente invention concerne des composés de formule (I) de structure, dans laquelle A est un hydrogène, un halogène ou un OH; B et D sont chacun, de manière indépendante, un hydrogène, un halogène, un CN, un alkyle contenant de 1 à 6 atomes de carbone, un aryle, un aralkyle contenant de 6 à 12 atomes de carbone, un nitro, un amino ou un OR; R est un hydrogène, un alkyle contenant de 1 à 6 atomes de carbone, un -COR1, un -CH¿2CO2R?1, un -CH(R1a)CO2R1, ou un -SO¿2?R?1; R1 et R1a¿ sont chacun, de manière indépendante, un hydrogène, un alkyle contenant de 1 à 6 atomes de carbone, un aralkyle contenant de 6 à 12 atomes de carbone, ou un aryle; E est un S, un SO, un SO¿2?, ou un O; X est un hydrogène, un halogène, un alkyle contenant de 1 à 6 atomes de carbone, un CN, un perfluoroalkyle contenant de 1 à 6 atomes de carbone, un alkoxy contenant de 1 à 6 atomes de carbone, un aryloxy, un arylalkoxy contenant de 6 à 12 atomes de carbone, un nitro, un amino, un alkylsulfanyle contenant de 1 à 6 atomes de carbone, un arylsulfanyle, un pyridylsulfanyle, un 2-N,N-diméthylaminoéthylsulfanyle, ou un -OCH2CO2R?1b; R1b¿ est un hydrogène ou un alkyle contenant de 1 à 6 atomes de carbone ; Y et Z sont chacun, de manière indépendante, un hydrogène ou un OR¿2; R?2 est un hydrogène, un alkyle contenant de 1 à 6 atomes de carbone, un aralkyle contenant de 6 à 12 atomes de carbone, ou un -CH2CO¿2R?3; R3 est un hydrogène ou un alkyle contenant de 1 à 6 atomes de carbone; C est un hydrogène, un halogène ou un OR4; R4 est un hydrogène, un alkyle contenant de 1 à 6 atomes de carbone, un -CH(R5)W, un -C(CH¿3?)2CO2R?6¿, un 5-thiazolidine-2,4-dione, un -CH(R7)CH2CO2R6, un -COR6, un -PO¿3(R?6)2, ou un -SO2R6; R5 est un hydrogène, un alkyle contenant de 1 à 6 atomes de carbone, un aralkyle, un aryle, un -CH¿2?(1H-imidazole-4-yl), un -CH2(3-1H-indolyl), un -CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), un -CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), un -CH2(3-pyridyl), ou un -CH2CO2H; W est un -CO2R?6¿, un -CONH¿2?, un -CONHOH, un CN, un -CONH(CH2)2CN, un 5-tétrazole, un -PO3(R?6)¿2, un -CH2OH, un -CH2Br ou un -CONR6CHR7CO2R8; R6 est un hydrogène, un alkyle contenant de 1 à 6 atomes de carbone, un aryle ou un aralkyle; R7 est est un hydrogène, un alkyle contenant de 1 à 6 atomes de carbone, un aryle ou un aralkyle; R8 est un hydrogène, un alkyle contenant de 1 à 6 atomes de carbone, un aryle ou un aralkyle. Ces composés ou un de leurs sels acceptables sur le plan pharmaceutique, sont utiles dans le traitement des troubles métaboliques qui se rapportent à la résistance insulinique ou à l'hyperglycémie.
EP99922897A 1998-05-12 1999-05-10 11-ARYL-BENZO B]NAPHTO 2,3-D]FURANES ET 11-ARYL-BENZO b]NAPHTO 2,3-d]THIOPHENES UTILES DANS LES TRAITEMENTS DE LA RESISTANCE INSULINIQUE ET DE L'HYPERGLYCEMIE Withdrawn EP1077970A1 (fr)

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JP2002514638A (ja) 2002-05-21
AU3979199A (en) 1999-11-29

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