WO1999058522A1 - Derives de naphto[2,3-b]heteroar-4-yle - Google Patents

Derives de naphto[2,3-b]heteroar-4-yle Download PDF

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WO1999058522A1
WO1999058522A1 PCT/US1999/010210 US9910210W WO9958522A1 WO 1999058522 A1 WO1999058522 A1 WO 1999058522A1 US 9910210 W US9910210 W US 9910210W WO 9958522 A1 WO9958522 A1 WO 9958522A1
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carbon atoms
dimethyl
alkyl
hydrogen
naphtho
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PCT/US1999/010210
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English (en)
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Paul Jeffrey Dollings
Arlene Joan Dietrich
Jay Edward Wrobel
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American Home Products Corporation
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Priority to AU37916/99A priority Critical patent/AU3791699A/en
Priority to EP99920418A priority patent/EP1077968A1/fr
Priority to JP2000548326A priority patent/JP2002514639A/ja
Priority to CA002330555A priority patent/CA2330555A1/fr
Publication of WO1999058522A1 publication Critical patent/WO1999058522A1/fr

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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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/74—Naphthothiophenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • Hyperinsulinemia can be present as a result of insulin resistance, such as is in obese and/or diabetic (NIDDM) subjects and/or glucose intolerant subjects, or in LDDM 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).
  • PTPases Protein-tyrosine phosphatases play an important role in the regulation of phosphorylation of proteins.
  • the interaction of insulin with its receptor leads to phosphorylation of certain tyrosine molecules within the receptor protein, thus activating the receptor kinase.
  • PTPases dephosphorylate the activated insulin receptor, attenuating the tyrosine kinase activity.
  • PTPases can also modulate post-receptor signaling by catalyzing the dephosphorylation of cellular substrates of the insulin receptor kinase.
  • the enzymes that appear most likely to closely associate with the insulin receptor and therefore, most likely to regulate the insulin receptor kinase activity include PTPIB, LAR, PTP ⁇ and SH-PTP2 (B. J. Goldstein, I. Cellular Biochemistry 1992, 48, 33; B. J. Goldstein, Receptor 1993, 3, 1-15,; F. Ahmad and B. J. Goldstein Biochim. Biophys Acta 1995, 1248,
  • the compounds of this invention have been shown to inhibit PTPases derived from rat liver microsomes and human-derived recombinant PTPase-lB (hPTP-lB) in vitro. They are useful in the treatment of insulin resistance associated with obesity, glucose intolerance, diabetes mellitus, hypertension and ischemic diseases of the large and small blood vessels.
  • hPTP-lB human-derived recombinant PTPase-lB
  • Bridges, et al. (EP 568289 A2) disclosed the thienothiopheneamidine B as a urokinase inhibitor.
  • R 1 and R 2 are each, independently, hydrogen, nitrile, nitro, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, cycloalkylamino of 3-8 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, halogen, cycloalkyl of 3-8 carbon atoms, thienyl, furyl, phenyl or phenyl mono-, di-, or tri- substituted with halogen, hydroxy, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, or perfluoroalkoxy of 1-6 carbon atoms;
  • R 3 and R 4 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, aminoalkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms;
  • R 5 is hydrogen, halogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, nitrile, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy of 2-12 carbon atoms, arylsulfanyl; W is S, O, or NR9;
  • R 9 is hydrogen or alkyl of 1-6 carbon atoms
  • X is O, -NR6-, or -(CH 2 ) p NR 6 - ;
  • R 6 is hydrogen, or alkyl of 1-6 carbon atoms; p is 1 to 4; Y is methylene, carbonyl, -SO 2 -, or -SO-; Z is phenyl, heteroaryl, or naphthyl;
  • R 7 and R 8 are each, independently, hydrogen, carboxy, acyl of 2-7 carbon atoms, hydroxy, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkanoyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, perfluoroalkoxycarbonyl of 2-7 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, aryl of 6-
  • R 10 is hydrogen, halogen, nitro, amino, alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, nitrile, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia
  • Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids when a compound of this invention contains a basic moiety.
  • organic and inorganic acids for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulf
  • 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, or similar moiety capable of forming base addition salts.
  • alkali metal salts for example, sodium, lithium, or potassium
  • alkyl, alkoxy, alkanoyl, acyl used alone or in conjunction with another term are defined as 1-6 carbons, branched or straight chained optionally substituted with fluorine, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s- butyl, t-butyl, pentyl or hexyl.
  • dialkyl used alone or in conjunction with another term is defined as 2-12 carbons optionally substituted with fluorine.
  • cycloalkyl used alone or in conjunction with another term is defined as 3-8 carbons optionally substituted with fluorine, e.g.
  • cyclopropyl, cyclobutyl or cyclopentyl cyclopropyl, cyclobutyl or cyclopentyl.
  • aryl, arylalkoxy, arylsufanyl used alone or in conjunction with another term are defined as 6-10 carbons optionally substituted with fluorine.
  • perfluoroalkyl, perfluoroalkoxy, perfluoroalkanoyloxy, perfluoroalkoxycarbonyl used alone or in conjunction with another term are defined as 1-6 carbons.
  • aroyl used alone or in conjunction with another term is defined phenylcarbonyl or naphthylcarbonyl optionally substituted with fluorine.
  • heteroaryl used alone or in conjunction with another term is defined as a stable 5 to 10 member mono or bicyclic heterocyclic ring system which consists of carbon atoms and from 1 to 3 heteroatoms selected from N, O and S and selected from the group consisting of quinoline, isoquinoline, pyridine, indole, isoindole, pyrrole, quinazoline, oxazole, oxazine, isoxazole, isothiazole, pyrazine, pyridazine, pyrimidine, thiophene, furan, benzofuran, benzimidazole, benzoxadiazole, pyrazole, pyrrolidinone, benzoxazole, benzpyrazzole, benzisoxazole, thiazole, thiadiazole, triazole, isobenzothiophene and benzothiophene.
  • 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.
  • Preferred compounds of this invention are those compounds of Formula I in which:
  • R 1 and R 2 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, bromine, iodine, cycloalkyl of 3-8 carbon atoms, phenyl or phenyl substituted with trifluoromethyl, chloro, methoxy,
  • R 3 and R 4 are each, independently, alkyl of 1-6 carbon atoms, or perfluoroalkyl of 1-6 carbon atoms;
  • R 5 is hydrogen, halogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, nitrile, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy, or arylsulfanyl; W is S, or O;
  • X is O, -NR 6 -, or -(CH 2 ) p NR 6 - ;
  • R 6 is hydrogen or, alkyl of 1-6 carbon atoms; p is 1 to 4; Y is methylene, carbonyl, -SO 2 -, or -SO-;
  • Z is phenyl, pyridyl, naphthyl, thienyl, furyl, pyrrolyl, pyrazolyl, isoxazolyl, or isothiazolyl;
  • R 7 and R 8 are, each independently, hydrogen, halogen, carboxy, acyl of 2-7 carbon atoms, acylamino of 1-6 carbon atoms, hydroxy, hydroxyalkyl of 1-6 carbon atoms, hydroxyalkanoyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, perfluoroalkoxycarbonyl of 2-7 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, aryloxy 6-10 carbon atoms, aryloxycarbonyl 7-11 carbon atoms, heteroaryloxycarbonyl, arylalkoxy of 7-13 carbon atoms, pyridyl, alkanoyloxy of 2-7 carbon atoms, perfluoroalkanoyloxy of 2-7 carbon atoms
  • More preferred compounds of this invention are those compounds of Formula I in which:
  • R 1 and R 2 are, each independently, hydrogen, alkyl of 1-6 carbon atoms, bromo, or cyclopentyl;
  • R 3 and R 4 are alkyl of 1-6 carbon atoms
  • R 5 is hydrogen or bromine; W is S, or O;
  • X is O, -NR6-, or -CH 2 NR 6 -;
  • R 6 is hydrogen or alkyl of 1-6 carbon atoms;
  • Y is methylene, carbonyl, or -SO 2 -;
  • Z is phenyl, thienyl, pyrazolyl, or thiazolyl
  • R 7 and R 8 are each, independently, hydrogen, halogen, acyl of 1-6 carbon atoms, carboxy, hydroxy, alkoxy of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, alkyl of 1-6 carbon atoms, pyridyl, alkanoyloxy of 2-7 carbon atoms, aroyloxy of 7-11 carbon atoms, aroyloxy of 7-11 carbon atoms substituted with R 10 , heteroaroyloxy, arylalkanoyloxy of 8-17 carbon atoms, tetrazolyl, isoxazolyl, nitrile, or pyrimidyl substituted with methylsulfanyl;
  • R 10 is hydrogen, halogen, nitro, alkoxy of 1-6 carbon atoms, nitrile, alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a process for the preparation of compounds of formula I which comprises:
  • Q is hydrogen or a metal atom, e.g. Na, Li or Mg, and all the other groups are as defined above, optionally in the presence of a base e.g. pyridine, triethylamine or sodium acetate, to provide a compound of formula I wherein Y is CO, SO or SO2;
  • Q' is a leaving group such a halogen atom (preferably I, Br or Cl) or the group -OSO2R" where R" is alkyl or an optionally substituted aromatic group (e.g.methyl or p-toyl) and R ⁇ R7 and Z are as defined above, with a compound of formula
  • Q is hydrogen or a metal atom, e.g. Na, Li or Mg, and all other groups are defined above, optionally in the presence of a base e.g. pyridine, triethylamine or sodium acetate, to provide a compound of formula I wherein Y is CH2;
  • R* wherein R", R> and Z are as defined above, such as the 1-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, 4-nitrophenyl ester or other suitable esters known in the art, with an amine of formula
  • Hal is a halogen and R", R ' and Z are as defined above, with a compound of formula
  • Q" is an alkyl group, such as methyl, and all the other groups are as defined above, to provide a compound of formula I wherein Y is SO2 and X is O;
  • 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.
  • 2,3-dimethylthiophene (II: W is S) is prepared from commercially available 3-mefhyl-thiophene-carboxaldehyde using Wolff-Kishner conditions (hydrazine followed by KOH/ethylene glycol reflux).
  • Compound (II) 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
  • a nonprotic solvent such as THF
  • a nonprotic solvent such as THF
  • This acylation is accomplished most readily using a one to five molar equivalents of a Lewis acid catalyst such as tin tetrachloride or aluminum chloride in an inert solvent such as dichloromethane, 1, 2-dichloroethane or carbon disulfide, generally at temperatures such as -78°C to room temperature.
  • a Lewis acid catalyst such as tin tetrachloride or aluminum chloride in an inert solvent such as dichloromethane, 1, 2-dichloroethane or carbon disulfide, generally at temperatures such as -78°C to room temperature.
  • the benzoic acid chloride (IV: X -OMe).
  • the acid starting material for benzoic acid chloride (TV) can be prepared using a modification of the method of Schuster, et al., I. Org. Chem. 1988, 53, 5819.
  • the commercially available 2,6-(mono or disubstituted)phenols can be methylated (iodomethane / potassium carbonate / DMF), acylated in the 4-position with 2-chlorobenzoyl chloride in the presence of aluminum chloride in an inert solvent such as dichloromethane, generally at ambient temperature and reacted with potassium-t-butoxide in H 2 O/ethylene glycol dimethyl ether at ambient temperature to give the desired 2,6-(mono or disubstituted)benzoic acid.
  • an inert solvent such as dichloromethane
  • 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 sulfonylating agent is generally a aryl or heteroaryl sulfonic acid chloride.
  • the reaction is run under standard conditions using a suitable base such sodium hydride, pyridine or Tris base in an appropriate solvent such as dichloromethane, THF or H 2 O at temperatures from 0°C to ambient temperature.
  • the starting sulfonyl chloride is commercially available or can be easily prepared by known procedures.
  • the aryl or heteroaryl sulfonic acid chloride can be prepared by reacting the aryl or heteroaryl sulfonic acid with one or more molar equivalents of oxalyl chloride or thionyl chloride, in a suitable solvent such as dichloromethane, chloroform or diethyl ether, to afford the aryl or heteroaryl sulfonic acid chloride.
  • 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.
  • the sulfonyl chlorides can prepared using a modification of Barraclough, et al., Arch. Pharm. (Weinheim) 1990, 323, 507.
  • the aniline of commercially available 4-aminosalicylic acid sodium salt dihydrate is diazotized with sodium nitrite in HOAc/HCl at -10°C and the subsequent the diazonium salt can converted to the sulfonyl chloride by introduction of sulfur dioxide into the reaction in the presence of copper (I) chloride.
  • the groups R 7 and R 8 connected to Z can be further derivatized.
  • R 7 or R 8 is an ester of a carboxylic acid or alcohol the compound can be transformed into the respective carboxylic acid or alcohol analog using standard conditions.
  • 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.
  • R 7 or R 8 When R 7 or R 8 is a carboxylic acid or ester the compound can be reduced to the respective primary alcohol analog using standard conditions such as lithium aluminum hydride in ethyl ether.
  • R 7 or R 8 When R 7 or R 8 is an aldehyde or ketone the compound can be reduced to the respective primary alcohol analog using a metal catalyst, by sodium in alcohol, sodium borohydride and by lithium aluminum hydride.
  • R 7 or R 8 is an ether, the compound can be transformed to the free alcohol by using one to ten molar equivalents of a strong Lewis acid such as a trihaloborane, most conveniently tribromoborane in a halocarbon solvent such as dichloromethane.
  • R 7 or R 8 is an alcohol
  • the compound can be oxidized to the respective aldehyde, carboxylic acid or ketone analog using a transition metal oxidant (chromium trioxide- pyridine, pyridinium chlorochromate, manganese dioxide) in an inert solvent such as ether, dichloromethane.
  • Alcohols can also be oxidized using DMSO with a number of electrophilic molecules (dicyclohexylcarbodiimide, acetic anhydride, trifluoro acetic anhydride, oxalyl chloride and sulfur dioxide).
  • R 7 or R 8 is a carboxylic acid the compound can be transformed into a carboxylic acid amide analog.
  • This transformation can be accomplished using standard methods to effect carboxylic acid to carboxylic acid amide transformations. These methods include converting the acid to an activated acid and reacting with one or more molar equivalents of the desired amine. Amines in this category include ammonia in the form of ammonium hydroxide, hydroxyl amine and 2- aminopropionitrile. Methods to activate the carboxylic acid include reacting said acid with one or more molar equivalents of oxalyl chloride or thionyl chloride to afford the carboxylic acid chloride in a suitable solvent such as dichloromethane, chloroform or diethyl ether. This reaction is often catalyzed by adding small amounts (0.01 to 0.1 molar equivalents) of dimethylformamide.
  • Other methods to activate the carboxylic acid include reacting said acid with one or more molar equivalents dicyclohexylcarbodiimide with or without one or more molar equivalents of hydroxybenzotriazole in a suitable solvent such as dichloromethane or dimethylformamide at temperatures ranging from 0°C to 60°C.
  • a suitable solvent such as dichloromethane or dimethylformamide
  • R 7 or R 8 is nitro
  • the compound can be reduced to the respective amino compound most readily using tin dichloride in ethyl acetate at 40 to 100°C or with hydrazine and Montmorillinite clay in ethanol at 40 to 100°C or by catalytic hydrogenation in the presence of a catalyst such as palladium on carbon.
  • R 7 or R 8 is an amino or an alcohol
  • the compound can be acylated using one or more molar equivalents of suitable acylating agent.
  • the acylating agent is generally a lower alkyl or aryl carboxylic acid anhydride or a lower alkyl 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.
  • R 7 or R 8 is an alcohol it can be acylated with a lower alkyl or aryl carboxylic acid anhydride in the presence of magnesium iodide in diethyl ether at ambient temperature to reflux.
  • R 7 or R 8 When R 7 or R 8 is a nitrile it can be reduced to the aminoalkyl compound by tin (II) chloride in refluxing ethyl acetate or by catalytic hydrogenation in the presence of a catalyst such as Raney nickel or by lithium aluminum hydride in an inert solvent such as ether.
  • a catalyst such as Raney nickel or by lithium aluminum hydride in an inert solvent such as ether.
  • R 7 or R 8 When R 7 or R 8 is a nitrile it can be converted to a carboxylic acid amide using standard conditions such as HCl/H 2 O at ambient temperatures to reflux or a milder procedure involves the reaction of the nitrile with an alkaline solution of hydrogen peroxide.
  • R 7 or R 8 When R 7 or R 8 is halogen or trifluoromethanesulfonate it can be converted to a 3-hydroxy-cyclobut-3-ene-4-yl-l,2-dione by methodology of Liebeskind et. al. (I. Org. Chem. 1990, 55, 5359).
  • R 7 or R 8 When R 7 or R 8 is an alcohol can be alkylated with a suitable alkylating agent such as one or more molar equivalents of alkyl halide in the presence a base such as potassium carbonate or sodium hydroxide in a suitable solvent such as THF, DMF or DMSO at temperatures ranging from 0°C to 60°C.
  • a suitable alkylating agent such as one or more molar equivalents of alkyl halide in the presence a base such as potassium carbonate or sodium hydroxide in a suitable solvent such as THF, DMF or DMSO at temperatures ranging from 0°C to 60°C.
  • R 3 or R 4 is a carboxylic acid
  • the compound can be coupled to tetronic acid with a coupling reagent such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide in the presence of a base such as triethylamine or DMAP in a suitable solvent such as DMF.
  • a coupling reagent such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide
  • a base such as triethylamine or DMAP
  • suitable solvent such as DMF
  • the phenols and amines of formula (VI: X NH 2 , OH, -CH 2 NH 2 ) can be alkylated with one or more molar equivalents of a haloalkylaryl or haloalkylheteroaryl of formula (VIII) and with one or more molar equivalents of an alkali metal carbonate such as potassium carbonate in a polar aprotic solvent such as DMF to afford the alkylated product of formula (I).
  • the other co-reagents necessary to effect the Mitsunobu Reaction include one or more molar equivalents of a lower alkyl 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.
  • a lower alkyl 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 starting hydroxyalkylaryl or hydroxyalkylheteroaryl of formula (IX) is commercially available or can be prepared by standard synthetic methods.
  • an aryl or heteroaryl carboxylic acid or ester can be reduced to the respective primary alcohol analog using standard conditions such as lithium aluminum hydride in ethyl ether.
  • An aryl or heteroaryl aldehyde or ketone can be reduced to the respective primary alcohol analog using a metal catalyst, by sodium in alcohol, sodium borohydride and by lithium aluminum hydride.
  • the starting haloalkylaryl or haloalkylheteroaryl of formula (VIII) is commercially available or can be prepared by standard synthetic methods.
  • a hydroxyalkylaryl or hydroxyalkylheteroaryl of formula (IX) can be converted to the halo derivative with reagents such as thionyl chloride, phosphorous trihalides, triphenylphosphine dihalides or triphenylphosphine in the presence of carbon tetrachloride.
  • the starting haloalkylaryl or haloalkylheteroaryl can be prepared by bromination of a alkylaryl or alkylheteroaryl with N-bromosuccinimide in the presence of AIBN in a solvent such as benzene with or without ultraviolet irradiation.
  • the compounds of formula (VI: X NH 2 , OH, -CH 2 NH 2 ) can be acylated on the phenolic oxygen or on the amino group using one or more molar equivalents of suitable acylating agent to provide the compounds of formula (I).
  • the acylating agent is generally a aryl carboxylic acid anhydride or a aryl/heteroaryl carboxylic acid chloride. The reaction is run under standard conditions, for example the use of pyridine as solvent with or without a co-solvent such as dichloromethane at 0°C to room temperature.
  • the triflate (X) can be converted to the carbonitrile (XI) with potassium cyanide or zinc cyanide in the presence of tetrakistriphenylphosphinenickel(O) which can be generated in situ from bistriphenylphosphinenickel (II) bromide and Zn/PPh 3 .
  • the monoiodophenol (VI: R 1 or R 2 is I; X is -OH) can be prepared from the phenol of formula (VI: R 1 or R 2 is H; X is -OH) 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
  • a alcohol solvent such as methanol
  • Either the monoiodophenol (VI: R 2 is I; X is -OH) or the diiodophenol (VI: R 1 and R 2 is I; X is -OH) can be converted to the respective methyl ether derivatives of formula (VI: R 2 is I; X is -OMe) or (VI: R 1 and R 2 is I; X is -OMe) by reacting the phenol moiety with a suitable methylating agent such as one or more molar equivalents of methyl iodide or dimethylsulfate employing a base such an alkali methyl carbonate or hydroxide such as potassium carbonate or sodium hydroxide in a suitable solvent such as THF, DMF or DMSO.
  • a suitable methylating agent such as one or more molar equivalents of methyl iodide or dimethylsulfate
  • a base such an alkali methyl carbonate or hydroxide such as potassium carbonate or sodium hydroxide in a suitable solvent such
  • the reaction is generally performed at temperatures ranging from 0°C to 60°C.
  • the mono or dibrominated derivatives of formula (VI: R 1 and/or R 2 is Br; X is -OMe) can be prepared in analogs fashion by substituting bromine for iodine in the sequence above.
  • the monoiodo methylether derivative of formula (VI: R 2 is I; X is -OMe) or the diiodo methylether of formula (VI: R 1 and R 2 is I; X is -OMe) 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 (VI: R 2 is -CN; X is -OMe) or the dicyanomethyl ether of formula (VI: R 1 and R 2 is -CN; X is -OMe).
  • the cyanation reaction is generally performed at temperatures ranging from 100°C to 250°C employing polar aprotic solvents such as DMF, l-methyl-2-pyrrolidinone or HMPA. Quinoline or pyridine can also be used.
  • the mono or dicyano methoxy analogs of formula (VI: R 1 and/or R 2 is -CN; X is -OMe); can be converted to the corresponding mono or dicyano phenol analogs of formula (VI: R 1 and/or R 2 is -CN; X is -OH) using standard demethylation procedures including one or more molar equivalents of boron tribromide or boron trichloride in dichloromethane at -78°C to room temperature.
  • the mono or diiodo methylether derivative of formula (VI: R 1 and/or R 2 is I; X is -OMe) can be reacted with an arylboronic acid or heteroarylboronic acid to afford the product of formula (VI: R 1 and/or R 2 is aryl or heteroaryl; X is -OMe) under the conditions of the Suzuki Reaction ( ournal of the Chemical Society Chemical Communications 1979 886 and Synthetic Communications 1981 11(7) 513).
  • the other co-reagents necessary to effect the Suzuki Reaction include one or more molar equivalents of a metal catalyst such as tetrakis(triphenylphosphine)palladium or palladium (II) acetate and a base such as barium hydroxide octahydrate or sodium carbonate in a solvent such as benzene, toluene or DME/H 2 O.
  • a metal catalyst such as tetrakis(triphenylphosphine)palladium or palladium (II) acetate
  • a base such as barium hydroxide octahydrate or sodium carbonate
  • a solvent such as benzene, toluene or DME/H 2 O.
  • the starting aryl or heteroaryl boronic acids are commercially available or can be prepared by standard synthetic methods.
  • the mono or diaryl or mono or diheteroaryl methoxy analogs of formula (VI: R 1 and/or R 2 is aryl or heteroaryl; X is -OMe) can be converted to the corresponding mono or diaryl or mono or diheteroaryl phenol analogs of formula (VI: R 1 and/or R 2 is aryl or heteroaryl; X is OH) using standard demethylation procedures including one or more molar equivalents of boron tribromide or boron trichloride in dichloromethane at -78°C to room temperature.
  • the acylating agent is generally a lower alkyl or aryl carboxylic acid anhydride or a lower alkyl 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.
  • 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 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.
  • 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 HCl or sulfuric acid in water with or without a co-solvent such as THF at temperatures ranging from room temperature to 80°C.
  • a mineral acid such as HCl or sulfuric acid
  • a co-solvent such as THF
  • the sulfonylating (R') agent is generally a lower alkyl or aryl sulfonic acid anhydride or a lower alkyl 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.
  • 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.
  • a sodium perfluorocarboxylate RCO 2 Na: R is perfluoroalkyl
  • copper (I) iodide in a high boiling inert solvent such as DMF, DMA or 1- methyl-2-pyrrolidinone at temperatures ranging from 140°C to 200°C.
  • a high boiling inert solvent such as DMF, DMA or 1- methyl-2-pyrrolidinone
  • 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.
  • R 5 alkylsulfanyl, arylsulfanyl
  • R 5 alkylsulfanyl, arylsulfanyl
  • a suitable methylating agent such as one or more molar equivalents of methyl iodide or dimethylsulfate
  • a base such an alkali methyl carbonate or hydroxide such as potassium carbonate or sodium hydroxide
  • a suitable solvent such as THF, DMF or DMSO.
  • the other co-reagents necessary to effect the Suzuki Reaction include one or more molar equivalents of a metal catalyst such as tetrakis(triphenylphosphine)palladium or palladium (II) acetate and a base such as barium hydroxide octahydrate or sodium carbonate in a solvent such as benzene, toluene or DME/H 2 O.
  • a metal catalyst such as tetrakis(triphenylphosphine)palladium or palladium (II) acetate
  • a base such as barium hydroxide octahydrate or sodium carbonate
  • a solvent such as benzene, toluene or DME/H 2 O.
  • the starting aryl or heteroaryl boronic acids are commercially available or can be prepared by standard synthetic methods.
  • the acetates of formula (VI: X is O-acyl; R 3 and R 4 are alkyl) 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 (VI: X is O-acyl; R 3 and/or R 4 are haloalkyl).
  • This reaction is conveniently done in a suitable solvent such as dichloromethane or carbontetrachloride at temperatures ranging from 0°C to room temperature.
  • halo acetates of formula (VI: X is O-acyl; R 3 and/or R 4 are haloalkyl
  • nucleophiles such as amines (NHR"R'") (wherein R" and R'" is H, lower alkyl) in a suitable solvent such as THF, DMF or dichloromethane to provide the compounds of formula (VI: X is O-acyl; R 3 and/or R 4 are aminoalkyl).
  • the compounds of formula (VI: X is O-acyl; R 3 and/or R 4 are aminoalkyl) can be deacylated to produce the compounds of formula (VI: X is OH; R 3 and/or R 4 are aminoalkyl).
  • 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 HCl or sulfuric acid in water with or without a co-solvent such as THF at temperatures ranging from room temperature to 80°C.
  • a mineral acid such as HCl or sulfuric acid
  • a co-solvent such as THF
  • All the compounds prepared in Scheme 8 of formula (VI: R 3 and/or R 4 are aminoalkyl, haloalkyl) can be utilized in other schemes to prepared compounds of formula (I).
  • All the compounds prepared in Scheme 8 of formula (VI: R 3 and/or R 4 are aminoalkyl, haloalkyl) can be utilized and further modified synthetically in Schemes 4, 5, 6 and 7.
  • 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 recombinant rat protein tyrosine phosphatase, PTPIB, activity using, as substrate, the phosphotyrosyl dodecapeptide corresponding to the 1142-1153 insulin receptor kinase domain, phosphorylated on the 1146, 1150 and 1151 tyrosine residues.
  • the procedure used and results obtained are briefly described below.
  • Human recombinant PTPIB was prepared as described by Goldstein (see
  • the enzyme preparation used was in microtubes containing 500-700 ⁇ g/ml protein in 33 mM Tris-HCl, 2 mM EDTA, 10% glycerol and 10 mM 2-mercaptoethanol.
  • the 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 PTPIB.
  • the test procedure uses, as substrate, a dodecaphosphopeptide custom synthesized by AnaSpec, Inc. (San Jose, CA).
  • the peptide, TRDIYETDYYRK corresponding to the 1142-1153 catalytic domain of the insulin receptor, is tyrosine phosphorylated on the 1146, 1150, and 1151 tyrosine residues.
  • the recombinant rPTPlB is diluted with buffer (pH 7.4, containing 33 mM Tris-HCl, 2 mM EDTA and 50 mM b-mercaptoethanol) to obtain an approximate activity of 1000- 2000 nmoles/min/mg protein.
  • the diluted enzyme (83.25 mL) is preincubated for 10 min at 37°C with or without test compound (6.25 mL) and 305.5 mL of the 81.83 mM HEPES reaction buffer, pH 7.4 peptide substrate, 10.5 ml at a final concentration of 50 mM, and is equilibrated to 37°C. in a LABLINE Multi-Blok heater equipped with a titerplate adapter.
  • the preincubated recombinant enzyme preparation (39.5 ml) with or without drug is added to initiate the dephosphorylation reaction, which proceeds at 37°C for 30 min.
  • the reaction is terminated by the addition of 200 mL of the malachite green-ammonium molybdate-Tween 20 stopping reagent (MG/AM/Tw).
  • the stopping reagent consists of 3 parts 0.45% malachite green hydrochloride, 1 part 4.2% ammonium molybdate tetrahydrate in 4 N HCl 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.
  • representative compounds of this invention have been shown to inhibit PTPase activity 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 ⁇ 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.
  • 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 hmited 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
  • Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s).
  • Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin.
  • Water soluble suppository bases such as polyethylene glycols of various molecular weights, may also be used.
  • the dosage, regimen and mode of administration of these compounds will vary according to the malady and the individual being treated and will be subject to the judgment of the medical practitioner involved. It is preferred that the administration of one or more of the compounds herein begin at a low dose and be increased until the desired effects are achieved.
  • Step 4 (2-Benzyl-4,5-dimethylthiophen-3-yl -(4-methoxy-3-isopropyl-pheny - methanone
  • Step 5 4-(2.3-dimethyl-naphthor2.3-blthiophen-4-y -2-isopropyl -phenol
  • Step 7 Acetic acid 2-isopropyl-4-(9-bromo-2.3-dimethyl-naphthor2.3-blthiophen-4- ylVphenyl ester
  • Step 8 4-(9-Bromo-2.3-dimethyl-naphtho[2.3-blthiophen-4-yl)-2-isopropyl-phenol
  • Step 9 4-r4-(9-Bromo-2.3-dimethyl-naphthol2.3-blthiophen-4-ylV2-isopropyl- phenoxysulfonyll-2-hydroxy-benzoic acid
  • Step 1 (2-Benzyl-4.5-dimethyl-thiophen-3-yl)-(4-methoxy-3.5-dimethyl-phenyD- methanone
  • Step 3 Acetic acid 4-(2.3-dimethyl-naphtho[2,3-b1thiophen-4-yl)-2,6-dimethyl-phenyl ester
  • the title compound was prepared according to the procedure in Example 1 , step
  • the title compound was prepared according to the procedure in Example 1 , step 8 using acetic acid 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6- dimethyl-phenyl ester (6.5 g, 14.3 mmol) and IN potassium hydroxide (17.2 mL, 17.2 mmol) in tetrahydrofura methanol (320 mL, 3:1). Purification on silica gel eluting with a 3 & 5% EtOAc/pet ether step gradient gave 5.5 g (93%) of the title compound as a white foamy solid.
  • Step 6 4-r4-(9-Bromo-2.3-dimethyl-naphthor2.3-blthiophen-4-vn-2.6-dimethyl- phenoxy sulf onyl] -2-hydroxy-benzoic acid
  • the title compound was prepared according to the procedure in Example 1, step
  • Step 2 2-Cvclopentyl-4-(2.3-dimethyl-naphthor2.3-blthiophen-4-ylVphenol The title compound was prepared according to the procedure in Example 1, step
  • Step 4 Acetic acid 2-cyclopentyl-4-(9-bromo-2.3-dimethyl-naphtho[2.3-b]thiophen-4- ylVphenyl ester
  • the title compound was prepared according to the procedure in Example 1, step
  • Step 5 4-(9-Bromo-2.3-dimethyl-naphthor2.3-blthiophen-4-yl)-2-cyclopentyl-phenol
  • the title compound was prepared according to the procedure in Example 1 , step
  • Step 6 4-r4-(9-Bromo-2.3-dimethv1-na ⁇ hthol2.3-b1thiophen-4-ylV2-cvclopentyl- phenoxysulfonyl]-2-hydroxy-benzoic acid
  • Step 1 (2-Benzyl-4.5-dimethyl-thiophen-3-yl)-(3.5-diisopropyl-4-methoxy-phenyl ' )- methanone
  • the title compound was prepared according to the procedure in Example 1, step 4, using 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- benzylthiophene (4.3 g, 21.2 mmol), tin(IV) chloride (5.0 mL, 42.7 mmol), and anhydrous methylene chloride (82 mL) to give 4.1 g (45%) of the title compound.
  • 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- benzylthiophene 4.3 g
  • Step 4 Acetic acid 4-(9-bromo-2.3-dimethyl-naphtho 2.3-blthiophen-4-y -2.6- diisopropyl-phenyl ester
  • the title compound was prepared according to the procedure in Example 1, step
  • Step 5 4-(9-Bromo-2.3-dimethyl-naphtho 2.3-blthiophen-4-yl ' )-2.6-diisopropyl- phenol
  • the title compound was prepared according to the procedure in Example 1 , step
  • Step 6 4-[4-(9-Bromo-2.3-dimethyl-naphthor2.3-blthiophen-4-yl)-2.6-diisopropyl- phenoxysulfonyn-2-hydroxy-benzoic acid
  • the title compound was prepared according to the procedure in Example 5, using 4-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phen- oxysulfonyl]-2-hydroxy-benzoic acid (0.300 g, 0.491 mmol), propionic anhydride (1.80 mL) and magnesium iodide (0.137 g, 0.491 mmol). Purification on 2% H 3 PO 4 /MeOH treated silica gel, eluting with 20% EtOAc/pet.
  • the title compound was prepared according to the procedure in Example 1 , step 9, using 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl- ⁇ henol (0.933 g, 2.07 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (1.47 g, 6.20 mmol). Purification on 2% H 3 PO 4 /MeOH treated silica gel eluting with a 0 & 10% EtOAc/hexane step gradient gave 0.66 g (56%) of the title compound as a pale yellow solid, mp 230 - 237°C.
  • the title compound was prepared according to the procedure in Example 1 , step 4 using 3-cyclopentyl-4-methoxy-benzoic acid (10.00 g, 45.4 mmol, RN-59216-82-9), oxalyl chloride (4.4 mL, 50.4 mmol), N,N-DMF (5 drops), tin(IV) chloride (5.8 mL, 49.7 mmol) and 2-benzyl-4,5-dimethylfuran (10.1 g, 54.3 mmol) in CH 2 C1 2 . The final organic extracts were concentrated to give 18.8 g of the title compound, synthetically pure. ⁇ NMR: consistent.
  • Step 5 3-Bromo-5-ethyl-4-methoxybenzoic acid
  • 2-bromo-4-(2- chlorobenzoyl)-6-ethylanisole (10.0 g, 28.2 mmol)
  • potassium t-butoxide (31.7 g
  • Step 7 2-Bromo-4-(2.3-dimethyl-naphthor2.3-b1furan-4-ylV6-ethyl-phenol The title compound was prepared according to the procedure in Example 1, step
  • Step 8 4-r2-Bromo-4-(2.3-dimethyl-naphthor2.3-blfuran-4-ylV6-ethyl- phenoxy sulfony 11 -2-hydroxy-benzoic acid
  • Step 6 4-r4-(2.3-Dimethyl-naphthol2.3-blfuran-4-ylV2.6-diethyl-phenoxysulfonyll-2- hydroxy-benzoic acid
  • Step 2 2-(4-Methoxy-benzovDoxy-4-r4-(9-bromo-2.3-dimethyl-naphthor2.3-bl- thiophen-4-ylV2.6-dimethyl-phenoxysulfonyll-benzoic acid
  • the tide compound was prepared according to the procedure in Example 10, step 1, using 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenol (0.604 g, 1.67 mmol), 60% sodium hydride/mineral oil (0.0669 g, 1.67 mmol) and 3- methoxy-4-(methoxycarbonyl)thiophene-2-sulphonylchloride (0.499 g, 1.84 mmol) to give 0.629 g (63%) of the title compound.
  • ⁇ NMR (DMSO-d6) ⁇ 1.10 (t, 6 H), 1.59
  • the tide compound was prepared according to the procedure in Example 10, step 1, using 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenol (0.300 g, 0.805 mmol), 60% sodium hydride/mineral oil (0.032 g, 0.805 mmol) and commercial 5-(pyrid-2-yl)thiophene-2-sulphonyl chloride (0.243 g, 0.935 mmol).
  • Purification on Biotage KP-Sil eluting with a 5 & 10% EtOAc/pet. ether step gradient gave 0.10 g (21%) of the title compound as a white solid, mp 141 - 142°C.
  • ⁇ NMR (DMSO-d6) ⁇ 1.29 - 1.38 (m, 2 H), 1.46 - 1.68 (m, 8 H), 1.82 - 1.85 (m, 1 H), 2.35
  • the tide compound was prepared according to the procedure in Example 5, using 5-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxysulfonyl]- 4-hydroxy-thiophene-3-carboxylic acid (0.288 g, 0.508 mmol), benzoic anhydride
  • the tide compound was prepared according to the procedure in Example 10, step 1, using 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenol (0.300 g, 0.805 mmol), 60% sodium hydride/mineral oil (0.032 g, 0.805 mmol) and commercial 5-[2-(methylthio)pyrimidin-4-yl]thiophene-2-sulphonyl chloride (0.272 g, 0.886 mmol). Purification on Biotage KP-Sil eluting with 25% EtOAc/pet. ether gave 0.299 g (58%) of the tide compound as a yellow solid, mp 100 - 110°C. ⁇ NMR (DMSO-d6) ⁇ 1.32 - 1.37 (m, 2 H), 1.45 - 1.65 (m, 8 H), 1.84 - 1.90 (m, 1 H), 2.37
  • Step 1 4-14-(2.3-Dimethyl-naphthor2.3-blthiophen-4-ylV2.6-dimethyl- phenoxy sulf onyll -2-hydroxy-benzoic acid
  • Step 2 4-r4-(2.3-dimethyl-naphthol2.3-blthiophen-4-vn-2.6-dimethyl- phenoxysulfonyll-2-hydroxy-benzoic acid tert-butyl ester
  • the tide compound was prepared according to the procedure in Example 16, using 4-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy- sulfonyl]-2-hydroxy-benzoic acid (0.100 g, 0.188 mmol) and t-butyl 2,2,2- trichloroacetimidate (0.0822 g, 0.375 mmol) to give 86 mg (78%) of the tide compound.
  • ⁇ NMR (DMSO-d6) ⁇ 1.58 (s, 9 H), 1.60 (s, 3 H), 2.17 (s, 6 H), 2.42
  • the tide compound was prepared according to the procedure in Example 17, step 1, using 4-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy- sulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.072 g, 0.131 mmol), pyridine (63.4 ⁇ L, 0.784 mmol) and benzoyl chloride (30.5 ⁇ L, 0.262 mmol) to give a quantitative yield of the title compound.
  • ⁇ NMR (DMSO-d6) ⁇ 1.33 (s, 9 H), 1.57
  • the tide compound was prepared according to the procedure in Example 17, step 2, using 2-benzoyloxy-4-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6- dimethyl-phenoxysulfonylj-benzoic acid tert-butyl ester to give 0.138 g of the tide compound as a white solid, mp 183 - 185°C. ⁇ NMR (DMSO-d6) ⁇ 1.55 (s, 3 H),
  • the tide compound was prepared according to the procedure in Example 17, step 1, using 4-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy- sulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.362 g, 0.615 mmol), pyridine (0.298 mL, 3.69 mmol) and 4-chlorobenzoyl chloride (0.156 mL, 1.23 mmol) to give the title compound.
  • ⁇ NMR (DMSO-d6) ⁇ 1.35 (s, 9 H), 1.57 (s, 3 H), 2.17 (s, 6
  • Step 2 2-(4-Chloro-benzovDoxy-4-r4-(2.3-dimethyl-naphthor2.3-blthiophen-4-ylV 2.6-dimethyl-phenoxysulfonyll-benzoic acid
  • the tide compound was prepared according to the procedure in Example 17, step 2, using 2-(4-chloro-benzoyl)oxy-4-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4- yl)-2,6-dimethyl-phenoxysulfonyl]-benzoic acid tert-butyl ester to give 0.282 g (68% two steps) of the title compound as a yellow solid, mp 186 - 193°C.
  • ⁇ NMR (DMSO- d6) ⁇ 1.56 (s, 3 H), 2.15 (s, 6 H), 2.32 (s, 3 H), 7.15 (s, 2 H), 7.34 - 7.37 (m, 2 H),
  • Step 1 2-(Pyrid-3-ylcarbonvnoxy-4-r4-(2.3-dimethyl-naphthor2.3-b1thiophen-4-ylV 2.6-dimethyl-phenoxysulfonyll-benzoic acid tert-butyl ester A stirred solution containing 4-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-
  • the tide compound was prepared according to the procedure in Example 17, step 2, using 2-(pyrid-3-ylcarbonyl)oxy-4-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4- yl)-2,6-dimethyl-phenoxysulfonyl]-benzoic acid tert-butyl ester (0.436 g, 0.628 mmol).
  • Purification on Biotage KP-Sil eluting with a 900:66:34, 850:100:50 & 800:133:67 (EtOAc:EtOH:H 2 O) step gradient gave 59 mg (15%) of the tide compound as a yellow solid, mp 161 - 171°C.
  • NMR (DMSO-d6) ⁇ 1.57 (s, 3 H), 2.16 (s, 6
  • the tide compound was prepared according to the procedure in Example 25, step 1, using 4-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl- phenoxysulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.500 g, 0.749 mmol), nicotinic acid (0.092 g, 0.749 mmol), 2-chloro-l -methy lpyridinium iodide (0.230 g, 0.899 mmol) and triethylamine (0.251 mL, 1.80 mmol).
  • the tide compound was prepared according to the procedure in Example 17, step 2, using 2-(pyrid-3-ylcarbonyl)oxy-4-[4-(9-bromo-2,3-dimethyl-naphtho[2,3- b]thiophen-4-yl)-2,6-dimethyl-phenoxysulfonyl]-benzoic acid tert-butyl ester (0.391 g,
  • Step 1 4-r4-(9-Bromo-2.3-dimethyl-naphthor2.3-blthiophen-4-ylV2.6-dimethyl- phenoxysulfonyll-2-phenylacetoxy-benzoic acid tert butyl ester
  • the tide compound was prepared according to the procedure in Example 17, step 1, using 4-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl- phenoxysulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.500 g, 0.691 mmol), pyridine (0.335 mL, 4.15 mmol) and phenylacetylchloride (0.183 mL, 1.38 mmol).
  • Step 2 4-r4-(9-Bromo-2.3-dimethyl-naphthor2.3-blthio ⁇ hen-4-ylV2.6-dimethyl- phenoxysulfonyll-2-phenylacetoxy-benzoic acid
  • the title compound was prepared according to the procedure in Example 17, step 2, using 4-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl- phenoxysulfonyl]-phenoxysulfonyl]-2-phenylacetoxy-benzoic acid tert butyl ester (0.272 g, 0.352 mmol).
  • Step 1 2-(4-Cyano-benzoyDoxy-4-r4-(9-bromo-2.3-dimethyl-naphthof2.3-blthiophen- 4-yl)-2.6-dimethyl-phenoxysulfonyll-benzoic acid tert-butyl ester
  • the title compound was prepared according to the procedure in Example 17, step 1, using 4-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl- phenoxysulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.400 g, 0.599 mmol), pyridine (0.291 mL, 3.59 mmol) and 4-cyanobenzoyl chloride (0.199 g, 1.20 mmol).
  • the tide compound was prepared according to the procedure in Example 17, step 2, using 2-(4-cyano-benzoyl)oxy-4-[4-(9-bromo-2,3-dimethyl-naphtho[2,3- b]thiophen-4-yl)-2,6-dimethyl-phenoxysulfonyl]-benzoic acid tert-butyl ester (0.440 g,
  • Step 1 2-(4-Methoxy-benzov oxy-4-r4-(9-bromo-2.3-dimethyl-naphthor2.3- blthiophen-4-yl)-2.6-dimethyl-phenoxysulfonyll-benzoic acid tert-butyl ester
  • the tide compound was prepared according to the procedure in Example 17, step 1, using 4-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl- phenoxysulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.500 g, 0.691 mmol), pyridine (0.335 mL, 4.15 mmol) and m-anisoyl chloride (0.194 mL, 1.38 mmol).
  • Step 2 2-(3-Methoxy-benzoyl oxy-4-14-(9-bromo-2.3-dimethyl-naphthor2.3- blthiophen-4-yiy2.6-dimethyl-phenoxysulfonyll-benzoic acid
  • the title compound was prepared according to the procedure in Example 17, step 2, using 2-(4-methoxy-benzoyl)oxy-4-[4-(9-bromo-2,3-dimethyl-naphtho[2,3- b]thiophen-4-yl)-2,6-dimethyl-phenoxysulfonyl]-benzoic acid tert-butyl ester (0.470 g, 0.595 mmol).
  • the tide compound was prepared according to the procedure in Example 25, step 1, using 4-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl- phenoxysulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.500 g, 0.691 mmol), isonicotinic acid (0.0851 g, 0.691 mmol), 2-chloro-l-methylpyridinium iodide (0.212g, 0.829 mmol) and triethylamine (0.327 mL, 2.35 mmol).
  • Step 2 Isonicotinic acid 5-[4-(9-bromo-2.3-dimethyl-naphthor2.3-blthiophen-4-ylV 2.6-dimethyl-phenoxysulfonyll-2-carboxy-phenyl ester
  • the tide compound was prepared according to the procedure in Example 17, step 2, using 2-(pyrid-4-ylcarbonyl)oxy-4-[4-(9-bromo-2,3-dimethyl-naphtho[2,3- b]thiophen-4-yl)-2,6-dimethyl-phenoxysulfonyl]-benzoic acid tert-butyl ester (0.445 g,

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Abstract

L'invention concerne des composés de la formule structurelle (I) dans laquelle R1 et R2 représentent chacun indépendamment, hydrogène, nitrile, nitro, amino, alkylamino C¿1-6?, dialkylamino comprenant 1 à 6 atomes de carbone par groupe alkyle, cycloalkyl-amino C3-8, alkyle C1-6, perfluoroalkyle C1-6, halogène, cycloalkyle C3-8, thiényle, furyle, phényle ou phényle mono-, di- ou tri-substitué par halogène, hydroxy, alkyle C1-6, perfluoroalkyle C1-6, alcoxy C1-6, ou perfluoroalcoxy C1-6; R?3 et R4¿ représentent chacun indépendamment hydrogène, alkyle C¿1-6?, perfluoroalkyle C1-6, hydroxyalkyle C1-6, aminoalkyle C1-6, acyle C2-7; R?5¿ représente hydrogène, halogène, alkyle C¿1-6?, perfluoroalkyle C1-6, nitrile, alcoxy C1-6, aryloxy, arylalcoxy C2-12, arylsulfanyle; W représente S, O ou NR?9; R9¿ représente hydrogène ou alkyle C¿1-6?, X représente O, -NR?6¿-, ou (CH¿2?)pNR?6-; R6¿ représente hydrogène, ou alkyle C¿1-6?; p vaut 1 à 4; Y représente méthylène, carbonyle, -SO2-, ou SO-; Z représente phényle, hétéroaryle ou naphtyle; R?7 et R8¿ représentent chacun indépendamment hydrogène, carboxyle, acyle C¿2-7?, hydroxyle, hydroxyalkyle C1-6, hydroxyalcanoyle C1-6, alcoxy C1-6, perfluoroalcoxy C1-6, alcoxycarbonyle C2-7, perfluoroalcoxycarbonyle C2-7, alkyle C1-6, perfluoroalkyle C1-6, aryle, aryloxy, aryloxycarbonyle, hétéroaryloxycarbonyle, arylalcoxy C6-12, héréroaryle, alcanoyloxy C1-6, perfluoroalcanoyloxy C1-6, hétéroaroyloxy, aroyloxy, tétrazolyle, mercapto, nitrile, amino, carbamoyle, aminoalkyle C1-6, -NHSO2CF3, carboxyaldéhyde, halogène, nitro, acylamino, ou pyrimidyle éventuellement substitué par mercapto, 3-hydroxy-cyclobut-3-ène-4-yl-1,2-dione, ou acide tétronique. L'invention concerne également des sels de ces composés, acceptables sur le plan pharmacologique. Ces sels et composés sont utiles dans le traitement de troubles métaboliques associés à l'insulinorésistance ou à l'hyperglycémie.
PCT/US1999/010210 1998-05-12 1999-05-10 Derives de naphto[2,3-b]heteroar-4-yle WO1999058522A1 (fr)

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AU37916/99A AU3791699A (en) 1998-05-12 1999-05-10 Naphtho{2,3-b}heteroar-4-yl derivatives
EP99920418A EP1077968A1 (fr) 1998-05-12 1999-05-10 Derives de naphto[2,3-b]heteroar-4-yle
JP2000548326A JP2002514639A (ja) 1998-05-12 1999-05-10 ナフト［２，３−ｂ］ヘテロアリー−４−イル誘導体
CA002330555A CA2330555A1 (fr) 1998-05-12 1999-05-10 Derives de naphto[2,3-b]heteroar-4-yle

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WO2004101569A1 (fr) * 2003-05-15 2004-11-25 F. Hoffmann-La Roche Ag Composes diaminopyrroloquinazoline en tant qu'inhibiteurs de proteine tyrosine phosphatases
US7141596B2 (en) 2003-10-08 2006-11-28 Incyte Corporation Inhibitors of proteins that bind phosphorylated molecules
EP1741446A2 (fr) 2000-01-21 2007-01-10 Novartis AG Combinaisons à base d'inhibiteurs de DPP-IV et d'antidiabetiques
US7163952B2 (en) 2001-12-03 2007-01-16 Japan Tobacco Inc. Azole compound and medicinal use thereof
WO2007033266A2 (fr) 2005-09-14 2007-03-22 Takeda Pharmaceutical Company Limited Administration d'inhibiteurs de dipeptidyl peptidase
US7371759B2 (en) 2003-09-25 2008-05-13 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US7420059B2 (en) 2003-11-20 2008-09-02 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
WO2011041293A1 (fr) 2009-09-30 2011-04-07 Takeda Pharmaceutical Company Limited Dérivés pyrazolo [1, 5—a] pyrimidines comme inhibiteurs de kinase 1 régulatrice de signal d'apoptose
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
WO2011097079A1 (fr) 2010-02-03 2011-08-11 Takeda Pharmaceutical Company Limited Inhibiteurs de kinase 1 régulant le signal d'apoptose
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
WO2014142364A2 (fr) 2013-03-15 2014-09-18 Mochida Pharmaceutical Co., Ltd. Compositions et méthodes de traitement de la stéatohépatite non alcoolique
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
US9126944B2 (en) 2013-02-28 2015-09-08 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
US9486433B2 (en) 2012-10-12 2016-11-08 Mochida Pharmaceuticals Co. Ltd. Compositions and methods for treating non-alcoholic steatohepatitis
CN106749169A (zh) * 2016-11-07 2017-05-31 浙江工业大学 一种Ertiprotafib的手性制备方法
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
US9828345B2 (en) 2013-02-28 2017-11-28 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US10441560B2 (en) 2013-03-15 2019-10-15 Mochida Pharmaceutical Co., Ltd. Compositions and methods for treating non-alcoholic steatohepatitis

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Publication number Priority date Publication date Assignee Title
EP1741446A2 (fr) 2000-01-21 2007-01-10 Novartis AG Combinaisons à base d'inhibiteurs de DPP-IV et d'antidiabetiques
EP1743655A1 (fr) 2000-01-21 2007-01-17 Novartis AG Combinaisons à base d'inhibiteurs de DPP-IV et d'antidiabétiques
US7163952B2 (en) 2001-12-03 2007-01-16 Japan Tobacco Inc. Azole compound and medicinal use thereof
US7226915B2 (en) 2003-05-15 2007-06-05 Hoffmann-La Roche Inc. Diaminopyrroloquinazolines compounds as protein tyrosine phosphatase inhibitors
WO2004101569A1 (fr) * 2003-05-15 2004-11-25 F. Hoffmann-La Roche Ag Composes diaminopyrroloquinazoline en tant qu'inhibiteurs de proteine tyrosine phosphatases
KR100755579B1 (ko) * 2003-05-15 2007-09-06 에프. 호프만-라 로슈 아게 단백질 티로신 포스파타제 억제제로서디아미노피롤로퀴나졸린 화합물
US7371759B2 (en) 2003-09-25 2008-05-13 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US7141596B2 (en) 2003-10-08 2006-11-28 Incyte Corporation Inhibitors of proteins that bind phosphorylated molecules
US7420059B2 (en) 2003-11-20 2008-09-02 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
WO2007033266A2 (fr) 2005-09-14 2007-03-22 Takeda Pharmaceutical Company Limited Administration d'inhibiteurs de dipeptidyl peptidase
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
WO2011041293A1 (fr) 2009-09-30 2011-04-07 Takeda Pharmaceutical Company Limited Dérivés pyrazolo [1, 5—a] pyrimidines comme inhibiteurs de kinase 1 régulatrice de signal d'apoptose
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
EP2923706A1 (fr) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de l'hypercholestérolémie
WO2011097079A1 (fr) 2010-02-03 2011-08-11 Takeda Pharmaceutical Company Limited Inhibiteurs de kinase 1 régulant le signal d'apoptose
EP3708179A1 (fr) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
EP4309673A2 (fr) 2012-03-15 2024-01-24 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
US10058528B2 (en) 2012-10-12 2018-08-28 Mochida Pharmaceutical Co., Ltd. Compositions and methods for treating non-alcoholic steatohepatitis
US9486433B2 (en) 2012-10-12 2016-11-08 Mochida Pharmaceuticals Co. Ltd. Compositions and methods for treating non-alcoholic steatohepatitis
US9126944B2 (en) 2013-02-28 2015-09-08 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9458110B2 (en) 2013-02-28 2016-10-04 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9828345B2 (en) 2013-02-28 2017-11-28 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
US9889108B2 (en) 2013-03-15 2018-02-13 Mochida Pharmaceutical Co., Ltd. Compositions and methods for treating non-alcoholic steatohepatitis
US10441560B2 (en) 2013-03-15 2019-10-15 Mochida Pharmaceutical Co., Ltd. Compositions and methods for treating non-alcoholic steatohepatitis
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014142364A2 (fr) 2013-03-15 2014-09-18 Mochida Pharmaceutical Co., Ltd. Compositions et méthodes de traitement de la stéatohépatite non alcoolique
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
CN106749169A (zh) * 2016-11-07 2017-05-31 浙江工业大学 一种Ertiprotafib的手性制备方法

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