WO2008061308A1 - Modulateurs de la protéine tyrosine phosphatase - Google Patents

Modulateurs de la protéine tyrosine phosphatase Download PDF

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WO2008061308A1
WO2008061308A1 PCT/AU2007/001794 AU2007001794W WO2008061308A1 WO 2008061308 A1 WO2008061308 A1 WO 2008061308A1 AU 2007001794 W AU2007001794 W AU 2007001794W WO 2008061308 A1 WO2008061308 A1 WO 2008061308A1
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optionally substituted
compound
alkyl
ptp
independently selected
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PCT/AU2007/001794
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English (en)
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Ambrogina Nicoletti
Kylie Suzanne White
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Biodiem Ltd
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Priority claimed from AU2006906525A external-priority patent/AU2006906525A0/en
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Publication of WO2008061308A1 publication Critical patent/WO2008061308A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/04—Nitro compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/01—Compounds containing nitro groups bound to a carbon skeleton having nitro groups bound to acyclic carbon atoms
    • C07C205/03—Compounds containing nitro groups bound to a carbon skeleton having nitro groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C205/04—Compounds containing nitro groups bound to a carbon skeleton having nitro groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/07—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms
    • C07C205/08—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms having nitro groups bound to acyclic carbon atoms
    • C07C205/09—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms having nitro groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
    • C07C205/17—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups bound to acyclic carbon atoms and hydroxy groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/32—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups bound to acyclic carbon atoms and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/39—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups
    • C07C205/42—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/52—Radicals substituted by halogen atoms or nitro radicals

Definitions

  • the present invention relates to protein tyrosine phosphatase (PTP) modulators, in particular PTP inhibitors and their use in the treatment or prophylaxis of disorders modulated by PTP such as cellular proliferation disorders; autoimmune diseases for example diabetes or inflammatory diseases; infections caused by viruses using PTPases for infectivity,- angiogenesis mediated disorders; bone disorders; and vascular tone, vascular permeability or vascular endothelial growth factor (VEGF) mediated disorders .
  • PTP protein tyrosine phosphatase
  • PTP plays an essential role in the regulation of various cellular functions including cell growth, proliferation, differentiation, metabolism and immune responses . They are therefore potentially important targets for therapeutic intervention in a number of diseases including cancer and autoimmune diseases such as diabetes or inflammatory diseases.
  • Modulation of PTP activity has important clinical significance. For example, because over-expression of PTP-IB activity has been correlated with neoplastic conditions, agents which modulate PTP-IB activity are needed for clarifying the role of PTP-IB in these conditions and for development of effective therapeutics against those disease states.
  • Some PTPs positively regulate the signalling of growth factor receptors and can be oncogenic.
  • PTPlB is over expressed in some human breast cancer patients.
  • the important role of the protein tyrosine phosphatase, CD45, in lymphocyte development likewise indicates a therapeutical utility for PTP inhibitors in conditions that are associated with autoimmune disease.
  • the role of CD45 in antibody- medicated degranulation of mast cells indicates a therapeutic utility of PTP inhibitors for allergic disorders .
  • PTPlB is down regulator of the insulin-stimulated signaling pathway, likely via dephosphorylation of the insulin receptor.
  • Over expression of PTPlB, LAR and PTPa leads to abnormal insulin resistance and is often associated with type II diabetes.
  • inhibition of PTPlB also has the potential to cause weight loss, which is a benefit because obesity is an important component of the type 2 diabetic.
  • PTP-IB plays a vital role in the dephosphorylation of the insulin receptor. This suggests that PTPlB inhibitors would be useful in the treatment of insulin resistance. More importantly, such an inhibitor could function as an agent for the treatment of non-insulin dependent diabetes mellitus without inducing hypoglycemia.
  • HSVl and HSV2 Herpes simplex viruses
  • HSVl and HSV2 cause a broad spectrum of diseases such as cold sores and genital herpes and serious viremia in the newborn and in immunosuppressed individuals .
  • Viral entry of HSVl and HSV2 has been associated with tyrosine phosphorylation of cellular proteins.
  • Vaccinia virus encodes a protein tyrosine phosphatase which has been shown to be essential for virus viability in cell culture and to block signal transduction by interferon gamma (IFN ⁇ ) , an essential cytokine protecting against viral infection.
  • IFN ⁇ interferon gamma
  • HPV human papilloma viruses
  • HPV oncoproteins associate with critical cell proteins to disrupt cell cycle regulation and differentiation, maintaining epithelial cells in a proliferative state allowing viral replication.
  • Tyrosine phosphatases such as cdc25A and PTPN3 are associated with cell cycle arrest.
  • HPV oncoproteins have been shown to degrade these phosphatases resulting in continued cell proliferation.
  • PTP inhibitors may be used to treat angiogenesis mediated disorders.
  • Acid phosphatases/PTPases may also be involved in negative regulation of osteoblast proliferation.
  • the use of the PTPase inhibitors may therapeutically enhance osteoblast proliferation and thereby treat bone disorders.
  • PTP inhibitors may be used to treat diseases which require the regulation of vascular tone, vascular permeability and/or VEGF.
  • the present invention relates to compounds which modulate and especially inhibit the phosphatase activity of one or more PTP enzymes and are useful in the treatment of disorders modulated by PTP such as cellular proliferative disorders,- autoimmune diseases,- infections caused by viruses using PTPases for infectivity,- angiogenesis mediated disorders; bone disorders; and vascular tone, vascular permeability or VEGF mediated disorders .
  • a PTP modulator such as PTP inhibitor comprising a compound of formula I
  • Ri and R 2 are independently selected from hydrogen and optionally substituted Ci -S alkyl,-
  • R 3 to R 5 are independently selected from hydrogen, optionally substituted Ci-galkyl, optionally substituted C 2 - 6 alkenyl, optionally substituted C 2 . s alkynyl, optionally substituted C 2-8 cycloalkyl, halo, halo Ci- S alkyl, haloC 2-s alkenyl, haloC 2 - ⁇ alkynyl, hydroxy, Ci- ⁇ alkoxy, C 2 - 6 alkenyloxy, C 2 - e alkynyloxy, haloCi- 6 alkoxy, haloC 2 _ ⁇ alkenyloxy, haloC 2 - 6 alkynyloxy, nitro, nitroCi. 6 alkyl, nitroC 2-6 alkenyl, nitroC 2-6 alkynyl, CORi, CO 2 Ri and NRiR 2 ;
  • R 5 and R 7 are independently selected from hydrogen, optionally substituted Ci_ ⁇ alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2 _ s alkynyl, optionally substituted C 2-8 cycloalkyl, halo, hydroxy, Ci-galkoxy, C 2 - ⁇ alkenyl oxy, nitro, nitroCi- ⁇ alkyl and nitroC 2 .
  • the compounds of formula I inhibit the phosphatase activity of one or more PTPase enzymes such as PTP-IB and /or CD45.
  • PTP inhibitors have been clinically validated as potential anti-cancer, anti-autoimmune, anti-viral and/or anti-angiogenesis agents for the treatment or prophylaxis of cellular proliferative disorders; autoimmune diseases for example diabetes or inflammatory diseases; infections caused by viruses using PTPases for infectivity,- angiogenesis mediated disorders; bone disorders; and vascular tone, vascular permeability or VEGF mediated disorders .
  • an anti-cancer, anti-autoimmune, anti-viral and/or anti-angiogenesis agent comprising the compound of formula I.
  • an anti-cancer, anti-autoimmune, anti-viral and/or anti-angiogenesis agent comprising the compound of formula I.
  • the compound of formula I for use as an anti-cancer or anti-autoimmune, anti-viral and/or anti-angiogenesis agent.
  • anti-cancer includes “anti-tumour” .
  • the compound of formula I may be administered in the form of a pharmaceutical composition together with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition additionally comprises a therapeutically effective amount of one or more other PTP modulators, anti-cancer agents, anti-autoimmune agents, anti-viral agents and/or anti-angiogenesis agents.
  • a method for the treatment of a disorder modulated by PTP such as a cellular proliferative disorder; autoimmune diseases for example diabetes or inflammatory diseases; infections caused by viruses using PTPases for infectivity; angiogenesis mediated disorders; and vascular tone, vascular permeability or VEGF mediated disorders which comprises administering an effective amount of the compound of formula I to a subject in need thereof.
  • a disorder modulated by PTP such as a cellular proliferative disorder; autoimmune disease for example diabetes or inflammatory diseases,- infections caused by viruses using PTPases for infectivity; angiogenesis mediated disorders; bone disorders; and vascular tone, vascular permeability VEGF mediated disorders .
  • a disorder modulated by PTP such as a cellular proliferative disorder; autoimmune disease for example diabetes or inflammatory diseases; infections caused by viruses using PTPases for infectivity; angiogenesis mediated disorders; bone disorders; and vascular tone, vascular permeability or VEGF mediated disorders .
  • a disorder modulated by PTP such as a cellular proliferative disorder; autoimmune disease for example diabetes or inflammatory diseases; infections caused by viruses using PTPases for infectivity; angiogenesis mediated disorders; bone disorders; and vascular tone, vascular permeability or VEGF mediated disorders .
  • a method of modulating the phosphatase activity of one or more PTP enzymes comprising exposing the enzyme to an effective amount of the compound of formula I under conditions where the phosphatase activity of the PTP enzyme is modulated.
  • the present invention relates to compounds of formula I which are PTP modulators in particular PTP inhibitors and are useful in the treatment of a disorder modulated by PTP such as a cellular proliferative disorder; autoimmune disease for example diabetes or inflammatory diseases; infections caused by viruses using PTPases for infectivity,- angiogenesis mediated disorders; bone disorders; and vascular tone, vascular permeability or VEGF mediated disorders .
  • a disorder modulated by PTP such as a cellular proliferative disorder; autoimmune disease for example diabetes or inflammatory diseases; infections caused by viruses using PTPases for infectivity,- angiogenesis mediated disorders; bone disorders; and vascular tone, vascular permeability or VEGF mediated disorders .
  • the present invention relates to the compounds of formula I, salts, solvates, derivatives, prodrugs, tautomers and/or isomers which are PTP modulators .
  • Ri is methyl and R 2 is hydrogen in the compounds of formula I .
  • R 3 to R 7 can be CORi, CO 2 Ri or NR x R 2 in which Ri and R 6 are as defined above which enables the compounds of formula I to form a peptide linkage .
  • Many inhibitors of protein tyrosine phosphatases are peptide-based, linking peptides to a tyrosine mimetic .
  • the polar tyrosine binding site is flanked by amino acids residues which contribute to efficient and high affinity PTP substrate recognition and binding.
  • the tyrosine binding site is highly conserved across many cell types.
  • the adjacent sites can be unique to particular phosphatases and can be targeted in designing improved specific PTP inhibitors with cognate peptide components.
  • compounds of formula I have the formula Ia:
  • X and Y are independently selected from N, 0 and
  • R 8 and R 9 are independently selected from hydrogen, optionally substituted Ci- S alkyl, optionally substituted C 2 - S alkenyl, optionally substituted C 2 - 6 alkynyl, halo, hydroxy, optionally substituted Ci_ 6 alkoxy, optionally substituted C 2 - S alkenyloxy, optionally substituted C 2 - ⁇ alkynynloxy, nitro, nitroCi_ 6 alkyl and nitroC 2 _ 6 alkenyl, nitroC 2 _ 6 alkynyl, aminoCi- 6 alkyl , aminoC 2 .
  • X and Y are independently selected from 0 and N, more preferably both X and Y are oxygen.
  • Ri is methyl and R 2 is hydrogen.
  • R 3 to R 5 are preferably independently selected from hydrogen, hydroxy, halo, nitro, optionally substituted C x-5 alkoxy and optionally substituted Ci_ 6 alkyl .
  • R 8 and R 9 are preferably independently selected from H and optionally substituted Ci_ e alkyl .
  • the E isomer of the compounds of formula Ia is preferred.
  • X and Y are O, R x is methyl and R 2 to R 7 are hydrogen (3 , 4-methylenedioxy- ⁇ -methyl- ⁇ - nitrostyrene)
  • X is N, Y is NH, R 1 to R 5 are hydrogen, R e is methyl and R 7 is absent (2-methyl benzimidazole-5- ⁇ -nitroethylene)
  • the compounds of formula I have the formula Ib:
  • R 1 to R 5 are as defined above,- and
  • R 6 and R 7 are independently selected from hydrogen, optionally substituted Ci_ 6 alkyl, optionally substituted C 2 - 6 alkenyl, optionally substituted C 2 - 6 alkynyl, halo, hydroxy, optionally substituted Ci_ 6 alkoxy, optionally substituted C 2 - S alkenyloxy, optionally substituted C 2 - 6 alkynyloxy, nitro, nitroCi- s alkyl, nitroC 2- ⁇ alkenyl, nitroC 2 . s alkynyl, aminoCi-galkyl , aminoC 2 - 6 alkenyl, aminoC 2 . 6 alkynyl, NR 1 R 2 , CO 2 R 1 and COR 1 . salts, solvates, derivatives, prodrugs, tautomers and/or isomers thereof .
  • R 1 is methyl and R 2 is hydrogen.
  • R 3 to R 5 are preferably independently selected from hydrogen and hydroxy.
  • R 5 and R 7 are independently selected from hydrogen, hydroxy, Ci-salkoxy, halo and aminoCi_ 6 alkyl .
  • Ci -6 alkyl when used either alone or in “haloCx-s alkyl", “nitroCi- e alkyl” or “amino C h alky! refers to straight chain or branched chain hydrocarbon groups having from 1 to 6 carbon atoms. Examples include ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl .
  • C 2 _ s alkenyl when used either alone or in “haloC 2-e alkenyl” , "nitroC 2 - e alkenyl” or “amino Ci- S alkenyl” refers to straight chain or branched chain hydrocarbon groups having at least one double bond of either E or Z stereochemistry where applicable and 2 to 6 carbon atoms. Examples include vinyl, 1-propenyl, 1- and 2-butenyl and 2-methyl-2-propenyl .
  • C 2 -s alkynyl when used either alone or in “C 2 - ⁇ alkynyl” , "nitroC 2 _ e alkynyl” or “amino Ci_ 6 alkynyl” refers to straight chain or branched chain hydrocarbon groups having at least one triple bond and 2 to 6 carbon atoms. Examples include ethynyl, 1- or 2-propynyl, 1-, 2- or 3- butynyl and methyl-2-propynyl .
  • C 3 _ 8 cycloalkyl refers to non-aromatic cyclic hydrocarbon groups having from 3 to 8 atoms . Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl .
  • Ci -6 alkoxy when used either alone or in "haloC ⁇ .- 6 alkoxy” refers to an oxy-containing radical having Ci- 6 alkyl as defined above . Examples include methoxy, ethoxy, propoxy, butoxy, tert-butoxy and pentoxy.
  • C 2 _ ⁇ alkenyloxy refers to an oxy containing radical having C 2 _ 6 alkenyl as defined above .
  • C 2 _ e alkynyloxy refers to an oxy containing radical having C 2 - 6 alkynyl as defined above .
  • halo refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
  • Suitable saturated or unsaturated 5-membered rings containing 1 or 2 heteroatoms selected from N, O or S include N-containing heterocyclic groups, such as, unsaturated 5-membered heteromonocyclic groups containing 1 or 2 N atoms for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, triazolyl or tetrazolyl; saturated 5-membered heteromonocyclic groups containing 1 or 2 N atoms, such as, pyrrolidinyl or imidazolidinyl ; unsaturated 5-membered heteromonocyclic group containing an 0 atom, such as, furyl; saturated 5-membered heteromonocyclic group containing 1 or 2 O atoms such as 1, 3-dioxiolanyl; unsaturated 5-membered heteromonocyclic group containing 1 or 2 S atoms, such as, thienyl; unsaturated 5-membered heteromonocyclic group containing an atom and
  • the term "optionally substituted” refers to a group that may or may not be further substituted with one or more groups selected from Ci -6 alkyl, C 3 - S cycloalkyl, C 2 - 6 alkenyl, C 2 -salkynyl, aryl, heterocycylyl, halo, haloCi- s alkyl, haloC 3 _ ⁇ cycloalkyl, haloC 2 - 6 alkenyl, haloC 2 - 6 alkynyl, haloaryl, haloheterocycylyl , hydroxy, Ci- 5 alkoxy, C 2 - 6 alkenyloxy, C 2 _ 6 alkynyloxy, aryloxy, heterocyclyloxy, carboxy, haloCx-galkoxy, haloC 2 _ 6 alkenyloxy, haloC 2 _ 6 alkynyloxy, haloaryloxy,
  • Preferred optional substituents are selected from the group consisting of Ci- 4 alkyl, C 3 - 6 cycloalkyl, C 2 . 6 alkenyl, C 2 - S alkynyl, aryl, heterocycylyl, halo, haloaryl, haloheterocycylyl, hydroxy, Ci_ 4 alkoxy, aryloxy, carboxy, amino, arylacyl, heterocycylylacyl, acylamino, acyloxy, arylsulphonyl, cyano and the like.
  • salts of the compound of formula I are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also -fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium and alky1ammonium; acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, orthophosphoric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids; or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, trihalomethanesulphonic, toluenesulphonic,
  • the salts may be formed by conventional means, such as by reacting the free base form of the compound with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
  • solvates may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.
  • the derivatives of the compound of formula I are preferably pharmaceutically acceptable.
  • pharmaceutically acceptable derivative refers to any pharmaceutically acceptable salt, hydrate, ester, amide, active metabolite, analogue, residue or any other compound which is not biologically or otherwise undesirable and induces the desired pharmacological and/or physiological effect.
  • pro-drug refers to functional derivatives of the compound of formula I which are readily convertible in vivo into the required compound of formula I .
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs” ed. H. Bundgaard, Elsevier, 1985.
  • a prodrug may be a pharmacologically inactive derivative of the active compound that requires transformation within the body in order to release the active compound, and that has improved delivery properties over the active compound.
  • the transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
  • tautomer refers to compounds of formula I which are capable of existing in a state of equilibrium between two isomeric forms. Such compounds may differ in the bond connecting two atoms or groups and the position of these atoms or groups in the compound.
  • the term “isomer” refers to structural, geometric and stereo isomers. As the compound of formula I may have one or more chiral centres, it is capable of existing in enantiomeric forms .
  • the ability of the compounds of formula I to modulate, in particular inhibit phosphatase activity of one or more PTPase enzymes such as PTP-IB and/or CD45 can be demonstrated by any assay capable of measuring phosphatase activity. Suitable assays are described in the examples .
  • the administration of the compound of the present invention may be any suitable means that results in a concentration of the compound that is effective to yield the desired therapeutic or prophylactic response.
  • the compound may be contained in any appropriate amount in any suitable carrier and is generally present in an amount of 1-95% by weight of the total weight of the composition.
  • the carrier must be "pharmaceutically acceptable" in the sense of being compatible with other ingredients of the composition and not injurious to the subject.
  • the pharmaceutically acceptable carrier is preferably an organic solvent such as acetone, benzene, acetonitrile, chloroform, canola oil, DMSO or an alcohol, for example, methanol or ethanol . While the compounds of formula I show a poor solubility in water, when water is combined with an organic solvent a stable mixture is formed.
  • organic solvent such as acetone, benzene, acetonitrile, chloroform, canola oil, DMSO or an alcohol, for example, methanol or ethanol .
  • the pharmaceutical composition contains the compound of formula I, DMSO, ethanol, Cremophor EL and saline.
  • the compound of the present invention may additionally be combined with other medicaments to provide an operative combination. It is intended to include any chemically compatible combination of pharmaceutically- active agents, as long as the combination does not eliminate the activity of the compound of formula I . It will be appreciated that the compound of the invention and the other medicament may be administered separately, sequentially or simultaneously.
  • Other medicaments may include, for example other PTP modulators, anti-cancer agents and/or anti-diabetes agents.
  • the composition may be provided in a dosage form that is suitable for oral, parenteral (including intravenous, intramuscular, subcutaneous and intradermal) , rectal, vaginal, nasal, inhalation, topical or ocular administration routes.
  • the composition may be in form of tablets, capsules, pills, powders, granulates, suspensions, emulsions, liquids, gels including hydrogels, pastes, ointments, creams, plasters, drenches, delivery devices, suppositories, enemas, injectables, implants, sprays or aerosols .
  • the pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, (19 th ed.). A. R. Gennaro, 1995, Mack Publishing Company, Easton, PA. and Encyclopedia of Pharmaceutical Technology, eds . J.Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
  • compositions may be formulated to release the active compound substantially immediately upon administration or at any predetermined time or time period after administration.
  • the latter types of compositions are generally known as controlled release formulations, which include (i) formulations that create a substantially constant concentration of the active compound within the body over an extended period of time,- (ii) formulations that after a predetermined lay time create a substantially constant concentration of the active compound within the body over an extended period of time; (iii) formulations that sustain active compound action during a predetermined time period by maintaining a relatively, constant, effective active compound level in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the active compound (sawtooth kinetic pattern) ; (iv) formulations that localise active compound action by, e.g., special placement of a controlled release composition adjacent to or in the diseased tissue or organ; and (v) formulations that target active compound action by using carriers or chemical derivatives to deliver the active compound to a particular target cell type.
  • Administration of compounds in the form of a controlled release formulation is especially preferred in cases in which the compound has (i) a narrow therapeutic index (i.e., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small; in general, the therapeutic index, TI, is defined as the ratio of median lethal dose (LD 50 ) to median effective dose (ED 50 ) ) ; (ii) a narrow absorption window in the gastro-intestinal tract; or (iii) a very short biological half-like so that frequent dosing during a day is required in order to sustain the plasma level at a therapeutic level.
  • a narrow therapeutic index i.e., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small
  • the therapeutic index, TI is defined as the ratio of median lethal dose (LD 50 ) to median effective dose (ED 50 ) ) ; (ii) a narrow absorption window in the gastro-intestinal tract; or (i
  • controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings .
  • the active compound is formulated with appropriate excipients into a pharmaceutical composition, that, upon administration to the subject, releases the active compound in a controlled manner. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches and liposomes.
  • Formulations for oral use include tablets containing the active compound in a mixture with non-toxic pharmaceutically acceptable excipients.
  • excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, mirocrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate or sodium phosphate) ; granulating and disintegrating agents ⁇ e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates or alginic acid); binding agents (e.g.
  • Other pharmaceutically acceptable excipients can be colourants, flavouring agents, plasticisers, humectants, buffering agents and the like.
  • the tablets may be uncoated or they may be coated by known techniques, optionally to delay disintegration and absorption in the gastrointestinal tract and thereby providing a sustained action over a longer period.
  • the coating may be adapted to release the active compound in a predetermined pattern (e.g., in order to achieve a controlled release formulation) or it may be adapted not to release the active compound until after passage of the stomach (enteric coating) .
  • the coating may be a sugar coating, a film coating (e.g.
  • a time delay material such as, glyceryl monostearate or glyceryl distearate may be employed.
  • the solid tablet compositions may include a coating adapted to protect the composition from unwanted chemical changes, ⁇ e.g., chemical degradation prior to the release of the active compound) .
  • the coating may be applied on the solid dosage form in a similar manner as that described in Encyclopedia of Pharmaceutical Technology, supra.
  • Formulations for oral use may also be presented as chewing tablets or as hard gelatin capsules wherein the active compound is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active compound is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example, peanut oil, liquid paraffin or olive oil.
  • Powders and granulates may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g, a mixer, a fluid bed apparatus or a spray drying equipment .
  • Powders, dispersible powders, or granules suitable for preparation of an aqueous suspension by addition of water are convenient dosage forms for oral administration.
  • Formulation as a suspension provides the active compound in a mixture with a dispersing or wetting agent, suspending agent, and one or more preservatives.
  • Suitable dispersing or wetting agents are, for example, naturally- occurring phosphatides (e.g., lecithin or condensation products of ethylene oxide with a fatty acid, a long chain aliphatic alcohol or a partial ester derived from fatty acids) and a hexitol or a hexitol anhydride (e.g., poIyoxyethylene stearate, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate and the like) .
  • Suitable suspending agents are, for example, sodium carboxymethylcellulose, methylcellulose, sodium alginate and the like .
  • the compound may be administered parenterally by injection, infusion or implantation (intravenous, intramuscular, subcutaneous or the like) in dosage forms, formulations or via suitable delivery devices or implants containing conventional, non-toxic pharmaceutically acceptable carriers .
  • injection, infusion or implantation intravenous, intramuscular, subcutaneous or the like
  • suitable delivery devices or implants containing conventional, non-toxic pharmaceutically acceptable carriers .
  • the formulation and preparation of such compositions is well known to those skilled in the art of pharmaceutical formulation. Specific formulations can be found in Remington: The Science and Practice of Pharmacy, supra.
  • compositions for parenteral use may be presented in unit dosage forms (e.g., in single-dose ampoules) or in vials containing several doses and in which a suitable preservative may be added (see below) .
  • the composition may be in form of a solution, a suspension, an emulsion, an infusion device or a delivery device for implantation or it may be presented as a dry powder to be reconstituted with water or another suitable vehicle before use.
  • the composition may include suitable parenterally acceptable carriers.
  • the active compound may be incorporated into microspheres, microcapsules, nanoparticles, liposomes or the like for controlled release.
  • the composition may include suspending, solubilizing, stabilizing, pH-adjusting agents and/or dispersing agents.
  • the pharmaceutical compositions may be in the form suitable for sterile injection.
  • a parenterally acceptable liquid vehicle that may be employed are water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1, 3-butanediol, Ringer's solution and isotonic sodium chloride solution.
  • the aqueous formulation may also contain one or more preservatives (e.g., methyl, ethyl or n-propyl p-hydroxybenzoate) .
  • a dissolution enhancing or solubilising agent can be added or the solvent may include 10- 60% w/w of propylene glycol or the like.
  • suitable dosage forms for a composition include suppositories (emulsion or suspension type) and rectal gelatin capsules (solutions or suspensions) .
  • the active compound is combined with an appropriate pharmaceutically acceptable suppository base such as cocoa butter, esterified fatty acids, glycerinated gelatin and various water-soluble or dispersible bases like polyethylene glycols and polyoxyethylene sorbitan fatty acid esters.
  • an appropriate pharmaceutically acceptable suppository base such as cocoa butter, esterified fatty acids, glycerinated gelatin and various water-soluble or dispersible bases like polyethylene glycols and polyoxyethylene sorbitan fatty acid esters.
  • Various additives, enhancers or surfactants may be incorporated.
  • compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate .
  • the active compound may be administered by any of the methods and formulations employed in the art for administration to the respiratory tract .
  • the active compound may be administered in the form of a solution or a suspension or as a dry powder.
  • Solutions and suspensions will generally be aqueous, for example prepared from water alone (for example sterile or pyrogen-free water) or water and a physiologically acceptable co-solvent (for example ethanol, propylene glycol or polyethylene glycols such as PEG 400) .
  • solutions or suspensions may additionally contain other excipients for example preservatives (such as benzalkonium chloride) , solubilising agents/surfactants such as polysorbates (eg. Tween 80, Span 80, benzalkonium chloride), buffering agents, isotonicity-adjusting agents (for example sodium chloride) , absorption enhancers and viscosity enhancers.
  • Suspensions may additionally contain suspending agents (for example microcrystalline cellulose and carboxymethyl cellulose sodium) . Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the formulations may be provided in single or multidose form. In the latter case a means of dose metering is desirably provided.
  • a dropper or pipette this may be achieved by the subject administering an appropriate, predetermined volume of the solution or suspension.
  • a spray this may be achieved for example by means of a metering atomising spray pump.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the compound is provided in a pressurised pack with a suitable propellant, such as a chlorofluorocarbon (CFC) , for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas .
  • a suitable propellant such as a chlorofluorocarbon (CFC)
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of active compound may be controlled by provision of a metered valve.
  • the active compound may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP) .
  • a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP) .
  • PVP polyvinylpyrrolidine
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form, for example in capsules or cartridges of eg. gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the active compound will generally have a small particle size, for example of the order of 5 microns or less . Such a particle size may be obtained by means known in the art, for example by micronisation.
  • formulations adapted to give sustained release of the active compound may be employed.
  • the active compound may be administered by oral inhalation as a free-flow powder via a "Diskhaler” (trade mark of Glaxo Wellcome pic) or a meter dose aerosol inhaler.
  • a "Diskhaler” trade mark of Glaxo Wellcome pic
  • compositions may also be administered topically on the skin for percutaneous absorption in dosage forms or formulations containing conventionally non-toxic pharmaceutical acceptable carriers and excipients including microspheres and liposomes.
  • the formulations include creams, ointments, lotions, liniments, gels, hydrogels, solutions, suspensions, sticks, sprays, pastes, plasters and other kinds of transdermal drug delivery systems .
  • the pharmaceutically acceptable carriers may include emulsifying agents, antioxidants, buffering agents, preservatives, humectants, penetration enhancers, chelating agents, gel forming agents, ointment bases, perfumes and skin protective agents.
  • emulsifying agents are naturally occurring gums (e.g., gum acacia or gum tragacanth) and naturally occurring phosphatides (e.g., soybean lecithin and sorbitan monooleate derivatives) .
  • antioxidants are butylated hydroxy anisole (BHA) , ascorbic acid and derivatives thereof, tocopherol and derivatives thereof, butylated hydroxy anisole and cysteine.
  • preservatives are parabens, such as methyl or propyl p- hydroxybenzoate and benzalonium chloride.
  • humectants are glycerin, propylene glycol, sorbitol and urea.
  • Examples of penetration enhancers are propylene glycol, DMSO, triethanolamine, N, N-dimethylacetamide, N,N- dimethylformamide, 2-pyrrolidone and derivatives thereof, tetrahydrofurfuryl alcohol and Azone.RTM.
  • Examples of chelating agents are sodium EDTA, citric acid and phosphoric acid.
  • Examples of gel forming agents are Carbopol, cellulose derivatives, bentonite, alginates, gelatin and polyvinylpyrrolidone.
  • ointment bases are beeswax, paraffin, cetyl palmitate, vegetable oils, sorbitan esters of fatty acids (Span) , polyethylene glycols and condensation products between sorbitan esters of fatty acids and ethylene oxide ⁇ e.g., polyoxyethylene sorbitan monooleate (Tween) ) .
  • compositions described above for topical administration on the skin may also be used in connection with topical administration onto or close to the part of the body that is to be treated.
  • the compositions may be adapted for direct application or for introduction into relevant orifice(s) of the body (e.g., rectal, urethral, vaginal or oral orifices) .
  • the composition may be applied by means of special delivery devices such as dressings or alternatively plasters, pads, sponges, strips or other forms of suitable flexible material .
  • the active compound may be in the form of a solution or suspension in a suitable sterile aqueous or non-aqueous vehicle.
  • Additives for instance buffers, preservatives including bactericidal and fungicidal agents, such as phenyl mercuric acetate or nitrate, benzalkonium chloride, or chlorohexidine and thickening agents such as hypromellose may also be included .
  • the active compounds may also be presented for use in the form of veterinary compositions, which may be prepared, for example, by methods that are conventional in the art .
  • veterinary compositions include those adapted for:
  • oral administration external application, for example drenches (e.g. aqueous or non-aqueous solutions or suspensions); tablets or boluses; powders, granules or pellets for admixture with feed stuffs; pastes for application to the tongue;
  • drenches e.g. aqueous or non-aqueous solutions or suspensions
  • tablets or boluses e.g. aqueous or non-aqueous solutions or suspensions
  • pastes for application to the tongue for example drenches (e.g. aqueous or non-aqueous solutions or suspensions); tablets or boluses; powders, granules or pellets for admixture with feed stuffs; pastes for application to the tongue;
  • parenteral administration for example by subcutaneous, intramuscular or intravenous injection, e.g. as a sterile solution or suspension; or (when appropriate) by intramammary injection where a suspension or solution is introduced in the udder via the teat,-
  • topical applications e.g. as a cream, ointment or spray applied to the skin,- or
  • Nanoformulations The compounds of the present invention may be formulated in a manner which increases their rate of dissolution. This may be achieved by increasing the surface area of the compound by decreasing the particle size of the compound. Increasing the rate of dissolution of a therapeutic agent is often desirable because it can result in an increased rate of absorption in vivo, increased bioavailability, and decreased variability in absorption of the agent.
  • the compounds of the invention may be formulated in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (for example hydroxymethylcellulose or gelatin- microcapsules and poly- (methylmethacylate) microcapsules, respectively) , in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) , or in macroemulsions .
  • coacervation techniques or by interfacial polymerization for example hydroxymethylcellulose or gelatin- microcapsules and poly- (methylmethacylate) microcapsules, respectively
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • Nanoformulations of the compounds of the present invention may also be in the form of semiconductor quantum dots (Qdots) .
  • Qdots are small ( ⁇ 10 nm) inorganic crystals that possess unique luminescent properties and have significant advantages over traditional fluorophores, particularly in terms of the brightness of the fluorescent signal they can generate, their range of colours and their stability. Since QDots stay lit for much longer periods of time than conventional dyes, Qdot formulations of the inhibitors of the invention can be tracked so as to monitor their delivery to targets of interest.
  • the compounds of formula I may be used in the treatment of a disorder modulated by PTP such as a cellular proliferative disorder; autoimmune disease for example diabetes or inflammatory diseases; infections caused by viruses using PTPases for infectivity,- angiogenesis mediated disorders; bone disorders; and vascular tone, vascular permeability or VEGF mediated disorders.
  • a disorder modulated by PTP such as a cellular proliferative disorder; autoimmune disease for example diabetes or inflammatory diseases; infections caused by viruses using PTPases for infectivity,- angiogenesis mediated disorders; bone disorders; and vascular tone, vascular permeability or VEGF mediated disorders.
  • treatment means affecting a subject, tissue or cell to obtain a desired pharmacological and/or physiological effect and include: (a) preventing the disorder from occurring in a subject that may be predisposed to the disorder, but has not yet been diagnosed as having it; (b) inhibiting the infection, i.e., arresting its development; or (c) relieving or ameliorating the effects of the disorder, i.e., cause regression of the effects of the disorder.
  • subject refers to any- animal having a disorder which requires treatment with a pharmaceutically-active agent.
  • the subject may be a mammal, preferably a human, or may be a non-human primate or non-primates such as used in animal model testing. While it is particularly contemplated that the compounds are suitable for use in medical treatment of humans, it is also applicable to veterinary treatment, including treatment of companion animals such as dogs and cats, and domestic animals such as horses, ponies, donkeys, mules, llama, alpaca, pigs, cattle and sheep, or zoo animals such as primates, felids, canids, bovids and ungulates.
  • cellular proliferative disorder refers to any cellular disorder in which the cells proliferate more rapidly than normal tissue growth.
  • Cellular proliferative disorder includes but is not limited to neoplasms.
  • a neoplasm is an abnormal tissue growth, generally forming a distinct mass, that grows by cellular proliferation more rapidly than normal tissue growth.
  • Neoplasms show partial or total lack of structural organisation and functional coordination with normal tissue. These can be broadly classified into three major types.
  • neoplasms arising from epithelial structures called carcinomas, malignant neoplasms that originate from connective tissues such as muscle, cartilage, fat or bone are called sarcomas and malignant tumours affecting hematopoietic structures (structures pertaining to the formation of blood cells) including components of the immune system called leukaemias and lymphomas.
  • a tumour is the neoplastic growth of the disease cancer.
  • a "neoplasm” also referred to as a "tumour” is intended to encompass hematop ⁇ itic neoplasms as well as solid neoplasms.
  • Other cellular proliferative disorders include, but are not limited to arthritis, graft rejection, inflammatory bowel disease, proliferation induced after medical procedures, including, but not limited to, surgery, angioplasty, and the like.
  • the compounds of formula I are particularly useful for the treatment of cancer including solid tumours such as skin, breast, brain, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma.
  • Liposarcoma myxoma, rhabdomyoma, fibroma, lipoma and teratoma;
  • Lung bronchogenic carcinoma (squamous cell, undifferentiatied small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;
  • Gastrointestinal esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma) , stomach (carcinoma; lymphoma, leiomyosarcoma) , pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumours, vipoma) , small bowel (adenocarcinoma, lymphoma, carcinoid tumours, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) , large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, WiIm' s tumour (nephroblastoma), lymph
  • lymphoma carcinoma
  • Hematologic blood (myeloid leukemia (acute and chronic) , acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin' s disease, non-Hodgkin' s lymphoma (malignant lymphoma);
  • Skin malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis,- and Adrenal glands; neuroblastoma.
  • autoimmune disease includes immunological and inflammatory diseases such as rheumatoid arthritis, polyarthritis, rheumatoid spondylitis, osteoarthritis, gout, asthma, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease, cystic fibrosis, inflammatory bowl disease, irritable bowl syndrome, mucous colitis, ulcerative colitis, diabrotic colitis, Crohn's disease, autoimmune thyroid disorders , gastritis, esophagitis, hepatitis, pancreatitis, nephritis, psoriasis, eczema, acne vulgaris, dermatitis, hives, multiple sclerosis, Alzheimer's disease, Lou Gehrig's disease, Paget' s disease, sepsis, conjunctivitis, neranl catarrh, chronic arthrorheumatism, systemic inflammatory- response syndrome (SIRS) , polyinflammatory-
  • diabetes refers to diabetes insipidus and diabetes mellitus .
  • Diabetes mellitus includes type I diabetes and type II diabetes.
  • Type I diabetes is often referred to as "insulin dependent diabetes mellitus" or
  • IDDM non- insulin dependent diabetes mellitus
  • NIDDM non- insulin dependent diabetes mellitus
  • Type II diabetes is a heterogenous non-autoimmune disorder and is the predominant form of diabetes mellitus.
  • infectiouss caused by viruses using PTPases for infectivity refers to viruses which encode proteins that interfere with host cell phosphatases involved in cell proliferation and differentiation, or produce phosphatases to facilitate virus entry and replication.
  • viruses examples include HSV which causes a broad spectrum of diseases such as cold sores and genital herpes and serious viremia in the newborn and in immunosuppressed individuals; vaccinia; and the oncogenic human papilloma virus (HPV) which causes benign and malignant epithelial tumours such as genital warts, cervical cancer and head and neck cancer.
  • HSV human papilloma virus
  • HPV human papilloma virus
  • angiogenesis refers to the formation of new blood vessels (also referred to as neovascularisation) , and/or the increase in the volume, diameter or length, or altering the permeability of existing blood vessels, such as blood vessels in a tumour or between a tumour and surrounding tissue.
  • Angiogenesis is a complex process that primarily occurs during embryonic development and is essential for normal growth. Under normal physiological conditions in adults, angiogenesis takes place only in very restricted situations, such as hair growth, wound healing, renewal of the endometrium during the menstrual cycle, formation and growth of the corpus luteum during pregnancy, and in the restoration of tissue structure and function after injury.
  • Angiogenesis requires a co-ordinated series of events mediated through the activity of multiple proteins, which may have either pro— or anti—angiogenic activities .
  • the process begins with an angiogenic stimulus to existing vasculature, which is usually mediated by growth factors such as VEGF and transforming growth factor-alpha (TGF- ⁇ ) , as well as by certain chemokines .
  • the angiogenic stimulus is followed by degradation of the extracellular matrix, cell adhesion changes and disruption, an increase in cell permeability, proliferation of endothelial cells, and migration of endothelial cells towards the site of vessel formation.
  • angiogenesis later stages include vessel lumen formation, basement membrane production, and the induction of vessel bed specialisations.
  • the final stages of vessel formation include what is known as remodelling, wherein a forming vasculature becomes a stable, mature vessel bed. Therefore the angiogenic process is highly dynamic, often requiring coordinated spatial and temporal waves of gene expression.
  • angiogenesis Due to its complex nature, the process of angiogenesis is subject to disruption through interference with one or more critical steps, and numerous disease states can result from, or be exacerbated by, an increase or decrease in angiogenesis.
  • uncontrolled angiogenesis has been implicated in disorders including cancer, tumour growth and tumour metastases which require neovascularization, age—related macular degeneration (wet or dry form) , diabetic retinopathy and other proliferative retinopathies including retinopathy of prematurity, retinal vascular disorders, macular disorders, cardiovascular disease, capillary proliferation in atherosclerotic plaques and osteoporosis, aberrant hypertrophy, arthritis, rheumatoid arthritis, osteoarthritis, chronic articular rheumatism, psoriasis, psoriatic plaques, sarcoidosis, atherosclerosis, atherosclerotic plaques, edema from myocardial infarction, uveitis, retinit
  • ARDS acute respiratory distress syndrome
  • sepsis hypertension (e.g., primary pulmonary hypertension), malignant pulmonary effusions, cerebral edema (e.g., associated with acute stroke/closed head injury/trauma)
  • synovial inflammation pannus formation in rheumatoid arthritis, myositis ossificans, hypertropic bone formation, refractory ascites, polycystic ovarian disease, endometriosis, 3rd spacing of fluid diseases (pancreatitis, compartment syndrome, burns, bowel disease), uterine fibroids, premature labor, chronic inflammation such as inflammatory bowel disease (Crohn' s disease and ulcerative colitis) , renal allograft rejection, nephrotic syndrome, undesired or aberrant benign tissue mass growth, obesity, adipose tissue mass growth, haemophilic joints, hypertrophic scars, inhibition of hair growth, Osier—Weber syndrome, pyogenic granul
  • vascular tone mediated disorder refers to a disorder that involves defects in endothelial PTK signalling and includes primary essential hypertension, secondary hypertension, pulmonary hypertension and portal hypertension.
  • vascular permeability mediated disorder refers to a disorder that involves defects in VEGF induced vascular permeability and includes stroke, septic shock, burns, respiratory distress syndrome an congestive heart failure.
  • VEGF mediated disorder refers to a disorder that involves defects in VEGF signalling and includes heart failure, myocardial infarction (MI) , diabetic and ischemic neuropathy, osteoporosis, bone fracture healing, wound healing and hair loss.
  • MI myocardial infarction
  • osteoporosis osteoporosis
  • bone fracture healing wound healing and hair loss.
  • Dosages The term "therapeutically effective amount” means an amount of the compound of formula I effective to yield a desired therapeutic response.
  • Dosage levels of the compound of formula I are of the order of about 0.5 mg to about 20 mg per kilogram body weight, with a preferred dosage range between about 0.5 mg to about 10 mg per kilogram body weight per day (from about 0.5 gms to about 3 gms per patient per day) .
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage will vary depending upon the subject treated and the particular mode of administration.
  • a formulation intended for oral administration to humans may contain about 5 mg to Ig of an active compound with an appropriate and convenient amount of carrier material which may vary from about 5 to 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 5 mg to 500 mg of active ingredient.
  • the compounds are administered in a divided dose schedule, such that there are at least two administrations in total in the schedule .
  • Administrations are given preferably at least every two hours for up to four hours or longer; for example the compound may be administered every hour or every half hour.
  • the divided-dose regimen comprises a second administration of the compound after an interval from the first administration sufficiently long that the level of active compound in the blood has decreased to approximately from 5-30% of the maximum plasma level reached after the first administration, so as to maintain an effective content of active compound in the blood.
  • one or more subsequent administrations may be given at a corresponding interval from each preceding administration, preferably when the plasma level has decreased to approximately from 10-50% of the immediately- preceding maximum.
  • the specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, active compound combination and the severity of the particular infection undergoing therapy.
  • Fig. 1 is a graph showing dose-dependent inhibition of human tyrosine phosphatases, PTPlB and CD45 and bacterial Yop phosphatase.
  • Fig. 2 and 3 are graphs showing the growth inhibition of human non small cell lung carcinoma (A549) and normal cell lines by Compound 1 using the sulforhodamine B(SRB) assay, respectively.
  • Figs 4 to 6 are graphs showing the growth inhibition of human neonatal foreskin fibroblasts and normal cell lines by Compound 1 using the SRB assay, respectively.
  • Fig. 8 are graphs showing the % weight change associated with twice weekly dosing of Compound 1 at 0 (A), 1 (B), 5 (C), 10 (D), 15 (E) and 20 (F) mg/kg . Each symbol represents an individual animal. Arrows ⁇ represent days on which the compound was administered.
  • Fig. 9 are graphs showing % weight change associated with twice weekly dosing of 0 (A) and 25 (B) mg/kg compound 1 in vehicle containing 15% DMSO, 12.5% ethanol, 12.5% Cremophor and 60% ethanol. Each symbol represents an individual animal . Arrows represent days on which the compound was administered.
  • Example 1 PROTEIN TYROSINE PHOSPHATASE INHIBITION
  • TP tyrosine phosphatases
  • Promega ProFluorTM Tyrosine Phosphatase Assay Specific inhibition of tyrosine phosphatase activity by a test compound is demonstrated by inhibition of dephosphorylation of a bisamide rhodaminellO-phospho-peptide. Release of fluorescent RIlO is achieved by addition of a protease which can only hydrolyse non-phosphorylated peptide. Fluorescence is therefore directly associated with phosphatase activity and inhibition of phosphatase activity is demonstrated by a decrease in fluorescence.
  • Non-specific protease inhibition in the test compound is assessed by inhibition of protease digestion of a control peptide containing 7- amino-4-methyl-coumarin (AMC) and resultant reduction in the release of fluorescent AMC. If the test compound is a specific inhibitor of tyrosine phosphatase and not a protease inhibitor, fluorescence from the phosphor-peptide RIlO substrate will decrease and fluorescence from liberated AMC from the control peptide will remain high. If the test compound is a general protease inhibitor, fluorescence from both substrates will decrease. Compounds 1 and 7 were tested from 3.7 to 900 ⁇ M. Sodium vanadate (SV) (10 to 100 nM) was used as a positive inhibitor control.
  • SV Sodium vanadate
  • the assay was incubated for a further 30 min at 24°C and then terminated by addition of a Stabiliser Solution (Promega) and the plate read on a fluorescent microplate reader (BMG Laboratories Fluostar Optima) with excitation at 485 nM and emission at 520 nM to detect rhodamine 110 and with excitation at 355 nM and emission at 460 nM to detect AMC fluorescence.
  • Stabiliser Solution Promega
  • Compounds 1 and 7 show dose-dependent inhibition of human tyrosine phosphatases, PTPlB and CD 45 and bacterial Yop phosphatase (Fig. 1) . Inhibitory concentrations (IC 50 or ICi 5 ) are shown in the table below. Compound 7 did not inhibit CD45.
  • Yop is produced by Yersinia enterocolitica, an enteric Gram negative rod and significant pathogen causing enterocolitis in humans and animals .
  • Bacterial protein phosphatases show a high degree of identity with human homologs and share the same catalytic mechanism. Genome homology searches have shown a general distribution of orthologs for eukaryotic protein tyrosine phosphatases in many bacteria. Bacterial PTPs are not as specialized as eukaryotic PTPs, show functional overlap, greater catalytic versatility and a heterogeneous distribution.
  • Tyrosine phosphorylation influences gene regulation and enzyme activity in bacteria and is frequently related to stress resistance and virulence mechanisms of many pathogens.
  • YopH is an extra-cellular protein, encoded in a virulence plasmid in pathogenic strains of Yersinia pseudotuberculosis Compound 1 and 7 have an MIC against Y. enterocolitica of 16 ⁇ g/mL and 64 ⁇ g/mL.
  • the plate was then incubated for a further 72 hr after which viable cells are measured using the sulforhodamine B assay (Skehan et al. , 1990; Monks et al., 1991) . Briefly, the cells were fixed with 10 % cold trichloroacetic acid for 1 hr at 4 0 C and the plates then rinsed with distilled water, left to air dry and then stained with 0.4 % SRB (Aldrich) in 1% acetic acid (v/v) for 30 min. Unbound dye was removed by washing twice with distilled water and finally with 1 % acetic acid.
  • SRB Aldrich
  • Protein- bound dye is then solubilised in 10 mM unbuffered Tris base and the absorbance read at 550 nm using an automatic plate reader.
  • the mean absorbance for time zero growth (Tz) , control growth (C) and test drug growth (Ti) is determined and the percentage growth is calculated at each drug concentration as : [ (Ti-Tz) / (C-Tz)] x 100 for concentrations where Ti > Tz [(Ti-Tz) /Tz] x 100 for concentrations where Ti ⁇ Tz
  • the Growth Inhibition (GI 50 ) is then determined as the drug concentration that results in a 50 % reduction in the net cellular protein increase in control cells following drug incubation.
  • the mean GI 50 for Compound 1 for human non small cell lung cancer cell line (1.7 ⁇ M) was seven-fold lower than its activity against normal human neonatal foreskin fibroblasts (12.5 ⁇ M) . This is an acceptable differential toxicity for cytotoxic agents.
  • GI 50 is the concentration required to inhibit cell growth by 50%.
  • Compound 1 in aqueous suspension by oral administration is not toxic to rats up to 1200 mg/kg. 1500 mg/kg is toxic.
  • Compound 1 in aqueous suspension by oral administration is non toxic to day-old chicks at > 400 mg/kg .
  • Compound 1 in DMSO or ethanol given orally to chicks is not toxic at 125 mg/kg and toxic at 150 mg/kg.
  • the aim of this example was to establish absorption and blood levels of Compound 1 in the rat after a single dose oral administration.
  • Sprague-Dawley rats (6 w/o) were acclimatised for 6 days in the Animal Facility under standardized environmental conditions (22°C ⁇ 3°C, rel hum 30-70%, artificial light, 12 h light/12 h dark) .
  • Rats were fed a conventional laboratory diet with food and water ad lib and caged 5 rats per cage.
  • Compound 1 was prepared as an aqueous suspension in sterile LPW. At higher concentrations the suspension was sonicated to reduce particle size sufficiently to pass through the gavage needle .
  • Compound 1 suspensions and the water control were administered at approx 100 mL/kg.
  • One control and five treatment rats were weighed immediately before each dose administration, the dose volume calculated and the dose delivered by gavage (22 gauge stainless steel, smooth- balled end attached to a syringe) .
  • Approximately 100-200 ⁇ L of blood (microfuge tube) was removed from the tail at 4 and 8 hours.
  • Tails were prewarmed using a heat lamp and snipped at the tip with a large scalpel .
  • Blood was massaged into a microfuge tube . Twenty four hour blood samples were not attempted because of the difficulty of snipping scarred tails and the distress caused to rats. Blood was allowed to clot, centrifuged in a microfuge for 3 minutes and the serum separated and stored at -2O 0 C.
  • Compound 1 was extracted (x2) from serum by toluene and absorbance measured at 370 nm (Hitachi U2000) .
  • Compound 1 appears to be well tolerated at dose below 1000 mg/kg.
  • Compound 1 dose Sample time Blood level ⁇ g/mL (mg/kg) (hours) Mean
  • Stage A commenced dosing at 2 days old and Stage B at 5 days old.
  • Compound 1 All doses of Compound 1 were administered orally using an automatic pipette in volumes less than lmL/lOOg body weight. Doses, based on the mean group weight for the group were administered by separating the beak and inserting the plastic tip (1 mL plastic disposable pipette tips) . Compound 1 was dissolved in canola oil in stock solutions of 12.5, 25 and 50 mg/mL. Stock solution 12.5 mg/ml required heating to 40° C and 25 & 45 mg/ml required heating to 50°C to dissolve Compound 1. Dosing solutions were prepared immediately before use and kept at 40 °C and administered warm. Control groups received an equal volume of canola oil . Results
  • Compound 1 was formulated in 12.5% DMSO, 12.5% ethanol, 12.5% Cremophor EL, 62.5% saline at concentrations of 0.2- 4 mg/mL or in 15% DMSO, 12.5% ethanol, 12.5% Cremophor EL, 60 % saline at a concentration of 5 mg/mL.
  • mice Animal Resources Centre, Western Australia
  • compound 1 (0. 1. 5. 10 15, 20 and 25 mg/kg) at a rate of 0.05 ml/10 g body weight) by intravenous injection twice weekly for three weeks. Mice were weighed daily and watched closely for signs of toxicity. Animals were given a feed supplement (Ensure) daily.
  • Compound 1 was formulated as a suspension in 1% CMC & 0.05% tween 80, and animals received a single oral dose at 1000mg/kg.
  • Compound 1 levels in the plasma were determined by an LC/MS assay.
  • the LLOQ was 200 ng/mL
  • the toxicokinetic parameters determined from the mean plasma concentration profile were:
  • AUCinf area under the curve extrapolated to infinite time
  • Compound 1 was formulated as a suspension in 1% CMC & 0.05% tween 80.
  • Each animal received a single dose by oral gavage (0, 500, 1000, 1500 & 2000 mg/kg) according to the following schedule .
  • the maximum tolerated oral dose is greater than 2g/kg.
  • Compound 1 was formulated as a solution in 100% DMSO. Each animal received a single dose by intravenous injection in the lateral tail vein (0, 0.5, 1 and 5 mg/kg) in a volume of 1 mL/kg, according to the schedule in table 32. All animals were observed daily for overt signs of toxicity for 7 days . On day 8 all surviving animals were sacrificed and subject to gross necropsy examination. Histopathology of the liver, kidney, heart, spleen and lung were conducted in 1 male and 1 female rat at 0.5 and 1 mg/kg, and in 3 male rats at 5 mg/kg.
  • the vehicle group did not show any clinical signs of toxicity during the study . There were no other mortalities during the study. All animals treated with Compound 1 exhibited struggling and vocalisation during injection. The animals dosed with 0.5 mg/kg did not show any other clinical abnormalities. The animals dosed with 1 mg/kg exhibited subdued behaviour and wobbly gait for 5- 10 minutes after injection. The animals dosed with 5 mg/kg exhibited subdued behaviour, eye closure, gasping, wobbly gait and prostration for up to 10 minutes after injection. The female of this group died 5 minutes after injection. There were no other clinical abnormalities throughout the study.
  • Compound 1 was formulated as a suspension in 1% CMC and 0.05% tween 80.
  • Each animal received a Compound 1 by oral gavage (0, 300, 1100 & 2000 mg/kg) , once a day for 7 days according to following schedule .
  • Clinical signs of toxicity noted in this study following administration of 1150 and 2000 mg/kg/day Compound 1 included brown staining around anus, soft faeces, red staining of the cage paper, abdomen and nares, decreased activity, and ruffled haircoat . Clinical signs of toxicity for the low-dose group (300 mg/kg/day) were limited to red staining of the cage paper in a few males on days 3 and 4.
  • Body weight data was limited due to the loss of most animals in the mid- and high-dose groups. Males dosed with 300 mg/kg/day Compound 1 had a decreased group mean weight gain and body weight on Day 7 as compared to controls. Decreased weight gain and body weight was also noted for the females in the low-and mid-dose groups.
  • Test article related changes in liver weights were noted for females at necropsy on Day 8. females had statistically significantly increased liver weights (absolute and relative to body and brain weight) for mid- dose animals. Low-dose females also has increased liver to body weight ratios . Although statistically significantly increased liver to body weight ratios were noted for males in the low-dose group, this was considered incidental as it was most likely associated with the decreased body weight. Increased adrenal to body and adrenal to brain weight ratios were noted for females in the mid-dose group.
  • the no-observed adverse-effect level was less than 300 mg/kg/day, while the lowest lethal dose (LLD) was less than 1150 mg/kg/day.
  • T-C tumour growth delay
  • Example 5 - ANTI-HERPES SIMPLEX TYPE 2 ACTIVITY IN MRC-5 CELLS
  • MRC-5 cells are inoculated with 500 tissue culture infectious doses (TCID 50 ) of HSV 2 in the presence of serial dilutions of Compound 1 and 7 in DMEM containing 2% fetal calf serum (FCS) supplemented with glutamine, penicillin and streptomycin.
  • Controls will be: Positive control-acyclovir (known inhibitor of HSV replication) Cytoxocity control - drug treated cells without virus Virus replication control - infected cells with no drug Cell viability control
  • MTS is incubated for 6 days at 37°C in 5% CO 2 .
  • MTS is added to each well and the plates incubated at 37°C in 5% CO 2 for 3 hours followed by addition of 25 ⁇ l of 20% sodium dodecyl sulphate (SDS) .
  • SDS sodium dodecyl sulphate
  • MTS is converted to a soluble coloured product by cell mitochondria.
  • the absorbance at 490 nM (with reference at 690 nM) is recorded (Multiskan, EX Microplate reader, Thermo Electron Corporation) .
  • Inhibition of virus replication and drug cytotoxicity are assessed by cell viability using the Promega CellTiter 96 Aqueous One Solution Cell Proliferation Assay.
  • This assay measures spectrophotometrically at 490 nm the reduction by cell mitochondria of MTS (3- (4, 5-dimethyl-2- yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H- tetrazolium) to a coloured product.
  • MTS 3- (4, 5-dimethyl-2- yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H- tetrazolium
  • IC 50 50% inhibitory concentration
  • CC 50 50% cytotoxic concentration
  • the cytotoxicity is calculated [ (0D T ) mock / (0D c ) moC k ] expressed as % where :
  • a dose response curve is generated using the XLfit program by plotting the drug concentration (log scale) against the percentage viability to determine the 50% cytotoxic concentration of the compound (CC 50 ) .

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Abstract

La présente invention concerne des modulateurs de la protéine tyrosine phosphatase (PTP), et en particulier des inhibiteurs de la PTP, ainsi que leur utilisation dans le traitement ou la prophylaxie de troubles modulés par la PTP, tels que les troubles suivants : troubles de la prolifération cellulaire ; maladies auto-immunes, par exemple diabète ou maladies inflammatoires ; infections provoquées par des virus utilisant la PTP pour l'infectivité ; troubles induits par l'angiogenèse ; troubles osseux ; et troubles du tonus vasculaire, troubles de la perméabilité vasculaire ou troubles induits par le facteur de croissance endothélial vasculaire.
PCT/AU2007/001794 2006-11-22 2007-11-22 Modulateurs de la protéine tyrosine phosphatase WO2008061308A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140128460A1 (en) * 2012-03-29 2014-05-08 Children's Hospital Medical Center Use of small molecule inhibitors targeting eya tyrosine phosphatase
CN104146989A (zh) * 2014-07-22 2014-11-19 华中师范大学 硝基苯乙烯类衍生物用于抑制果糖-1,6-二磷酸酶的新用途
JP2015518007A (ja) * 2012-05-30 2015-06-25 バイオディエム、リミテッドＢｉｏｄｉｅｍ Ｌｉｍｉｔｅｄ スケドスポリウム属感染症の治療方法
EP2982368A1 (fr) * 2014-08-04 2016-02-10 Universität Konstanz Composés à petite molécule de déplacement des composants de noyau d'adhésion focale
US9725430B2 (en) 2013-01-16 2017-08-08 Children's Hospital Medical Center Use of small molecule inhibitors targeting EYA tyrosine phosphatase

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140128460A1 (en) * 2012-03-29 2014-05-08 Children's Hospital Medical Center Use of small molecule inhibitors targeting eya tyrosine phosphatase
US9962362B2 (en) * 2012-03-29 2018-05-08 Children's Hospital Medical Center Use of small molecule inhibitors targeting EYA tyrosine phosphatase
JP2015518007A (ja) * 2012-05-30 2015-06-25 バイオディエム、リミテッドＢｉｏｄｉｅｍ Ｌｉｍｉｔｅｄ スケドスポリウム属感染症の治療方法
US9725430B2 (en) 2013-01-16 2017-08-08 Children's Hospital Medical Center Use of small molecule inhibitors targeting EYA tyrosine phosphatase
US10221151B2 (en) 2013-01-16 2019-03-05 Children's Hospital Medical Center Use of small molecule inhibitors targeting EYA tyrosine phosphatase
CN104146989A (zh) * 2014-07-22 2014-11-19 华中师范大学 硝基苯乙烯类衍生物用于抑制果糖-1,6-二磷酸酶的新用途
CN104146989B (zh) * 2014-07-22 2019-05-24 华中师范大学 硝基苯乙烯类衍生物用于抑制果糖-1,6-二磷酸酶的用途
EP2982368A1 (fr) * 2014-08-04 2016-02-10 Universität Konstanz Composés à petite molécule de déplacement des composants de noyau d'adhésion focale

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