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WO2008132454A1 - Carbolines et leur utilisation comme agents d'imagerie - Google Patents

Carbolines et leur utilisation comme agents d'imagerie Download PDF

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Publication number
WO2008132454A1
WO2008132454A1 PCT/GB2008/001455 GB2008001455W WO2008132454A1 WO 2008132454 A1 WO2008132454 A1 WO 2008132454A1 GB 2008001455 W GB2008001455 W GB 2008001455W WO 2008132454 A1 WO2008132454 A1 WO 2008132454A1
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Prior art keywords
hydrogen
compound
βalkyl
ealkyl
hydroxy
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English (en)
Inventor
Denis Raymond Christophe Bouvet
Ian Martin Newington
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GE Healthcare Ltd
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GE Healthcare Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • 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

Definitions

  • the present invention relates to the field of medical diagnostics and imaging, in one 5 particular aspect to positron emission tomography (PET) and or single photon emission computed tomography (SPECT) and provides compounds and methods for visualising central nervous system (CNS) receptors.
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • CNS central nervous system
  • this invention relates to carbolines which are selective ligands for the GABAA receptor and which carry a radiolabel suitable for imaging with PET or SPECT or a radiolabel suitable for o localisation of GABAA receptors in vitro.
  • the compounds of the present invention are thus useful for in vitro diagnostics and in vivo imaging of the GABAA receptor.
  • GABA ⁇ -aminobutyric acid
  • GABA central nervous system
  • GABAA receptors are worthy of particular attention owing to the discovery of many GABAA receptor subtypes and development of novel chemical structures which are selective for these subtypes.
  • the field of GABA receptor imaging therefore appears to be poised at an exciting stage where5 development of radioligands for quantifying GABA receptor changes offer the potential to provide useful insight into numerous CNS disorders, such as those associated with epilepsy, anxiety and cognitive (neurodegenerative) disorders.
  • EP0161575, EP0030254, and EP0054507 describe various ⁇ -carbolines and their 0 pharmacalogical properties.
  • a number of compounds have been investigated as potential radioligands for studying the GABAA receptor in vivo using PET including [ n C]flumazenil ([ 11 C]FMZ), [ 18 F]fluoroflumazenil ([ 1S F]FFMZ), [ 18 F]fluoroethylflumazenil ([ 18 F]FEFMZ), and [ 123 l]iomazenil ([ 123 I]IMZ).
  • PET [ n C]flumazenil ([ 11 C]FMZ), [ 18 F]fluoroflumazenil ([ 1S F]FFMZ), [ 18 F]fluoroethylflumazenil ([ 18 F]FEFMZ), and [ 123 l]iomazenil ([ 123 I]IMZ).
  • the present invention seeks to provide radioligands suitable for studying the GABAA receptor in vitro and in vivo having improved properties over those in the prior art.
  • X is oxygen, sulphur, or NR 10 wherein R 10 is hydrogen or Ci- ⁇ alkyl;
  • R 1 is either: (a) Ci-6alkoxy, aryloxy, or arylCi-6alkoxy each optionally substituted by 1 to 3 groups selected from halo, hydroxy, Ci- ⁇ alkyl , Ci- ⁇ haloalkyl, Ci- ⁇ alkoxy, Ci- ⁇ haloalkoxy, -NR 11 R 12 , and -C(O)OR 11 wherein R 11 and R 12 are each independently selected from hydrogen, Ci-6haloalkyl and Ci- ⁇ alkyl; or (b) NR 13 R 14 wherein R 13 and R 14 are independently selected from hydrogen, hydroxy, Ci- ealkyl, aryl, arylCi-ealkyl and are each optionally substituted by a group selected from halo, hydroxy, Cualkyl, -C(O)NR 14 R 1S , -C(O)OR 14 wherein R 14
  • R 2 is selected from hydrogen, Ci- ⁇ alkyl, aryl, arylCi- ⁇ alkyl and is optionally substituted by 1 to 3 groups selected from halo, hydroxy, Ci- ⁇ alkyl , Ci- ⁇ haloalkyl, Ci-6alkoxy, -NR 16 R 17 , and -C(O)OR 16 wherein R 16 and R 17 are each independently selected from hydrogen Ci-ealkyl and Ci-ehaloalkyl;
  • R 3 , R 4 , R 5 , R 6 , and R 8 are each independently selected from hydrogen, halo, nitro, Ci-6alkyl, Ci-6haloalkyl, hydroxy, Ci-6alkoxy, Ci- ⁇ haloalkoxy, aryl, arylCi- ⁇ alkyl, aryloxy, arylCi-ealkoxy, cyano. thiocyanate, -NR 18 R 19 , -NR 18 C(O)R 19 , -SR 1S -SO 2 NR 18 R 19 , -C(O)R 18 and -C(O)OR 18 wherein R 18 and R 19 are each independently selected from hydrogen, Ci- ⁇ haloalkyl, and Ci- ⁇ alkyl;
  • R 7 is selected from hydrogen, Ci- ⁇ alkyl, Ci-6 haloalkyl, -CO2H, Ci-6 haloalkoxycarbonyl and Ci- ⁇ alkoxycarbonyl;
  • At least one Of -C(X)R 1 or R 2 to R 8 comprises a detectable label; provided that the compound of formula (I) is not N'-methyl-9H- ⁇ -carboline-3-[carbonyl- n C]carboxamide or ⁇ -[6- 3 H]carboline-3-carboxylic acid ethyl ester, or [ 3 H]propyl- ⁇ - carboline-3-carboxylate.
  • X is preferably oxygen
  • R 1 is preferably either: ( ⁇ ) Ci-e ⁇ lkoxy or Ci-e h ⁇ lo ⁇ lkoxy; or
  • R 13 and R 14 are independently selected from hydrogen, Ci-ealkyl, aryl, and arylCi- ⁇ alkyl and are each optionally substituted by a group selected from halo, hydroxy, and Ci-- + alkyl;
  • R 2 is preferably selected from hydrogen, Ci- ⁇ alkyl, Ci- ⁇ haloalkyl, Ci-6 hydroxyalkyl, Ci-ehalohydroxyalkyl, Ci-ealkoxyalkyl, and Ci-ehaloalkoxyalkyl;
  • R 3 , R 4 , R 5 , R 6 , and R 8 are preferably each independently selected from hydrogen, halo, nitro, Ci-ealkyl, Ci- ⁇ haloalkyl, hydroxy, Ci- ⁇ alkoxy, and Ci- ⁇ haloalkoxy ; suitably R 3 , R 5 , R 6 , and R 8 are each hydrogen, and R 4 is selected from halo, nitro, Ci- ⁇ alkyl, Ci-ehaloalkyl, hydroxy, Ci-ealkoxy, and Ci-6haloalkoxy; and
  • R 7 is preferably selected from hydrogen, Ci-ealkyl, and Ci-6 haloalkyl.
  • Suitable detectable labels in a compound of formula (I) and in more specific aspects of the invention below are a radiolabel suitable for imaging with PET or SPECT such as 131 - 123.124 , 122I 1 75 ⁇ r, 76Br, 77 Br, 13 N, 11 C, or 18 F, or a radiolabel suitable for localisation of GABAA receptors in vitro or in vivo such as 3 H 1 14 C, 35 S, or 125 I.
  • the detectable label is a radiolabel suitable for imaging with PET or SPECT, suitably selected from "l.123 , 124 , 122I 1 75 Br , 76 Br ⁇ 77 Br> i3N, 1 1 C, and 18 F, and is preferably 18 F.
  • the detectable label is a radiolabel suitable for localisation of GABAA receptors in vitro, suitably selected from such as 3 H, 14 C, 35 S 1 or 125 I.
  • the detectable label is incorporated as part of one or more of groups -C(X)R 1 or R 2 to R 8 , for example where the detectable label is "l.123 , 124 , 125 , 122I 1 75B ⁇ , 76B n 77Br 1 or 18 F it may be incorporated where one or more of groups -C(X)R 1 or R 2 to R 8 comprises halo and where the detectable label is 11 C, it may be incorporated where one or more of groups -C(X)R 1 or R 2 to R 8 comprises carbon. In one aspect of the invention, the detectable label is incorporated as part of group -C(X)R 1 .
  • R 1 is either:
  • R 13 and R 14 are independently selected from hydrogen, Ci-ealkyl, aryl, and arylCi-6alkyl and are each optionally substituted by a group selected from halo, hydroxy, and
  • R 2 is selected from hydrogen, Ci- ⁇ alkyl, Ci- ⁇ haloalkyl, Ci- ⁇ hydroxyalkyl, Ci-6halohydroxyalkyl, Ci-6alkoxyalkyl, and Ci-ehaloalkoxyalkyl;
  • R 3 , R 4 , R 5 , R 6 , and R 8 are each independently selected from hydrogen, halo, nitro, Ci- ⁇ alkyl, Ci-6haloalkyl, hydroxy, Ci- ⁇ alkoxy, and Ci- ⁇ haloalkoxy ;
  • R 7 is selected from hydrogen, Ci- ⁇ alkyl, and Ci-e haloalkyl
  • At least one of -C(X)R 1 or R 2 to R 8 comprises a detectable label selected from " 1 . 123 . 124, i22
  • R 1 is either:
  • R 13 and R 14 are independently selected from hydrogen, Ci- ⁇ alkyl, aryl, and arylCi- ⁇ alkyl and are each optionally substituted by a group selected from halo, hydroxy, and
  • R 2 is selected from hydrogen, Ci- ⁇ alkyl, Ci- ⁇ haloalkyl, Ci-e hydroxyalkyl, Ci- ⁇ halohydroxyalkyl, Ci- ⁇ alkoxyalkyl, and Ci- ⁇ haloalkoxyalkyl;
  • R 3 , R 5 , R 6 , and R 8 are each hydrogen and R 4 is selected from halo, Ci- ⁇ alkyl, Ci-ehaloalkyl, hydroxy, Ci-6alkoxy, and Ci-ehaloalkoxy;
  • R 7 is selected from hydrogen, Ci- ⁇ alkyl, and Ci-e haloalkyl and is suitably hydrogen;
  • R 4 is suitably Ci- ⁇ haloalkoxy, more suitably [ 18 F]Ci-6fluoroalkoxy such as [ 18 F]Ci-6fluoroethoxy.
  • Particular compounds of formula (I) include (2-[ 18 F]Fluoroethyl)- ⁇ -carboline-3-carboxylate 3-[ 18 F]Fluoropropyl)- ⁇ -carboline-3-carboxylate (2-[ 18 F]Fluoroethyl)- ⁇ -carboline-3-carboxamide (3-[ 18 F]Fluoropropyl)- ⁇ -carboline-3-carboxamide (2-[ 18 F]Fluoroethyl)-6-methoxy-4-methoxymethyl- ⁇ -c ⁇ rboline -3-c ⁇ rbox ⁇ mide (3-[ 18 F] Fluoropropyll- ⁇ -methoxy ⁇ -methoxymethyl- ⁇ -c ⁇ rboline-S-c ⁇ rbox ⁇ mide (2-[ i8 F]Fluoroethyl)-6-fluoro-A-methoxymethyl- ⁇ -c ⁇ rboline-3-c ⁇ rbox ⁇ mide (3
  • compositions of formula (I) include : 6-(2-[ 18 F] Fluoroethoxy)-9H- ⁇ -carboline-3-carboxylic acid ethyl ester; 6-(2-[ 18 F]Fluoroethoxy)-9H- ⁇ -carboline-3-carboxylic acid ethylamide; 6-(2-[ 18 F]Fluoroethoxy)-4-methoxymethyl-9H- ⁇ -carboline-3-carboxylicacid ethyl ester; 6-(2-[ 18 F]Fluoroethoxy)-4-methoxymethyl-9H- ⁇ -carboline-3-carboxylic acid ethylamide; or a salt or solvate of any thereof .
  • Suitable salts according to the invention include (i) physiologically acceptable acid addition salts such as those derived from mineral acids, for example hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and those derived from organic acids, for example tartaric, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycollic, gluconic, succinic, methanesulphonic, and para- toluenesulphonic acids; and (ii) physiologically acceptable base salts such as ammonium salts, alkali metal salts (for example those of sodium and potassium), alkaline earth metal salts (for example those of calcium and magnesium), salts with organic bases such as triethanolamine, N-methyl-D-glucamine, piperidine, pyridine, piperazine, and morpholine, and salts with amino acids such as arginine and lysine.
  • physiologically acceptable acid addition salts such as those derived from mineral acids
  • Suitable solvates according to the invention include those formed with ethanol, water, saline, physiological buffer and glycol.
  • halo either alone or as part of another term means iodo, bromo, chloro, or fluoro.
  • alkyl either alone or as part of another term means a straight, branched or cyclic alkyl group.
  • aryl either alone or as part of another term means a c ⁇ rbocyclic aromatic system, suitable examples being phenyl or naphthyl, more suitably phenyl.
  • a compound of formula (I), (Ia), or (Ib) as defined above, or a salt or solvate thereof may also be used to image the GABAA receptor in healthy human volunteers for example for clinical research purposes.
  • the compounds of formula (I) , (Ia), or (Ib) or salt or solvate thereof are useful for in vivo imaging of GABAA receptors and thus have utility in the diagnosis of GABAA- mediated disorders.
  • GABAA-mediated disorders means neurological and neuropsychiatric disorders such as stroke, epilepsy, Alzheimer's disease, Parkinson's disease, Huntington's disease, sleep disorders, alcoholism , and neuropathic pain.
  • GABAA-mediated disorder is epilepsy and in particular post-traumatic epilepsy.
  • a compound of formula (I), (Ia), or (Ib) or a salt or solvate thereof in the manufacture of a radiopharmaceutical for the in vivo diagnosis or imaging of a GABAA-mediated disorder.
  • a compound of formula (I), (Ia), or (Ib) or a salt or solvate thereof for use in the in vivo diagnosis or imaging of a GABAA-mediated disorder.
  • a method for the in vivo diagnosis or imaging of GABAA- mediated disorder in a subject comprising administration of a compound of formula (I) , (Ia), or (Ib) or a salt or solvate thereof and detecting the uptake of said compound by an in vivo imaging technique such as SPECT or PET.
  • the method is especially preferred for the in vivo diagnosis or imaging of stroke, epilepsy, Alzheimer's disease, Parkinson's disease, and neuropathic pain, especially epilepsy and in particular post-traumatic epilepsy.
  • the invention further provides a method of monitoring the effect of treatment of a subject, preferably a human with a drug to combat a GABAA- mediated disorder, said method comprising administering to said subject a compound of formula (I) , (Ia), or (Ib) or ⁇ salt or solvate thereof and detecting the uptake of said compound by an in vivo imaging technique such as SPECT or PET, said administration and detection optionally but preferably being effected repeatedly, e.g. before, during and after treatment with said drug.
  • an in vivo imaging technique such as SPECT or PET
  • a compound of formula (I) , (Ia), or (Ib) or a salt thereof is preferably administered for in vivo use in a radiopharmaceutical formulation comprising the compound of the invention and a pharmaceutically acceptable excipient
  • a "radiopharmaceutical formulation” is defined in the present invention as a formulation comprising compound of formula (I) , (Ia), or (Ib) or a salt thereof in a form suitable for administration to humans. Administration is preferably carried out by injection of the formulation as an aqueous solution.
  • Such a formulation may optionally contain further ingredients such as buffers; pharmaceutically acceptable solubilisers (e.g. cyclodextrins or surfactants such as Pluronic, Tween or phospholipids); pharmaceutically acceptable stabilisers or antioxidants (such as ascorbic acid, gentisic acid or por ⁇ -aminobenzoic acid).
  • the effective in vivo dose of a compound of formula (I), (Ia) , (Ib), or a salt thereof will vary depending on the exact compound to be administered, the weight of the patient, and other variables as would be apparent to a physician skilled in the art. Generally, the dose would lie in the range 0.001 ⁇ g/kg to 10 ⁇ g /kg, preferably 0.01 ⁇ g /kg to
  • the compounds of formula (I), (Ib), and salts thereof may also have use in the field of in vitro diagnostics for localisation of GABAA receptors in vitro.
  • the detectable label in the compound of formula (I) 1 (Ib), or a salt thereof is suitably 3 H, 14 C, 35 S 1 or 125 I.
  • GABAA may be localised in biopsy or postmortem tissue by incubating the tissue with a solution comprising a compound of formula (I) 1 (Ib), or a salt thereof.
  • the solution is suitably aqueous, or an aqueous organic solvent mix such as aqueous ethanol.
  • the compound of formula (I), (Ib), or a salt thereof labels the GABAA receptor in the tissue and may be detected by any standard technique, for example by autoradiography, or gamma counter.
  • R 1 is as defined for the compound of formula (I) and comprises a detectable label.
  • the reaction of a compound of formula (II) with a compound of formula (III) may be effected by any standard esterification or amidation method.
  • the compound of formula (I I) is converted to the corresponding activated ester, for exam pie to an acid chloride by reaction with thionyl chloride or to a pentafluorophenyl ester before addition of the compound of formula (III) in the presence of a base, such as a trialkylamine, for example diisopropylethylamine or triethylamine.
  • a base such as a trialkylamine, for example diisopropylethylamine or triethylamine.
  • Compounds of formula (II) are either commercially available or may be prepared by methods such as those described in EP0030254.
  • Compounds of formula (III) may be prepared by radiohalogenation, radiohaloalkylation, or [ n C]alkylation methods, such as those described in Lasne et a/, Topics in Current Chemistry, VoI 222, pp201-256 and MJ Welch and CS Redvanly, Handbook of Radiopharmaceuticals, Radiochemistry and
  • protected derivatives of synthetic intermediates such as a compound of formula (II) comprise one or more protecting groups to prevent unwanted reaction of certain reactive groups.
  • Suitable protecting groups may be found in Protecting Groups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wuts, published by John Wiley & Sons Inc. which describes methods for incorporating and removing such protecting groups.
  • Compounds of formula (I) wherein one of the groups R 2 to R 6 or R 8 comprises a detectable label may be prepared by conventional radiolabelling techniques, such as aromatic nucleophilic [ 18 F]fluorination involving displacement of a nitro, iodonium, or tetraalkylammonium group, or by radioiodide or radiobromide displacement of a trialkyltin precursor, such as a tributylstannyl precursor, in the presence of an oxidising agent such as peracetic acid, N-chlorosuccinimide, and N-chlorotolylsulphonamide (for example chloramine-T or iodogen), at non-extreme temperature and in a suitable solvent such as an aqueous buffer. Radiohalogenation methods are reviewed in detail in Bolton, J Label. Compd Radiopharm 2002, 45, 485-528.
  • a compound of formula (I) wherein R 4 comprises an 18 F detectable label may be prepared according to the following scheme 1.
  • Other compounds of formula (I) for example having an 18 F detectable label in a different ring position may be prepared by analogy.
  • the starting phenol in Scheme 1 may be prepared by the method of Scheme 2, or by analogy.
  • R 7 comprises a detectable label
  • R 7 comprises a detectable label
  • R 7 comprises a detectable label
  • [ n C]alkylation reactions such as those described in Lasne et a/, Topics in Current Chemistry, VoI 222, pp201-256 and MJ Welch and CS Redvanly, Handbook of Radiopharmaceuticals, Radiochemistry and Applications (Wiley, 2003).
  • kits for the preparation of a radiopharmaceutical formulation comprising a compound of formula (II) as defined above.
  • the compound of formula (II) would be converted to the corresponding compound of formula (I) by reaction with a compound of formula (III) using the process described above.
  • UV ultraviolet
  • HATU O-(7-Azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • BpyPOP (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate.
  • Yields are typically between 15 and 30 %
  • Compounds 1 to 4 may be prepared with a detectable label, by using the appropriately labelled alcohol or amine in an analogous synthesis.
  • the labelled/protected fluoropropylamine was purified on preparative HPLC followed by solide phase extraction (SPE) removal of mobile phase.
  • Compounds 5 to 8 may be prepared with a detectable label, by using the appropriately labelled amine in an analogous synthesis.

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Abstract

L'invention porte sur des carbolines de formule (I) qui sont des ligands sélectifs pour le récepteur GABAA et qui portent un radiomarqueur approprié pour l'imagerie avec PET ou SPECT ou un radiomarqueur approprié pour la localisation de récepteurs GABAA in vitro. Les composés de la présente invention sont ainsi utiles pour des diagnostics in vitro et une imagerie in vivo du récepteur GABAA.
PCT/GB2008/001455 2007-04-26 2008-04-24 Carbolines et leur utilisation comme agents d'imagerie Ceased WO2008132454A1 (fr)

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Cited By (11)

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WO2009102498A1 (fr) * 2008-02-14 2009-08-20 Siemens Medical Solutions Usa, Inc. Nouveaux agents d’imagerie pour la détection d’une dysfonction neurologique
WO2009143445A1 (fr) * 2008-05-22 2009-11-26 The Uwm Research Foundation, Inc Aza-bêta-carbolines et leurs procédés d’utilisation
WO2010133851A1 (fr) * 2009-05-20 2010-11-25 Isis Innovation Limited Préparation de composés marqués
WO2011119565A1 (fr) * 2010-03-23 2011-09-29 Siemens Medical Solutions Usa, Inc. Agents d'imagerie pour détecter des troubles neurologiques
US8420052B2 (en) 2008-07-24 2013-04-16 Siemens Medical Solutions Usa, Inc. Imaging agents useful for identifying AD pathology
US8491869B2 (en) 2009-03-23 2013-07-23 Eli Lilly And Company Imaging agents for detecting neurological disorders
WO2013176698A1 (fr) * 2012-05-22 2013-11-28 Eli Lilly And Company Agents d'imagerie à base de carboline et de carbazole pour la détection de dysfonction neurologique
US8932557B2 (en) 2008-02-14 2015-01-13 Eli Lilly And Company Imaging agents for detecting neurological dysfunction
WO2015110263A1 (fr) * 2014-01-21 2015-07-30 Ac Immune Sa Composés de carbazole et de carboline destinés à être utilisés dans le diagnostic, le traitement, l'atténuation ou la prévention de troubles associés aux protéines amyloïdes et de type amyloïde
WO2016124508A1 (fr) * 2015-02-02 2016-08-11 Ucb Biopharma Sprl Dérivés de 9h-pyrrolo-dipyridine
EP3318563A1 (fr) 2016-11-07 2018-05-09 Sanofi Pyrido[3,4-b]indoles substitués pour le traitement de troubles du cartilage

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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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