US20100233086A1 - Compounds for use in imaging, diagnosing and/or treatment of diseases of the central nervous system or of tumors - Google Patents

Compounds for use in imaging, diagnosing and/or treatment of diseases of the central nervous system or of tumors Download PDF

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US20100233086A1
US20100233086A1 US12/739,479 US73947908A US2010233086A1 US 20100233086 A1 US20100233086 A1 US 20100233086A1 US 73947908 A US73947908 A US 73947908A US 2010233086 A1 US2010233086 A1 US 2010233086A1
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phenyl
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Lutz Lehmann
Andrea Thiele
Tobias Heinrich
Thomas Brumby
Christer Halldin
Balazs Gulyas
Sangram Nag
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Bayer Pharma AG
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Bayer Schering Pharma AG
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
    • C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
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    • A—HUMAN NECESSITIES
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    • C07—ORGANIC CHEMISTRY
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    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • This invention relates to novel compounds suitable for labelling or already labelled by 8 F, methods of preparing such a compound, compositions comprising such compounds, kits comprising such compounds or compositions and uses of such compounds, compositions or kits for diagnostic imaging by positron emission tomography (PET).
  • PET positron emission tomography
  • Molecular imaging has the potential to detect disease progression or therapeutic effectiveness earlier than most conventional methods in the fields of oncology, neurology and cardiology.
  • optical imaging MRI, SPECT and PET
  • PET is of particular interest for drug development because of its high sensitivity and ability to provide quantitative and kinetic data.
  • positron emitting isotopes include carbon, iodine, nitrogen, and oxygen. These isotopes can replace their non-radioactive counterparts in target compounds to produce tracers that function biologically and are chemically identical to the original molecules for PET imaging.
  • 18 F is the most convenient labelling isotope due to its relatively long half life (110 min) which permits the preparation of diagnostic tracers and subsequent study of biochemical processes.
  • its low ⁇ + energy (634 keV) is also advantageous.
  • nucleophilic aromatic and aliphatic [ 18 F]-fluoro-fluorination reaction is of great importance for [ 18 F]-fluoro-labelled radiopharmaceuticals which are used as in vivo imaging agents targeting and visualizing diseases, e.g. solid tumours or diseases of brain.
  • a very important technical goal in using [ 18 F]-fluoro-labelled radiopharmaceuticals is the quick preparation and administration of the radioactive compound due to the fact that the 18 F isotopes have a short half-life of about only 110 minutes.
  • MAO Monoamine Oxidases
  • Deprenyl (1) (Biochem Pharmacol. 1972, 5, 393-408) and clorgyline (2) are potent inhibitor of mono amine oxidase inducing irreversible inhibition of the enzymes.
  • the L-isomer of deprenyl (3) is a more potent inhibitor than the D-isomer.
  • MAO B inhibitors are for example used to increase DOPA levels in CNS (Progr. Drug Res. 1992, 38, 171-297) and they have been used in clinical trials for the treatment of Alzheimer's disease based on the fact that an increased level of MAO B is involved in astrocytes accociated with Alzheimer plaques (Neuroscience, 1994, 62, 15-30).
  • Fluorinated MAO inhibitors have been synthesized and biochemically evaluated (review: Kirk et al. in press). F-18 and C-11 labeled MAO inhibitors have been studied in vivo (Journal of the Neurological Science, (2007), 255, 17-22; review: Methods 2002, 27, 263-277). F-18 labeled deprenyl and deprenyl analogues 4-5 have also been reported (int. J. Radiat. Appl. instrument. Part A, Applied Radiat isotopes, 1991, 42, 121, J. Med. Chem. 1990, 33, 2015-2019 and Nucl. Med. Biol. 1990, 26, 111-116, respectively).
  • compounds of this invention are useful for the imaging of multiple sclerosis, Alzheimer's disease, frontotemporal dementia, dementia with Levy bodies, leukoencephalopathy, epilepsy, neuropathic pain, amyotrophic lateral sclerosis, Parkinson's Disease, encephalopathies, brain tumors, depression, drug abuse, chronic inflammatory intestinal diseases, atheroma, atherosclerosis, arthritis, rheumatoid arthritis, pharmacologically triggered inflammation, systemic inflammation of unclear origin.
  • compounds of this invention are useful for the imaging of multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's Disease, leukoencephalopathy, encephalopathies, epilepsy, brain tumors, drug abuse, chronic inflammatory intestinal diseases, atheroma, rheumatoid arthritis, pharmacologically triggered inflammation and systemic inflammation of unclear origin.
  • W is —CH 2 —C ⁇ CH.
  • A is selected from the group comprising substituted or unsubstituted phenyl, substituted or unsubstituted furanyl, (C 1 -C 4 )alkyl, G 4 -(C 3 -C 4 ), alkynyl, G 4 -(C 1 -C 3 )alkoxy, (G 4 -(C 1 -C 3 )alkyl)phenyl, (G 4 -(C 1 -C 3 )alkoxy)phenyl, wherein, preferably, A is selected from the group comprising phenyl, furanyl, (G 4 -(C 1 -C 3 )alkyl)phenyl, (G 4 -(C 1 -C 3 )alkoxy)phenyl, preferably, substituted phenyl, hydroxy-phenyl, halo-phenyl, methoxy-phenyl, dimethoxy-phenyl, trifluormethyl-phenyl, and ((C 1 -C
  • G 1 , G 2 , G 3 and G 4 in formula Ia, and G 3 and G 4 in formula Ib are independently and individually, at each occurrence, selected from the group comprising hydrogen, (C 1 -C 4 )alkyl, preferably methyl, L, and —(C 1 -C 4 )alkyl-L,
  • G 1 -G 4 in formula Ia and exactly one of G 3 -G 4 in formula Ib are selected from L and —(C 1 -C 4 )alkyl-L, wherein, preferably G 1 , G 2 , G 3 and G 4 in formula Ia, and G 3 and G 4 in formula Ib are independently and individually, at each occurrence, selected from the group comprising hydrogen, methyl, L, and —(C 1 -C 2 )alkyl-L,
  • G 1 -G 4 in formula Ia and exactly one of G 3 -G 4 in formula Ib are selected from L and —(C 1 -C 2 )alkyl-L and wherein, more preferably, G 1 , G 2 , G 3 and G 4 in formula Ia, and G 3 and G 4 in formula Ib are independently and individually, at each occurrence, selected from the group comprising hydrogen, methyl, L, and -methyl-L,
  • L is a leaving group selected from the group comprising halo, in particular chloro, bromo, iodo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, nona-fluorobutylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, (2,4,6-tri-isopropyl-phenyl)sulfonyloxy, (2,4,6-trimethyl-phenyl)sulfonyloxy, (4-tertbutyl-phenyl)sulfonyloxy, and (4-methoxy-phenyl)sulfonyloxy.
  • halo in particular chloro, bromo, iodo, mesyloxy, tos
  • L is selected from the group comprising chloro, bromo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, and (2,4,6-tri-isopropyl-phenyl)sulfonyloxy.
  • L is not F, in particular not 18 F and not 19 F; these are the aforementioned “precursor compounds”.
  • L is 18 F, or the mesyloxy-group, shown in any of the specific precursor compounds above, is replaced by 18 F.
  • 18 F-labelled compounds having formula Ia or Ib are the 18 F-labelled compounds having formula Ia or Ib.
  • L is 19 F, or the mesyloxy-group, shown in any of the specific precursor compounds above, is replaced by 19 F.
  • aryl refers to an aromatic system
  • this also includes the possibility that such aromatic system is substituted by one or more appropriate substituents, such as OH, halo, alkyl, NH 2 , NO 2 , SO 3 etc.
  • aryl refers to monocyclic or bicyclic aromatic groups containing from 6 to 12 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl, which themselves can be substituted with one, two or three substituents independently and individually selected from the group comprising halo, nitro, (C 1 -C 6 )carbonyl, cyano, nitrile, hydroxyl, trifluoromethyl, (C 1 -C 6 )sulfonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy and (C 1 -C 6 )sulfanyl, As outlined above such “aryl” may additionally be substituted by one or several substituents.
  • heteroaryl refers to groups having 5 to 14 ring atoms; 6, 10 or 14 ⁇ (pi) electrons shared in a cyclic array; and containing carbon atoms (which can be substituted with halo, nitro, (C 1 -C 6 )carbonyl, cyano, nitrile, trifluormethyl, (C 1 -C 6 )sulfonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )sulfanyl) and 1, 2, 3 or 4 oxygen, nitrogen or sulfur heteroatoms (where examples of heteroaryl groups are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, furanyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl,
  • Heteroaryl can be substituted with one, two or three substituents independently and individually selected from the group comprising halo, nitro, (C 1 -C 6 )carbonyl, cyano, nitrile, hydroxyl, trifluounethyl, (C 1 -C 6 )sulfonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy and (C 1 -C 6 )sulfanyl.
  • substituents independently and individually selected from the group comprising halo, nitro, (C 1 -C 6 )carbonyl, cyano, nitrile, hydroxyl, trifluounethyl, (C 1 -C 6 )sulfonyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy and (C 1 -C 6 )sulfanyl.
  • substituents independently and individually selected from the group comprising halo
  • alkyl refers to a straight chain or branched chain alkyl group with 1 to 10 carbon atoms such as, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.
  • Alkyl groups can also be substituted, such as by halogen atoms, hydroxyl groups, C 1 -C 4 alkoxy groups or C 6 -C 12 aryl groups (which, intern, can also be substituted, such as by 1 to 3 halogen atoms). More preferably alkyl is C 1 -C 10 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl.
  • alkynyl is similarly defined as for alkyl, but contain at least one carbon-carbon double or triple bond, respectively, more preferably C 3 -C 4 alkynyl.
  • alkoxy or alkyl oxy refers to alkyl groups respectively linked by an oxygen atom, with the alkyl portion being as defined above.
  • substituted it is meant to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group, provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a pharmaceutical composition.
  • the substituent groups may be selected from halogen atoms, hydroxyl groups, nitro, (C 1 -C 6 )carbonyl, cyano, nitrile, trifluoromethyl, (C 1 -C 6 )sulfonyl, (C 1 -C 6 ) alkyl, (C 1 -C 6 )alkoxy and (C 1 -C 6 )sulfanyl.
  • Preferred examples of 18 F-labelled compounds of formulae Ia or Ib are:
  • the 18 F-labelled compounds of formula Ia and Ib, and the 19 F standard reference compounds of formulae Ia and Ib are provided as a medicament or pharmaceutical.
  • the invention relates also to the use of the 18 F-labelled compounds of formula Ia and Ib, and of the 19 F standard reference compounds of formulae Ia and Ib I for the manufacture of a medicament or a pharmaceutical for treatment.
  • CNS diseases include but are not limited to inflammatory and autoimmune, allergic, infectious and toxin-triggered and ischemia-triggered diseases, pharmacologically triggered inflammation with pathophysiological relevance, neuroinflammatory, and neurodegenerative diseases.
  • the CNS disease is selected from multiple sclerosis, Alzheimer's disease, frontotemporal dementia, dementia with Levy bodies, leukoencephalopathy, epilepsy, neuropathic pain, amyotrophic lateral sclerosis, Parkinson's Disease, encephalopathies, brain tumors, depression, drug abuse, chronic inflammatory intestinal diseases, atheroma, atherosclerosis, arthritis, rheumatoid arthritis, pharmacologically triggered inflammation, systemic inflammation of unclear origin.
  • the present invention is also directed to a method of treatment of a disease of the central nervous system, as defined above, comprising the step of introducing into a patient a suitable quantity of a compound of formulae Ia or Ib, preferably an 18 F-labelled compound of formulae Ia or Ib, or of a 19 F standard reference compound of formulae Ia or lb.
  • 18 F-labelled compounds of formulae Ia or Ib are provided as diagnostic imaging agent or imaging agent, preferably as imaging agent for PET applications.
  • the invention relates also to the use of 18 F-labelled compounds of formulae Ia or Ib for the manufacture of an imaging agent.
  • CNS diseases include but are not limited to inflammatory and autoimmune, allergic, infectious and toxin-triggered and ischemia-triggered diseases, pharmacologically triggered inflammation with pathophysiological relevance, neuroinflammatory, neurodegenerative diseases.
  • the CNS disease is selected from multiple sclerosis, Alzheimer's disease, frontotemporal dementia, dementia with Levy bodies, leukoencephalopathy, epilepsy, neuropathic pain, amyotrophic lateral sclerosis, Parkinson's Disease, encephalopathies, brain tumors, depression, drug abuse, chronic inflammatory intestinal diseases, atheroma, atherosclerosis, arthritis, rheumatoid arthritis, pharmacologically triggered inflammation, systemic inflammation of unclear origin.
  • the present invention is also directed to a method of imaging comprising the step of introducing into a patient a detectable quantity of an 18 F-labelled compound of formulae Ia or Ib and imaging said patient.
  • compositions comprising a compound according to formulae Ia or Ib, preferably 18 F-labelled compounds of formulae Ia or Ib, or 19 F standard reference compounds of formulae Ia or Ib or a pharmaceutically acceptable salt of an inorganic or organic acid thereof, a hydrate, a complex, an ester, an amide, a solvate or a prodrug thereof.
  • the pharmaceutical composition comprises a physiologically acceptable carrier, diluent, adjuvant or excipient.
  • compositions according to the present invention comprise a compound of formula Ia or Ib that is a pharmaceutical acceptable hydrate, complex, ester, amide, solvate or a prodrug thereof.
  • organic acid refers to mineral acids, including, but not being limited to: acids such as carbonic, nitric, phosphoric, hydrochloric, perchloric or sulphuric acid or the acidic salts thereof such as potassium hydrogen sulphate, or to appropriate organic acids which include, but are not limited to: acids such as aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulphonic acids, examples of which are formic, acetic, trifluoracetic, propionic, succinic, glycolic, gluconic, lactic, malic, fumaric, pyruvic, benzoic, anthranilic, mesylic, fumaric, salicylic, phenylacetic, mandelic, embonic, methansulfonic, ethanesulfonic, benzenesulfonic, phantothenic
  • a radiopharmaceutical composition comprising an 18 F-labelled compound of formulae Ia or Ib or a pharmaceutically acceptable salt of an inorganic or organic acid thereof, a hydrate, a complex, an ester, an amide, a solvate or a prodrug thereof.
  • the pharmaceutical composition comprises a physiologically acceptable carrier, diluent, adjuvant or excipient.
  • the compounds according to the present invention may be administered intravenously in any pharmaceutically acceptable carrier, e.g. conventional medium such as an aqueous saline medium, or in blood plasma medium, as a pharmaceutical composition for intravenous injection.
  • a pharmaceutically acceptable carrier e.g. conventional medium such as an aqueous saline medium, or in blood plasma medium
  • Such medium may also contain conventional pharmaceutical materials such as, for example, pharmaceutically acceptable salts to adjust the osmotic pressure, buffers, preservatives and the like.
  • pharmaceutically acceptable carrier e.g. conventional medium such as an aqueous saline medium, or in blood plasma medium
  • Such medium may also contain conventional pharmaceutical materials such as, for example, pharmaceutically acceptable salts to adjust the osmotic pressure, buffers, preservatives and the like.
  • the preferred media are normal saline solution and plasma.
  • Suitable pharmaceutical acceptable carriers are known to someone skilled in the art. In this regard reference can be made to e.g. Remington's Practice of Pharmacy, 13th ed. and in J. of. Pharmaceutical Science & Technology, Vol. 52, No. 5, September-October, p. 238-311, included herein by reference.
  • concentration of the compounds of formulae Ia and Ib, preferably of the 18 F-labelled compound according to the present invention and the pharmaceutically acceptable carrier, for example, in an aqueous medium varies with the particular field of use. A sufficient amount is present in the pharmaceutically acceptable carrier when satisfactory visualization of the imaging target (e.g. a tumor) is achievable.
  • the compounds according to the present invention in particular the 18 F-radioactively labeled compounds according to the present invention, i.e. the 18 F-labelled compounds of formulae Ia or Ib, provided by the invention may be administered intravenously in any pharmaceutically acceptable carrier, e.g., conventional medium such as an aqueous saline medium, or in blood plasma medium, as a pharmaceutical composition for intravenous injection.
  • a pharmaceutically acceptable carrier e.g., conventional medium such as an aqueous saline medium, or in blood plasma medium
  • Such medium may also contain conventional pharmaceutical materials such as, for example, pharmaceutically acceptable salts to adjust the osmotic pressure, buffers, preservatives and the like.
  • the preferred media are normal saline and plasma.
  • Suitable pharmaceutical acceptable carriers are known to the person skilled in the art. In this regard reference can be made to e.g., Remington's Practice of Pharmacy, 11th ed. and in J. of Pharmaceutical Science & Technology, Vol. 52, No.
  • the radiolabeled compounds having general chemical Formula II either as a neutral composition or as a salt with a pharmaceutically acceptable counter-ion are administered in a single unit injectable dose.
  • the unit dose to be administered for a diagnostic agent has a radioactivity of about 0.1 mCi to about 100 mCi, preferably 1 mCi to 20 mCi.
  • the radioactivity of the therapeutic unit dose is about 10 mCi to 700 mCi, preferably 50 mCi to 400 mCi.
  • the solution to be injected at unit dosage is from about 0.01 ml to about 30 ml.
  • imaging of the organ or disease in vivo can take place in a matter of a few minutes. However, imaging takes place, if desired, in hours or even longer, after injecting into patients. In most instances, a sufficient amount of the administered dose will accumulate in the area to be imaged within about 0.1 of an hour to permit the taking of scintigraphic images. Any conventional method of scintigraphic imaging for diagnostic purposes can be utilized in accordance with this invention.
  • prodrug means any covalently bonded compound, which releases the active parent pharmaceutical according to formulae Ia or Ib, preferably the 18 F labelled compound of formulae Ia or Ib.
  • prodrug means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds of formula (I).
  • the reference by Goodman and Gilman The Pharmaco-logical Basis of Therapeutics, 8 ed, McGraw-HiM, Int. Ed.
  • Prodrugs of a compound of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • Prodrugs of the compounds of the present invention include those compounds wherein for instance a hydroxy group, such as the hydroxy group on the asymmetric carbon atom, or an amino group is bonded to any group that, when the prodrug is administered to a patient, cleaves to form a free hydroxyl or free amino, respectively.
  • prodrugs are described for instance in WO 99/33795, WO 99/33815, WO 99/33793 and WO 99/33792 all incorporated herein by reference.
  • Prodrugs are characterized by excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo.
  • the present invention is directed to compounds of Formula Ia or Ib, wherein L is 19 F, with the proviso that such compound contains exactly one 19 F-atom which is attached to an sp 3 -hybridised carbon atom.
  • sp 3 -hybridized carbon atom refers to a carbon atom which is linked, beside the above mentioned [F-19]-fluoro atom, to three further atoms via a chemical single-bond, so that this carbon atom has got four binding partners in total.
  • Preferred compounds of Formulae Ia or Ib, with L being 19 F are:
  • a chiral center or another form of an isomeric center is present in a compound according to the present invention, all forms of such isomer, including enantiomers and diastereoisomers, are intended to be covered herein.
  • Compounds containing a chiral center may be used as racemic mixture or as an enantiomericaily enriched mixture or the racemic mixture may be separated using well-known techniques and an individual enantiomer maybe used alone. In cases in which compounds have unsaturated carbon-carbon bonds double bonds, both the cis-isomer and trans-isomers are within the scope of this invention.
  • compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
  • the present invention includes all of the hydrates, solvates, complexes, and prodrugs of the compounds of the invention.
  • Prodrugs are any covalently bonded compounds, which releases the active parent pharmaceutical according to formulae Ia or Ib.
  • halo refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).
  • a seventh aspect of the invention is directed to a method for obtaining compounds of Formula Ia or Ib, wherein L is 18 F or 19 F.
  • a precursor compound according to formula Ia or Ib, wherein L is a leaving group as defined above is reacted with an F-fluorinating agent.
  • said F-fluorinating agent is a compound comprising F-anions, preferably a compound selected from the group comprising 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane K F, i.e. crownether salt Kryptofix KF, KF, HF, KH F 2 , CsF, NaF and tetraalkylammonium salts of F, such as [ 18 F]-tetrabutylammonium fluoride, and wherein F ⁇ 18 F or 19 F.
  • F-anions preferably a compound selected from the group comprising 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane K F, i.e. crownether salt Kryptofix KF, KF, HF, KH F 2 , CsF, NaF and
  • the first embodiment of a radiolabeling method for obtaining an 18 F-labelled compound of formula Ia or Ib comprises the step of
  • radiolabelling a molecule, as used herein, usually refers to the introduction of an 18 F-atom into the molecule.
  • the fluorination agent is defined as above, wherein F ⁇ 18 F.
  • a method of synthesis of compounds of Formula Ia and Ib, wherein L is 18 F or 19 F comprises the steps:
  • F is 18 F or 19 F
  • a is an integer from 0 to 4, preferably from 0 to 2, more preferably from 0 to 1,
  • B is a leaving group, preferably halo, in particular chloro, bromo, iodo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, nona-fluorobutylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, (2,4,6-tri-isopropyl-phenyl)sulfonyloxy, (2,4,6-trimethyl-phenyl)sulfonyloxy, (4-tertbutyl-phenyl)sulfonyloxy, and (4-methoxy-phenyl)sulfonyloxy,
  • W 2 is W as defined in any of claims 1 - 2 , and above,
  • a 2 is selected from the group comprising R 12 —O-aryl, R 12 —O-heteroaryl, aryl, heteroaryl, such as furanyl, (C 1 -C 10 )alkyl, (C 2 -C 4 )alkynyl, (C 1 -C 4 )alkoxy, ((C 1 -C 4 )alkoxy)aryl, ((C 1 -C 4 )alkyl)aryl,
  • R 9 and R 10 are independently and individually, at each occurrence, selected from the group comprising (C 1 -C 6 )alkyl and hydrogen,
  • R 11 is selected from the group comprising (C 1 -C 6 ) alkyl and R 12 ,
  • R 12 is hydrogen
  • d is an integer from 0 to 4, preferably from 0-2, more preferably from 0-1, and wherein said F-fluorinating agent is as defined above,
  • B is selected from the group comprising iodo, bromo, chloro, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, and nona-fluorobutylsulfonyloxy.
  • a 2 is selected from the group comprising R 12 —O-phenyl, phenyl, furanyl, (C 1 -C 4 )alkyl, (C 3 -C 4 )alkynyl, (C 1 -C 3 ) alkoxy and substituted phenyl, more preferably from the group comprising R 12 —O-phenyl, phenyl, furanyl, ((C 1 -C 3 )alkoxy)phenyl, hydroxyphenyl, halo-phenyl, methoxy-phenyl, dimethoxy-phenyl, trifluormethyl-phenyl and ((C 1 -C 4 )alkyl)phenyl, even more preferably from the group comprising R 12 —O-phenyl, phenyl, furanyl, hydroxyphenyl, fluoro-phenyl, methoxy-phenyl, and methyl-phenyl.
  • R 9 and R 10 are independently and individually, at each occurrence, selected from the group comprising (C 1 -C 4 )alkyl and hydrogen, preferably from the group comprising methyl and hydrogen.
  • R 11 is selected from the group comprising (C 1 -C 4 )alkyl and R 12 , preferably from the group comprising methyl and R 12 .
  • the second embodiment of a radiolabeling method for obtaining an 18 F-labelled compound of formula Ia or Ib comprises the steps of
  • a is an integer from 0 to 4, preferably a is an integer of from 0 to 2 and more preferably a is an integer of from 0 to 1;
  • a 2 is selected from the group comprising
  • a 2 is selected from the group comprising
  • W 2 is selected from the group comprising
  • U 3 and U 4 are independently and individually selected from the group comprising
  • R 9 and R 10 are independently selected from the group
  • R 11 is selected from the group comprising
  • d is an integer from 0-4, in a preferred embodiment m is an integer from 0-2, in a more preferred embodiment m is an integer from 0-1;
  • R 12 is hydrogen
  • the fluorination agent is a fluorine radioactive isotope derivative. More preferably the fluorine radioactive isotope derivative is a 18 F derivative. More preferably, the 18 F derivative is 4,7,13,16,21,24-Hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane K 18 F (crownether salt Kryptofix K 18 F), K 18 F, H 18 F, KH 18 F 2 , Cs“F, Na 18 F or tetraalkylammonium salt of 18 F (e.g.[F-18] tetrabutylammonium fluoride). More preferably, the fluorination agent is K 18 F, H 18 F, or KH 18 F 2 , most preferably K 18 F ( 18 F fluoride anion).
  • the radiofluorination reaction can be carried out, for example in a typical reaction vessel (e.g. Wheaton vial) which is known to someone skilled in the art or in a microreactor.
  • the reaction can be heated by typical methods, e.g. oil bath, heating block or microwave.
  • the radiofluorination reactions are carried out in dimethylformamide with potassium carbonate as base and “kryptofix” as crown-ether.
  • solvents can be used which are well known to experts. These possible conditions include, but are not limited to: dimethylsulfoxid and acetonitril as solvent and tetraalkyl ammonium and tertraalkyl phosphonium carbonate as base. Water and/or alcohol can be involved in such a reaction as co-solvent.
  • the radiofluorination reactions are conducted for one to 60 minutes. Preferred reaction times are five to 50 minutes. Further preferred reaction times are 10 to 40 min. This and other conditions for such radiofluorination are known to experts (Coenen, Fluorine-18 Labeling Methods: Features and Possibilities of Basic Reactions, (2006), in: Schubiger P. A., Friebe M., Lehmann L., (eds), PET-Chemistry—The Driving Force in Molecular Imaging. Springer, Berlin Heidelberg, pp. 15-50).
  • the radiofluorination can be carried out in a “hot-cell” and/or by use of a module (eview: Krasikowa, Synthesis Modules and Automation in F-18 labeling (2006), in: Schubiger P. A., Friebe M., Lehmann L., (eds), PET-Chemistry—The Driving Force in Molecular Imaging. Springer, Berlin Heidelberg, pp. 289-316) which allows an automated or semi-automated synthesis.
  • the invention provides for a composition
  • a composition comprising a compound according to the present invention and a pharmaceutically acceptable carrier or diluent.
  • said compound is an 18 F-labelled compound.
  • said compound is a 19 F-labelled compound.
  • said compound is a precursor compound.
  • the invention also provides for a compound according to the present invention, preferably an 18 F- or 19 F-labelled compound according the present invention, or a composition according to the present invention for use as a pharmaceutical or diagnostic agent or imaging agent.
  • the invention also provides for the use of a compound according to the present invention, preferably an 18F- or 19 F-labelled compound according to the present invention, or a composition according to the present invention for the manufacture of a medicament for the treatment and/or diagnosis and/or imaging of diseases of the central nervous system (CNS).
  • a compound according to the present invention preferably an 18F- or 19 F-labelled compound according to the present invention, or a composition according to the present invention for the manufacture of a medicament for the treatment and/or diagnosis and/or imaging of diseases of the central nervous system (CNS).
  • CNS central nervous system
  • the invention also provides for an 18 F-labelled compound of formulae Ia or Ib or a composition containing such compound for use as a diagnostic agent or imaging agent, in particular for diseases of the central nervous system.
  • the invention also provides for a kit comprising a sealed vial containing a predetermined quantity of a compound
  • the invention also provides for a method for detecting the presence of monoamine oxidase in a patient's body, preferably for imaging a disease of the central nervous system in a patient, comprising:
  • PET positron emission tomography
  • the invention also provides for a method of treatment of a disease of the central nervous system comprising the step of introducing into a patient a suitable quantity of a compound according to the present invention, preferably of an 18 F- or 19 F-labelled compound according to the present invention.
  • a fluoro atom (F-19 or F-18) or a leaving group (compare G 3 ) is attached via a linker to the central nitrogen atom:
  • a series of different suited ⁇ -substituted 1-(alkyl)alkyl amines (see scheme 1) are commercially available. They serve as starting material for the alkylation with e.g. propargyl bromide.
  • ⁇ -substituted 2-bromo-alkanes (A2) can serve as electrophile in a chemical reaction with propargyl amine or cyclobutyl amine.
  • Compound A3 can be alkylated with [F-18]- ⁇ -fluoro-alkyl-bromide (A6), which is generated from the corresponding triflate (A7), towards compound A4.
  • Compound A3 can also be alkylated with a ⁇ -functionalized building block towards A5, so that a later leaving group (V) of A5 is then converted to the [F-18] fluoro atom of compound A4.
  • Amino alcohols (see B1, scheme 3) of which many examples are known in literature or which are commercially available can be alkylated with e.g. propargyl bromide towards compound B2.
  • the introduction of a leaving group (mesyloxy shown, but also other leaving groups possible) can be generated by standard methods to obtain compound B3.
  • the leaving group of compound B3 is substituted by using a fluorinating agent to obtain compound B4.
  • Compound 9 (compare J. Organomet. Chem.; 317; 1986; 93-104) is N-alkylated with propargyl bromide. This reaction can be carried out in dimethylformamide and potassium carbonate (e.g. Org. Lett.; 8; 14; 2006; 2945-2947) in dimethylformamide to obtain alcohol 10.
  • bases including but not limited to caesium or sodium carbonate, sodium hydroxid, potassium hydroxid, lithium hydroxid, tetra-alkyl ammonium hydroxid, sodium hydrid and other solvents, including but not limited to acetone, tetrahydrofuran, eventually mixed with water, are possible.
  • the resulting alcohol 10 is then converted to compound 11 by use of e.g. mesylchloride, triethylamin and dichloromethane.
  • Other possible solvents and bases including but not limited to, are dichloroethane, ethers, ethyl acetate, diisopropyl ethyl amine, DABCO ect..
  • the mesylate 11 serves just as intermediate which forms an corresponding “in-situ”aziridine.
  • This derivative (not shown) is then opened by the chloro-anion-nucleophile which is present in solution leading to a suited chloro-precursor molecules (compare scheme 11, compound 42 and 43).
  • mesylation reagents might be also considered, like mesyl anhydride (compare e.g. Tetrahedron; 63; 25; 2007; 5470-5476) to generate the mesylate as stable derivative.
  • chloro precursor compounds 42 and 43 are also suited to generate F-18 labelled molecules (compare scheme 11 compound 13 and 39.
  • the subsequent radiofluorination reaction of compound 11 towards compound 13 is carried out in dimethylformamide with potassium carbonate as base and “kryptofix” as crown-ether.
  • solvents can be used which are well known to experts.
  • These possible conditions include, but are not limited to: dimethylsulfoxid and acetonitril as solvent and tetraalkyl ammonium, tertraalkyl phosphonium carbonate or caesium carbonate as base. Water and/or alcohol can be involved in such a reaction as co-solvent.
  • the radiofluorination reaction is conducted at 105° C. for ca. 10 min.
  • the mesylate 11 can also be converted to the non-radioactive fluoride 12.
  • Suited reagents for this reaction are potassium fluoride and “kryptofix” in acetonitrile.
  • the reaction mixture is optionally heated by microwave technique.
  • compound 12 can also be obtained from compound 10 by treatment with DAST in dichloromethane. This procedure is known to experts in the field (e.g. J. Med. Chem.; 49; 8; 2006; 2496-2511).
  • C1 can be alkylated with e.g. propargyl bromide towards compound C2.
  • the introduction of a leaving group (mesyloxy shown, but also other leaving groups possible) can be generated by standard methods to obtain compound C3.
  • the leaving group of compound C3 is substituted by using a fluorinating agent to obtain compound C4.
  • Alcohol 15 can be converted to the mesylate 16 by standard methods which comprise e.g. mesylchloride in dichloromethane.and triethyl amine as base.
  • Triflate 16 serves as precursor for the radiofluorination.
  • the conversion towards compound 17 is carried out using potassium fluoride and “kryptofix” in acetonitrile.
  • Compound 18 serves as standard reference compound for the described radiofluorination reaction.
  • the mesylate 16 can also be converted to the non-radioactive fluoride 16. Suited reagents for this reaction are potassium fluoride and “kryptofix” in acetonitrile.
  • the reaction mixture is optionally heated by microwave technique.
  • compound 16 can also be obtained from compound 15 by treatment with DAST in dichloromethane. This procedure is known to experts in the field (e.g. J. Med. Chem.; 49; 8; 2006; 2496-2511).
  • Amino alcohols see D1, scheme 7 (hydroxyl functionality can optionally be protected; “spacer” according to substituent A in formula Ia) of which many examples are known in literature or which are commercially available can be alkylated with e.g. propargyl bromide towards compound D2.
  • the introduction of a leaving group (mesyloxy shown, but also other leaving groups possible) can be generated by standard methods to obtain compound D3.
  • the leaving group of compound D3 is substituted by using a fluorinating agent to obtain compound D4.
  • methyl ester 19 (Pharmazie (1997), 52, 12, 937) is reduced to the corresponding alcohol by use of sodium boro hydride (e.g. Tetrahedron; 63; 9; 2007; 2000-2008).
  • the amino protecting group is subsequently removed by dissolving the intermediate in MeOH(aq) and alkali (sodium or potassium) carbonate (e.g J. Org. Chem., 53, (1988), 3108).
  • the amino group of compound 20 is alkylated with propargyl bromide in DMF and potassium carbonate (e.g. Org. Lett.; 8; 14; 2006; 2945-2947) to obtain compound 21.
  • the alcohol 21 is converted in the corresponding mesylate 22 which is fluorinated towards 23 and 24 by using fluorinating agents.
  • Compound 25 (Chem. Europ. J.; 11; 19; 2005; 5777-5785) is alkylated with sodium hydride as base in DMF by use of propargyl bromide (compare e.g. J. Org. Chem.; 71; 13; (2006); 5023-5026).
  • Boc-protected amine 26 is deprotected with trifluoroacetic acid or other acids to obtain compound 27.
  • This secondary amine (27) is alkylated with [F-18]-fluoro ethyl bromide (compare A6 scheme 1) obtaining compound (32).
  • Compound 27 can also be alkylated by 2-(2-tetrahydropyranyloxy)-ethyl bromide (Aldrich) and potassium carbonate in DMF.
  • the protection group (THP) is removed using acid (e.g. tosyl acid in dichloromethane) and then alcohol (29) is converted to mesylate 30 using mesylchloride and triethylamine in dichloromethane.
  • Compound 30 is either converted in compound 31 or compound 32 by F-19 and F-18 fluorinating reagents.
  • compound 29 can be converted into compound 31 by using DAST in dichloromethane.
  • the alcohol 35 is converted into the corresponding triflate 36 by use of trifluoromethylsulfonylchloride and triethyl amine as base.
  • the triflate 36 is converted into [F-18]-fluoro derivative 37 using typical [F-18] fluorinating agents.
  • Alcohol 35 can also be converted into fluoride 38 using nonafluorobutylsulfonyl fluoride in DBU (Tetrahedron Letters, Vol. 36, No. 15, pp. 2611-2614, 1995).
  • the aim of the present invention was to find an improved F-18 labelled compound in comparison to the current state of the art that can be used to detect reactive astrocytes by means of PET Imaging targeting monoamine oxidase B.
  • [ 18 F]compound 13 surprisingly showed an improved metabolic stability when compared to [ 11 C]Deprenyl (compare compound 3) and compound 5 ([ 18 F]FHMP; Nuclear Medicine Biology, Vol. 26, pp 111-116, (1999).
  • Binding of the [ 18 F]compound 13 was investigated on human brain sections from patients with Alzheimer's disease and normal controls using a standard protocol
  • the tissue was cut at a 18 ⁇ m thickness in a Cryostat (Leica, Germany), thaw mounted onto glass slides and kept at ⁇ 20° C. for at least 48 hours before use. Thereafter, the slides were removed and brought to room temperature.
  • the sections were washed in 25 mM HEPES buffer for 5 min, incubated with 10 Bq/ ⁇ l [ 18 F]compound 13 in 25 mM HEPES/0.1% BSA for 60 min at room temperature in a humidified chamber and washed again 5 times for 2 min each in 25 mM HEPES/0.1% BSA.
  • FIGS. 1 and 2 The sections were dipped two times into ice cold distilled water, dried at room temperature and exposed to PhosphorImanger plates (FUJI BAS 5000) over night. For detection of the specificity of the signals an excess (10 ⁇ M) of Deprenyl, Pargylin (both for MAO B) and Clorgyline (for MAO A), respectively, was used. After exposure, the sections were immunohistochemically stained using a standard protocol with an anti-GFAP antibody to detect reactive astrocytes. Amyloid B plaques were detected with BAY 949172 (Rowe CC et al. Lancet Neutol 2008; 7: 129-135) using the binding protocol as described above. The specificity of [ 18 F]compound 13 for MAO B is presented in FIGS. 1 and 2 . FIGS. 3 and 4 demonstrate the relation of the radioactive signals to the underlying pathology, i.e. amyloid B plaques ( FIG. 3 ) and reactive astrocytes ( FIG. 4 ), respectively.
  • the [ 18 F]compound 13 has been tested in a cynomolgus monkey. 155 MBq [ 11 C]Deprenyl and 178 MBq [ 18 F]compound 13, respectively, have been injected into the same monkey. Time activity curves have been monitored by calculating the standard uptake values (SUV) as [ 18 F]compound 13 compared to the [ 11 C]compound. Plasma radioactivity profiles have been monitored over time. As can be seen from the comparison of the curves for the mother compound in FIGS. 8 and 9 the plasma radioactivity for [ 18 F]compound 13 was about double of that observed for [ 11 C]Deprenyl at the 30 and 45 min time points. In addition, metabolites occurring in plasma over time have been monitored ( FIGS.
  • Compound 10 can be also converted to the mixture of fluorides 12 and 41 whereas compound 41 is a rearranged reaction product (scheme 11). Fluorides 12 and 41 can be separated on a column (compare TLC FIG. 15 ). The conversion of alcohol 10 with mesylchloride leads under certain circumstances to the mixture of chlorides 42 and 43 which is a suited pair of precursor compounds being radiofluorinated towards F-18 labelled compound 13 and 39. F-18 labelled products 13 and 39 are separable on HPLC column (compare FIG. 11 and FIG. 12 ) and can be investigated separately.
  • Alcohol 10 can be also converted to tosylate 44 using tosylanhydride. This derivative is also suited precursor for the radiolabeling towards compound 13.
  • Derivative 15 can be converted by using DAST towards compound 18 (compare scheme 12).
  • the conversion of compound 15 towards chloride 45 is realized using mesylchloride.
  • Chloride 45 is a suited precursor molecule for the radiofluorination towards compound 46 (compare FIG. 14 ).
  • the diastereoisomer of compound 18 is compound 47 which is synthesized from (1R,2R)pseudoehedrine 48 in tow steps via alcohol 49 (see scheme 13).
  • the conversion of alcohol 49 which is synthesized from (1R,2R)pseudoehedrine by alkylation with propargyl bromide towards fluoride 47 is realized by use of DAST.
  • Compound 49 can also be converted to precursor molecule 50 by use of mesylchloride.
  • Compound 8 is the product of the radiofluorination of chloride 52. This precursor chloride is derived from alcohol 51 by use of mesylchloride. The cold reference compound (53) of F-18 labelled fluoride 8 is also shown in scheme 14 and can be synthesized from alcohol 51 using DAST.
  • Amino alcohol 54 (commercially available) is converted to the sulfamidate 55 by use of SO 2 Cl 2 (compare Tetrahedron Assymetry (1990), 1, 12, 877-880).
  • the Mitsonobu reaction using prop-2-yn-1-ol triphenylphosphin and, dipropan-2-yl (E)-diazene-1,2-dicarboxylate leads to the precursor compound 56 which then can be converted by [ 18 F]fluorination with tetrabutylammonium hydrodide and subsequent deprotection of the sufate moiety (compare F-19 analogue 57) towards compound 58.
  • a similar approach is possible to obtain the corresponding F-19 derivative 59 (compare: Posakony et al. Synthesis (2002), 6, 766-770).
  • A is selected from the group comprising substituted or unsubstituted phenyl, substituted or unsubstituted furanyl, in particular furan-2-yl, furan-3-yl, (C 1 -C 4 )alkyl, G 4 -(C 3 -C 4 ), alkynyl, G 4 -(C 1 -C 3 )alkoxy, (G 4 -(C 1 -C 3 )alkyl)phenyl, (G 4 -(C 1 -C 3 )alkoxy)phenyl.
  • A is selected from the group comprising substituted or unsubstituted phenyl, substituted or unsubstituted furanyl, (G 4 -(C 1 -C 3 )alkyl)phenyl, (G 4 -(C 1 -C 3 )alkoxy)phenyl, hydroxy-phenyl, halo-phenyl, methoxy-phenyl, dimethoxy-phenyl, trifluormethyl-phenyl, and ((C 1 -C 4 )alkyl)-phenyl.
  • A is selected from the group comprising substituted or unsubstituted phenyl, (G 4 -(C 1 -C 3 )alkoxy)phenyl, hydroxyl-phenyl, fluorophenyl, methoxyphenyl, and methylphenyl.
  • G 1 , G 2 , G 3 and G 4 in formula Ia, and G 3 and G 4 in formula Ib are independently and individually, at each occurrence, selected from the group comprising hydrogen, (C 1 -C 4 )alkyl, preferably methyl, L, and —(C 1 -C 4 )alkyl-L,
  • G 1 , G 2 , G 3 and G 4 in formula Ia, and G 3 and G 4 in formula Ib are independently and individually, at each occurrence, selected from the group comprising hydrogen, methyl, L, and —(C 1 -C 2 )alkyl-L,
  • G 1 , G 2 , G 3 and G 4 in formula Ia, and G 3 and G 4 in formula Ib are independently and individually, at each occurrence, selected from the group comprising hydrogen, methyl, L, and -methyl-L,
  • L is a leaving group selected from the group comprising halo, in particular chloro, bromo, iodo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, nona-fluorobutylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, (2,4,6-tri-isopropyl-phenyl)sulfonyloxy, (2,4,6-trimethyl-phenyl)sulfonyloxy, (4-tertbutyl-phenyl)sulfonyloxy, and (4-methoxy-phenyl)sulfonyloxy.
  • halo in particular chloro, bromo, iodo, mesyloxy, tos
  • L is selected from the group comprising chloro, bromo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, and (2,4,6-tri-isopropyl-phenyl)sulfonyloxy.
  • said F-fluorinating agent is a compound comprising F-anions, preferably a compound selected from the group comprising 4, 7, 13, 16, 21, 24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane K F, i.e. crownether salt Kryptofix KF, KF, HF, KH F 2 , CsF, NaF and tetraalkylammonium salts of F, such as [ 18 F]tetrabutylammonium fluoride, and wherein F ⁇ 18 F or 19 F.
  • F-fluorinating agent is a compound comprising F-anions, preferably a compound selected from the group comprising 4, 7, 13, 16, 21, 24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane K F, i.e. crownether salt Kryptofix KF, KF, HF, KH F 2 , CsF, Na
  • F is 18 F or 19 F
  • a is an integer from 0 to 4, preferably from 0 to 2, more preferably from 0 to 1,
  • B is a leaving group, preferably halo, in particular chloro, bromo, iodo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, nona-fluorobutylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, (2,4,6-tri-isopropyl-phenyl)sulfonyloxy, (2,4,6-trimethyl-phenyl)sulfonyloxy, (4-tertbutyl-phenyl)sulfonyloxy, and (4-methoxy-phenyl)sulfonyloxy,
  • a 2 is selected from the group comprising R 12 —O-aryl, R 12 —O-heteroaryl, aryl, heteroaryl, such as furanyl, (C 1 -C 10 )alkyl, (C 2 -C 4 )alkynyl, (C 1 -C 4 )alkoxy, ((C 1 -C 4 )alkoxy)aryl, ((C 1 -C 4 )alkyl)aryl,
  • R 9 and R 10 are independently and individually, at each occurrence, selected from the group comprising (C 1 -C 6 )alkyl and hydrogen,
  • R 11 is selected from the group comprising (C 1 -C 6 ) alkyl and R 12 ,
  • R 12 is hydrogen
  • d is an integer from 0 to 4, preferably from 0-2, more preferably from 0-1, and wherein said F-fluorinating agent is as defined in count 16,
  • B is selected from the group comprising iodo, bromo, chloro, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, and nona-fluorobutylsulfonyloxy.
  • a 2 is selected from the group comprising R 12 —O-phenyl, phenyl, furanyl, (C 1 -C 4 )alkyl, (C 3 -C 4 )alkynyl, (C 1 -C 3 )alkoxy and substituted phenyl, more preferably from the group comprising R 12 —O-phenyl, phenyl, furanyl, ((C 1 -C 3 )alkoxy)phenyl, hydroxyphenyl, halo-phenyl, methoxy-phenyl, dimethoxy-phenyl, trifluormethyl-phenyl and ((C 1 -C 4 )alkyl)phenyl, even more preferably from the group comprising R 12 —O-phenyl, phenyl, furanyl, hydroxyphenyl, fluoro-phenyl, methoxy-phenyl, and methyl-phenyl.
  • R 9 and R 10 are independently and individually, at each occurrence, selected from the group comprising (C 1 -C 4 )alkyl and hydrogen, preferably from the group comprising methyl and hydrogen.
  • composition comprising a compound according to any of counts 1-14 and a pharmaceutically acceptable carrier or diluent.
  • composition according to count 22 wherein said compound is a compound according to count 13.
  • composition according to count 22 wherein said compound is a compound according to count 14.
  • composition according to count 22 wherein said compound is a compound according to count 12.
  • a compound according to any of counts 1-14 preferably a compound according to count 13 or 14, or a composition according to any of counts 22, 23, 24 or 25 for use as a pharmaceutical or diagnostic agent or imaging agent.
  • kits comprising a sealed vial containing a predetermined quantity of a compound according to
  • a method for detecting the presence of monoamine oxidase in a patient's body, preferably for imaging a disease of the central nervous system in a patient comprising:
  • PET positron emission tomography
  • a method of treatment of a disease of the central nervous system comprising the step of introducing into a patient a suitable quantity of a compound according to any of counts 1-14, preferably of a compound according to count 13 or 14.
  • FIG. 1 Autoradiography using [ 18 F]compound 13 on human brain slices from four brains from patients with diagnosis of Alzheimer's disease.
  • A Autoradiographic signal after exposure on the PhosphorImager plate. Note the black dots in the tissue slices corresponding to areas with amyloid ⁇ plaques (see examples in FIG. 3 ).
  • B and (C) the signals could be blocked with deprenyl and pargylin, respectively, showing the specificity of [ 18 F]compound 13 for MAO B.
  • FIG. 2 Autoradiography using [ 18 F]compound 13 on human brain slices from four brains from patients with diagnosis of Alzheimer's disease.
  • A Autoradiographic signal after exposure on the PhosphorImager plate. Note the black dots in the tissue slices corresponding to areas with amyloid ⁇ plaques (see examples in FIG. 3 ).
  • B the signals could be completely blocked with deprenyl but not with clorgyline (MAO A inhibitor) as seen in (C), showing the specificity of [ 18 F]compound 13 for MAO B.
  • MAO A inhibitor clorgyline
  • FIG. 3 Tissue samples from three brains from patients with Alzheimer's disease which were processed for [ 18 F]compound 13 autoradiography and subsequently for binding with the amyloid detecting substance BAY 949172.
  • A) and (B) the square marked in the brain slice is shown in higher magnification in (a) and (b) demonstrates the underlying amyloid B pathology.
  • C two squares, (a) and (b), are marked in the brain slice and are shown in higher magnification in (a′) and (b′).
  • (c) and (d) represent the amyloid ⁇ pathology in the regions shown in higher magnification. Note that the signal density and intensity corresponds with the amyloid ⁇ plaque load.
  • the square (b) is devoid of specific signals in the autoradiography did also not show BAY 949172 binding (d).
  • FIG. 4 The correspondence of the autoradiographic signal to reactive astrocytes is demonstrated.
  • A On a human brain slice from a patient with AD [ 18 F]compound 13 binding is shown.
  • B The square marked in A is shown in higher magnification. In this area immunoreactivity for GFAP, showing reactive astrocytes, is demonstrated in (C).
  • FIG. 5 Distribution of [ 18 F]compound 13 detected via a gamma-detector is shown in a time frame of 4 hours for brain and blood.
  • FIG. 6 The time activity curve for [ 11 C]Deprenyl (C-11 labelled compound 3) in the btrain of the cynomolgus monkey expressed in standard uptake values (SUV %) over a time of 120 min is shown.
  • FIG. 7 The time activity curve [ 18 F]compound 13 in the btrain of the cynomolgus monkey expressed in standard uptake values (SUV %) over a time of 120 min is shown.
  • FIG. 8 Demonstration of in vivo metabolism of [ 11 C]Deprenyl (C-11 labelled compound 3) in the cynomolgus monkey.
  • the mother compound [ 11 C]Deprenyl (C-11 labelled compound 3) as well as metabolites a and b are shown.
  • FIG. 9 Demonstration of in vivo metabolism of [ 18 F]compound 13 in the cynomolgus monkey.
  • FIG. 10 Images of three planes (transversal, coronal and saggital) of the brain of the same cynomolgus monkey after the injection of (A) [ 11 C]Deprenyl (C-11 labelled compound 3) and (B) [ 18 F]compound 13.
  • C Time activity curves for (a) [ 11 C]Deprenyl (C-11 labelled compound 3) and (b) [ 18 F]compound 13 in the striatum and cerebellum of the monkey brain.
  • FIG. 13 Analytical chromatogram of compound 8 on reverse phase HPLC on a ⁇ -Bondapak C-18 column (300 ⁇ 3.9 mm, 10 ⁇ m; waters instruments) and MeCN—H 3 PO 4 (0.01 M) (15:85 v/v) was used as the eluting solvent at a flow rate of 2 mL/min.
  • FIG. 14 Analytical chromatogram of compound 40 on reverse phase HPLC on a ⁇ -Bondapak C-18 column (300 ⁇ 3.9 mm, 10 ⁇ m; waters instruments) and MeCN—H 3 PO 4 (0.01 M) (15:85 v/v) was used as the eluting solvent at a flow rate of 2 mL/min.
  • FIG. 15 TLC analysis (silica gel, molybdato phosphoric acid diving bath; ethylacetate:hexane: 1:2) of fluorination reaction starting from compound 10 towards compound 12 and 41.
  • e column fraction containing compound 12 and 41.
  • the crude reaction mixture is analyzed using analytical HPLC: ACE3-C18 50 mm ⁇ 4.6 mm; solvent gradient: start 5% acetonitril-95% acetonitril in water in 7 min., flow: 2 ml/min.
  • the desired F-18 labeled product is confirmed by co-injection with the corresponding non-radioactive F-19 fluoro-standard on the analytical HPLC.
  • the crude product (50-400 MBq) is purified by preparative HPLC column: The desired product is obtained (15-200 MBq) as reconfirmed by co-injection with the non-radioactive F-19 fluoro standard on the analytical HPLC.
  • F-18 labelled compounds 13, 39, 8 and 40 were also purified by reverse phase HPLC on a ⁇ -Bondapak C-18 column (300 ⁇ 7.8 mm, 10 ⁇ m; waters instruments) and MeCN—H 3 PO 4 (0.01 M) (15:85 v/v) was used as the eluting solvent at a flow rate of 4 mL/min (compare FIGS. 11 , 12 , 13 and 14 ).
  • the radiochemical purity was >99% for all three compounds.
  • the collected HPLC fraction was diluted with 40 ml water and immobilized on a Sep-Pak Plus C18 cartridge (Waters), which was washed with 5 ml water and eluted with 1 ml ethanol to deliver the product in a radiochemical purity >99% as well.
  • the stability and radiochemical yield was analyzed with HPLC and TLC on silica gel. TLC plate was scanned with an AR-2000 Imaging Scanner and analyzed with Winscan 2.2 software. The incorporation yield of the fluorination reaction varied from 40% to 70%. The radiochemical purity was more than 99% for all three radioligands. Radioligands were found to be stable in PBS buffer solution for the duration of experiments. Radiochemical purity was >99% at 3 h after formulation with PBS which was determined by HPLC and TLC. Alternatively, compound 13 and 39 were also separated via an preparative HPLC column and method (comp. FIG. 11 ): ACE 5-C18-HL 250 mm ⁇ 10 mm, Advanced Chromatography Technologies; Cat.
  • the collected HPLC fraction was diluted with 40 ml water and immobilized on a Sep-Pak Plus C18 cartridge (Waters), which was washed with 5 ml water and eluted with 1 ml ethanol to deliver compound 13 in a radiochemical purity >99%.
  • the desired product 13 was characterized by co-injection with the non-radioactive F-19 fluoro standard 12 on the analytical HPLC.
  • [ 18 F]fluoride was transferred to a Vacutainer that had previously been treated with tetrabutylammonium hydroxide (2 micro liter).
  • the [ 18 O]H 2 O was removed by azeotropic distillation with acetonitrile (3_times 0.75 mL), N 2 , and heat (compare Nucl. Med. Biol. 2003, 30, 397-404).
  • Precursor (3.0 micro mol) was added to the vessel and dissolved in DMSO (400 micro liter). The resulting mixture was heated by microwave irradiation (3 times for 20 sec).
  • the crude mixture was passed over a silica pipet column (50 mg) with CH 3 CN (3 mL), and the volatile organics were then removed using reduced pressure.
  • the vial containing a crude mixture of [ 18 F]product was dissolved in CH 3 CN (500 micro L) and was treated with 4N sulfuric acid (0.5 ml). The resulting mixture was heated by microwave irradiation (3 times for 20 sec). The desired product was separated via an preparative HPLC column and method: ACE 5-C18-HL 250 mm ⁇ 10 mm, Advanced Chromatography Technologies; Cat. No.: ACE 321-2510; isocratic, 35% acetonitrile in 0.1% trifluoroacetic acid, flow: 4 ml/min).
  • the collected HPLC fraction was diluted with 40m1 water and immobilized on a Sep-Pak Plus C18 cartridge (Waters), which was washed with 5 ml water and eluted with 1 ml ethanol to deliver compound 13 in a radiochemical purity >99%.
  • the desired product 13 was characterized by co-injection with the non-radioactive F-19 fluoro standard 12 on the analytical HPLC.
  • NMR spectra were recorded on 400 MHz, 600 MHz ( 1 H), 100 MHz and 151 MHz ( 13 C) NMR instruments.
  • 1 H NMR spectra were referenced internally on CDCl 3 ( ⁇ 1 H 7.26) and 13 C NMR spectra were referenced internally on CDCl 3 ( ⁇ 13 C 77.20).
  • Liquid chromatographic analysis (LC) was performed with a Merck-Hitachi gradient pump and a Merck-Hitachi, L-4000 variable wavelength UV-detector.
  • a ⁇ -Bondapak C-18 column 300 ⁇ 7.8 mm, 10 ⁇ m; waters instruments) was used with a flow of 2 ml/min.
  • LC-MS was performed using a Waters Quattra-Tof Premier micro mass coupled with Waters Acquity UPLC instrument.
  • the ionization mode used was electro spray positive ionization (ESI+).
  • ESI+ electro spray positive ionization
  • Analytical TLC was carried out on 0.25 mm silica gel plates.
  • Compound 1f is prepared from compound 1e by general procedure B.
  • the desired product 1e is obtained with 254 MBq starting from 1.12 GBq F-18 fluoride (decay corrected).
  • the solvent was removed under reduced pressure to obtain the crude product as light yellow oil.
  • the crude product was purified by silica-gel column chromatography (hexane/ether 3:1) and analyzed by NMR, HPLC and LC-MS. The final product was obtained as mixture of 1h and 1i.
  • the crude products 1f and 1m were obtained according to genaral procedure C.
  • the products 1f and 1m were separated according to general procedure C and investigated separately after HPLC separation (compare HPLC chromatograms FIG. 11 and FIG. 12 ).
  • Compound 2a is synthesized from (4R,5S)-(+)-4-Methyl-5-phenyl-2-oxazolidinone (Aldrich) according to general procedure F using 15 mmol (1.79 g) propargyl bromide (Aldrich). Compound 2a is obtained in 76% yield (7.6 mmol, 1.61 g).
  • Compound 2b is synthesized by general procedure Q from starting material 2a in 89% yield (0.91 g, 4.5 mmol).
  • Compound 2d is prepared from compound 2c by general procedure B.
  • the desired product 2d is obtained with 198 MBq starting from 1.09 GBq F-18 fluoride (decay corrected).
  • the desired product (2g) was obtained from 2f according to the general procedure C.
  • Compound 3a is synthesized according to general procedure F in 4 mmol scale from starting material 4-furan-2-ylmethyl-oxazolidin-2-one (J. Am. Chem. Soc.; 125; 42; 2003; 12694-12695).
  • the desired compound 3a is obtained in 60% yield (2.4 mmol) using 6 mmol propagyl bromide as alkylating agent.
  • Compound 3b is synthesized by general procedure Q (half scale) from starting material 3a in 70% yield (338 mg, 1.75 mmol).
  • Compound 3e is synthesized by general procedure A from starting material 3c with F-18 fluoride 0.96 GBq. The desired compound is obtained (124 MBq).
  • Compound 4a is synthesized by general procedure F from starting material (S)-4-Benzyl-oxazolidin-2-one (Aldrich) in 72% yield (1.58 g, 7.2 mmol).
  • Compound 4c is synthesized by general procedure K from 4b p-bromo-benzene sulfonyl chloride in 47% yield (1.58g, 1.41 mmol).
  • Compound 5a is synthesized by general procedure H from (S)-( ⁇ )-4-(4-hydroxybenzyl)-2-oxazolidinone (Tetrahedron; EN; 57; 39; 2001; 8313-8322) and 2-bromo-ethyl-methoxy-methyl-ether (Aldrich) at 10-fold scale in 77% yield (15.4 mmol, 4.33 g).
  • Compound 5b is synthesized by general procedure F from compound 5a in 65% yield (6.5 mmol, 2.07 g).
  • Compound 5h is synthesized by general procedure B from compound 5f (isolated 210 MBq from 1.41 GBq).
  • Compound 6c is synthesized by general procedure G from compound 6a and [F-18]-2-fluoro-ethyl-bromide (Bioorg. Med. Chem.; 13; 20; 2005; 5779-5786).
  • the desired product 6c is obtained with 178 MBq starting from 1.98 GBq F-18 fluoride (decay corrected).
  • N-[(2R)-1-phenylpropan-2-yl]prop-2-yn-1-aminium chloride (Sigma 100 mg, 0.578 mmol) in dry DMF (2 mL) was added sodium hydride (48.0 mg, 2 mmol).
  • the reaction mixture was stirred at room temperature for 30 min, after which 1-bromo-2-fluoro ethane (0.85 mg, 0.603 mmol) was added.
  • the reaction mixture was stirred over night, diluted with water (10 mL) and extracted with CH 2 Cl 2 (3 ⁇ 15 mL). The organic phase was separated and washed with saturated NaHCO 3 (15 ml) and brine (15 ml) and dried over MgSO 4 and filtered.
  • the solvent was removed under reduced pressure to obtain the crude product as light yellow oil.
  • the crude product was purified by silica-gel column chromatography (hexane/ether 80:20) and analyzed by NMR, HPLC and LC-MS.
  • the desired product 6c was obtained from 6e according to the general procedure C.
  • the desired product 8e was obtained according to the general procedure E

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150031768A1 (en) * 2011-08-19 2015-01-29 The Trustees Of Princeton University C-halogen bond formation
US9314540B2 (en) 2010-10-22 2016-04-19 Piramal Imaging Sa Compounds for use in imaging, diagnosing and/or treatment of diseases of the central nervous system
US10196341B2 (en) 2011-08-19 2019-02-05 The Trustees Of Princeton University C-halogen bond formation

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2053033A1 (en) * 2007-10-26 2009-04-29 Bayer Schering Pharma AG Compounds for use in imaging, diagnosing and/or treatment of diseases of the central nervous system or of tumors
BRPI1015532A2 (pt) * 2009-04-23 2019-09-24 Bayer Pharma AG moléculas precursoras para rastreadores de tep marcados com f-18
WO2012126913A1 (en) * 2011-03-23 2012-09-27 Piramal Imaging Sa Compounds for use in imaging, diagnosing and/or treatment of diseases of the central nervous system
US9187484B2 (en) 2012-05-02 2015-11-17 Southern Research Institute Triazolopyridazine compounds, use as inhibitors of the kinase LRRK2, and methods for preparation thereof
WO2015054476A1 (en) * 2013-10-09 2015-04-16 The Trustees Of Princeton University C-halogen bond formation
WO2016097351A1 (en) * 2014-12-19 2016-06-23 Ge Healthcare Limited 18f labelled thiazolylhydrazone derivatives
AR115584A1 (es) * 2018-06-20 2021-02-03 Bwxt Isotope Tech Group Inc SISTEMA Y MÉTODO PARA LA EVALUACIÓN DE LA EFECTIVIDAD DE LA ELUSIÓN Y LA RADIOPUREZA DE LOS GENERADORES DE Tc-99m
GB202108605D0 (en) * 2021-06-16 2021-07-28 Ge Healthcare Uk Ltd Effect of water content

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3160664A (en) * 1959-04-10 1964-12-08 Miles Lab Acetylenic omega-haloalkylamines
US3253037A (en) * 1962-06-19 1966-05-24 Ciba Geigy Corp N-2-alkynyl-amino-benzocylo-alkanes
US5169868A (en) * 1991-03-01 1992-12-08 University Of Saskatchewan Aliphatic propargylamines as specific mao-b inhibitors
US5486541A (en) * 1991-10-16 1996-01-23 Teva Pharmaceutical Industries, Ltd. Monofluorinated derivatives of N-propargyl-1-aminoindan and their use as inhibitors of monoamine oxidase
WO2007148088A2 (en) * 2006-06-21 2007-12-27 Ge Healthcare Limited Radiopharmaceutical products

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1121857A (en) * 1965-01-05 1968-07-31 Science Union & Cie New phenylisopropylamine derivatives and process for their preparation and pharmaceutical preparations of such derivatives
US4377587A (en) * 1980-07-25 1983-03-22 Ciba-Geigy Corporation Arylamine derivatives and use thereof as microbicides
US4448773A (en) * 1981-04-29 1984-05-15 Ciba-Geigy Corporation Microbicidal N-alkoxycarbonyl-alkyl-N-substituted acetyl-anilines and -naphthylamines
HU207282B (en) * 1984-05-31 1993-03-29 Chinoin Gyogyszer Es Vegyeszet Process for producing phenyl-alkyl-amine derivatives and pharmaceutical compositions containing them
IT1240676B (it) * 1990-04-24 1993-12-17 Agrimont Spa Composizioni ad attivita' erbicida
US5844003A (en) * 1991-04-04 1998-12-01 Innovations Foundation Use of deprenyl compounds to maintain, prevent loss, or recover nerve cell function
HUT63579A (en) * 1991-12-20 1993-09-28 Chinoin Gyogyszer Es Vegyeszet Process for producing double-phase pharmaceutical compositions suitable for treating diseases occurring during neurodegenerative processes
JPH0797450A (ja) * 1993-09-29 1995-04-11 Mitsubishi Cable Ind Ltd クラウン系ポリマーの製造方法および固体電解質
SK284383B6 (sk) 1995-03-02 2005-02-04 R.P. Scherer Limited Farmaceutický prostriedok na orálne podávanie obsahujúci inhibítory monoaminoxidázy B a jeho použitie
US6436989B1 (en) 1997-12-24 2002-08-20 Vertex Pharmaceuticals, Incorporated Prodrugs of aspartyl protease inhibitors
AU2012199A (en) 1997-12-24 1999-07-19 Vertex Pharmaceuticals Incorporated Prodrugs of aspartyl protease inhibitors
WO1999033792A2 (en) 1997-12-24 1999-07-08 Vertex Pharmaceuticals Incorporated Prodrugs os aspartyl protease inhibitors
AP2000001856A0 (en) 1997-12-24 2000-09-30 Vertex Pharma Prodrugs of aspartyl protease inhibitors.
US8097608B2 (en) * 2003-11-25 2012-01-17 Technion Research And Development Foundation Ltd. Methods for treatment of cardiovascular disorders and diseases
WO2006130707A2 (en) * 2005-06-02 2006-12-07 Jenrin Discovery Mao-b inhibitors useful for treating obesity
CN101262867A (zh) * 2005-07-01 2008-09-10 叶林发现公司 用于治疗肥胖的mao-b抑制剂
US7833259B2 (en) 2005-07-25 2010-11-16 Cook Incorporated Fenestrated endoluminal stent system
FR2918370B1 (fr) * 2007-07-02 2009-08-28 Servier Lab Nouveaux derives naphtaleniques,leur procede de preparation et les compositions pharmaceutiques qui les contiennent
AR066162A1 (es) * 2007-07-31 2009-07-29 Bayer Cropscience Sa Derivados fungicidas de n- cicloalquil -n- carboxamida- biciclica
EP2053033A1 (en) * 2007-10-26 2009-04-29 Bayer Schering Pharma AG Compounds for use in imaging, diagnosing and/or treatment of diseases of the central nervous system or of tumors
EP2450332A1 (en) * 2010-10-22 2012-05-09 Bayer Pharma Aktiengesellschaft Compounds for use in Imaging, diagnosing and/or treatment of diseases of the central nervous system (F-D2-Deprenyl)

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3160664A (en) * 1959-04-10 1964-12-08 Miles Lab Acetylenic omega-haloalkylamines
US3253037A (en) * 1962-06-19 1966-05-24 Ciba Geigy Corp N-2-alkynyl-amino-benzocylo-alkanes
US5169868A (en) * 1991-03-01 1992-12-08 University Of Saskatchewan Aliphatic propargylamines as specific mao-b inhibitors
US5486541A (en) * 1991-10-16 1996-01-23 Teva Pharmaceutical Industries, Ltd. Monofluorinated derivatives of N-propargyl-1-aminoindan and their use as inhibitors of monoamine oxidase
WO2007148088A2 (en) * 2006-06-21 2007-12-27 Ge Healthcare Limited Radiopharmaceutical products

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Chi et al. J. Org. Chem. 1987, 52, 658-664. *
Fowler et al. Methods 27 (2002) 263-277. *
Fowler J et al. Science. 1987, 481-485. *
Mukherjee et al. Nucl. Med. Biol. 1999, 26, 619-625. *
Plenevaux et al. Int. J. Radiat. Appl. Instrum. Part A. 1991, 42, 121-127. *
Zhang et al. Curr. Top. Med. Chem. 2007, 7, 1817-1828. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9314540B2 (en) 2010-10-22 2016-04-19 Piramal Imaging Sa Compounds for use in imaging, diagnosing and/or treatment of diseases of the central nervous system
US20150031768A1 (en) * 2011-08-19 2015-01-29 The Trustees Of Princeton University C-halogen bond formation
US10196341B2 (en) 2011-08-19 2019-02-05 The Trustees Of Princeton University C-halogen bond formation

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