WO2013010573A1 - Composés avec activité inhibitrice de métalloprotéinase de matrice - Google Patents

Composés avec activité inhibitrice de métalloprotéinase de matrice Download PDF

Info

Publication number
WO2013010573A1
WO2013010573A1 PCT/EP2011/062211 EP2011062211W WO2013010573A1 WO 2013010573 A1 WO2013010573 A1 WO 2013010573A1 EP 2011062211 W EP2011062211 W EP 2011062211W WO 2013010573 A1 WO2013010573 A1 WO 2013010573A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
ots
halogen
triazol
Prior art date
Application number
PCT/EP2011/062211
Other languages
English (en)
Inventor
Guenter Haufe
Klaus Kopka
Stefan Wagner
Verena Hugenberg
Sven Hermann
Michael Schaefers
Hartmuth Kolb
Original Assignee
Universitaet Muenster
Siemens Medical Solutions Usa, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universitaet Muenster, Siemens Medical Solutions Usa, Inc. filed Critical Universitaet Muenster
Priority to PCT/EP2011/062211 priority Critical patent/WO2013010573A1/fr
Publication of WO2013010573A1 publication Critical patent/WO2013010573A1/fr
Priority to US13/849,646 priority patent/US9023318B2/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/056—Triazole or tetrazole radicals

Definitions

  • the present invention relates to the field of pharmaceutical and diagnostic agents and more specifically to compounds that are inhibitors of matrix metalloproteinases (MMPs) and are useful in the treatment of diseases related thereto such as cardiovascular diseases, inflammatory diseases and malignant diseases.
  • MMPs matrix metalloproteinases
  • the compounds are useful for the field of in vivo diagnostic imaging and in particular in Positiron Emission Tomography (PET) imaging, as well.
  • PET Positiron Emission Tomography
  • MMPs matrix metalloproteinases
  • ECM extracellular matrix
  • MMPs are therefore targets for therapeutic inhibitors in many inflammatory, malignant and degenerative diseases [Whittaker et al., Chem Rev 99 2735-76 (1999)].
  • WO 01/60416 discloses compounds which are proposed to be useful in the diagnosis of cardiovascular pathologies associated-with-extracellular matrix degradation such as atherosclerosis, heart failure and restenosis.
  • the compounds disclosed therein comprise MMP inhibitors linked, via an optional linker, to a chelator capable of conjugating to a diagnostic metal.
  • Preferred MMP inhibitors, chelators and linkers are described therein.
  • Novel compounds of the invention having very potent MMP inhibitory activity, in particular against MMP-2, -8-, -9 and -13 are disclosed which possess high potency and fine-tuned hydrophilicity (fine-tuned) lipophilicity properties.
  • Lipophilicity is an important parameter for any pharmaceutical and for any in vivo diagnostic agent as well, as a high lipophilicity can increase a generic non-specific binding of the drug to macromolecules resulting in a poor binding to the target tissue and at the same time in a poor system elimination.
  • this aspect is of even more relevance in case of diagnostic imaging that aims at a selective and at the same time specific accumulation of the diagnostic compound within the target tissue in combination with a fast elimination from non-target tissues which results in a very sensitive detection of the diagnostic compound and in a high signal to noise ratio (S/N).
  • the compounds of the present invention achieve a good balance between the MMP inhibition potency and lipophilicity which render them particularly useful in the prevention, treatment and diagnostic imaging of diseases associated with a dysregulated MMP-activity.
  • the mentioned properties achieved by the compounds of the invention are in particular notable with respect to the lead compound FEtO CGS 25966 and CGS 27023A.
  • the introduction of a triazole group in the molecules of the present invention improves the inhibition potency and increases the hydrophilicity resulting in a fine-tuned balance between both parameters.
  • the present properties are achieved by substituting the phenyl moiety of lead compound CGS 25966 or the pyridine moiety of lead compound CGS 27023A with a triazole ring. Additionally, it has been surprisingly observed that the above disclosed effects are maintained even if the triazole moiety is relatively "distant" from the "core" of the lead structure FEtO CGS 25966 .
  • Another aspect of the present invention relates to pharmaceutical compositions, useful in the prevention, treatment and diagnostic imaging of diseases associated with a dysregulated MMP-activity.
  • the compounds of the present invention are useful for the prevention, the treatment and the in vivo diagnostic imaging of a range of disease states (inflammatory, malignant and degenerative diseases) where specific matrix metalloproteinases are known to be involved. These include:
  • Figure 1 shows the synthesis of a precursor HUG 19 of the compounds of the invention.
  • Figure 2 shows the synthesis of the compound of the invention HUG 38 starting from the precursor HUG 19.
  • Figure 3 shows the synthesis of the compound of the invention HUG 30 starting from the precursor HUG 19.
  • Figure 4 shows the synthesis of the compounds of the invention HUG 30 and HUG 38 using the common precursors HUG 1 , HUG 12, HUG 15, HUG 17 and HUG 19.
  • Figure 5 shows the synthesis of HUG 41 starting from commercially available te/f-butylester of D-valine hydrochloride 1.
  • Figure 6 shows the IC 50 values of the compounds of the present invention tested for their activity on MMP-2, -8, -9 and -13.
  • the first aspect of the present invention provides a compound of formula (I)
  • A-R is an optionally substituted 1 /-/-1 ,2,3-triazol-4-yl of structure A' or an optionally substituted 1 ,2,3-triazol-1-yl-methyl of structure A A'
  • R is H, Ci-C 6 alkyl, preferably ethyl or propyl, C C 6 haloalkyi, preferably C C 6 fluoroalkyi, more preferably CH 2 -CH 2 -F, and CH 2 -CH 2 -CH 2 -F, -(CH 2 -CH 2 -0) m -(pyrid-3-yl) wherein the pyridyl moiety bears one substituent R 5 preferably in position 2 (i.e.
  • R is H, Ci-C 6 alkyl, C C 6 haloalkyi, preferably C C 6 fluoroalkyi, more preferably CH 2 -CH 2 -F and CH2-CH2-CH2-F, -(CH2-CH 2 -0) m -(pyrid-3-yl) wherein the pyridyl moiety bears one substituent R 5 preferably in position 2 i.e.
  • R 10 is H or C C 6 alkyl, preferably H or methyl
  • R is 1-(R5-(CH2-CH2-0) m -CH2-CH 2 )-1 ,2,3-triazol-4-yl-CH2-(0-CH2-CH2-)p-OCH2- of structure: .fib
  • R is a 1-(glucopyranosyl)-1 ,2,3-triazol-4-yl-CH 2 -(0-CH 2 -CH 2 -)p-0- of structure and is an optionally substituted C C 6 alkyl, preferably methyl or ethyl wherein the substituent is selected from halogen, preferably F, or is -(CH2-CH2-0)n-CH2-CH 2 -R4, preferably R ⁇ is
  • R 2 is Ci-C 6 alkyl, preferably isopropyl, C C 6 haloalkyl, preferably fluoroalkyl, preferably CH 2 - CH 2 -F
  • R 3 is OH or C C 6 alkoxy, preferably OH, f-butyloxy or tetrahydropyranyloxy
  • R 4 is H, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf, 0 3 SCH2CH2(CF 2 )tCF 3 , perfluorophenyl sulfonate or halogen, preferably F
  • R 5 is H, N0 2 , N + (R 9 ) 3 , OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf (triflate), 0 3 SCH 2 CH2(CF 2 )7CF 3 , perfluorophenyl sulfonate or halogen, preferably F
  • Rg is CrC 6 alkyl, preferably methyl m is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably m is 0, 1 , 2, 3, n is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 p is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably m is 0, 1 , 2, 3, t is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably t is 7 and enantiomers, esters and pharmaceutically acceptable salts thereof.
  • m is 0, 1 , 2, 3 or 4; n is 0, 1 , 2, 3 or 4, p is 0, 1 , 2, 3 or 4; in a further embodiment preferably m is 0, 1 , 2, 3 or 4; n is 0, 1 , 2, 3 or 4, p is 0, 1 , 2, 3 or 4 and t is 7.
  • R 4 is H or halogen, preferably F.
  • R 5 is H, or halogen, preferably F.
  • R 4 is H or halogen, preferably F and R 5 is H, or halogen, preferably F.
  • R 4 is H and R 5 is F.ln a further embodiment R ⁇ is methyl.
  • R ⁇ is methyl and
  • A-R is an optionally substituted 1 /-/-1 ,2,3-triazol-4-yl of structure A' or an optionally substituted 1 ,2,3-triazol-1-yl-methyl of structure A" and R is C C 6 fluoroalkyl, more preferably CH 2 -CH 2 -F or R is glucopyranosyl, preferably 2-deoxy-2- fluoro ⁇ -D-glucopyranosyl and
  • Ri is methyl, CH 2 -CH 2 -F or R ⁇ is -(CH 2 -CH 2 -0) n -CH 2 -CH 2 -R 4
  • R 2 is isopropyl
  • R 3 is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH
  • R 4 is H, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf, 0 3 SCH 2 CH 2 (CF 2 ) 7 CF 3 , perfluorophenyl sulfonate or halogen, preferably F
  • R 5 is H, -C ⁇ CH, N 3 , OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf (triflate), 0 3 SCH 2 CH 2 (CF 2 ) 7 CF 3 , perfluorophenyl sulfonate or halogen, preferably F; m is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 n is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 p is O, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 preferably m is 1 , 2, 3 or 4; n is 1 , 2, 3 or 4 or enantiomers, esters or pharmaceutically acceptable salts thereof; more preferably R 4 is H or halogen, preferably F; R 5 is H, or halogen, preferably F; more preferably R 4 is H or halogen, preferably F and R 5 is H, or halogen, preferably F; more preferably R 4 is H and R 5 is F; more
  • the present invention is directed to a compound of formula (la)
  • Ri is methyl, CH 2 -CH 2 -F or Ri is -(CH 2 -CH 2 -0) n -CH 2 -CH 2 -R 4
  • R 2 is isopropyl
  • R 3 is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH
  • R 4 is H, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf, 0 3 SCH 2 CH 2 (CF 2 )7CF 3 , perfluorophenyl sulfonate or halogen, preferably F
  • R 5 is H, C ⁇ CH, N 3 , OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf,
  • R 4 is H or halogen, preferably F; in a further embodiment R 5 is H , or halogen, preferably F; in a further preferredembodiment R 4 is H or halogen, preferably F and R 5 is H, or halogen, preferably F; more preferably R 4 is H and R 5 is F; more preferably is methyl and R 5 is F.
  • the present invention is directed to a compound of formula (lb)
  • Ri is methyl, CH 2 -CH 2 -F or is -(CH 2 -CH 2 -0) n -CH 2 -CH 2 -R 4 R 2 is isopropyl,
  • R 3 is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH
  • R 4 is H, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf, 0 3 SCH 2 CH 2 (CF 2 ) 7 CF 3 , perfluorophenyl sulfonate or halogen, preferably F
  • R 5 is H, C ⁇ CH, N 3 , OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf,
  • R 4 is H or halogen, preferably F; in a further embodiment R 5 is H , or halogen, preferably F; in a further preferred embodiment in formula (lb) R 4 is H or halogen, preferably F and R 5 is H, or halogen, preferably F; more preferably R 4 is H and R 5 is F; more preferably is methyl and R 5 is F.
  • the resent invention is directed to a compound of formula (Ic)
  • Ri is methyl, CH 2 -CH 2 -F or Ri is -(CH 2 -CH2-0)n-CH2-CH 2 -R 4 R 2 is isopropyl,
  • R 3 is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH
  • R 4 is H, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf, OsSCHzCHz CFz ⁇ CFs, perfluorophenyl sulfonate or halogen, preferably F
  • R 5 is H, C ⁇ CH , N 3 , OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf,
  • R 4 is H or halogen, preferably F; in a further embodiment R 5 is H , or halogen, preferably F; in a further preferred embodiment in formula (lc) R 4 is H or halogen, preferably F and R 5 is H , or halogen, preferably F; more preferably R 4 is H and R 5 is F; more preferably R ⁇ is methyl and R 5 is F.
  • the resent invention is directed to a compound of formula (Id)
  • Ri is methyl, CH 2 -CH 2 -F or is -(CH 2 -CH2-0)n-CH2-CH 2 -R 4
  • R 2 is isopropyl
  • R 3 is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH
  • R 4 is H, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf, OsSCHzCHz CFz ⁇ CFs, perfluorophenyl sulfonate or halogen, preferably F
  • R 5 is H, C ⁇ CH, N 3 , OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf,
  • R 4 is H or halogen, preferably F; in a further embodiment R 5 is H , or halogen, preferably F; in a further preferred embodiment in formula (Id) R 4 is H or halogen, preferably F and R 5 is H , or halogen, preferably F; more preferably R 4 is H and R 5 is F; more preferably R ⁇ is methyl and R 5 is F.
  • the present invention is directed to a compound of formula (le)
  • Ri is methyl, CH 2 -CH 2 -F or R, is -(CH 2 -CH2-0)n-CH2-CH 2 -R 4 R 2 is isopropyl,
  • R 3 is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH
  • R 4 is H, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf, OsSCHzCHz CFz ⁇ CFs, perfluorophenyl sulfonate or halogen, preferably F
  • R 5 is H, C ⁇ CH, N 3 , OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf,
  • R 4 is H or halogen, preferably F; in a further embodiment R 5 is H, or halogen, preferably F; in a further preferred embodiment in formula (le) R 4 is H or halogen, preferably F and R 5 is H , or halogen, preferably F; more preferably R 4 is H and R 5 is F; more preferably R ⁇ is methyl and R 5 is F.
  • the present invention is directed to a compound of formula (If)
  • F is methyl, CH 2 -CH 2 -F or is -(CH 2 -CH2-0)n-CH2-CH 2 -R4 R 2 is isopropyl,
  • R 3 is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH
  • R 4 is H, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf, OsSCHzCHzCCFz ⁇ CFs, perfluorophenyl sulfonate or halogen, preferably F
  • R 5 is H, C ⁇ CH , N 3 , OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf,
  • R 4 is H or halogen, preferably F; in a further embodiment R 5 is H, or halogen, preferably F; in a further preferred embodiment in formula (If) R 4 is H or halogen, preferably F and R 5 is H, or halogen, preferably F; more preferably R 4 is H and R 5 is F; more preferably is methyl and R 5 is F.
  • the present invention is directed to a compound of formula (Ig)
  • Ri is methyl, CH 2 -CH 2 -F or Ri is -(CH 2 -CH2-0)n-CH2-CH 2 -R4 R 2 is isopropyl,
  • R 3 is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH
  • R 4 is H, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf, 0 3 SCH2CH2(CF 2 )7CF 3 , perfluorophenyl sulfonate or halogen, preferably F
  • R 5 is H, C ⁇ CH, N 3 , OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf,
  • F p is O, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 preferably p is 1 , 2, 3 or 4 or enantiomers, esters or pharmaceutically acceptable salts thereof, preferably F.
  • R 4 is H or halogen, preferably F; in a further embodiment R 5 is H , or halogen, preferably F; in a further preferred embodiment in formula (Ig) R 4 is H or halogen, preferably F and R 5 is H, or halogen, preferably F; more preferably R 4 is H and R 5 is F; more preferably is methyl and R 5 is F.
  • the present invention is directed to a compound of formula (Ih)
  • Ri is methyl, CH 2 -CH 2 -F or Ri is -(CH 2 -CH2-0)n-CH2-CH 2 -R4 R 2 is isopropyl,
  • R 3 is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH
  • R 4 is H, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf, 0 3 SCH 2 CH 2 (CF 2 ) 7 CF 3 , perfluorophenyl sulfonate or halogen, preferably F
  • R 5 is H, C ⁇ CH, N 3 , OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf,
  • R 4 is H or halogen, preferably F; in a further embodiment R 5 is H , or halogen, preferably F; in a further preferred embodiment in formula (Ih) R 4 is H or halogen, preferably F and R 5 is H, or halogen, preferably F; more preferably R 4 is H and R 5 is F; more preferably is methyl and R 5 is F.
  • the present invention is directed to a compound of formula (li)
  • F is methyl, CH 2 -CH 2 -F or R, is -(CH 2 -CH2-0)n-CH2-CH 2 -R4 R 2 is isopropyl,
  • R 3 is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH
  • R 4 is H, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf, 0 3 SCH 2 CH 2 (CF 2 )7CF3, perfluorophenyl sulfonate or halogen, preferably F
  • R 5 is H, C ⁇ CH , N 3 , OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf,
  • R 4 is H or halogen, preferably F; in a further embodiment R 5 is H, or halogen, preferably F; in a further preferred embodiment in formula (li) R 4 is H or halogen, preferably F and R 5 is H, or halogen, preferably F; more preferably R 4 is H and R 5 is F; more preferably is methyl and R 5 is F.
  • the present invention is directed to a compound of formula (II) wherein
  • F is methyl, CH 2 -CH 2 -F or is -(CH 2 -CH2-0)n-CH2-CH 2 -R4 R 2 is isopropyl,
  • R 3 is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH
  • R 4 is H, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf, OsSCHzCHzCCFz ⁇ CFs, perfluorophenyl sulfonate or halogen, preferably F
  • R 5 is H, C ⁇ CH , N 3 , OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf,
  • R 4 is H or halogen, preferably F; in a further embodiment R 5 is H, or halogen, preferably F; in a further preferred embodiment in formula (II) R 4 is H or halogen, preferably F and R 5 is H, or halogen, preferably F; more preferably R 4 is H and R 5 is F; more preferably is methyl and R 5 is F.
  • the compounds of the above mentioned formulae and embodiments have a carbon atom bearing radical R 2 having a "S" configuration or a "R” configuration.
  • the compounds of formulae I, la, lb, Ic, Id, le, If, Ig, Ih, li, II, the preferred and more preferred embodiment of formulae I, la, lb, Ic, Id, le, If, Ig, Ih, li, II, and the above individualized compounds have a carbon atom that bears a 18 F as a substituent in addition or in place to a substituent already present on said carbon atom.
  • R 5 is 18 F.
  • R 4 is 18 F or alternatively is 18 F-C C 6 alkyl; preferably F ⁇ is 18 F-CH 2 -CH 2 . More preferably, R 5 is 18 F. More preferably, there is one 18 F atom in a molecule.
  • R may be 18 F-C C 6 alkyl, preferably 18 F-CH 2 -CH 2 .
  • Preferred compounds are the following compounds:
  • the compounds of the invention are for use as a medicament.
  • the present invention related to compounds for use in the prevention and/or treatment of pathological conditions associated with unpaired expression of matrix-metalloproteases in human and animal, in particular mammals.
  • the present invention relates to compounds of formula (I) which are labeled with a 18 F atom for use as a diagnostic or imaging agent, in particular as an in vivo diagnostic or imaging agent and more in particular as diagnostic or imaging agent for Positron Emission Tomography (PET).
  • a diagnostic or imaging agent in particular as an in vivo diagnostic or imaging agent and more in particular as diagnostic or imaging agent for Positron Emission Tomography (PET).
  • PET Positron Emission Tomography
  • Said diagnostic or molecular imaging agents are for the visualization, assessment and quantitation of MMP-activity in cells and tissues.
  • said molecular imaging agents are for the visualization and quantitation of MMP-activity in mammalian cells and tissues, including human cells and tissues.
  • Said quantitation may comprise the analysis of cellular or tissue radioactivity content, or the rate of uptake, displacement, dissociation or partitioning.
  • the compounds of the invention are for use in the prevention or treatment of pathological conditions associated with a dysregulated expression of matrix metalloproteinase in human and animal.
  • the radiolabeled compounds of the invention are for use in the diagnosis of pathological conditions associated with a dysregulated expression of matrix metalloproteinase in human and animal.
  • the pathological condition is selected from the group consisting of cardiovascular diseases, inflammatory diseases, autoimmune diseases and malignant diseases.
  • cardiovascular diseases are selected from atherosclerosis and congestive heart failure.
  • Inflammatory disease is chronic obstructive pulmonary disease.
  • Autoimmune diseases are diabetes mellitus type 1 , rheumatoid arthritis, multiple sclerosis, and malignant diseases are cancers.
  • the use of the diagnostic imaging compound of the invention permits the identification of active plaque burden, which allows risk stratification of patients with known or suspected coronary artery disease, i. e. patients with pain or a history of pain, or identified as high risk but asymptomatic.
  • the diagnostic imaging agents of the invention permit identification of vulnerable plaques in symptomatic patients, which allows identification of high risk of acute myocardial infarction or stroke irrespective of stenosis and permits immediate risk stratification when the patient suffers from chest pain
  • angioplasty of vulnerable plaques is high risk, and may lead to embolism of the artery tree post surgery. Thus imaging of this subtype of plaques may help reduce post-surgical complication.
  • the present invention relates to pharmaceutical composition
  • a compound of formula (I) comprising a compound of formula (I).
  • the present invention also provides a pharmaceutical or diagnostic composition comprising the compounds of the invention for the visualization, assessment and quantitation of MMP- activity.
  • the present invention provides pharmaceutical compositions comprising the compounds of the invention for in vivo imaging of MMP-activity in mammalian cells or tissue.
  • the present invention relates to pharmaceutical composition comprising a compound of formula (I).
  • suitable preparations include for example tablets, capsules, suppositories, solutions, - particularly solutions for injection (s.c, i.v., i.m.) and infusion - syrups, elixirs, solution for inhalation.
  • the invention relates to pharmaceutical compositions comprising an effective amount, especially an amount effective in the treatment of one of the above-mentioned disorders, of the active ingredient together with pharmaceutically acceptable carriers that are suitable for topical, enteral, for example oral or rectal, or intravenous or parenteral administration and that may be inorganic or organic, solid or liquid.
  • tablets or gelatin capsules that comprise the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycerol, and/or lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate and/or polyethylene glycol.
  • diluents for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycerol
  • lubricants for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate and/or polyethylene glycol.
  • Tablets may also comprise binders, for example magnesium aluminum silicate, starches, such as corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate and/or effervescent mixtures or adsorbents, dyes, flavorings and sweeteners.
  • binders for example magnesium aluminum silicate, starches, such as corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone
  • disintegrators for example starches, agar, alginic acid or a salt thereof, such as sodium alginate and/or effervescent mixtures or adsorbents, dyes, flavorings and sweeteners.
  • compositions of the present invention in the form of intravenously and parentally administrable compositions or in the form of infusion solutions.
  • solutions are preferably isotonic aqueous solutions or suspensions which, for example in the case of lyophilized compositions that comprise the active ingredient alone or together with a carrier, for example mannitol, can be made up prior to use.
  • the pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizes, salts for regulating the osmotic pressure and/or buffers.
  • compositions are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilizing processes, and comprise approximately from 1 % to 95%, especially from approximately 1 % to approximately 20%, active ingredient (s).
  • the present invention therefore provides a method for the molecular imaging of MM P-activity which comprises the steps of: a) contacting said cells or tissues with a radiolabeled compound of the present invention or composition of the present invention and b) detecting said MM P-activity.
  • the step of detecting said MMP-activity comprises the steps of positioning the subject within the detection field of a detection device and detecting said compounds in the subject with said detection device.
  • This method may be carried out also in vitro by contacting the cells or tissues with a compound or composition of the present invention by exposing, incubating, touching, associating or making the compound accessible to the cells or tissue.
  • the compound or composition of the present invention is radiolabeled, said MMP-activity can be detected in vitro, ex vivo and in vivo using any appropriate radiation detection device.
  • the compounds or compositions may be administered to a subject by any suitable administration method (oral, injection (intravenous (IV), intramuscular (IM), and subcutaneous, parenteral), via inhalation, etc.).
  • oral injection
  • IM intramuscular
  • parenteral subcutaneous, parenteral
  • the compounds are administered intravenously.
  • said MMP- activity may be detected using a radiation detection device.
  • Said radiation detection device may include a Positron Emission Tomography (PET) scanner or a Single Photon Emission Computed Tomography (SPECT) scanner.
  • said radiation detection device is a Positron Emission Tomography (PET) scanner combined with Computer Tomography (PET/CT) or Magnetic Resonance Tomography (PET/MR).
  • PET scanner can detect pairs of gamma rays, emitted indirectly by positron-emitting radioisotopes such as 18 F to produce a reconstructed 3D image of the radioactivity distribution within tissues. PET can therefore be used to produce a 3D image of the distribution of the radiolabeled compounds and compositions of the present invention within mammalian or human tissues.
  • the present invention is a direct method for in vivo imaging.
  • the method may involve: a) administering to the subject a compound of the present invention or a composition of present invention; b) positioning the subject within the detection field of a detection device; and c) detecting said compounds in the subject with said detection device.
  • Said compound or composition may be administered to the subject by injection.
  • the imaging moiety can either be detected externally in a non-invasive manner or internally by the use of detectors designed for use in vivo, such as intravascular radiation detectors or radiation detectors designed for intra-operative use.
  • the imaging moiety is detected in a non-invasive manner.
  • the compounds are labeled and are detected by measuring the radiation emitted from the labeled compounds with a detection device for detecting radiation.
  • a further aspect of the present invention provides the use of the compounds of the present invention or the pharmaceutical compositions of the present invention for assessing the therapeutic effect of a test substance on MMP-activity in mammalian cells or tissues.
  • This method may involve: a) contacting mammalian cells or tissues with a compound of the present invention or a composition according to the present invention; b) positioning said mammalian cells or tissues within the detection field of a detection device; c) detecting the compounds with said detection device; d) repeating steps a), b) and c).
  • the compounds are labeled and are detected by measuring the radiation emitted from the labeled compounds with a detection device for detecting radiation.
  • the present invention is directed to intermediate compounds useful in the preparation of the compounds of the invention i.e. the compounds of formula (I), (la), (lb), (lc), (Id), (le), (If), (Ig), (Ih), (li), (II)
  • the intermediate is a compound of any of formulae (Ilia) to (lllh)
  • R 2 and p are as defined in formulae I, la, lb, Ic, Id, le, If, Ig, Ih and preferred and more preferred embodiment thereof
  • R 7 is NH-OH, NH-ORs, OH, C C 6 -alkoxy and
  • R 8 is CrC 6 alkyl or tetrahydropyranyl.
  • the intermediates are compounds:
  • the intermediates of the invention are used in a process for preparing the compounds of the invention, comprising compounds of formulae (Ilia), (1Mb), (lllc), (I I Id), (llle), (lllf), (I I lg) or (lllh) wherein R 7 is NH-OH or one of the above individualized intermediate compounds to a 1 ,3 dipolar cycloaddition.
  • the process comprises reacting a compound of formulae (Ilia), (lllc), (llle), or (lllg) wherein R 7 is NH-OH or the above individualized intermediate compounds, with a compound of formulae N 3 -CH 2 -CH 2 -F, N 3 -CH 2 -CH 2 - 18 F, N 3 -(CH 2 -CH 2 -0) r CH 2 -CH 2 -F or N 3 -(CH 2 -CH 2 -0) r - CH 2 -CH 2 - 18 F wherein r is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 3.
  • the process may further comprise preparing a compound of formula N 3 -CH 2 -CH 2 - 18 F or a compound of formula N 3 -(CH 2 -CH 2 -0) r CH 2 -CH 2 - 18 F by reaction of a compound of formula N 3 -CH 2 -CH 2 -OTs or a compound of formula N 3 -(CH 2 -CH 2 -0) r -CH 2 -CH 2 -OTs with a 18 F containing reagent for nucleophile substitution.
  • any other suitable leaving group may be used.
  • Suitable leaving groups are: ONos (3- nitrobenzenesulfonate), mesylate, OTf (triflate), 0 3 SCH 2 CH 2 (CF 2 ) 7 CF 3 , perfluorophenyl sulfonate, CI, Br, I.
  • Examples of 18 F containing reagents for nucleophile substitution are the reagents [ 18 F](Kryptofix222)KF and [ 18 F]TBAF (tetrabutylammonium fluoride).
  • the process for preparing the compounds of formula (I) comprises reacting a compound of formulae 1Mb, llld, lllf, or lllh wherein R 7 is NH-OH, with a compound of formulae HC ⁇ C-CH 2 - CH2-CH2-F, HC ⁇ C-CH 2 -CH 2 -CH 2 - 18 F, HC ⁇ C-(CH 2 -CH 2 -0) r -CH 2 -CH 2 -F or HC ⁇ C-(CH 2 -CH 2 - 0) r -CH 2 -CH 2 - 18 F, wherein r is 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 3.
  • the process may further comprise preparing a compound of formula HC ⁇ C-CH 2 -CH 2 -CH 2 - 18 F or a compound of formula HC ⁇ C-(CH 2 -CH 2 -0) r CH 2 -CH 2 - 18 F by reaction of a compound of formula HC ⁇ C-CH 2 -CH 2 -CH 2 -OTs or a compound of formula HC ⁇ C-(CH 2 -CH 2 -0) r -CH 2 - CH 2 -OTs with a 18 F containing reagent for nucleophile substitution.
  • any other suitable leaving group may be used.
  • Suitable leaving groups are: ONos (3-nitrobenzenesulfonate), mesylate, OTf, 0 3 SCH 2 CH 2 (CF 2 ) 7 CF 3 , perfluorophenyl sulfonate, CI, Br, I.
  • Examples of 18 F containing reagents for nucleophile substitution are the reagents
  • A, R, A-R, RL R 2 , R 3 , R 9 , R 10 , m, n, and p are as defined in any of the above formulae I, la, lb, lc, Id, le, If, Ig, Ih, li and II
  • R 5 is OTs, ONos (3-nitrobenzenesulfonate), mesylate or OTf or
  • A, R, A-R, RL R 2 , R 3 , R 9 , R 10 , m, n, and p are as defined are as defined in any of the above formulae I, la, lb, lc, Id, le, If, Ig, Ih, li and II
  • R 5 is OTs, ONos (3-nitrobenzenesulfonate), mesylate or OTf and R 4 is H or halogen.
  • formula IV (a) is methyl.
  • HUG 15 is converted to the corresponding hydroxamic acid ester HUG 17 with O-terf-butylhydroxylamine hydrochloride, A/-((dimethylamino)-propyl)-/ ⁇ /'-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole hydrate (HOBT) and 4-methylmorpholine (NMM).
  • EDC O-terf-butylhydroxylamine hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • NMM 4-methylmorpholine
  • 1 ,3-Dipolar cycloaddition of the propargylic hydroxamic acid HUG 19 and an azide derivative provided the 1 /-/-1 ,2,3-triazol-4-yl substituted hydroxamic acid.
  • this reaction is conducted using copper(ll) sulfate and sodium ascorbate in DMF.
  • the 1 ,3- dipolar cycloaddition of HUG 19 and 2-fluoroethylazide (HUG 37) using copper(ll) sulfate and sodium ascorbate in DMF provided the /V-fluoroethyl-triazole substituted hydroxamic acid HUG 38 (Fig. 2).
  • the fluoro-PEG-triazole substituted hydroxamic acid HUG 30 is prepared in 53% yield using HUG 19 and the PEG derivative HUG 27 that was synthesized following literature procedures (Fig. 3).
  • the new class of triazole containing hydroxamic acid derivatives wherein A is para- substituted phenol derivative, is prepared by the reaction of commercially available tert- butylester of D-valine hydrochloride 1 and 4-methoxybenzenesulfonyl chloride in the presence of pyridine yielding the sulfonamide HUG 1.
  • /V-alkylation with a bromide derivative such as compound 4 in Fig. 4
  • acidic hydrolysis of the obtained ester such as compound 5 of Fig 4
  • gaseous hydrochloric acid in dichloromethane provided the carboxylic acid 6.
  • the carboxylic acid e. g. compound 6 of Fig.
  • hydroxamic acid ester e. g. compound 7 of Fig. 4
  • O-terf-butylhydroxylamine hydrochloride A/-((dimethylamino)- propyl)-/V'-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole hydrate (HOBT) and 4-methylmorpholine (NMM).
  • EDC O-terf-butylhydroxylamine hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • NMM 4-methylmorpholine
  • CrC 6 alkyl when used either alone or within other terms such as “haloalkyl” and “arylalkyl” or “heteroarylalkyl” embraces linear or branched radicals having C1-C6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, te/f-butyl, pentyl, isoamyl, hexyl.
  • alkylenyl embraces bridging divalent alkyl radicals such as methylenyl and ethylenyl.
  • C 2 -C 6 alkenyl when used alone or in combination, embraces linear or branched radicals having at least one carbon-carbon double bond in a moiety having between two and six carbon atoms.
  • alkenyl radicals include, without limitation, ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.
  • alkenyl encompasses radicals having "c/ ' s" and “trans” orientations, or alternatively, "E” and "Z” orientations.
  • CrC 6 alkoxy or "alkoxyl”, when used alone or in combination, embraces linear or branched oxygen-containing radicals each having alkyl portions of one or more carbon atoms.
  • examples of such radicals include methoxy, ethoxy, propoxy, butoxy and te/f-butoxy.
  • Alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals.
  • halo atoms such as fluoro, chloro or bromo
  • examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
  • arylalkyl is any C 7 -C 2 o group consisting of an alkyl and an aryl group as defined above.
  • halo when used alone or in combination, means halogens such as fluorine, chlorine, bromine or iodine atoms, preferably fluorine.
  • haloalkyl when used alone or in combination, embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. For example, this term includes monohaloalkyi, dihaloalkyi and polyhaloalkyi radicals such as a perhaloalkyl.
  • a monohaloalkyi radical for example, may have either an iodo, bromo, chloro or fluoro atom within the radical, preferably a fluoro atom.
  • Dihalo and polyhaloalkyi radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • CrC 6 haloalkyl embraces radicals having 1-6 carbon atoms and, for example, haloalkyl radicals having one to three carbon atoms.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, fluoroethyl, difluoroethyl, fluoropropyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • C 2 -C 6 haloalkenyl when used alone or in combination, embraces radicals wherein any one or more of the alkyl carbon atoms are substituted with halo as defined above, preferably a fluorine atom.
  • this term includes monohaloalkenyl, dihaloalkenyl and polyhaloalkenyl radicals.
  • a monohaloalkenyl radical for example, may have either an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkenyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • haloalkenyl radicals include fluorovinyl, fluoropropenyl, fluorobutenyl.
  • aryl when used alone or in combination, means a carbocyclic aromatic moiety containing one, two or even three rings wherein such rings may be attached together in a fused manner.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, dihydrobenzafuranyl, anthracenyl, indanyl, benzodioxazinyl.
  • the "aryl” group may be substituted, such as with 1 to 5 substituents including lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and C C 6 alkylamino.
  • heteroaryl means a fully unsaturated (aromatic) ring moiety formed from carbon atoms and having one or more heteroatoms selected from nitrogen, oxygen and sulfur.
  • the ring moiety or ring system may contain one ("monocyclic"), two ("bicyclic") or even three (“tricyclic") rings wherein such rings are attached together in a fused manner. Every ring of a “heteroaryl” ring system need not be aromatic, and the ring(s) fused thereto (to the heteroaromatic ring) may be partially or fully saturated and optionally include one or more heteroatoms selected from nitrogen, oxygen and sulfur.
  • unsaturated heteroaryl radicals including unsaturated 5- to 6- membered heteromonocyclyl groups, containing 1 to 4 nitrogen atoms, including for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.
  • unsaturated 7- to 10-membered heterobicyclic groups containing 1 to 4 nitrogen atoms including for example, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, aza-quinazolinyl; unsaturated 5- to 6- membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2- furyl, 3-furyl, benzofuryl, etc.; unsaturated 5 to 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, benzothienyl, etc.; unsaturated 5- to 6- membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, aza-quinazolinyl; unsaturated 5- to 6- member
  • aryl-alkyl is any C 7 -C 2 o group consisting of an alkyl and an aryl group as defined above, preferably a benzyl group.
  • hetero-aryl-alkyl is any C 7 -C 2 o group consisting of an alkyl and a heteroaryl group as defined above, preferably a picolyl group, more preferably a 3-picolyl group.
  • labeled with a 18 F means that one of the atoms or substituents of formula (I) comprises a 18 F either as an artificially enriched level of an atom intrinsic to the substructure, or as an additional essential feature that has been chemically attached via a functionality suitable for coupling said 18 F.
  • biocompatible carrier a fluid, especially a liquid, in which the imaging agent can be suspended or dissolved, such that the composition is physiologically tolerable, i. e. it can be administered to the mammalian body without toxicity or undue discomfort.
  • the biocompatible carrier is suitably an injectable carrier liquid such as sterile, pyrogen-free water for injection; an aqueous solution such as saline (which may advantageously be balanced so that the final product for injection is either isotonic or not hypotonic); an aqueous solution of one or more tonicity-adjusting substances (e. g. salts of plasma cations with biocompatible counterions), sugars (e. g. glucose or sucrose), sugar alcohols (e. g. sorbitol or mannitol), glycols (e. g. glycerol), or other non-ionic polyol materials (e. g. polyethyleneglycols, propylene glycols and the like).
  • injectable carrier liquid such as
  • biocompatible cation is meant a positively charged counterion which forms a salt with an ionised, negatively charged group, where said positively charged counterion is also non-toxic and hence suitable for administration to the mammalian body, especially the human body.
  • suitable biocompatible cations include the alkali metals sodium or potassium; the alkaline earth metals calcium and magnesium; and the ammonium ion.
  • Preferred biocompatible cations are sodium and potassium, most preferably sodium.
  • radioprotectant is meant a compound which inhibits degradation reactions, such as redox processes, by trapping highly-reactive free radicals, such as oxygen- containing free radicals arising from the radiolysis of water.
  • the radioprotectants of the present invention are suitably chosen from: ascorbic acid, para-aminobenzoic acid (i. e. 4- aminobenzoic acid), gentisic acid (i. e. 2, 5-dihydroxybenzoic acid) and salts thereof with a biocompatible cation as described above.
  • antimicrobial preservative an agent which inhibits the growth of potentially harmful micro-organisms such as bacteria, yeasts or moulds.
  • the antimicrobial preservative may also exhibit some bactericidal properties, depending on the dose.
  • the main role of the antimicrobial preservative(s) of the present invention is to inhibit the growth of any such microorganism in the pharmaceutical composition post-reconstitution, i. e. in the radioactive diagnostic product itself.
  • the antimicrobial preservative may, however, also optionally be used to inhibit the growth of potentially harmful microorganisms in one or more components of the kit of the present invention prior to reconstitution.
  • Suitable antimicrobial preservatives include: the parabens, i. e.
  • Preferred antimicrobial preservative (s) are the parabens.
  • pH-adjusting agent means a compound or mixture of compounds useful to ensure that the pH of the reconstituted kit is within acceptable limits (approximately pH 4.0 to 10.5) for human or mammalian administration.
  • Suitable such pH-adjusting agents include pharmaceutically acceptable buffers, such as tricine, phosphate or TRIS [i. e. tris (hydroxymethyl) aminomethane], and pharmaceutical acceptable bases such as sodium carbonate, sodium bicarbonate or mixtures thereof.
  • the pH-adjusting agent may optionally be provided in a separate vial or container, so that the user of the kit can adjust the pH as part of a multi-step procedure.
  • filler is meant a pharmaceutically acceptable bulking agent which may facilitate material handling during production and lyophilisation.
  • suitable fillers include inorganic salts such as sodium chloride, and water soluble sugars or sugar alcohols such as sucrose, maltose, mannitol or trehalose.
  • the melting points (mp) were determined in capillary tubes on a Stuart Scientific SMP3 capillary melting point apparatus. Column chromatography was performed on Merck silica gel 60 (0.040-0.063 mm). Thin layer chromatography (TLC) was carried out on silica gel-coated polyester backed TLC plates (Polygram, SIL G/UV254, Macherey-Nagel) using solvent mixtures of cyclohexane (CH), ethyl acetate (EA) and methanol (MeOH). Compounds were visualized by UV light (254 nm).
  • each new non-radioactive compound was ⁇ 90% assessed by analytical gradient reversed phase HPLC with a Nucleosil Eurosphere 100-5 C-18 column (250 mm x 4.6 mm) using solvent A (water/TFA 1000: 1 (v/v)) and solvent B (acetonitrile/TFA 1000: 1 (v/v)).
  • the HPLC system started with 90% A and 10% B with a linear gradient to 10% A and 90% B over 18 min, holding for 20 min and back to 90% A and 10% B in 2 min, with a flow rate of 1.5 ml/min.
  • HUG 15 is converted to the corresponding hydroxamic acid ester HUG 17 with O-tert- butylhydroxylamine hydrochloride, A/-((dimethylamino)-propyl)-A/'-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole hydrate (HOBT) and 4-methylmorpholine (NMM).
  • EDC O-tert- butylhydroxylamine hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • NMM 4-methylmorpholine
  • the compound was obtained as a white solid.
  • the hydroxamic acid ester HUG 17 (17.3 g, 43.67 mmol) was dissolved in dichloroethane (0.06 mmol/mL, 400 mL) containing 1.0 eq. of ethanol (1.3 mL). The solution was cooled to 0°C and hydrochloric acid gas was bubbled through it. TLC was used to monitor the reaction progress (EA). After complete conversion the solvent was removed under reduced pressure. Column chromatography on silica gel (CH/EA 1 :1) yielded HUG 19 as a white solid (7.4 g, 21.75 mmol, 50%), mp 149°C.
  • HUG 38 was obtained from HUG 19 (340 mg, 1 .0 mmol) and fluoroethylazide (HUG 37, 1 .0 mmol), prepared from fluoroethyltosylate and sodium azide following literature procedure, after 5 h stirring at room temperature. Column chromatographic purification with EA gave a white solid (1 16 mg, 0.31 mmol, 31 %), mp 125°C (decomposition).
  • HUG 30 was obtained from HUG 19 (340 mg, 1.0 mmol) and 2-(2-(2-(2-(2- azidoethoxy)ethoxy)ethoxy)ethylfluoride (HUG 27, 221 mg, 1.0 mmol, prepared following literature procedure), after 2 h stirring at room temperature.
  • Column chromatographic purification (silica gel, EA) gave a colorless, waxy oil (300 mg, 0.53 mmol, 53%).
  • Example 4 In vitro Assay for MMP-2, -8, -9 and -13 inhibitory activity
  • the synthetic fluorogenic substrate (7-methoxycoumarin-4-yl) acetyl pro-Leu-Gly-Leu-(3- (2,4-dinitrophenyl)-L-2,3-diamino-propionyl)-Ala-Arg-NH 2 (R & D Systems, Minneapolis, MN) was used to assay activated MMP-2, MMP-8, MMP-9 and MMP-13 as described previously [Huang et al, J. Biol. Chem. 272, 22086-22091 (1997) ].
  • the inhibitions of human active MMPs by the compounds were assayed by preincubating MMP-2, MMP-8, MMP-9 and MMP-13 (each at 2 nM) and inhibitor compounds at varying concentrations (1 pM - 1 mM) in Tris HCI (50 mM), pH 7.5, containing NaCI (0.2 M), CaCI 2 (5 mM), ZnS0 4 (20 ⁇ ) and 0.05% Brij 35 at 37 °C for 30 min. An aliquot of substrate (10 ⁇ of a 50 ⁇ solution) was then added to the preincubated MMP/inhibitor mixture (90 ⁇ _), and the fluorescence was determined at 37 °C by following product release with time.
  • the fluorescence changes were monitored using a Fusion Universal Microplate Analyzer (Packard Bioscience, Massachusetts, USA) with excitation and emission wavelengths of 330 and 390 nm, respectively. Reaction rates were measured from the initial 10 min of the reaction profile where product release was linear with time and plotted as a function of inhibitor dose. From the resulting inhibition curves, the IC 50 values for each inhibitor were calculated by non-linear regression analysis, performed using the Grace 5.1.8 software (Linux).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne le domaine des agents thérapeutiques et diagnostiques et plus spécifiquement des composés de formule (I) qui sont des inhibiteurs de métalloprotéinases de matrice (MMP) et sont utiles dans le traitement de maladies associées à celles-ci telles que des maladies cardiovasculaires, des maladies inflammatoires et des maladies malignes. Un mode de réalisation de l'invention est un composé de formule (I) marqué avec un atome de 18-fluor ayant une activité inhibitrice de métalloprotéinase de matrice adaptée pour l'imagerie diagnostique. La présente invention concerne en outre une composition pharmaceutique comprenant les inhibiteurs de métalloprotéinases de matrice (MMP) de l'invention ou les composés marqués correspondants utiles en tant qu'agents d'imagerie diagnostique de l'invention sous une forme adaptée pour administration à des mammifères. L'invention concerne en outre des intermédiaires dans la synthèse des inhibiteurs de métalloprotéinases de matrice (MMP) de l'invention et des agents d'imagerie diagnostique de l'invention.
PCT/EP2011/062211 2011-06-08 2011-07-18 Composés avec activité inhibitrice de métalloprotéinase de matrice WO2013010573A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/EP2011/062211 WO2013010573A1 (fr) 2011-07-18 2011-07-18 Composés avec activité inhibitrice de métalloprotéinase de matrice
US13/849,646 US9023318B2 (en) 2011-06-08 2013-03-25 Compounds with matrix-metalloproteinase inhibitory activity and imaging agents thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2011/062211 WO2013010573A1 (fr) 2011-07-18 2011-07-18 Composés avec activité inhibitrice de métalloprotéinase de matrice

Publications (1)

Publication Number Publication Date
WO2013010573A1 true WO2013010573A1 (fr) 2013-01-24

Family

ID=44628920

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2011/062211 WO2013010573A1 (fr) 2011-06-08 2011-07-18 Composés avec activité inhibitrice de métalloprotéinase de matrice

Country Status (1)

Country Link
WO (1) WO2013010573A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2644601A1 (fr) * 2012-03-28 2013-10-02 Westfälische Wilhelms-Universität Münster Composés à activité inhibitrice de matrice-métalloprotéinase et agents d'imagerie de ceux-ci
WO2017201111A1 (fr) * 2016-05-19 2017-11-23 Bristol-Myers Squibb Company Immunomodulateurs pour l'imagerie tep
WO2017210335A1 (fr) * 2016-06-01 2017-12-07 Bristol-Myers Squibb Company Méthodes d'imagerie faisant intervenir des substances biologiques radiomarquées au 18f
US10406251B2 (en) 2014-11-25 2019-09-10 Bristol-Myers Squibb Company PD-L1 binding polypeptides for imaging
US10736976B2 (en) 2016-12-01 2020-08-11 Regeneron Pharmaceuticals, Inc. Radiolabeled anti-PD-L1 antibodies for immuno-PET imaging
US10988507B2 (en) 2016-11-07 2021-04-27 Bristol-Myers Squibb Company Immunomodulators
US11066445B2 (en) 2017-06-23 2021-07-20 Bristol-Myers Squibb Company Immunomodulators acting as antagonists of PD-1
US11229713B2 (en) 2014-11-25 2022-01-25 Bristol-Myers Squibb Company Methods and compositions for 18F-radiolabeling of biologics
US11344639B2 (en) 2016-06-01 2022-05-31 Bristol-Myers Squibb Company PET imaging with PD-L1 binding polypeptides
US11358988B2 (en) 2014-11-14 2022-06-14 Bristol-Myers Squibb Company Immunomodulators
US11492375B2 (en) 2017-10-03 2022-11-08 Bristol-Myers Squibb Company Cyclic peptide immunomodulators

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996000214A1 (fr) * 1994-06-24 1996-01-04 Ciba-Geigy Ag Acides hydroxamiques substitues par arylsulfonamino utilises comme inhibiteurs de metalloproteinases matricielles
WO2001060416A2 (fr) 2000-02-15 2001-08-23 Bristol-Myers Squibb Pharma Company Inhibiteurs de la metalloprotease matricielle
WO2004069365A1 (fr) * 2003-02-10 2004-08-19 Ge Healthcare Limited Agents d'imagerie diagnostiques a activite inhibitrice de mmp

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996000214A1 (fr) * 1994-06-24 1996-01-04 Ciba-Geigy Ag Acides hydroxamiques substitues par arylsulfonamino utilises comme inhibiteurs de metalloproteinases matricielles
WO2001060416A2 (fr) 2000-02-15 2001-08-23 Bristol-Myers Squibb Pharma Company Inhibiteurs de la metalloprotease matricielle
WO2004069365A1 (fr) * 2003-02-10 2004-08-19 Ge Healthcare Limited Agents d'imagerie diagnostiques a activite inhibitrice de mmp

Non-Patent Citations (22)

* Cited by examiner, † Cited by third party
Title
ANDREAS FAUST ET AL: "Synthesis and evaluation of a novel hydroxamate based fluorescent photoprobe for imaging of matrix metalloproteinases", BIOCONJUGATE CHEMISTRY, ACS, WASHINGTON, DC, US, vol. 20, 20 May 2009 (2009-05-20), pages 904 - 912, XP002615481, ISSN: 1043-1802, [retrieved on 20090417], DOI: 10.1021/BC8004478 *
BACKSTROM ET AL., J NEUROCHEM, vol. 58, 1992, pages 983 - 992
GEORGE, EXP OPIN INVEST DRUGS, vol. 9, 2000, pages 993 - 1007
HERMAN ET AL., CIRCULATION, vol. 104, 2001, pages 1899 - 1904
HEROUY, INT J MOL MED, vol. 7, 2001, pages 3 - 12
HUANG ET AL., J. BIOL. CHEM., vol. 272, 1997, pages 22086 - 22091
JACSON ET AL., INFLAMM RES, vol. 50, 2001, pages 183 - 186
KURPAKUS-WHEATER ET AL., PROG HISTO CYTOCHEM, vol. 36, 2001, pages 179 - 259
LI ET AL., AM J PATHOL, vol. 148, 1996, pages 121 - 128
LIM ET AL., J NEUROCHEM, vol. 67, 1996, pages 251 - 259
LUKES ET AL., MOL NEUROBIOL, vol. 19, 1999, pages 267 - 284
MASSOVA ET AL., FASEB J, vol. 12, 1998, pages 1075 - 95
MUN-BRYCE ET AL., BRAIN RES, vol. 933, 2002, pages 42 - 49
NAGASE, WOESSNER, J BIOL CHEM, vol. 274, 1999, pages 21491 - 4
PETERSON ET AL., DRUG DEV RES, vol. 55, 2002, pages 29 - 44
SEGURA-VALDEZ ET AL., CHEST, vol. 117, 2000, pages 684 - 694
SPINALE, CIRC RES, vol. 90, 2002, pages 520 - 530
VIHINEN ET AL., INT J CANCER, vol. 99, 2002, pages 57 - 186
WAGNER S ET AL: "Novel fluorinated derivatives of the broad-spectrum MMP inhibitors N-hydroxy-2(R)-[[(4-methoxyphenyl)sulfonyl](benzyl)- and (3-picolyl)-amino]-3- methyl-butanamide as potential tools for the molecular imaging of activated MMPs with PET", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 50, no. 23, 15 November 2007 (2007-11-15), pages 5752 - 5764, XP002497359, ISSN: 0022-2623, [retrieved on 20071023], DOI: 10.1021/JM0708533 *
WHITTAKER ET AL., CHEM REV, vol. 99, 1999, pages 2735 - 76
XIONG Y ET AL: "The discovery of a potent and selective lethal factor inhibitor for adjunct therapy of anthrax infection", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 16, no. 4, 15 February 2006 (2006-02-15), pages 964 - 968, XP025106420, ISSN: 0960-894X, [retrieved on 20060215], DOI: 10.1016/J.BMCL.2005.10.088 *
ZHENG ET AL., NUCL MED BIOL, vol. 29, 2002, pages 761 - 770

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2644601A1 (fr) * 2012-03-28 2013-10-02 Westfälische Wilhelms-Universität Münster Composés à activité inhibitrice de matrice-métalloprotéinase et agents d'imagerie de ceux-ci
US11952434B2 (en) 2014-11-14 2024-04-09 Bristol-Myers Squibb Company Immunomodulators
US11358988B2 (en) 2014-11-14 2022-06-14 Bristol-Myers Squibb Company Immunomodulators
US11229713B2 (en) 2014-11-25 2022-01-25 Bristol-Myers Squibb Company Methods and compositions for 18F-radiolabeling of biologics
US11173219B2 (en) 2014-11-25 2021-11-16 Bristol-Myers Squibb Company PD-L1 binding polypeptides for imaging
US10406251B2 (en) 2014-11-25 2019-09-10 Bristol-Myers Squibb Company PD-L1 binding polypeptides for imaging
EA038019B1 (ru) * 2016-05-19 2021-06-23 Бристол-Маерс Сквибб Компани Иммуномодуляторы для пэт-визуализации
KR102378288B1 (ko) 2016-05-19 2022-03-23 브리스톨-마이어스 스큅 컴퍼니 Pet-영상화 면역조정제
WO2017201111A1 (fr) * 2016-05-19 2017-11-23 Bristol-Myers Squibb Company Immunomodulateurs pour l'imagerie tep
EP3827849A1 (fr) * 2016-05-19 2021-06-02 Bristol-Myers Squibb Company Immunomodulateurs pour l'imagerie tep
CN109414514B (zh) * 2016-05-19 2022-03-11 百时美施贵宝公司 Pet成像免疫调节剂
KR20190009330A (ko) * 2016-05-19 2019-01-28 브리스톨-마이어스 스큅 컴퍼니 Pet-영상화 면역조정제
US11103605B2 (en) 2016-05-19 2021-08-31 Bristol-Myers Squibb Company PET-imaging immunomodulators
CN109414514A (zh) * 2016-05-19 2019-03-01 百时美施贵宝公司 Pet成像免疫调节剂
US11806409B2 (en) 2016-06-01 2023-11-07 Bristol-Myers Squibb Company Imaging methods using 18F-radiolabeled biologics
US11344639B2 (en) 2016-06-01 2022-05-31 Bristol-Myers Squibb Company PET imaging with PD-L1 binding polypeptides
WO2017210335A1 (fr) * 2016-06-01 2017-12-07 Bristol-Myers Squibb Company Méthodes d'imagerie faisant intervenir des substances biologiques radiomarquées au 18f
US10994033B2 (en) 2016-06-01 2021-05-04 Bristol-Myers Squibb Company Imaging methods using 18F-radiolabeled biologics
US11511000B2 (en) 2016-06-01 2022-11-29 Bristol-Myers Squibb Company Imaging methods using 18F-radiolabeled biologics
US10988507B2 (en) 2016-11-07 2021-04-27 Bristol-Myers Squibb Company Immunomodulators
US10736976B2 (en) 2016-12-01 2020-08-11 Regeneron Pharmaceuticals, Inc. Radiolabeled anti-PD-L1 antibodies for immuno-PET imaging
US11066445B2 (en) 2017-06-23 2021-07-20 Bristol-Myers Squibb Company Immunomodulators acting as antagonists of PD-1
US11492375B2 (en) 2017-10-03 2022-11-08 Bristol-Myers Squibb Company Cyclic peptide immunomodulators

Similar Documents

Publication Publication Date Title
WO2013010573A1 (fr) Composés avec activité inhibitrice de métalloprotéinase de matrice
JP2019522679A (ja) ニコチニルアルコールエーテル誘導体、調製及び医薬組成物及び使用
WO2010147666A1 (fr) Composés utiles en tant que modulateurs de l'anhydrase carbonique et leurs utilisations
BRPI0912878A2 (pt) derivados de indazóis substituídos por fenila e benzodioxinila
WO2015060365A1 (fr) Sonde d'imagerie de la protéine tau
US9862678B2 (en) 3,4-diaminobenzenesulfonamide derivatives for inhibiting cell death
US8231858B2 (en) Diagnostic imaging agents with MMP inhibitory activity
US7754188B2 (en) Radiolabeled cannabinoid-1 receptor modulators
JP2012511526A (ja) アミロイドベータを検出するためのベンゾチアゾールアミド
JP2012502070A (ja) アミロイド斑結合及び造影のためのピペラジン誘導体及びそれらの使用
ES2871079T3 (es) Acidos hidroxámicos N-sustituidos con grupos salientes a base de carbono como donantes eficaces de HNO y usos de los mismos
JP6087386B2 (ja) 造影剤としてのｎ−アルコキシアミド抱合体
EP2520573A1 (fr) Composés avec activité inhibitrice de métalloprotéinase de matrice
US20120282180A1 (en) Compounds with Matrix-Metalloproteinase Inhibitory Activity and Imaging Agents Thereof
KR101920902B1 (ko) 심혈관 질환 조기진단 pet 조영용 화합물 및 그의 용도
JP7008299B2 (ja) 神経難病の画像診断薬及び体外診断薬
JP2012510958A (ja) 放射性同位体で標識されたリジン及びオルニチン誘導体、それらの使用及び製造方法
EP3889133A1 (fr) Antagoniste du récepteur des ?strogènes
JP2009067762A (ja) 神経難病の画像診断薬
JP2016079108A (ja) 放射性ヨウ素標識スチリル置換芳香族ヘテロ環化合物
EP0661273B1 (fr) Dérivés d'indane et procédés pour leur préparation
Konken et al. Influence of N-arylsulfonamido d-valine N-substituents on the selectivity and potency of matrix metalloproteinase inhibitors
TW201302736A (zh) 組織蛋白酶（Ｃａｔｈｅｐｓｉｎ）Ｃ抑制劑
WO2020214767A2 (fr) Composés et procédés pour imager l'activité immune
JP2021102593A (ja) タウを画像化する新規化合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11735859

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11735859

Country of ref document: EP

Kind code of ref document: A1