WO2002004458A1 - Modulateurs de proteine tyrosine phosphatases (ptpases) - Google Patents

Modulateurs de proteine tyrosine phosphatases (ptpases) Download PDF

Info

Publication number
WO2002004458A1
WO2002004458A1 PCT/DK2001/000450 DK0100450W WO0204458A1 WO 2002004458 A1 WO2002004458 A1 WO 2002004458A1 DK 0100450 W DK0100450 W DK 0100450W WO 0204458 A1 WO0204458 A1 WO 0204458A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
aryl
methyl
carboxylic acid
thieno
Prior art date
Application number
PCT/DK2001/000450
Other languages
English (en)
Inventor
Thomas Kruse Hansen
Jesper Lau
Niels Peter Hundahl Møller
Ole Hvilsted Olsen
Frank Urban Axe
Farid Bakir
Yu Ge
Daniel Dale Holsworth
Luke Milburn Judge
Michael James Newman
Roy Teruyuki Uyeda
Barry Zvi Shapira
Henrik Sune Andersen
Original Assignee
Novo Nordisk A/S
Ontogen Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novo Nordisk A/S, Ontogen Corporation filed Critical Novo Nordisk A/S
Priority to AU2001268951A priority Critical patent/AU2001268951A1/en
Publication of WO2002004458A1 publication Critical patent/WO2002004458A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel thienopyridines, to methods for their preparation, to compositions comprising the compounds, to the use of these compounds as medicaments and their use in therapy, where such compounds of Formula 1 are pharmacologically useful inhibitors or modulators of Protein Tyrosine Phosphatases (PTPases) including PTP1 B and T cell PTP (TC-PTP),
  • PTPases Protein Tyrosine Phosphatases
  • TC-PTP T cell PTP
  • PTPases play a major role in the modulation and regulation of fundamental cellular signaling mechanisms involved in metabolism, growth, proliferation and differentiation (Fischer et al, Science 253:401-6 (1991); Tonks and Neel, Cell 87: 365-368 (1996); Neel and Tonks, Current Opinion in Cell Biology 9: 193-204 (1997); Hunter, Phil. Trans. R. Soc. Lond. B 353: 583- 605 (1998); Zhang, Critical Reviews in Biochemistry and Molecular Biology 33:1- 52 (1998)).
  • PTPase inhibitors may help treat or manage certain types of diseases such as type 1 and type 2 diabetes, obesity, autoimmune diseases, acute and chronic inflammation, osteoporosis and various forms of cancer.
  • certain infectious diseases may also be treated or managed by administration PTPase inhibitors (Clemens et al. , Molecular Microbiology 5: 2617-2620 (1991 )).
  • Protein phosphorylation is now well recognized as an important mechanism utilized by cells to transduce and regulate signals during different stages of cellular function (Hunter, vide supra; Chan et al., Annu. Rev. Immunol. 12: 555- 592 (1994); Zhang, Curr. Top. Cell. Reg. 35: 21-68 (1997); Matozaki and Kasuga, Cell. Signal. 8: 113-19 (1996); Fischer et al, vide supra).
  • the level of tyrosine phosphorylation is balanced by the opposing action of protein tyrosine kinases and protein tyrosine phosphatases (PTPases).
  • phosphatases There are at least two major classes of phosphatases: (1) those that dephosphorylate proteins (or peptides) that contain a phosphate group(s) on a serine or threonine moiety (termed Ser/Thr phosphatases) and (2) those that remove a phosphate group(s) from the amino acid tyrosine (termed protein tyrosine phosphatases or PTPases or PTPs).
  • the PTPases are a family of enzymes that can be classified into two groups: a) intracellular or nontransmembrane PTPases and b) receptor-type or transmembrane PTPases.
  • dual-specificity phosphatases and low molecular weight phosphatases can also dephosphorylate phosphotyrosyl proteins (WO97/39748, WO97/40017, WO99/15529, WO97/08934, WO98/27065, WO99/46236, WO99/46244, WO99/46267, WO99/46268, WO99/46237).
  • PTPases play a major role in the above modulation and regulation of fundamental cellular signaling mechanisms involved in metabolism, growth, proliferation and differentiation (Fischer et al, Science 253:401-6 (1991); Tonks and Neel, Ce// 87: 365-368 (1996); Neel and Tonks, Current Opinion in Cell Biology 9: 193-204 (1997); Hunter, Phil. Trans. R. Soc. Lond. B 353: 583-605 (1998); Zhang, Critical Reviews in Biochemistry and
  • PTPases can act both as positive and negative regulators of signal transduction processes.
  • PTPases have been implicated in a variety of human diseases, including type 1 and type 2 diabetes, obesity, autoimmune diseases, acute and chronic inflammation, osteoporosis, proliferative disorders including various forms of cancer, growth disorders, and defective platelet aggregation (WO97/39748, WO97/40017, WO99/15529, WO97/08934, WO98/27065, WO99/46236, WO99/46244, WO99/46267, WO99/46268, WO99/46237).
  • Both selective PTPase inhibitors and inhibitors that bind to several PTPases can be used therapeutically to partially or completely restore PTPase-mediated perturbed signal transduction processes and thus for management, treatment or prevention of the above diseases.
  • WO 99/46267 discloses compounds, which are pharmacologically useful inhibitors of PTPases.
  • the present invention which represents a novel selection under WO 99/46267, discloses a class of compounds, which surprisingly are more potent against protein tyrosine phosphatases (e.g. PTP1B) than those disclosed in WO 99/46267.
  • the present invention relates to compounds of the Formula 1 wherein X, R ⁇ R 2 , R 3 , and R are defined below;
  • X is -C(O)- or -S(O) 2 -;
  • R ! and R 2 are independently hydrogen, C C 6 alkyl, aryl-R 5 -, R 6 -C(O)-O-R 7 - or aryl-R 8 -C(O)-O-R 9 - wherein aryl is phenyl, naphthyl or thiophenyl, which aryl group is optionally substituted with halogen, nitro, trihalomethyl, C C ⁇ alkyl or C C 6 alkyloxy;
  • R 3 is hydrogen, C Cealkyl, H 2 N-R 37 -, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, aryl-R ⁇ 0 -, aryl-N(R35)-, aryl-R 11 -N(R 36 )- , C C 6 alkyloxy or aryl-R 13 -O- where
  • R 4 is hydrogen, C C 6 alkyl, aryl-R 26 -, R 27 -O-C(O)-, aryl-R 28 -O-C(O)-, R 29 -C(O)-O- R 30 -O-C(O)- or aryl-R 3 C(O)-O-R 32 -O-C(O)- wherein aryl is phenyl, naphthyl or thiophenyl, which aryl group is optionally substituted with halogen, nitro, cyano, trihalomethyl, aryl, aryl-R 33 -, C C 6 aIkyloxy or aryl-R 34 -O- and wherein aryl group is phenyl, naphthyl or thiophenyl; and wherein R5, R 7 , R 8 , Rg, R10, Rn, R ⁇ 3> R ⁇ 4 , R15.
  • R 2 3 > R 2 ⁇ .
  • R3i > R3 2 .
  • R 25 , R 27 and R 29 independently are C 1-6 alkyl and wherein R 6 , R ⁇ 9 , R 2 ⁇ , R 24 , R 35 ,
  • R 36 and R 38 independently are hydrogen or C 1-6 alkyl; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any f tautomeric form.
  • the compounds of the invention can be further modified to act as prodrugs.
  • a preferred prodrug is acetoxymethyl esters or acetoxymethyl carbamates of the compounds of the present invention.
  • acetoxymethyl esters or acetoxymethyl carbamates of the compounds of the present invention As a general procedure preparation of an acetoxymethyl ester is given below (C.Schultz et al, The Journal of Biological Chemistry, 1993, 268, 6316-6322.;.-
  • attachment or "-" signifies a stable covalent bond, certain preferred points of attachment points being apparent to those skilled in the art.
  • halogen and halo includes fluorine, chlorine, bromine, and iodine.
  • alkyl includes C ⁇ Ce straight chain saturated, C C 6 branched chain saturated and C 3 -C 6 cyclic saturated hydrocarbon groups.
  • this definition shall include but is not limited to methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, isopropyl (i-Pr), isobutyl (i-Bu), fe/f-butyl (t- u), sec-butyl
  • alkenyl includes C 2 -C 6 unsaturated aliphatic hydrocarbon groups and
  • C 2 -C 6 branched unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms and at lest one double bond.
  • this definition shall include but is not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, isopentenyl, neopentenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.
  • alkynyl includes C 2 -C 6 straight chain unsaturated aliphatic, C 2 -C 6 branched unsaturated and cyclic C 6 unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms and at lest one triple bond.
  • this definition shall include but is not limited to acetynyl, propynyl, butynyl, pentynyl, hexynyl, cyclohexynyl and the like.
  • alkyloxy (e.g. methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy) represents an "alkyl” group as defined above having the indicated number of carbon atoms attached through an oxygen bridge.
  • aryloxy e.g. phenoxy, naphthyloxy and the like
  • aryloxy represents an aryl group as defined below attached through an oxygen bridge.
  • aryl represents an unsubstituted, mono-, di- or trisubstituted monocyclic, polycyclic, biaryl or heterocyclic aromatic group(s) covalently attached at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art (e.g., 3- indolyl, 4(5)-imidazolyl).
  • aryl includes phenyl, biphenyl, indenyl, naphthyl (1 -naphthyl, 2- naphthyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1 ,2,3-triazoM-yl, 1 ,2,3-triazol-2-yl 1 ,2,3-triazol-4-yl, 1 ,2,4-triazol-3-yl), thiophenyl (2-thiophenyl, 3-thiophenyl, 4-thiophenyl, 5-thiophenyl), pyridyl (2- pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl,
  • modified compounds which are not intended in any way to limit the scope of the invention, are compounds that have been, cyclized at specific positions - so called 'cyclic compounds' - which upon uptake in cells or mammals become hydrolyzed at the same specific position(s) in the molecule to yield the compounds of the invention, the original compounds, which are then said to be 'non-cyclic'.
  • the latter original compounds in most cases will contain other cyclic or heterocyclic structures that will not be hydrolyzed after uptake in cells or mammals.
  • said modified compounds may not show behavior in biochemical assays similar to that of the original compound, i.e. the corresponding compounds of the invention without the attached chemical groups or said modifications.
  • Said modified compounds may even be inactive in biochemical assays. However, after uptake in cells or mammals these attached chemical groups of the modified compounds may in turn be removed spontaneously or by endogenous enzymes or enzyme systems to yield compounds of the invention, original compounds. 'Uptake' is defined as any process that will lead to a substantial concentration of the compound inside cells or in mammals. After uptake in cells or mammals and after removal of said attached chemical group or hydrolysis of said cyclic compound, the compounds may have the same structure as the original compounds and thereby regain their activity and hence become active in cells and/or in vivo after uptake.
  • the term 'a functional group which can be converted to hydrogen in vivo' is intended to include any group which upon administering the present compounds to the subjects in need thereof can be converted to hydrogen e.g. enzymatically or by the acidic environment in the stomach.
  • the compounds of the present invention have asymmetric centres and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms being included in the present invention as well as mixtures thereof.
  • salts of the compounds of Formula 1 where a basic or acidic group is present in the structure, are also included within the scope of this invention.
  • an acidic substituent such as -COOH, 5- tetrazolyl or -P(O)(OH) 2 ⁇ there can be formed the ammonium, morpholinium, sodium, potassium, barium, calcium salt, and the like, for use as the dosage form.
  • an acidic salt such as hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacetate, acetate, oxalate, maleate, pyruvate, malonate, succinate, citrate, tartarate, fumarate, mandelate, benzoate, cinnamate, ethanesulfonate, ethane sulfonate, picrate and the like, and include acids related to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) and incorporated herein by reference, can be used as the dosage form.
  • an acidic salt such as hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacetate, acetate, oxalate, maleate, pyruvate, malonate, succinate, citrate, tartarate, fumarate, mandelate, benzoate, cinnamate,
  • esters can be employed, e.g., methyl, tert-butyl, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.
  • terapéuticaally effective amount shall mean that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other.
  • the present invention is concerned with compounds of Formula 1
  • Ri and R 2 are independently hydrogen, d-C 6 alkyl, aryl-R 5 -, R 6 -C(O)-O-R 7 - or aryl-R 8 -C(O)-O-R 9 - wherein aryl is phenyl, naphthyl, thiophenyl, which aryl group is optionally substituted with halogen, trihalomethyl, aryl, aryl- , Rio-, C C 6 alkyloxy or aryl-R ⁇ O-;
  • R 3 is CrC 6 alkyl, H 2 N-R 35 -, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl-R ⁇ 2 -, aryl, aryl-R 13 -, aryl-N(R ⁇ 4 )-, aryl-R 5 -N(R 16 )-, R 38 -aryl-, C C 6 alkyloxy or aryl-R ⁇
  • R 2 o, R 22 , R 2 3, R 24 , R 2 5, R 2 6, and R 35 independently are d-C ⁇ -alkylene, wherein R ⁇ 2 is alkenylene, wherein R 6 , R 2 ⁇ , and R 38 independently are CrC 6 alkyl and wherein R 14 and R 16 independently are hydrogen or C ⁇ -6 alkyl;
  • More preferred compounds of the invention are compounds of Formula 1
  • X is -C(O)-
  • Ri and R 2 are independently hydrogen or C C 6 alkyl
  • R 3 is CrC 6 alkyl, H 2 N-R 18 , aryl-R 5 -, aryl, aryl-R 6 -, aryl-N(R 7 )-, aryl-R 8 -O- or R 19 - aryl- wherein aryl is phenyl, biphenyl, naphthyl, 1 ,2,3-triazolyl, thiophenyl, pyridyl, quinolyl, isoquinolyl, or indolyl, which aryl group is optionally substituted with halogen, hydroxy, CrCealkyl, aryl, aryl-R 9 -, C C 6 alkyloxy, aryloxy, aryl-R 10 -O-;
  • R 4 is hydrogen, aryl-Rn-, R ⁇ 2 -C(O)-O-R 13 -O-C(O)- or aryl-R ⁇ -C(O)-O-R 15
  • R3 is CrC 6 alkyl, H 2 N-R ⁇ 2 -, aryl, aryl-R 5 -, aryl-N(R 6 )-, aryl-R 7 -O- or R 13 -aryl-, wherein aryl is phenyl, biphenyl, naphthyl, 1 ,2,3-triazolyl, thiophenyl, pyridyl, quinolyl, isoquinolyl, or indolyl, which aryl group is optionally substituted with halogen, hydroxy, d-Cealkyl, aryl, aryl-R 8 -, CrC 6 alkyloxy, aryloxy, aryl-R 9 -O- wherein aryl is phenyl or thiophenyl, which aryl group is optionally substituted with halogen, hydroxy, nitro, cyano, trihalomethyl, aryl, aryl-R 10 -, Cr
  • any optical isomer or mixture of optical isomers including a racemic mixture, or any tautomeric form.
  • the invention relates to a compound of Formula 1
  • X is -C(O)- or -S(O) 2 -;
  • Ri and R 2 are independently hydrogen or a functional group that can be converted to hydrogen in vivo;
  • R 3 is hydrogen, CrC 6 alkyl, H 2 N-R 35 -, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, aryl-R ⁇ 0 -, aryl-N(R 35 )-, aryl-Rn-N(R 36 )- , d-C 6 alkyloxy or aryl-R 13 -O- wherein aryl is phenyl, biphenyl, indenyl, naphthyl, imidazolyl, 1 ,2,3-triazolyl, thiophenyl, pyridyl, quinolyl, isoquinolyl, indolyl or benzimidazolyl, which aryl group is optionally substituted with halogen, nitro, cyano, hydroxy, trihalomethyl, CrC 6 alkyl, R 37 -aryl-, R 38 -, R 38 - R 14 -, CrCealky
  • R 4 is hydrogen, CrC 6 alkyl, aryl-R 26 -, R 27 -O-C(O)-, aryl-R 28 -O-C(O)-, R 29 -C(O)-O- R 30 -O-C(O)- or aryl-R 3 rC(O)-O-R 32 -O-C(O)- wherein aryl is phenyl, naphthyl or thiophenyl, which aryl group is optionally substituted with halogen, nitro, cyano, trihalomethyl, R 39 -, R 39 -R 33 -, C C 6 alkyloxy or R 39 -R 34 -O-; and wherein R5, R 7 , R 8 , R 9 , R 0, Rn, R13, R ⁇ 4 , R15, R 2 3.
  • R and R 2 are independently hydrogen, C ⁇ -C 6 alkyl, aryl- R 5 -, R 6 -C(O)-O-R 7 - or aryl-R 8 -C(O)-O-R 9 - wherein aryl is phenyl, naphthyl or thiophenyl, which aryl group is optionally substituted with halogen, nitro, trihalomethyl, CrC 6 alkyl or d-C 6 alkyloxy;
  • X is C(O).
  • X is S(O) 2 .
  • R 1 and R 2 are independently hydrogen, CrC 6 alkyl, aryl- R -, or R 6 -C(O)-O-R 7 -, wherein aryl is phenyl, naphthyl or thiophenyl, which aryl group is optionally substituted with halogen, nitro, trihalomethyl, d-C 6 alkyl or Ci- Cealkyloxy.
  • Ri and R 2 are independently hydrogen or d-Cealkyl.
  • Ri and R 2 are hydrogen.
  • R 3 is C C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, aryl- R 1 0-, CrC 6 alkyloxy, H 2 N-R 35 - or aryl-R ⁇ 3 -O- wherein aryl is phenyl, biphenyl, indenyl, naphthyl, imidazolyl, 1 ,2,3-triazolyl, thiophenyl, pyridyl, quinolyl, isoquinolyl, indolyl or benzimidazolyl, which aryl group is optionally substituted with halogen, nitro, cyano, hydroxy, trihalomethyl, CrC 6 alkyl, R 37 -aryl-, R 38 -, R 38 - Ri 4 -, CrCealkyloxy, Ras-O-, R 38 -R ⁇ 5 -O-, R3 8 -N(R ⁇ 6
  • R 3 is CrC 6 alkyl, C 2 -C 6 alkenyl, aryl, H 2 N-R 35 - or aryl-R 13 - O- wherein aryl is phenyl, biphenyl, indenyl, naphthyl, imidazolyl, 1 ,2,3-triazolyl, thiophenyl, pyridyl, quinolyl, isoquinolyl, indolyl or benzimidazolyl, which aryl , group is optionally substituted with halogen, nitro, cyano, hydroxy, trihalomethyl, CrCealkyl, R 37 -aryl-, R 38 -, R 38 -Ri4-, d-C 6 alkyloxy, R 38 -O-, R 38 -R ⁇ 5 -O-, Rs 8 -N(R ⁇ 6 )- , R ⁇ 8 -C(O)-N(R ⁇ 9 )-, R 38
  • R 3 is d-C 6 alkyl or aryl, wherein aryl is phenyl, biphenyl, . indenyl, naphthyl, imidazolyl, 1 ,2,3-triazolyl, thiophenyl, pyridyl, quinolyl, isoquinolyl, indolyl or benzimidazolyl, which aryl group is optionally substituted with halogen, nitro, cyano, hydroxy, trihalomethyl, CrC 6 alkyl, R 37 -aryl-, R 38 -, R 38 - R ⁇ 4 -, CrCealkyloxy, R 38 -O-, R 38 -R ⁇ 5 -O-, R 38 -N(R ⁇ 6 )-, R ⁇ 8 -C(O)-N(R ⁇ 9 )-, R 38 -C(O)- N(R 2 ⁇ )- or R 38 -R 23 -C(O)-N
  • R 3 is aryl, wherein aryl is phenyl, biphenyl, indenyl, naphthyl, imidazolyl, 1 ,2,3-triazolyl, thiophenyl, pyridyl, quinolyl, isoquinolyl, indolyl or benzimidazolyl, which aryl group is optionally substituted with halogen, nitro, cyano, hydroxy, trihalomethyl, CrC 6 alkyl, R 37 -aryl-, R 38 -, R ⁇ -R ⁇ -, Ci- Cealkyloxy, R 38 -O-, R 38 -Ri 5 -O-, R 38 -N(R ⁇ 6 )-, R ⁇ 8 -C(O)-N(R ⁇ 9 )-, R 38 -C(O)-N(R 2 ⁇ )- or R 38 -R 23 -C(O)-N(R 24 )-.
  • aryl is pheny
  • aryl of R 3 is phenyl, naphthyl, or indolyl.
  • aryl of R 3 is phenyl
  • the aryl of R 3 is substituted by halogen, hydroxy, d- C 6 alkyl, R 37 -aryl-, R 38 -, R 38 -R ⁇ -, CrC 6 alkyloxy, R 38 -O-, R 38 -R ⁇ 5 -O-, R ⁇ 8 -C(O)- N(R ⁇ 9 )-, or R 38 -C(O)-N(R 2 ⁇ )-.
  • the aryl of R 3 is substituted by hydroxy, CrC 6 alkyl, R 38 -, R 38 -R ⁇ -, CrCealkyloxy, R 38 -O-, R ⁇ 8 -C(O)-N(R ⁇ 9 )-, or R 38 -C(O)-N(R 2 ⁇ )-.
  • R 38 is phenyl or thiophenyl.
  • R 4 is hydrogen, CrC 6 alkyl, aryl-R 26 -, R 29 -C(O)-O-R 30 -O-, C(O)- or aryl-R 3 rC(O)-O-R 32 -O-C(O)- wherein aryl is phenyl, naphthyl or thiophenyl, which aryl group is optionally substituted with halogen, nitro, cyano, trihalomethyl, R 39 -, R 39 -R 33 -, CrCealkyloxy or R 39 -R 34 -O-.
  • R 4 is hydrogen, CrC 6 alkyl, or aryl-R 26 - wherein aryl is phenyl, naphthyl or thiophenyl, which aryl group is optionally substituted with halogen, nitro, cyano, trihalomethyl, R 39 -, R 39 -R 33 -, CrC 6 alkyloxy or R 39 -R 34 -O-.
  • R is hydrogen or aryl-R 26 - wherein aryl is phenyl, naphthyl or thiophenyl, which aryl group is optionally substituted with halogen, nitro, cyano, trihalomethyl, R 39 -, R 39 -R 33 -, CrC 6 alkyloxy or R 39 -R 34 -O-.
  • R 4 is hydrogen
  • R 4 is aryl-R 26 - wherein aryl is phenyl, naphthyl or thiophenyl, which aryl group is optionally substituted with halogen, nitro, cyano, trihalomethyl, R 39 -, R3 9 -R 33 -, d-C 6 alkyloxy or R 39 -R 3 -O-.
  • aryl of R 4 is phenyl. In another embodiment the aryl of R 4 is substituted by R ⁇ -.
  • R 39 is CrC 6 alkyloxy.
  • R 39 is methoxy
  • Another aspect of the invention is compounds according to the invention that act as inhibitors of Protein Tyrosine Phosphatases.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture; of , optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.
  • Another aspect of the invention is a pharmaceutical composition suitable for treating type 1 diabetes, type 2 diabetes, impaired glucose tolerance, insulin resistance or obesity comprising a compound of the invention or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.
  • Another aspect of the invention is a pharmaceutical composition suitable for treating immune dysfunctions including autoimmunity, diseases with dysfunctions of the coagulation system, allergic diseases, osteoporosis, proliferative disorders including cancer and psoriasis, diseases with decreased or increased synthesis or effects of growth hormone, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of/or response to growth hormone, diseases of the brain including Alzheimer's disease and schizophrenia, and infectious diseases comprising a compound of the invention or a pharmaceutical acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.
  • the composition may be in the form of an oral dosage unit or parenteral dosage unit.
  • the pharmaceutical composition may said may contain a compound of the invention such that it is administered as a dose in a range from about 0.05 to 1000 mg, preferably from about 0.1 to 500 mg and especially in the range from 50 to 200 mg per day
  • Another aspect of the invention is a compound of the invention or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable aqid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use in the treatment or , prevention of type 1 diabetes, type 2 diabetes, impaired glucose tolerance, insulin resistance or obesity.
  • Another aspect of the invention is a compound of the invention or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use in the treatment or preventing of immune dysfunctions including autoimmunity, diseases with dysfunctions of the coagulation system, allergic diseases, osteoporosis, proliferative disorders including cancer and psoriasis, diseases with decreased or increased synthesis or effects of growth hormone, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of/or response to growth hormone, diseases of the brain including Alzheimer's disease and schizophrenia, and infectious diseases.
  • immune dysfunctions including autoimmunity, diseases with dysfunctions of the coagulation system, allergic diseases, osteoporosis, proliferative disorders including cancer and psoriasis, diseases with decreased or increased synthesis or effects of growth hormone, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of/or
  • Another aspect of the invention is the use of a compound of the invention or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form as a medicament.
  • Another aspect of the invention is the use of a compound of the invention for preparing a medicament.
  • Another aspect of the invention is the use of a compound of the invention or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for the preparation of a medicament suitable for the treatment or preventing of type 1 diabetes, type 2 diabetes, impaired glucose tolerance, insulin resistance or obesity.
  • Another aspect of the invention is the use of a compound of the invention or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for the preparation of a medicament suitable for the treatment or preventing of immune dysfunctions including autoimmunity, diseases with dysfunctions of the coagulation system, allergic diseases, osteoporosis, proliferative disorders including cancer and psoriasis, diseases with decreased or increased synthesis or effects of growth hormone, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of/or response to growth hormone, diseases of the brain including Alzheimer's disease and schizophrenia, and infectious diseases.
  • immune dysfunctions including autoimmunity, diseases with dysfunctions of the coagulation system, allergic diseases, osteoporosis, proliferative disorders including cancer and psoriasis, diseases with decreased or increased synthesis or effects of growth hormone, diseases with decreased or increased synthesis of hormones or cytokines
  • Another aspect of the invention is a method of treating type 1 diabetes, type 2 diabetes, impaired glucose tolerance, insulin resistance or obesity comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • Another aspect of the invention is a method of treating immune dysfunctions including autoimmunity, diseases with dysfunctions of the coagulation system, allergic diseases, osteoporosis, proliferative disorders including cancer and psoriasis, diseases with decreased or increased synthesis or effects of growth hormone, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of/or response to growth hormone, diseases of the brain including Alzheimer's disease and schizophrenia, and infectious diseases comprising administering to a subject in need thereof an effective amount of a compound of the invention to said subject.
  • Another aspect of the invention is a process for the manufacture of a medicament, particular to be used in the treatment or prevention of type 1 diabetes, type 2 diabetes, impaired glucose tolerance, insulin resistance or obesity which process comprising bringing a compound of the invention or a pharmaceutically acceptable salt thereof into a galenic dosage form.
  • Another aspect of the invention is a process for the manufacture of a medicament, particular to be used in the treatment or prevention of immune dysfunctions including autoimmunity, diseases with dysfunctions of the coagulation system, allergic diseases, osteoporosis, proliferative disorders including cancer and psoriasis, diseases with decreased or increased synthesis or effects of growth hormone, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of/or response to growth hormone, diseases of the brain including Alzheimer's disease and schizophrenia, and infectious diseases which process comprising bringing a compound of the invention or a pharmaceutically acceptable salt thereof into a galenic dosage form.
  • Another aspect of the invention is a method for preparing a compound of formula
  • the compounds are evaluated for biological activity with a truncated form of PTP1 B (corresponding to the first 321 amino acids), which was expressed in E. coli and purified to apparent homogeneity using published procedures well- known to those skilled in the art.
  • the enzyme reactions are carried out using standard conditions essentially as described by Burke et al. (Biochemistry 35; 15989-15996 (1996)).
  • the assay conditions are as follows. Appropriate concentrations of the compounds of the invention are added to the reaction mixtures containing different concentrations of the substrate, p-nitrophenyl phosphate (range: 0.16 to 10 mM - final assay concentration).
  • the buffer used was 100 mM sodium acetate pH 5.5, 50 mM sodium chloride, 0.1 % (w/v) bovine serum albumin and 5 mM dithiothreitol (total volume 100 ml).
  • the reaction was started by addition of the enzyme and carried out in microtiter plates at 25 °C for 60 minutes. The reactions are stopped by addition of NaOH.
  • the enzyme activity was determined by measurement of the absorbance at 405 nm with appropriate corrections for absorbance at 405 nm of the compounds and p-nitrophenyl phosphate.
  • the data are analyzed using nonlinear regression fit to classical Michaelis Menten enzyme kinetic models. Inhibition is expressed as K
  • Table 1 The results of representative experiments are shown in Table 1.
  • reaction step a) in Method A gives a mixture of regioisomers which can be separated by use of column chromatography known to thus skilled in the art.
  • C(CO)- and W is -OH, -OSO 2 Me, halogen, R 4 COO- or X is -SO 2 - and W is chloride, a substituted 5-aminomethyl-tetrahydro-thieno[2,3-c]pyridine (II) to react under conditions known to thus skilled in the art which favour amide or sulfon amide bond formation followed by b) R 2 -O-C(O)-C(O)-imidazol-1-yl, tetrahydrofuran and c) 25% trifluoroacetic acid/dichloromethane; to yield (III) wherein R 1 ( R 2 , R 3 , and R 4 are defined above;
  • dosages suitable for oral administration comprise from about 0.5 mg to about 1000 mg, preferably , from about 1 mg to about 500 mg of the compounds of the invention admixed with a pharmaceutical carrier or diluent.
  • the compounds of the invention may be administered in a pharmaceutically acceptable acid addition salt form or where possible as a metal or a - ⁇ - alkylammonium salt.
  • Such salt forms exhibit approximately the same order of activity as the free acid forms.
  • compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutical carrier or diluent.
  • compositions containing the compounds of this invention may be prepared by conventional techniques and appear in conventional forms, for example capsules, tablets, solutions or suspensions.
  • the pharmaceutical carrier employed may be a conventional solid or liquid carrier.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatine, agar, pectin, acacia, magnesium stearate and stearic acid.
  • liquid carriers are syrup, peanut oil, olive oil and water.
  • the carrier or diluent may include any time delay material known to the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. If a solid carrier for oral administration is used, the preparation can be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the compounds of this invention are dispensed in unit dosage form comprising 10-200 mg of active ingredient in or together with a pharmaceutically acceptable carrier per unit dosage.
  • the dosage of the compounds according to this invention is 1-500 mg/day, e.g. about 100 mg per dose, when administered to patients, e.g. humans, as a drug.
  • a typical tablet that may be prepared by conventional tabletting techniques contains Core: Active compound (as free compound 100 mg or salt thereof)
  • the route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intranasal, intramuscular, , topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
  • oral or parenteral e.g. rectal, transdermal, subcutaneous, intranasal, intramuscular, , topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
  • a mammalian cell line which can be obtained from the American Tissue Type Collection or other similar governmental or commercial sources, is , incubated with said modified compound. After incubation at conditions well known to those skilled in the art, the cells are washed appropriately, lysed and the lysate is isolated. Appropriate controls, well known to those skilled in the art, must be included.
  • a number of different procedures may in turn be used to extract and purify said compound from said lysate. Said compound may or may not retain the attached chemical group or said cyclic compound may or may not have been hydrolyzed.
  • a number of different procedures - well known to those skilled in the art may be used to structurally and chemically characterize said purified compound. Since said purified compound has been isolated from said cell lysate and hence has been taken up by said cell line, a comparison of said structurally and chemically characterized compound with that of the original unmodified compound (i.e.
  • said purified compound may be subjected to enzyme kinetic analysis as described in detail in the present invention. If the kinetic profile is similar to that of the original compound without said attached chemical group, but different from said modified compound, this confirms that said chemical group has been removed or said cyclic compounds has been hydrolyzed. Similar techniques may be used to analyze compounds of the invention in whole animals and mammals.
  • TLC thin layer chromatography
  • CDCI 3 deuterio chloroform
  • CD 3 OD tetradeuterio methanol
  • DMSO-d 6 hexadeuterio dimethylsulfoxide.
  • H NMR shifts ( ⁇ H ) are given in parts per million (ppm) down field from tetramethylsilane as internal reference standard.
  • M.p.: is melting point and is given in °C and is not corrected. Column chromatography was carried out using the technique described by W.C. Still et al., J. Org. Chem.
  • Example 2 The title compound was prepared in a similar way as described in Example 1 using 5-methyl-2-phenyl-2A-/-[1 ,2,3]triazole-4-carboxylic acid and 2-amino-5- aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid ferf-butyl ester as the starting material.
  • the hydrogenation step in Example 1 was omitted.
  • Example 2 The title compound was prepared in a similar way as described in Example 1 using 2-hydroxy-4-ethoxybenzoic acid and 2-amino-5-aminomethyl-6-(4- methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid ferf- butyl ester as the starting material.
  • the hydrogenation step in Example 1 was omitted.
  • the title compound was prepared in a similar way as described in Example 1 using 2-hydroxy-4-ethoxybenzoic acid and 2-amino-5-aminomethyl-6-(4- methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid ferf- butyl ester as the starting material.
  • the titie compound was prepared in a similar way as described in Example 1 using 5-methyI-2-phenyl-2H-[1 ,2,3]triazole-4-carboxylic acid and 2-amino- 5- aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylic acid ferf-butyl ester as the starting material.
  • LC-MS: m/z: 485.2 [M+H] + HPLC (A1): R t 22.04 min
  • the titie compound was prepared in a similar way as described in Example 1 using 1H-indole-2-carboxylic acid and 2-amino-5-aminomethyl-6-(4-ethoxy- benzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ferf-butyl ester as the starting material.
  • the titie compound was prepared in a similar way as described in Example 1 using 3-(biphenyl-4-yl)acrylic acid and 2-amino-5-aminomethyl-6-(4-methoxy- benzyI)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid ferf-butyl ester as the starting material.
  • the titie compound was prepared in a similar way as described in Example 1 using 1-naphthyI-carboxylic acid and 2-amino-5-aminomethyl-6-(4-ethoxy- benzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ferf-butyl ester as the starting material.
  • the hydrogenation step in Example 1 was omitted.
  • the cooled reaction mixture was concentration in vacuo and the residual oil was purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (6:1) as eluent affording 474 mg (77 %) of a 1:1 mixture of 2-amino-7- (benzyloxycarbonylamino-methyl)-4,7-dihydro-5W-thieno[2,3-c]pyridine-3,6- dicarboxylic acid di-ferf-butyl ester and 2-amino-5-(benzyloxy-carbonylamino- methyl)-4,7-dihydro-5AV-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-ferf-butyl ester as a solids.
  • Salicylic acid (1.25 g, 9.05 mmol) was dissolved in anhydrous N,N-dimethyl- formamide (15 ml) and placed under nitrogen atmosphere.
  • Sodium hydride (0.76 g, 18.1 mmol) was added and the reaction stirred for 10 minutes, then benzyl bromide (4.3 ml, 36.2 mmol) was added.
  • the reaction was stirred at ambient temperature for 4 days.
  • the reaction mixture was diluted with ethyl acetate (75 ml) and washed with water (3 x 25 ml) followed by brine (15 ml).
  • the organic layer was dried (MgSO ), filtered, and the solvent evaporated in vacuo.
  • the residue was purified by silica gel chromatography affording 2.61 g (90 %) of 2- benzyloxy-benzoic acid benzyl ester as an oil.
  • the mixture was stirred overnight at room temperature.
  • the layers wee separated and the aqueous phase extracted with dichloromethane.
  • the combined organic phases were filtered through a plug of silica eluting with dichloromethane.
  • the relevant fractions were concentrated in vacuo.
  • the residue was dissolved in hot heptane and cooled. This leaves a yellowish gummy material on the side of the flask and crystals starts forming.
  • the heptane solution was heated again to dissolve crystals, leaving the gummy material on the side of the flask and the mixture was filtered hot.
  • the band consisting of a mixture of 5- and 7-isomer was collected and purified on a reverse phase (C 8 ) column using a Flash 40 system. The residue was applied in a minimum volume of acetonitrile and eluted with a mixture of 40% acetonitrile in water containing 0.1 % trifluoroacetic acid. When the first isomer (the 5-isomer) was collected the eluent was changed to 50% acetonitrile in water with 0.1% trifluoroacetic acid and the 7-isomer was collected.
  • the ⁇ -methyl benzyl protected amine was dissolved in a mixture of methanol/formic acid (9:1) (app. 10 ml/100 mg ⁇ -methyl benzyl protected amine). The solution was degassed by purging with nitrogen for 1 minute before 10% Pd/C (50% H 2 O content) was added. The reaction mixture was stirred at room temperature until TLC showed that all the starting material was consumed (typical 1-4 days). The Pd/C was filtered off using Celite and the filter cage was washed with plenty of methanol. The filtrate was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was separated, dried (MgSO 4 ) and filtered. The solvent was removed in vacuo and the crude product was purified using column chromatography (SiO 2 , and a mixture of ethyl acetate/methanol as eluent).
  • the ⁇ -methyl benzyl protected amine was dissolved in a mixture of isopropyl alcohol/formic acid (9:1) (app. 10 ml/100 mg ⁇ -methyl benzyl protected amine). The solution was degassed by purging with nitrogen for 1 minute before 10% Pd/C (dry) was added. The reaction mixture was stirred at room temperature until TLC showed that all the starting material was consumed (typical 1-4 days). The Pd/C was filtered off using Celite and the filter cage was washed with plenty of methanol. The filtrate was concentrated in vacuo and partitioned between ethyl acetate and water. The organic phase was separated, dried (MgSO 4 ) and filtered. The solvent was removed in vacuo and the crude product was purified using column chromatography (SiO 2 , and a mixture of ethyl acetate/methanol as eluent)
  • the carboxylic acid ferf-butyl ester was dissolved in a mixture of trifluoroacetic acid/dichloromethane (1 :1) (app. 1 ml/100 mg carboxylic acid ferf-butyl ester).
  • the reaction mixture was stirred for 16 hours at room temperature before diethyl ether (2 x the reaction volume) was added drop-wise.
  • the precipitate was filtered off/spun down on a centrifuge and washed with diethyl ether to give analytical pure titie compound.
  • thienor2,3-clpyridine-3-carboxylic acid The titie compound was prepared using 3-phenoxy-benzoic acid and 2-amino-5- (S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid ferf-butyl ester as the starting material and Method A, B, C and D as described above.
  • the title compound was prepared using 4-benzoylamino-benzoic acid and 2- amino-5-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acid ferf-butyl ester as the starting material and Method A,
  • the title compound was prepared using 4-benzoylamino-benzoic acid and 2- amino-5-(R)-aminomethyl-6-(1-(S)-phenyI-ethyl)-4,5,6,7-tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acid ferf-butyl ester as the starting material and Method A, B, C and D as described above.
  • the titie compound was prepared using 3-hydroxy-7-methoxy-naphthalene-2- carboxylic acid and 2-amino-5-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7- tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid ferf-butyl ester as the starting material and Method A, B, C and D as described above. Calculated for C 22 H ⁇ 9 N 3 O 7 S, 1xH 2 O, 0.7xC 2 HF 3 O 2 C, 49.06%; H, 4.00%; N, 7.03%. Found: C, 49.30%; H, 4.37%; N, 6.66%
  • the titie compound was obtained using the above ureido-compound and Method
  • the title compound was prepared using 4-acetylamino-benzenesulfonyI chloride and 2-amino-5-( ?)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro- thieno[2,3-c]pyridine-3-carboxylic acid ferf-butyl ester as the starting material. Formation of the sulpfonamide was performed in pyridine at room temperature using a slight excess of the sulfonyl chloride followed by Method B, C and D as described above.
  • the titie compound was prepared using 4-acetylamino-benzenesulfonyl chloride and 2-amino-5-(S)-aminomethyl-6-(1 -(S)-phenyl-ethyl)-4,5,6,7-tetrahydro- thieno[2,3-c]pyridine-3-carboxylic acid ferf-butyl ester as the starting material.
  • the title compound was prepared in a similar way as described in Example 1 using 4-benzyl-benzoic acid and 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)- 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid ferf-butyl ester as the starting material.
  • the titie compound was prepared in a similar way as described in Example 1 using 5-ferf-butoxycarbonylamino-5-methyl-hex-2-enoic acid (prepared as described by Hansen et al. in J. Med. Chem. 41; (1998); 3705-3714) and 2- amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acid ferf-butyl ester as the starting material.
  • the titie compound was prepared from 2-(4,4-diethoxy-1-methylpiperidin-2- yImethyl)isoindole-1 ,3-dione using the same methods as in Example 1 and method A, B, C and D in "General chiral synthesis"
  • the titie compound was prepared from 2-(4,4-diethoxy-1-methylpiperidin-2- ylmethyl)isoindole-1 ,3-dione using the same methods as in Example 1 and method A, B, C and D in "General chiral synthesis"
  • 1 H-NMR 400 MHz, DMSO-d 6 ): ⁇ 13.78 (bs, 1H), 12.34 (bs, 1 H), 11.67 (s, 1H), 10.33 (bs, 1H), 8.79 (bs, 1 H, -CONWCH 2 ), 7.64 (d, 1 H), 7.44 (d, 1 H), 7.18 (m, 2H), 7.04 (m, 1 H), 4.46 (dd, 2H), 3.84-3.71 (m, 3H), 3.53 (bs, 1 H), 3.28 (d, 1H), 3.03 (m, 3H).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouvelles thiénopyridines, de nouvelles compositions, leurs procédés d'utilisation et leurs procédés de fabrication. Les composés de la formule 1 sont des inhibiteurs de protéine tyrosine phosphatases (PTPases) pharmacologiquement utiles comprenant PTP1B, PTP de cellule T, X, R1, R2, R3 et R4 étant définis plus en détail dans le descriptif. Les composés sont utiles dans le traitement des diabètes des types I et II, de l'intolérance au glucose, de la résistance insulinique, de l'obésité et d'autres maladies.
PCT/DK2001/000450 2000-07-07 2001-06-28 Modulateurs de proteine tyrosine phosphatases (ptpases) WO2002004458A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001268951A AU2001268951A1 (en) 2000-07-07 2001-06-28 Modulators of protein tyrosine phosphatases (ptpases)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DKPA200001066 2000-07-07
DKPA200001066 2000-07-07

Publications (1)

Publication Number Publication Date
WO2002004458A1 true WO2002004458A1 (fr) 2002-01-17

Family

ID=8159609

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK2001/000450 WO2002004458A1 (fr) 2000-07-07 2001-06-28 Modulateurs de proteine tyrosine phosphatases (ptpases)

Country Status (2)

Country Link
AU (1) AU2001268951A1 (fr)
WO (1) WO2002004458A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003082841A1 (fr) 2002-04-03 2003-10-09 Novartis Ag Derives 5-substitues 1,1-dioxo-`1,2,5!thiazolidine-3-one utilises en tant qu'inhibiteurs de ptpase 1b
US6818787B2 (en) 2001-06-11 2004-11-16 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
WO2004099192A2 (fr) * 2003-04-30 2004-11-18 The Institutes Of Pharmaceutical Discovery, Llc Acides carboxyliques substitues par des heterocycles
US6833140B2 (en) * 2001-06-11 2004-12-21 Xenoport, Inc. Orally administered dosage forms of GABA analog prodrugs having reduced toxicity
EP1534264A2 (fr) * 2002-03-01 2005-06-01 Sunesis Pharmaceuticals, Inc. Composes modulant l'activite de ptp-1b et de tc-ptp
WO2006055708A2 (fr) * 2004-11-18 2006-05-26 The Institutes For Pharmaceutical Discovery, Llc Acides carboxyliques a substitution heterocyclique
US7475572B2 (en) * 2003-05-27 2009-01-13 Whirlpool Corporation Washing machine with a device for the security during transport
US7790708B2 (en) 2001-06-11 2010-09-07 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
WO2010118241A2 (fr) * 2009-04-08 2010-10-14 Indiana University Research & Technology Corporation Inhibiteurs des protéine-tyrosine phosphatases
US8048917B2 (en) 2005-04-06 2011-11-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US8795725B2 (en) 2004-11-04 2014-08-05 Xenoport, Inc. GABA analog prodrug sustained release oral dosage forms
JP2021520415A (ja) * 2018-04-04 2021-08-19 エピオダイン，インク． オピオイド受容体モジュレーター、およびそれに関連する生成物ならびに方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999046267A1 (fr) * 1998-03-12 1999-09-16 Novo Nordisk A/S Modulateurs de proteine tyrosine phosphatases (ptpases)
WO1999046237A1 (fr) * 1998-03-12 1999-09-16 Novo Nordisk A/S Modulateurs de proteine-tyrosine-phosphatases
WO2001017516A2 (fr) * 1999-09-10 2001-03-15 Novo Nordisk A/S Procede d'inhibition de la proteine tyrosine phosphatase 1b et/ou de la proteine tyrosine phosphatase de lymphocytes et/ou d'autres ptpases possedant un reste aps en position 48
WO2001019830A1 (fr) * 1999-09-10 2001-03-22 Novo Nordisk A/S MODULATEURS DE PROTEINE TYROSINE PHOSPHATASE (PTPases)

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999046267A1 (fr) * 1998-03-12 1999-09-16 Novo Nordisk A/S Modulateurs de proteine tyrosine phosphatases (ptpases)
WO1999046237A1 (fr) * 1998-03-12 1999-09-16 Novo Nordisk A/S Modulateurs de proteine-tyrosine-phosphatases
WO2001017516A2 (fr) * 1999-09-10 2001-03-15 Novo Nordisk A/S Procede d'inhibition de la proteine tyrosine phosphatase 1b et/ou de la proteine tyrosine phosphatase de lymphocytes et/ou d'autres ptpases possedant un reste aps en position 48
WO2001019830A1 (fr) * 1999-09-10 2001-03-22 Novo Nordisk A/S MODULATEURS DE PROTEINE TYROSINE PHOSPHATASE (PTPases)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LARS FOGH IVERSEN ET AL: "Structure-based design of a low molecular weight, nonphosphorus, nonpeptide, and highly selective inhibitor of protein-tyrosine phosphatase IB", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 275, no. 14, 2000, pages 10300 - 10307, XP002902040 *

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9238616B2 (en) 2001-06-11 2016-01-19 Xenoport, Inc. Prodrugs of gaba analogs, compositions and uses thereof
US8168623B2 (en) 2001-06-11 2012-05-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US6833140B2 (en) * 2001-06-11 2004-12-21 Xenoport, Inc. Orally administered dosage forms of GABA analog prodrugs having reduced toxicity
US6818787B2 (en) 2001-06-11 2004-11-16 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US7790708B2 (en) 2001-06-11 2010-09-07 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
EP1534264A4 (fr) * 2002-03-01 2007-06-13 Sunesis Pharmaceuticals Inc Composes modulant l'activite de ptp-1b et de tc-ptp
EP1534264A2 (fr) * 2002-03-01 2005-06-01 Sunesis Pharmaceuticals, Inc. Composes modulant l'activite de ptp-1b et de tc-ptp
WO2003082841A1 (fr) 2002-04-03 2003-10-09 Novartis Ag Derives 5-substitues 1,1-dioxo-`1,2,5!thiazolidine-3-one utilises en tant qu'inhibiteurs de ptpase 1b
EP2341049A1 (fr) 2002-04-03 2011-07-06 Novartis AG Derives 5-substitues 1,1-dioxo-[1,2,5]thiazolidine-3-one utilises en tant qu'inhibiteurs de PTPASE 1B
WO2004099192A3 (fr) * 2003-04-30 2005-01-13 Inst Of Pharmaceutical Discove Acides carboxyliques substitues par des heterocycles
JP2006525366A (ja) * 2003-04-30 2006-11-09 ジ インスチチュート フォー ファーマシューティカル ディスカバリー、エルエルシー 複素環式カルボン酸置換基
US7329680B2 (en) 2003-04-30 2008-02-12 The Institute For Pharmaceutical Discovery, Llc Heterocycle substituted carboxylic acids
WO2004099192A2 (fr) * 2003-04-30 2004-11-18 The Institutes Of Pharmaceutical Discovery, Llc Acides carboxyliques substitues par des heterocycles
US7475572B2 (en) * 2003-05-27 2009-01-13 Whirlpool Corporation Washing machine with a device for the security during transport
US8795725B2 (en) 2004-11-04 2014-08-05 Xenoport, Inc. GABA analog prodrug sustained release oral dosage forms
US8906412B2 (en) 2004-11-04 2014-12-09 Xenoport, Inc. GABA analog prodrug sustained release oral dosage forms
WO2006055708A3 (fr) * 2004-11-18 2006-08-03 Inst For Pharm Discovery Inc Acides carboxyliques a substitution heterocyclique
WO2006055708A2 (fr) * 2004-11-18 2006-05-26 The Institutes For Pharmaceutical Discovery, Llc Acides carboxyliques a substitution heterocyclique
US8048917B2 (en) 2005-04-06 2011-11-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
WO2010118241A2 (fr) * 2009-04-08 2010-10-14 Indiana University Research & Technology Corporation Inhibiteurs des protéine-tyrosine phosphatases
WO2010118241A3 (fr) * 2009-04-08 2014-03-20 Indiana University Research & Technology Corporation Inhibiteurs des protéine-tyrosine phosphatases
US9217012B2 (en) 2009-04-08 2015-12-22 Indiana University Research And Technology Corporation Inhibitors of protein tyrosine phosphatases
US10072043B2 (en) 2009-04-08 2018-09-11 Indiana University Research And Technology Corporation Inhibitors of protein tyrosine phosphatases
JP2021520415A (ja) * 2018-04-04 2021-08-19 エピオダイン，インク． オピオイド受容体モジュレーター、およびそれに関連する生成物ならびに方法
JP7402857B2 (ja) 2018-04-04 2023-12-21 エピオダイン，インク． オピオイド受容体モジュレーター、およびそれに関連する生成物ならびに方法

Also Published As

Publication number Publication date
AU2001268951A1 (en) 2002-01-21

Similar Documents

Publication Publication Date Title
DE60028791T2 (de) Modulatoren der protein tyrosin phosphatase (ptpases)
JP6782255B2 (ja) ヒストンデアセチラーゼ阻害薬及び組成物並びにそれらの使用の方法
US7019026B1 (en) Modulators of Protein Tyrosine Phosphatases (PTPases)
EP1301516B1 (fr) Modulateurs des proteines tyrosines phosphatases (ptpases)
US11352345B2 (en) Cyclohexyl acid pyrazole azoles as LPA antagonists
BR112018007021B1 (pt) Composto, composição compreendendo os ditos compostos e uso dos mesmos para tratar fibrose cística
AU2006216713A1 (en) PGD2 receptor antagonists for the treatment of inflammatory diseases
CN109516982B (zh) μ-阿片受体激动剂及其制备方法和在医药领域的应用
JP2022500469A (ja) Ｌｐａアンタゴニストとしてのシクロヘプチル酸
AU2713599A (en) Modulators of protein tyrosine phosphatases (ptpases)
MX2011009314A (es) Compuesto de quinoxalina.
JP2022500473A (ja) Ｌｐａアンタゴニストとしてのオキサビシクロ酸
CA2810696A1 (fr) Compose de pyrazoloquinoline
US10106535B2 (en) Histone deacetylase inhibitors and compositions and methods of use thereof
WO2002004458A1 (fr) Modulateurs de proteine tyrosine phosphatases (ptpases)
WO2019154395A1 (fr) Composé de tétrahydroisoquinoléine, son procédé de préparation, composition pharmaceutique le contenant et utilisation associée
TW202115083A (zh) 肽醯精胺酸脫亞胺酶抑制劑及其用途
KR20220141331A (ko) P2x3 조정제
DE60206174T2 (de) Verfahren zur hemmung von tyrosinphosphatase 1b und/oder t-zellenprotein-tyrosinphosphatase und/oder anderen ptpasen mit einem asp-rest in position 48
TW202245753A (zh) 用於治療疾病之類似物
US6613903B2 (en) Modulators of protein tyrosine phosphatases (PTPases)
US6410556B1 (en) Modulators of protein tyrosine phosphateses (PTPases)
US20020099073A1 (en) Modulators of protein tyrosine phosphatases (PTPases)
US20030064979A1 (en) Method of inhibiting PTP 1B and /or T-cell PTP and/or other PTPases with an Asp residue at position 48
EP2129675A2 (fr) Dérivés d'imidazo, pyrimido et diazépine pyrimidine-dione et leur utilisation comme médicament

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP