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WO2014098593A9 - Composés analogues au vérapamil - Google Patents

Composés analogues au vérapamil Download PDF

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Publication number
WO2014098593A9
WO2014098593A9 PCT/NL2013/050925 NL2013050925W WO2014098593A9 WO 2014098593 A9 WO2014098593 A9 WO 2014098593A9 NL 2013050925 W NL2013050925 W NL 2013050925W WO 2014098593 A9 WO2014098593 A9 WO 2014098593A9
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WO
WIPO (PCT)
Prior art keywords
group
methyl
compound according
compounds
fluoroalkyl
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Ceased
Application number
PCT/NL2013/050925
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English (en)
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WO2014098593A1 (fr
Inventor
Renske RAAPHORST
Gert LUURTSEMA
Albert Dirk Windhorst
Adriaan LAMMERTSMA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Stichting voor de Technische Wetenschappen STW
Rijksuniversiteit Groningen
Academisch Ziekenhuis Groningen
Vrije Universiteit Amsterdam
Original Assignee
Stichting voor de Technische Wetenschappen STW
Rijksuniversiteit Groningen
Academisch Ziekenhuis Groningen
Stichting VU VUMC
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Publication of WO2014098593A1 publication Critical patent/WO2014098593A1/fr
Publication of WO2014098593A9 publication Critical patent/WO2014098593A9/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds

Definitions

  • the present invention relates to verapamiMike compounds or verapamil analogues, their use as a P-gSycoprotein inhibitor or substrate, a radiopharmaceutical formulation comprising specific verapamil like compounds, compound, a radiopharmaceutical formulation comprising specific verapamiMike compounds for use in vivo diagnostic or in vivo imaging method, a method for the in vivo diagnosis or in vivo imaging of a P- glycoprotein related disease in a subject, and a method to prepare the novel verapamiMike compounds.
  • PET Positron emission tomography
  • P-glycoprotem is an ABC efflux transporter mainly expressed in the btood brain barrier,a s disclosed in Mature 1984; 309:626-628, and Science 1983, 221:1285-1288. it transports xenobiotic and structurally diverse compounds out of the cell.
  • Overexpression of P-gp leads to decreased uptake of pharmaceuticals aimed at the brain.
  • this protein is involved in diseases like epilepsy, Alzheimer's disease and Parkinson's disease. Imaging of this particular protein may therefore give insights into its role in the healthy and diseased state of a person.
  • a disadvantage of the P-gp [ ⁇ Cjverapamil compound is that it has a very short half- life of only 20 minutes. This short half-life limits the application of this compound.
  • the object of this invention is to provide an alternative for [ ⁇ Cjverapamii.
  • R is a ( ?J-cyano group or a (S)-cyano group; or wherein is hydrogen or a methyl group, R2, R3, R4 and R5 are each independently a methyl,
  • R5 is a (R)-cyano group or a (S)-cyano group, wherein at least one of R2, R3, R4 and R5 is a fluoroalkyi or [ 18 F]fluoroalkyl group.
  • the invention preferably relates to a compound according to general formula (I) wherein R ⁇ is hydrogen, an optionally branched [ 18 F]fluoroalkyl group, R2, R3, R4 and R5 are each independently a methyl, [ 3 H]methyl , fluoroalkyi or [ 18 F]fluoroalkyl group, and Rg is a ⁇ R)- cyano group or a (S)-cyano group. It further preferably relates to a compound according to gen eral formula (I) wherein R ⁇ is a methyl group and R3 is a [l 8 F]fluoroalkyl group.
  • the compound according to this invention can be referred to as a verapamil like compound.
  • the fluoroalkyi analogs of verapamil according to the above may be provided in an unlabeled and radiolabeled state.
  • the radiolabeled compounds may advantageously be used as a radiopharmaceutical for use as a tracer for P-gp with a longer half-life than the existing tracers.
  • the fluorine-18 labeled P-gp tracer is preferred, since the half-life of fluorine-18 is 110 minutes compared to 20 min for carbon-11. This is more practical and allows transport of the radiolabeled compound to hospitals which do not have their own cyclotron capacities.
  • the tritium labeled compounds according to the present invention may advantageously be used for in vitro studies to investigate the interaction with P-gp at low concentration levels, better mimicking the in vivo situation than with unlabeled compounds.
  • the subject invention relates to a first group of preferred verapamil like compounds are compounds wherein R ⁇ is a fluoroalkyi group or more preferably a
  • [l 8 F]fluoroalkyl group Preferably the alkyl group has 1 to 3 carbon atoms of which methyl or ethyl are especially suited.
  • R2, R3, R4 and R5 are a methyl group. If R ⁇ is a fluo roalkyi group R2, R4 and R5 may be all a methyl group and R3 is a [ ⁇ HJmethyl group.
  • the subject invention also relates to a second group of compounds, wherein is a methyl group, and R3 is a [ 18 F]fluoroalkyl group.
  • R2, R4 and R5 are a methyl groups.
  • the alkyl group has 1 to 3 carbon atoms, suitably methyl or ethyl.
  • Figures 1 to 13 depict the molecular structures of exemplary compounds according to the invention, wherein Figure 13 shows ( ?)-0-[ 18 F]fluoroethylverapamil.
  • Figure 14 shows the resulting ex vivo biodistribution of (R)-N- [ 18 F]fluoroethylverapamil in male wister rats.
  • Figure 15 shows the ex vivo biodistribution of (R)-N-[ 18 F]fluoroethylverapamil at 15 minutes in male wistar rats, after treatment with 15 mg/kg tariquidar (1 st set of blocks), compared to the ex vivo biodistribution of (R)-N-[ ls F]fluoroethylverapamil at 15 minutes in non-treated male wistar rats (second set of blocks).
  • the result of the same experiments for ex vivo biodistribution of (R)-[ u C]verapamil is depicted in the third and fourth set of blocks, respectively.
  • Figure 16 shows the metabolite analysis of (R)-N-[ 18 F]fluoroethylverapamil in male wistar rats.
  • Figure 17 discloses the ex vivo biodistribution, corrected for metabolism, of (R)-N- [ 18 F]fluoroethylverapamil at 15 minutes in male wistar rats, after treatment with 15 mg/kg tariquidar, compared to the ex vivo biodistribution of (R)-N-[ 18 F]fluoroethylverapamil at 15 minutes in non-treated male wistar rats.
  • Figure 18 shows two base line PET scans of 450g Wistar rats, without (left), and with blocking by 15mg Tariquidar (right).
  • Figure 19 shows time activity curves of the brain uptake of (fl)-N- [ 18 F]fluoroethylverapamil.
  • the non-radiolabeled compounds according to this first group may advantageously be used as reference compounds.
  • Examples of such preferred compounds are illustrated in the attached Figures as compounds 1: (5)- and (/?)-N-Fluoroethylverapamil, wherein R ⁇ is a fluoroethyl group and R2, R3, R4 and R5 are each a methyl group; compounds 2: (S) ⁇ and (/?)- N-Fluoromethylverapamil, wherein is a fluoromethyl group and R2, R3, R4 and R5 are each a methyl group.
  • radiolabeled compounds examples include compound 5: (5)- and (fiJ-N-t ⁇ Fjfluoroethylverapamil, wherein R ⁇ is a [ ⁇ FJfluoroethyl group and R2, R3, R4 and R5 are each a methyl group; compound 6, (S)- and ( ?)-N-
  • [ ⁇ F]fluoromethylverapamil wherein R ⁇ is a [l ⁇ F]fluoromethyl group and R2, R3, R4 and R5 are each a methyl group.
  • the radiolabeled compounds are preferably prepared starting from a suitable precursor. These precursors are actually the more important compounds as they are the compounds which are stored and used to prepare the radiolabeled compounds hours before their actual use. These compounds should have a molecular structure which enables one to easily, preferably by means of one synthesis step, prepare the desired radiolabeled compound. Applicants found that compounds 9 and 10, wherein R ⁇ is a fluoromethyl or fluoroethyl group and R2, R4 and R5 are a methyl group and R3 is hydrogen are suited precursors for preparing compounds 7 and 8 respectively by means of a methylation.
  • Preferred precursor compounds are compounds wherein ⁇ is hydrogen and wherein group R ⁇ is substituted by the desired fluoroalkyl group by means of an alkylation.
  • R ⁇ is a methyl group.
  • R2, R4 and R5 are a methyl groups and R3 is a fluoroalkyl group or a more preferably a [ ⁇ FJfluoroalkyl group.
  • the alkyl group has 1 to 3 carbon atoms, suitably methyl or ethyl.
  • Examples are compound 3, (S)- and (/?)-0-fluoroethylverapamil, wherein R ⁇ , 2, R4 and R5 are each a methyl group and R3 is a fluoroethyl group; compound 4, (5)- and (R)-0- fluoromethylverapamil, wherein Rj_, R2, R4 and R5 are each a methyl group and R3 is a fluoromethyl group.
  • radiolabeled compounds are compound 12, (5)- and ⁇ R)-0-
  • radiolabeled compounds are preferably prepared from a precursor compound wherein R3 is hydrogen or a leaving protective group that preferably increases the nucleophilicity of the oxygen atom, such as preferably alkyltosylate.
  • the - optionally actived- hydroxyl group may be substituted by the desired fluoroalkyl group by means of a!kylation.
  • An example of a suitable precursor compound is compound 14, (S)- and ( ?)-desmethylverapamil, wherein R ⁇ , R2, R4 and R5 are each a methyl group and R3 is hydrogen.
  • the radio labelled compounds and non-radio labelled compounds according to the present invention may be purified according to those methods known to the person skilled in the art, for example by means of HPLC purification or Solid Phase Extraction (SPE).
  • HPLC purification is preferable carried out on a preparative HPLC column packed with reverse phase material such as, but not limited to, C18, C18-EPS or C8, a mobile phase consisting of a mixture of methanol, ethanol or acetonitrile mixed with water or water containing buffer like, but not limited to, ammonium dihydrogen phosphate or an acid like phosphoric acid or trifluoracetic acid .
  • the Solid Phase Extraction is preferably performed on a Sep-Pak or similar device, such as, but not limited to, a C18, a tC18, a Silica or a n Oasis Sep-Pak.
  • the compound is preferably eluted from the Sep-Pak with a solvent suitable for injection in vivo, like ethanol.
  • the above treated compounds may be formulated to a desired formulation for their intended use.
  • the collected HPLC fraction from the preparative HPLC, containing a com pound according to the invention may be diluted with water or water containing such as, but not limited to, sodium hydroxide or hydrogen chloride.
  • the diluted fraction as prepared is preferably trapped on a bonded silica sample preparation devices for solid-phase extraction for sample preparation, e.g.
  • Sep-Pak or similar, but not limited to, such as preferably a C18, tC18, Silica or an Oasis Sep-Pak (Sep-Pak is a registered trademark of Water Corporation), and the compound is subsequently preferably eluted from the Sep- Pak with a solvent suitable for injection in vivo, such as ethanol.
  • a solvent suitable for injection in vivo such as ethanol.
  • the obtained eluate is preferable diluted with pharmaceutically acceptable buffers such as, but not limited to 0.9% sodi um chloride, sodium dihydrogenphosphate 7.09 mM in 0.9 % sodium chloride or citrate buffer, pharmaceutically acceptable solubilisers such as, but not limited to, ethanol, tween or phospholipids and/or with pharmaceutically acceptable stabilizers or antioxidants such as, but not limited to, ascorbic acid, gentisic acid or p-aminobenzoic acid.
  • pharmaceutically acceptable buffers such as, but not limited to 0.9% sodi um chloride, sodium dihydrogenphosphate 7.09 mM in 0.9 % sodium chloride or citrate buffer
  • pharmaceutically acceptable solubilisers such as, but not limited to, ethanol, tween or phospholipids
  • pharmaceutically acceptable stabilizers or antioxidants such as, but not limited to, ascorbic acid, gentisic acid or p-aminobenzoic acid.
  • Suitable salts according to the invention include physiologically acceptable acid addition salts such as those derived from mineral acids, but not limited to, hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric or sulphuric acids or those derived from organic acids such as, but not limited to, tartaric, fumaric, malonic, citric, benzoic, trifluoroacetic, lactic, glycolic, gluconic, methanesulphonic or p-toluenesulphonic acids.
  • physiologically acceptable acid addition salts such as those derived from mineral acids, but not limited to, hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric or sulphuric acids or those derived from organic acids such as, but not limited to, tartaric, fumaric, malonic, citric, benzoic, trifluoroacetic, lactic, glycolic, gluconic, methanesulphonic or p-toluenesulphonic acids.
  • the compounds may be used as part of a pharmaceutical formulation for use in diagnostics of/studying diseases like, but not limited to, epilepsy, Alzheimer's disease and Parkinson's disease.
  • the invention is especially directed to a radiopharmaceutical formulation
  • radiolabeled compounds comprising the above described radiolabeled compounds. More especially the invention is directed to a radiopharmaceutical formulation comprising the above described radiolabeled
  • [! ⁇ F] compounds for use in an in-vivo diagnostic or an in-vivo imaging method.
  • the diagnostic or imaging method of the P-glycoprotein will provide insight into diseases where this protein plays a role, like for example epilepsy, Alzheimer's disease and Parkinson's disease.
  • the imaging method may be positron emission tomography (PET).
  • the invention is thus also directed to a method for the in vivo diagnosis or in vivo imaging of a P-glycoprotein related disease in a subject, preferably a human, comprising administration of a radiolabeled [ ⁇ F]compound according to the invention or a formulation comprising such a a radiolabeled
  • Suitable precursors or compounds include are those depicted in the following structural formulae la,b to 5 a,b, namely (R)-0-[18F]fluoronorverapamil and (S)-O- [18F]fluoronorverapamil (la,b); (R)-O-fluoronorverapamil and (S)-O-fluoronorverapamil (2a,b) that may serve as "cold", i.e.
  • the reaction was quenched with 1 ml acetonitrile and purified by HPLC, using a Kromasil 100-10-C18 250*22 mm column (Kromasil is a registered trademark of EKA Chemicals AB ) concentrated on a tC- IS Sep-Pak and formulated in a phosphate buffer/saline mixture, with a yield of 10-30%, as corrected for decay, a purity of > 95%, and a specific activity > 20 GBq/ ⁇ .
  • 2-bromo [ F]fluoroethane was synthesized starting from 2-bromoethyltosylate in DMF, which was added to a dried 18 F/K 2 .2.2/I 2C03 solution. This mixture was heated for 10 min at 90 °C, after which the product was distilled at 90 °C through a heated (200°C) AgOTf column into a cooled (0 °C) vessel containing 1.5 mg (3.5 ⁇ ) of nor-verapamil and 5.0 mg (3.6 ⁇ ) of K 2 C0 3 .
  • Example 7 Blocking study: The behavior of ( ?)-/V-[ 18 F]fluoroethylverapamil with respect to P-gp was tested in a blocking study, with the use of the well-known P-gp inhibitor tariquidar.
  • the inhibitor was injected i.v. in healthy Wistar rats at a 15 mg/kg dose during a 15 minute injection period. 5 minutes after the tariquidar injection, 50 MBq of the (R)-N- [ 18 F]fluoroethylverapamil was injected.
  • the animals were sacrificed 15 minutes after the (/?)- A/-[ 18 F]fluoroethylverapamil injection and the indicated organs were collected, weighted and counted for activity.
  • the data shows a 2-fold increased brain uptake of the tracer in the P-gp blocked brain 15 minutes after tracer injection. This is a significant increase, however, a lower increase compared to [ C]verapamil.
  • the brain uptake of [ C] verapamil increases 10-fold in the presence of tariquidar, as illustrated in Figure 15.
  • Metabolite studies The metabolism of (/?)-/V-[ 18 F]fluoroethylverapamil was assessed in blood plasma and brain of healthy male Wistar rats. The rats were injected with 35-50 MBq of (/?)-/V-[ 18 F]fIuoroethylverapamil and were sacrificed at 5, 15 and 60 minutes after injection (from left to right in Figure 16).
  • Homogenized brain and blood plasma were passed over a SPE cartridge to separate the polar from the non-polar fractions.
  • the activity of all fractions was measured and only the non-polar fractions were analyzed with HPLC.
  • PET Imaging studies confirmed an increased uptake of (R)-N- [ 18 F]fluoroethylverapamil in the brain in combination with the inhibitor tariquidar (15 mg/kg).
  • the second day the animals were injected with 15 mg/kg tariquidar and after 30 minutes ⁇ R)-N- [ 18 F]fluoroethylverapamil was administered.
  • the time-activity curve (Figure 17) shows a 4- fold increased brain uptake of the tracer in the blocked animals in the first 10 minutes of the scan. However, still after 60 minutes, when according to metabolite studies only 3% of the tracer is still intact, the brain uptake is still 2-fold higher compared to the baseline scans, as illustrated in Figure 18.
  • Figure 19 depicts the time-activity curve, which shows a 4-fold increased brain uptake of the tracer in the blocked animals in the first 10 minutes of the scan. However, still after 60 minutes, when according to metabolite studies only 3% of the tracer is still intact, the brain uptake is still 2-fold higher compared to the baseline scans.

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Abstract

La présente invention concerne un composé, un sel ou un solvate de celui-ci selon (I) dans laquelle R1 est un groupe fluoroalkyle ou un groupe [18F]-fluoroalkyle facultativement ramifié, R2, R3, R4 et R5 sont chacun indépendamment un groupe méthyle, [3H]-méthyle, fluoroalkyle ou [18F]-fluoroalkyle, et R6 est un groupe (R)-cyano ou un groupe (S)-cyano ; ou dans laquelle R1 est un groupe méthyle, et R3<sb /> est un groupe fluoroalkyle ou un groupe [18F]-fluoroalkyle, R2, R4 et R5 sont chacun indépendamment un groupe méthyle, [3H]-méthyle, fluoroalkyle ou [18F]-fluoroalkyle, et R6 est un groupe (R)-cyano ou un groupe (S)-cyano ; ou dans lequel, si R1 est hydrogène, au moins l'un de R2, R3, R4 est un groupe fluoroalkyle ou [18F]-fluoroalkyle facultativement ramifié.
PCT/NL2013/050925 2012-12-21 2013-12-19 Composés analogues au vérapamil Ceased WO2014098593A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NL2010036 2012-12-21
NL2010036A NL2010036C2 (en) 2012-12-21 2012-12-21 Verapamil like compounds.

Publications (2)

Publication Number Publication Date
WO2014098593A1 WO2014098593A1 (fr) 2014-06-26
WO2014098593A9 true WO2014098593A9 (fr) 2014-10-23

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WO2010081036A2 (fr) * 2009-01-09 2010-07-15 President And Fellows Of Harvard College Composés fluorés et leurs procédés d'utilisation

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WO2014098593A1 (fr) 2014-06-26

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