WO1997040017A2 - Modulateurs de molecules possedant des unites de reconnaissance de la phosphotyrosine - Google Patents

Modulateurs de molecules possedant des unites de reconnaissance de la phosphotyrosine Download PDF

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WO1997040017A2
WO1997040017A2 PCT/DK1997/000166 DK9700166W WO9740017A2 WO 1997040017 A2 WO1997040017 A2 WO 1997040017A2 DK 9700166 W DK9700166 W DK 9700166W WO 9740017 A2 WO9740017 A2 WO 9740017A2
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Henrik Sune Andersen
Niels Peter Hundahl Møller
Peter Madsen
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Novo Nordisk A/S
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    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
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    • C07F9/3882—Arylalkanephosphonic acids

Definitions

  • the present invention relates to novel organic compounds, to methods for their preparation, to compositions containing them, to their use for treatment of human and animal disorders, to their use for purification of proteins or glycoproteins, and to their use in diagnosis.
  • the invention relates to modulation of the activity of molecules with phospho-tyrosine recognition units, including protein tyrosine phosphatases (PTPases) and proteins with Src-homology-2 domains, in in vitro systems, micro-organisms, eukaryotic cells, whole animals and human beings.
  • PTPases protein tyrosine phosphatases
  • PTKs protein tyrosine kinases
  • PTPases protein tyrosine phosphatases
  • the protein phosphatases are composed of at least two separate and distinct families (Hunter, T., Cell 58: 1013-1016 (1989)) the protein serine/threonine phosphatases and the PTPases.
  • 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.
  • Intracellular PTPases All known intracellular type PTPases contain a single conserved catalytic phosphatase domain consisting of 220-240 amino acid residues. The regions outside the PTPase domains are believed to play important roles in localizing the intracellular PTPases subcellularly (Maura, LJ. and Dixon, J.E. TIBS 19: 151-155 (1994)). The first intracellular PTPase to be purified and characterized was PTP1 B which was isolated from human placenta (Tonks etal., J. Biol. Chem. 263: 6722-6730 (1988)). Shortly after, PTP1B was cloned (Charbonneau et al., Proc. Natl.
  • intracellular PTPases include (1) T-cell PTPase (Cool et al. Proc. Natl. Acad. Sci. USA 86: 5257-5261 (1989)), (2) rat brain PTPase (Guan ef al., Proc. Natl. Acad. Sci. USA 87:1501-1502
  • LMW-PTPase Low molecular weight phosphotyrosine-protein phosphatase shows very little sequence identity to the intracellular PTPases described above.
  • this enzyme belongs to the PTPase family due to the following characteristics: (i) it possesses the PTPase active site motif: Cys-Xxx-Xxx-Xxx-Xxx-Xxx-Arg (Cirri etal, Eur. J. Biochem. 214: 647-657 (1993)); (ii) this Cys residue forms a phospho-intermediate during the catalytic reaction similar to the situation with 'classical' PTPases (Cirri et al., supra; Chiarugi etal, FEBS Lett.
  • Receptor-type PTPases consist of a) a putative ligand-binding extracellular domain, b) a transmembrane segment, and c) an intracellular catalytic region.
  • the structures and sizes of the putative ligand-binding extracellular domains of receptor-type PTPases are quite divergent.
  • the intracellular catalytic regions of receptor-type PTPases are very homologous to each other and to the intracellular PTPases.
  • Most receptor-type PTPases have two tandemly duplicated catalytic PTPase domains.
  • the first receptor-type PTPases to be identified were (1) CD45/LCA (Ralph, S.J., EMBO J. 6: 1251-1257 (1987)) and (2) LAR (Streuli et al., J. Exp. Med. 168: 1523-1530 (1988)) that were recognized to belong to this class of enzymes based on homology to PTP1B (Charbonneau etal, Proc. Natl. Acad. Sci. USA 86: 5252-5256 (1989)).
  • CD45 is a family of high molecular weight glycoproteins and is one of the most abundant leukocyte cell surface glycoproteins and appears to be exclusively expressed upon cells of the hematopoietic system (Trowbridge and Thomas, Ann. Rev. Immunol. 12: 85-116 (1994)).
  • PTP-U2/GLEPP1 (Seimiya etal., Oncogene 10: 1731-1738 (1995); (Thomas ef al., J. Biol. Chem. 269: 19953-19962 (1994)), and (14) DEP-1; (IV) PTP ⁇ ,_PTP ⁇ . All receptor-type PTPases except Type IV contain two PTPase domains. Novel PTPases are continously identified, and it is anticipated that more than 500 different species will be found in the human genome, i.e. close to the predicted size of the protein tyrosine kinase superfamily (Hanks and Hunter, FASEB J. 9: 576-596 (1995)).
  • PTPases are the biological counterparts to protein tyrosine kinases (PTKs). Therefore, one important function of PTPases is to control, down-regulate, the activity of PTKs.
  • PTKs protein tyrosine kinases
  • a more complex picture of the function of PTPases now emerges.
  • Several studies have shown that some PTPases may actually act as positive mediators of cellular signalling.
  • the SH2 domain-containing PTP1D seems to act as a positive mediator in insulin- stimulated Ras activation (Noguchi etal, Mol. Cell. Biol. 14: 6674-6682 (1994)) and of growth factor-induced mitogenic signal transduction (Xiao ef al, J. Biol. Chem.
  • PTPases as positive regulators has been provided by studies designed to define the activation of the Src-family of tyrosine kinases. In particular, several lines of evidence indicate that CD45 is positively regulating the activation of hematopoietic cells, possibly througn dephosphorylation of the C-terminal tyrosine of Fyn and Lck (Chan et al., Annu. Rev. Immunol. 12: 555-592 (1994)).
  • Dual specificity protein tyrosine phosphatases define a subclass within the PTPases family that can hydrolyze phosphate from phosphortyrosine as well as from phosphor-serine/threonine.
  • dsPTPases contain the signature sequence of PTPases: His- Cys-Xxx-Xxx-Gly-Xxx-Xxx-Arg. At least three dsPTPases have been shown to dephosphorylate and inactivate extracellular signal-regulated kinase (ERKs)/mitogen- activated protein kinase (MAPK): MAPK phosphatase (CL100, 3CH134) (Charles etal, Proc. Natl. Acad.
  • dsPTPases Transcription of dsPTPases are induced by different stimuli, e.g. oxidative stress or heat shock (Ishibashi et al., J. Biol. Chem. 269: 29897-29902 (1994); Keyse and Emslie, Nature 359: 644-647 (1992)).
  • stimuli e.g. oxidative stress or heat shock (Ishibashi et al., J. Biol. Chem. 269: 29897-29902 (1994); Keyse and Emslie, Nature 359: 644-647 (1992)).
  • cdc25 Millar and Russell, Cell 68: 407-410 (1992)
  • KAP Hannon etal, Proc. Natl. Acad. Sci. USA 91: 1731- 1735 (1994)
  • tyrosine dephosphorylation of cdc2 by a dual specific phosphatase, cdc25 is required for induction of mitosis in yeast (review by Walton and Dixon, Annu. Rev. Biochem. 62: 101-120 (1993)).
  • Hormones, growth factors, cytokines, antigens, extracellular matrix components as well as molecules positioned at the cell surface induce signal transduction by binding to specific cell surface structures or receptors on target cells (reviewed in Pawson, Nature 373: 573-580 (1995)).
  • the resulting cellular signal is often mediated through a series of phosphorylation and dephosphorylation reactions on tyrosine residues of signalling molecules.
  • pTyr phosphotyrosine
  • SH2 domains and PTB domains primarily act as docking molecules with little or no catalytic activity.
  • tyrosine phosphorylated proteins have the capacity to bind other proteins containing SH2 domains or PTB domains thereby controlling the subcellular location of signalling molecules.
  • SH2 domains from the Src kinase family bind the peptide pTyr-Glu-Glu-lle in a relatively selective manner, whereas the PTPD1 seems to recognize at least five, primarily hydrophobic residues C-terminal to the pTyr (Pawson, supra).
  • Inhibition of signal transduction processes could, in principle, be achieved by using non-hydrolyzable pTyr-containing peptides with preferential affinity for specific PTPases, SH2 domains or PTB domains.
  • pTyr-containing peptides with preferential affinity for specific PTPases, SH2 domains or PTB domains.
  • Such selective compounds can either initiate, increase or decrease defined signal transduction processes.
  • Vanadate was found to inhibit protein-tyrosine phosphatases in mammalian cells with a concomitant increase in the level of phosphotyrosine in cellular proteins leading to transformation (Klariund, Cell 41: 707-717 (1985)).
  • Vanadium-based phosphatase inhibitors are relatively unspecific. Therefore, to assess the importance of specific structures on PTPase activity more selective inhibitors are needed.
  • One possibility for obtaining selective PTPase inhibitors would be through design of different ancillary ligands for peroxovanadium-based compounds (Posner et al., J. Biol. Chem. 269: 4596-4604 (1994)).
  • PTPases the insulin receptor signalling pathway/diabetes
  • Insulin is an important regulator of different metabolic processes and plays a key role in the control of blood glucose. Defects related to its synthesis or signalling lead to diabetes mellitus. Binding of insulin to its receptor causes rapid (auto) phosphorylation of several tyrosine residues in the intracellular part of the ⁇ -subunit. Three closely positioned tyrosine residues (the tyrosine-1150 domain) must all be phosphorylated to obtain full activity of the insulin receptor tyrosine kinase (IRTK) which transmits the signal further downstream by tyrosine phosphorylation of other cellular substrates, including insulin receptor substrate-1 (IRS-1) (Wilden et al, J. Biol. Chem.
  • IRTK appears to be tightly regulated by PTP- mediated dephosphorylation in vivo (Khan et al., J. Biol. Chem. 264: 12931-12940 (1989); Faure et al., J. Biol. Chem. 267: 11215-11221 (1992); Rothenberg et al, J. Biol. Chem. 266: 8302-8311 (1991)).
  • PTPases ⁇ and ⁇ While it appears that the target of the negative regulatory activity of PTPases ⁇ and ⁇ is the receptor itself, the downmodulating effect of the intracellular TC-PTP seems to be due to a downstream function in the IR-activated signal. Although PTP1B and TC-PTP are closely related, PTP1B had only little influence on the phosphorylation pattern of insulin-treated cells. Both PTPases have distinct structural features that determine their subcellular localization and thereby their access to defined cellular substrates (Frangione ef al., Cell 68: 545-560 (1992); Faure and Posner, Glia 9: 311- 314 (1993)).
  • the tack of activity of PTP1B and TC-PTP towards the IRTK may, at least in part, be explained by the fact that they do not co-localize with the activated insulin receptor.
  • PTP1B and TC-PTP have been excluded as candidates for the IR-associated PTPases in hepatocytes based on subcellular localization studies (Faure etal, J. Biol. Chem. 267: 11215-11221 (1992)).
  • the transmembrane PTPase CD45 which is believed to be hematopoietic cell-specific, was in a recent study found to negatively regulate the insulin receptor tyrosine kinase in the human multiple myeloma cell line U266 (Kulas ef al, J. Biol. Chem. 271: 755-760 (1996)).
  • Somatostatin inhibits several biological functions including cellular proliferation (Lamberts ef al, Molec. Endocrinol. 8: 1289-1297 (1994)). While part of the antiproliferative activities of somatostatin are secondary to its inhibition of hormone and growth factor secretion (e.g. growth hormone and epidermal growth factor), other antiproliferative effects of somatostatin are due to a direct effect on the target cells. As an example, somatostatin analogs inhibit the growth of pancreatic cancer presumably via stimulation of a single PTPase, or a subset of PTPases, rather than a general activation of PTPase levels in the cells (Liebow ef a/., Proc. Natl.
  • PTPases the immune svstem/autoimmunity
  • CD45 a lymphocyte-specific member of the Src family protein-tyrosine kinase (Mustelin et al, Proc. Natl. Acad. Sci. USA 86: 6302-6306 (1989); Ostergaard etal, Proc. Natl. Acad. Sci. USA 86: 8959-8963 (1989)).
  • Fyn another member of the Src family protein-tyrosine kinases, Fyn, seems to be a selective substrate for CD45 compared to Lck and Syk (Katagiri et al., J. Biol. Chem. 270: 27987- 27990 (1995)).
  • HePTP a hematopoietic cell specific PTPase
  • PTPase a hematopoietic cell specific PTPase
  • the hematopoietic cell specific PTP1C seems to act as a negative regulator and play an essential role in immune cell development
  • selective PTPase inhibitors may be attractive drug candidates both as immunosuppressors and as immunostimulants.
  • PTPase inhibitors as immunmodulators by demonstrating the capacity of the vanadium- based PTPase inhibitor, BMLOV, to induce apparent B cell selective apoptosis compared to T cells (Schieven etal, J. Biol. Chem. 270: 20824-20831 (1995)).
  • BMLOV vanadium- based PTPase inhibitor
  • Focal adhesion plaques an in vitro phenomenon in which specific contact points are formed when fibroblasts grow on appropriate substrates, seem to mimic, at least in part, cells and their natural surroundings.
  • Several focal adhesion proteins are phosphorylated on tyrosine residues when fibroblasts adhere to and spread on extracellular matrix (Gumbiner, Neuron 11, 551-564 (1993)).
  • Aberrant tyrosine phosphorylation of these proteins can lead to cellular transformation.
  • the intimate association between PTPases and focal adhesions is supported by the finding of several intracellular PTPases with ezrin-like N-terminal domains, e.g. PTPMEG1 (Gu ef a/., Proc. Natl. Acad. Sci.
  • PTPH1 Yang and Tonks, Proc. Natl. Acad. Sci. USA 88: 5949-5953 (1991)
  • PTPD1 Yang and Tonks, Proc. Natl. Acad. Sci. USA 88: 5949-5953 (1991)
  • PTPD1 M ⁇ ller et al, Proc. Natl. Acad. Sci. USA 91: 7477-7481 (1994)
  • the ezrin-like domain show similarity to several proteins that are believed to act as links between the cell membrane and the cytoskeleton.
  • PTPD1 was found to be phosphorylated by and associated with c-src in vitro and is hypothesized to be involved in the regulation of phosphorylation of focal adhesions (M ⁇ ller et al., supra).
  • PTPases may oppose the action of tyrosine kinases, including those responsible for phosphorylation of focal adhesion proteins, and may therefore function as natural inhibitors of transf ormation.
  • TC-PTP and especially the truncated form of this enzyme (Cool et al, Proc. Natl. Acad. Sci. USA 87: 7280-7284 (1990)), can inhibit the transforming activity of v- erb and (Lammers ef al., J. Biol. Chem. 268: 22456-22462 (1993); Zander et al, Oncogene 8: 1175-1182 (1993)).
  • PTP1B The expression level of PTP1B was found to be increased in a mammary cell line transformed with neu (Zhay ef al., Can ⁇ rRes. 53: 2272-2278 (1993)).
  • the intimate relationship between tyrosine kinases and PTPases in the development of cancer is further evidenced by the recent finding that PTP ⁇ is highly expressed in murine mammary tumors in transgenic mice over-expressing c-neu and v-Ha-ras, but not c-myc or int-2 (Elson and Leder, J. Biol. Chem. 270: 26116-26122 (1995)).
  • PTPK and PTP ⁇ Two closely related receptor-type PTPases, PTPK and PTP ⁇ , can mediate homophilic cell- cell interaction when expressed in non-adherent insect cells, suggesting that these PTPases might have a normal physiological function in cell-to-cell signalling (Gebbink et al, J. Biol. Chem. 268: 16101-16104 (1993); Brady-Kalnay et al., J. Cell Biol. 122: 961-972 (1993); Sap etal, Mol. Cell. Biol. 14: 1-9 (1994)).
  • PTPK and PTP ⁇ do not interact with each other, despite their structural similarity (Zondag etal, J. Biol. Chem.
  • PTPases may play an important role in regulating normal cell growth.
  • PTPases may also function as positive mediators of intracellular signalling and thereby induce or enhance mitogenic responses. Increased activity of certain PTPases might therefore result in cellular transformation and tumor formation.
  • over-expression of PTP ⁇ was found to lead to transformation of rat embryo fibroblasts (Zheng, supra).
  • SAP-1 a novel PTP, SAP-1, was found to be highly expressed in pancreatic and colorectal cancer cells.
  • SAP-1 is mapped to chromosome 19 region q13.4 and might be related to carcinoembryonic antigen mapped to 19q13.2 (Uchida et al, J. Biol. Chem. 269: 12220-12228 (1994)). Further, the dsPTPase, cdc25, dephosphorylates cdc2 at Thr14/Tyr-15 and thereby functions as positive regulator of mitosis (reviewed by Hunter, Cell 80: 225-236 (1995)). Inhibitors of specific PTPases are therefore likely to be of significant therapeutic value in the treatment of certain forms of cancer.
  • PTPases platelet aggregation
  • PTPases are centrally involved in platelet aggregation.
  • Agonist- induced platelet activation results in calpain-catalyzed cleavage of PTP1 B with a concomitant 2-fold stimulation of PTPase activity (Frangioni et al, EMBO J. 12: 4843-4856 (1993)).
  • the cleavage of PTP1 B leads to subcellular relocation of the enzyme and correlates with the transition from reversible to irreversible platelet aggregation in platelet-rich plasma.
  • the rate of bone formation is determined by the number and the activity of osteoblasts, which in term are determined by the rate of proliferation and differentiation of osteoblas progenitor cells, respectively. Histomo ⁇ hometric studies indicate that the osteoblast number is the primary determinant of the rate of bone formation in humans (Gruber ef a/., Mineral Electrolyte Metab. 12: 246-254 (1987); reviewed in Lau ef a/., Biochem. J. 257: 23-36 (1989)). Acid phosphatases/PTPases may be involved in negative regulation of osteoblast proliferation. Thus, fluoride, which has phosphatase inhibitory activity, has been found to increase spinal bone density in osteoporotics by increasing osteoblast proliferation (Lau et al., supra).
  • OST-PTP parathyroid regulated, receptor-like PTPase
  • PTPases microorganisms
  • the inventors have identified a novel class of compounds that has the capacity to modulate the activity of molecules with tyrosine recognition units, including PTPases, preferably a selective modulation.
  • the present invention relates to novel organic compounds thereof of general formula (I)
  • the present invention relates to novel organic compounds thereof of formula (I)
  • n 1 , 2, 3, 4, or 5 and (L) lake represents up to five (5) substituents which independentiy of each other are hydrogen, d -6 -alkyl, C 1-6 -alkoxy, C ⁇ alkylthio, hydroxy, halogen, tirihalogenomethyl, hydroxy-C L ⁇ -alkyl, amino-C ⁇ -alkyl, -COR 2 , -NO 2 , -CN, -CHO, -C ⁇ .
  • R 2 is Ci-e-alkyl, aryl optionally substituted, aralkyl optionally substituted, -OH, -NR 3 R 4 wherein R 3 and R 4 independently of each other are hydrogen, Ci-e-alkyl. aryl optionally substituted, aralkyl optionally substituted;
  • R 5 and R 6 are independently of each other hydrogen or Ci-e-alkyl, aryl optionally substituted, aralkyl optionally substituted or-COZi wherein Zi is d ⁇ -alkyl, aryl optionally substituted, aralkyl optionally substituted;
  • L is A ⁇ -Y ⁇ -(W ⁇ )-X-(W 2 )-Y 2 - wherein X is a chemical bond, -CO, -CONR 7 , -NR 7 CO, -NR 7 ,-
  • Yi and Y 2 are independently a chemical bond, -O-, -S-, or -NR 7 ;
  • R 7 is hydrogen, Ci- ⁇ -alkyl, aryl optionally substituted, aralkyl optionally substituted, heteroaryl optionally substituted, -COZ 2 wherein Z 2 is Ci-e-alkyl, aryl optionally substituted, aralkyl optionally substituted;
  • Wi and W 2 are independently a chemical bond or saturated or unsaturated Ci- ⁇ -alkylene
  • Ai is aryl optionally substituted, heteroaryl optionally substituted, biaryl optionally substituted, arylheteroaryl optionally substituted, -NR 8 Rg wherein R 8 and Rg independently are hydrogen, Ci-e-alkyl, aryl optionally substituted, aralkyl optionally substituted, heteroaryl optionally substituted, -COZ 3 wherein Z 3 is Ci-e-alkyl, aryl optionally substituted, aralkyl optionally substituted, heteroaryl optionally substituted or when R 8 and R 9 together with the nitrogen atom forms a ring system
  • Ai is a saturated or partially saturated heterocyclic ring system optionally substituted with Ci-e-alkyl, aryl optionally substituted, aralkyl optionally substituted, heteroaryl optionally substituted, -OH, d-e-alkoxy, Ci-e-alkylthio, hydroxy-d-e-alkyl, amino-C ⁇ .
  • A is -PO(OR ⁇ 8 )(OR, 9 ), -NH-SO3H, -NH-SO2-CH3, -NH-S0 2 -CF 3 , -CO-NH-OH or a heterocycle as shown in scheme 1 wherein the point of attachment is indicated with a I
  • R 20 is hydrogen, -OH, d-e-alkoxy, -SH, d-e-alkylthio, Ci ⁇ -alkylcarbonyloxy , -COR 21 , -SOR22,
  • R21, R22, and R 23 are -OR 2 e, Ci-e-alkyl, -NR24R25, trihalogenomethyl;
  • R 24 and R 25 independently are hydrogen, Ci-e-alkyl, -SO 2 R 2 6, -COZ 5 wherein Zs is
  • R 2 e is hydrogen, Ci- ⁇ -alkyl, trihalogenomethyl; nn is 1 or 2; and An is aryl or heteroaryl;
  • aryl, heteroaryl, An or Ai are exemplified by the following examples.
  • Specific examples of the aryl and biaryl residues include phenyl, biphenyi, indenyl, fluorenyl, naphthyl (1-naphthyl, 2-naphthyl), anthracenyl (1-anthracenyl, 2-anthracenyl, 9- anthracenyl).
  • heteroaryl examples include pyrrolyl (2-pyrrolyl), pyrazolyl (3- pyrazolyl), imidazolyl (1 -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3- triazol-1-yl, 1 ,2,3-triazol-2-yt 1,2,3-triazo!-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4- oxazolyl, 5-oxazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiophenyl (2-thiophenyl, 3-thiophenyl), pyridyl (2-pyridyl, 3-pyridyl, 4- pyridyl, 2-
  • arylheteroaryl residue examples include phenylpyridyl (2-phenylpyridyl, 3- phenylpyridyl, 4-phenylpyridyl), phenylpyrimidinyl (2-phenylpyrimidinyl, 4-phenylpyrimidinyl, 5- phenylpyrimidinyl, 6-phenylpyrimidinyl), phenylpyrazinyl, phenylpyridazinyl (3-phenyl- pyridazinyl, 4-phenylpyridazinyl, 5-phenylpyridazinyl).
  • the Ci-e-alkyl residues include aliphatic hydrocarbon residues, unsaturated aliphatic hydrocarbon residues, alicyclic hydrocarbon residues.
  • Examples of the aliphatic hydrocarbon residues include saturated aliphatic hydrocarbon residues having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tertbutyl, n-pentyl, isopentyl, neopentyl, tertpentyl, n-hexyl, isohexyl.
  • Example of the unsaturated aliphatic hydrocarbon residues include those having 2 to 6 carbon atoms such as ethenyl, 1-propenyl, 2-propenyl, 1- butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4- pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, ethynyl, 1-propionyl, 2-propionyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl.
  • Examples of the alicyclic hydrocarbon residue include
  • C 5 C 5 . s unsaturated alicyclic hydrocarbon residues having 5 to 6 carbon atoms such as 1- cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1 -cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl.
  • the Ci -e-alkoxy residues include aliphatic hydrocarbon residues connected to an oxygene atom.
  • the aliphatic hydrocarbon residues include saturated aliphatic hydrocarbon residues having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, iso ⁇ propoxy, butoxy, isobutoxy, sec.butoxy, tertbutoxy, pentoxy, isopentoxy, neopentoxy, tert.pentoxy, hexyloxy, isohexyloxy.
  • the Ci-e-alkylthio residues include aliphatic hydrocarbon residues connected to an sulphur atom.
  • the aliphatic hydrocarbon residues include saturated aliphatic hydrocarbon residues having 1 to 6 carbon atoms such as methythio, ethylthio, propoylthio, iso-propylthio, butylthio, isobutylthio, sec.butylthio, tert.butylthio, pentylthio, isopentylthio, neopentylthio, tert. pentylthio, hexylylthio, isohexylythio.
  • the C ⁇ .6-alkoxycarbonyl residues include a Ci-e-alkoxy residue connected to a carbonyl residue such as methoxycarbonyl, ethoxy-carbonyl, propoxycarbonyl, and tert- butoxyca ⁇ onyl.
  • the Ci-e-alkylcarbonyloxy residues include a Ci-e-alkyl residue connected to a carbonyloxy residue such as acetic acid, propionic acid, butyric acid.
  • the Ci-e-alkanoyloxy residues include a acyl residue connected to an oxygen atom wherein the acyl residue is an aliphatic hydrocarbon residues connected to an carbonyl residue such as acetyloxy, propionyloxy, isopropionyloxy.
  • the aralkyl residue include an aryl residue connected to an Ci-e-alkyl residue e.g. phenyl alkyls having 7 to 9 carbon atoms such as benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenyipropyl and 1-phenylpropyl; and naphthyl alkyl having 11 to 13 carbon atoms such as 1-naphthylmethyl, 1-naphthylethyl, 2-naphthylmethyl, and 2-naphthylethyl.
  • phenyl alkyls having 7 to 9 carbon atoms such as benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenyipropyl and 1-phenylpropyl
  • naphthyl alkyl having 11 to 13 carbon atoms such as 1-naphthylmethyl, 1-naphth
  • Aryloxy include an aryl connected to an oxygen atom such as phenyloxy, naphthyloxy.
  • Aralkyloxy include an aralkyl connected to an oxygen atom such as benzyloxy, phenethyloxy, naphthylmethyloxy.
  • Biaryl include an aryl connected to an aryl residue such as biphenyi, 1-phenylnaphthyl, 2- phenylnaphthyl .
  • Biaryloxy include an biaryl connected to an oxygen atom such as biphenyloxy, 4-(naphthalene-1 -yl)phenoxy, 4-(naphthalene-2-yl)phenoxy.
  • the heteroaryl residue is a 5- or 6-membered aromatic ring, which can be fused to one or more phenyl rings and contains, besides carbon atoms, 1 to 4 atoms selected from N, O, and S as atoms constituting the ring, which is bonded through ca ⁇ on atoms such as defined above.
  • the halogen residue include fluorine, chlorine, bromine, and iodine.
  • optionally substituted means an aryl residue, a heteroaryl residue, or a Ci-6-alkyl residue that may be unsubstituted or may have 1 or more preferably 1 to 5 substituents, which are the same as or different from one another.
  • substituents include, halogen (fluorine, chlorine, bromine, iodine), hydroxyl, cyano, nitro, trifluoromethyl, carbamoyl, d ⁇ -acy! (e.g. acetyl, propionyl, isopropionyl), Ci-e-alkoxy (e.g.
  • Ci-e-alkyl e.g. methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, and tert.butyl
  • Ci- ⁇ -alkoxycarbonyl e.g. ones having 2 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl
  • C 1 - 6 - alkanoyloxy e.g. ones having 2 to 6 carbon atoms such as acetyloxy, propionyloxy, isopropionyloxy
  • C ⁇ _ 4 -alky!thio e.g.
  • the compounds of formula (I) may exist as geometric and optical isomers and all isomers and mixtures thereof are included herein. Isomers may be separated by means of standard methods such as chromatographic techniques or fractionated crystallisation of e.g. suitable salts. It is to be understood that the heterocyclic moieties depicted throughout this application is capable of undergoing tautomerisation. Example of tautomerisation is given by the following example, thus:
  • the compounds according to the invention may optionally exist as pharmaceutically acceptable salts comprising acid addition salts or metal salts or - optionally alkylated - ammonium salts.
  • salts include the alkali metal or amine salts of 1 H- or 2H-tetrazoles of this invention, such as the sodium, potassium, Ci- ⁇ -alkylamine, di (Ci-e-alkyl) amine, tri (Ci-e-alkyl) amine and the four (4) corresponding omega-hydroxy analogues (e.g.
  • tetrazole derivatives and their salts thus obtained can be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, crystallisation, recrystaliisation, extraction and chromatography.
  • nitrile derivatives (II) used as starting materials in the method A of this invention can be produced by, for example, the following manner.
  • NMP N-methyl pyrrolidone
  • DMF dimethylformamide
  • THF tetrahydrofuran
  • acetone dibutyl ether, 2-butanone, methyl tert-butyl ether, methyl ethyl ketone, ethyl acetate or toluene
  • a base e.g. potassium carbonate or sodium hydride
  • a catalyst e.g. an alkali metal iodide, copper or a copper salt e.g. (CuCl, CuBr, Cul, or Cu 2 O) or in the case of a Mitsunobu reaction (for a review see, O.
  • a solvent such as triethylamine (TEA), methanol, ethanol or dimethylsulfoxid (DMSO) in the presence of a palladium catalyst, e.g. (Pd/C, Pd/AI 2 O 3 , Pd/BaSO 4 , Pd/Si0 2 or Pd(OAc) 2 (a Heck reaction) ) and a triaryl-phosphine catalyst as e.g. (triphenyl-phosphine or tri-o-tolyl-phosphine) at temperatures ranging from 50 °C to 150 °C for 1 to 60 hours.
  • a palladium catalyst e.g. (Pd/C, Pd/AI 2 O 3 , Pd/BaSO 4 , Pd/Si0 2 or Pd(OAc) 2 (a Heck reaction)
  • a triaryl-phosphine catalyst as e.g. (triphenyl-phosphine or tri-o-tolyl-phosphin
  • reaction may be carried out in a solvent such as methanol, ethanol, tetrahydrofuran (THF). toluene, N,N-dimethylfo ⁇ mamide (DMF) or dimethylsulfoxid (DMSO) in the presence of a base such as triethylamine, pyridine, piperidine, sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, lithium diisopropylamide at temperatures ranging from -50 °C to 150 °C for 1 to 60 hours.
  • a solvent such as methanol, ethanol, tetrahydrofuran (THF). toluene, N,N-dimethylfo ⁇ mamide (DMF) or dimethylsulfoxid (DMSO)
  • a base such as triethylamine, pyridine, piperidine, sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, lithium diis
  • the tetrazole group can, for example, be protected by a trityl group.
  • Introduction and removal of such groups is e.g. described in "Protective Groups in Organic Synthesis” T.W. Greene and P.G.M. Wuts, ed. Second edition (1991).
  • the compounds of the invention modulate the activity of protein tyrosine phosphatases or other molecules with phosphotyrosine recognition unit(s).
  • the compounds of the invention act as inhibitors of PTPases, e.g. protein tyrosine phosphatases involved in regulation of tyrosine kinase signalling pathways.
  • PTPases e.g. protein tyrosine phosphatases involved in regulation of tyrosine kinase signalling pathways.
  • Preferred embodiments include modulation of receptor-tyrosine kinase signalling pathways via interaction with regulatory PTPases, e.g. the signalling pathways of the insulin receptor, the IGF-I receptor and other members of the insulin receptor family, the EGF- receptor family, the platelet-derived growth factor receptor family, the nerve growth factor receptor family, the hepatocyte growth factor receptor family, the growth hormone receptor family and members of other receptor-type tyrosine kinase families.
  • regulatory PTPases e.g. the signalling pathways of the insulin receptor, the IGF-I receptor and other members of the insulin receptor family, the EGF- receptor family, the platelet-
  • Further preferred embodiments of the inventions is modulation of non-receptor tyrosine kinase signalling through modulation of regulatory PTPases, e.g. modulation of members of the Src kinase family.
  • PTPases e.g. modulation of members of the Src kinase family.
  • One type of preferred embodiments of the inventions relate to modulation of the activity of PTPases that negatively regulate signal transduction pathways.
  • Another type of preferred embodiments of the inventions relate to modulation of the activity of PTPases that positively regulate signal transduction pathways.
  • the compounds of the invention act as modulators of the active site of PTPases.
  • the compounds of the invention modulate the activity of PTPases via interaction with structures positioned outside of the active sites of the enzymes, preferably SH2 domains.
  • Further preferred embodiments include modulation of signal transduction pathways via binding of the compounds of the invention to SH2 domains or PTB domains of non-PTPase signalling molecules.
  • Other preferred embodiments include use of the compounds of the invention for modulation of cell-cell interactions as well as cell-matrix interactions.
  • the present invention include within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of formula (I) in association with a pharmaceutical carrier or diluent.
  • the pharmaceutical composition can comprise at least one of the compounds of formula (I) combined with compounds exhibiting a different activity, e.g. an antibiotic or other pharmacologically active material.
  • the compounds of the invention may be used as therapeuticals to inhibit of PTPases involved in regulation of the insulin receptor tyrosine kinase signalling pathway in patients with type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, and obesity.
  • Further preferred embodiments include use of the compounds of the invention for treatment of disorders with general or specific dysfunction's of PTPase activity, e.g. proliferarive disorders such as psoriasis and neoplastic diseases.
  • the compounds of the invention may be used in pharmaceutical preparations for treatment of osteoporosis.
  • Preferred embodiments of the invention further include use of compound of formula (I) in pharmaceutical preparations to increase the secretion or action of growth hormone and its analogous or somatomedins including IGF-1 and IGF-2 by modulating the activity of PTPases or other signal transduction molecules with affinity for phosphotyrosine involved controlling or inducing the action of these hormones or any regulating molecule.
  • compounds of the invention can be administered for pu ⁇ oses of stimulating the release of growth hormone from the pituitary or increase its action on target tissues thereby leading to similar effects or uses as growth hormone itself.
  • growth hormone may be summarized as follows: stimulation of growth hormone release in the elderly; prevention of catabolic side effects of glucocorticoids; treatment of osteoporosis, stimulation of the immune system; treatment of retardation, acceleration of wound healing; accelerating bone fracture repair; treatment of growth retardation; treating renal failure or insufficiency resulting in growth retardation; treatment of physiological short stature including growth hormone deficient children and short stature associated with chronic illness; treatment of obesity and growth retardation associated with obesity; treating growth retardation associated with the Prader-Willi syndrome and Turner's syndrome; accelerating the recovery and reducing hospitalization of bum patients; treatment of intrauterine growth retardation, skeletal dysplasia, hypercortisolism and Cushings syndrome; induction of pulsatile growth hormone release; replacement of growth hormone in stressed patients; treatment of osteochondro-dysplasias, Noonans syndrome, schizophrenia, depressions, Alzheimer's disease, delayed wound healing and psychosocial deprivation; treatment of pulmonary dysfunction and ventilator dependency; attenuation
  • the compounds of the invention may be used in pharmaceutical preparations for treatment of various disorders of the immune system, either as a stimulant or suppressor of normal or perturbed immune functions, including autoimmune reactions. Further embodiments of the invention include use of the compounds of the invention for treatment of allergic reactions, e.g. asthma, dermal reactions, conjunctivitis.
  • allergic reactions e.g. asthma, dermal reactions, conjunctivitis.
  • compounds of the invention may be used in pharmaceutical preparations for prevention or induction of platelet aggregation.
  • compounds of the invention may be used in pharmaceutical preparations for treatment of infectious disorders.
  • the compounds of the invention may be used for treatment of infectious disorders caused by Yersinia and other bacteria as well as disorders caused by viruses or other micro-organisms.
  • Compounds of the invention may additionally be used for treatment or prevention of diseases in animals, including commercially important animals.
  • Also included in the present invention is a process for isolation of PTPases via affinity purification procedures based on tine use of immobilised compounds of the invention using procedures well-known to those skilled in the art.
  • the invention is further directed to a method for detecting the presence of PTPases in cell or in a subject comprising:
  • the invention further relates to analysis and identification of the specific functions of certain PTPases by modulating their activity by using compounds of the invention in cellular assay systems or in whole animals.
  • Signal transduction is a collective term used to define all cellular processes that follow the activation of a given cell or tissue.
  • Examples of signal transduction which are not intended to be in any way limiting to the scope of the invention claimed, are cellular events that are induced by polypeptide hormones and growth factors (e.g. insulin, insulin-like growth factors I and II, growth hormone, epidermal growth factor, platelet-derived growth factor), cytokines (e.g. inter-leukins), extracellular matrix components, and cell-cell interactions.
  • polypeptide hormones and growth factors e.g. insulin, insulin-like growth factors I and II, growth hormone, epidermal growth factor, platelet-derived growth factor
  • cytokines e.g. inter-leukins
  • Phosphotyrosine recognition units/tyrosine phosphate recognition units/pTyr recognition units are defined as areas or domains of proteins or glycoproteins that have affinity for molecules containing phosphorylated tyrosine residues (pTyr).
  • Examples of pTyr recognition units which are not intended to be in any way limiting to the scope of the invention claimed, are: PTPases, SH2 domains and PTB domains.
  • PTPases are defined as enzymes with the capacity to dephosphorylate pTyr-containing proteins or glycoproteins.
  • Examples of PTPases which are not intended to be in any way limiting to the scope of the invention claimed, are: 'classical' PTPases (intracellular PTPases (e.g. PTP1B, TC-PTP, PTP1C, PTP1D, PTPD1, PTPD2) and receptor-type PTPases (e.g. PTP ⁇ , PTP ⁇ , PTP ⁇ , PTP ⁇ , CD45, PTPK, PTP ⁇ ), dual specificty phosphatases (VH1, VHR, cdc25), LMW-PTPases or acid phosphatases.
  • intracellular PTPases e.g. PTP1B, TC-PTP, PTP1C, PTP1D, PTPD1, PTPD2
  • receptor-type PTPases e.g. PTP ⁇ , PTP ⁇ , PTP ⁇ , P
  • Modulation of cellular processes is defined as the capacity of compounds of the invention to 1) either increase or decrease ongoing, normal or abnormal, signal transduction, 2) initiate normal signal transduction, and 3) initiate abnormal signal transduction.
  • Modulation of pTyr-mediated signal transduction/modulation of the activity of molecules with pTyr recognition units is defined as the capacity of compounds of the invention to 1) increase or decrease the activity of proteins or glycoproteins with pTyr recognition units (e.g. PTPases, SH2 domains or PTB domains) or to 2) decrease or increase the association of a pTyr-containing molecule with a protein or glyco-protein with pTyr recognition units either via a direct action on the pTyr recognition site or via an indirect mechanism.
  • proteins or glycoproteins with pTyr recognition units e.g. PTPases, SH2 domains or PTB domains
  • Examples of modulation of pTyr-mediated signal transduction/modulation of the activity of molecules with pTyr recognition units are: a) inhibition of PTPase activity leading to either increased or decreased signal transduction of ongoing cellular processes; b) inhibition of PTPase activity leading to initiation of normal or abnormal cellular activity; c) stimulation of PTPase activity leading to either increased or decreased signal transduction of ongoing cellular processes; d) stimulation of PTPase activity leading to initiation of normal or abnormal cellular activity; e) inhibition of binding of SH2 domains or PTB domains to proteins or glycoproteins with pTyr leading to increase or decrease of ongoing cellular processes; f) inhibition of binding of SH2 domains or PTB domains to proteins or glycoproteins with pTyr leading to initiation of normal or abnormal cellular activity.
  • a subject is defined as any mammalian species, including humans.
  • dosage will vary depending on the compound of formula (I) employed, on the mode of administration and on the therapy desired. However, in general, satisfactory results are obtained with a dosage of from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of compounds of formula (I), conveniently given from 1 to 5 times daily, optionally in sustained release form.
  • dosage forms 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 formula (I) admixed with a pharmaceutical carrier or diluent.
  • the compounds of formula (I) may be administered in a pharmaceutically acceptable acid addition salt form or where possible as a metal or a Ci-e-alkylammonium salt. Such salt forms exhibit approximately the same order of activity as the free acid forms.
  • This invention also relates to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutical earner or diluent.
  • the 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 earner 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.
  • 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 earner will vary widely but will usually be from about 25 mg to about 1 g.
  • 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 which 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.
  • reaction mixture was quenched with water (250 ml) and extracted with diethyl ether (2 x 100 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (2 x 80 ml), dried (MgSO 4 ), filtered and evaporated in vacuo affording 5.2 g (84%) of naphthalene-2-carbonyl isothiocyanate.
  • the cooled reaction mixture was quenched by addition of 1 N sodium hydroxide (150 ml) and diluted by ad ⁇ dition of diethyl ether.
  • the precipitate was filtered off, washed with water (2 x 10 ml) and diethyl ether (2 x 10 ml) and dried at 50 °C which af- forded 0.25 g (39%) of the title compound as a solid.
  • the solid was first washed with a mixture of ethyl acetate, heptane and dichloromethane (1 :1:6, 40 ml) and then washed with dichloromethane (20 ml). Drying in vacuo at 50 °C afforded 1.88 g (28%) of the titie compound as a solid.
  • Carbazole (8.25 g, 49 mmol) was dissolved in N,N'-dimethylformamide (100 ml). Under a atmosphere of nitrogen was added sodium hydride (2.56 g, 64 mmol of a 60% suspen- sion in mineral oil) in portion during 15 minutes. The mixture was then stirred at room temperature for 0.5 h. To the resulting mixture was added 4-phenylbenzylchloride (10 g, 49 mmol) in portions during 10 minutes. Then additional N,N'-dimethylformamide (100 ml) was added and the mixture was stirred at room temperature for 3.5 h.
  • Diethylaminosulfur trifluonde (2 2 ml, 8 2 mmol) was dissolved in dichloromethane (25 ml) and the solution was cooled to -70 °C and added dropwise to a solution of the above hydroxymethylphosphonic acid di-tert-butyl ester (4.0 g, 8 3 mmol) in dichloromethane (15 ml) at -70 °C. The mixture was stirred at -70 °C for 3 h and at room temperature for 20 h.
  • EXAMPLE 25 The PTP1B and PTP ⁇ cDNA was obtained by standard polymerase chain reaction technique using the Gene Amp Kit according to the manufacturer's instructions (Perkin Elmer/Cetus).
  • the oligonucleotide primers were designed according to published sequences (Chernoff et al., Proc. Natl. Acad. Sci. U.S.A. 87: 2735-2739 (1990); Krueger et al.EMBO J. 9: 3241-3252 (1990)) including convenient restriction nuclease sites to allow cloning into expression vectors.
  • the cDNA corresponding to the full-length sequence of PTP1B and the intracellular part of PTP ⁇ were introduced into the insect cell expression vector pVL1392.
  • the proteins were expressed according to standard procedures.
  • PTP1 B was semi-purified by ion exchange chromatography, and PTP ⁇ was purified to apparent homogeneity using a combination of ion exchange chromatography and gel filtration techniques using standard procedures.
  • TC-PTP and LAR domain 1 were obtained from New England Biolabs.
  • Yersinia PTP was a kind gift from J.E. Dixon, The University of Michigan, Ann Arbor, USA p- Nitrophenyl phosphate was purchased from Sigma and used without further purification.
  • p-Nitrophenyl phosphate is a general phosphatase substrate including a substrate for PTPases.
  • pNPP colourless
  • pNPP hydrolysed by a phosphatase to phosphate and p- nitrophenolate (yellow in alkaline solutions)
  • the enzyme reaction can be followed by measuring the optical density at 410 nm after adjusting the pH appropriately.
  • pNPP was used as general substrate to analyse the PTPase inhibitory capacity of the compounds of the invention.
  • the inhibiting effect of a compound is given by its Kj value, which expresses the concentration of inhibitor ( ⁇ M) in the reaction mixture necessary for a 50 percent reduction of the enzyme activity.
  • the Kj may be determined by a titration curve using several appropriately diluted solutions of the inhibitor or by using the following more simple formula, when the concentration of inhibitor is in large excess of the enzyme concentration:
  • Ki lo x E/(Eo - E) where l 0 is the concentration of inhibitor ( ⁇ M) added to the reaction mixture, E is the activity of the enzyme in the reaction mixture containing the inhibitor, and Eo is the enzyme activity in a corresponding control reaction mixture without the inhibitor.
  • the Kj values of inhibitors towards PTP1B were measured as follows. In all cases the inhibiting effects were determined at pH 5.5 and at 37 °C with a reaction time of 60 minutes.
  • reaction mixtures were:
  • the substrate solution contained 0.2 M acetate buffer, pH 5.5, 11 mM p-nitrophenyl phosphate, 5.5 mM dithiotreitol.
  • the reaction was stopped by addition of 4 ml 0.2 N NaOH, and the enzyme activity was determined by measuring the release of p-nitrophenol at 410 nm.
  • the inhibiting effect was calculated as shown above.
  • the Kj values of inhibitors towards TdPTP, LAR domainl, PTP ⁇ domain 1+2, and Yersinia PTP were measured essentially as described for PTP1B with the exception that all reactions were carried out in 96-wells microtiter plates. In all cases the inhibiting effects were determined at pH 5.5 and at room temperature with a reaction time of 15 minutes.
  • the reaction mixtures were:
  • the final concentrations 0.2 M acetate buffer, pH 5.5, 5 mM p-nitrophenyl phosphate, 5 mM dithiotreitol.
  • the reaction was stopped by addition of 100 ⁇ l 0.4 N NaOH, and the enzyme activity was determined by measuring the release of p-nitrophenol at 405 nm. The inhibiting effect was calculated as shown above.

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Abstract

Cette invention concerne de nouveaux composés organiques, des procédés de préparation de ces composés et des compositions les contenant. Cette invention concerne également l'utilisation de ces composés dans le traitement de troubles chez l'homme et chez les animaux, dans la purification de protéines ou de glycoprotéines, et dans des diagnostics. Cette invention concerne en outre la modulation, dans des systèmes in vitro, de l'activité de molécules possédant des unités de reconnaissance de la phosphotyrosine, y compris des protéines tyrosine phosphatases (PTPases) et des protéines possédant des domaines Src-homologie-2. Cette invention concerne enfin des micro-organismes, des cellules eucaryotes, ainsi que des animaux et des êtres humains dans leur ensemble. Ces nouveaux composés organiques correspondent à la formule générale (I) (L)n--Ar1--R1--A où (L)n, n, Ar1, R1 et A sont tels que définis dans la description.
PCT/DK1997/000166 1996-04-19 1997-04-17 Modulateurs de molecules possedant des unites de reconnaissance de la phosphotyrosine WO1997040017A2 (fr)

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JP09537609A JP2000511883A (ja) 1996-04-19 1997-04-17 ホスホチロシン認識ユニットを有する分子のモジュレーター

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US6503935B1 (en) 1998-08-07 2003-01-07 Abbott Laboratories Imidazoles and related compounds as α1A agonists
US6174874B1 (en) 1998-09-21 2001-01-16 Merck Frosst Canada & Co. Phosphonic acids derivatives as inhibitors of protein tyrosine phosphate 1B (PTP-1B)
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WO2000043006A1 (fr) * 1999-01-19 2000-07-27 Sankyo Company, Limited Inhibiteur de la mort des cellules nerveuses imputable à la cytotoxicité de l'acide glutamique
US6713473B1 (en) 1999-04-20 2004-03-30 Meiji Seika Kaisha, Ltd. Tricyclic compounds
US6365592B1 (en) 1999-05-14 2002-04-02 Merck Frosst Canada & Co. Phosphonic and carboxylic acid derivatives as inhibitors of protein tyrosine phosphatase-1B (PTP-1B)
US6855719B1 (en) 1999-08-21 2005-02-15 Astrazeneca Ab Imidazo[1,2-A]pyridine and pyrazolo[2,3-A]pyridine derivatives
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
US7115624B1 (en) 1999-09-10 2006-10-03 Novo Nordisk A/S Method of inhibiting protein tyrosine phosphatase 1B and/or T-cell protein tyrosine phosphatase 4 and/or other PTPases with an Asp residue at position 48
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US6777433B2 (en) 1999-12-22 2004-08-17 Merck Frosst Canada & Co. Protein tyrosine phosphatase 1B (PTP-1B) inhibitors containing two ortho-substituted aromatic phosphonates
US6486142B2 (en) 1999-12-22 2002-11-26 Merck Frosst Canada & Co. Phosphonic acid derivatives as inhibitors of protein tyrosine phosphatase 1B (PTP-1B)
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US6448429B1 (en) 1999-12-22 2002-09-10 Merck Frosst Canada & Co. Protein tyrosine phosphatase 1B (PTP-1B) inhibitors containing two ortho-substituted aromatic phosphonates
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US6486141B2 (en) 1999-12-22 2002-11-26 Merck Frosst Canada & Co. Phosphonic acid biaryl derivatives as inhibitors of protein tyrosine phosphatase 1B (PTP-1B)
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US6498151B2 (en) 2000-03-22 2002-12-24 Merck Frosst Canada & Co. Aryldifluoromethylphosphonic acids with sulfur-containing substituents as PTP-1B inhibitors
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AU2381397A (en) 1997-11-12

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