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WO1997039748A1 - Modulateurs de molecules possedant des unites de reconnaissance de la phosphotyrosine - Google Patents

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

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WO1997039748A1
WO1997039748A1 PCT/DK1997/000167 DK9700167W WO9739748A1 WO 1997039748 A1 WO1997039748 A1 WO 1997039748A1 DK 9700167 W DK9700167 W DK 9700167W WO 9739748 A1 WO9739748 A1 WO 9739748A1
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optionally substituted
compound
alkyl
compound according
protein
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Henrik Sune Andersen
Niels Peter Hundahl Møller
Peter Madsen
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Novo Nordisk A/S
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Publication of WO1997039748A1 publication Critical patent/WO1997039748A1/fr

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Definitions

  • the present invention relates to novel substituted acrylic acids, to methods for their preparation, to compositions containing them, to their use for treatment of human and animal disorders, to their use for purification of proteins or glycoproteins, and to their use in diagnosis.
  • the invention relates to modulation of the activity of molecules with phospho-tyrosine recognition units, including protein tyrosine phosphatases (PTPases) and proteins with Src-homology-2 domains, in in vitro systems, microorganisms, eukaryotic cells, whole animals and human beings.
  • PTPases protein tyrosine phosphatases
  • PTKs protein tyrosine kinases
  • PTPases protein tyrosine phosphatases
  • the protein phosphatases are composed of at least two separate and distinct families (Hunter, T., Cell 58: 1013-1016 (1989)) the protein serine/threonine phosphatases and the PTPases.
  • the PTPases are a family of enzymes that can be classified into two groups: a) intracellular or nontransmembrane PTPases and b) receptor-type or transmembrane PTPases.
  • Intracellular PTPases All known intracellular type PTPases contain a single conserved catalytic phosphatase domain consisting of 220-240 amino acid residues. The regions outside the PTPase domains are believed to play important roles in localizing the intracellular PTPases subcellularly (Mauro, L.J. and Dixon, J.E. T/J3S 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)).
  • PTP1 B was cloned (Charbonneau et at., Proc. Natl. Acad. Sci. USA 86: 5252-5256 (1989); Chernoff et al., Proc. Natl. Acad. Sci. USA 87: 2735-2789 (1989)).
  • Other examples of 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.
  • 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 PTP1 B (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)).
  • PTP-U2/GLEPP1 (Seimiya et ai, Oncogene 10: 1731-1738 (1995); (Thomas et ai, J. Biol. Chem. 269: 19953-19962 (1994)), and (14) DEP-1; (IV) PTP ⁇ ,_PTP ⁇ . All receptor-type PTPases except Type IV contain two PTPase domains. Novel PTPases are continously identified, and it is anticipated that more than 500 different species will be found in the human genome, i.e. close to the predicted size of the protein tyrosine kinase superfamily (Hanks and Hunter, FASEB J. 9: 576-596 (1995)).
  • PTPases are the biological counterparts to protein tyrosine kinases (PTKs). Therefore, one important function of PTPases is to control, down-regulate, the activity of PTKs.
  • PTKs protein tyrosine kinases
  • Several studies have shown that some PTPases may actually act as positive mediators of cellular signaling. As an example, the SH2 domain-containing PTP1 D seems to act as a positive mediator in insulin-stimulated Ras activation (Noguchi etal., Mol. Cell. Biol. 14: 6674-6682 (1994)) and of growth factor-induced mitogenic signal transduction (Xiao et ai, 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 ai, 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 ai, 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 ef ai, Proc. Natl. Acad. Sci. USA 91: 1731-1735 (1994)
  • tyrosine dephosphorylation of cdc2 by a dual specific phosphatase, cdc25 is required for induction of mitosis in yeast (review by Walton and Dixon, Annu. Rev. Biochem. 62: 101-120 (1993)).
  • Hormones, growth factors, cytokines, antigens, extracellular matrix components as well as molecules positioned at the cell surface induce signal transduction by binding to specific cell surface structures or receptors on target cells (reviewed in Pawson, Nature 373: 573-580 (1995)).
  • the resulting cellular signal is often mediated through a series of phosphorylation and dephosphorylation reactions on tyrosine residues of signaling molecules.
  • pTyr phosphotyrosine
  • SH2 domains and PTB domains primarily act as docking molecules with little or no catalytic activity.
  • tyrosine phosphorylated proteins have the capacity to bind other proteins containing SH2 domains or PTB domains thereby controlling the subcellular location of signaling molecules.
  • SH2 domains from the Src kinase family bind the peptide pTyr-Glu-Glu-lle in a relatively selective manner, whereas the PTPD1 seems to recognize at least five, primarily hydrophobic residues C-terminal to the pTyr (Pawson, supra).
  • Inhibition of signal transduction processes could, in principle, be achieved by using non-hydrolyzable pTyr-containing peptides with preferential affinity for specific PTPases, SH2 domains or PTB domains.
  • pTyr-containing peptides with preferential affinity for specific PTPases, SH2 domains or PTB domains.
  • Such selective compounds can either initiate, increase or decrease defined signal transduction processes.
  • Vanadate was found to inhibit protein-tyrosine phosphatases in mammalian cells with a concomitant increase in the level of phosphotyrosine in cellular proteins leading to transformation (Klarlund, Cell 41: 707-717 (1985)).
  • Vanadium-based phosphatase inhibitors are relatively unspecific. Therefore, to assess the importance of specific structures on PTPase activity more selective inhibitors are needed.
  • One possibility for obtaining selective PTPase inhibitors would be through design of different ancillary ligands for peroxovanadium-based compounds (Posner et al., J. Biol. Chem. 269: 4596-4604 (1994)).
  • PTPases the insulin receptor signaling 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 signaling lead to diabetes mellitus. Binding of insulin to its receptor causes rapid (auto)phosphorylation of several tyrosine residues in the intracellular part of the ⁇ -subunit. Three closely positioned tyrosine residues (the tyrosine-1150 domain) must all be phosphorylated to obtain full activity of the insulin receptor tyrosine kinase (IRTK) which transmits the signal further downstream by tyrosine phosphorylation of other cellular substrates, including insulin receptor substrate-1 (IRS-1) (Wilden ef ai, J. Biol. Chem. 267:
  • 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)). Therefore, the lack of activity of PTP1 B and TC- PTP towards the IRTK may, at least in part, be explained by the fact that they do not co-localize with the activated insulin receptor. In support of this view, PTP1 B 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.
  • 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 ef al , Molec Endocnnol 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
  • 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 USA 86 2003-2007 (1989), Colas et al, Eur J Biochem 207 1017-1024 (1992))
  • somatostatin stimulation of somatostatin receptors SSTR1 but not SSTR2, stably expressed
  • CD45 a lymphocyte-specific member of the Src family protein-tyrosine kinase (Mustelin ef ai, 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 ai, J. Biol. Chem. 270: 27987-27990 (1995)).
  • HePTP a hematopoietic cell specific PTPase
  • PTPase a hematopoietic cell specific PTPase
  • CD45 CD45
  • HePTP and PTP1 C selective PTPase inhibitors may be attractive drug candidates both as immunosuppressors and as immunostimulants.
  • 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 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 cytoskeleton.
  • PTPD1 was found to be phosphorylated by and associated with c-src in vitro and is hypothesized to be involved in the regulation of phosphorylation of focal adhesions (M ⁇ ller et al., supra).
  • PTPases may oppose the action of tyrosine kinases, including those responsible for phosphorylation of focal adhesion proteins, and may therefore function as natural inhibitors of transformation.
  • TC-PTP and especially the truncated form of this enzyme (Cool ef at, Proc. Natl. Acad. Sci. USA 87: 7280-7284 (1990)), can inhibit the transforming activity of v-erb and v-fms (Lammers ef ai, J. Biol. Chem. 268: 22456- 22462 (1993); Zander ef ai, Oncogene 8: 1175-1182 (1993)).
  • PTP1 B The expression level of PTP1 B was found to be increased in a mammary cell line transformed with neu (Zhay ef ai, 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-netv 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.
  • PTPK and PTP ⁇ Two closely related receptor-type PTPases, PTPK and PTP ⁇ , can mediate homophilic cell-cell interaction when expressed in non-adherent insect cells, suggesting that these PTPases might have a normal physiological function in cell-to-cell signaling (Gebbink ef at, J. Biol. Chem. 268: 16101-16104 (1993); Brady-Kalnay ef ai, 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 ai, J. Biol. Chem.
  • PTPases may play an important role in regulating normal cell growth.
  • PTPases may also function as positive mediators of intracellular signaling and thereby induce or enhance mitogenic responses. Increased activity of certain PTPases might therefore result in cellular transformation and tumor formation.
  • over- expression of PTP ⁇ was found to lead to transformation of rat embryo fibroblasts (Zheng, supra).
  • SAP-1 a novel PTP, SAP-1, was found to be highly expressed in pancreatic and colorectal cancer cells.
  • SAP-1 is mapped to chromosome 19 region q13.4 and might be related to carcinoembryonic antigen mapped to 19q13.2 (Uchida ef ai, J. Biol. Chem. 269: 12220-12228 (1994)). Further, the dsPTPase, cdc25, dephosphorylates cdc2 at Thr14 Tyr-15 and thereby functions as positive regulator of mitosis (reviewed by Hunter, Cell 80: 225-236 (1995)). Inhibitors of specific PTPases are therefore likely to be of significant therapeutic value in the treatment of certain forms of cancer.
  • PTPases platelet aggregation
  • PTPases are centrally involved in platelet aggregation.
  • Agonist-induced platelet activation results in calpain-catalyzed cleavage of PTP1 B with a concomitant 2-fold stimulation of PTPase activity (Frangioni ef ai, EMBO J. 12: 4843 ⁇ 1856 (1993)).
  • the cleavage of PTP1 B leads to subcellular relocation of the enzyme and correlates with the transition from reversible to irreversible platelet aggregation in platelet-rich plasma.
  • the rate of bone formation is determined by the number and the activity of osteoblasts, which in term are determined by the rate of proliferation and differentiation of osteoblas progenitor cells, respectively. Histomorphometric studies indicate that the osteoblast number is the primary determinant of the rate of bone formation in humans (Gruber et ai, 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 ef ai, supra).
  • an osteoblastic acid phosphatase with PTPase activity was found to be highly sensitive to mitogenic concentrations of fluoride (Lau et ai, J. Biol. Chem. 260: 4653-4660 (1985); Lau et al., J. Biol. Chem. 262: 1389-1397 (1987); Lau et al., Adv. Protein Phosphatases 4: 165-198 (1987)).
  • the level of membrane-bound PTPase activity was increased dramatically when the osteoblast-like cell line UMR 106.06 was grown on collagen type-l matrix compared to uncoated tissue culture plates.
  • OST-PTP parathyroid regulated, receptor-like PTPase
  • PTPases microorganisms
  • the inventors have identified a novel class of compounds that has the capacity to modulate the activity of molecules with tyrosine recognition units, including PTPases, preferably a selective modulation.
  • the present invention relates to novel acrylic acids of general formula (I)
  • the present invention relates to novel acrylic acids of formula (I)
  • n is 1 , 2, 3, 4, or 5 and (L) n represents up to five (5) substituents which independently of each other are hydrogen, d- ⁇ -alkyl, d-e-alkoxy, hydroxy, halogen, trihalogenomethyl, hydroxy-C 1-6 -alkyl, amino-d-e-alkyl, COR 2 , NO 2 , CN, CHO, d-e- alkanoyloxy, carbamoyl, NRsRe, aryloxy optionally substituted; R 2 is d-s-atkyl, aryl optionally substituted, aralkyl optionally substituted, OH, NR 3 R, wherein R 3 and R independently of each other are hydrogen, C ⁇ . 6 -alkyl, aryl optionally substituted, aralkyl optionally substituted;
  • R 5 and Re are independently of each other hydrogen, d ⁇ -alkyl, aryl optionally substituted, aralkyl optionally substituted or COZ, wherein Z, is d. 6 -alkyl, aryl optionally substituted, aralkyl optionally substituted,
  • L is A-Y -( ⁇ N,)-X-(W 2 )-Y 2 wherein X is a chemical bond, CO, CONR 7 , NR 7 CO, NR 7 ,0,
  • Yi and Y 2 are independently a chemical bond, O, S, or NR 7 ;
  • R 7 is hydrogen, d. 6 -alkyl, aryl optionally substituted, aralkyl optionally substituted, heteroaryl optionally substituted, COZ 2 wherein Z 2 is d. 6 -alkyl, aryl optionally substituted, aralkyl optionally substituted;
  • W ! and W 2 are independently a chemical bond or saturated or unsaturated C1.6- alkylene;
  • A is aryl optionally substituted, heteroaryl optionally substituted, biaryl optionally substituted, arylheteroaryl optionally substituted, NReR 9 wherein R_ and R 9 independently are hydrogen, C ⁇ -6 -alkyl, aryl optionally substituted, aralkyl optionally substituted, heteroaryl optionally substituted, COZ 3 wherein Z 3 is C,. 6 -alkyl, aryl optionally substituted, aralkyl optionally substituted, heteroaryl optionally substituted or when R 8 and R 9 together with the nitrogen atom forms a ring system A is a saturated or partially saturated heterocyclic ring system optionally substituted with C ⁇ - .
  • a ⁇ is aryl or heteroaryl
  • aryl, heteroaryl, Ar, and A are exemplified by the following examples.
  • Specific examples of the aryl and biaryl residues include phenyl, biphenyl, indene, fluorene, naphthyl (1 -naphthyl, 2-naphthyl), anthracene (1- anthracenyl, 2-anthracenyl, 3-anthracenyl).
  • heteroaryl examples include pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1 -imidazolyl, 2- imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1 ,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1 ,2,3-triazol-4-yl, 1 ,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyI, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3
  • arylheteroaryl residue examples include phenylpyridyl (2-phenylpyridyl, 3-phenylpyridyl, 4-phenylpyridyl), phenylpyrimidinyl (2-phenylpyrimidi ⁇ yl, 4- phenylpyrimidinyl, 5-phenylpyrimidinyl, 6-phenylpyrimidinyl), phenylpyrazinyl, phenylpyridazinyl (3-phenyl-pyridazinyl, 4-phenylpyridazinyl, 5-phenylpyridazinyl).
  • examples of L is quinolinyl- piperazinylethyl such as 2-(4-quinolin-2-yl-piperazin-1-yl)ethyl, biphenyloxymethyl such as biphenyl-4-yloxymethyl, phenyl-piperazinylmethyl such as 4-phenylpiperazin- 1-ylmethyl, biphenylmethyl such as 1-biphenyl-4-ylmethyl.
  • the d. 6 -alkyl residues include aliphatic hydrocarbon residues, unsaturated aliphatic hydrocarbon residues, alicyclic hydrocarbon residues.
  • Examples of the aliphatic hydrocarbon residues include saturated aliphatic hydrocarbon residues having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.butyl, n-pentyl, isopentyl, neopentyl, tert.pentyl, n-hexyl, isohexyl.
  • Example of the unsaturated aliphatic hydrocarbon residues include those having 2 to 6 carbon atoms such as ethenyl, 1-propenyl, 2-propenyl, 1 -butenyl, 2-butenyl, 3-butenyl, 2-methyl-1- propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1- hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, ethynyl, 1-propionyl, 2-propionyl, 1- butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- hexynyl, 3-hexynyl, 2,4-hexadiy ⁇ yl, 5-hexynyl.
  • alicyclic hydrocarbon residue examples include saturated alicyclic hydrocarbon residues having 3 to 6 carbon atoms such as cydopropyl, cyclobutyl, cyclopentyl, cyclohexyl; and Cs-s unsaturated alicyclic hydrocarbon residues having 5 to 6 carbon atoms such as 1-cyclopentenyl, 2- cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl.
  • the C ⁇ . 6 -alkoxy residues include aliphatic hydrocarbon residues connected to an oxygene atom.
  • the aliphatic hydrocarbon residues include saturated aliphatic hydrocarbon residues having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, iso-propoxy, butoxy, isobutoxy, sec.butoxy, tert.butoxy, pentoxy, isopentoxy, neopentoxy, tert. pentoxy, hexyloxy, isohexyloxy.
  • the C ⁇ _6-alkoxycarbonyl residues include a d. 6 -alkoxy residue connected to a carbonyl residue such as methoxycarbonyl, ethoxy-earbonyl, propoxycarbonyl, and tert-butoxycarbonyl .
  • the Ci.e-alkanoyloxy residues include a acyl residue connected to an oxygen atom wherein the acyl residue is an aliphatic hydrocarbon residues connected to an carbonyl residue such as acetyloxy, propionyloxy, isopropionyloxy.
  • the aralkyl residue include an aryl residue connected to an d-e-alkyl residue e.g. phenyl alkyls having 7 to 9 carbon atoms such as benzyl, phenethyl, 1-phenylethyl, 3- phenylpropyl, 2-phenylpropyl and 1 -phenylpropyl; and naphthyl alkyl having 11 to 13 carbon atoms such as 1-naphthylmethyl, 1-naphthylethyl, 2-naphthylmethyl, and 2- naphthylethyl.
  • phenyl alkyls having 7 to 9 carbon atoms such as benzyl, phenethyl, 1-phenylethyl, 3- phenylpropyl, 2-phenylpropyl and 1 -phenylpropyl
  • naphthyl alkyl having 11 to 13 carbon atoms such as 1-naphthylmethyl, 1-
  • Aryloxy include an aryl connected to an oxygen atom such as phenyloxy, naphthyloxy.
  • Aralkyloxy include an aralkyl connected to an oxygen atom such as benzyloxy, phenethyloxy, naphthylmethyloxy.
  • Biaryl include an aryl connected to an aryl residue such as biphenyl, 1- phenylnaphthyl, 2-phenylnaphthyl .
  • Biaryloxy include an biaryl connected to an oxygen atom such as biphenyl ether, 1 - naphthylphenyl ether, 2-naphthylphenyl ether.
  • the heteroaryl residue is a 5- or 6-membered aromatic ring, which can be fused to one or more phenyl rings and contains, besides carbon atoms, 1 to 4 atoms selected from N, O, and S as atoms constituting the ring, which is bonded through carbon atoms such as defined above.
  • the halogen residue include fluorine, chlorine, bromine, and iodine.
  • optionally substituted means an aryl residue, a heteroaryl residue, or a d. 6 - alkyl residue that may be unsubstituted or may have 1 or more preferably 1 to 5 substituents, which are the same as or different from one another.
  • substituents include, halogen (fluorine, chlorine, bromine, iodine), hydroxyl, cyano, nitro, trifluoromethyl, carbamoyl, d-a-acy! (e.g. acetyl, propionyl, isopropionyl), C1.6- alkoxy (e.g.
  • C ⁇ -alkyl e.g. methyl, ethyl, propyl, cydopropyl, isopropyl, butyl, and tert. butyl
  • Ci-s- alkoxycarbonyl e.g. ones having 2 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl
  • C ⁇ -alkanoyloxy e.g. ones having 2 to 6 carbon atoms such as acetyloxy, propionyloxy, isopropionyloxy
  • C ⁇ . 4 -alkylthio e.g.
  • the compounds of formula (I) may exist as geometric and optical isomers and all isomers and mixtures thereof are included herein. Isomers may be separated by means of standard methods such as chromatographic techniques or fractionated crystallisation of e.g. suitable salts.
  • the compounds according to the invention may optionally exist as pharmaceutically acceptable salts comprising acid addition salts or metal salts or - optionally alkylated ammonium salts.
  • salts include the alkali metal or amine salts of 1 H- or 2H-tetrazoles of this invention, such as the sodium, potassium, d. 6 -alkylamine, di (C ⁇ _s-alkyl) amine, tri (C ⁇ .6-alkyl) amine and the four (4) corresponding omega-hydroxy analogues (e.g. methylamine, ethylamine, propylamine, dimethylamine, diethylamine, dipropylamine, trimethylamine, triethylamine, tripropylamine, di(hydroxyethyl)amine, and the like;
  • alkali metal or amine salts of 1 H- or 2H-tetrazoles of this invention such as the sodium, potassium, d. 6 -alkylamine, di (C ⁇ _s-alkyl) amine, tri (C ⁇ .6-alkyl) amine and the four (4) corresponding omega-hydroxy analogues (e.g. methylamine,
  • inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate or similar pharmaceutically acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science 66: 2 (1977) which are hereby incorporated by reference.
  • the compounds of formula (I) may be prepared by art-recognised procedures from known compounds or readily preparable intermediates.
  • An exemplary general procedure is as follows:
  • a triaryl-phosphine catalyst as e.g. (triphenyl-phosphine or tri-o-tolyl-phosphine) at temperatures ranging from 50 °C to 150 °C for 1 to 60 hours.
  • reaction may be carried out in a solvent such as methanol, ethanol, tetrahydrofuran (THF), toluene, N,N-dimethylformamide (DMF) or dimethylsulfoxide (DMSO) in the presence of a base such as triethylamine, pyridine, piperidine, sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium tert- butoxide, lithium diisopropylamide at temperatures ranging from -50°C to 150°C for 1 to 60 hours.
  • a solvent such as methanol, ethanol, tetrahydrofuran (THF), toluene, N,N-dimethylformamide (DMF) or dimethylsulfoxide (DMSO)
  • a base such as triethylamine, pyridine, piperidine, sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium tert- butoxide, lithium
  • the compounds of the invention modulate the activity of protein tyrosine phosphatases or other molecules with phosphotyrosine recognition unit(s).
  • the compounds of the invention act as inhibitors of PTPases, e.g. protein tyrosine phosphatases involved in regulation of tyrosine kinase signaling pathways.
  • PTPases e.g. protein tyrosine phosphatases involved in regulation of tyrosine kinase signaling pathways.
  • Preferred embodiments include modulation of receptor-tyrosine kinase signaling pathways via interaction with regulatory PTPases, e.g.
  • inventions is modulation of non-receptor tyrosine kinase signaling through modulation of regulatory PTPases, e.g. modulation of members of the Src kinase family.
  • PTPases e.g. modulation of members of the Src kinase family.
  • One type of preferred embodiments of the inventions relate to modulation of the activity of PTPases that negatively regulate signal transduction pathways.
  • Another type of preferred embodiments of the inventions relate to modulation of the activity of PTPases that positively regulate signal transduction pathways.
  • the compounds of the invention act as modulators of the active site of PTPases.
  • the compounds of the invention modulate the adivity of PTPases via interaction with structures positioned outside of the active sites of the enzymes, preferably SH2 domains.
  • Further preferred embodiments include modulation of signal transduction pathways via binding of the compounds of the invention to SH2 domains or PTB domains of non-PTPase signaling molecules.
  • Other preferred embodiments include use of the compounds of the invention for modulation of cell-cell interactions as well as cell-matrix interactions.
  • the present invention include within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of formula (I) in association with a pharmaceutical carrier or diluent.
  • the pharmaceutical composition can comprise at least one of the compounds of formula (I) combined with compounds exhibiting a different activity, e.g. an antibiotic or other pharmacologically active material.
  • the compounds of the invention may be used as therapeuticals to inhibit of PTPases involved in regulation of the insulin receptor tyrosine kinase signaling pathway in patients with type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, and obesity.
  • Further preferred embodiments include use of the compounds of the invention for treatment of disorders with general or specific dysfunctions of PTPase activity, e.g. proliferarive disorders such as psoriasis and neoplastic diseases.
  • the compounds of the invention may be used in pharmaceutical preparations for treatment of osteoporosis.
  • Preferred embodiments of the invention further include use of compound of formula (I) in pharmaceutical preparations to increase the secretion or adion of growth hormone and its analogs or somatomedins including IGF-1 and IGF-2 by modulating the activity of PTPases or other signal transduction molecules with affinity for phosphotyrosine involved controlling or inducing the action of these hormones or any regulating molecule.
  • compounds of the invention can be administered for purposes of stimulating the release of growth hormone from the pituitary or increase its action on target tissues thereby leading to similar effects or uses as growth hormone itself.
  • growth hormone may be summarized as follows: stimulation of growth hormone release in the elderly; prevention of catabolic side effects of glucocorticoids; treatment of osteoporosis, stimulation of the immune system; treatment of retardation, acceleration of wound healing; accelerating bone fracture repair; treatment of growth retardation; treating renal failure or insufficiency resulting in growth retardation; treatment of physiological short stature including growth hormone deficient children and short stature associated with chronic illness; treatment of obesity and growth retardation associated with obesity; treating growth retardation associated with the Prader-Willi syndrome and Turner's syndrome; accelerating the recovery and reducing hospitalization of burn patients; treatment of intrauterine growth retardation, skeletal dysplasia, hypercortisolism and Cushings syndrome; induction of pulsatile growth hormone release; replacement of growth hormone in stressed patients; treatment of osteochondro-dysplasias, Noonans 25
  • the compounds of the invention may be used in pharmaceutical preparations for treatment of various disorders of the immune system, either as a stimulant or suppressor of normal or perturbed immune functions, including autoimmune reactions. Further embodiments of the invention include use of the compounds of the invention for treatment of allergic reactions, e.g. asthma, dermal reactions, conjunctivitis.
  • allergic reactions e.g. asthma, dermal reactions, conjunctivitis.
  • compounds of the invention may be used in pharmaceutical preparations for prevention or indudion of platelet aggregation.
  • compounds of the invention may be used in pharmaceutical preparations for treatment of infectious disorders.
  • the compounds of the invention may be used for treatment of infectious disorders caused by Yersinia and other bacteria as well as disorders caused by viruses or other micro ⁇ organisms.
  • Compounds of the invention may additionally be used for treatment or prevention of diseases in animals, induing commercially important animals.
  • the invention is further directed to a method for detecting the presence of PTPases in cell or in a subject comprising:
  • the invention further relates to analysis and identification of the specific functions of certain PTPases by modulating their activity by using compounds of the invention in cellular assay systems or in whole animals.
  • Signal transduction is a colledive term used to define all cellular processes that follow the activation of a given cell or tissue.
  • Examples of signal transduction which are not intended to be in any way limiting to the scope of the invention claimed, are cellular events that are induced by polypeptide hormones and growth factors (e.g. insulin, insulin-like growth factors I and II, growth hormone, epidermal growth factor, platelet- derived growth factor), cytokines (e.g. inter-leukins), extracellular matrix components, and cell-cell interactions.
  • polypeptide hormones and growth factors e.g. insulin, insulin-like growth factors I and II, growth hormone, epidermal growth factor, platelet- derived growth factor
  • cytokines e.g. inter-leukins
  • Phosphotyrosine recognition units/tyrosine phosphate recognition units/pTyr recognition units are defined as areas or domains of proteins or glycoproteins that have affinity for molecules containing phosphorylated tyrosine residues (pTyr).
  • Examples of pTyr recognition units which are not intended to be in any way limiting to the scope of the invention claimed, are: PTPases, SH2 domains and PTB domains.
  • PTPases are defined as enzymes with the capacity to dephosphorylate pTyr- containing proteins or glycoproteins.
  • Examples of PTPases which are not intended to be in any way limiting to the scope of the invention claimed, are: 'classical' PTPases (intracellular PTPases (e.g. PTP1B, TC-PTP, PTP1C, PTP1D, PTPD1, PTPD2) and receptor-type PTPases (e.g. PTP ⁇ , PTP ⁇ , PTP ⁇ , PTP ⁇ , CD45, PTPK, PTP ⁇ ), dual specif icty phosphatases (VH , VHR, cdc25), LMW-PTPases or acid phosphatases.
  • Modulation of cellular processes is defined as the capacity of compounds of the invention to 1 ) either increase or decrease ongoing, normal or abnormal, signal transduction, 2) initiate normal signal transduction, and 3) initiate abnormal signal transduction.
  • Modulation of pTyr-mediated signal transduction/modulation of the activity of molecules with pTyr recognition units is defined as the capacity of compounds of the invention to 1 ) increase or decrease the activity of proteins or glycoproteins with pTyr recognition units (e.g. PTPases, SH2 domains or PTB domains) or to 2) decrease or increase the association of a pTyr-containing molecule with a protein or glyco-protein with pTyr recognition units either via a direct action on the pTyr recognition site or via an indirect mechanism.
  • proteins or glycoproteins with pTyr recognition units e.g. PTPases, SH2 domains or PTB domains
  • Examples of modulation of pTyr-mediated signal transduction/modulation of the activity of molecules with pTyr recognition units are: a) inhibition of PTPase activity leading to either increased or decreased signal transduction of ongoing cellular processes; b) inhibition of PTPase activity leading to initiation of normal or abnormal cellular activity; c) stimulation of PTPase adivity leading to either increased or decreased signal transduction of ongoing cellular processes; d) stimulation of PTPase activity leading to initiation of normal or abnormal cellular activity; e) inhibition of binding of SH2 domains or PTB domains to proteins or glycoproteins with pTyr leading to increase or decrease of ongoing cellular processes; f) inhibition of binding of SH2 domains or PTB domains to proteins or glycoproteins with pTyr leading to initiation of normal or abnormal cellular activity.
  • a subject is defined as any mammalian species, including humans.
  • dosage will vary depending on the compound of formula (I) employed, on the mode of administration and on the therapy desired. However, in general, satisfactory results are obtained with a dosage of from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of compounds of formula (I), conveniently given from 1 to 5 times daily, optionally in sustained release form.
  • dosage forms suitable for oral administration comprise from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of the compounds of formula (I) admixed with a pharmaceutical carrier or diluent
  • the compounds of formula (I) may be administered in a pharmaceutically acceptable acid addition salt form or where possible as a metal or a d 6 -alkylammon ⁇ um salt Such salt forms exhibit approximately the same order of activity as the free acid forms
  • compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutical carrier or diluent
  • compositions containing the compounds of this invention may be prepared by conventional techniques and appear in conventional forms, for example capsules, tablets, solutions or suspensions
  • the pharmaceutical carrier employed may be a conventional solid or liquid carrier
  • solid carriers are lactose, terra alba, sucrose, talc, gelatine, agar, pectin, acacia, magnesium stearate and steanc acid
  • liquid carriers are syrup, peanut oil, olive oil and water
  • the carrier or diluent may include any time delay material known to the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax
  • the preparation can be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge
  • the amount of solid 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 injedable 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 29
  • a typical tablet which may be prepared by conventional tabletting techniques contains
  • Active compound (as free compound 100 mg or salt thereof)
  • the route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. redal, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
  • oral or parenteral e.g. redal, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
  • the compounds of formula I may be useful in vitro and/or in vivo diagnostic tools.
  • the PTP1B and PTP ⁇ cDNA was obtained by standard polymerase chain reaction technique using the Gene Amp Kit according to the manufacturer's instrudions (Perkin Elmer/Cetus).
  • the oligonucleotide primers were designed according to published sequences (Chemoff ef ai, Proc. Natl. Acad. Sci. U.S.A. 87: 2735-2739 (1990); Krueger ef ai.EMBO J. 9: 3241-3252 (1990)) including convenient restridion nuclease sites to allow cloning into expression vectors.
  • the cDNA corresponding to the full- length sequence of PTP1B and the intracellular part of PTP ⁇ were introduced into the insect cell expression vector pVL1392.
  • the proteins were expressed according to standard procedures.
  • PTP1 B was semi-purified by ion exchange chromatography, and PTP ⁇ was purified to apparent homogeneity using a combination of ion exchange chromatography and gel filtration techniques using standard procedures.
  • TC-PTP and LAR domain 1 were obtained from New England Biolabs.
  • Yersinia PTP was a kind gift from J.E. Dixon, The University of Michigan, Ann Arbor, U.S.A.
  • p-Nitrophenyl phosphate was purchased from Sigma and used without further purification.
  • p-Nitrophenyl phosphate is a general phosphatase substrate including a substrate for PTPases.
  • pNPP colorless
  • pNPP hydrolyzed by a phosphatase to phosphate and p-nitrophenolate (yellow in alkaline solutions) the enzyme reaction can be followed by measuring the optical density at 410 nm after adjusting the pH appropriately.
  • pNPP was used as general substrate to analyze the PTPase inhibitory capacity of the compounds of the invention.
  • the inhibiting effect of a compound is given by its Kj value, which expresses the concentration of inhibitor ( ⁇ M) in the reaction mixture necessary for a 50 percent reduction of the enzyme adivity.
  • the Kj may be determined by a titration curve using several appropriately diluted solutions of the inhibitor or by using the following more simple formula, when the concentration of inhibitor is in large excess of the enzyme concentration:
  • l 0 is the concentration of inhibitor ( ⁇ M) added to the reaction mixture
  • E is the activity of the enzyme in the reaction mixture containing the inhibitor
  • E 0 is the enzyme activity in a corresponding control reaction mixture without the inhibitor.
  • the Kj values of inhibitors towards PTP1 B were measured as follows. In all cases the inhibiting effects were determined at pH 5.5 and at 37 °C with a reaction time of 60 minutes.
  • reaction mixtures were: 1 ) 25 ⁇ l enzyme solution
  • the substrate solution contained 0.2 M acetate buffer, pH 5.5, 11 mM p-nitrophenyl phosphate, 5.5 mM dithiotreitol.
  • the reaction was stopped by addition of 4 ml 0.2 N NaOH, and the enzyme activity was determined by measuring the release of p-nitrophenol at 410 nm.
  • the inhibiting effed was calculated as shown above.
  • Yersinia PTP were measured essentially as described for PTP1 B with the exception that all reactions were carried out in 96-wells microtiter plates. In all cases the inhibiting effects were determined at pH 5.5 and at room temperature with a reaction time of 15 minutes.
  • reaction mixtures were: 1 ) 5 ⁇ l enzyme solution
  • the final concentrations 0.2 M acetate buffer, pH 5.5, 5 mM p-nitrophenyl phosphate, 5 mM dithiotreitol.
  • the reaction was stopped by addition of 100 ⁇ l 0.4 N NaOH, and the enzyme activity was determined by measuring the release of p-nitrophenol at 405 nm. The inhibiting effect was calculated as shown above.

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Abstract

Cette invention concerne de nouveaux composés organiques, des procédés de préparation de ces composés et des compositions les contenant: cette invention concerne également l'utilisation de ces composés dans le traitement de troubles chez l'homme et chez les animaux, dans la purification de protéines ou de glycoprotéines, et dans des diagnostics. Cette invention concerne en outre la modulation, dans des systèmes in vitro, de l'activité de molécules possédant des unités de reconnaissance de la phosphotyrosine, y compris des protéines tyrosine phosphatases (PTPases) et des protéines possédant des domaines Src-homologie-2. Cette invention concerne enfin des micro-organismes, des cellules eucaryotes, ainsi que des animaux et des êtres humains dans leur ensemble. Ces nouveaux composés organiques correspondent à la formule générale (I) où (L)n, n, Ar1 et R1 sont tels que définis dans la description.
PCT/DK1997/000167 1996-04-19 1997-04-17 Modulateurs de molecules possedant des unites de reconnaissance de la phosphotyrosine WO1997039748A1 (fr)

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0833629A2 (fr) * 1995-06-19 1998-04-08 Ontogen Corporation Derives d'acide aryl-acrylique convenant comme inhibiteurs de proteine-tyrosine-phosphatase
WO1999040071A1 (fr) * 1998-02-05 1999-08-12 Senju Pharmaceutical Co., Ltd. Derives d'acide urocanique
WO1999061410A1 (fr) * 1998-05-12 1999-12-02 American Home Products Corporation Diphenyles 2,3,5-substitues utiles pour le traitement de la resistance insulinique et de l'hyperglycemie
US6040448A (en) * 1997-10-24 2000-03-21 Neurogen Corporation Certain 1-(2-naphthyl) and 1-(2-azanaphthyl)-4-(1-phenylmethyl) piperazines, dopamine receptor subtype specific ligands
US6451827B2 (en) 1998-05-12 2002-09-17 Wyeth 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia
US6613903B2 (en) 2000-07-07 2003-09-02 Novo Nordisk A/S Modulators of protein tyrosine phosphatases (PTPases)
WO2004071447A2 (fr) * 2003-02-12 2004-08-26 Transtech Pharma Inc. Utilisation de derives d'azoles substitues en tant qu'agents therapeutiques
WO2004099168A2 (fr) * 2003-04-30 2004-11-18 The Institutes For Pharmaceutical Discovery, Llc Acides carboxyliques substitues
WO2005000781A1 (fr) * 2003-06-24 2005-01-06 F. Hoffmann-La Roche Ag Acides biaryloxymethylarenecarboxyliques
US7521473B2 (en) 2004-02-25 2009-04-21 Wyeth Inhibitors of protein tyrosine phosphatase 1B
US9155727B2 (en) 2013-05-28 2015-10-13 Astrazeneca Ab Chemical compounds
EP2845882A3 (fr) * 2008-10-29 2015-11-18 Fujifilm Corporation Colorant, élément de conversion photoélectrique et cellule photoélectrochimique

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2316881A1 (de) * 1972-04-04 1973-10-11 Beecham Group Ltd Biologisch aktive verbindungen, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneipraeparate
DE2517229A1 (de) * 1975-04-18 1976-10-28 Boehringer Mannheim Gmbh Phenylalkylcarbonsaeure-derivate und verfahren zu ihrer herstellung
GB2205240A (en) * 1987-06-03 1988-12-07 Erba Carlo Spa N-imidazolyl derivatives for treating nephropathies
WO1993021783A1 (fr) * 1992-05-06 1993-11-11 The Penn State Research Foundation Procedes de traitement de l'obesite au moyen de composes apparentes a la purine
WO1997008934A2 (fr) * 1995-06-19 1997-03-13 Ontogen Corporation Derives d'acide aryl-acrylique convenant comme inhibiteurs de proteine-tyrosine-phosphatase

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2316881A1 (de) * 1972-04-04 1973-10-11 Beecham Group Ltd Biologisch aktive verbindungen, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneipraeparate
DE2517229A1 (de) * 1975-04-18 1976-10-28 Boehringer Mannheim Gmbh Phenylalkylcarbonsaeure-derivate und verfahren zu ihrer herstellung
GB2205240A (en) * 1987-06-03 1988-12-07 Erba Carlo Spa N-imidazolyl derivatives for treating nephropathies
WO1993021783A1 (fr) * 1992-05-06 1993-11-11 The Penn State Research Foundation Procedes de traitement de l'obesite au moyen de composes apparentes a la purine
WO1997008934A2 (fr) * 1995-06-19 1997-03-13 Ontogen Corporation Derives d'acide aryl-acrylique convenant comme inhibiteurs de proteine-tyrosine-phosphatase

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ARZNEIM-FORSCH. (DRUG RES.), Volume 24, No. 10, 1974, H. SUGIHARA et al., "Oral Hypoglycemic Agents: 1-(2-Carboxyphenyl)Pyrroles", pages 1560-1563. *
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, Volume 5, No. 24, 1995, XIAODONG CAO et al., "Synthesis of NH-Acyl-X-Aminoamides on Rink Resin: Inhibitors of the Hematopoietic Protein Tyrosine Phosphatase", pages 2953-2958. *
J. AM. CHEM. SOC., Volume 117, 1995, EDMUND J. MORAN et al., "Radio Frequency Tag Encoded Combinatoril Library Method for the Discovery of Tripeptide-Substituted Cinnamic Acid Inhibitors of the Protein Tyrosine Phosphatase PTP1B", pages 10787-10788. *
JOURNAL OF MEDICAL CHEMISTRY, Volume 22, No. 7, 1979, BENJAMIN BLANK et al., "Synthesis and Hypoglycemic Activity of Pyridyl Alcohols", pages 840-844. *

Cited By (31)

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EP0833629A4 (fr) * 1995-06-19 1998-09-16 Ontogen Corp Derives d'acide aryl-acrylique convenant comme inhibiteurs de proteine-tyrosine-phosphatase
EP0833629A2 (fr) * 1995-06-19 1998-04-08 Ontogen Corporation Derives d'acide aryl-acrylique convenant comme inhibiteurs de proteine-tyrosine-phosphatase
US6331629B1 (en) 1997-10-24 2001-12-18 Neurogen Corporation Certain 1-(2-naphthyl) and 1-(2-azanaphthyl)-4-(1-phenylmethyl)piperazines; dopamine receptor subtype specific ligands
US6040448A (en) * 1997-10-24 2000-03-21 Neurogen Corporation Certain 1-(2-naphthyl) and 1-(2-azanaphthyl)-4-(1-phenylmethyl) piperazines, dopamine receptor subtype specific ligands
US6384224B2 (en) * 1997-10-24 2002-05-07 Neurogen Corporation Certain 1-(2-naphthyl) and 1-(2-azanaphthyl)-4-(1-phenylmethyl) piperazines; dopamine receptor subtype specific ligands
WO1999040071A1 (fr) * 1998-02-05 1999-08-12 Senju Pharmaceutical Co., Ltd. Derives d'acide urocanique
EP1054003A1 (fr) * 1998-02-05 2000-11-22 Senju Pharmaceutical Co., Ltd. Derives d'acide urocanique
EP1054003A4 (fr) * 1998-02-05 2001-05-02 Senju Pharma Co Derives d'acide urocanique
US6310067B1 (en) 1998-02-05 2001-10-30 Senju Pharmaceutical Co., Ltd. Urocanic acid derivatives
WO1999061410A1 (fr) * 1998-05-12 1999-12-02 American Home Products Corporation Diphenyles 2,3,5-substitues utiles pour le traitement de la resistance insulinique et de l'hyperglycemie
US6214877B1 (en) 1998-05-12 2001-04-10 John A. Butera 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia
US6451827B2 (en) 1998-05-12 2002-09-17 Wyeth 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia
US6765021B2 (en) 1998-05-12 2004-07-20 Wyeth 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia
US7008636B2 (en) 1998-05-12 2006-03-07 Wyeth 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia
US6613903B2 (en) 2000-07-07 2003-09-02 Novo Nordisk A/S Modulators of protein tyrosine phosphatases (PTPases)
WO2004071447A2 (fr) * 2003-02-12 2004-08-26 Transtech Pharma Inc. Utilisation de derives d'azoles substitues en tant qu'agents therapeutiques
WO2004071447A3 (fr) * 2003-02-12 2004-12-23 Transtech Pharma Inc Utilisation de derives d'azoles substitues en tant qu'agents therapeutiques
US7358364B2 (en) 2003-04-30 2008-04-15 The Institute For Pharmaceutical Discovery Llc Substituted carboxylic acids
WO2004099168A3 (fr) * 2003-04-30 2005-02-24 Inst For Pharm Discovery Inc Acides carboxyliques substitues
WO2004099168A2 (fr) * 2003-04-30 2004-11-18 The Institutes For Pharmaceutical Discovery, Llc Acides carboxyliques substitues
US7842825B2 (en) 2003-06-24 2010-11-30 Hoffmann-La Roche Inc. Biaryloxymethylarenecarboxylic acids as glycogen synthase activator
US7355049B2 (en) 2003-06-24 2008-04-08 Hoffmann-La Roche Inc. Biaryloxymethylarenecarboxylic acids as glycogen synthase activator
AU2004251846B2 (en) * 2003-06-24 2010-02-04 F. Hoffmann-La Roche Ag Biaryloxymethylarene-carboxylic acids
US7700632B2 (en) 2003-06-24 2010-04-20 Hoffmann-La Roche Inc. Biaryloxymethylarenecarboxylic acids as glycogen synthase activator
WO2005000781A1 (fr) * 2003-06-24 2005-01-06 F. Hoffmann-La Roche Ag Acides biaryloxymethylarenecarboxyliques
US7521473B2 (en) 2004-02-25 2009-04-21 Wyeth Inhibitors of protein tyrosine phosphatase 1B
EP2845882A3 (fr) * 2008-10-29 2015-11-18 Fujifilm Corporation Colorant, élément de conversion photoélectrique et cellule photoélectrochimique
US9424998B2 (en) 2008-10-29 2016-08-23 Fujifilm Corporation Dye, photoelectric conversion element using the same, photoelectrochemical cell, and method of producing dye
US9155727B2 (en) 2013-05-28 2015-10-13 Astrazeneca Ab Chemical compounds
US9616050B2 (en) 2013-05-28 2017-04-11 Astrazeneca Ab Chemical compounds
US10130617B2 (en) 2013-05-28 2018-11-20 Astrazeneca Ab Chemical compounds

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