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WO2004041799A1 - Thiadiazolidine-3-ones 5-(phenyle substitue) et leur utilisation en tant qu'inhibiteurs de ptp1b - Google Patents

Thiadiazolidine-3-ones 5-(phenyle substitue) et leur utilisation en tant qu'inhibiteurs de ptp1b Download PDF

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Publication number
WO2004041799A1
WO2004041799A1 PCT/GB2003/004721 GB0304721W WO2004041799A1 WO 2004041799 A1 WO2004041799 A1 WO 2004041799A1 GB 0304721 W GB0304721 W GB 0304721W WO 2004041799 A1 WO2004041799 A1 WO 2004041799A1
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Prior art keywords
alkyl
alkoxy
aryl
aryloxy
formula
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Alan Martin Birch
Peter Wedderburn Kenny
Andrew David Morley
Daniel John Russell
Dorin Toader
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AstraZeneca UK Ltd
AstraZeneca AB
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AstraZeneca UK Ltd
AstraZeneca AB
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Priority to AU2003278392A priority Critical patent/AU2003278392A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • This invention relates to chemical compounds, or pharmaceutically acceptable salts thereof, more particularly to certain substituted thiadiazolidines or pharmaceutically acceptable salts thereof, which inhibit protein tyrosine phosphatase PTP1B and are accordingly useful in methods of treatment of the human or animal body.
  • the invention also relates to processes for the manufacture of said compounds, to pharmaceutical compositions containing them and to their use as therapeutic agents.
  • Protein phosphorylation is a post-translational event, which is responsible for the regulation of most cell signalling pathways. This phosphorylation is regulated by enzymes which either act to phosphorylate (protein kinases) or dephosphorylate (protein phosphatases) proteins. Protein phosphatases are divided into two major groups, i.e. those that dephosphorylate proteins which contain phosphorylated serine or threonine residues (Ser/Thr phosphatases) and those that dephosphorylate proteins which contain phosphorylated tyrosine residues (protein tyrosine phosphatases or PTPases). Unlike the protein kinase family, there is no sequence identity between these two groups of phosphatases.
  • the PTPases are a large family of enzymes, which all contain the PTP signature motif in a highly conserved region of approximately 250 amino acids that make up the catalytic domain.
  • the invariant cysteine residue has been shown to be critical to PTPase activity (reviewed by Cheng et al, Eur.J.Biochem. 269:1050-1059 (2002)).
  • the PTPases can be subdivided into three different classes, namely classical tyrosine specific PTPases; dual specific PTPases and low molecular weight PTPases.
  • the classical tyrosine specific PTPases can be further subdivided into two groups: (i) receptor-type PTPases, which include CD45 and LAR, and which consist of an extracellular domain, a single transmembrane domain and most have two tandem repeated cytoplasmic PTP domains (although generally only one is active); and (ii) intracellular PTPases, which include PTP1B, TC-PTP and FAP, and which contain a single catalytic domain.
  • the numerous amino and/or carboxyl domains may be involved in the subcellular localisation or regulatory function of these intracellular PTPases.
  • Initial analysis of the data generated from the human genome project has identified approximately 120 human protein phosphatases and a role for members of this family of proteins in disease is becoming clearer.
  • PTPases which have the potential to act as both positive and negative regulators of cell signalling.
  • a number of these PTPases have been shown to play a vital role in the regulation of cell signalling pathways associated with metabolism, growth, proliferation and differentiation, such that abnormal regulation may lead to a number of important disease states including diabetes and cancers (reviewed by Zhang, Annu. Rev. Pharmacol. Toxicol. 42:209-234 (2002)).
  • Insulin plays a key role in the control of blood glucose and defects in its synthesis or signalling lead to insulin resistance, diabetes and its associated complications.
  • the glucose lowering and other effects of insulin are a consequence of insulin binding to its receptor and the subsequent activation of a number of downstream signalling cascades.
  • Phosphorylation of tyrosine residues in a number of proteins in the insulin signalling cascade is critical to this signalling process.
  • the insulin receptor is a tyrosine kinase that is autophosphorylated on tyrosine residues following activation by insulin.
  • the phosphorylated insulin receptor catalyses the phosphorylation of its downstream substrates, including the insulin receptor substrates (IRSs).
  • PTP1B was the first PTP to be purified to homogeneity. It was purified from human placenta, cloned and subsequently identified as a PTPase, shortly afterwards. Data generated in vitro, using a tri-phosphorylated peptide corresponding to the catalytic region of the insulin receptor kinase domain, showed that the activity of this peptide could be inhibited following dephosphorylation with PTP1B. Experiments involving cells in culture using antibodies, and antisense oligonucleotides suggested PTP1B to act as a negative regulator of insulin signalling (Ostman and Bohmer TRENDS in Cell Biology 11(6): 258-266 (2001)).
  • PTP1B null mice are phenotypically normal with a normal lifespan, as compared to their wild type littermates. However, PTP1B null mice demonstrate tissue specific up-regulation of the insulin receptor (in liver and muscle) and improved insulin sensitivity as demonstrated using an oral glucose tolerance test. Surprisingly, as well as having improved insulin sensitivity, the PTP IB null mice are resistant to diet induced obesity (DIO). This resistance to DIO may suggest that PTP1B has a role in the central regulation of energy balance and work is on going to try to understand further this mechanism.
  • DIO diet induced obesity
  • JAK2 is another substrate for PTPIB (Cheng et al, Dev. Cell 2:497-503 (2002).
  • Leptin a satiety hormone released from the adipocytes, binds to the leptin receptor and induces JAK2 phosphorylation.
  • JAK2 has a number of substrates. It is thought that PTPIB dephosphorylation of JAK2 may result in changes to the subsequent downstream signalling cascade and may be responsible, at least in part, for the resistance to DIO, in the PTPIB null mice.
  • PTPIB inhibitors are of benefit in the treatment of type 1 or type 2 diabetes, obesity and other conditions which may result from the abnormal regulation of tyrosine phosphatase PTPIB, such as metabolic syndrome (syndrome X), hyperglycemia, hyperinsulinemia, dyslipidemia, polycystic ovarian disease, hypertension, cardiovascular disease (Ukkola and Santaniemi, Journal of Internal Medicine 251:467-475 (2002)).
  • Ri is hydrogen, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylthio, halogeno, halogeno(l-6C)alkyl, halogeno(l-6C)alkoxy, halogeno(l-6C)alkylthio, hydroxy(l-6C)alkoxy, dihydroxy(l- 6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy, aryloxy, aryl(l-6C)alkoxy, aryloxy(l-6C)alkoxy, heteroaryl(l-6C)alkoxy, heteroaryloxy, heteroaryloxy(l-6C)alkoxy, (l-6C)alkoxy(l- 6C)alkylthio, (l-6C)alkylthio(l-6C)alkoxy, (l-6C)alkylsulfinyl(l-6C)alkoxy, (1- 6C)alkylsulfony
  • R 2 is selected from H, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylthio and halogeno; or R] and R 2 together with the carbon atoms to which they are attached form a 5-7 membered carbocyclic or heterocyclic ring;
  • R 3 and R 4 are selected such that
  • R 3 is hydrogen, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylthio or halogeno and R 4 is aryl, biaryl, heteroaryl, (2-6C)alkynyl, (3-7C)cycloalkyl, arylcarbonyl, heteroarylcarbonyl, aryl(2-6C)alkenyl, aryl(2-6C)alkynyl or heteroaryl(2- 6C)alkenyl; or
  • R 4 is hydrogen, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylthio or halogeno and R 3 is aryl, biaryl, heteroaryl, (2-6C)alkynyl, (3-7C)cycloalkyl, arylcarbonyl, heteroarylcarbonyl, aryl(2-6C)alkenyl, aryl(2-6C)alkynyl or heteroaryl(2- 6C)alkenyl;
  • R 5 is hydrogen, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylthio, halo(l-6C)alkyl or halogeno;
  • R 6 is hydrogen or (l-6C)alkyl; and wherein any aryl, biaryl or heteroaryl group within or part of the definition of R ls R 3 or R is unsubstituted or bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (1- 6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l- 6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarb
  • Ri is hydrogen, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylthio, halogeno, halogeno(l-6C)alkyl, halogeno(l-6C)alkoxy, halogeno(l-6C)alkylthio, hydroxy(l-6C)alkoxy, dihydroxy(l- 6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy, aryloxy, aryl(l-6C)alkoxy, aryloxy(l-6C)alkoxy, heteroaryl(l-6C)alkoxy, heteroaryloxy(l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkylthio, (1- 6C)alkylthio(l-6C)alkoxy, (l-6C)alkylsulfinyl(l-6C)alk
  • 6C)alkanoylamino(l-6C)alkoxy (2-6C)alkanoylamino(l-6C)alkyl, aryl(l-6C)alkyl, heteroaryl(l-6C)alkyl, hydroxy(l-6C)alkyl, amino(l-6C)alkyl, carboxy(l-6C)alkyl, sulfamoyl(l-6C)alkyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (2-8C)alkenyl, (2- 8C)alkynyl, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylsulphinyl, (1- 6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl] amino, (l-6C)alkoxycarbonyl, N-(l- 6C)alkylcarbamoy
  • R 7 is hydrogen, (l-6C)alkyl, aryl, heteroaryl, aryl(l-6C)alkyl, hydroxy or (l-6C)alkoxy;
  • X is -C(O)-, -S(O)- or -S(O) 2 -; and
  • R 8 and R 9 are independently selected from hydrogen, (1- 6C)alkyl, aryl and heteroaryl; or R 8 and R 9 together with the nitrogen atom to which they are attached form a heterocyclic ring; or X is a covalent bond,
  • R 8 is hydrogen, (l-6C)alkyl or aryl, and
  • R 9 is -COR 10 or SO 2 R 10 wherein R 10 is (l-6C)alkyl, aryl, heteroaryl, aryl(l-6C)alkyl or heteroaryl(l-6C)alkyl; and
  • Z is a covalent bond, O or S; with the proviso that no two heteroatoms are attached through single bonds to the same carbon atom;
  • R 2 is H or (l-6C)alkyl; or Ri and R 2 together with the carbon atoms to which they are attached form a 5-7 membered carbocyclic or heterocyclic ring;
  • R 3 and R 4 are selected such that (iii) R 3 is hydrogen, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylthio or halogeno and R 4 is aryl, biaryl, heteroaryl, (3-7C)cycloalkyl, arylcarbonyl, heteroarylcarbonyl, aryl(2- 6C)alkenyl or heteroaryl(2-6C)alkenyl; or (iv) R 4 is hydrogen, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylthio or halogeno and R 3 is
  • R 5 is hydrogen, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylthio or halogeno;
  • R 6 is hydrogen or (l-6C)alkyl; and wherein any aryl, biaryl or heteroaryl group within or part of the definition of R 1;
  • R 3 or R 4 is unsubstituted or bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (1- 6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamin
  • alkyl includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl, and also
  • (3-7C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • references to individual alkyl groups such as "propyl” are specific for the straight-chain version only
  • references to individual branched-chain alkyl groups such as “isopropyl” are specific for the branched-chain version only
  • references to individual cycloalkyl groups such as "cyclopentyl” are specific for that 5-membered ring only.
  • An analogous convention applies to other generic terms, for example (l-6C)alkoxy includes methoxy, ethoxy, cyclopropyloxy and cyclopentyloxy. Where halogenoalkyl is referred to, this includes mono-, di-, tri- and per-halogenoalkyl. An analogous convention applies to halogenoalkoxy and halogenoalkylthio.
  • optically active or racemic forms by virtue of one or more asymmetric carbon atoms
  • the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
  • a suitable value for aryl, or for aryl which is part of a value defined herein for Ri to R 10 is, for example, a totally unsaturated, mono or bicyclic carbon ring that contains 6-12 atoms.
  • Suitable values for aryl include phenyl or naphthyl, particularly phenyl.
  • a suitable value for biaryl is, for example, biphenyl.
  • a suitable value for heteroaryl, or for heteroaryl which is part of a value defined herein for R] to R 10 is, for example, a totally unsaturated mono or bicyclic ring containing 5- 12 atoms of which at least one atom is chosen from oxygen, sulphur and nitrogen.
  • Suitable values for Ri to R 10 or for groups which are part of a value defined herein for 0 , or for substituents on an aryl or heteroaryl group include :- C)alkyl: (l-4C)alkyl, such as methyl, ethyl, propyl, isopropyl and tert-butyl; and
  • (l-3C)alkyl such as methyl, ethyl, propyl and isopropyl
  • (l-3C)alkoxy such as methoxy, ethoxy, propoxy and isopropoxy
  • C)alkylthio (l-4C)alkylthio, such as (l-3C)alkylthio, such as methylthio, ethylthio and propylthio
  • geno fluoro chloro, bromo and iodo
  • geno-(l-6C)alkyl halogeno(l-4C)alkyl, such as chloromethyl, 2- chloroethyl, 1-chloroethyl,
  • 3C)alkoxy such as methoxymethoxy, 2- methoxyethoxy, ethoxymethoxy and 2-
  • (l-6C)alkylthio(l-6C)alkoxy (l-4C)alkylthio(l-4C)alkoxy, such as methylthiomethoxy, 2-(methylthio)ethoxy, ethylthiomethoxy and 2-(ethylthio)ethoxy;
  • (l-6C)alkylsulfinyl(l-6C)alkoxy (l-4C)alkylsulfinyl(l-4C)alkoxy, such as methylsulfinylmethoxy, 2-(methylsulfinyl)ethoxy, ethylsulfinylmethoxy and 2-(ethylsulfinyl)ethoxy;
  • aryl(l-6C)alkyl 2-acetamidoethyl
  • aryl(l-6C)alkyl aryl(l-4C)alkyl, such as benzyl, 1-phenylethyl, 2- phenylethyl, 3-phenylpropyl, 1-naphthylmethyl, 2- naphthylmethyl, 2-(l-naphthyl)ethyl, 2-(2- naphthyl)ethyl, 3-(l-naphthyl)propyl and 3-(2- naphthyl)propyl;
  • aryl(2-6C)alkenyl aryl(2-4C)alkenyl, such as cis- or trans-styryl;
  • aryl(2-6C)alkynyl aryl(2-4C)alkylnyl, such as phenylethynyl and 3- phenylpropyn- 1 -yl ; for
  • N-(l-6C)alkylcarbamoyl N-(l-4C)alkylcarbamoyl, such as N-(l- 3C)alkylcarbamoyl, such as N-methylcarbamoyl, N- ethylcarbamoyl and N-propylcarbamoyl;
  • N,N-di-[(l-6C)alkyl]carbamoyl N,N-di-[(l-4C)alkyl]carbamoyl, such as N,N-di-[(l- 3C)alkyl]carbamoyl, such as N,N- dimethylcarbamoyl, N-ethyl- N-methylcarbamoyl and N,N-diethylcarbamoyl;
  • N-(l-6C)alkyl-(2-6C)alkanoylamino N-(l-4C)alkyl-(2-4C)alkanoylamino, such as N-(l-
  • N-(l-6C)alkylsulfamoyl N-(l-4C)alkylsulfamoyl, such as N-(l-
  • N-methylsulfamoyl and N-ethylsulphamoyl such as N-methylsulfamoyl and N-ethylsulphamoyl
  • N,N-di-[(l-6C)alkyl]sulfamoyl N,N-di-[(l-4C)alkyl]sulfamoyl, such as N,N-di-[(l- 3C)alkyl]sulfamoyl, such as ⁇ /Y-dimethylsulfamoyl
  • (l-6C)alkanesulfonylamino (l-4C)alkanesulfonylamino, such as (1-
  • N-(l-6C)alkyl-(l-6C)alkanesulfonylamino N-(l-4C)alkyl-(l- 4C)alkanesulfonylamino, such as N-(l-3C)alkyl-(l-
  • 3C)alkanesulfonylamino such as N- methylmethanesulfonylamino and N-methylethanesulfonylamino;
  • a suitable value for a divalent radical of formula -O(CH 2 ) 1-4 O- includes, for example, methylenedioxy and ethylenedioxy.
  • a suitable value for R 8 and R 9 when, together with the nitrogen atom to which they are attached, they form a heterocyclic ring includes, for example, a saturated or partially saturated heterocyclic ring optionally substituted with a (l-6C)alkyl group, such as pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino or N-methylpiperazino.
  • a saturated or partially saturated heterocyclic ring optionally substituted with a (l-6C)alkyl group, such as pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino or N-methylpiperazino.
  • R 3 or R 4 when any aryl, biaryl or heteroaryl group within or part of the definition of R 1 ; R 3 or R 4 bears 1, 2 or 3 substituents, which may be the same or different, said substituents are independently selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, carboxy, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2- 6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (1- 6C)alkylsulphonyl, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, N-pyrrolidinylcarbonyl,
  • R 3 or R 4 when any aryl, biaryl or heteroaryl group within or part of the definition of R 1; R 3 or R 4 bears 1, 2 or 3 substituents, which may be the same or different, said substituents are independently selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, carboxy, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (1- 6C)alkylthio, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, N-pyrrolidinylcarbonyl, N-piperidinylcarbonyl, N-(l-6C)alkylcarbamoyloxy(l-6C)alkyl, (2-6C)alkanoyl, (2-6C)
  • R 3 or R 4 bears 1, 2 or 3 substituents, which may be the same or different, said substituents are independently selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, carboxy, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (l-6C)alkoxy, (l-6C)alkylthio, N,N-di-[(l -6C)alkyl]carbamoyl, N-pyrrolidinylcarbonyl, N-piperidinylcarbonyl, N-(l-6C)alkylcarbamoyloxy(l-6C)alkyl, (2-6C)alkanoyl, (2-6C)alkanoylamino, (1- 6C)alkoxy(l-6C)alkyl, carboxy(l-6C)alkyl, aryloxy(
  • R 3 or R 4 bears 1, 2 or 3 substituents, which may be the same or different, said substituents are independently selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, carboxy, carbamoyl, (l-4C)alkyl, (2-4C)alkenyl, (l-4C)alkoxy, (l-4C)alkylthio, N,N-di-[(l-4C)alkyl]carbamoyl, N-pyrrolidinylcarbonyl, N-piperidinylcarbonyl, N-(l-4C)alkylcarbamoyloxy(l-4C)alkyl, (2-4C)alkanoyl, (2-4C)alkanoylamino, (1- 4)alkoxy(l-4C)alkyl, carboxy(l-4C)alkyl, aryloxy(l
  • Suitable values for optional substituents on an aryl or heteroaryl moiety of an aryl(l- 6C)alkyl, heteroaryl(l-6C)alkyl, aryloxy(l-6C)alkyl, heteroaryloxy(l-6C)alkyl, aryl(l- 6C)alkoxy, heteroaryl(l-6C)alkoxy, aryloxy(l-6C)alkoxy, heteroaryloxy(l-6C)alkoxy, aryloxy(l-6C)alkylcarbamoyl, aryloxy(l-6C)alkylsulphamoyl, aryloxy or heteroaryloxy substituent include, for example, halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyl
  • aryl(l-6C)alkyl, heteroaryl(l-6C)alkyl, aryloxy(l-6C)alkyl, heteroaryloxy(l-6C)alkyl, aryl(l-6C)alkoxy, heteroaryl(l-6C)alkoxy, aryloxy(l-6C)alkoxy, heteroaryloxy(l-6C) alkoxy, aryloxy(l-6C)alkylcarbamoyl, aryloxy(l-6C)alkylsulphamoyl, aryloxy or heteroaryloxy substituent include, for example, halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)
  • aryl(l-6C)alkyl, heteroaryl(l-6C)alkyl, aryloxy(l-6C)alkyl, heteroaryloxy(l-6C)alkyl, aryl(l-6C)alkoxy, heteroaryl(l-6C)alkoxy, aryloxy(l-6C)alkoxy, heteroaryloxy(l-6C) alkoxy, aryloxy(l-6C)alkylcarbamoyl, aryloxy(l-6C)alkylsulphamoyl, aryloxy or heteroaryloxy substituent include, for example, halogeno, trifluoromethyl, cyano, hydroxy, amino, carboxy, carbamoyl, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)al
  • aryl(l-6C)alkyl, heteroaryl(l-6C)alkyl, aryloxy(l-6C)alkyl, heteroaryloxy(l-6C)alkyl, aryl(l-6C)alkoxy, heteroaryl(l-6C)alkoxy, aryloxy(l-6C)alkoxy, heteroaryloxy(l-6C)alkoxy, aryloxy(l-6C)alkylcarbamoyl, aryloxy(l-6C)alkylsulphamoyl, aryloxy or heteroaryloxy substituent include, for example, halogeno, trifluoromethyl, cyano, hydroxy, amino, carboxy, carbamoyl, (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkylsulfonyl, (l-4C)alkoxycarbonyl, (1- 4C)
  • aryl(l-6C)alkyl, heteroaryl(l-6C)alkyl, aryloxy(l-6C)alkyl, heteroaryloxy(l-6C)alkyl, aryl(l-6C)alkoxy, heteroaryl(l-6C)alkoxy, aryloxy(l-6C)alkoxy, heteroaryloxy(l-6C)alkoxy, aryloxy(l-6C)alkylcarbamoyl, aryloxy(l-6C)alkylsulphamoyl, aryloxy or heteroaryloxy substituent include, for example, halogeno, hydroxy, carboxy, carbamoyl, (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkylsulfonyl, (l-4C)alkoxycarbonyl, (l-4C)alkoxy(l-4C)alkyl,
  • aryl(l-6C)alkyl, heteroaryl(l-6C)alkyl, aryloxy(l-6C)alkyl, heteroaryloxy(l-6C)alkyl, aryl(l-6C)alkoxy, heteroaryl(l-6C)alkoxy, aryloxy(l-6C)alkoxy, heteroaryloxy(l-6C)alkoxy, aryloxy(l-6C)alkylcarbamoyl, aryloxy(l-6C)alkylsulphamoyl, aryloxy or heteroaryloxy substituent include, for example, halogeno, cyano, nitro, hydroxy, carboxy, carbamoyl, (l-3C)alkyl, (2-4C)alkenyl), (2-4C)alkynyl, (l-3C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkyny
  • aryl(l-6C)alkyl, heteroaryl(l-6C)alkyl, aryloxy(l-6C)alkyl, heteroaryloxy(l-6C)alkyl, aryl(l-6C)alkoxy, heteroaryl(l-6C)alkoxy, aryloxy(l-6C)alkoxy, heteroaryloxy(l-6C)alkoxy, aryloxy(l-6C)alkylcarbamoyl, aryloxy(l-6C)alkylsulphamoyl, aryloxy or heteroaryloxy substituent include, for example, halogeno, hydroxy, carboxy, carbamoyl, (l-3C)alkyl, (l-3C)alkoxy, (l-3C)alkylsulfonyl, (l-3C)alkoxycarbonyl, (l-3C)alkoxy(l-3C)alkyl,
  • a suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation
  • a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxye
  • the invention relates to any and all tautomeric forms of the compounds of the formula (I) that possess PTPIB inhibitory activity. It is also to be understood that certain compounds of the formula (I) may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess PTPIB inhibitory activity. Particular values of variable groups are as follows. Such values may be used where appropriate with any of the other values, definitions, claims or embodiments defined hereinbefore or hereinafter.
  • Ri has any of the values defined herein other than hydrogen
  • R 5 is hydrogen and Ri has any of the values defined herein other than hydrogen
  • R 5 is hydrogen and Ri is (l-6C)alkoxy, such as (l-4C)alkoxy, for example methoxy
  • R 5 is hydrogen and Ri is hydroxy- (1-6C) alkoxy, such as hydroxy(l-4C)alkoxy, for example, 2-hydroxyethoxy
  • R 5 is hydrogen and R] is (l-6C)alkoxy(l-6C)alkoxy, such as (l-4C)alkoxy(l- 4C)alkoxy, for example.
  • R 5 is hydrogen and R x is (l-6C)alkylthio(l-6C)alkoxy, such as (l-4C)alkylthio(l- 4C)alkoxy, for example, 2-(methylthio)ethoxy
  • R 5 is hydrogen and Ri is (l-6C)alkylsulfinyl(l-6C)alkoxy, such as (1- 4C)alkylsulfinyl(l-4C)alkoxy, for example, 2-(methylsulfinyl)ethoxy (9)
  • R 5 is hydrogen and Ri is (l-6C)alkylsulfonyl(l-6C)alkoxy, such as (1- 4C)alkylsulfonyl(l-4C)alkoxy, for example, 2-(methylsulfonyl)ethoxy
  • R 5 is hydrogen and Ri is aryl(l-6C)alkoxy, such as aryl(l-4C)alkoxy, for example, benzyloxy or phenethyloxy
  • R 5 is hydrogen and Ri is fluoro(l-6C)alkoxy, such as fluoro(l-4C)alkoxy, for example trifluoromethoxy or 2,2,2-trifluoroethoxy
  • R 5 is hydrogen and Ri is carbamoyl(l-6C)alkoxy, such as carbamoyl(l-4C)alkoxy, for example, carbamoylmethoxy or 2-carbamoylethoxy
  • R 5 is hydrogen and Ri is (2-6C)alkanoylamino(l-6C)alkoxy, such as (2- 4C)alkanoylamino(l-4C)alkoxy, for example acetamidomethoxy
  • R 5 is hydrogen and Ri is (l-6C)alkoxy-(l-6C)alkyl, such as (l-4C)alkoxy-(l-4C)alkyl, for example, 2-methoxyethyl
  • R 5 is hydrogen and Ri is aryloxy(l-6C)alkyl, such as aryloxy(l-4C)alkyl, for example, phenyloxymethyl or 2-(phenyloxy)ethyl
  • R 5 is hydrogen and Ri is (l-6C)alkylsulfinyl(l-6C)alkyl, such as (1- 4C)alkylsulfinyl(l-4C)alkyl, for example, methylsulfinylmethyl or 2-(methylsulfinyl)ethyl
  • R 5 is hydrogen and Ri is (l-6C)alkylsulfonyl(l-6C)alkyl, such as (1- 4C)alkylsulfonyl(l-4C)alkyl, for example, methylsulfonylmethyl or 2-(methylsulfonyl)ethyl (18) R 5 is hydrogen and Ri is (2-6C)alkanoylamino(l-6C)alkyl, such as (2-
  • R 5 is hydrogen and Ri is carbamoyl(l-6C)alkyl, such as carbamoyl(l-4C)alkyl, for example, carbamoylmethyl or 2-carbamoylethyl
  • R 2 is hydrogen (21) R 2 is hydrogen or (l-6C)alkyl
  • R 4 is hydrogen and R 3 is unsubstituted or substituted aryl
  • R 4 is hydrogen and R 3 is unsubstituted aryl or aryl bearing 1, 2 or 3 substituents independently selected from (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkylthio, halogeno, (2- 4C)alkanoylaminophenoxy, cyano, nitro, hydroxy, trifluoromethyl, (2-4C)alkanoyl, carboxy, carboxy(l-4C)alkyl, hydroxymethyl, benzyloxy, (l-4C)alkoxy(l-4C)alkyl, amino and N,N- (l-4C)dialkylamino
  • R is hydrogen and R 3 is unsubstituted aryl or aryl bearing 1, 2 or 3 substituents independently selected from (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkylthio, halogeno, (2- 4C)alkanoylamino, N-tert-butylcarbamoyloxymethyl, phenoxy, cyano, nitro, hydroxy, trifluoromethyl, (2-4C)alkanoyl, carboxy, carboxy(l-4C)alkyl, hydroxymethyl, benzyloxy, (1- 4C)alkoxy(l-4C)alkyl, amino, N,N-(l-4C)dialkylamino, N-pyrrolidinylcarbonyl and N- piperidinylc arbonyl
  • R 4 is hydrogen and R 3 is aryl bearing 1 substituent independently selected from
  • aryl(l-6C)alkyl (i) aryl(l-6C)alkyl; (ii) aryloxy(l-6C)alkyl; (iii) aryl(l-6C)alkoxy; (iv) aryloxy(l-6C)alkoxy; (v) aryloxy; (vi) aryloxy(l-6C)alkylcarbamoyl; and (vii) aryloxy(l-6C)alkylsulfamoyl; wherein the aryl moiety of groups (i) to (vii) is unsubstituted or is substituted with 1, 2 or 3 substituents independently selected from any of the values defined hereinbefore or hereinafter as suitable values for such substituents; each of the groups (i) to (vii) may be selected independently and used where appropriate with any of the other values, definitions, claims or embodiments defined hereinbefore or hereinafter
  • R 4 is hydrogen and R 3 is aryl bearing 1 substituent selected from
  • R 4 is hydrogen and R 3 is unsubstituted or substituted heteroaryl
  • R 4 is hydrogen and R 3 is (3-7C)cycloalkyl
  • R 4 is hydrogen and R 3 is unsubstituted or substituted arylcarbonyl
  • R is hydrogen and R 3 is unsubstituted or substituted heteroarylcarbonyl (32) R 4 is hydrogen and R 3 is unsubstituted or substituted aryl(2-6C)alkenyl
  • R 4 is hydrogen and R 3 is unsubstituted or substituted aryl(2-6C)alkynyl
  • R 4 is hydrogen and R 3 is unsubstituted or substituted heteroaryl(2-6C)alkenyl
  • R 3 is hydrogen and R 4 is unsubstituted or substituted aryl
  • R 3 is hydrogen and R 4 is unsubstituted aryl or aryl bearing 1, 2 or 3 substituents, which may be the same or different, selected from (l-4C)alkyl, (l-4C)alkoxy, (1-
  • R 3 is hydrogen and R 4 is unsubstituted aryl or aryl bearing 1, 2 or 3 substituents, which may be the same or different, selected from (l-4C)alkyl, (l-4C)alkoxy, (1-
  • R 3 is hydrogen and R 4 is aryl bearing 1 substituent independently selected from
  • aryl(l-6C)alkyl (i) aryl(l-6C)alkyl; (ii) aryloxy(l-6C)alkyl; (iii) aryl(l-6C)alkoxy; (iv) aryloxy(l-6C)alkoxy;
  • R 3 is hydrogen and R 4 is aryl bearing 1 substituent independently selected from (i) aryl(l-6C)alkyl; (ii) aryloxy(l-6C)alkyl; (iii) aryl(l-6C)alkoxy; (iv) aryloxy(l-6C)alkoxy; (v) aryloxy; (vi) aryloxy(l-6C)alkylcarbamoyl; and (vii) aryloxy(l-6C)alkylsulfamoyl; wherein the aryl moiety of groups (i) to (vii) is an aryl group bearing a 3-hydroxy and a 2- carboxy or 2-(l-4C)alkoxycarbonyl group; each of the groups (i) to (vii) may be selected independently and used where appropriate with any of the other values, definitions, claims or embodiments defined hereinbefore or hereinafter
  • R 3 is hydrogen and R is unsubstituted or substituted biaryl
  • R 3 is hydrogen and R 4 is unsubstituted or substituted heteroaryl
  • R 3 is hydrogen and R is (3-7C)cycloalkyl (43) R 3 is hydrogen and R 4 is unsubstituted or substituted arylcarbonyl
  • R 3 is hydrogen and R 4 is unsubstituted or substituted heteroarylcarbonyl
  • R 3 is hydrogen and R is unsubstituted or substituted aryl(2-6C)alkenyl
  • R 3 is hydrogen and R 4 is unsubstituted or substituted aryl(2-6C)alkynyl
  • R 3 is hydrogen and R 4 is unsubstituted or substituted heteroaryl(2-6C)alkenyl (48) R 6 is hydrogen
  • R 8 is (l-4C)alkyl
  • R 9 is -C(O)(l-4C)alkyl (53) R 9 is -S(O) 2 (l-4C)alkyl
  • n 1
  • a compound of the formula I or a pharmaceutically acceptable salt thereof, wherein Ri has any of the values defined above, R 2 , R 5 and R 6 are each hydrogen, R 3 is unsubstituted aryl or aryl bearing 1, 2 or 3 substituents having any of the values defined above; and R 4 is H, (l-6C)alkyl, (l-6C)alkoxy, (1- 6C)alkylthio or halogeno.
  • R has any of the values defined above other than hydrogen.
  • Ri is (l-6C)alkoxy, hydroxy-(l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy, (l-6C)alkylthio(l-6C)alkoxy, (l-6C)alkylsulfinyl(l-6C)alkoxy, (l-6C)alkylsulfonyl(l-6C)alkoxy, aryl(l-6C)alkoxy, fluoro(l-6C)alkoxy, carbamoyl(l- 6C)alkoxy, (2-6C)alkanoylamino(l-6C)alkoxy, (l-6C)alkoxy-(l-6C)alkyl, aryloxy(l- 6C)alkyl, (l-6C)alkylsulfinyl(l-6C)alkyl, (l-6C)alkyl
  • a compound of the formula I or a pharmaceutically acceptable salt thereof, wherein R] is (l-6C)alkoxy, hydroxy-(l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy, (l-6C)alkylthio(l-6C)alkoxy, (l-6C)alkylsulfinyl(l-6C)alkoxy, (l-6C)alkylsulfonyl(l-6C)alkoxy, aryl(l-6C)alkoxy, fluoro(l-6C)alkoxy, carbamoyl(l- 6C)alkoxy, (2-6C)alkanoylamino(l-6C)alkoxy, (l-6C)alkoxy-(l-6C)alkyl, aryloxy(l- 6C)alkyl, (l-6C)alkylsulfinyl(l-6C)alkyl, (l-6C)alkyl, (l-6C)alky
  • a compound of the formula I or a pharmaceutically acceptable salt thereof, wherein Ri has any of the values defined above, R 2 , R 5 and R 6 are each hydrogen, R 4 is unsubstituted aryl or aryl bearing 1,2 or 3 substituents having any of the values defined above; and R 3 is H, (l-6C)alkyl, (l-6C)alkoxy, (1- 6C)alkylthio or halogeno.
  • Ri is (l-6C)alkoxy, hydroxy-(l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy, (l-6C)alkylthio(l-6C)alkoxy, (l-6C)alkylsulfinyl(l-6C)alkoxy, (l-6C)alkylsulfonyl(l-6C)alkoxy, aryl(l-6C)alkoxy, fluoro(l-6C)alkoxy, carbamoyl(l- 6C)alkoxy, (l-6C)alkylcarbonylamino(l-6C)alkoxy, (l-6C)alkoxy-(l-6C)alkyl, aryloxy(l- 6C)alkyl, (l-6C)alkylsulfinyl(l-6C)alkyl, (l-6C)alkyl
  • Ri is (l-6C)alkoxy, hydroxy-(l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy, (l-6C)alkylthio(l-6C)alkoxy, (l-6C)alkylsulfinyl(l-6C)alkoxy, (l-6C)alkylsulfonyl(l-6C)alkoxy, aryl(l-6C)alkoxy, fluoro(l-6C)alkoxy, carbamoyl(l- 6C)alkoxy, (l-6C)alkylcarbonylamino(l-6C)alkoxy, (l-6C)alkoxy-(l-6C)alkyl, aryloxy(l- 6C)alkyl, (l-6C)alkylsulfinyl(l-6C)alkyl, (l-6C)alkyl
  • compounds of the invention are any one of the Examples, or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof which process (wherein variable groups are, unless otherwise specified, as defined in formula (I)) comprises of: (a) cyclisation of a compound of the formula (II)
  • A is a (l-6C)alkyl, aryl or aryl(l-6C)alkyl group, such as methyl, ethyl or benzyl, or A is a linking group to a solid phase resin, for example polystyrene/Wang resin;
  • L is a displaceable group, with a boronic acid of formula R 3 -B(OH) 2 , or ester thereof, or with a compound of the formula R 3 -Sn(Q ⁇ )(Q 2 )(Q 3 ) wherein Q 1; Q 2 and Q 3 are independently selected from (l-6C)alkyl and phenyl, the latter optionally substituted by a (1- 4C)alkyl, (l-4C)alkoxy or halogeno group, in the presence of a suitable catalyst;
  • Suitable values for L include bromo, chloro, iodo, or trifluoromethanesulfonyloxy, particularly bromo.
  • Suitable values for Qi, Q 2 and Q 3 include, for example, (l-4C)alkyl, such as methyl, ethyl, propyl and butyl. Particularly suitable values for -Sn(Qi)(Q 2 )(Q 3 ) include - Sn(methyl) 3 and -Sn(butyl) 3 .
  • Suitable catalysts for the reaction are described in the review by N. Miyaura and A. Suzuki, Chem. Rev.
  • catalysts include, for example, tetrakis-(triphenylphosphine)nickel(0), bis(triphenylphosphine)nickel(II) chloride, nickel(II)chloride, palladium(U) chloride, bis(triphenylphosphine)palladium(LI) chloride and terakis(triphenylphosphine)palladium(0).
  • the latter catalyst is particularly useful.
  • the cyclisation of process (a) may be carried out using a base, such as sodium hydride or piperidine.
  • a base such as sodium hydride or piperidine.
  • the reaction is generally carried out in an inert solvent or diluent, such as tetrahydrofuran, at or about ambient temperature.
  • a boronic acid When a boronic acid is used in process (b) or (c), the reaction is carried out in the presence of a suitable base and in the presence of a suitable solvent or diluent.
  • a suitable base for use in the reaction is, for example, an alkali metal alkoxide such as sodium methoxide, an alkali metal carbonate such as sodium carbonate, potassium carbonate or cesium carbonate, or an organic base such as tri(l-6C)alkylamine, for example, triethylamine.
  • An alkali metal carbonate is particularly suitable.
  • a suitable solvent or diluent includes, for example, a hydrocarbon, such as toluene or xylene, an ether, such as dioxan or tetrahydrofuran, an (l-4C)alcohol such as methanol, ethanol or butanol, water, or mixtures thereof.
  • Particularly suitable mixtures of solvents or diluents include, for example, a mixture of dimethoxymethane, ethanol and water and a mixture of toluene, ethanol and water.
  • the reaction is generally performed at a temperature in the range, for example, 50-180°C. Heating with a source of microwave energy is advantageous for these couplings.
  • R 3 -B(OH) 2 and R 4 -B(OH) 2 may be obtained by procedures well known in the art, for example by lithiation of a compound R 3 -Br or R 4 -Br with n-BuLi in THF at -70°C under argon, followed by reaction with a trialkylborate (such as trimethylborate or triisobutylborate) at -70°C.
  • a trialkylborate such as trimethylborate or triisobutylborate
  • the ester initially formed may be isolated or hydrolysed in situ to the boronic acid by addition, for example by the addition of saturated aqueous ammonium chloride.
  • reaction is generally carried out in the presence of a suitable solvent or diluent, for example a hydrocarbon, such as toluene or xylene, or an ether, such as dioxan or tetrahydrofuran, and at a temperature in the range, for example, 20-150°C.
  • a suitable solvent or diluent for example a hydrocarbon, such as toluene or xylene, or an ether, such as dioxan or tetrahydrofuran, and at a temperature in the range, for example, 20-150°C.
  • a suitable solvent or diluent for example a hydrocarbon, such as toluene or xylene, or an ether, such as dioxan or tetrahydrofuran
  • compounds of the formula R 3 -Br and R -Br may be reacted to form a Grignard reagent which is subsequently reacted with a trialkyltin halide, such as tributyltin chloride, in a suitable solvent such as THF, at a temperature in the range of, for example, 0-25°C.
  • a trialkyltin halide such as tributyltin chloride
  • a tert-butoxycarbonyl protecting group may be removed under acidic conditions, for example using aqueous trifluoroacetic acid at ambient temperature.
  • a 9- fluorenylmethoxycarbonyl protecting group may be removed using basic conditions, for example using piperidine or l,8-diazabicyclo[5.4.0]undec-7-ene. When basic conditions are used to remove the protecting group, concomitant cyclisation to a compound of formula (I) may occur.
  • A is a (l-6C)alkyl, aryl or aryl(l-6C)alkyl group, such as methyl, ethyl or benzyl, or A is a linking group to a solid phase resin, for example polystyrene/Wang resin.
  • the cyclisation may be carried out using analogous conditions to those described herein for the cyclisation of a compound of formula (II).
  • Compounds of the formula (IV) may be prepared by cyclisation of a compound of the formula (VII)
  • Y is a protecting group, for example a tert-butoxycarbonyl or 9- fluorenylmethoxycarbonyl group.
  • a tert-butoxycarbonyl protecting group may be removed under acidic conditions, for example using aqueous trifluoroacetic acid at ambient temperature.
  • a 9-fluorenylmethoxycarbonyl protecting group may be removed using basic conditions, for example using piperidine or l,8-diazabicyclo[5.4.0]undec-7-ene. When basic conditions are used to remove the protecting group, concomitant cyclisation to a compound of formula (III) may occur.
  • (IX) may be deprotected to give a compound of the formula (VII), or (IV) if the deprotection is carried out under basic conditions.
  • a compound of the formula (V) may be prepared by sulphamoylation of a compound of the formula (X)
  • a compound of the formula (X) may be prepared by reaction of a compound of the formula (XIV)
  • Li is a displaceable group, for example chloro, bromo, iodo, tosyloxy, mesyloxy or trifluoromethanesulfonyloxy
  • A is (l-6C)alkyl, aryl or aryl(l-6C)alkyl, for example methyl, ethyl or benzyl, or A is a linking group to a solid phase resin, for example polystyrene/Wang resin.
  • a compound of the formula (X) may be prepared by reaction of a compound of the formula (XIV) with an aldehyde or ketone of formula (XVIII)
  • compounds of the formula (XII) and (XIII) may be prepared by reaction of a compound of the formula (XVI) and (XVII) respectively with a compound of the formula (XVIII), in the presence of a reducing agent.
  • a reducing agent for example sodium cyanoborohydride.
  • a compound of formula ArL (wherein L is a displaceable group and Ar represents an optionally substituted aryl, optionally substituted biaryl, or optionally substituted heteroaryl radical) may be reacted with a boronic acid or boronic ester containing compound of formula (XIX) using generic coupling conditions as described previously. Suitable values of L are those described previously.
  • Suitable values for Z are dihydroxyboryl, di(l-6C)alkoxyboryl or cyclic borate esters such as (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl).
  • a compound of formula ArL (wherein L is a displaceable group and Ar represents a an optionally substituted aryl, optionally substituted biaryl, or optionally substituted heteroaryl radical) may be reacted with a boronic acid or boronic ester containing compound of formula (XX) using generic coupling conditions as described previously.
  • Suitable values of L are those described previously.
  • Suitable values for Z are dihydroxyboryl, di(l-6C)alkoxyboryl or preferably cyclic borate esters such as (4,4,5,5-tetramethyl-l,3,2-dioxaborolan ⁇ 2-yl).
  • Compounds of formulae (XLX) and (XX) wherein Z is a cyclic borate ester may be prepared by reaction of a compound where Z is a halogen, preferably iodo, with a borylating agent such as bis(pinacolato)boron in the presence of a suitable catalyst such as [1,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(II).
  • a borylating agent such as bis(pinacolato)boron
  • a suitable catalyst such as [1,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(II).
  • R 3 or R is phenyl substituted with a 3- or 4- (aryloxyalkyl)carbamoyl group
  • aryloxyalkyl)carbamoyl group may be prepared by coupling of the corresponding 3- or 4- carboxy compounds to the appropriate (aryloxyalkyl)amines, for example by use of the peptide coupling reagents HOBt and EDCI in the presence of a suitable base such as DIPEA.
  • the (aryloxyalkyl)amines may be prepared by coupling appropriately substituted phenolic compounds with appropriately N-protected hydroxyalkylamines, for example using triphenylphosphine DEAD, followed by removing of the protecting group, which is suitably tert-butoxycarbonyl.
  • aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group.
  • modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a base such as sodium hydroxide
  • a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
  • a further aspect of the invention comprises novel intermediates used in the manufacture of the compounds of formula I.
  • the compounds defined in the present invention possess PTPIB inhibitory activity. These properties may be assessed using the following assay. Assay
  • the bacteria were grown at 37°C in high yeast extract (HYE) 20 medium containing 3.0g/l KH 2 PO 4 , 6.0g/l Na 2 HPO 4 , 0.5g/l NaCl, 2.0g/l casein hydrolysate, lO.Og/1 (NB ) 2 SO 4 , 35.0g/l glycerol, 20.0g/l yeast extract, 0.5g/l MgSO 4 .7H 2 O, 0.0294g/l CaCl 2 .2H 2 O, 0.008g/l thiamine, 40mg/l FeSO 4 , 20mg/l citric acid, lOug/ml tetracycline, and trace elements, pH 6.7.
  • HOE high yeast extract
  • IPTG isopropyl b-d-thiogalacto- pyranoside
  • lysis buffer 75mM 2-(N- morpholino)ethanesulfonic acid (MES), ImM EDTA, ImM DTT, pH6.3.
  • the cells are lysed by two passages through an ⁇ mulsiflex C5' homogeniser (available from Glen-Creston, 16 Dalston Gardens, Stanmore, HA7 IDA, England) and the soluble fraction clarified by centrifugation (58,000g for 1 hour).
  • the supernatant is passed over an 'SP-Sepharose' column (available from Amersham Biosciences UK Ltd, Amersham Place, Little Chalfont, Bucks, HP7 9 ⁇ A, England) (typically 0.5ml - 1ml resin per gram of starting paste) pre-equilibrated in lysis buffer. After passaging the supernatant, the column is washed to baseline with 4 column volumes of lysis buffer.
  • Bound proteins are eluted from the column with a 20 column volume OmM to 500mM sodium chloride gradient. Fractions are collected and those containing PTPIB, as judged by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), are pooled and concentrated using an 'Amicon stirred cell' with a 10,000 molecular weight cut off membrane (available from Millipore (U.K.) Limited, Units 3&5, The Courtyards, Hatters Lane, Watford, WD18 8YH, England).
  • the PTPIB pool is further purified by passing down a 'Superdex 75' (available from Amersham Biosciences UK Ltd) size exclusion column equilibrated in storage buffer( 75mM MES, lOOmM NaCl, ImM dithiothreitol (DTT), ImM ethylenediaminetetraacetic acid (EDTA), 30% glycerol. Fractions are collected and those containing the PTPIB are pooled and stored at -20 °C prior to use.
  • Human PTPIB activity was measured using p-nitrophenol phosphate (pNPP) as a substrate in
  • PTPIB truncated form of PTPIB (corresponding to the first 314 amino acids) as described above.
  • Compounds were prepared in dimethyl sulfoxide (DMSO) and transferred to column 1 of a 96 well microtitre plate. A 1:3 serial dilution of each compound in DMSO was carried out in across the plate.
  • DMSO dimethyl sulfoxide
  • the compounds were assayed with pNPP either at Km (0.4mM final) or lOx Km (4mM final). Reactions were stopped 15 minutes after the addition of substrate, by the addition of lO ⁇ l 1M NaOH. The enzyme activity was determined by measurement of the absorbance at 405nm. Each plate carried both DMSO vehicle controls (maximum signal) and enzyme buffer controls (minimum signal). Data was calculated with appropriate corrections for absorbance at 405nm of the compounds and pNPP. Inhibition was expressed as IC 50 values in ⁇ M. Generally the compounds, when assayed with pNPP at Km (0.4mM final) or lOxKm (4mM final), gave IC 50 values of 300 ⁇ M or less. Example 96 gave an IC 50 of 4 ⁇ M.
  • a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
  • the composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
  • a sterile solution, suspension or emulsion for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the above compositions may be prepared in a conventional manner using conventional excipients.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof will normally be administered to a warm-blooded animal at a unit dose within the range 0.1 - 50 mg/kg that normally provides a therapeutically-effective dose.
  • a unit dose form such as a tablet or capsule will usually contain, for example 1-1000 mg of active ingredient.
  • the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • the compounds defined in the present invention, or a pharmaceutically acceptable salt thereof are effective PTB1B inhibitors, and accordingly have value in the treatment of disease states mediated by this enzyme.
  • Such disease states may include, for example, any of those previously referred to herein.
  • a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in a method of prophylactic or therapeutic treatment of a warm-blooded animal, such as man, and in particular for use in the treatment of diabetes mellitus.
  • a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use as a medicament, and more particularly for use as a medicament for producing a PTPIB inhibitory effect in a warm-blooded mammal, such as man.
  • a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of diabetes mellitus.
  • a method for producing a PTPIB inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • a method for treating diabetes mellitus in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • the compounds of formula (I), or a pharmaceutically acceptable salt thereof are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of PTPIB in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • the inhibition of PTPIB described herein may be applied as a sole therapy or may involve, in addition to the subject of the present invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. Simultaneous treatment may be in a single tablet or in separate tablets.
  • agents than might be co-administered with PTPIB inhibitors may include other antidiabetic agents, such as sulfonylureas and other insulin secretagogues, PPAR ⁇ agonists and other insulin sensitisers, biguanides, glucosidase inhibitors, SGLT2 inhibitors, PPAR oc/ ⁇ dual agonists, aP2 inhibitors, glycogen phoshporylase inhibitors, glucokinase activators, advanced glycosylation end product inhibitors, meglitinides and insulin.
  • antidiabetic agents such as sulfonylureas and other insulin secretagogues, PPAR ⁇ agonists and other insulin sensitisers, biguanides, glucosidase inhibitors, SGLT2 inhibitors, PPAR oc/ ⁇ dual agonists, aP2 inhibitors, glycogen phoshporylase inhibitors, glucokinase activ
  • temperatures are given in degrees Celsius (°C); operations were carried out under an atmosphere of an inert gas such as argon or nitrogen;
  • Examples 14 to 16 were conveniently carried out using a 'Trident' automated library synthesizer (from Argonaut Technologies, 1101 Chess drive,
  • NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm), determined at 300 MHz using perdeuterio dimethyl sulphoxide (DMSO-d 6 ) as solvent;
  • DMSO-d 6 perdeuterio dimethyl sulphoxide
  • Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh 3 ) 4 ), 17.3-20 mg, -0.017 mmol, 5mol%) was added as a solid to a 4 ml reaction vial, followed by automated delivery of 7:3:2 DME/EtOH/H 2 O (1150 ⁇ l), 1.0 M 4-tolylboronic acid in anhydrous DMF (420 ⁇ l, 0.42 mmol, 1.2 eq), 0.5 M 5-(4-bromophenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide in anhydrous DMF (Method 7; 700 ⁇ l, 0.35 mmol, 1.0 eq) and 2.0 M aqueous cesium carbonate (degassed, 210 ⁇ l, 0.42 mmol, 1.2 eq) .
  • Tetrakis(triphenylphosphine)palladium(0) (17.3-20 mg, -0.017 mmol, 5mol%) was added as a solid to a 4 ml reaction vial, followed by automated delivery of 7:3:2 DME/EtOH H 2 O (1500 ⁇ l), 1.0 M 3-chlorophenylboronic acid in anhydrous DMF (420 ⁇ l, 0.42 mmol, 1.2 eq), 1.0 M 5-(3-bromophenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide in anhydrous DMF (Method 8; 350 ⁇ l, 0.35 mmol, 1.0 eq) and 2.0 M aqueous cesium carbonate (degassed, 210 ⁇ l, 0.42 mmol, 1.2 eq) .
  • the mixture was acidified with 2M HCl.
  • the aqueous fraction was extracted with dichloromethane.
  • the organic fraction was concentrated and was purified by flash chromatography on silica gel eluted with 10 % MeOH in DCM and further reverse phase HPLC on a YMCAQ C 18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluant.
  • the suspension was heated at 50 °C for 5 hours, allowed to cool to ambient temperature, drained, and washed serially with DMF (5 x 2 ml), tetrahydrofuran (5 x 2ml), and dichloromethane (5 x 2ml).
  • DMF 5 x 2 ml
  • tetrahydrofuran 5 x 2ml
  • dichloromethane 5 x 2ml
  • a solution of diisopropylethylamine in dichloromethane 0.5 ml, 2M
  • the reaction vial was cooled to -20 °C and a freshly prepared solution of 9H-fluoren-9-ylmethyl chlorosulfonylcarbamate in dichloromethane (2.9 ml, 0.15 M, 0.44meq) was added.
  • the reaction vial was shaken for 2 hours at -20 °C and gradually (over 1 hour) warmed to 0 °C, followed by shaking at ambient temperature for 3 hours.
  • the reaction vial was drained and washed serially with dichloromethane (3 x 2ml), tetrahydrofuran (3 2 ml), and DMF (3 x 2ml).
  • An 8% solution of 1,8 diazabicyclo [5.4.0] undec-7-ene in DMF (3 ml) was added to the reaction vial.
  • the reaction vial was shaken for 75 hours at ambient temperature and the liquid contents collected.
  • the remaining resin was washed with DMF (3 x 3 ml) and the washings combined with the initial collected liquid.
  • the solvent was removed at reduced pressure to give the crude product.
  • This example is Method 9.
  • Example 81 5- ⁇ 3'-[2-(2-carboxy-3-hydroxyphenoxy)ethyl1-4-methoxy-l ⁇ '-biphenyl-3-yl ⁇ - l,2,5-thiadiazolidin-3-one 1,1-dioxide and
  • Example 82 5- ⁇ 4-methoxy-3'-r2-(3-hydroxy-2-methoxycarbonylphenoxy s )ethyn-l,r- biphenyl-3 -yl 1 - 1 ,2,5-thiadiazolidin-3-one 1 , 1 -dioxide
  • the starting materials for the Examples above are either commercially available or are readily prepared by standard methods from known materials. For example the following reactions are illustrations but not limitations of the preparation of some of the starting materials used in the above reactions.
  • N,N-diisopropylethylamine (30 ml, 172 mmol) and methyl bromoacetate (0.95 eq, 32.68 mmol) were added to a solution of 4-bromoaniline (1 eq, 34.4 mmol) in anhydrous DMF (12 ml) under nitrogen.
  • the solution was heated for 17 hours at 60°C before cooling in an ice bath.
  • the cool mixture was then poured into cold water (100 ml) and refrigerated for 2 hours.
  • the title compound was isolated as an off-white, brownish solid (7.768 g).
  • 1H ⁇ MR (CDC1 3 ) 7.32 (2H, d), 6.605 (2H, d), 3.93 (2H, s), 3.81 (3H, s); m/z (M+H) + 246.
  • Methyl N-(4-bromophenyl)glycinate (Method 1; 7.768 g, 1 eq, 31.8 mmol) in anhydrous DCM (90 ml) under nitrogen was cooled to 0°C.
  • a solution of tert-butyl chlorosulfonylcarbamate (Method 4; 1.2 eq, 38.16 mmol) was prepared in-situ and transferred via cannula to the mixture under nitrogen.
  • Triethylamine (2 eq, 63.6 mmol) was slowly added under nitrogen at 0°C. The ice bath was removed and the mixture stirred at ambient temperature for 1.5 hours.
  • sodium hydride (60% suspension in mineral oil, 3 eq, 159 mmol) was dissolved in anhydrous THF (57 ml) and nitrogen bubbled through the solution.
  • the sodium hydride in THF solution was slowly added to the flask containing deprotected starting material under nitrogen and stirred for 1 hour at ambient temperature.
  • the reaction was quenched via slow addition of water (250 ml), basified with 10% sodium hydroxide to pH 14 and 400 ml ethyl acetate was added.
  • the aqueous layer was extracted 3 x 400 ml hexane to remove mineral oil, maintaining pH 14 between washes to prevent product loss.
  • the aqueous layer was separated and acidify to pH 1 with 10% aqueous hydrochloric acid.
  • the acidic aqueous layer was extracted with 4 x 500 ml ethyl acetate until no product was present by TLC.
  • the combined ethyl acetate layers were concentrated under reduced pressure to approximately 100 ml.
  • the partially concentrated solution was dried over sodium sulfate, filtered and concentrated under reduced pressure to dryness.
  • the product was dried overnight under high vacuum in the presence of phosphorus pentoxide.
  • the title compound was isolated as a yellow solid (7.075 g).
  • 1H NMR (CDC1 3 ) 7.55 (2H, d), 7.23 (2H, d), 4.59 (2H, s); m/z (M-H) " 291.
  • Diisopropylcarbodiimide (26.8 ml) was added in 5 aliquots to a solution/suspension of bromoacetic acid (47.5 g, 342 meq) at 0°C.
  • the reaction mixture was stirred for 2.5 hours and solvent was removed by rotary evaporation at reduced pressure.
  • the residue was taken up in dry, degassed DMF and added to a suspension of polystyrene/Wang linker resin (38.0 g, 0.9 meq/g, 34.2 meq) pre-swollen in DMF.
  • 4-Dimethylaminopyridine (0.4 g, 3.42 meq) was then added to this solution/suspension.
  • the entire mixture was stirred at ambient temperature for 24 hours, filtered through a coarse sintered glass funnel, and washed serially with 5 x 500 ml DMF, tetrahydrofuran, dichloromethane, and DMF.
  • the resin was subjected to the above reaction conditions a second time using only half the number of equivalents of the reagents (solvent volumes remained the same).
  • the resin mixture was filtered and washed serially with 5 x 500 ml each of DMF, THF, dichloromethane, and diethyl ether.
  • the resin was dried under vacuum/N 2 for lhour followed by high vacuum at 50 °C for 2 days. Quantitative incorporation of bromoacetate was showed by elemental analysis for bromine content.
  • NN-diisopropylethylamine 52.60 mmol, 1.4 eq was slowly added under nitrogen at 0°C. The ice bath was removed and the mixture was stirred at ambient temperature for 3 hours.
  • the reaction was quenched by slow addition of water (10 ml). The solvent was removed under reduced pressure. The residue was dissolved in water (200 ml), extracted with ether (2 x 100 ml) to remove the mineral oil. The aqueous layer was separated, acidified to pH 1 with 10 % aqueous hydrochloric acid and extracted with ethyl acetate (3 x 40 ml) until no product was present in aqueous layer. The pH was maintained at 1 between each extraction. The organic extracts were combined and concentrated under reduced pressure. The title compound was crystallized from DCM to afford an off-white solid (3.5 g).
  • Methyl 2-( ⁇ 6-[(tert-butoxycarbonyl)amino]hexylloxy)-6-hvdroxybenzoate Methyl 2,6-dihydroxybenzoate (0.454 g, 2.7 mmol, 1.0 eq.), triphenylphosphine (0.787 g, 3.0 mmol, 1.1 eq.) and tert-butyl (6-hydroxyhexyl)carbamate were added to the reaction flask and this was degassed using three evacuation/nitrogen fill cycles. THF (10 mL) was added and the whole cooled in an ice-water bath.
  • Method 26 Methyl 2-(2-aminoethoxy)-6-hvdroxybenzoate Hydrochloride Methyl 2-( ⁇ 2-[(tert-butoxycarbonyl)amino]ethyl ⁇ oxy)-6-hydroxybenzoate (Method 23) (0.100 g, 0.32 mmol, 1 eq.) was charged to the reaction flask and cooled to 0 °C. A solution of HCl in dioxane (4 M, 0.5 mL, 1.92 mmol, 6 eq.) was then added, the reaction allowed to reach ambient temperature and stirred for a further 3.5 hours.
  • Method 32 5-(5-Iodo-2-methoxyphenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide Methyl N-(aminosulfonyl)-N-(5-iodo-2-methoxyphenyl)glycinate (Method 31, 14.406 g, 36 mmol) was dissolved in dry THF (360 mL) under ⁇ , and was cooled to 0 °C on an ice-water bath. Potassium tert-butoxide in t-butanol (1 M, 40 mL, 40 mmol) was added slowly (10 min) via a syringe.
  • the compound of Method 32 shows PTPIB inhibitory activity and provides a further aspect of the invention.

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Abstract

L'invention concerne des composés de la formule (I) ou des sels pharmaceutiquement acceptables de ceux-ci, formule dans laquelle R1, R2, R3, R4, R5 et R6 ont n'importe quelle signification définie dans la description. L'invention concerne également des procédés de production de composés de la formule (I), des compositions les contenant, leur utilisation en tant qu'inhibiteurs de protéine tyrosine phosphatase PTP1B et leur utilisation dans le traitement du diabète sucré.
PCT/GB2003/004721 2002-11-07 2003-11-03 Thiadiazolidine-3-ones 5-(phenyle substitue) et leur utilisation en tant qu'inhibiteurs de ptp1b Ceased WO2004041799A1 (fr)

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Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7141596B2 (en) 2003-10-08 2006-11-28 Incyte Corporation Inhibitors of proteins that bind phosphorylated molecules
WO2007067614A1 (fr) * 2005-12-08 2007-06-14 Novartis Ag L, l, 3-tri0x0-l, 2, 5-thiadiaz0lidines et leur utilisation comme inhibiteurs des ptp-ases
WO2007067612A1 (fr) * 2005-12-08 2007-06-14 Novartis Ag Dérivés de 1-orthofluorophényl substitués 1, 2, 5-thiazolidinédione utilisés comme inhibiteurs de la ptp-ase
WO2007067615A3 (fr) * 2005-12-08 2007-11-15 Novartis Ag Composés organiques
WO2007115058A3 (fr) * 2006-03-31 2008-03-20 Novartis Ag Composés organiques
US7381736B2 (en) 2004-09-02 2008-06-03 Metabasis Therapeutics, Inc. Thiazole and thiadiazole inhibitors of tyrosine phosphatases
WO2008067527A1 (fr) * 2006-12-01 2008-06-05 Novartis Ag Inhibiteurs de la protéine tyrosine phosphatase pour le traitement d'une atrophie musculaire et de troubles associés
WO2008070552A3 (fr) * 2006-12-01 2008-07-24 Novartis Ag Inhibiteurs de la protéine tyrosine phosphatase permettant de favoriser l'hypertrophie cardiaque physiologique
WO2008148744A1 (fr) * 2007-06-04 2008-12-11 Novartis Ag Dérivés de thiadiazole utilisés en tant qu'agents antidiabétiques
JP2009518420A (ja) * 2005-12-08 2009-05-07 ノバルティス アクチエンゲゼルシャフト タンパク質チロシンホスファターゼ（ｐｔｐａｓｅ）により介在する状態の処置のために有用である１，２，５−チアゾリジン誘導体
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
WO2010149598A3 (fr) * 2009-06-24 2011-05-19 F. Hoffmann-La Roche Ag Compose antiviral heterocyclique
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
JP2014015483A (ja) * 2007-08-02 2014-01-30 Millennium Pharmaceuticals Inc Ｅ１活性化酵素阻害剤の合成のためのプロセス
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WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques
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WO2024137727A1 (fr) * 2022-12-21 2024-06-27 Bristol-Myers Squibb Company Inhibiteurs de 1,2,4-thiazolidin-3-one-1,1-dioxyde de protéine tyrosine phosphatase, compositions et procédés d'utilisation
WO2025055985A1 (fr) * 2023-09-15 2025-03-20 深圳众格生物科技有限公司 Inhibiteur de protéine tyrosine phosphatase, composition et utilisation médicale

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996016951A1 (fr) * 1994-12-02 1996-06-06 Sanofi Winthrop, Inc. Derives substitues du 1,1-dioxyde de 2-arylcarbonyloxymethyl-1,2,5-thiadiazolidin-3-one, compositions les contenant et procedes d'utilisation
WO1997040017A2 (fr) * 1996-04-19 1997-10-30 Novo Nordisk A/S Modulateurs de molecules possedant des unites de reconnaissance de la phosphotyrosine
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996016951A1 (fr) * 1994-12-02 1996-06-06 Sanofi Winthrop, Inc. Derives substitues du 1,1-dioxyde de 2-arylcarbonyloxymethyl-1,2,5-thiadiazolidin-3-one, compositions les contenant et procedes d'utilisation
WO1997040017A2 (fr) * 1996-04-19 1997-10-30 Novo Nordisk A/S Modulateurs de molecules possedant des unites de reconnaissance de la phosphotyrosine
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BRIGHT S W ET AL: "Competitive particle concentration fluorescence immunoassays for measuring anti-diabetic drug levels in mouse plasma", JOURNAL OF IMMUNOLOGICAL METHODS, ELSEVIER SCIENCE PUBLISHERS B.V.,AMSTERDAM, NL, vol. 207, no. 1, 22 August 1997 (1997-08-22), pages 23 - 31, XP004093137, ISSN: 0022-1759 *

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US7141596B2 (en) 2003-10-08 2006-11-28 Incyte Corporation Inhibitors of proteins that bind phosphorylated molecules
US7381736B2 (en) 2004-09-02 2008-06-03 Metabasis Therapeutics, Inc. Thiazole and thiadiazole inhibitors of tyrosine phosphatases
AU2006321902B2 (en) * 2005-12-08 2011-11-10 Novartis Ag 1-orthofluorophenyl substituted 1, 2 , 5-thiazolidinedione derivatives as PTP-as inhibitors
US7700633B2 (en) 2005-12-08 2010-04-20 Novartis Ag Organic compounds
US8252820B2 (en) 2005-12-08 2012-08-28 Novartis Ag 1-orthofluorophenyl substituted 1,2,5-thiazolidinedione derivatives as PTP-as inhibitors
WO2007067612A1 (fr) * 2005-12-08 2007-06-14 Novartis Ag Dérivés de 1-orthofluorophényl substitués 1, 2, 5-thiazolidinédione utilisés comme inhibiteurs de la ptp-ase
WO2007067614A1 (fr) * 2005-12-08 2007-06-14 Novartis Ag L, l, 3-tri0x0-l, 2, 5-thiadiaz0lidines et leur utilisation comme inhibiteurs des ptp-ases
WO2007067615A3 (fr) * 2005-12-08 2007-11-15 Novartis Ag Composés organiques
AU2006321905B2 (en) * 2005-12-08 2011-08-11 Novartis Ag Thiadiazole derivatives as antidiabetic agents
JP2009518419A (ja) * 2005-12-08 2009-05-07 ノバルティス アクチエンゲゼルシャフト ＰＴＰａｓｅ阻害剤としての１−オルトフルオロフェニル置換１，２，５−チアゾリジンジオン誘導体
JP2009518421A (ja) * 2005-12-08 2009-05-07 ノバルティス アクチエンゲゼルシャフト １，１，３−トリオキソ−１，２，５−チアジアゾリジンおよびＰＴＰａｓｅ阻害剤としてのそれらの使用
JP2009518420A (ja) * 2005-12-08 2009-05-07 ノバルティス アクチエンゲゼルシャフト タンパク質チロシンホスファターゼ（ｐｔｐａｓｅ）により介在する状態の処置のために有用である１，２，５−チアゾリジン誘導体
JP2009519248A (ja) * 2005-12-08 2009-05-14 ノバルティス アクチエンゲゼルシャフト 抗糖尿病剤としてのチアジアゾール誘導体
JP2009532379A (ja) * 2006-03-31 2009-09-10 ノバルティス アクチエンゲゼルシャフト ＰＴＰａｓｅのチアジアゾリジノン阻害剤
US8084448B2 (en) 2006-03-31 2011-12-27 Novartis Ag Organic compounds
WO2007115058A3 (fr) * 2006-03-31 2008-03-20 Novartis Ag Composés organiques
WO2008070552A3 (fr) * 2006-12-01 2008-07-24 Novartis Ag Inhibiteurs de la protéine tyrosine phosphatase permettant de favoriser l'hypertrophie cardiaque physiologique
WO2008067527A1 (fr) * 2006-12-01 2008-06-05 Novartis Ag Inhibiteurs de la protéine tyrosine phosphatase pour le traitement d'une atrophie musculaire et de troubles associés
WO2008148744A1 (fr) * 2007-06-04 2008-12-11 Novartis Ag Dérivés de thiadiazole utilisés en tant qu'agents antidiabétiques
JP2014015483A (ja) * 2007-08-02 2014-01-30 Millennium Pharmaceuticals Inc Ｅ１活性化酵素阻害剤の合成のためのプロセス
US10745404B2 (en) 2007-08-02 2020-08-18 Millennium Pharmaceuticals, Inc. Process for the synthesis of E1 activating enzyme inhibitors
US9802938B2 (en) 2007-08-02 2017-10-31 Millennium Pharmaceuticals, Inc. Sulfamoylating reagents
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
WO2010149598A3 (fr) * 2009-06-24 2011-05-19 F. Hoffmann-La Roche Ag Compose antiviral heterocyclique
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
EP3243385A1 (fr) 2011-02-25 2017-11-15 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques
CN112955438A (zh) * 2018-06-21 2021-06-11 卡里科生命科学有限责任公司 蛋白质酪氨酸磷酸酶抑制剂和其使用方法
JP2023055771A (ja) * 2018-06-21 2023-04-18 カリコ ライフ サイエンシーズ エルエルシー タンパク質チロシンホスファターゼ阻害剤及びそれらの使用方法
RU2799446C2 (ru) * 2018-06-21 2023-07-05 КАЛИКО ЛАЙФ САЙЕНСИЗ ЭлЭлСи Ингибиторы протеин-тирозинфосфатазы и способы их применения
JP7704787B2 (ja) 2018-06-21 2025-07-08 カリコ ライフ サイエンシーズ エルエルシー タンパク質チロシンホスファターゼ阻害剤及びそれらの使用方法
RU2833220C2 (ru) * 2019-03-14 2025-01-15 КАЛИКО ЛАЙФ САЙЕНСИЗ ЭлЭлСи Ингибиторы белковых тирозинфосфатаз и способы их применения
WO2023096928A1 (fr) * 2021-11-23 2023-06-01 Kumquat Biosciences Inc. Composés contenant des hétéroatomes et leurs utilisations
WO2024137727A1 (fr) * 2022-12-21 2024-06-27 Bristol-Myers Squibb Company Inhibiteurs de 1,2,4-thiazolidin-3-one-1,1-dioxyde de protéine tyrosine phosphatase, compositions et procédés d'utilisation
WO2025055985A1 (fr) * 2023-09-15 2025-03-20 深圳众格生物科技有限公司 Inhibiteur de protéine tyrosine phosphatase, composition et utilisation médicale

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