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WO1999061435A1 - Benzothiophenes, benzofuranes et indoles utiles dans le traitement de la resistance insulinique et de l'hyperglycemie - Google Patents

Benzothiophenes, benzofuranes et indoles utiles dans le traitement de la resistance insulinique et de l'hyperglycemie Download PDF

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Publication number
WO1999061435A1
WO1999061435A1 PCT/US1999/010209 US9910209W WO9961435A1 WO 1999061435 A1 WO1999061435 A1 WO 1999061435A1 US 9910209 W US9910209 W US 9910209W WO 9961435 A1 WO9961435 A1 WO 9961435A1
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Prior art keywords
carbon atoms
dimethyl
bromo
naphtho
thiophen
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PCT/US1999/010209
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English (en)
Inventor
Jay Edward Wrobel
Arlene Joan Dietrich
Madelene Miyoko Antane
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American Home Products Corporation
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Priority to EA200001175A priority Critical patent/EA200001175A1/ru
Priority to JP2000550841A priority patent/JP2002516321A/ja
Priority to KR1020007012649A priority patent/KR20010043539A/ko
Priority to IL13913299A priority patent/IL139132A0/xx
Priority to HU0101792A priority patent/HUP0101792A3/hu
Priority to EP99921829A priority patent/EP1077969A1/fr
Priority to EEP200000653A priority patent/EE200000653A/xx
Priority to CA002330620A priority patent/CA2330620A1/fr
Application filed by American Home Products Corporation filed Critical American Home Products Corporation
Priority to AU38939/99A priority patent/AU756337B2/en
Priority to BR9911779-7A priority patent/BR9911779A/pt
Priority to SK1699-2000A priority patent/SK16992000A3/sk
Publication of WO1999061435A1 publication Critical patent/WO1999061435A1/fr
Priority to BG104918A priority patent/BG104918A/bg
Priority to NO20005677A priority patent/NO20005677L/no
Priority to HR20000767A priority patent/HRP20000767A2/hr

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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
    • C07D307/92—Naphthofurans; Hydrogenated naphthofurans
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
    • 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

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, 7, 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, PTP and SH-PTP2 (B. J. Goldstein, J. Cellular Biochemistry 1992, 48, 33; B. J. Goldstein, Receptor 1993, 3, 1-15,; F. Ahmad and B. J. Goldstein Biochim. Biophys Acta 1995, 1248, 57-69).
  • Bridges, et al. (EP 568289 A2) disclosed the thienothiopheneamidine B as a urokinase inhibitor.
  • CA: 117:36570 disclosed six compounds containing the 4-aryl-naphtho[2,3- b]thiophene ring system. These compounds were cyclobutenediylium dimers of that ring system made as electrophotographic photoreceptors.
  • One typical example is shown by structure H below.
  • This invention provides a compound of formula I having the structure
  • A is hydrogen, halogen, or OH;
  • B and D are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, -NR!R l a , -NR ⁇ OR 13 , -NR'CO 2 R l a , cycloalkylamino of 3-8 carbon atoms, morpholino, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl,
  • R is hydrogen, alkyl of 1-6 carbon atoms, -COR 1 , -(CH ⁇ CO ⁇ 1 , -CH(R l a )CO 2 R 1 ,
  • R 1 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, or
  • R 1 ' is hydrogen or alkyl of 1-6 carbon atoms
  • E is S, SO, SO 2 , O, or NR lc ;
  • X is hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, CN, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy; arylalkoxy, nitro, amino, NR 2 R 2a ,
  • NR 2 COR 2a cycloalkylamino of 3-8 carbon atoms, morpholino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino- ethylsulfanyl, -OCH 2 CO 2 R 2b or -COR 2c ;
  • Y is hydrogen, halogen, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12 carbon atoms,
  • R l a , R l c , R 2 , R 2a R 3 , R 3a are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl;
  • R lb is alkyl of 1-6 carbon atoms or aryl
  • R 2b is hydrogen, alkyl of 1-6 carbon atoms
  • R 2c and R 3b are each, independently, alkyl of 1-6 carbon atoms, aryl, or aralkyl of 6-12 carbon atoms;
  • C is hydrogen, halogen or OR 4 ;
  • R 5 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, 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), -CH 2 CH 2 (l-oxo-l,3-dihydro-isoindol-2-yl), -CH 2 (3- pyridyl), -CH 2 CO 2 H, or -(CH 2 ) n G;
  • G is NR 6a R 7a , NR 6a COR 7a , ;
  • W is CO 2 R 6 , CONH 2 , CONHOH, CN, CONH(CH 2 ) 2 CN, 5-tetrazole, -PO 3 (R 6 ) 2 ,
  • R 6 , R 6a , R 7 , R 7a are each, independently, is hydrogen, alkyl of 1-6 carbon atoms, or aryl;
  • R 6b is hydrogen or -COR 6c ;
  • R 6c is alkyl of 1-6 carbon atoms or aryl
  • R 7b is hydrogen, alkyl of 1-6 carbon atoms, or hydroxyalkyl of 1-6 carbon atoms
  • R 8 is hydrogen, alkyl of 1-6 carbon atoms, or aryl
  • R 9 , R 10 , and R 1 1 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl, halogen, hydroxy, or alkoxy of 1-6 carbon atoms; m is 1 to 4; n is 1 or 2; p is 1 to 4; q is 1 to 4; 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 CH2(3-pyridyl), or Y is morpholine 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 naphthyl; 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-tricyclic or aryl-bicyle 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), having the structure
  • A is hydrogen or halogen
  • B and D are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, branched alkyl, cycloalkyl of 3-8 carbon atoms, nitro or OR;
  • R is hydrogen or alkyl of 1-6 carbon atoms;
  • E is S, or 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, nitro, amino, NR 2 R 2a ,
  • NR 2 COR 2a cycloalkylamino, morpholino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl;
  • R 1 , R la , R 2 , R a , R 3 , and R 3a are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl;
  • Y is hydrogen, halogen, OR 3 , SR 3 , NR 3 R 3a or morpholine;
  • 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 of 6-12 carbon atoms, 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), -CH 2 CH 2 ( 1 -oxo- 1 ,3-dihydro-isoindol-2-yl), or -CH 2 (3-pyridyl);
  • W is CO 2 R 6 , -CONH 2 , -CONHOH, or 5-tetrazole, or -CONR 6b CHR 7b CO 2 R 6 ;
  • R 6 , R 6a , R 6b ,R 7 , R 7a , and R 7b are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or aryl;
  • R 9 and R 10 are independently, hydrogen, or alkyl of 1-6 carbon atoms; p is 1 to 4; q is 1 to 4; or a pharmaceutically acceptable salt thereof.
  • More preferred compounds of this invention include compounds of formula (I), having the structure
  • A is hydrogen; B and D are each, independently, halogen, alkyl of 1 -6 carbon atoms, aryl, aralkyl of 6-
  • E is S or 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;
  • Y is hydrogen or -NR'R 2 , or morpholine;
  • R 1 and R 2 are each, independently, hydrogen or alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl;
  • R 4 is hydrogen, alkyl of 1-6 carbon atoms, -CH(R 5 )W, or 5-thiazolidine-2,4-dione;
  • R 5 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, -CH 2 (3- lH-indolyl), -CH 2 CH 2 (l,3-dioxo-l,3-dihydro-isoindol-2-yl), or -CH 2 CH 2 (1- oxo- 1 ,3-dihydro-isoindol-2-yl) ;
  • W is -CO 2 R 6 , -CONH 2 , -CONHOH, 5-tetrazole, -PO 3 (R 6 ) 2 , or -CONR 6 CHR CO 2 R 6 ;
  • R 6 is hydrogen or alkyl of 1-6 carbon atoms;
  • 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.
  • 3-dimethylthiophene (II: E is S) is prepared from commercially available 3-methyl-thiophene-carboxaldehyde using Wolff-Kishner conditions (hydrazine followed by KOH/ethylene glycol reflux).
  • Compound (II: E is S or O) is treated with one to 1.3 molar equivalents of an alkyl lithium reagent such as N-butyl lithium most preferably in a nonprotic solvent such as THF at temperatures ranging from -78°C to room temperature under an inert atmosphere such as nitrogen or argon to provide the 2-lithiated-thiophene or furan derivative.
  • an alkyl lithium reagent such as N-butyl lithium most preferably in a nonprotic solvent such as THF at temperatures ranging from -78°C to room temperature under an inert atmosphere such as nitrogen or argon to provide the 2-lithiated-thiophene or furan derivative.
  • a nonprotic solvent such as THF
  • A, B, C, D, combination of substituents having at least one OMe group but not more than three OMe groups; E is S or O) is generally best accomplished using one to ten molar equivalents of a strong Lewis acid such as a trihaloborane, most conveniently tribromoborane.
  • the reaction is best performed at -78°C with warming to room temperature or heating to 50°C 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 or fluoro; C is OH; E is S or O) can be prepared starting from the compound of formula (III: Q is H; E is S or O) and the appropriate benzoic acid chloride (TV: A is H; B, D is alkyl of 1-6 carbon atoms or fluoro; C is OMe).
  • the benzoic acid chloride (IN: A is H; B, D is alkyl of 1-6 carbon atoms or fluoro; C is OMe).
  • the starting benzoic acid of the benzoic acid chloride (TV: A is H; B, D is alkyl of 1-6 carbon atoms or fluoro; 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 isopropyl; C is OMe) can be prepared using a modification of the method of Schuster, et al., J. Org. Chem. 1988, 53, 5819.
  • the monoiodophenol (lb: B is I; X, D is H; C is OH; E is S or O) can be prepared from the phenol of formula (lb: B, D, X is H; C is OH; E is S or 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 a 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 or O) or the diiodophenol (lb: B, D is I; X is H; C is OH; E is S or 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 or O) or (lb: B, D is I; X is H; C is OMe; E is S or 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 or O) or the diiodo methylether of formula (lb: B, D is I; X is H; C is OMe; E is S or 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 or O) or the dicyanomethyl ether of formula (lb: B, D is CN; X is H; C is OMe; E is S or 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 monoiodo methylether derivative of formula (lb: B is I; X, D is H; C is OMe; E is S or O) or the diiodo methylether of formula (lb: B, D is I; X is H; C is OMe; E is S or 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 or O) or the dibromo-methyl ether of formula (lb: B, D is Br; X is H; C is OMe; E is S or 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 or 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 or 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°
  • acylating agent is generally alkyl of 1-6 carbon atoms or aryl carboxylic acid anhydride or 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.
  • This bromination reaction is generally done using 1 to 1.3 molar equivalents of molecular bromine in the dark with a catalytic amount of iron (III) chloride in an inert solvent such as dichloromethane or carbon tetrachloride at temperatures ranging from - 78 °C to room temperature.
  • the phenols of formula (Id: B, D is alkyl of 1-6 carbon atoms, C is OH; E is S or O) can then be brominated in the 9-position of the naphtho[2,3-b]thiophene hene or the naphtho[2,3-b]furan ring to form the bromophenols of formula (Ie: B, D is alkyl of 1-6 carbon atoms, C is OH; X is Br; E is S or O) (Scheme 3).
  • This bromination reaction is generally done using 1 to 1.3 molar equivalents of molecular bromine in the dark with a catalytic amount of iron (III) chloride 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 (Ie: 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 or O) to provide the bromophenols of formula (Ie: 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 or 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 1-6 carbon alcohol such as methanol or mixtures of THF and a 1-6 carbon atom 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 or O) can be nitrated to provide the nitro compounds of formula (Ie: 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 or 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 (Ie: B, C, D is H or OCOR; C, D cannot both be H; R is alkyl fo 1-6 carbon atoms, aryl; X is NO 2 ; E is S or 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 fo 1-6 carbon atoms, aryl; X is NH 2 ; E is S or 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 (Ie: 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 or O) can be removed using standard conditions.
  • the acylated bromophenols of formula (Ie: 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 or O) (Scheme 3) can be converted to the acylated cyanophenols of formula (Ie: 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 or 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 (Ie: 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 or O) to provide the cyanophenols of formula (Ie: 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 CN; E is S or 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 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 or 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 or 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 or O) can be treated with iodinating reagents to effect iodination at the 9-position of the naphtho[2,3-d]thiophene or the naphtho[2,3-d]furan ring to afford the iodo sulfonic acid esters of formula (Ie: 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 or 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 (Ie: 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 or O) to provide the iodophenols of formula (Ie: 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 or 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 equivalents of a sodium perfluorocarboxylate (RCO 2 Na: R is perfluoroalkyl) and one to five 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 lower perfluoroalkyl; E is S or 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 or 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 or O) can be reacted with 0.5 to two molar equivalents of bis(trifluoromethyl)mercury 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 or O).
  • a high boiling inert solvent such as DMF, DMA or l-methyl-2-pyrrolidinone
  • 9-alkyl 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 or 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 or 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(triphenylphosphine)pal
  • 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 lower perfluoroalkyl; E is S or 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 lower perfluoroalkyl; E is S or 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 HF, 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 HF, 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.
  • 9-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 or 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 or O) with three or more molar equivalents of lower alkali metal alkoxide such as sodium methoxide 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 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
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, amino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl;
  • E is S or O
  • R la is alkyl of 1-6 carbon atoms aralkyl and aryl).
  • acylations can be performed in the presence of one or more equivlents of a suitable base such as an alkali metal hydroxide, carbonate or bicarbonate or an organic amine base such as triethylamine or pyridine and with or without a suitable solvent such a chloroform, dichloromethane, THF, dioxane and water or mixtures of these solvents and with or without the presence of a catalyst such as 4-N, N-dimethylpyridine .
  • a suitable base such as an alkali metal hydroxide, carbonate or bicarbonate or an organic amine base such as triethylamine or pyridine
  • a suitable solvent such as chloroform, dichloromethane, THF, dioxane and water or mixtures of these solvents and with or without the presence of a catalyst such as 4-N, N-dimethylpyridine .
  • the dibromo-bisphenols of formula (Ii: A is OH; B, D is Br; X is H; E is S or O) can be further brominated in the 9-position of the naphtho[2,3-b]thiophene or the naphtho[2,3-b]furan ring to form the bisphenols of formula (Ii: A is OH; B, D, X is Br; E is S or O).
  • This bromination reaction is generally done using 1 to 1.3 molar equivalents of molecular bromine in the dark with a catalytic amount of iron (III) chloride 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, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N- dimethylaminoethylsulfanyl;
  • E is S or O
  • A is H;
  • B is Br;
  • C, D is OH;
  • X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridyls
  • 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, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl;
  • R 6 , R 6a is alkyl of 1 - 6 carbon atoms, aralkyl, aryl;
  • E is S or O) as well as the diesters of formula (Im:
  • A, B is H or Br;
  • C is OCH 2 CO 2 R 6 ,
  • X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms,
  • 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.
  • acetates of formula (In: X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N- dimethylaminoethylsulfanyl; Y is H; E is S or O) can be reacted with a halogenating agent, specifically one that causes benzylic type bromination or chlorination such as one or more molar equivalents of N-bromosuccinimide, N-chlorosuccinimide or sulfuryl chloride to provide the halo acetates of formula (In: X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluor
  • halo acetates of formula (In: X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is Cl, Br; E is S or O) can be reacted with one or more equivalents of nucleophiles such as alkoxides (MOR 1 ), sulfides (MSR 1 ) or amines (NHR'R 2 ) (wherein M is a alkali metal such as Na, Li or K; R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl) in a suitable solvent such as THF, DMF or dichloromethane to
  • X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is Cl, Br; E is S or O) with nucleophiles there can be concomitent loss of the acetyl group to afford the compounds of formula (Io: B, D is H; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl;
  • X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl;
  • Y is OR 1 , SR 1 , NR'R 2 , where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be deacylated to produce the compounds of formula (Io: B, D is H; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon
  • the deacylation 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 (Io: B, D is H;
  • X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N- dimethylaminoethylsulfanyl;
  • Y is Cl, Br, OR 1 , SR 1 , NR'R 2 , where R', R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be brominated in two positions to afford the dibromphenols of formula (Io: B, D is Br;
  • X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms
  • the phenols of formula (Ip: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
  • Y is H, Cl, Br, OR 1 , SR 1 , NR'R 2 , where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be reacted with a 2-hydroxy carboxylic acid ester of formula CH(OH)(R 5 )CO 2 R
  • 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 (3-1 H-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.
  • esters of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
  • esters of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
  • Y is H, Cl, Br, OR 1 , SR 1 , NR'R 2 , where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CO 2 R 6 ;
  • R 5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH 2
  • halogen alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N- dimethylamino-ethylsulfanyl;
  • Y is H, Cl, Br, OR 1 , SR 1 , NR'R 2 , where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CO 2 H;
  • 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 (l,3-dioxo- 1 ,3-dihydro-isoindo
  • 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 aboved 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.
  • the phenols of formula (Ip: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
  • Y is H, Cl, Br, OR', SR', NR'R 2 , where R ⁇ R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be alkylated with one or more molar equivalents of diethyl trifluoromethylsulfonyloxymethylpho
  • D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl
  • Y is H, Cl, Br, OR', SR 1 , NR'R 2 , where R 1 , R 2 is
  • the phenols of formula (Ip: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
  • Y is H, Cl, Br, OR 1 , SR 1 , NR'R 2 , where R', R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be reacted with a 2-hydroxy phosphonic acid diester of formula CH(OH)(R 5 )PO 3 (R
  • 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.
  • the phosphonic acid diesters of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
  • Y is H, Cl, Br, OR', SR', NR'R 2 , where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is PO 3 (R 6 ) 2 ;
  • R 5 is H, alkyl of 1-6 carbon atoms, aralky
  • esters of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
  • Y is H, Cl, Br, OR', SR', NR'R 2 , where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CO 2 R 6 ;
  • R 5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH 2 (1H
  • the carboxylic acids of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N- dimethylamino-ethylsulfanyl;
  • Y is H, Cl, Br, OR', SR', NR'R 2 , where R", R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CO 2 H;
  • R 5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH 2 (lH-
  • 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.
  • the phenols of formula (Ip: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
  • Y is H, Br, OR', SR', NR'R 2 , where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be alkylated with one or more molar equivalents of a haloacetonitrile of formula (X 2 CH 2
  • the carboxylic acid amide analogs of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N- dimethylamino-ethylsulfanyl;
  • Y is H, Cl, Br, OR 1 , SR !
  • R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CONH 2 ;
  • R 5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH 2 (lH-imidazol-4-yl), CH 2 (3-1 H-indolyl), CH 2 CH 2 (l,3-dioxo- l,3-dihydro-isoindol-2-yl), CH 2 CH 2 (l-oxo-l,3-dihydro-isoindol-2-yl), CH 2 (3- pyridyl);
  • E is S or O) can be converted to their nitrile analogs of formula (Iq:
  • B is H , halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
  • X is H, halogen, alkyl of 1-6 carbon
  • 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.
  • nitriles analogs of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
  • Y is H, Cl, Br, OR', SR 1 , NR'R 2 , where R' , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CN;
  • R 5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH
  • R 4 is (R, S)-5-thiazolidine-2,4-dione
  • B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N- dimethylamino-ethylsulfanyl
  • Y is H, Cl, Br, OR 1 , SR 1 , NR'R 2 , where R 1 , R 2 is H
  • the phenols of formula (Ir: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
  • Y is H, Cl, Br, OR 1 , SR 1 , NR'R 2 , where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be reacted with one or more molar equivalents of tetrazole and di-tert-butyl
  • R 4 is P(O)(OtBu) 2
  • B D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N- dimethylamino-ethylsulfanyl
  • Y is H, Cl, Br, OR', SR', NR'R 2 , where R 1 , R 2 is H , alkyl of 1-6 carbon atoms, aryl or aralkyl; E
  • R 4 is P(O)(OH) 2 ;
  • B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2- N,N-dimethylamino-ethylsulfanyl;
  • Y is H, Cl, Br, OR 1 , SR', NR'R 2 , where R 1 , R 2 is H, alkyl of 1-6 carbon atoms,
  • the phenols of formula (Ir: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
  • Y is H, Cl, Br, OR', SR 1 , NR'R 2 , where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be transformed to the carboxylic acids of formula (Is: R 4 is C(CH 3 ) 2 CO 2 H; B,
  • the phenols of formula (Ir: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
  • Y is H, Cl, Br, OR 1 , SR 1 , NR !
  • R 2 where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or 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, nitro
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl
  • Y is H, Cl, Br, OR 1 , SR 1 , NR'R 2 , where R 1 , R 2 is H, alkyl of
  • the phenols of formula (Ir: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
  • Y is H, Cl, Br, OR 1 , SR', NR'R 2 , where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be reacted with a 3-hydroxy carboxylic acid ester of formula CH(OH)(R 7 )CH 2 CO 2
  • 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.
  • esters of formula (Is: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
  • Y is H, Cl, Br, OR 1 , SR 1 , NR'R 2 , where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be transformed to the acids of formula (Is: R 4 is (R)- CH(R 7 )CH 2 CO 2 H; B
  • esters of formula (Is) include reacting the esters of formula (Is) 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.
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N- dimethylaminoethylsulfanyl;
  • Y is H, OR 1 , SR', NR'R 2 , where R 1 , R 2 is H, alkyl of 1- 6 carbon atoms, aryl or aralkyl; E is S or O) can be alkylated with one or more molar equivalents of an alkyl or aralkyl halide of formula (XR 4 where X is Cl, Br or I and R 4 is alkyl of 1-6 carbon atoms,
  • the amino compounds of formula (Is: B is NH 2 ; D is H or Br; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2- N,N-dimethylaminoethylsulfanyl; Y is H, OR', SR', NR'R 2 , where R', R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O; R 4 is alkyl of 1-6 carbon atoms, aralkyl) can be alkylated with one or more molar equivalents of an alkyl haloacetate of formula (X 2 CHR 6a CO 2 R 6 where X 2 is Cl, Br or
  • esters can be transformed into their carboxylic acid analogs using standard conditions to afford the carboxylic acids of formula (Is: B is NCHR 6a CO 2 H; R 6a is H or alkyl of 1-6 carbon atoms; D is H or Br; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is H, OR 1 , SR', NR'R 2 , where R', R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O; R 4 is alkyl of 1-6 carbon atoms, aralkyl).
  • 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.
  • CN alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro;
  • Y is Cl, Br, OR 1 where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; 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 sulfoxide derivatives of formula (Iu: n is 1; B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro;
  • Y is Cl, Br, OR 1 where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; R 5 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; R 6 is H, alkyl of 1-6 carbon atoms) using one molar equivalent of an oxidizing agent such as m-chloroperbenzoic acid in dichloromethane at temperatures ranging from -20°C to 40°C or peracetic aid in acetic acid and water at temperatures ranging from room temperature to 100°C.
  • an oxidizing agent such as m-chloroperbenzoic acid in dichloromethane at temperatures ranging from -20°C to 40°C or peracetic aid in acetic acid and water at temperatures ranging from room temperature to 100°C.
  • the compounds of formula (It: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
  • X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro;
  • Y is Cl, Br, OR' where R', R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl;
  • 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 (Iu: n is 2;
  • B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
  • X is H
  • 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 co ⁇ esponding to the 1142-1153 insulin receptor kinase domain, phosphorylated on the
  • 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. J Clin Invest 1991; 57:1286-1294 and Alberts B, Bray D, Lewis J, Raff M,
  • 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-HCI (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
  • 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.
  • 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. 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). 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.
  • the enzyme preparation used was in microtubes containing 500-700 ⁇ g/ml protein in 33 mM Tris-HCI, 2 mM EDTA, 10% glycerol and 10 mM 2-mercaptoethanol.
  • 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-HCI, 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 LABLENE 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 PTPIB by test compounds is calculated as percent of phosphatase control.
  • the non-insulin dependent diabetic (NTDDM) syndrome can be typically characterizes by obesity, hyperglycemia, abnormal insulin secretion, hyperinsulinemia and insulin resistance.
  • NIDDM non-insulin dependent diabetic
  • 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 U 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, microcrystalline
  • 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.
  • Tin tetrachloride (4.6 mL, 71.76 mmol) was added dropwise over a 10 minute period to a stirred, -78°C solution of 2-benzyl-4, 5 -dimethylthiophene (6.6 g, 32.62 mmol), anisoyl chloride (5.90 g, 34.6 mmol) and dichloromethane (120 mL) under a dry nitrogen atmosphere. After 5 hours at -78°C, the reaction mixture was slowly warmed to room temperature over a 2 h period. The reaction mixture was added to water and extracted with ether. The ether extract was washed with sat. aq. sodium bicarbonate and brine.
  • Neat boron tribromide (20 mL, 212 mmol) was added dropwise to a stirrred solution of (2-benzyl-4, 5-dimethyl-thiophen-3-yl)-(4-methoxy-phenyl)-methanone (9.40 g, 27.9 mmol) in dichloromethane (95 mL) at -78°C under a dry nitrogen atomosphere.
  • the solution was allowed to warm to ambient temperature and was stirred for 4 h.
  • the reaction mixture was cooled to 0°C and carefully quenched with water and the solvent was removed. More water was added and the resultant solid was filtered and washed with water and triturated with pet.
  • Acetic anhydride (0.68 mL, 7.20 mmol) was added to a 0°C, stirred solution of 4-(2, 3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (2.0 g, 6.57mmol) in pyridine (8.6 mL). After 17 h the reaction mixture was added to 5% aqueous HCl and the resulting solid was filtered and washed with 5% aqueous HCl, water and triturated with pet. ether.
  • Acetic Acid 4-(9-bromo-2. 3-dimethyl-naphthor2.3-blthiophen-4-ylVphenyl ester A solution of bromine (0.326 mL, 6.15 mmol) in dichloromethane (9 mL) was added dropwise over a 15 minute period to a solution that was stirred in the absence of light of acetic acid 4-(2, 3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (1.87 g, 5.41 mmol) and iron (IU) chloride (50 mg, 0.31 mmol) in dichloromethane (47 mL) at -78°C under a dry nitrogen atmosphere.
  • the vial was sealed and heated at 102°C.
  • the reaction was done (as indicated by thin layer chromatography) the mixture was cooled to room temperature, diluted with water, and acidified with hydrochloric acid. The organics were extracted with ether, combined with silica gel and the solvents were removed.
  • the ether was removed and the solid (0.162 g, 0.265 mmol) was dissolved in tetrahydrofuran (100 mL) and a 1 N aqueous solution of sodium hydroxide (0.265 mL, 0.265 mmol) was added dropwise. After sti ⁇ ing 20 minutes the solvent was removed and the residue was stirred in water (100 mL). The water was removed by decantation and the residue was stirred in petroleum ether overnight. The solvent was removed. The residue was dissolved in tetrahydrofuran ether and silica gel was added.
  • Methyl bromoacetate (0.150 mL, 1.58 mmol) was added to a stirred suspension of potassium carbonate (0.223 g, 1.61 mmol), 2-bromo-4-(9-bromo-2, 3-dimethyl- naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol (0.400 g, 0.789 mmol) in DMF (2.8 mL). After 15 h, the reaction mixture was added to water and extracted with ethyl acetate. Silica gel was added to the ethyl acetate and the solvent was removed.
  • the adsorbate was flashed (9:1 petroleum ether: ethyl actetate) to provide the title compound as a yellow solid (0.305 g, 67%).
  • This solid (0.050g, 0.086 mmol) was dissolved in 1:1 THF:methanol (2 mL) and treated with aqueous potassium hydroxide (1.0 N, 0.30 mL, 0.30 mmol). After 25 min the reaction mixture was diluted with water, acidified with 10% aqeous HCl and extracted with ether.
  • the reaction mixture was diluted with diethyl ether and combined with silica gel.
  • the solvents were removed and the adsorbate was flash chromatographed (75/25 petroleum ether/methylene chloride) to provide a white solid (0.283 g, 81%).
  • Example 19 Prepared from dibromo-4-(9-bromo-3-methyl-2-morpholin-4-yl-methyl- naphtho[2,3-b]thiophen-4-yl)-phenol (Example 19) and commercially available methyl (S)-(-)-lactate according to theprocedure of Example 30. Yellow solid: Opt. rot.
  • Step 1 2-Isopropyl-4-(2.3 -dimethyl-naphtho ⁇ 2.3-bl thiophen-4-y 11-phenol
  • 3-isopropyl-p-anisic acid (3.0 g, 16.5 mmol, RN-33537-78-9)
  • oxalyl chloride 1.7 mL, 19.5 mmol
  • N,N-dimethylformamide (2 drops)
  • 2,3-dimethyl-5-benzyl- thiophene 4.0 g, 19.8 mmol
  • tin(IV) chloride 2.1 mL, 18.2 mmol
  • anhydrous methylene chloride (65 mL) the title compound as a dark red oil (6.5 g), which was used without further purification.
  • Step 2 (2R -2-r2-Bromo-4-(9-bromo-2.3-dimethyl-naphthor2.3-blthiophen-4-ylV6-isopropyl- phenoxyl-3-phenyl-propionic acid
  • Step 1 ⁇ -Sec-butyl ⁇ -r ⁇ -dimethyl-naphthor ⁇ .S-blthiophen ⁇ -yll-phenol
  • Step 1 there was obtained from 3-sec-butyl-p-anisic acid (3.0 g, 14.4 mmol, prepared by the method of M.
  • Step 1 there was obtained from (2-benzyl-4,5-dimethyl-thiophen-3-yl)-(3-sec-butyl-4-methoxy-phenyl)- methanone (6.2 g, 15.8 mmol), boron tribromide (7.1 mL, 74.8 mmol), and methylene chloride (54 mL) the title compound as a solid (2.34 g, 41%): MS(EI): [M+] 360.
  • Step 1 (2-Benzyl-4.5-dimethyl-thiophen-3-yl -(3-ethyl-4-methoxy-pheny -methanone
  • 3-ethyl-p-anisic acid 5.0 g, 27.7 mmol, RN-22934-35-6
  • oxalyl chloride 2.7 mL, 30.5 mmol
  • N,N-dimethylformamide 2 drops
  • 2,3-dimethyl-5-benzylthiophene 6 6.7 g, 33.2 mmol
  • tin(IN) chloride 3.6 mL, 30.5 mmol
  • anhydrous methylene chloride 177 mL
  • Step 3 (R -2-r2-Bromo-4-r9-bromo-2.3-dimethyl-naphthol2.3-blthiophen-4-ylV6- ethyl-phenoxyl-3-phenyl-propionic acid methyl ester
  • Step 6 there was obtained from 2-ethyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (2.6 g, 7.8 mmol), bromine (0.83 mL, 15.7 mmol), potassium acetate (7.7 g, 78.5 mmol), and glacial acetic acid (78 mL) the title compound as a solid (0.73 g), which was used without further purification.
  • Step 4 (RV2-r2-Bromo-4-r9-bromo-2.3-dimethyl-naphthor2.3-b1thiophen-4-vn-6- ethyl-phenoxy]-3-phenyl-propionic acid
  • Step 1 ( ' 2R -2-f4-(9-Bromo-2.3-dimethyl-naphthor2.3-blthiophen-4-ylV2-isopropyl- phenoxyl-3-phenyl-propionic acid methyl ester
  • 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-isopropyl-phenol (0.26 g, 0.67 mmol)
  • (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.32 g, 1.8 mmol
  • triphenylphosphine (0.46 g, 1.8 mmol
  • diethylazodicarboxylate (0.28 mL, 1.8 mmol
  • anhydrous benzene (7.0 mL) in an oil bath (90°C) for 4.5 h the tide compound as a white
  • Step 2 f2RV2-r4-r9-Bromo-2.3-dimethyl-naphthor2.3-b1thiophen-4-ylV2-isopropyl- phenoxyl-3-phenyl-propionic acid
  • Step 3 (RV2-[2-Cvclopentyl-4-r2.3-dimethyl-na ⁇ hthor2.3-blthiophen-4-yl -phenoxyl- 3-phenyl-propionic acid methyl ester
  • Step 4 rRV2-r2-Cvclopentyl-4-(2.3-dimethyl-naphthor2.3-b1thiophen-4-vn-phenoxyl- 3-phenyl-propionic acid
  • Step 2 (RV2-r4-(2.3-Dimethyl-naphthor2.3-b1thiophen-4-vn-2.6-dimethyl-phenoxyl- 3-phenyl-propionic acid
  • (R)-2-[4-(2, 3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2, 6-dimethyl-phenoxy]-3- phenyl-propionic acid methyl ester (0.23 g, 0.46 mmol)
  • aqueous potassium hydroxide (0.91 mL of a 1 N solution, 0.91 mmol), tetrahydrofuran (12 mL), and methanol (4 mL) the title compound as a white solid (0.19 g, 86%):
  • Opt. Rot. [a]25/D +33.04° (10.170 mg/mL, MeOH); (DMSO-d6): ⁇ 12.9 (broad s,
  • Step 4 (RV2-r4-f9-Bromo-2.3-dimethyl-naphthor2.3-blthiophen-4-vn-2-cvclopentyl- phenoxy]-3-phenyl-propionic acid methyl ester
  • Step 2 r2RV2-[2-Bromo-4-(9-bromo-2.3-dimethyl-naphthol2.3-blthiophen-4-vn-6- cycIopentyl-phenoxyl-3-phenyl-propionic acid methyl ester
  • 2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4- yl)-2,6-cyclopentyl-phenol 1.2 g, 2.2 mmol
  • (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.60 g, 3.3 mmol)
  • triphenylphosphine (0.87 g, 3.3 mmol) in anhydrous benzene (20 mL) at room temperature under nitrogen was added dropwise diethylazodicarboxylate (0.52 mL, 3.3 mmol).
  • reaction mixmre was then poured onto ice water (IL) containing some sodium bisulfite, and the resulting mixmre was extracted once with diethyl ether (1 L), and a second time with diethyl ether (300 mL).
  • the combined diethyl ether extracts were washed twice with water (1 L), brine (IL), and then dried (Na2SO4).
  • Step 7 ('2RV2-r4-(9-bromo-2.3-dimethyl-naphthol2.3-b1thiophen-4-ylV2.6-dimethyl- phenoxyl-3-phenyl-propionic acid
  • aqueous potassium hydroxide (19.5 mL of a IN solution, 19.5 mmol) was added, and the reaction mixmre was allowed to stir at room temperature for 9.5 h. Concentration under reduced pressure gave a residue which was diluted with water (1 L). The aqueous layer was acidified with concentrated hydrochloric acid to a pH of 1, and extracted with diethyl ether (700 mL). The diethyl ether layer was washed twice with water (500 mL), and then dried (Na2SO4).
  • Step 1 (2-Benzyl-4.5-dimethyl-thiophen-3-yl -(3.5-diisopropyl-4-methoxy-phenylV methanone
  • Step 1 there was obtained from 3,5-diisopropyl-p-anisic acid (5.0 g, 21.2 mmol, RN- 117439-59-5), oxalyl chloride (2.2 mL, 25.4 mmol), N,N-dimethylformamide (2 drops), 2,3-dimethyl-5- benzyltiiiophene (4.3 g, 21.2 mmol), tin(IV) chloride (5.0 mL, 42.7 mmol), and anhydrous methylene chloride (82 mL) the title compound as a yellow oil (4.1 g, 45%):
  • Step 4 (2R -2-r4-f2.3-Dimethyl-naphthor2.3-blthiophen-4-ylV2.6-diisopropyl- phenoxyl-3-phenyl-propionic acid
  • Step 1 (2-Benzyl-4.5-dimethyl-thiophen-3-yl -(3-fluoro-4-methoxy-pheny -methanone
  • 3-fluoro-p-anisic acid (10.0 g, 58.8 mmol)
  • oxalyl chloride (6.2 mL, 71.0 mmol)
  • N,N-dimethylformamide (12 drops)
  • 2,3-dimethyl-5-benzylthiophene (11.9 g, 58.8 mmol
  • tin(IV) chloride (10.3 mL, 88.0 mmol
  • anhydrous methylene chloride 130 mL
  • Step 3 there was obtained from 2-fluoro-4-(2,3-dimethyl-naphtho[2.3-b]thiophen-4-yl)-phenol (1.0 g, 3.1 mmol), acetic anhydride (0.36 mL, 3.8 mmol), and pyridine (7.5 mL) a yellow solid (1.1 g), which was used without further purification.
  • Step 4 there was obtained from acetic acid 2-fluoro-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester
  • Step 3 (RV2-r4-( ' 9-Bromo-2.3-dimethyl-naphthor2.3-blthiophen-4-ylV2-fluoro- phenoxyl-3-phenyl-propionic acid methyl ester
  • Step 4 (RV2-r4-f9-Bromo-2.3-dimethyl-naphthor2.3-blthiophen-4-ylV2-fluoro- phenoxy]-3-phenyl-propionic acid
  • Step 1 Acetic acid 4-(2.3-dimethyI-naphthor2.3-blthiophen-4-ylV2.6-diisopropyl- phenyl ester
  • Step 3 4-(9-Bromo-2.3-dimethyl-naphthor2.3-b1thiophen-4-yl ' )-2.6-diisopropyl-phenol
  • Step 5 [4-(9-Bromo-2.3-dimethyl-naphthor2.3-blthiophen-4-yl)-2.6-diisopropyl- phenoxy]-acetic acid
  • Step 7 [4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phen- oxy]-acetic acid methyl ester (0.40 g, 0.74 mmol), aqueous potassium hydroxide (0.89 mL of a 1 N solution, 0.89 mmol), tetrahydrofuran (6 mL), and methanol (2 mL) the title compound as a white solid (0.37 g, 95%): mp 228-231°C NMR (DMSO-d6): ⁇ 12.98 (broad s, IH), 8.19 (d, IH), 7.65-7.
  • Step 1 C2RV2-r4-( " 9-bromo-2.3-dimethyl-naphthor2.3-blthiophen-4-ylV2.6-diiso- propyl-phenoxyl-3-phenyl-propionic acid methyl ester
  • 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenol (0.46 g, 0.98 mmol)
  • (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.70 g, 3.9 mmol
  • triphenylphosphine (1.02 g, 3.9 mmol
  • diethylazodicarboxylate 0.62 mL, 3.9 mmol
  • anhydrous benzene 1.0 mL in an oil bath (90°C) for 24 h the tide compound as
  • Step 2 C2RV2-r4-( ' 9-Bromo-2.3-dimethyl-naphthor2.3-blthiophen-4-ylV2.6-diiso- propy 1-phenoxy 1 -3-phenyl-propionic acid
  • Example 57 9-Bromo-4-f3-bromo-methoxy-5-nitro-phenyl ' )-2. 3-dimethyl-naphthor2.3-blthiophene Iodomethane (0.22 mL, 3.55 mmol) and potassium carbonate (0.490 g, 3.55 mmol) were added to a stirred, room temperature solution of 9-bromo-4-(3-bromo- methoxy-5-nitro-phenyl)-2,3-dimethyl-naphtho[2,3-b]thiophene (0.600 g, 1.183 mmol) in DMF (8 mL).
  • Methyl bromoacetate (0.285 mL, 3.01 mmol) was added to a stirred, room temperature suspension of 3-bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen- 4-yl)-2-methoxy-phenylamine (0.260 g, 0.529 mmol) and potassium carbonate (0.411 g, 3.00 mmol) in DMF (1.7 mL). After two days, more methyl bromoacetate (0.135 mL, 1.5 mmol) and the reaction mixmre was stirred for a day longer. The reaction mixture was added to water and the solid was filtered and washed with water. The solid was trimrated with pet.
  • Aqueous potassium hydroxide ( IN, 0.64 mL, 0.64 mmol) was added to a stirred room temperature solution of [3-bromo-5-(9-bromo-2, 3-dimethyl-naphtho[2,3- b]thiophen-4-yl)-2-methoxy-phenylamino]-acetic acid methyl ester (0.180 g, 0.320 mmol) in THF (2.5 mL), methanol (1.5 mL). After 4 h, the solvent was removed and water was added. The suspension was acidified and extracted with ether. Silica gel was added. The ether was removed and the adsorbate was flash chromatographed (Gradient: 7:3pet.
  • Step 1 (2-Benzyl-4.5-dimethyl-thiophen-3-yl)-(4-methoxy-3.5-diethyl-pheny - methanone
  • Step 1 (2-Benzyl-4.5-dimethyl-thiophen-3-yl)-(4-methoxy-3.5-diethyl-pheny - methanone
  • 3,5-diethyl-p-anisic acid 9.45 g, 45.4 mmol, prepared by the method of J.
  • Step 4 Acetic acid 4-f9-bromo-2.3-dimethyl-naphtho[2.3-blthiophen-4-ylV2.6-diethyl- phenyl ester
  • Step 7 ( ' 2R -2-r4-(9-Bromo-2.3-dimethyl-naphthor2.3-blthio ⁇ hen-4-ylV2.6-diethyl- phenoxyl-3-phenyl-propionic acid
  • (2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl- phenoxy]-3-phenyl-propionic acid methyl ester (0.70 g, 1.16 mmol)
  • aqueous potassium hydroxide (2.3 mL of a 1 N solution, 2.3 mmol)
  • tetrahydrofuran (11.6 mL)
  • methanol methanol
  • reaction mixture was adsorbed onto silica gel and chromatographed with hexane:ethyl acetate (90:10) to give a solid (0.17 g), which was treated with potassium hydroxide (1.32 mL of a IN solution, 1.32 mmol), tetrahydrofuran (10 mL), and enough methanol to create a homogeneous solution.
  • the reaction mixture was diluted with diethyl ether, washed once with IN aqueous hydrochloric acid, once with water, once with brine, and then dried (Na2SO4).
  • the solution was concentrated under reduced pressure, dissolved in methylene chloride, and dried (Na2SO4). Concentration under reduced pressure gave a white solid (0.14 g, 26%): NMR (DMSO-d6): ⁇ 12.51
  • Step 2 f2RV2-r4-(9-Bromo-2.3-dimethyl-naphthor2.3-b1thio ⁇ hen-4-ylVphenoxy1-3- phenyl-propionic Acid
  • Step 7 there was obtained from (2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3- phenyl-propionic acid methyl ester (0.6 g, 1.10 mmol), aqueous potassium hydroxide (1.3 mL of a 1 N solution, 1.3 mmol), tetrahydrofuran (15.7 mL), and enough methanol to create a homogeneous solution the title compound as a solid (0.58 g, 99%):
  • Step 1 r2S -2-r4-(9-Bromo-2.3-dimethyl-naphthor2.3-blthiophen-4-ylV2.6-dimethyl- phenoxyl-3-phenyl-propionic acid methyl ester
  • Step 6 there was obtained from 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenol (10.4 g, 25.4 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (13.7 g, 76.0 mmol), triphenylphosphine (20.0 g, 76.3 mmol), diethylazodicarboxylate (12.0 mL, 76.2 mmol), and anhydrous THF (139 mL) at room temperature the tide compound as a sticky foam (8.66 g, 59%): Opt. Rot. [a]25/
  • Step 7 there was obtained from (2S)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl- phenoxy]-3-phenyl-propionic acid methyl ester (4.0 g, 6.97 mmol), aqueous potassium hydroxide (8.4 mL of a 1 N solution, 8.4 mmol), tetrahydrofuran (99.6 mL), and enough methanol to create a homogeneous solution a solid.
  • Step 2 (2R -2-r4-( , 2.3-Dimethyl-naphthor2.3-blthiophen-4-ylV2.6-diethyl-phenoxyl- 3 -phenyl-propionic acid
  • Step 7 there was obtained from (2R)-2-[4-(2,3-dimethyl-na ⁇ htho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3- phenyl-propionic acid methyl ester (0.46 g, 0.88 mmol), aqueous potassium hydroxide (1.1 mL of a 1 N solution, 1.1 mmol), tetrahydrofuran (12.6 mL), and enough methanol to create a homogeneous solution the title compound as a white solid (0.43 g ,
  • Step 1 (2-Benzyl-4.5-dimethyl-furan-3-yl -(4-methoxy-3.5-diethyl-phenyl)-methanone
  • 3,5-diethyl-p-anisic acid (10.66 g, 51.2 mmol; prepared in three steps from 4- bromo-2,6-diethyl aniline by the methods of J. Lipowitz and T. Cohen, J. Org. Chem. 1965, 30, 3891-3894; C.K. Bradsher. et al; J. Am. Chem. Soc. 1954, 76, 2357- 2362; J. Alexander, Org. Prep. Proced.
  • Step 3 there was obtained from 4-(2,3-dimethyl-naphtho[2.3-b]furan-4-yl)-2,6-diethyl-phenol (1.75 g, 5.1 mmol), acetic anhydride (0.62 mL, 6.6 mmol), and pyridine (10.2 mL) a solid (2.23 g), which was used without further purification.
  • Step 6 there was obtained from 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phenol (0.26 g, 0.64 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (1.38 g, 7.66 mmol), triphenylphosphine (1.98 g, 7.55 mmol), diethylazodicarboxylate (1.2 mL, 7.62 mmol), and anhydrous benzene (0.85 mL) at 100° for 36 h a solid (0.15 g, 39%), which was used without further purification.
  • Step 7 there was obtained from (2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phen- oxy]-3-phenyl-propionic acid methyl ester (0.15 g, 0.25 mmol), aqueous potassium hydroxide (0.98 mL of a 1 N solution, 0.98 mmol), tetrahydrofuran (2.5 mL), and enough methanol to create a homogeneous solution the tide compound as a white solid
  • Step 2 2RV2-r2-Cvclopentyl-4-( ' 2-.3-dimethyl-naphthor2.3-b1thiophen-4-ylV phenoxy] -propionic acid
  • Step 6 there was obtained from 2-cyclopentyl-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (0.37 g, 0.99 mmol), methyl (S)-(-)-lactate (0.75 mL, 7.9 mmol), triphenylphosphine
  • Step 1 4-[4-(9-Bromo-2-,3-dimethyl-naphthor2.3-b]thiophen-4-yl ' )-2-cyclopentyl- phenoxy]-butyric acid methyl ester
  • Step 2 4-(9-Bromo-2-.3-dimethyl-naphthor2.3-b1thiophen-4-ylV2-cvclopentyl- phenoxyl-butyric acid
  • Step 7 there was obtained from 4-[4-(9-bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl- phenoxy]-butyric acid methyl ester (0.23 g, 0.42 mmol), aqueous potassium hydroxide
  • Example 75 Acetic acid 2-cvclopentyl-4-(2-.3-dimethyl-naphthor2.3-b]furan-4-y -phenyl ester
  • 2- cyclopentyl-4-(2,3-dimethyl-naphtho[2.3-b]furan-4-yl)-phenol (4.81 g, 13.5 mmol)
  • acetic anhydride (1.60 mL, 17.0 mmol
  • pyridine 27 mL
  • methylene chloride 27 mL
  • Step 1 Acetic acid 4-(2.3-dimethyl-naphthor2.3-b]thiophen-4-ylV2-ethyl-phenyl ester
  • Step 2 Acetic acid 4-(9-bromo-2.3-dimethyl-naphthor2.3-b1thiophen-4-yl -2-ethyl- phenyl ester
  • Step 3 4-r9-Bromo-2.3-dimethyl-naphthor2.3-blthiophen-4-ylV2-ethyl- ⁇ henol
  • Step 5 C2RV2-r4-( ' 9-Bromo-2.3-dimethyl-naphthor2.3-b1thiophen-4-ylV2-ethyl- phenoxy]-3-phenyl-propionic acid
  • Step 1 there was obtained from 3-bromo-5-ethyl-p-anisic acid (4.95 g, 19.1 mmol), oxalyl chloride (1.8 mL,
  • Step 6 there was obtained from 2-bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenol (0.30 g, 0.76 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.54 g, 3.0 mmol), triphenylphosphine (0.80 g, 3.1 mmol), diethylazodicarboxylate (0.48 mL, 3.0 mmol), and anhydrous benzene (1.0 mL) at 100° for 12 h the title compound as a solid (0.37 g,
  • Step 7 there was obtained from (2R)-2-[2-bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-3- phenyl-propionic acid methyl ester (0.34 g, 0.61 mmol), aqueous potassium hydroxide (1.2 mL of a 1 N solution, 1.2 mmol), tetrahydrofuran (6.0 mL), and enough methanol to create a homogeneous solution the tide compound as a white foam (0.31 g, 94%):
  • Step 1 4-r2-Bromo-4-(2.3-dimethyl-naphthol2.3-b1furan-4-yl)-6-ethyl-phenoxy]- butyric acid methyl ester
  • Step 2 4-[2-Bromo-4-f2.3-dimethyl-naphthor2.3-blfuran-4-ylV6-ethyl-phenoxyl- butyric acid
  • Step 7 there was obtained from 4-[2-bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-butyric acid methyl ester (0.31 g, 0.63 mmol), aqueous potassium hydroxide (1.25 mL of a 1 N solution, 1.25 mmol), tetrahydrofuran (6.3 mL), and enough methanol to create a homogeneous solution the tide compound as a white foam (0.26 g, 87%): NMR
  • Step 1 (2-Benzyl-4.5-dimethyl-furan-3-ylV(4-methoxy-3-ethyl-phenyl)-methanone
  • 3-ethyl-p-anisic acid 5.0 g, 27.7 mmol
  • oxalyl chloride 2.7 mL, 31.0 mmol
  • N,N-dimethylformamide 2 drops
  • 2,3-dimethyl-5-benzylfuran 6.2 g, 33.3 mmol
  • tin(IV) chloride 3.6 mL, 30.8 mmol
  • anhydrous methylene chloride 177 mL
  • Step 2 4-( , 2.3-Dimethyl-naphthor2.3-blfuran-4-ylV2-ethyl-phenol
  • Step 2 there was obtained from (2-benzyl-4,5-dimethyl-furan-3-yl)-(4-methoxy-3-ethyl-phenyl)-methanone (7.0 g, 20.1 mmol), boron tribromide (14.4 mL, 152.3 mmol), and methylene chloride (69 mL) the title compound as an off-white solid (0.61 g, 9.6%): (DMSO-d6): ⁇ 9.45 (s,
  • Step 1 (2-Benzyl-4.5-dimethyl-thiophen-3-ylV(4-methoxy-3-propyl-phenylVmethanone
  • 3-propyl-p-anisic acid (3.0 g, 15.4 mmol)
  • oxalyl chloride (1.48mL, 17.0 mmol)
  • N,N-dimethylformamide (2 drops)
  • 2,3-dimethyl-5-benzylthiophene (3.75 g, 18.5 mmol
  • tin(IN) chloride (1.99 mL, 17.0 mmol)
  • anhydrous methylene chloride 99 mL
  • Step 2 4-(2.3-Dimethyl-naphthor2.3-b1thiophen-4-ylV2-pro ⁇ yl-phenol
  • Step2 there was obtained from (2-benzyl-4,5-dimethyl-thiophen-3-yl)-(4-methoxy-3-propyl-phenyl)-methanone (2.70 g, 7.1 mmol), boron tribromide (5.12 mL, 54.2 mmol), and methylene chloride
  • Step 3 Acetic acid 4-(2.3-dimethyl-naphthor2.3-b1thiophen-4-yl)-2-propyl-phenyl ester
  • Step 3 there was obtained from 4-(2,3-dimethyl-naphtho[2.3-b]thiophen-4-yl)-2-propyl-phenol (1.3 g, 3.8 mmol), acetic anhydride (0.46 mL, 4.9 mmol), and pyridine (7.5 mL) a residue, which was chromatographed with hexane/ethyl acetate to give the tide compound as a solid
  • Step 4 Acetic acid 4-(9-bromo-2.3-dimethyl-naphthor2.3-b]thiophen-4-yl)-2-propyl- phenyl ester
  • Step 5 there was obtained from acetic acid 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl- phenyl ester (0.36 g, 0.77 mmol), aqueous potassium hydroxide (0.92 mL of a 1 N solution, 0.92 mmol), tetrahydrofuran (11.4 mL), and methanol (7.6 mL) a solid, 4-(9- bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenol (0.62 g), which was used without further purification.
  • Step 6 there was obtained from 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenol (0.77 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (1.12 g, 6.2 mmol), triphenylphosphine (1.60 g, 6.1 mmol), diethylazodicarboxylate (0.96 mL, 6.1 mmol), and anhydrous benzene (2.5 mL) at 85° for 3 days a solid, (2R)-2-[4-(9-bromo-2,3- dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenoxy]-3-phenyl-propionic acid methyl ester (0.23 g), which was used without further purification.
  • Step 7 there was obtained from (2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phen- oxy]-3-phenyl-propionic acid methyl ester (0.23 g, 0.39 mmol), aqueous potassium hydroxide (0.93 mL of a 1 N solution, 0.93 mmol), tetrahydrofuran (4.6 mL), and enough methanol to create a homogeneous solution the title compound as a yellow foam
  • Step 1 Acetic acid 4-(2.3-dimethyl-naphtho[2.3-blthiophen-4-yl ' )-2-methyl-phenyl ester
  • 3-methyl-p-anisic acid (10 g, 60.2 mmol)
  • oxalyl chloride (5.77 mL, 66.1 mmol)
  • N,N-dimethylformamide (2 drops)
  • 2,3-dimethyl-5-benzylthiophene (14.6 g,
  • Step 2 4-(9-Bromo-2-.3-dimethyl-naphtho[2.3-b1thien-4-ylV2-methyl-phenyl acetate
  • Step 1 Acetic acid 4-(9-bromo-2-bromomethyl-3-methyl-naphthor2.3-b1thiophen-4- yl)-2.6-dimethyl-phenyl ester
  • Step4 there was obtained from acetic acid 4-(2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6- dimethyl-phenyl ester (10.0 g, 26.7 mmol), ferric chloride (0.23 g, 1.42 mmol), bromine (1.51 mL in methylene chloride (38 mL), 29.4 mmol), and methylene chloride (231 mL) acetic acid 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6- dimethyl-phenyl ester (6.68 g, 55%) and the title compound as a yellow solid (1.60 g):
  • Step 2 Acetic acid 4-(9-bromo-2-diethylaminomethyl-3-methyl-naphthor2.3-b1thio- phen-4-ylV2.6-dimethyl-phenyl ester Acetic acid 4-(9-bromo-2-bromomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-
  • Step 1 4-( ' 9-Bromo-2-diethylaminomethyl-3-methyl-naphthor2.3-blthiophen-4-yl ' )-2.6- dimethyl-phenol
  • Step 5 there was obtained from acetic acid 4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-
  • Step 6 there was obtained from 4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6- dimethyl-phenol (0.90 g, 1.87mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.67g, 3.73 mmol), triphenylphosphine (0.98 g, 3.73 mmol), diethylazodicarboxylate (0.59 mL, 3.73 mmol), and anhydrous benzene (10 mL) at
  • Step 7 there was obtained from (2R)-2-[4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4- yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionic acid methyl ester (0.35 g, 0.98 mmol), aqueous potassium hydroxide (1.95 mL of a 1 N solution, 1.95 mmol), tetrahydrofuran (9 mL), and methanol (3 mL) the tide compound as a solid (0.35 g, >100%): NMR (DMSO-d6): ⁇ 12.90 (br s, IH), 8.19 (d, IH), 7.66-7.61 (m. IH), 7.50-7.43 (m,
  • Example 88 r2RV2-r4-r9-Bromo-2-diethylaminomethyl-3-methyl-naphthor2.3-blthiophen-4-vn- 2.6-diisopropyl-phenoxy]-3-phenyl-propionic acid
  • This compound was prepared in a manner similar to Example 87 using appropriate starting materials to afford the tide compound as a yellow solid: (DMSO- d6): ⁇ 13.00 (br s, IH), 8.18 (d, IH), 7.63-7.60 (m, IH), 7.46-7.44 (m, 2H), 7.36-

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Abstract

La présente invention concerne des composés de formule I, dans laquelle Ar est (a), (b) ou (c), et où A, B, C, D, E, X, Y, Z1, Z2 sont définis dans la description. Ces composés, ou leurs sels, acceptables sur le plan pharmaceutique, sont utiles dans le traitement des troubles métaboliques de la résistance insulinique et de l'hyperglycémie.
PCT/US1999/010209 1998-05-12 1999-05-10 Benzothiophenes, benzofuranes et indoles utiles dans le traitement de la resistance insulinique et de l'hyperglycemie WO1999061435A1 (fr)

Priority Applications (14)

Application Number Priority Date Filing Date Title
EEP200000653A EE200000653A (et) 1998-05-12 1999-05-10 Bensotiofeenid, bensofuraanid ja indoolid kasutamiseks insuliiniresistentsuse ning hüperglükeemia ravis
KR1020007012649A KR20010043539A (ko) 1998-05-12 1999-05-10 인슐린 내성 및 과혈당증의 치료에 유용한 벤조티오펜,벤조푸란 및 인돌
IL13913299A IL139132A0 (en) 1998-05-12 1999-05-10 Benzothiophenes, benzofurans and indoles useful in the treatment of insulin resistance and hyperglycemia
HU0101792A HUP0101792A3 (en) 1998-05-12 1999-05-10 Benzothiophenes, benzofurans, and indoles, their use for producing medicaments and this medicaments useful in the treatment of insulin resistance and hyperglycemia
EP99921829A EP1077969A1 (fr) 1998-05-12 1999-05-10 Benzothiophenes, benzofuranes et indoles utiles dans le traitement de la resistance insulinique et de l'hyperglycemie
CA002330620A CA2330620A1 (fr) 1998-05-12 1999-05-10 Benzothiophenes, benzofuranes et indoles utiles dans le traitement de la resistance insulinique et de l'hyperglycemie
AU38939/99A AU756337B2 (en) 1998-05-12 1999-05-10 Benzothiophenes, benzofurans, and indoles useful in the treatment of insulin resistance and hyperglycemia
EA200001175A EA200001175A1 (ru) 1998-05-12 1999-05-10 Бензотиофены, бензофураны и индолы, полезные в лечении устойчивости к инсулину и гипергликемии
JP2000550841A JP2002516321A (ja) 1998-05-12 1999-05-10 インスリン耐性および高血糖の治療に有用なベンゾチオフェン、ベンゾフラン、およびインドール
BR9911779-7A BR9911779A (pt) 1998-05-12 1999-05-10 Benzotiofenos, benzofuranos e indóis úteis no tratamento de resistência à insulina e hiperglicemia
SK1699-2000A SK16992000A3 (sk) 1998-05-12 1999-05-10 Benzotiofény, benzofurány, indoly, farmaceutický prostriedok s ich obsahom a ich použitie
BG104918A BG104918A (bg) 1998-05-12 2000-11-07 Бензотиофени, бензофурани и индоли, полезни при лечение на резистентност към инсулин и хипергликемия
NO20005677A NO20005677L (no) 1998-05-12 2000-11-10 Benzotiofener, benzofuraner og indoler som er anvendelige ved behandling av insulinresistens og hyperglykemi
HR20000767A HRP20000767A2 (en) 1998-05-12 2000-11-10 Benzothiophenes, benzofurans and indoles useful in the treatment of insulin resistance and hyperglycemia

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US6472545B2 (en) 2000-08-29 2002-10-29 Abbott Laboratories Protein tyrosine phosphatase inhibitors
WO2002098407A1 (fr) * 2001-06-07 2002-12-12 Wyeth Combinaison d'un inhibiteur de ptpase et d'un inhibiteur d'alpha-glucosidase
WO2002098510A1 (fr) * 2001-06-07 2002-12-12 Wyeth Combinaison d'un inhibiteur de ptpase et d'un inhibiteur d'aldose reductase
WO2002098408A1 (fr) * 2001-06-07 2002-12-12 Wyeth Inhibiteurs de la proteine tyrosine phosphatase (ptpase) destines a la reduction des risques cardiovasculaires
WO2002098410A1 (fr) * 2001-06-07 2002-12-12 Wyeth Combinaison d'un inhibiteur de ptpase et d'un agent sulfonyluree
WO2002098414A1 (fr) * 2001-06-07 2002-12-12 Wyeth Procedes d'utilisation d'inhibiteurs de ptpase et d'insuline
WO2002098409A1 (fr) * 2001-06-07 2002-12-12 Wyeth Therapie combinee pour le diabete de type ii ou le syndrome x
WO2002100397A1 (fr) * 2001-06-07 2002-12-19 Wyeth Combinaison d'un inhibiteur de proteine-tyrosine phosphatase et d'un agent hypolipemiant
WO2002100398A1 (fr) * 2001-06-07 2002-12-19 Wyeth Combinaison d'un inhibiteur de proteine-tyrosine phosphatase et d'un inhibiteur de l'enzyme de conversion d'angiotensine
WO2002100396A1 (fr) * 2001-06-07 2002-12-19 Wyeth Combinaison d'un inhibiteur de la ptpase et d'un agent thiazolidinedione
US6498182B2 (en) 2000-09-26 2002-12-24 Biovitrum Ab Compounds
WO2003032982A1 (fr) * 2001-10-19 2003-04-24 Transtech Pharma, Inc. Bis-heteroaryl alcanes utilises comme agents therapeutiques
WO2004035562A1 (fr) * 2002-10-14 2004-04-29 Clariant Life Science Molecules (Italia) S.P.A. Procede d'elaboration de 3-alkylthiophenes a disubstitution en 2,5
FR2862645A1 (fr) * 2003-11-20 2005-05-27 Merck Sante Sas Composes antidiabetiques contenant des derives benzofuranes, benzothiophenes
US6969730B2 (en) 2001-03-16 2005-11-29 Abbott Laboratories Amines as histamine-3 receptor ligands and their therapeutic applications
US6984645B2 (en) 2001-11-16 2006-01-10 Bristol-Myers Squibb Company Dual inhibitors of adipocyte fatty acid binding protein and keratinocyte fatty acid binding protein
US7056943B2 (en) 2002-12-10 2006-06-06 Wyeth Substituted indole oxo-acetyl amino acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7074817B2 (en) 2001-06-20 2006-07-11 Wyeth Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7078429B2 (en) 2002-12-10 2006-07-18 Wyeth Substituted 3-carbonyl-1H-indol-1-yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7101903B2 (en) 2002-12-10 2006-09-05 Wyeth Substituted dihydropyrano indole-3,4-dione derivatives as inhibitiors of plasminogen activator inhibitor-1 (PAI-1)
US7141592B2 (en) 2003-09-25 2006-11-28 Wyeth Substituted oxadiazolidinediones
US7163952B2 (en) 2001-12-03 2007-01-16 Japan Tobacco Inc. Azole compound and medicinal use thereof
US7163954B2 (en) 2003-09-25 2007-01-16 Wyeth Substituted naphthyl benzothiophene acids
US7186749B2 (en) 2004-08-23 2007-03-06 Wyeth Pyrrolo-naphthyl acids and methods for using them
US7259182B2 (en) 2002-12-10 2007-08-21 Wyeth Aryl, aryloxy, and aklyloxy substituted 1H-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7265148B2 (en) 2003-09-25 2007-09-04 Wyeth Substituted pyrrole-indoles
US7268159B2 (en) 2003-09-25 2007-09-11 Wyeth Substituted indoles
US7332521B2 (en) 2003-09-25 2008-02-19 Wyeth Substituted indoles
US7342039B2 (en) 2003-09-25 2008-03-11 Wyeth Substituted indole oximes
US7348351B2 (en) 2002-12-10 2008-03-25 Wyeth Substituted 3-alkyl and 3-arylalkyl 1H-indol-1yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7351726B2 (en) 2003-09-25 2008-04-01 Wyeth Substituted oxadiazolidinediones
US7351730B2 (en) 2001-06-20 2008-04-01 Wyeth Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
US7371759B2 (en) 2003-09-25 2008-05-13 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US7411083B2 (en) 2003-09-25 2008-08-12 Wyeth Substituted acetic acid derivatives
US7420083B2 (en) 2003-09-25 2008-09-02 Wyeth Substituted aryloximes
US7420059B2 (en) 2003-11-20 2008-09-02 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US7435837B2 (en) 2003-10-24 2008-10-14 Wyeth Dihydrobenzofuranyl alkanamine derivatives and methods for using same
US7442805B2 (en) 2003-09-25 2008-10-28 Wyeth Substituted sulfonamide-indoles
US7446201B2 (en) 2003-09-25 2008-11-04 Wyeth Substituted heteroaryl benzofuran acids
US7504401B2 (en) 2003-08-29 2009-03-17 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof
US7534894B2 (en) 2003-09-25 2009-05-19 Wyeth Biphenyloxy-acids
US7582773B2 (en) 2003-09-25 2009-09-01 Wyeth Substituted phenyl indoles
US7605172B2 (en) 2004-08-23 2009-10-20 Wyeth Thiazolo-naphthyl acids
US7683091B2 (en) 2005-08-17 2010-03-23 Wyeth Substituted indoles and methods of their use
US7718377B2 (en) 2003-05-29 2010-05-18 Kyoto Pharmaceutical Industries, Ltd. Insulin resistance curative and method of screening the same
WO2010067069A1 (fr) 2008-12-10 2010-06-17 The University Of Liverpool Composés pour utilisation dans le traitement de la douleur
US7754747B2 (en) 2004-08-23 2010-07-13 Wyeth Llc Oxazolo-naphthyl acids
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
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US6472545B2 (en) 2000-08-29 2002-10-29 Abbott Laboratories Protein tyrosine phosphatase inhibitors
WO2002018363A2 (fr) * 2000-08-29 2002-03-07 Abbott Laboratories Inhibiteurs de la proteine tyrosine phosphatase
WO2002026707A1 (fr) * 2000-09-26 2002-04-04 Biovitrum Ab Nouveaux composes
US6498182B2 (en) 2000-09-26 2002-12-24 Biovitrum Ab Compounds
US6969730B2 (en) 2001-03-16 2005-11-29 Abbott Laboratories Amines as histamine-3 receptor ligands and their therapeutic applications
US7538138B2 (en) 2001-03-16 2009-05-26 Abbott Laboratories Amines as histamine-3 receptor ligands and their therapeutic applications
WO2002098414A1 (fr) * 2001-06-07 2002-12-12 Wyeth Procedes d'utilisation d'inhibiteurs de ptpase et d'insuline
WO2002098410A1 (fr) * 2001-06-07 2002-12-12 Wyeth Combinaison d'un inhibiteur de ptpase et d'un agent sulfonyluree
WO2002098409A1 (fr) * 2001-06-07 2002-12-12 Wyeth Therapie combinee pour le diabete de type ii ou le syndrome x
WO2002100397A1 (fr) * 2001-06-07 2002-12-19 Wyeth Combinaison d'un inhibiteur de proteine-tyrosine phosphatase et d'un agent hypolipemiant
WO2002100398A1 (fr) * 2001-06-07 2002-12-19 Wyeth Combinaison d'un inhibiteur de proteine-tyrosine phosphatase et d'un inhibiteur de l'enzyme de conversion d'angiotensine
WO2002100396A1 (fr) * 2001-06-07 2002-12-19 Wyeth Combinaison d'un inhibiteur de la ptpase et d'un agent thiazolidinedione
WO2002098408A1 (fr) * 2001-06-07 2002-12-12 Wyeth Inhibiteurs de la proteine tyrosine phosphatase (ptpase) destines a la reduction des risques cardiovasculaires
WO2002098510A1 (fr) * 2001-06-07 2002-12-12 Wyeth Combinaison d'un inhibiteur de ptpase et d'un inhibiteur d'aldose reductase
WO2002098407A1 (fr) * 2001-06-07 2002-12-12 Wyeth Combinaison d'un inhibiteur de ptpase et d'un inhibiteur d'alpha-glucosidase
US6734197B2 (en) 2001-06-07 2004-05-11 Wyeth Combination therapy for type II diabetes or Syndrome X
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US7351730B2 (en) 2001-06-20 2008-04-01 Wyeth Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
US7368471B2 (en) 2001-06-20 2008-05-06 Wyeth Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7074817B2 (en) 2001-06-20 2006-07-11 Wyeth Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7022730B2 (en) 2001-10-19 2006-04-04 Transtech Pharma, Inc. Bis-heteroaryl alkanes as therapeutic agents
WO2003032982A1 (fr) * 2001-10-19 2003-04-24 Transtech Pharma, Inc. Bis-heteroaryl alcanes utilises comme agents therapeutiques
US6984645B2 (en) 2001-11-16 2006-01-10 Bristol-Myers Squibb Company Dual inhibitors of adipocyte fatty acid binding protein and keratinocyte fatty acid binding protein
US7163952B2 (en) 2001-12-03 2007-01-16 Japan Tobacco Inc. Azole compound and medicinal use thereof
WO2004035562A1 (fr) * 2002-10-14 2004-04-29 Clariant Life Science Molecules (Italia) S.P.A. Procede d'elaboration de 3-alkylthiophenes a disubstitution en 2,5
US7101903B2 (en) 2002-12-10 2006-09-05 Wyeth Substituted dihydropyrano indole-3,4-dione derivatives as inhibitiors of plasminogen activator inhibitor-1 (PAI-1)
US7160918B2 (en) 2002-12-10 2007-01-09 Hassan Mahmoud Elokdah Substituted indole oxo-acetyl amino acetic acid derivatives as inhibitors of plasminogen activator inhibitor (PAI-1)
US7078429B2 (en) 2002-12-10 2006-07-18 Wyeth Substituted 3-carbonyl-1H-indol-1-yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
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US7674818B2 (en) 2002-12-10 2010-03-09 Wyeth Llc Aryl, aryloxy, alkyloxy substituted 1H-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7259182B2 (en) 2002-12-10 2007-08-21 Wyeth Aryl, aryloxy, and aklyloxy substituted 1H-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
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US7718377B2 (en) 2003-05-29 2010-05-18 Kyoto Pharmaceutical Industries, Ltd. Insulin resistance curative and method of screening the same
US7504401B2 (en) 2003-08-29 2009-03-17 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof
US7411083B2 (en) 2003-09-25 2008-08-12 Wyeth Substituted acetic acid derivatives
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US7342039B2 (en) 2003-09-25 2008-03-11 Wyeth Substituted indole oximes
US7371759B2 (en) 2003-09-25 2008-05-13 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US7803835B2 (en) 2003-09-25 2010-09-28 Wyeth Llc Substituted acetic acid derivatives
US7332521B2 (en) 2003-09-25 2008-02-19 Wyeth Substituted indoles
US7420083B2 (en) 2003-09-25 2008-09-02 Wyeth Substituted aryloximes
US7582773B2 (en) 2003-09-25 2009-09-01 Wyeth Substituted phenyl indoles
US7163954B2 (en) 2003-09-25 2007-01-16 Wyeth Substituted naphthyl benzothiophene acids
US7442805B2 (en) 2003-09-25 2008-10-28 Wyeth Substituted sulfonamide-indoles
US7446201B2 (en) 2003-09-25 2008-11-04 Wyeth Substituted heteroaryl benzofuran acids
US7268159B2 (en) 2003-09-25 2007-09-11 Wyeth Substituted indoles
US7265148B2 (en) 2003-09-25 2007-09-04 Wyeth Substituted pyrrole-indoles
US7534894B2 (en) 2003-09-25 2009-05-19 Wyeth Biphenyloxy-acids
US7141592B2 (en) 2003-09-25 2006-11-28 Wyeth Substituted oxadiazolidinediones
US7435837B2 (en) 2003-10-24 2008-10-14 Wyeth Dihydrobenzofuranyl alkanamine derivatives and methods for using same
US7420059B2 (en) 2003-11-20 2008-09-02 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
WO2005054225A1 (fr) * 2003-11-20 2005-06-16 Merck Patent Gmbh Composes antidiabetiques comprenant des derives de benzofurane et de benzothiophene
AU2004295029B2 (en) * 2003-11-20 2010-03-11 Merck Patent Gmbh Antidiabetic compounds comprising benzofuran and benzothiophene derivatives
FR2862645A1 (fr) * 2003-11-20 2005-05-27 Merck Sante Sas Composes antidiabetiques contenant des derives benzofuranes, benzothiophenes
US7375130B2 (en) 2003-11-20 2008-05-20 Merck Patent Gesellschaft Mit Beschrankter Haftung Antidiabetic compounds comprising benzofuran and benzothiophene derivatives
US7605172B2 (en) 2004-08-23 2009-10-20 Wyeth Thiazolo-naphthyl acids
US7186749B2 (en) 2004-08-23 2007-03-06 Wyeth Pyrrolo-naphthyl acids and methods for using them
US7754747B2 (en) 2004-08-23 2010-07-13 Wyeth Llc Oxazolo-naphthyl acids
US7683091B2 (en) 2005-08-17 2010-03-23 Wyeth Substituted indoles and methods of their use
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NO20005677D0 (no) 2000-11-10
NO20005677L (no) 2000-12-05
SK16992000A3 (sk) 2001-04-09
EE200000653A (et) 2002-04-15
EP1077969A1 (fr) 2001-02-28
TW510900B (en) 2002-11-21
AU756337B2 (en) 2003-01-09
ID26244A (id) 2000-12-07
TR200003333T2 (tr) 2001-02-21
AR015294A1 (es) 2001-04-18
IL139132A0 (en) 2001-11-25
ZA200005961B (en) 2001-10-24
HUP0101792A3 (en) 2003-01-28
HUP0101792A2 (hu) 2002-01-28
BG104918A (bg) 2001-08-31
CA2330620A1 (fr) 1999-12-02
AU3893999A (en) 1999-12-13
KR20010043539A (ko) 2001-05-25
JP2002516321A (ja) 2002-06-04
EA200001175A1 (ru) 2001-06-25
PL344081A1 (en) 2001-09-24
CN1308626A (zh) 2001-08-15
HRP20000767A2 (en) 2001-10-31

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