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EP1062199A1 - Modulateurs de proteine tyrosine phosphatases (ptpases) - Google Patents

Modulateurs de proteine tyrosine phosphatases (ptpases)

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Publication number
EP1062199A1
EP1062199A1 EP99907333A EP99907333A EP1062199A1 EP 1062199 A1 EP1062199 A1 EP 1062199A1 EP 99907333 A EP99907333 A EP 99907333A EP 99907333 A EP99907333 A EP 99907333A EP 1062199 A1 EP1062199 A1 EP 1062199A1
Authority
EP
European Patent Office
Prior art keywords
amino
oxalyl
alkyl
benzoic acid
arylc
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Withdrawn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
EP99907333A
Other languages
German (de)
English (en)
Inventor
Lutz Stefan Richter
Henrik Sune Andersen
Josef Vagner
Claus Bekker Jeppesen
Niels Peter Hundahl Moller
Sven Branner
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
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Filing date
Publication date
Application filed by Novo Nordisk AS, Ontogen Corp filed Critical Novo Nordisk AS
Priority claimed from PCT/DK1999/000122 external-priority patent/WO1999046236A1/fr
Publication of EP1062199A1 publication Critical patent/EP1062199A1/fr
Withdrawn legal-status Critical Current

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Definitions

  • the present invention relates to novel compounds, to methods for their preparation, to compositions comprising the compounds, to the use of these compounds as medicaments and their use in therapy, where such compounds of Formula 1 are pharmacologically useful inhibitors of Protein Tyrosine Phosphatases (PTPases) such as PTP1B, CD45, SHP-1 , SHP-2, PTP ⁇ , LAR and HePTP or the like,
  • PTPases Protein Tyrosine Phosphatases
  • Protein phosphorylation is now well recognized as an important mechanism utilized by cells 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) intracellular 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 er a/., 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 etal., Proc. Natl. Acad. Sci. USA 87:1501-1502 (1990)), (3) neuronal phosphatase STEP (Lombroso etal., 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 expressed upon cells of the hematopoietic system (Trowbridge and Thomas, Ann. Rev. Immunol. 12: 85-116 (1994)).
  • PTPa,_PTPe All receptor-type PTPases except Type IV 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 superfamily (Hanks and Hunter, FASEB J. 9: 576-596 (1995)).
  • PTPases are the biological counterparts to protein tyrosine kinases (PTKs). Therefore, one important function of PTPases is to control, down-regulate, the activity of PTKs.
  • PTKs protein tyrosine kinases
  • a more complex picture of the function of PTPases now emerges.
  • Several studies have shown that some PTPases may actually act as positive mediators of cellular signalling.
  • the SH2 domain- containing PTP1D seems to act as a positive mediator in insulin-stimulated Ras activation (Noguchi et al., Mol. Cell. Biol. 14: 6674-6682 (1994)) and of growth factor-induced mitogenic signal transduction (Xiao et al., J. Biol. Chem.
  • PTPases as positive regulators has been provided by studies designed to define the activation of the Src-family of tyrosine kinases. In particular, several lines of evidence indicate that CD45 is positively regulating the activation of hematopoietic cells, possibly through dephosphorylation of the C-terminal tyrosine of Fyn and Lck (Chan et al., Annu. Rev. Immunol. 12: 555-592 (1994)).
  • Dual specificity protein tyrosine phosphatases define a subclass within the PTPases family that can hydrolyze phosphate from phosphortyrosine as well as from phosphor-serine/threonine.
  • dsPTPases contain the signature sequence of PTPases: His-Cys-Xxx-Xxx-Gly-Xxx-Xxx-Arg. At least three dsPTPases have been shown to dephosphorylate and inactivate extracellular signal-regulated kinase (ERKs)/mitogen-activated protein kinase (MAPK): MAPK phosphatase (CL100, 3CH134) (Charles et al., Proc. Natl.
  • 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 usually 6 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.
  • PTP1B 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.
  • 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 positioned tyrosine residues (the tyrosine-1150 domain) must all be phosphorylated to obtain full activity of the insulin receptor tyrosine kinase (IRTK) which transmits the signal further downstream by tyrosine phosphorylation of other cellular substrates, including insulin receptor substrate-1 (IRS-1) (Wilden et al., J. Biol. Chem.
  • IRTK appears to be tightly regulated by PTP- mediated dephosphorylation in vivo (Khan et al., J. Biol. Chem. 264: 12931-12940 (1989); Faure et al., J. Biol. Chem. 267: 11215-11221 (1992); Rothenberg et al., J. Biol. Chem. 266: 8302-8311 (1991)).
  • PTPases have distinct structural features that determine their subcellular localization and thereby their access to defined cellular substrates (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 localization 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)).
  • Somatostatin inhibits several biological functions including cellular proliferation (Lamberts et al., Molec: Endocrinol. 8: 1289-1297 (1994)). While part of the antiproliferative activities of somatostatin are secondary to its inhibition of hormone and growth factor secretion (e.g. growth hormone and epidermal growth factor), other antiproliferative effects of somatostatin are due to a direct effect on the target cells. As an example, somatostatin analogs inhibit the growth of pancreatic cancer presumably via stimulation of a single PTPase, or a subset of PTPases, rather than a general activation of PTPase levels in the cells (Liebow et al., Proc. Natl.
  • 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. In particular, evidence has suggested that 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)). Several studies suggest 11 that the PTPase activity of CD45 plays a role in the activation of Lck, a lymphocyte- specific member of the Src family protein-tyrosine kinase (Mustelin etal., Proc. Natl. Acad.
  • the p56lck-CD45 interaction seems to be mediated via a nonconventional SH2 domain interaction not requiring phosphotyrosine.
  • 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
  • HePTP may function during sustained stimulation to modulate the immune response through dephosphorylation of specific residues. Its exact role, however remains to be defined.
  • PTPase inhibitors may be attractive drug candidates both as immunosuppressors and as immunostimulants.
  • BMLOV vanadium-based PTPase inhibitor
  • 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 intracellular PTPases with ezrin-like N-terminal domains, e.g. PTPMEG1 (Gu etal., Proc. Natl. Acad. Sci.
  • PTPH1 Yang and Tonks, Proc. Natl. Acad. Sci. USA 88: 5949-5953 (1991)
  • PTPD1 Yang and Tonks, Proc. Natl. Acad. Sci. USA 88: 5949-5953 (1991)
  • PTPD1 M ⁇ ller et al., Proc. Natl. Acad. Sci. USA 91: 7477-7481 (1994)
  • the ezrin-like domain show similarity to several proteins that are believed to act as links between the cell membrane and the cytoskeleton.
  • PTPD1 was found to be phosphorylated by and associated with c-src in vitro and is hypothesized to be involved in the regulation of phosphorylation of focal adhesions (M ⁇ ller et al., supra). 13
  • 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 ⁇ -erb and v-fms (Lammers 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 PTPe 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)).
  • 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.
  • over-expression of PTP ⁇ was found to lead to transformation of rat embryo fibroblasts (Zheng, supra).
  • SAP-1 a novel PTP, SAP-1, was found to be highly expressed in pancreatic and coiorectal cancer cells.
  • SAP-1 is mapped to chromosome 19 region q13.4 and might be related to carcinoembryonic antigen mapped to 19q13.2 (Uchida et al., J. Biol. Chem. 269: 12220-12228 (1994)). Further, the dsPTPase, cdc25, dephosphorylates cdc2 at Thr14/Tyr-15 and thereby functions as positive regulator of mitosis (reviewed by Hunter, Cell 80: 225-236 (1995)). Inhibitors of specific PTPases are therefore likely to be of significant therapeutic value in the treatment of certain forms of cancer.
  • PTPases platelet aggregation
  • 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 humans (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 osteoporotics by increasing osteoblast proliferation (Lau et al., supra).
  • OST-PTP parathyroid regulated, receptor-like PTPase
  • PTPases microorganisms
  • the present invention relates to compounds of the general formula I, wherein A, R 1 t R 2 , R 3 , R 4 , R 16 and R 17 are as defined in the detailed part of the present description, wherein such compounds are pharmacologically useful inhibitors of Protein Tyrosine Phosphatases (PTPases) such as PTP1B, CD45, SHP-1 , SHP-2, PTP ⁇ , LAR and HePTP or the like.
  • PTPases Protein Tyrosine Phosphatases
  • the present compounds are useful for the treatment, prevention, elimination, alleviation or amelioration of an indication related to 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 including asthma, 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 present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
  • the method of treatment may be described as the treatment, prevention, elimination, alleviation or amelioration of one of the above indications, which comprises the step of administering to the said subject a neurologically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • a further aspect of the invention relates to the use of a compound of the present invention for the preparation of a pharmaceutical composition for the treatment of all 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 including asthma, 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 schizo- phrenia, and infectious diseases.
  • the present invention relates to Compounds of the Formula 1 wherein A, R., R 2 , R 3 , R 4 , R 16 and R 17 are defined below; 19
  • A is together with the double bond in Formula 1 phenyl, biphenyl, indenyl, fluorenyl, fluorenyl-9-one, naphthyl, pyridyl, pyridazinyl, pyrimidyl or pyrazinyl;
  • R- is hydrogen, COR 5 , OR 6 , CF 3 , nitro, cyano, SO 3 H, SO 2 NR 7 R 8 , PO(OH) 2 ,
  • R 12 , R 13 , and R 14 are independently hydrogen, C 1 -C 6 alkyl, aryl, arylC C 6 alkyl and the alkyl and aryl groups are optionally substituted;
  • R 3 , R 16 and R 17 are independently hydrogen, halo, nitro, cyano, trihalomethyl, C r C 6 alkyl, aryl, arylC r C 6 -alkyl, hydroxy, carboxy, carboxyC r C 6 alkyl, C C 6 alkyloxycarbonyl, aryloxycarbonyl, arylC C 6 alkyloxycarbonyl, C ⁇ Cgalkyloxy, C,- C 6 alkyloxyC C 6 alkyl, aryloxy, arylC r C 6 alkyloxy, arylC 1 -C 6 aIkyloxyC 1 -C 6 alkyl, thio, C r C 6 alkyIthio, C CealkylthioC.-Cgal yl, arylthio, arylC r C 6 alkylthio, arylC 1 -C 6 alkylthioC 1 - C 6 alkyl, NR 7 R 8
  • R 12 , R 13 , and R 14 are independently hydrogen, C C 6 alkyl, aryl, arylC r C 6 alkyl and the alkyl and aryl groups are optionally substituted;
  • R 4 is hydrogen, hydroxy, C r C ⁇ alkyl, aryl, aryIC r C 6 alkyl, NR 7 R 8 , C C 6 alkyloxy; wherein the alkyl and aryl groups are optionally substituted;
  • R 5 is hydroxy, C C 6 alkyl, aryl, arylC ⁇ Cgalkyl, C r C 6 alkyIoxy, C Cealkyl-oxyC ! -
  • R 6 is hydrogen, C C 6 alkyl, aryl, arylC 1 -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, arylC r C 6 alkyl, C C 6 alkylcarbonyl, arylcarbonyl, arylC 1 -C 6 alkylcarbonyl, C C 6 alkylcarboxy 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 tricyclic 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 r C 6 alkyl, aryl, arylC r C 6 alkyl, hydroxy, oxo, C ⁇ Cgalkyioxy, arylC C 6 alkyloxy, C C 6 alkyloxyC r
  • R 7 and R 8 are independently a saturated or partial saturated cyclic 5, 6 or 7 membe- red amine, imide or lactam;
  • any optical iso- mer or mixture of optical isomers including a racemic mixture, or any tautomeric forms.
  • 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 clai- med, 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. interleukins), 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. interleukins
  • Phosphotyrosine recognition units/tyrosine phosphate recognition units/pTyr recognition units are defined as areas or domains of proteins or glycoproteins that have affinity for molecules containing phosphorylated tyrosine residues (pTyr).
  • Examples of pTyr recognition units which are not intended to be in any way limiting to the scope of the invention claimed, are: PTPases, SH2 do- mains and PTB domains.
  • PTPases are defined as enzymes with the capacity to dephosphorylate pTyr- containing proteins or glycoproteins.
  • Examples of PTPases which are not intended to be in any way limiting to the scope of the invention claimed, are: 'classical' PTPases (intracellular PTPases (e.g. PTP1 B, TC-PTP, PTP1 C, PTP1 D, PTPD1 , PTPD2) and 23 receptor-type PTPases (e.g.
  • 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 following 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. 304:15-20 (1992); Pawson, Nature 373: 573-580 (1995); Sawyer, Biopolymers (Peptide Science) 47: 243-261 (1998); and references herein).
  • 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 hydrocar- bon 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, bute- nyl, penentyl, hexenyl, isopropyl (i-Pr), isobutyl (i-Bu), te/ ⁇ -butyl (f-Bu), sec-butyl (s- Bu), isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopen- tenyl, cyclohexenyl, methylcyclopropyl, ethylcyclohexenyl, butenylcyclopentyl, and the like.
  • substituted alkyl represents an alkyl group as defined above wherein the substitutents are independently selected from halo, cyano, nitro, trihalomethyl, 24 carbamoyl, hydroxy, oxo, COR 5 , C C 6 alkyl, C r C 6 alkyloxy, aryloxy, arylC C 6 alkyloxy, thio, C r C 6 alkylthio, arylthio, arylC C 6 alkylthio, NR 7 R 8 , C 1 -C 6 alkylamino, arylamino, arylC ⁇ Cgalkylamino, di(arylC C 6 alkyl)amino, C C 6 alkylcarbonyl, arylC C 6 alkylcarbonyl, C C 6 alkylcarboxy, arylcarboxy, arylC 1 -C 6 alkylcarboxy, C C 6 alkylcarbonyl-amino
  • saturated, partially saturated or aromatic cyclic, bicyclic or tricyclic ring system represents but are not limit to aziridinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imida- zolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, 1 ,2,3-triazolyl, 1 ,2,4- triazolyl, morpholinyl, piperidinyl, thiomorpholinyl, piperazinyl, indolyl, isoindolyl, 1 ,2,3,4-tetrahydro-quinolinyl, 1 ,2,3,4-tetrahydro-isoquinolinyl, 1 ,2,3,4-tetrahydro- quinoxalinyl, indolinyl, indazolyl, benzimidazolyl, benzotriazolyl, purinyl, carbazo
  • alkyloxy (e.g. methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy) represents an "alkyl” group as defined above having the indicated number of carbon atoms attached through an oxygen bridge.
  • alkyloxyalkyl represents an "alkyloxy” group attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • alkyloxyalkyloxy represents an "alkyloxyalkyl” group attached through an oxygen atom as defined above having the indicated number of carbon atoms.
  • aryloxy e.g. phenoxy, naphthyloxy and the like
  • arylalkyloxy e.g. phenethyloxy, naphthylmethyloxy and the like
  • arylalkyloxyalkyl represents an "arylalkyloxy” 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
  • arylalkyloxycarbonyl e.g. benzylformiat, phenyletylformiat and the like
  • alkyloxycarbonylalkyl 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 repre- sents 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 tricyclic 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 C 6 alkyl, aryl, arylC C 6 alkyl, hydroxy, oxo, C 1 -C 6 alkyloxy, arylC r C 6 alkyloxy, C 1 -C 6 alkyloxyC 1 -C 6 alkyl, NR 9 R 10 or 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 tricyclic 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 C 6 alkyl, aryl, aryIC r C 6 alkyl, hydroxy, oxo, C r Cgalkyloxy, arylC 1 -C 6 alkyloxy, C r C 6 alkyloxyC 1 -C 6 alkyl, NR 9 R 10 or 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.
  • alkylaminoalkyl represents an "alkylamino" group attached through an al- kyl group as defined above
  • arylalkylaminoalkyl 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-hexenylcarbonyl
  • alkylcarbonyl represents an "alkyl” group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
  • arylcarbonyl (benzoyl) represents an "aryl” group as defined above at- tached through a carbonyl group.
  • 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.
  • arylalkylcarbonylalkyl 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.
  • arylcarboxyalkyl (e.g. phenylcarboxymethyl) represents an "arylcarbonyl” group defined above wherein the carbonyl is in turn attached through an oxygen bridge to an alkyl chain having the indicated number of carbon atoms.
  • 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 represents an "alkylcarbonyl" group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of 28 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.
  • arylalkylcarbonylaminoalkyi 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, polycyclic, 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 C 6 alkyl, aryl, arylC r C 6 alkyl, hydroxy, COR 5 , C r C 6 alkyloxy, C 1 -CgalkyloxyC 1 -Cgalkyl, aryloxy, arylC r C 6 aIkyloxy, arylC 1 -C 6 alkyloxyC 1 -Cgalkyl, thio, C r C 6 alkylthio, C 1 -C 6 alkylthioC 1 -C 6 alkyl, arylthio, arylC r C 6 alkylthio, arylC r C 6 alkylthio, arylC r
  • CgalkylCOR ⁇ arylC 1 -C 6 alkylcarbonyl-amino, arylC 1 -C 6 alkylcarbonylaminoC 1 -C 6 alkyl, - CONRgR 9 , or -C ⁇ Cgalkyl-CONRgRg; wherein R 7 , R 8 , R 9 , and R ⁇ are defined as above and the alkyl and aryl groups are optionally substituted as defined in the definition section;
  • aryl includes but is not limited to phenyl, biphenyl, indenyl, fluorenyl, naphthyl (1 -naphthyl, 2-naphthyl), pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imida- zolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1 ,2,3-triazol-l-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-isoxazolyl, 5-isoxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl (2-
  • arylcarbonyl e.g. 2-thiophenylcarbonyl, 3-methoxy-anthrylcarbonyl, oxa- zolylcarbonyl
  • 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 have asymmetric centers and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms being included in the present invention as well as mixtures thereof.
  • salts of the compounds of formula 1 where a basic or acidic group is present in the structure, are also included within the scope of this invention.
  • an acidic substituent such as -COOH, 5-tetrazolyl or - P(O)(OH) 2 ⁇ there can be formed the ammonium, morpholinium, sodium, potassium, barium, calcium salt, and the like, for use as the dosage form.
  • an acidic salt such as hydrochloride, hydrobromide, phosphate, sulfate, trifiuoroacetate, trichloroa- cetate, acetate, oxalate, maleate, pyruvate, malonate, succinate, citrate, tartarate, fu- marate, mandelate, benzoate, cinnamate, methanesulfonate, ethane sulfonate, pi- crate and the like, and include acids related to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) and incorporated herein by reference, can be used as the dosage form.
  • an acidic salt such as hydrochloride, hydrobromide, phosphate, sulfate, trifiuoroacetate, trichloroa- cetate, acetate, oxalate, maleate, pyruvate, malonate, succinate, citrate, tartarate, fu- marate, mande
  • esters can be employed, e.g., methyl, tert-butyl, acetoxy methyl, pivaloy- loxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.
  • the term "therapeutically 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. 32
  • A is together with the double bond in Formula 1a phenyl, biphenyl, indenyl, fluorenyl, fluorenyl-9-one or naphthyl;
  • R 12 , R 13 , and R 14 are independently hydrogen, C C 6 alkyl, aryl, arylC C 6 alkyl and the alkyl and aryl groups are optionally substituted;
  • R 3 , R 16 and R 17 are independently hydrogen, halo, nitro, cyano, trihalomethyl, C C 6 alkyl, aryl, arylC r C 6 -alkyl, hydroxy, carboxy, carboxyC r C 6 alkyl, C 1 -C 6 alkyloxy- carbonyl, aryloxycarbonyl, arylC r C 6 alkyloxycarbonyl, C r C 6 alkyloxy, C r C 6 alkyl- oxyC r C 6 alkyl, aryloxy, arylC r C 6 alkyloxy, arylC 1 -C 6 alkyl-oxyC 1 -C 6 alkyl, thio, C
  • C g alkyO-aminoC T Cgalkyl C C 6 alkylcarbonyl, C 1 -C 6 alkylcarbonylC 1 -C 6 alkyi, arylC C 6 alkylcarbonyl, arylC 1 -CgalkylcarbonylC 1 -C 6 alkyl, C 1 -C 6 alkyl-carboxy, C 1 -C 6 alkyl- carboxyC Cg-alkyl, arylcarboxy, aryIC C 6 alkyl-carboxy, arylC 1 -C 6 alkylcarboxyC 1 - C 6 alkyl, C 1 -C 6 alkylcarbonyiamino, C 1 -C 6 alkylcarbonyl-aminoC 1 -C 6 alkyl, -carbonylNR 7 C 1 -C 6 alkylCOR 11 , aryIC r C 6 alkyl-carbonylamino, arylC r C 6 alky
  • R 12 , R 13 , and R 14 are independently hydrogen, C,-C ⁇ alkyl, aryl, arylC C 6 alkyl and the alkyl and aryl groups are optionally substituted;
  • R 4 is hydrogen, hydroxy, C r C 6 alkyl, aryl, arylC.-Cgalkyl, NR 7 R 8 , C r C 6 alkyloxy; wherein the alkyl and aryl groups are optionally substituted;
  • R 5 is hydroxy, C r C 6 alkyl, aryl, arylC 1 -C 6 alkyl, CF 3 , NR 7 R 8 ; wherein the alkyl and aryl groups are optionally substituted;
  • R 6 is hydrogen, C 1 -C 6 alkyl, aryl, arylC.,-C ⁇ alkyl; wherein the alkyl and aryl groups are optionally substituted;
  • R 7 and R 8 are independently selected from hydrogen, C 1 -C 6 alkyl, aryl, arylC r C 6 alkyl, C r C 6 alkyl-carbonyl, arylcarbonyl, arylC r C 6 alkyl-carbonyl, C r C 6 alkyl-carboxy or a- rylC ⁇ Cgalkylcarboxy wherein the alkyl and aryl groups are optionally substituted; or R 7 and R 8 are taken together with the nitrogen to which they are attached forming a cyclic or bicyclic system containing 3 to 11 carbon atoms and 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system can optionally be substituted with at least one C C 6 alkyl, aryl, arylC 1 -C 6 alkyl, hydroxy, C ⁇ Cgalkyloxy, 35 arylC C 6 alkyloxy, C 1 -CgalkyloxyC 1 -Cgalkyl, NR 9
  • R 7 and R 8 are independently a saturated or partial saturated cyclic 5, 6 or 7 membe- red amine or lactam;
  • A is together with the double bond in Formula 1c pyridyl, pyridazinyl, pyrimidyl or pyrazinyl;
  • R 12 , R 13 , and R 14 are independently hydrogen, C C 6 alkyl, aryl, arylC C 6 alkyl and the alkyl and aryl groups are optionally substituted;
  • R 3 , R 16 and R 17 are independently hydrogen, halo, nitro, cyano, trihalomethyl, C r C 6 alkyl, aryl, arylC C 6 -alkyl, hydroxy, carboxy, carboxyC 1 -C 6 alkyl, C r C 6 alkyloxy- carbonyl, aryloxycarbonyl, arylC 1 -C 6 alkyloxycarbonyl, C C 6 alkyloxy, C C 6 alkyI- oxyC C 6 aIkyl, aryloxy, aryIC C 6 alkyloxy, arylC 1 -C 6 alkyI-oxyC 1 -C 6 alkyl, thio, C C 6 alkylthio, C 1 -C 6 alkylthioC 1 -C 6 alkyl, arylthio, arylC r C 6 alkylthio, arylC 1 -C 6 alkylthioC 1 - C 6 alkyl,
  • R 12 , R 13 , and R 14 are independently hydrogen, C r C 6 alkyl, aryl, arylC C 6 alkyl and the alkyl and aryl groups are optionally substituted;
  • R 4 is hydrogen, hydroxy, C ⁇ Cgalkyl, aryl, arylC 1 -C 6 alkyl, NR 7 R 8 , C C 6 alkyloxy; whe- rein the alkyl and aryl groups are optionally substituted;
  • R 5 is hydroxy, C r C 6 alkyl, aryl, arylC r C 6 alkyI, CF 3 , NR 7 R 8 ; wherein the alkyl and aryl groups are optionally substituted;
  • R 6 is hydrogen, C 1 -C 6 alkyl, aryl, arylC 1 -C 6 aIkyl; 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, arylC ⁇ C g alkyl, C 1 -C 6 alkyl-carbonyl, arylcarbonyl, aryIC C 6 alkyl-carbonyl, C r C 6 alkyl-carboxy or a- rylC 1 -C 6 alkylcarboxy wherein the alkyl and aryl groups are optionally substituted; or R 7 and R 8 are taken together with the nitrogen to which they are attached forming a cyclic or bicyclic system containing 3 to 11 carbon atoms and 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system can optionally be substituted with at least one C r Cgalkyl, aryl, arylC 1 -C 6 alkyl, hydroxy, C 1 -C 6 alkyloxy, arylC C 6 alkyloxy, C CgalkyloxyC Cgalkyl, NR 9 R 10 or
  • preferred compounds of the invention are compounds of formula 1a or formula 1c wherein R 16 and R 17 are hydrogen.
  • A is together with the double bond in Formula 1b is aryl
  • R 12 , R 13 , and R 14 are independently hydrogen, C C 6 alkyl, aryl, arylC r Cgalkyl and the alkyl and aryl groups are optionally substituted;
  • R 3 , R 16 and R 17 are independently hydrogen, halo, nitro, cyano, trihalomethyl, C,- C 6 alkyl, aryl, arylC C 6 -alkyl, hydroxy, carboxy, carbdxyC 1 -C 6 alkyl, C
  • R 12 , R 13 , and R 14 are independently hydrogen, C r C 6 alkyl, aryl, arylC C 6 alkyl and the alkyl and aryl groups are optionally substituted;
  • R 4 is hydrogen, hydroxy, C,-C 6 alkyl, aryl, arylC ⁇ Cgalkyl, NR 7 R 8 , C 1 -C 6 alkyloxy; wherein the alkyl and aryl groups are optionally substituted;
  • R 5 is hydroxy, C r C 6 alkyl, aryl, arylC 1 -C 6 alkyl, CF 3 , NR 7 R 8 ; wherein the alkyl and aryl groups are optionally substituted;
  • R 6 is hydrogen, C C 6 alkyl, aryl, arylC C 6 alkyl; wherein the alkyl and aryl groups are optionally substituted;
  • R 7 and R 8 are taken together with the nitrogen to which they are attached forming a saturated, partially saturated or aromatic cyclic, bicyclic or tricyclic ring system containing 3 to 14 carbon atoms and 0 to 3 additional heteroatoms selected from nitro- gen, oxygen or sulfur, the ring system can optionally be substituted with at least one C C ⁇ alkyl, aryl, arylC C 6 alkyl, hydroxy, oxo, C r C 6 alkyloxy, arylC r C 6 alkyloxy, C r C 6 alkyloxyC r C 6 alkyl, NR 9 R 10 or C 1 -C 6 alkylaminoC 1 -C 6 alkyl, wherein R 9 and R 10 are independently selected from hydrogen, C 1 -C 6 alkyl, aryl, arylC Cgalkyl, C r C 6 alkylcarbonyl, arylcarbonyl, arylC T Cgalkylcarbonyl, C r C
  • R 7 and R 8 are independently a saturated or partial saturated cyclic 5, 6 or 7 membe- red amine, imide or lactam; 42
  • any optical isomer or mixture of optical isomers including a racemic mixture, or any tautomeric forms.
  • PHARMACOLOGICAL METHODS The compounds are evaluated for biological activity with a truncated form of PTP1 B (corresponding to the first 321 amino acids), which was expressed in E. coli and purified to apparent homogeneity using published procedures well-known to those skilled in the art.
  • the enzyme reactions are carried out using standard conditions essentially as described by Burke et al. (Biochemistry 35; 15989-15996 (1996)).
  • the assay conditions are as follows. Appropriate concentrations of the compounds of the invention are added to the reaction mixtures containing different concentrations of the substrate, p-nitrophenyl phosphate (range: 0.16 to 10 mM - final assay concentration).
  • the buffer used was 100 mM sodium acetate pH 5.5, 50 mM sodium chloride, 0.1 % (w/v) bovine serum albumin and 5 mM dithiothreitol (total volume 100 ml).
  • the reaction was started by addition of the enzyme and carried out in microtiter plates at 25° C for 60 minutes. The reactions are stopped by addition of NaOH.
  • the enzyme activity was determined by measurement of the absorbance at 405 nm with appropriate corrections for absorbance at 405 nm of the compounds and p- nitrophenyl phosphate.
  • the data are analyzed using nonlinear regression fit to clas- sical Michaelis Menten enzyme kinetic models. Inhibition is expressed as K j values in ⁇ M.
  • Table 1 The results of representative experiments are shown in Table 1
  • the compounds are evaluated for biological activity as regards their effect as inhibitors of PTP ⁇ in essentially the same way as described for inhibition of PTP1 B. Derived from their activity as evaluated above the compounds of the invention may be useful in the treatment of diseases selected from the group consisting of type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance and obesity.
  • the compounds of the invention may be useful in the treatment of diseases selected from the group consisting of immune dysfunctions including autoimmunity, diseases with dysfunctions of the coagulation system, allergic diseases including asthma, osteoporosis, proliferati- ve 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.
  • diseases selected from the group consisting of immune dysfunctions including autoimmunity, diseases with dysfunctions of the coagulation system, allergic diseases including asthma, osteoporosis, proliferati- ve 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 are prepared as illustrated in the following reaction scheme:
  • R 12 , R 13 , R 14 , and R 15 are independently selected from the group consisting of hydrogen, C r C 6 alkyl, aryl, arylC C 6 alkyl as defined above and the alkyl and aryl groups are optionally substituted as defined above; or R 12 , R 13 , R 14 , and R 15 are independently selected from
  • R 1 R 2 and R 4 are defined as above.
  • the above described four component Ugi reaction can be carried out by attaching any one of the components to a solid support. Hence, the synthesis can be accomplished in a combinatorial chemistry fashion.
  • the present invention also has the objective of providing suitable topical, oral, and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention.
  • the compounds of the present invention may be administered orally as tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups or elixirs.
  • the composition for oral use may contain one or more agents selected from the group of sweetening agents, flavoring agents, coloring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations.
  • the tablets contain the acting ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manu- facture of tablets.
  • excipients may be, for example, (1) inert diluents, such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents, such as corn starch or alginic acid; (3) binding agents, such as starch, gelatin or acacia; and (4) lubricating agents, such as magnesium stearate, stearic acid or talc.
  • inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents such as corn starch or alginic acid
  • binding agents such as starch, gelatin or acacia
  • lubricating agents such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as gly
  • Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin.
  • the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions normally contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspension.
  • expicients may be (1) suspending agent such as sodium carboxymethyl cellulose, methyl cellulose, hy- droxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; (2) dispersing or wetting agents which may be (a) naturally occurring phosphatide such as lecithin; (b) a condensation product of an alkylene oxide 48 with a fatty acid, for example, polyoxyethylene stearate; (c) a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethylen- oxycetanol; (d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate, or (e)
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a sol- vent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the Compounds of the invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
  • the compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar ve- sides, and multilamellar vesicles. Liposomes can be formed from a variety of phos- pholipids, such as cholesterol, stearylamine, or phosphatidyl-cholines.
  • Dosage levels of the compounds of the present invention are of the order of about 0.5 mg to about 100 mg per kilogram body weight, with a preferred dosage range between about 20 mg to about 50 mg per kilogram body weight per day (from about 49
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for oral administration to humans may contain 5 mg to 1 g of an active compound with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 5 mg to about 500 mg of active ingredient. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, gender, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. The dosage needs to be individualized by the clinician.
  • TLC thin layer chromatography
  • CDCI 3 deuterio chloroform
  • CD 3 OD tetradeutereio methanol
  • DMSO-d 6 hexadeuterio dimethylsulfoxide.
  • the structures of the compounds are confirmed by either elemental analysis or NMR, where peaks assigned to characteristic protons in the title compounds are presented where appropriate.
  • 1 H NMR shifts ( ⁇ H ) are given in parts per million (ppm) downfield from tetramethylsilane as internal reference standard.
  • M.p. is melting point and is given in °C and is not corrected. Column chromatography was carried out using the technique described by W.C. Still et al., J. Org. Chem.
  • the aqueous phase was extracted with ethyl acetate (100 ml) and the combined organic pha- ses 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 jn 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 evapo- rated in vacuo affording 2.7 g (91 %) of 4-amino-biphenyl-3-carboxylic acid methyl ester.
  • 5-(3-Dimethylamino-prop-1-ynylV2-(oxalyl-aminoVbenzoic 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 terf-butyl ester (4.47 g, 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).

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne de nouveaux composés, de nouvelles compositions, des méthodes d'utilisation et des méthodes de fabrication associées. Lesdits composés sont des inhibiteurs de protéine tyrosine phosphatases (PTPases) pharmacologiquement utiles, tels que PTP1B, CD45, SHP-1, SHP-2, PTPα, LAR et HePTP ou analogues. Ces composés sont utiles dans le traitement du diabète du type I, du diabète du type II, de l'intolérance au glucose, de la résistance insulinique, de l'obésité, des dysfonctionnements immunitaires parmi lesquels les maladies auto-immunes entraînant un dysfonctionnement du système de coagulation, des maladies allergiques parmi lesquelles l'asthme, de l'ostéoporose, des troubles proliférants parmi lesquels le cancer et le psoriasis, des maladies entraînant une baisse ou une augmentation de la synthèse ou des effets des hormones de croissance, des maladies entraînant une baisse ou une augmentation de la synthèse des hormones ou cytokines qui régulent la libération d'hormones de croissance ou la réaction à ces hormones, des maladies cérébrales parmi lesquelles la maladie d'Alzheimer et la schizophrénie, et des maladies infectieuses.
EP99907333A 1998-03-12 1999-03-11 Modulateurs de proteine tyrosine phosphatases (ptpases) Withdrawn EP1062199A1 (fr)

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Application Number Priority Date Filing Date Title
DK34298 1998-03-12
DK34298 1998-03-12
DK34598 1998-03-12
DK34598 1998-03-12
DK47298 1998-04-03
DK47998 1998-04-03
DK47998 1998-04-03
DK47298 1998-04-03
DKPA199800940 1998-07-15
DK94098 1998-07-15
PCT/DK1999/000122 WO1999046236A1 (fr) 1998-03-12 1999-03-11 Modulateurs de proteine tyrosine phosphatases (ptpases)

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WO2017078499A2 (fr) * 2015-11-06 2017-05-11 경북대학교 산학협력단 Composition pour la prévention ou le traitement d'une maladie neuroinflammatoire, contenant un inhibiteur de la protéine tyrosine phosphatase
WO2020104635A1 (fr) * 2018-11-23 2020-05-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation d'inhibiteurs de shp2 pour le traitement de la résistance à l'insuline

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Title
See references of WO9946236A1 *

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* Cited by examiner, † Cited by third party
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CN115297860A (zh) * 2020-04-06 2022-11-04 普渡研究基金会 新型n-芳基草氨酸
CN115297860B (zh) * 2020-04-06 2024-10-15 普渡研究基金会 新型n-芳基草氨酸

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