EP1080068A1 - Modulators of protein tyrosine phosphatases - Google Patents

Modulators of protein tyrosine phosphatases

Info

Publication number
EP1080068A1
EP1080068A1 EP99907336A EP99907336A EP1080068A1 EP 1080068 A1 EP1080068 A1 EP 1080068A1 EP 99907336 A EP99907336 A EP 99907336A EP 99907336 A EP99907336 A EP 99907336A EP 1080068 A1 EP1080068 A1 EP 1080068A1
Authority
EP
European Patent Office
Prior art keywords
compound according
selective
ptpases
compound
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99907336A
Other languages
German (de)
English (en)
French (fr)
Inventor
Lutz Stefan Richter
Henrik Sune Andersen
Josef Vagner
Claus Becker Jeppesen
Niels P H Moeller
Sven Branner
Lone Jeppesen
Ole Hvilsted Olsen
Lars Fogh Iversen
Daniel Dale Holsworth
Frank Urban Axe
Yu Ge
Todd Kevin Jones
William Charles Ripka
Roy Teruyuki Uyeda
Jing Su
Farid Bakir
Luke Milburn Judge
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novo Nordisk AS
Ontogen Corp
Original Assignee
Novo Nordisk AS
Ontogen Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novo Nordisk AS, Ontogen Corp filed Critical Novo Nordisk AS
Publication of EP1080068A1 publication Critical patent/EP1080068A1/en
Withdrawn legal-status Critical Current

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    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems

Definitions

  • the present invention provides novel compounds, novel compositions, methods of their use, and methods of their identification, where such compounds are pharmacologically useful inhibitors of Protein Tyrosine Phosphatases (PTPases, PTPs) such as PTP1B, TC-PTP, CD45, SHP-1 , SHP-2, PTP ⁇ , PTP ⁇ , PTP ⁇ , PTP ⁇ , PTP ⁇ , PTP ⁇ , PTP ⁇ , PTPD1 , PTPD2, PTPH1 , PTP-MEG1 , PTP-LAR, and HePTP or ligands of phosphotyrosine units.
  • PTPases Protein Tyrosine Phosphatases
  • PTPases protein tyrosine phosphatases
  • PTPases protein tyrosine phosphatases
  • PTP ⁇ , LAR, TC-PTP, SHP-1 , SHP-2, PTP ⁇ , CD45, PTP1 B, HePTP protein tyrosine phosphatases
  • tyrosine phosphatases can also contribute to the symptoms and progression of various diseases (Wiener, et al., J. Natl. cancer Inst. 86:372-8, 1994; Hunter and Cooper, Ann. Rev. Biochem, 54:897-930, 1985). Furthermore, there is increasing evidence which suggests that inhibition of these PTPases may help treat certain types of diseases such as diabetes, autoimmune disease, acute and chronic inflammation and various forms of cancer.
  • Protein phosphorylation is now well recognized as an important mechanism utilized by ceils to transduce signals during different stages of cellular function (Fischer et al, Science 253:401-6 (1991); Flint et al., The EMBO J. 12:1937-46 (1993)).
  • phosphatases There are at least two major classes of phosphatases: (1) those that dephosphorylate proteins (or peptides) that contain a phosphate group(s) on a serine or threonine moiety (termed Ser/Thr phosphatases) and (2) those that remove a phosphate group(s) from the amino acid tyrosine (termed protein tyrosine phosphatases or PTPases).
  • the PTPases are a family of enzymes that can be classified into two groups: a) intra- cellular or nontransmembrane PTPases and b) receptor-type or transmembrane PTPases.
  • Intracellular PTPases Most 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 (Mauro, L.J. and Dixon, J.E. TIBS 19: 151-155 (1994)). The first intracellular PTPase to be purified and characterized was PTP1B which was isolated from human placenta (Tonks et al., J. Biol. Chem. 263: 6722-6730 (1988)). Shortly after, PTP1B was cloned (Charbonneau et al., Proc.
  • intracellular PTPases include (1) T-cell PTPase (Cool et al. Proc. Natl. Acad. Sci. USA 86: 5257-5261 (1989)), (2) rat brain PTPase (Guan et al., Proc. Natl. Acad. Sci. USA 87:1501-1502 (1990)), (3) neuronal phosphatase STEP (Lombroso et al., Proc. Natl. Acad. Sci.
  • 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 et al., 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 et al., 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 et al., 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 ex- pressed upon cells of the hematopoietic system (Trowbridge and Thomas, Ann. Rev. Immunol. 12: 85-116 (1994)).
  • PTP-U2/GLEPP1 (Seimiya et al., Oncogene 10: 1731-1738 (1995); Thomas et al., J. Biol. Chem. 269: 19953-19962 (1994)), and (14) DEP-1; (IV) PTP ⁇ ,_PTP ⁇ . All receptor-type PTPases except Type III contain two PTPase domains. Novel PTPases are continuously 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 superfamiiy (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 SHP-2 seems to act as a positive mediator in insulin-stimulated Ras activation (Noguchi et al., Mol. Cell. Biol. 14: 6674-6682 (1994)) and of growth factor-induced mitogenic signal trans- duction (Xiao et al., J. Biol. Chem.
  • 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: Cys-Xxx-Xxx-Xxx ⁇ 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 et al., 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 et al., 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)).
  • PTPases were originally identified and purified from cell and tissue lysates using a variety of artificial substrates and therefore their natural function of dephosphorylation was not well known. Since tyrosine phosphorylation by tyrosine kinases is usu- ally associated with cell proliferation, cell transformation and cell differentiation, it was assumed that PTPases were also associated with these events. This association has now been proven to be the case with many PTPases.
  • PTP1 B a phosphatase whose structure was recently elucidated (Barford et al., Science 263:1397- 1404 (1994)) has been shown to be involved in insulin-induced oocyte maturation (Flint et al., The EMBO J. 12:1937-46 (1993)) and recently it has been suggested
  • _-_rb B2 that the overexpression of this enzyme may be involved in p185 -associated breast and ovarian cancers (Wiener, et al., J. Natl. cancer Inst. 86:372-8 (1994); Weiner et al., Am. J. Obstet. Gynecol. 170:1177-883 (1994)).
  • the insulin-induced oocyte maturation mechanism has been correlated with the ability of PTP1B to block activation of S6 kinase.
  • the association with cancer is recent evidence which suggests that overexpression of PTP1 B is statistically correlated with increased levels of p 185 c - erb B2 jn ovar j an anc j breast cancer.
  • PTP1 B The role of PTP1 B in the etiology and pro ⁇ gression of the disease has not yet been elucidated. Inhibitors of PTP1 B may therefore help clarify the role of PTP1B in cancer and in some cases provide thera-Guinic treatment for certain forms of cancer.
  • 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 b-subunit. Three closely po- sitioned 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.
  • PTP1B and TC- PTP are closely related, PTP1 B 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 sub- strates (Frangione et al, Cell 68: 545-560 (1992); Faure and Posner, Glia 9: 311-314 (1993)).
  • PTP1 B and TC-PTP 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 local- ization studies (Faure et al, 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 et al., J. Biol. Chem. 271 : 755-760 (1996)).
  • Knock-out mice have been useful in elucidating the importance of specific genes in a number of cases. From the results presented above, it would be expected that in particular LAR K.O. mice, PTP ⁇ K.O. mice and PTP1 B K.O. mice, respectively, could provide important information in relation to insulin signaling.
  • Two groups have generated LAR K.O. mice (Schaapveld at al., Developmental Biology 188: 134-146 (1997); Skarnes et al., Proc. Natl Acad.Sci. U.S.A. 92:6592-6596 (1995)). Goldstein and co- workers analyzed the LAR K.O. mice from Skarnes et al.
  • PTP1 B -/- mice were compared with +/+ and +/- mice of the same genetic background (Elchebly et al., Science 283: 1544-1548 (1999)). In this latter study (Elcheby et al., supra), it was found that disruption of the gene encoding the PTP1 B yielded healthy mice that - in the fed state - had blood glucose levels that were slightly lower and concentrations of insulin that were about Vi of those found in their PTP1 B+/+ littermates. Further, both insulin and glucose tolerance tests showed enhanced insulin sensitivity in the PTP K.O. mice.
  • PTP1B-/- and PTP1B-/+ mice were resistant to weight gain and remained insulin sensitive - in contrast to the PTP1B +/+ mice that rapidly gained weight and became insulin resistant.
  • Analysis of the levels of tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1) showed increased phosphorylation of these proteins in PTP1B -/- mice (liver and muscle) in comparison with the PTP1B +/+ mice. All of these findings are in accordance with the notion that PTP1 B is likely to play a major role as negative regulator of the insulin receptor signaling pathway - and in contrast to the above-mentioned in vitro studies. The authors conclude that 'these results make PTP-1 B a potential therapeutic target for treatment of type 2 diabetes and obesity' (Elcheby et al., supra).
  • Somatostatin inhibits several biological functions including cellular proliferation
  • 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 et al, Proc. Natl. Acad. Sci.
  • stably expressed in CHO-K1 ceils can stimulate PTPase activity and that this stimulation is pertussis toxin-sensitive. Whether the inhibitory effect of somatostatin on hormone and growth factor secretion is caused by a similar stimulation of PTPase activity in hormone producing cells remains to be determined.
  • PTPases the immune system/autoimmunity
  • CD45 is one of the most abundant of the cell surface glycoproteins and is expressed exclusively on hemopoetic cells. In T cells, it has been shown that CD45 is one of the critical components of the signal transduction machinery of lymphocytes.
  • CD45 phosphatase plays a pivotal role in antigen-stimulated proliferation of T lymphocytes after an antigen has bound to the T cell receptor (Trowbridge, Ann. Rev. Immunol, 12:85-116 (1994)).
  • Lck a lymphocyte-specific member of the Src family protein-tyrosine kinase (Mustelin etal., Proc. Natl. Acad. Sci. USA 86: 6302-6306 (1989); Ostergaard et al., 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)).
  • CD45 has also been shown to be essential for the antibody mediated degranulation of mast cells (Berger et al., J. Exp. Med. 180:471-6 (1994)). These studies were also done with mice that were CD45-deficient. In this case, an IgE-mediated degranulation was demonstrated in wild type but not CD45-deficient T cells from mice. These data suggest that CD45 inhibitors could also play a role in the symptomatic or therapeutic treatment of allergic disorders.
  • HePTP lymphoid-specific protein tyrosine phosphatase
  • SHP-1 plays a significant role in regulating the erythropoietin signalling pathway, which is enhanced in mice lacking intact SHP-1 (Schultz et al. Cell 73: 1445-1454.
  • selective PTPase inhibitors may be attractive drug candidates both as immunosup- pressors and as immunostimulants as well as inhibitors and stimulants of the hematopoietic system.
  • 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 et al., J. Biol. Chem. 270: 20824-20831 (1995)). 12 PTPases: cell-cell interactions/cancer
  • 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 in- tracellular PTPases with ezrin-iike N-terminal domains, e.g. PTPMEG1 (Gu et al, 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 cy- toskeleton.
  • 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 transformation.
  • 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-en and v-fms (Lam ers et 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 et al, Cancer Res. 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)).
  • the human 13 gene encoding PTPg was mapped to 3p21 , a chromosomal region which is frequently deleted in renal and lung carcinomas (LaForgia et al, Proc. Natl. Acad. Sci. USA 88: 5036-5040 (1991)).
  • PTPases appear to be involved in controlling the growth of fibroblasts.
  • Swiss 3T3 cells harvested at high density contain a membrane-associated PTPase whose activity on an average is 8-fold higher than that of cells harvested at low or medium density (Pallen and Tong, Proc. Natl. Acad. Sci. USA 88: 6996-7000 (1991)). It was hypothesized by the authors that density-dependent inhibition of cell growth involves the regulated elevation of the activity of the PTPase(s) in question.
  • PTPases 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 et al, Mol. Cell. Biol. 14: 1-9 (1994)).
  • PTPk and PTP ⁇ do not interact with each other, despite their structural similarity (Zondag et al, 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.
  • overexpression 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 14 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-cataiyzed cleavage of PTP1B 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 osteoblast progenitor cells, respectively. Histomorphometric studies indicate that the osteoblast number is the primary determinant of the rate of bone formation in hu- mans (Gruber et al, Mineral Electrolyte Metab. 12: 246-254 (1987); reviewed in Lau et al, 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 osteopo- rotics by increasing osteoblast proliferation (Lau et al, supra).
  • OST-PTP parathyroid regulated, recep- tor-like PTPase
  • PTPases microorganisms
  • PTPases are essential elements in a variety of cellular signalling processes. Inhibitors or modulators of these enzymes, or a given subset of PTPases, or even one specific PTPase, are therefore attractive drug candidates. However, until now only a limited set of inhibitors has been reported in the literature. Some of the most potent inhibitors are analogs of tyrosine-phosphorylated peptides and therefore not suitable candidates for oral use.
  • Vanadate and Pervanadate induce insulin-like effects in cells and animals.
  • a few anecdotal, clinical studies with formulas of vanadate have shown positive effects in humans with type II diabetes.
  • the mechanism of action at the cellular level is believed to be via inhibition of PTPases.
  • Pervanadate the complexes of vanadate and hydrogen peroxide
  • the effects are very sensitive to the assay constituents such as EDTA and reducing agents (e.g.
  • vanadate and peroxovana- dium-based compounds inhibit a broad range of PTPases. It conceivable that the mechanism of action, i.e. oxidation of the active site cysteine, will cause substantial problems when attempting to develop compounds that selectively inhibit specific PTPases. Further, the toxic effects of vanadate, pervanadate and peroxovanadium- based inhibitors will likely prevent their use for treatment of chronic diseases such as diabetes. 17
  • Bisphosphonates have been successfully used as therapeutic agents for treatment of bone disorders such as osteoporosis and Paget's disease. Bisphosphonates inhibits osteoclast resorption which results in reduced bone turnover and a net gain in bone mineral density (for review, see Rodan and Fleisch, J. Clin. Invest. 97: 2692-2696 (1996)). It is currently believed that the mechanism of action at the cellular level is via bisphosphonates' inhibitory activity against PTPases (in the osteoclasts) (Skorey et al., J. Biol. Chem. 272: 22472-22480 (1997); Opas et al., Biochemical Pharmacology 54: 721-727 (1997)).
  • AuTM disodium aurothiomalate
  • PTPases autoimmune and inflammatory dis- orders
  • AuTM appears to inhibit PTPases via its interaction with the active site nucleophilic cysteine in these enzymes.
  • Dithiothreitol can prevent or almost completely prevent this inhibition, which is in contrast to compounds of the present invention.
  • bisphosphonates substantial problems are likely to arise if the gold compounds were to be used to develop selective inhibitors.
  • the inhibitors described above are non-selective. Some of the observed toxic effects or side effects are likely to be caused, at least in part, by their lack of selectivity.
  • FIG. 1 Steady State Enzyme Kinetic Analysis.
  • PTP1 B was incubated in 96 well plates with different concentrations of the substrate, para-nitrophenyl phosphate (pNPP), and the inhibitor, 2-(oxalylamino)benzoic acid: 0, 7.4, 22.2, 66.7 and 200 ⁇ M - final assay concentration).
  • Buffer 100 mM sodium acetate pH 5.5, 50 mM NaCl, 5 mM dithiothreitol, 0.1 % (w/v) bovine serum albumin, incubation time: 45 minutes; temperature: 25°C.
  • Sodium hydroxide was added and the absorbance read at 405 nm.
  • Figure 2 Steady State Enzyme Kinetic Analysis. Conditions as in Figure 2, except that the buffer was (final assay concentration): 100 mM sodium acetate pH 5.5, 50 mM NaCl, 5 mM glutathione, 1 mM EDTA, and 0.1 % bovine serum albumin. Incubation time: 60 mins. Exp. 1167-3
  • FIG. 3 Time course experiments.
  • PTP1 B was incubated in 96 well plates at room temperature with 2.5 M para-nitrophenol phosphate (pNPP) in a buffer containing.
  • the compound, 2-(oxalylamino)benzoic acid was added at final assay concentrations of 250, 125 and 62.5 ⁇ M.
  • the reaction was started by addition of the enzyme, and the stopped at the indicated time intervals by addition of NaOH.
  • the absorbance at 405 nm was finally measured in all wells.
  • B As in (A), except that EDTA was added to a final concentration of 1 mM.
  • FIG. 6 Steady State Enzyme Kinetic Analysis.
  • PTP ⁇ was incubated in 96 well plates with different concentrations of the substrate, para-nitrophenyl phosphate (pNPP), and the inhibitor, 5-(1 ,3-dioxo-1 ,3-dihydro- isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid: 0, 7.4, 22.2, 66.7 and 200 ⁇ M - final assay concentrations.
  • pNPP para-nitrophenyl phosphate
  • Buffer final assay concentration: 100 mM sodium acetate pH 5.5, 50 mM NaCl, 5 mM glutathione, 1 mM EDTA, and 0.1 % bovine serum albumin. Reaction temperature: 25 °C. After 60 minutes, 10 ⁇ l of a 0.5 M sodium hydroxide solution (in 50 percent (vol/vol) ethanol) was added to each well and the absorbance was read at 405 nm. (B) Michaelis Menten Plots.
  • PTP ⁇ was incubated in 96 well plates with different concentrations of the substrate, para-nitrophenyl phosphate, and the inhibitor, 5-(1 ,3-dioxo-1 ,3- dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3- carboxylic acid: 0, 37, 111.1 , 333.3 and 1000 ⁇ M - final assay concentrations.
  • a high throughput screening scintillation proximity assay (SPA - Amersham) was developed using PTP1 B and a synthetic, biotinylated, 33 P-phosphorylated peptide as substrate.
  • This peptide substrate which corresponds to the activation loop of the insulin receptor kinase, i.e. Thr-Arg-Asp-lle-Tyr-Glu-Thr-Asp-Tyr-Tyr-Arg-Lys-NH 2 , was 33 P-phosphorylated on tyrosine residues using the insulin receptor tyrosine kinase.
  • a compound library was screened and a number of hits identified.
  • analogues of this hit i.e. 2-(oxalyl-amino) benzoic acid
  • the compounds of the invention can be derived by changing in a systematic fashion the elements needed for binding to/inhibition of/modulation of the active sites of PTPases and/or to other molecules with pTyr recognition units using procedures well known to those skilled in the art.
  • Such novel compounds may be inhibitors or modulators of protein-tyrosine phosphatases or other molecules with pTyr recognition units and they may be classical, competitive inhibitors or mixed-type inhibitors.
  • the present invention pro- vides methods for making both non-selective and selective inhibitors and modulators of molecules with pTyr recognition units including protein-tyrosine phosphatases.
  • the compounds of the invention can be further modified to act as prodrugs.
  • the Original compound 1 it is within the scope of the invention to modify the compounds of the invention, termed the Original compound 1 , by attaching chemical groups that will improve the bioavailability of said compounds in such a way that the uptake in cells or mammals is facilitated.
  • modifications which are not intended in any way to limit the scope of the invention, include changing of one or more carboxy groups to esters (for instance methyl esters, ethyl esters, acetoxymethyl esters or other acyloxymethyl esters).
  • esters for instance methyl esters, ethyl esters, acetoxymethyl esters or other acyloxymethyl esters.
  • Compounds of the invention, original compounds, such modified by attaching chemical groups are termed 'modified compounds'. Said chemical groups may or may not be apparent in the claims of this invention.
  • modified compounds which are not intended in any way to limit the scope of the invention, are compounds that have been cyclized at specific positions - socalled 'cyclic compounds' - which upon uptake in cells or mammals become hy- drolyzed at the same specific position(s) in the molecule to yield the compounds of the invention, the original compounds, which are then said to be 'non-cyclic'.
  • the latter original compounds in most cases will contain other cyclic or heterocyclic structures that will not be hydrolyzed after uptake in cells or mammals.
  • said modified compounds will not show a be- 23 havior in biochemical assays similar to that of the original compound, i.e.
  • the corresponding compounds of the invention without the attached chemical groups or said modifications.
  • Said modified compounds may even be inactive in biochemical assays.
  • these attached chemical groups of the modified compounds may in turn be removed spontaneously or by endogenous enzymes or enzyme systems to yield compounds of the invention, original compounds.
  • 'Uptake' is defined as any process that will lead to a substantial concentration of the compound inside cells or in mammals.
  • the compounds After uptake in cells or mammals and after removal of said attached chemical group or hydrolysis of said cyclic com- pound, the compounds may have the same structure as the original compounds and thereby regain their activity and hence become active in cells and/or in vivo after uptake.
  • a mammalian cell line which can be obtained from the American Tissue Type Collection or other similar governmental or commercial sources, is incubated with said modified compound. After incubation at conditions well known to those skilled in the art, the cells are washed appropriately, lysed and the lysate is isolated. Appropriate controls, well known to those skilled in the art, must be included.
  • a number of different procedures may in turn be used to extract and purify said compound from said lysate. Said compound may or may not retain the attached chemical group or said cyclic compound may or may not have been hydrolyzed.
  • a number of different procedures - well known to those skilled in the art may be used to structurally and chemically characterize said purified compound. Since said purified compound has been isolated from said cell lysate and hence has been taken up by said cell line, a comparison of said structurally and chemically characterized compound with that of the original unmodified compound (i.e.
  • said purified compound may be subjected to enzyme kinetic analysis as described in detail in the present invention. If the kinetic profile is similar to that of the original compound without said attached chemical group, but different 24 from said modified compound, this confirms that said chemical group has been removed or said cyclic compounds has been hydrolyzed. Similar techniques may be used to analyze compounds of the invention in whole animals and mammals.
  • a preferred prodrug is acetoxymethyl esters of the compounds of the present invention which may be prepared by the following general procedure (C.Schultz et al, The Journal of Biological Chemistry, 1993, 268, 6316-6322. J;
  • a carboxylic acid (1 equivalent) is suspended in dry acetonitrile (2 ml per 0.1 mmol).
  • Diisopropyl amine (3.0 equivalents) is added followed by bromomethyl acetate (1.5 equivalents).
  • the mixture is stirred under nitrogen overnight at room temperature.
  • Acetonitrile is removed under reduced pressure to yield an oil which is diluted in eth- ylacetate and washed with water (3 x).
  • the organic layer is dried over anhydrous magnesium sulfate. Filtration followed by solvent removal under reduced pressure afford a crude oil.
  • the product is purified by column chromatography on silica gel, using an appropriate solvent system.
  • 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 gly- coproteins 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. Further, in some receptor-type or receptor-like PTPases, the second domain (the C-terminal domain) most likely does not pos- 25 sess catalytic activity.
  • the second domain of CD45 does not seem to act as an active PTPase (see Kashio et al., J. Biol. Chem. 273, 33856-22863 (1998) and references herein). However, the second domain of CD45 seems to play an important role as a phosphotyrosine recognition unit and to be critical for interleukin-2 secretion and substrate recruitment of TCRz in vivo (Kashio et al., supra). Thus, the second domain of CD45 in this case may play a similar role as a SH2 domain and hence act as a phosphotyrosine recognition unit. Although not formally proven, other molecules that are similar to PTPases, such as IA-2 and IA-2b, may act as pTyr recognition units.
  • Proteins with phosphotyrosine recognition units are defined as proteins or glycoproteins that contain phosphotyrosine recognition units.
  • a ligand is defined as a molecule or compound that binds to another molecule.
  • An example of a ligand, which is not intended in any way to limit the scope of the definition, is a non-peptide molecule with a molecular weight equal to or below 2500 daltons which binds to a protein or a glycoprotein.
  • a phosphotyrosine recognition unit ligand is defined as a molecule that binds to the phosphotyrosine recognition unit(s) of a protein or a glycoprotein with phosphotyrosine recognition unit(s).
  • a phosphotyrosine recognition unit ligand include PTPase inhibitors and/or PTPase modulators.
  • Another non-limiting example of a phosphotyrosine recognition unit ligand is a compound that binds to an SH2 domain and/or to a PTB domain.
  • 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.
  • a list of currently known classical and other PTPases reported to GenBank is shown in Table 1 (with the appropriate accession number indicated). 26
  • hPTPFMI X95712 hPTPgamma 09247 X54132 hPTPHl M64572 hPTPHE M64322 hPTPIA2 L18983 Z48226 hPTPIA2beta U65065 hPTPIAR AF007555 L76258 hPTPICA512 X62899 hPTPkappa L77886 Z70660 hPTPLl X80289 hPTPmu X58288 hPTPPCP2 X97198 hPTPpi U81561 hPTPPNPl X79676 hPTPpsi U60289 U73727 hPTPrho AF043644 AL024473 A1022239 AQ02047 hPTPRO U71075 hPTPS31 132035 132036 132037 132038 132039 hPTPSAPl D15049 hPTPsigma U35234 U40317 U41725 h
  • rPTP2E U17971 U18293 rPTPalpha L01702 rPTPBEMl (partial . cds) D45412 rPTPBEM2 D45413 rPTPBEM3 D45414 rPTPD30 (complet cds) U28938 rPTPDEPl U40790 rPTPepsilon D78610 D78613 rPTPGMCl AF063249 rPTPICA105 X925G3 D38222 rPTPNE6 U73458 Z50735 rPTPOST L36884 rPTPPl L19180 rPTPPS 19181 rPTPpsi U66566 rPTPsigma L11587 12329 19933 rPTPzeta U09357 rRKPTP D38072 rSTEP S49400 rSHPl U77038 rTCPTP X58828 rPTPTD14 AF077000
  • hPTPCAAXl U48296 hPTPCAAX2 U48297 hPTPCIP2 L25876 hPTPCdil U02681 hPTPICAAR Y08569 hPTPTEPl U96180 hPTPkiaa0283 AB006621 hPTPPRL-1 AF051160 hPTPPR -3 AF041434 hPTP_putative_ AF007118 mPTP-IFl Y17345 mPTP-IF2 Y17344 mPTP-IF2P Y17343
  • Microbial PTPases ie. eubacteria & vira
  • Oher eukaryotes ie. Drosophila, yeast, fungi, xenopus etc.
  • a modulator of PTPases is compound that causes a change of the activity of a PTPase.
  • PTPase modulators may either make the PTPase less active or more active.
  • PTPase modulators may according to the present definition bind to the active site of PTPases or to areas outside the active site of PTPases (so-called allosteric modula- tors).
  • Another, non-limiting example of a PTPase modulator is a compound that changes the substrate specificity of a PTPase.
  • a PTPase domain is defined as a part of the full PTPase molecule, which typically - but not always - possess characteristic enzymatic activity, i.e. the capacity to dephos- phorylate pTyr-containing proteins or glycoproteins.
  • a PTPase domain of a classical PTPase will typically consist of 220-350 amino acid residues and correspond to amino acid residues number 30 to 270 of PTP1 B.
  • PTPase domains may be expressed in eukaryotic and prokaryotic expression system either as the domain itself or as part of a fusion protein.
  • SH2 domains Src homology 2 (SH2) domains are non-catalytic protein modules that bind to pTyr (phosphotyrosine residue) containing proteins, i.e. SH2 domains are pTyr recognition units. SH2 domains, which consist of ⁇ 100 amino acid residues, are found in a number of different molecules involved in signal transduction processes. The fol- lowing is a non-limiting list of proteins containing SH2 domains: Src, Hck, Lck, Syk, Zap70, SHP-1 , SHP-2, STATs, Grb-2, She, p85/PI3K, Gap, vav (see Russell et al, FEBS Lett.
  • PTB domain phos- photyrosine binding domain
  • a PTPase family is defined as a group of PTPases that are structurally related. Thus, one accepted way of defining a PTPase family is based on the primary structures of PTPases outside the PTPase domain(s) or their overall structures (Fischer et al. (1991) Science 253: 401-406; B.J. Goldstein (1995) in Protein Profile, volume 2, num- ber 13, Academic Press Ltd., London..
  • PTPase families defined in such way are:
  • PTP1B family PTP1B; TC-PTP
  • PEST Proiine-Glutamic acid-Serine-Threonine sequence containing PTPases: PTP-PEST; PEP
  • PTPases containing very small, highly giycosylated extracellular regions the PTP ⁇ family: PTP ⁇ ; PTP ⁇ .
  • PTP ⁇ family PTP ⁇ , PTP ⁇ (k) The IA-2 family (I) The PTP ⁇ family (m) The CD45 family
  • PTPases may also be divided into families based on sequence alignments of the primary sequence (Goldstein vide supra). Computer programs well- known to those skilled in the arts (e.g. GCG University of Wisconsin, refs.) may be used to performed such alignments. Further analysis is performed with computer pro- grams such as CLUSTALX resulting in a so-called phylogenetic tree. An example of said phylogenetic tree is shown in Figure 7. It should be pointed out that the above described ways of dividing PTPases into families show considerable overlap.
  • PTPases into families is the latter based on primary sequence alignments of PTPases, since it is likely that this definition in turn can be used to es- tablish assays that will allow development of PTPase inhibitors or modulators that selectively react with a given PTPase family or members of a specific family (i.e. selective inhibitors). 37
  • 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) de- crease 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 ac- tivity; 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.
  • a compound is defined as a PTPase inhibitor if the following criteria are fulfilled: (a) the inhibitory capacity must be determined as described in detail below and the inhibition constant, K,, value must be below 1000 ⁇ M; (b) at least one PTPase must be inhibited by the compounds of the invention. Any PTPase may be used for the analyses.
  • PTPases are: PTP1 B; SHP-1 , SHP-2; PTP-PEST; 38
  • PTP ⁇ ; PTP ⁇ ; LAR; CD45 Further examples are given in Table 1. In addition, any PTPase not mentioned herein may be used.
  • K inhibitor constants
  • values may be performed according to a number of different experimental procedures including inhibitor fluorescence quenching. However, in all cases, to evaluate the compounds of the present invention such methods must be supplemented with procedures that measure the effect of the com- pounds on the catalytic activity of the enzymes. The conditions for such assays are illustrated below.
  • PTPases used for the analyses may be expressed as intact molecules or as PTPase domains.
  • Assay conditions must be selected to ensure enzyme stability, i.e. the enzyme must in the absence of substrate retain at least 50 per cent of the initial activity over the assay period.
  • buffer system well known to those skilled in the art may be selected for analysis of compounds of the invention.
  • Preferred buffers used for analysis of PTPase inhibi- tion or modulation are listed below.
  • the reaction time is preferred to be between 2 and 60 minutes.
  • reaction temperature well known to those skilled in the art may be selected for analysis of compounds of the invention.
  • the preferred temperature is in the following range: 4° C to 37° C.
  • Substrates used in the reaction may be selected from the following: (a) p-nitrophenyl phosphate (pNPP); (b) tyrosine-phosphorylated peptides; (c) natural substrates (e.g. autophosphorylated insulin receptor) or parts thereof (e.g. autophosphorylated tyrosine kinase domain of the insulin receptor).
  • pNPP p-nitrophenyl phosphate
  • tyrosine-phosphorylated peptides e.g. autophosphorylated insulin receptor
  • parts thereof e.g. autophosphorylated tyrosine kinase domain of the insulin receptor.
  • the enzyme reaction may be followed by measurement of released phosphate or by spectrophotometric/fluorometric methods according to procedures well known to those skilled in the art.
  • the concentration of substrate and inhibitor must be varied independently according to the following guidelines.
  • a range of substrate concentrations must be varied with a preferred maximum, final assay concentration at least 10-fold above that of the K m value for the enzyme determined under the same conditions.
  • the minimum final assay concentration is pref- 41
  • inhibitor concentrations At least 2 different inhibitor concentrations must be used. The concentrations will depend on the actual compounds, but they must be selected in such a way that nonlinear regression analysis allows determination of inhibitor constants with an accuracy acceptable to those skilled in the art.
  • V 0 the initial velocity
  • K m is defined as the concentration of substrate used to obtain an initial velocity corresponding to 50 percent of the maximal obtainable velocity (V max ) at full substrate saturation of the enzyme. K m is measured without addition of inhibitor.
  • V max is the maximum obtainable initial velocity (limiting rate) determined at full sub- strate saturation.
  • K app is the apparent K m value determined in the presence of inhibitor.
  • V ap p is the apparent V max value determined in the presence of inhibitor.
  • Mixed-type inhibitors are defined as inhibitors that affect both K m and V, max 42
  • Non-competitive inhibitors are defined as inhibitors that decrease V app without any effect on K m .
  • K s the inhibitor constant of competitive inhibitors
  • K app (K m / Kir[i] + K m (equation 1) where [i] is the concentration of the inhibitor
  • the K, values for a given compound may be calculated either using linear transformation procedures or nonlinear regression fit to classical Michaelis Menten enzyme kinetic models as defined above assuming competitive or mixed-type inhibition.
  • Preferred compounds of the invention belongs to the class of competitive or mixed-type inhibitors.
  • PTP1 B was incubated with a compound of the invention (described in Example 2).
  • PTP1 B A truncated form of PTP1 B, corresponding to the N-terminal 321 amino acids was expressed in E. coli and purified to apparent homogeneity using published procedures well-known to those skilled in the art.
  • the enzyme reactions were carried out using standard conditions essentially as described by Burke et al (Biochemistry 35; 15989-15996 (1996)).
  • the assay conditions were as follows. Half of a 96-well plate was used for this experiment, p-nitrophenyl phosphate (pNPP) was used as substrate (see Table 2).
  • 3-(Oxalyl- amino)naphthalene-2-carboxylic acid dissolved in DMSO was used as inhibitor and used at the following final assay concentrations: 100 ⁇ M (added to all wells in column 1), 33.3 ⁇ M (added to all wells in column 2); 11.1 ⁇ M (added to all wells in column 3); 3.7 ⁇ M (added to all wells in column 4).
  • Assay buffer was added in columns 5 and 6 instead of the inhibitor (same volume as the inhibitor in columns 1-4).
  • Assay buffer 100 mM sodium acetate pH 5.5, 50 mM NaCl, 5 mM glutathione, 1 mM EDTA, and 0.1 % bovine serum albumin.
  • the reaction was started by addition of the enzyme, PTP1B.
  • Assay buffer was added in column 6 instead of the enzyme (same volume as the enzyme in columns 1-5).
  • the total volume in each well was 100 ⁇ l, including 10 ⁇ l of inhibitor dissolved in DMSO or 10 ⁇ l DMSO added to the control wells that did not receive inhibitor.
  • the tem- perature was 25 °C. After 60 minutes, NaOH was added and the absorbance was read at 405 nm. The results are shown in Table 2. 44
  • the values in wells H1 through H5 indicated any color (OD 405 value) derived from the inhibitor itself. In the present example, the inhibitor does not give rise to any OD 405 value.
  • the values in column 6 indicate the OD 405 values due to the absorbance of the substrate. Therefore, the corrected OD 405 values in Table 4 must be further corrected for the absorbance at 405 nm which is caused by the inhibitor and/or the substrate, as shown in Table 5.
  • Selectivity of an inhibitor is defined as the property of such compound to inhibit or modulate a certain PTPase or certain PTPases more efficiently than other PTPases.
  • a selective inhibitor may inhibit one PTPase only or one PTPase family only.
  • other selective inhibitors also include compounds that inhibit a set of several PTPases or PTPase families more efficiently than other sets of PTPases or PTPase families.
  • selectivity which is not intended in any way to limit the scope of the invention, is a competitive inhibitor that has a K, value of 50 ⁇ M against PTP1B and a K j value of 500 ⁇ M or more against PTP ⁇ .
  • An example of a selective modulator which is not intended in any way to limit the scope of the invention, is a modulator that causes a 2-fold increase of the activity of SHP-1 without affecting the activity of PTP ⁇ .
  • RNA total or messenger RNA
  • RNA can be isolated from placenta, liver, skeletal muscle, fat tissue, and peripheral blood leukocytes. Using standard procedures (Ausubel, F. M., et al. (Eds.).
  • the PCR technique was used to prepare cDNA corresponding to the following PTPase domains (Ausubel et al., supra): PTP1 B; PTP ⁇ domain 1 ; PTP ⁇ domain 1 ; PTP ⁇ ; CD45 domain 1 and 2.
  • Ap- 48 intestinalte restriction sites have been included in the oligonucleotides to allow cloning into appropriate expression vectors.
  • the pGEX expression vectors (Pharmacia) were used.
  • an additional N-terminal methionine (Met - M) was included in some of the constructs (indicated as (M)).
  • GST fusion proteins were then induced by addition of isopropyl-1-thio-b-D-galactopyranoside, and the cultures were grown for additional 3 hrs at room temperature.
  • the GST fusion proteins were purified according to the manufacturer's instructions (Pharmacia) with minor modifications. In brief, all purification steps were conducted at approx. 4 °C.
  • the cell pellets were suspended (5 ml/g) in lysis buffer (50 mM imidazole, 5 mM EDTA, 0.1 % b-mercaptoetanol, 10 % glycerol, 10 ⁇ g/ml aprotinin, 0.1 % lysozyme and 1 mM PMSF; pH 7.2) by stirring for 1h prior to lysis under nitrogen pressure (>2000 psi) in a Parr cell disruption bomb. Triton X-100 (0.1 %) was added to the lysate and stirring continued for 1h prior to centrifugation at 40000 g for 30 min.
  • lysis buffer 50 mM imidazole, 5 mM EDTA, 0.1 % b-mercaptoetanol, 10 % glycerol, 10 ⁇ g/ml aprotinin, 0.1 % lysozyme and 1 mM PMSF; pH 7.2
  • the supematant was applied to a Glutathione Sepharose column (Pharmacia) equilibrated with GST-equilibration buffer (50 mM imidazole, 1 mM EDTA, 150 mM NaCl and 10 % glycerol; pH 7.2) and initially washed with the same buffer. The flow direction was changed and washing was continued with a washing buffer (50 mM Tris, 1 mM EDTA and 10 % glycerol; pH 8). Finally, the bound protein was eluted with 10 mM glutathione in the washing buffer.
  • the CD45 fusion protein was further purified on G25 and Mono Q columns (Pharmacia). The purified PTP domains are stored at -80 °C until use. Immediately prior to use the enzyme preparations are diluted appropriately.
  • the following final assay concentrations of pNPP were used: 20 mM, 10 mM, 5 mM, 2.5 mM, 1.25 mM, 0.63 mM, 0.31 mM.
  • the compound, 5-(1 ,3-dioxo-1 ,3-dihydro-isoindol- 2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid, dissolved in dimethyisulfoxide (DMSO) was used as inhibitor and used at the following final assay concentrations: 200 ⁇ M, 66.6 ⁇ M; 22.2 ⁇ M; 7.4 ⁇ M.
  • Assay buffer instead of enzyme, and/or substrate was added to appropriate control wells as de- scribed in detail for PTP1 B above.
  • Assay buffer final assay concentration: 100 mM sodium acetate pH 5.5, 50 mM NaCl, 5 mM glutathione, 1 mM EDTA, and 0.1 % bovine serum albumin.
  • the reaction was started by addition of the enzyme, GST-PTP ⁇ domain 1 (final dilution 1 :10000).
  • the assay total volume in each well was 100 ⁇ l, including 10 ⁇ l of inhibitor dissolved in DMSO or 10 ⁇ l DMSO added to the control wells that did not receive inhibitor. The temperature was 25 °C.
  • Figure 6B shows the results when the same compound (5-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl- amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid) is tested against PTP ⁇ (final dilution 1 :2000) in the following buffer: 50 mM HEPES pH 7.0, 100 mM NaCl, 5 mM glutathione, 1 mM EDTA, and 0.1 % bovine serum albumin.
  • a selective inhibitor is defined as an inhibitor that shows selectivity.
  • a non-selective inhibitor is defined as an inhibitor that does not show selectivity.
  • a selective modulator is defined as a modulator that shows selectivity.
  • the compound of example 82 is an example of a non-selective inhibitor, whereas the compound of example 83 behaves like a selective inhibitor. It should be noted that the compound in example 83 when tested against other PTPases might be inhibitory against these. Yet, according to the present definition, the compound in example 83 is a selective inhibitor due to the fact that it inhibits PTP1B with little effect on the other PTPases tested in Table 10. Also, according to the present definition, the compound in example 82 is a non-selective inhibitor due to its inhibitory capacity against several PTPases, even though it has weak activity, if any, against PTP-LAR. 52 A chemical group is defined as any single atom or any group of covalently linked atoms or any molecule, including any radical thereof.
  • halogen or halo include fluorine, chlorine, bromine, and iodine.
  • alkyl includes C C 6 straight chain saturated and C 2 -C 6 unsaturated aliphatic hydrocarbon groups, C C 6 branched saturated and C 2 -C 6 unsaturated aliphatic hydrocarbon groups, C 3 -C 6 cyclic saturated and C 5 -C 6 unsaturated aliphatic hydrocarbon groups, and C C 6 straight chain or branched saturated and C 2 -C 6 straight chain or branched unsaturated aliphatic hydrocarbon groups substituted with C 3 -C 6 cyclic saturated and unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • this definition shall include but is not limited to methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, heptyl, ethenyl, propenyl, butenyl, penentyl, hexenyl, isopropyl (i-Pr), isobutyl (i-Bu), tert-butyl (t-B ), sec-butyl (s-Bu), isopentyl, neopentyl, cyclopropyl, cyclobutyl, cy- clopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, methylcyclopropyl, ethylcyclohexenyl, butenylcyclopentyl, and the like.
  • substituted alkyl represents an alkyl group as defined above wherein the substi- tutents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, hy- droxy, COR 5 , C ⁇ Ceaikyl, C C ⁇ alkyloxy, aryloxy, arylC Cealkyloxy, thio, C ⁇ C ⁇ alkylthio, arylthio, arylC ⁇ Cealkylthio, NR 7 R 8 , CrCgalkylamino, arylamino, arylC ⁇ C ⁇ alkylamino, di(arylC 1 -C 6 alkyl)amino, C ⁇ Cealkylcarbonyl, arylC r C 6 alkylcarbonyl, C ⁇ Cgalkyl-carboxy, arylC r C 6 alkylcarboxy, C r C 6 alkylcarbonylamino, -
  • alkyloxy (e.g. methoxy, ethoxy, propyloxy, allyioxy, cyclohexyloxy) represents an "alkyl” group as defined above having the indicated number of carbon atoms attached through an oxygen bridge.
  • alkyloxyalkyl represents an "alkyloxy” group attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • aryloxy (e.g. phenoxy, naphthyloxy and the like) represents an aryl group as defined below attached through an oxygen bridge.
  • arylalkyioxy e.g. phenethyloxy, naphthylmethyloxy and the like
  • arylalkyl represents an “arylalkyl” group as defined below attached through an oxygen bridge.
  • arylalkyloxyalkyl represents an "arylalkyioxy” group as defined above attached through an “alkyl” group defined above having the indicated number of carbon atoms.
  • arylthio e.g. phenylthio, naphthylthio and the like
  • arylthio represents an “aryl” group as defined below attached through an sulfur bridge.
  • alkyloxycarbonyl e.g. methylformiat, ethylformiat and the like
  • alkyloxycarbonyl represents an “alkyloxy” group as defined above attached through a carbonyl group.
  • aryloxycarbonyl e.g. phenylformiat, 2-thiazolylformiat and the like
  • aryloxycarbonyl represents an “aryloxy” group as defined above attached through a carbonyl group.
  • arylalkyloxycarbonyl e.g. benzylformiat, phenyletylformiat and the like repre- sents an "arylalkyioxy” group as defined above attached through a carbonyl group.
  • alkyloxycarbonyialkyl represents an "alkyloxycarbonyl” group as defined above attached through an “alkyl” group as defined above having the indicated number of carbon atoms.
  • arylalkyloxycarbonylalkyl represents an "arylalkyloxycarbonyl” group as defined above attached through an “alkyl” group as defined above having the indicated number of carbon atoms.
  • alkylthio (e.g. methylthio, ethylthio, propylthio, cyclohexenylthio and the like) represents an “alkyl” group as defined above having the indicated number of carbon atoms attached through a sulfur bridge.
  • arylalkylthio (e.g. phenylmethylthio, phenylethylthio, and the like) represents an "arylalkyl” group as defined above having the indicated number of carbon atoms attached through a sulfur bridge.
  • alkylthioalkyl represents an "alkylthio" group attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • arylalkylthioalkyl represents an "arylalkylthio" group attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • alkylamino e.g. methylamino, diethylamino, butylamino, N-propyl-N-hexylamino, (2-cyclopentyl)propylamino, hexenylamino, pyrrolidinyl, piperidinyl and the like
  • alkylamino represents one or two "alkyl” groups as defined above having the indicated number of carbon atoms attached through an amine bridge.
  • the two alkyl groups may be taken together with the nitrogen to which they are attached forming a saturated, partially saturated or aromatic cyclic, bicyclic or tricyciic ring system containing 3 to 14 carbon atoms and 0 to 3 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system can optionally be substituted with at least one d-C ⁇ alkyl, aryl, aryld-Cealkyl, hydroxy, oxo, d-Cealkyloxy, C r CealkyloxyCrCealkyl, NR 9 R 10 , C 1 -C 6 alkylaminoC 1 -C 6 alkyl substituent wherein the alkyl and aryl groups are optionally substituted as defined in the definition section and R 9 and R 10 are defined as above.
  • arylalkylamino e.g. benzylamino, diphenylethylamino and the like
  • arylalkylamino represents one or two "arylalkyl” groups as defined above having the indicated number of carbon atoms attached through an amine bridge.
  • the two "arylalkyl” groups may be taken together with the nitrogen to which they are attached forming a saturated, partially saturated or aromatic cyclic, bicyclic or tricyciic ring system containing 3 to 14 carbon atoms and 0 to 3 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system can optionally be substituted with at least one C Cealkyl, aryl, arylCrCealkyl, hydroxy, oxo, CrCealkyloxy, C r C 6 alkyloxyC r C 6 alkyl, NR 9 R 10 , C CealkylaminoC Cgalkyl substituent wherein the alkyl and aryl groups are optionally substituted as defined in the definition section and R 9 and R 10 are defined as above.
  • alkylaminoalkyl represents an "alkylamino" group attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • arylalkyla inoalkyl represents an "arylalkylamino" group attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • arylalkyl e.g. benzyl, phenylethyl
  • arylalkyl represents an "aryl” group as defined below attached through an alkyl having the indicated number of carbon atoms or substituted alkyl group as defined above.
  • alkylcarbonyl e.g. cyclooctylcarbonyl, pentylcarbonyl, 3-hexenylcarbonyi
  • arylalkylcarbonyl e.g. phenylcyclopropylcarbonyl, phenylethylcarbonyl and the like
  • arylalkylcarbonyl represents an "arylalkyl” group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
  • alkylcarbonylalkyl represents an “alkylcarbonyl” group attached through an “alkyl” group as defined above having the indicated number of carbon atoms.
  • arylalkylcarbonylalkyi represents an "arylalkylcarbonyl” group attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • alkylcarboxy e.g. heptylcarboxy, cyclopropylcarboxy, 3-pentenylcarboxy
  • alkylcarbonyl represents an "alkylcarbonyl” group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • arylalkylcarboxy e.g. benzylcarboxy, phenylcyclopropylcarboxy and the like
  • arylalkylcarbonyl represents an "arylalkylcarbonyl” group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • alkylcarboxyalkyl represents an “alkylcarboxy” group attached through an “alkyl” group as defined above having the indicated number of carbon atoms.
  • arylalkylcarboxyalkyl represents an "arylalkylcarboxy” group attached through an “alkyl” group as defined above having the indicated number of carbon atoms.
  • alkylcarbonylamino e.g. hexylcarbonylamino, cyclopentylcarbonyl-aminomethyl, methylcarbonylaminophenyl
  • alkylcarbonylamino represents an "alkylcarbonyl” group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of an amino group.
  • the nitrogen atom may itself be substituted with an alkyl or aryl group.
  • arylalkylcarbonylamino (e.g. benzylcarbonylamino and the like) represents an “arylalkylcarbonyl” group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of an amino group.
  • the nitrogen atom may itself be substituted with an alkyl or aryl group.
  • alkylcarbonylaminoalkyl represents an "alkylcarbonylamino” group attached through an “alkyl” group as defined above having the indicated number of carbon atoms.
  • the nitrogen atom may itself be substituted with an alkyl or aryl group.
  • arylalkylcarbonylaminoalkyl represents an “arylalkylcarbonylamino” group attached through an “alkyl” group as defined above having the indicated number of carbon atoms.
  • the nitrogen atom may itself be substituted with an alkyl or aryl group.
  • alkylcarbonylaminoalkylcarbonyl represents an alkylcarbonylaminoalkyl group attached through a carbonyl group.
  • the nitrogen atom may be further substituted with an "alkyl” or "aryl” group.
  • aryl represents an unsubstituted, mono-, di- or trisubstituted monocyclic, polycy- die, biaryl and heterocyclic aromatic groups covalently attached at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art (e.g., 3-indolyl, 4-imidazolyl).
  • the aryl substituents are independently selected from the group consisting of halo, nitro, cyano, trihalomethyl, C r C 6 alkyl, aryl, arylCrCealkyl, hydroxy, COR 5 , CrC- ⁇ alkyloxy, d-CealkyloxyCrC- ⁇ alkyl, aryloxy, arylC,- C 6 alkyloxy, aryld-CealkyloxyCrCealkyl, thio, d-Cgalkylthio, C C ⁇ alkylthioC C ⁇ al yl, arylthio, arylC r C 6 alkylthio, arylCrCsalkylthioC C ⁇ alkyl, NR 8 R 9 , C r C 6 -alkylamino, CrC ⁇ alkylaminoC C 6 alkyl, arylamino, arylC C 6 alkylamino,
  • aryl includes but is not limited to phenyl, biphenyl, indenyl, fluorenyl, naphthyl (1-naphthyl, 2-naphthyl), pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1- imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1 ,2,3-triazoM-yl, 1 ,2,3-triazol-2- yl 1 ,2,3-triazol-4-yl, 1 ,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazoiyl, 5-isoxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazo
  • arylcarbonyl e.g. 2-thiophenyicarbonyl, 3-methoxy-anthrylcarbonyl, oxazolylcar- bonyl
  • arylcarbonyl represents an "aryl” group as defined above attached through a carbonyl group.
  • arylalkylcarbonyl e.g. (2,3-dimethoxyphenyl)-propylcarbonyl, (2- chloronaphthyl)pentenylcarbonyl, imidazolylcyclo-pentylcarbonyl
  • arylalkylcarbonyl represents an "arylalkyl” group as defined above wherein the "alkyl” group is in turn attached through a carbonyl.
  • the compounds of the present invention which have asymmetric centers may occur as ra- cemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all iso- meric forms being included in the present invention as well as mixtures thereof.
  • salts of the compounds of the invention where a basic or acidic group is present in the structure, are also included within the scope of this invention.
  • an acidic substituent such as -COOH, 5-tetrazolyl and P(O)(OH)2
  • an acidic salt such as hydrochloride, hydrobromide, acetate, maleate, palmoate, methanesulfonate, p-toluenesulfonate, and the like
  • an acidic salt such as hydrochloride, hydrobromide, acetate, maleate, palmoate, methanesulfonate, p-toluenesulfonate, and the like, can be used as the dosage form.
  • esters can be employed, e.g., methyl, tert-butyl, pivaloyioxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • solvates may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.
  • terapéuticaally effective amount shall mean that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other.
  • the present invention relates to compounds that fulfills all of the following 3 criteria:
  • R, R and R 4 are any chemical group or combination of chemical groups
  • (2) acts as a phosphotyrosine recognition unit ligand, preferably an inhibitor or modulator of one or more PTPases or proteins that contain SH2 domains;
  • R, R,and R 4 are any chemical group or combination of chemical groups, and R- preferably is H.
  • R 1 ? R 2 , R 3 , R 4 and R 5 are any chemical group or combination of chemical groups, and R 3 and R 5 may be covalently linked to each other; 61
  • (2) acts as a phosphotyrosine recognition unit ligand, preferably an inhibitor or modulator of one or more PTPases or proteins that contain SH2 domains;
  • (3) has a molecular weight below or equal to 2500 daltons.
  • R,, R 3 , R 4 and R 5 are any chemical group or combination of chemical groups, and R 3 and R 5 may be covalently linked to each other, and R preferably is H.
  • R 1 t R 3 , R 4 and R 5 are any chemical group or combination of chemical groups, and R 3 and R 5 may be covalently linked to each other, and R is preferably H. 62
  • the compounds of the invention has a structure represented by Formula VI
  • R 3 , R 4 and R 5 are any chemical group or combination of chemical groups, and R 3 and R 5 may be covalently linked to each other, and R is preferably H.
  • a together with the double bond in formula VII represents any aryl as defined above, and R,, R 2 , R 3 and R 4 are any chemical group or combination of chemical groups.
  • Formula VIII 63 wherein A together with the double bond in formula VIII represents any aryl as defined above, and R, R 1 f R 3 and R 4 are any chemical group or combination of chemical groups, and R preferably is H.
  • a together with the double bond in formula IX represents any aryl as defined above, and R R 2 , R 3 and R 4 are any chemical group or combination of chemical groups.
  • a together with the double bond in formula X represents any aryl as defined above, and R 2 , R 3 and R 4 are any chemical group or combination of chemical groups.
  • a together with the double bond in formula XI represents any aryl as defined above, and R, R 3 and R 4 are any chemical group or combination of chemical groups, and R prefera- bly is H.
  • R is a chemical group capable of being a proton donor and/or a proton acceptor, preferably -COOH, 5-tetrazolyl, -NH 2 , -CONH 2 , and R, R 2 , R 3 and R 4 are any chemical group or combination of chemical groups.
  • A is together with the double bond in Formula 1 phenyl, biphenyl, indenyl, fluorenyl, fluo- renyl-9-one, naphthyl, pyridyl, pyridazinyl, pyrimidyl or pyrazinyl;
  • R 3 , R 16 and R 17 are hydrogen, halo, nitro, cyano, trihalomethyl, Chalky!, aryl, arylC r C 6 - alkyl, hydroxy, carboxy, carboxyC ⁇ Cgalkyl, C 1 -C 6 alkyioxycarbonyl, aryloxycarbonyl, arylC r C 6 alkyloxycarbonyl, C Cgalkyioxy, CrC ⁇ alkyloxyd-C ⁇ alkyl, aryloxy, arylC C 6 alkyloxy, arylCrCealkyloxyCrC ⁇ alkyl, thio, C r C 6 alkylthio, d-CealkylthioCrCealkyl, arylthio, arylC r C 6 alkylthio, arylC CealkylthioC Cealkyl, NR 7 R 8 , d-Cealkyl-aminod-C ⁇ alky
  • A-B-C-D-C r C 6 alkyl wherein A is CrC ⁇ alkyl, aryl or arylC r C 6 alkyl; B is amino, thio, SO, SO 2 or oxo; C is C C ⁇ alkyl, amino; D is a chemical bond, amino or C ⁇ Cgalkyl wherein the alkyl and aryl groups are optionally substituted; or 67
  • R 12 , R 13 , and R 14 are independently hydrogen, C r C 6 alkyl, aryl, arylC r C 6 alkyl and the alkyl and aryl groups are optionally substituted;
  • R 4 is hydrogen, hydroxy, d-C 6 alkyl, aryl, aryld-C 6 alkyl, NR 7 R 8 , d-C 6 alkyloxy; wherein the alkyl and aryl groups are optionally substituted;
  • R 5 is hydroxy, d-C 6 alkyl, aryl, aryld-C 6 alkyl, CF 3 , NR 7 R 8 ; wherein the alkyl and aryl groups are optionally substituted;
  • R 6 is hydrogen, C r C 6 alkyl, aryl, aryld-C 6 alkyl; wherein the alkyl and aryl groups are optionally substituted;
  • R 7 and R 8 are independently selected from hydrogen, C r C 6 alkyl, aryl, aryld-C 6 alkyl, C-- C 6 alkylcarbonyl, arylcarbonyl, aryld-C 6 alkyicarbonyl, d-C 6 alkyl-carboxy or arylC r C 6 alkylcarboxy wherein the alkyl and aryl groups are optionally substituted; or R 7 and R 8 are together with the nitrogen to which they are attached forming a saturated, partially saturated or aromatic cyclic, bicyclic or tricyciic ring system containing from 3 to 14 carbon atoms and from 0 to 3 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system can optionally be substituted with at least one C 1 -C 6 alkyl, aryl, aryld-C 6 alkyl, hydroxy, oxo, C r C 6 alkyloxy, aryld-C 6 alkyloxy, d
  • R 7 and R 8 are independently a saturated or partial saturated cyclic 5, 6 or 7 membered amine, imide or lactam; 68
  • Compounds of the invention may modulate or inhibit the activity of protein tyrosine phosphatases or other molecules with phosphotyrosine recognition unit(s) via different mechanisms of action. Examples of such mechanism of actions, which are not intended in any way to limit the scope of the invention, are (a) classical competitive inhibition; (b) uncom- petitive inhibition; (c) mixed-type inhibition as defined above.
  • the invention furthermore relates to compounds which after uptake in cells or mammals has a structure as defined above.
  • the compounds of the invention act as classical, competitive inhibitors of one or more PTPases.
  • the compounds of the invention act as mixed-type inhibitors of one or more PTPases.
  • the compounds of the invention substantially act as an inhibitor of one or more PTPases involved in regulation of tyrosine kinase signalling pathways.
  • the compounds of the invention substantially inhibit or modulate receptor-tyrosine kinase signalling pathways via interaction with one or more regulatory PTPases, preferably the signalling pathways of the insulin receptor, the IGF-I receptor and/or 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/or members of other receptor-type tyrosine kinase families.
  • regulatory PTPases preferably the signalling pathways of the insulin receptor, the IGF-I receptor and/or 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/or members of other receptor-type tyrosine kinase families.
  • the compounds of the invention substantially inhibit or modulate non-receptor tyrosine kinase signalling through modulation of one or more regulatory PTPases, preferably modulation of members of the Src kinase family or other intracellular kinases. 69 in another preferred embodiment, the compounds of the invention substantially inhibit or modulate the activity of one or more PTPases that negatively regulate signal transduction pathways.
  • the compounds of the invention inhibit or modulate the activity of one or more PTPases that positively regulate signal transduction pathways, preferably CD45.
  • the compounds of the invention inhibit or modulate the activity of one or more PTPases that positively regulate signal transduction pathways in immune ceils.
  • the compounds of the invention inhibit or modulate the activity of one or more PTPases that negatively regulate signal transduction pathway.
  • the compounds of the invention inhibit one or more PTPases via binding to the active site of said PTPase(s) or to other sites that negatively influences the binding of substrate to said PTPase(s), an allosteric modulator.
  • the compounds of the invention modulate the activity of one or more PTPases via interaction with structures positioned outside of the active sites of the enzymes, preferably SH2 domains.
  • the compounds of the invention modulate the signal trans- duction pathways via binding of the compounds of the invention to SH2 domains or PTB domains of non-PTPase signalling molecules.
  • the compounds of the invention are characterized by being selective PTPase inhibitors or compounds that are selective phosphotyrosine recognition unit ligands.
  • the compound of the invention can e.g. be selective for a PTPase not described herein or, preferably, a PTPase listed in Table 1.
  • the compounds of the invention are characterized by being non-selective PTPase inhibitors such as inhibitors or modulators of at least 4 PTPases or 4 PTPase families.
  • the compounds of the invention are selective for the PTP ⁇ family.
  • the compounds of the invention are selective for PTP ⁇ .
  • the compounds of the invention are selective for PTP ⁇ .
  • the compounds of the invention are selective for CD45.
  • the compounds of the invention are selective for PTP ⁇ fam- ily.
  • the compounds of the invention are selective for PTP ⁇ .
  • the compounds of the invention are selective for PTP- DEP1.
  • the compounds of the invention are selective for PTP-LAR family.
  • the compounds of the invention are selective for PTP-LAR.
  • the compounds of the invention are selective for PTP ⁇ .
  • the compounds of the invention are selective for PTP ⁇ .
  • the compounds of the invention are selective for PTP ⁇ family. 71 In one preferred embodiment, the compounds of the invention are selective for PTP ⁇ .
  • the compounds of the invention are selective for PTPK.
  • the compounds of the invention are selective for PTP1 B family.
  • the compounds of the invention are selective for PTP1B.
  • the compounds of the invention are selective for TC-PTP.
  • the compounds of the invention are selective for SHP-PTP family.
  • the compounds of the invention are selective for SHP-1.
  • the compounds of the invention are selective for SHP-2.
  • the compounds of the invention are selective for PTP ⁇ fam- ily.
  • the compounds of the invention are selective for PTP ⁇ .
  • the compounds of the invention are selective for PTP-PEST family.
  • the compounds of the invention are selective for PTPH1 family.
  • the compounds of the invention are selective for PTPH1.
  • the compounds of the invention are selective for PTPD1. 72 In one preferred embodiment, the compounds of the invention are selective for PTPD2.
  • the compounds of the invention are selective for PTPMEG1.
  • the compounds of the invention are selective for IA-2 family.
  • the compounds of the invention are selective for IA-2.
  • the compounds of the invention are selective for IA-2 ⁇ .
  • the compounds of the invention are selective for the PTP ⁇ family.
  • the compounds of the invention are selective for PTP ⁇ .
  • the compounds of the invention are selective for PTPp.
  • the compounds of the invention are selective for PTP ⁇ .
  • the compounds of the invention have a molecular weight of less than 1000 Daltons, and preferably of more than 100 Daltons.
  • the compounds of the invention have K, values of less than 200 ⁇ M against one or more PTPases.
  • the compounds of the invention have K j values of less than 2 ⁇ M against one or more PTPases.
  • the compounds of the invention have K j values of less than 100 nM against one or more PTPases. 73 In another preferred embodiment, the compounds of the invention have a K j value of ⁇ 2 ⁇ M against one or two PTPase or PTPase families and a K j value of > 50 ⁇ M against at least two other PTPases or PTPase families.
  • the compounds of the invention have a K, value of ⁇
  • the compounds of the invention have a IC 50 value of less than 200 M against one or more molecules with phosphotyrosine recognition unit(s).
  • the compounds of the invention have a IC 50 value of less than 2 M against one or more molecules with phosphotyrosine recognition unit(s).
  • the compounds of the invention have a IC 50 value of less than 100 nM against one or more molecules with phosphotyrosine recognition unit(s).
  • the compounds of the invention act as inhibitors of one or more 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-re
  • 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 and other non-receptor tyrosine kinases.
  • PTPases e.g. modulation of members of the Src kinase family and other non-receptor tyrosine kinases.
  • One type of preferred embodiment of the inventions relates to modulation of the activity of PTPases that negatively regulate signal transduction pathways.
  • An example, which is not intended in any way to limit the scope of the invention, is SHP-1 that negatively regulates 74 the erythropoietin signalling pathway.
  • Another type of preferred embodiments of the inventions relate to modulation of the activity of PTPases that positively regulate signal transduction pathways.
  • CD45 which dephosphorylates tyrosine kinase of the Src family and thereby plays a positive role in signalling in cells from the hematopoietic system.
  • One type of preferred CD45 inhibitor can be used to regulate the activity of lymphocytes, including T- and/or B-lymphocytes.
  • the compounds of the invention act as modulators or inhibitors of the active site of one or more PTPases.
  • the compounds of the invention modulate the activity of one or more 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.
  • the compounds of the invention are selective inhibitors that are more than 10-fold potent against one PTPase family than against another PTP family.
  • the compounds of the invention can be used for managing, treating or preventing type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, obesity, immune dysfunctions including autoimmunity and AIDS, diseases with dysfunctions of the coagulation system, allergic diseases, osteoporosis, proliferative disorders including cancer and psoriasis, diseases with decreased or increased synthesis or effects of growth hormone, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of/or response to growth hormone, diseases of the brain including Alzheimer's disease and schizophrenia, and infectious diseases.
  • the compounds of the invention can be used for the following reasons.
  • the compounds of the invention can be used for managing, treating or preventing type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, and/or obesity. 75 In another embodiment, the compounds of the invention can be used for managing, treating or preventing conditions with immune dysfunctions, including autoimmunity such as rheumatoid arthritis, systemic lupus erythematosus.
  • the compounds of the invention can be used as immunosuppres- sants.
  • the compounds of the invention can be used for managing or treating conditions with immune dysfunctions including AIDS.
  • the compounds of the invention can be used for managing, treating or preventing allergic diseases, including asthma and allergic skin diseases.
  • the compounds of the invention can be used for managing, treat- ing or preventing proliferative disorders, including cancer.
  • the compounds of the invention can be used for managing, treating or preventing osteoporosis.
  • the compounds of the invention can be used for managing, treating or preventing psoriasis.
  • the compounds of the invention can be used for managing, treating or preventing diseases with decreased or increased synthesis or effects of growth hormone, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of/or response to growth hormone.
  • the compounds of the invention can be used for managing, treating or preventing diseases with dysfunctions of the coagulation system.
  • the compounds of the invention can be used for managing, treating or preventing diseases of the brain including Alzheimer's disease and schizophrenia. 76 In another embodiment, the compounds of the invention can be used for managing, treating or preventing infectious diseases.
  • the compounds of the invention can furthermore be used to manufacture of medicaments for managing, treating or preventing the above-mentioned diseases and disorders.
  • 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 is furthermore concerned with pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the present invention in association with a pharmaceutical carrier or diluent.
  • the pharmaceutical composition can comprise at least one of the compounds of the invention 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 therapeuti- cals to inhibit or modulate one or more 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 management of disorders with general or specific dysfunctions of PTPase activity, e.g. proliferarive disorders such as psoriasis and neopiastic diseases.
  • the compounds of the invention may be used in pharmaceutical preparations for management of osteoporosis.
  • Preferred embodiments of the invention further include use of compound of the invention 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 one or more PTPases or other signal transduction molecules with affinity for phosphotyro- sine involved controlling or inducing the action of these hormones or any regulating molecule.
  • the compounds of the invention may be used in pharmaceutical preparations for management of various disorders of the immune system, either as a stimulant or suppressor 77 of normal or perturbed immune functions, including autoimmune reactions. Further embodiments of the invention include use of the compounds of the invention for management of allergic reactions, e.g. asthma, dermal reactions, conjunctivitis.
  • the compounds of the invention may be used in pharmaceutical preparations used for immunosuppression.
  • a non-limiting example of such use is in connection with management of organ and/or tissue transplantation.
  • 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 management of infectious disorders, in particular, the compounds of the invention may be used for management 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 management 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 the use of immobilized compounds of the invention using procedures well-known to those skilled in the art. Such methods, well-known to those skilled in the arts, may be used to identify novel PTPases or other molecules with phosphotyrosine recognition units.
  • compounds of the invention may be immobilized by coupling to a solid-phase.
  • a tissue sample or a sample from a cell line prepared as a lysate by methods well-known to those skilled in the art may be passed over said solid-phase coupled with a compound of the invention.
  • PTPases or other molecules with phosphotyrosine recognition units will be bound to the compounds of the invention coupled to the solid phase.
  • Said PTPases or other molecules with phosphotyrosine recognition units may in turn be released by procedures well-known in the art and further subjected to amino acid sequence analysis according to standard procedures well- known to those skilled in the art.
  • amino acid sequence analysis By back-translation of said amino acid sequence into a 78 nucleotide sequence of the corresponding cDNA can be deduced using the appropriate genetic code.
  • Said nucleotide sequence can be used to design and produce an equivalent oligonucleotide, which in turn can be used to identify partial or full-length cDNA clones from appropriate cDNA libraries encoding a protein or glycoprotein corresponding to or similar to the isolated PTPase or molecule with pTyr recognition units.
  • Said oligonucleotide or isolated cDNA clone(s) can similariy be used to isolate genomic clones corresponding to said cDNA clones.
  • Said partial or full-length cDNA can be inserted into appropriate vectors and expressed and purified proteins with procedures well known to those skilled in the arts. Said purified proteins, in particular PTPases, may be used to further analyze the inhibitory capacity and selectivity of compounds of the invention as described.
  • the invention is further directed to compounds of the invention coupled to a suitable solid- phase matrix such as a Wang-resin or a Rink-resin
  • the invention is further diected to a method for isolating a protein or a glycoprotein with affinity for a compound according to the invention from a biological sample, comprising:
  • the invention is further directed to a method for isolating a protein-tyrosine phosphatase with affinity for a compound according to the invention from a biological sample, compris- ing
  • the invention is further directed to a method for isolating a Src-homology 2 domain containing protein or a phosphotyrosine binding domain containing protein with affinity for a compound of the present invention from a biological sample, comprising 79
  • the present invention also relates to a compound of the invention coupled to a fluorescent or radioactive molecule.
  • the invention furthermore relates to a method for coupling a fluorescent or radioactive molecule to a compound of the invention comprising
  • the invention is further directed to a method for detecting protein-tyrosine phosphatase or other molecules with phosphotyrosine recognition unit(s) in a cell or in a subject using a compound of the invention coupled to a fluorescent or radioactive molecule comprising
  • the invention is further directed to a method for quantifying the amount of protein-tyrosine phosphatases or other molecules with phosphotyrosine recognition unit(s) in a cell or in a subject using a compound of the invention coupled to a fluorescent or radioactive molecule comprising
  • the invention is also concerned with a method for determining the function of a given protein-tyrosine phosphatase or group of protein-tyrosine phosphatases or said molecules with phosphotyrosine recognition unit(s) in a cell or a subject using a compound of the invention coupled to a fluorescent or radioactive molecule comprising • contacting said cell or an extract thereof or a biological sample from said subject or by injecting said compound into said subject in order for said compound to produce a complex with said protein-tyrosine phosphatase or said molecules with phosphotyrosine recognition unit(s)
  • dosages suitable for oral administration comprise from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of the compounds of the invention ad- mixed with a pharmaceutical carrier or diluent.
  • the compounds of the invention may be administered in a pharmaceutically acceptable acid addition salt form or where possible as a metal or a C ⁇ -aikylammonium salt.
  • Such salt forms exhibit approximately the same order of activity as the free acid forms.
  • compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutical carrier or diluent.
  • compositions containing the com- 81 pounds of this invention may be prepared by conventional techniques and appear in conventional forms, for example capsules, tablets, solutions or suspensions.
  • the pharmaceutical carrier employed may be a conventional solid or liquid carrier.
  • Exam- pies of solid carriers are lactose, terra alba, sucrose, talc, gelatine, agar, pectin, acacia, magnesium stearate and stearic acid.
  • Examples of 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 carrier 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 that may be prepared by conventional tabletting techniques contains
  • Active compound (as free compound 100 mg or salt thereof) Colloidal silicon dioxide (Areosil ® ) 1.5 mg
  • 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. redal, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethrai, ophthalmic solution or an ointment, the oral route being preferred.
  • oral or parenteral e.g. redal, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethrai, ophthalmic solution or an ointment, the oral route being preferred.
  • TLC thin layer chromatography
  • CDCI 3 is deuterio chloroform
  • CD3OD is tetradeuterio methanol
  • DMSO-d 6 is hexadeuterio dimethylsulfoxide.
  • the structures of the compounds are confirmed by either elemental analysis or NMR, where peaks as- signed to characteristic protons in the title compounds are presented where appropriate.
  • the aqueous phase was extracted with ethyl acetate 85 (100 ml) and the combined organic phases were washed with water (2 x 80 ml), diluted aqueous ammoniac (80 ml) and saturated aqueous sodium chloride (80 ml).
  • the organic phase was dried (MgSO 4 ), filtered and evaporated in vacuo affording 3.4 g of crude 4-amino- biphenyl-3-carboxylic acid methyl ester which was purified on silicagel (1 I) using a mixture of ethyl acetate and heptane (1 :3) as eluent. Pure fractions were collected and evaporated in vacuo affording 2.7 g (91 %) of 4-amino-biphenyl-3-carboxylic acid methyl ester.
  • 5-(3-Dimethylamino-prop-1 -yny0-2-(oxalyl-amino)-benzoic acid To a solution of 5-lodoanthranilic acid (3.0 g, 11.4 mmol) and N,N-diisopropylethylamine (4 ml, 22.8 mmol) in anhydrous tetrahydrofuran (40 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (4.47g, 22.8 mmol). The reaction was stirred at room temperature for 3 h. The solvents were evaporated in vacuo and the crude mixture extracted into ethyl acetate (70 ml).
  • the dried product (0.65 g) was purified by silica gel (400 ml) chromatography using 5 % acetic acid in ethyl acetate as eluent. Pure fractions were collected and the volatiles were evaporated in vacuo. The residue was washed with water and dried in vacuo at 50 °C for 16 h affording 0.4 g (36 %) of the tjtle compound as a solid.
  • Example 54 The following examples were prepared in a similar way as described in Example 54.

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Families Citing this family (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6262044B1 (en) 1998-03-12 2001-07-17 Novo Nordisk A/S Modulators of protein tyrosine phosphatases (PTPASES)
DE19946301A1 (de) 1998-04-02 2001-04-19 Asta Medica Ag Indolyl-3-glyoxylsäure-Derivate mit therapeutisch wertvollen Eigenschaften
DE19814838C2 (de) 1998-04-02 2001-01-18 Asta Medica Ag Indolyl-3-glyoxylsäure-Derivate mit Antitumorwirkung
CA2365945A1 (en) * 1999-04-09 2000-10-19 Max-Planck-Institute For Biochemistry Products and methods for treating ptp lar related diseases
WO2001017516A2 (en) * 1999-09-10 2001-03-15 Novo Nordisk A/S Method of inhibiting protein tyrosine phosphatase 1b and/or t-cell protein tyrosine phosphatase and/or other ptpases with an asp residue at position 48
US6410556B1 (en) 1999-09-10 2002-06-25 Novo Nordisk A/S Modulators of protein tyrosine phosphateses (PTPases)
AU6985200A (en) * 1999-09-10 2001-04-17 Novo Nordisk A/S Modulators of protein tyrosine phosphatases (ptpases)
US7019026B1 (en) 1999-09-10 2006-03-28 Novo Nordisk A/S Modulators of Protein Tyrosine Phosphatases (PTPases)
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
TWI269654B (en) * 1999-09-28 2007-01-01 Baxter Healthcare Sa N-substituted indole-3-glyoxylamide compounds having anti-tumor action
DE60132723T2 (de) 2000-01-21 2009-01-29 Novartis Pharma Ag Zusammensetzungen bestehend aus Dipeptidylpeptidase-IV Inhibitoren und Antidiabetica
US6867299B2 (en) * 2000-02-24 2005-03-15 Hoffmann-La Roche Inc. Oxamide IMPDH inhibitors
WO2002002593A2 (en) * 2000-06-29 2002-01-10 North Shore-Long Island Jewish Health System Modulators of cellular proliferation and angiogenesis, methods for use and identification thereof
WO2002004458A1 (en) * 2000-07-07 2002-01-17 Novo Nordisk A/S Modulators of protein tyrosine phosphatases (ptpases)
AU2001270475A1 (en) * 2000-07-07 2002-01-21 Novo-Nordisk A/S Modulators of protein tyrosine phosphatases (ptpases)
US6613903B2 (en) 2000-07-07 2003-09-02 Novo Nordisk A/S Modulators of protein tyrosine phosphatases (PTPases)
DE10038709A1 (de) * 2000-08-09 2002-02-28 Aventis Pharma Gmbh Substituierte und unsubstituierte Benzooxathiazole sowie daraus abgeleitete Verbindungen
US20020169157A1 (en) * 2000-08-29 2002-11-14 Gang Liu Selective protein tyrosine phosphatatase inhibitors
US6627767B2 (en) 2000-08-29 2003-09-30 Abbott Laboratories Amino(oxo) acetic acid protein tyrosine phosphatase inhibitors
US6972340B2 (en) 2000-08-29 2005-12-06 Abbott Laboratories Selective protein tyrosine phosphatatase inhibitors
US6569853B1 (en) 2000-11-06 2003-05-27 Combinatorx, Incorporated Combinations of chlorpromazine and pentamidine for the treatment of neoplastic disorders
US20020116729A1 (en) * 2000-12-06 2002-08-22 Allen Keith D. Transgenic mice containing NTTP1 phosphatase gene disruptions
US20020152493A1 (en) * 2000-12-06 2002-10-17 Allen Keith D. Transgenic mice containing PTP36 tyrosine phosphatase gene disruptions
WO2003002569A1 (en) * 2001-06-29 2003-01-09 Novo Nordisk A/S Method of inhibiting ptp 1b and/or t-cell ptp and/or other ptpases with an asp residue at position 48
FR2829766A1 (fr) * 2001-09-14 2003-03-21 Lipha Derives d'oxamates comportant un heterocycle azote diversement substitue
AR047894A1 (es) 2004-02-25 2006-03-01 Wyeth Corp Derivados de tiofeno como inhibidores de la proteina tirosina fosfatasa 1b (ptpasa 1b); metodos para su preparacion, composiciones farmaceuticas que los contienen y su uso en el tratamiento de enfermedades mediadas por ptpasa 1b
ME02799B (me) 2004-06-24 2018-01-20 Vertex Pharma Modulatori ATP-vezujućih kasetnih transportera
CA2609659C (en) 2005-05-26 2014-01-28 Neuron Systems, Inc. Azanaphthalenes, compositions and methods for treating retinal disease
GEP20135791B (en) 2005-09-14 2013-03-25 Takeda Pharmaceutical Use of dipeptidyl peptidase inhibitors
CA2635581C (en) 2005-12-28 2017-02-28 Vertex Pharmaceuticals Incorporated Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US20100074949A1 (en) 2008-08-13 2010-03-25 William Rowe Pharmaceutical composition and administration thereof
US12458635B2 (en) 2008-08-13 2025-11-04 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
SI2408750T1 (sl) 2009-03-20 2015-11-30 Vertex Pharmaceuticals Incorporated Postopek za izdelavo modulatorjev cistično-fibroznega transmembranskega regulatorja prevodnosti
WO2011041293A1 (en) 2009-09-30 2011-04-07 Takeda Pharmaceutical Company Limited Pyrazolo [1, 5-a] pyrimidine derivatives as apoptosis signal-regulating kinase 1 inhibitors
WO2011069063A2 (en) 2009-12-04 2011-06-09 Sunovion Pharmaceuticals, Inc. Multicyclic compounds and methods of use thereof
CA2782015C (en) 2009-12-11 2020-08-25 Neuron Systems, Inc. Topical ophthalmic compositions and methods for the treatment of macular degeneration
US8802695B2 (en) 2010-02-03 2014-08-12 Takeda Pharmaceutical Company Limited Apoptosis signal-regulating kinase 1 inhibitors
HK1203840A1 (en) 2012-02-27 2015-11-06 沃泰克斯药物股份有限公司 Pharmaceutical composition and administration thereof
HK1217325A1 (zh) 2012-12-20 2017-01-06 奥尔德拉医疗公司 迫位原醇
AU2014209387B2 (en) 2013-01-23 2018-11-01 Aldeyra Therapeutics, Inc. Toxic aldehyde related diseases and treatment
RU2015126015A (ru) 2013-01-25 2017-03-03 Альдейра Терапьютикс, Инк. Новые улавливатели в лечении макулодистрофии
ES2691944T3 (es) 2013-08-08 2018-11-29 Galapagos Nv Tieno[2,3-c]piranos como moduladores CFTR
JP6746569B2 (ja) 2014-10-07 2020-08-26 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ 嚢胞性線維症膜貫通コンダクタンス制御因子のモジュレーターの共結晶
EP4400106A1 (en) 2015-08-21 2024-07-17 Aldeyra Therapeutics, Inc. Deuterated compounds and uses thereof
CA3022665A1 (en) 2016-05-09 2017-11-16 Aldeyra Therapeutics, Inc. Combination treatment of ocular inflammatory disorders and diseases
HUE070203T2 (hu) 2016-07-29 2025-05-28 Sumitomo Pharma America Inc Vegyületek és készítmények és alkalmazásaik
AU2017301767A1 (en) 2016-07-29 2019-02-14 Pgi Drug Discovery Llc Compounds and compositions and uses thereof
WO2018151861A1 (en) 2017-02-16 2018-08-23 Sunovion Pharamaceuticials Inc. Methods of treating schizophrenia
WO2018170476A1 (en) 2017-03-16 2018-09-20 Aldeyra Therapeutics, Inc. Polymorphic compounds and uses thereof
AU2018312559B2 (en) 2017-08-02 2022-06-02 Pgi Drug Discovery Llc Isochroman compounds and uses thereof
WO2019075136A1 (en) 2017-10-10 2019-04-18 Aldeyra Therapeutics, Inc. TREATMENT OF INFLAMMATORY DISORDERS
CN111133035B (zh) * 2017-12-19 2022-03-11 瓦克化学股份公司 包含草酰胺基酯基团的硅氧烷的制备方法
CA3091292A1 (en) 2018-02-16 2019-08-22 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US12006298B2 (en) 2018-08-06 2024-06-11 Aldeyra Therapeutics, Inc. Polymorphic compounds and uses thereof
KR20210139376A (ko) 2019-03-14 2021-11-22 선오비온 파마슈티컬스 인코포레이티드 이소크로마닐 화합물의 염, 및 이의 결정성 형태, 제조방법, 치료 용도 및 약제학적 조성물
US12098132B2 (en) 2019-05-02 2024-09-24 Aldeyra Therapeutics, Inc. Process for preparation of aldehyde scavenger and intermediates
CN113784954A (zh) 2019-05-02 2021-12-10 奥尔德拉医疗公司 多晶型化合物和其用途
EP4135690A1 (en) 2020-04-14 2023-02-22 Sunovion Pharmaceuticals Inc. (s)-(4,5-dihydro-7h-thieno[2,3-c]pyran-7-yl)-n-methylmethanamine for treating neurological and psychiatric disorders
CA3175856A1 (en) 2020-05-13 2021-11-18 Todd Brady Pharmaceutical formulations and uses thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996040113A2 (en) * 1995-06-07 1996-12-19 Sugen, Inc. Phosphatase inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9946237A1 *

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