WO2009073677A1 - Fluoroalkyl tetrabenazine carbinol compounds as imaging agents and probes - Google Patents

Fluoroalkyl tetrabenazine carbinol compounds as imaging agents and probes Download PDF

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Publication number
WO2009073677A1
WO2009073677A1 PCT/US2008/085304 US2008085304W WO2009073677A1 WO 2009073677 A1 WO2009073677 A1 WO 2009073677A1 US 2008085304 W US2008085304 W US 2008085304W WO 2009073677 A1 WO2009073677 A1 WO 2009073677A1
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Prior art keywords
aliphatic radical
radical
hydrogen
compound according
compound
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PCT/US2008/085304
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French (fr)
Inventor
Kande Kankananamalage Dayarathna Amarasinghe
Michael James Rishel
Sean Richard Dinn
Bruce Fletcher Johnson
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General Electric Company
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Priority claimed from US11/952,340 external-priority patent/US7919622B2/en
Priority claimed from US11/952,325 external-priority patent/US8013161B1/en
Application filed by General Electric Company filed Critical General Electric Company
Priority to JP2010537023A priority Critical patent/JP5597835B2/en
Priority to EP08856745.8A priority patent/EP2220085B1/en
Priority to ES08856745.8T priority patent/ES2451661T3/en
Priority to CN200880119947.7A priority patent/CN101889013B/en
Publication of WO2009073677A1 publication Critical patent/WO2009073677A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems

Definitions

  • This invention relates to carbinol compounds related to tetrabenazine and intermediates useful in the preparation of such fluoroalkyl tetrabenazine carbinol compounds
  • dihydrotetrabenazine has been identified as an agent for the treatment of schizophrenia and other psychoses (See for example WO 2007017654 Al), and tetrabenazine has shown promise as an agent in the treatment of Huntington's disease (Neurology (2006), 66(3), 366-372).
  • tetrabenazine has shown promise as an agent in the treatment of Huntington's disease (Neurology (2006), 66(3), 366-372).
  • most preparations used in biological studies of tetrabenazine and its derivatives have been carried out on racemates, in at least one instance the biological activity exhibited by enantiomers tested separately was highly differentiated (See Koeppe, R. A. et al. (1999) Assessment of extrastriatal vesicular monoamine transporter binding site density using stereoisomers of [HC] dihydrotetrabenazine, J Cereb Blood Flow Metab 19, 1376-1384).
  • the present invention provides both a new class of fluorinated tetrabenazine derivatives and fluorinated tetrabenazine analogs, and discloses efficient synthetic methodology, which may be used to prepare such compounds in enantiomerically enriched or racemic forms.
  • the fluoroalkyl tetrabenazine carbinol compounds provided by the present invention are useful as PET imaging agents, probes for the development of PET imaging agents, and therapeutic agents.
  • the present invention provides novel synthetic intermediate compositions, which may be used to prepare either or both enantiomers of the subject tetrabenazine derivatives.
  • the present invention provides a fluoroalkyl tetrabenazine carbinol compound having structure I
  • R 1 is a C 1 -C 1O fluorinated aliphatic radical
  • R 2 is a C 1 -C 1O aliphatic radical
  • R 3 is hydrogen or a C 1 -C 1 O aliphatic radical
  • R 4 is hydrogen or a C 1 -C 1 O aliphatic radical
  • R is hydrogen, a C 1 -C 1 O aliphatic radical, a C 2 -C 1 O cycloaliphatic radical, or a C 2 - C 2 o aromatic radical.
  • the present invention provides a PET imaging agent comprising a fluoroalkyl tetrabenazine carbinol compounds having structure I
  • R 1 is a C 1 -C 1O fluorinated aliphatic radical comprising at least one fluorine- 18 atom
  • R 2 is a C 1 -C 1 O aliphatic radical
  • R 3 is hydrogen or a C 1 -C 1 O aliphatic radical
  • R 4 is hydrogen or a C 1 -C 1O aliphatic radical
  • R is hydrogen, a C 1 -C 1O aliphatic radical, a C 2 -C 1O cycloaliphatic radical, or a C 2 -C 2O aromatic radical.
  • the present invention provides fluoroalkyl tetrabenazine carbinol compounds having structure IV
  • R 1 is a C 1 -C 1 O fluorinated aliphatic radical
  • R 2 is a C 1 -C 1 O aliphatic radical
  • R 3 is hydrogen or a C 1 -C 1 O aliphatic radical
  • R 4 is hydrogen or a C 1 -C 1 O aliphatic radical.
  • the present invention provides a PET imaging agent comprising a fluoroalkyl tetrabenazine carbinol compounds having structure IV
  • R 1 is a C 1 -C 1 O fluorinated aliphatic radical
  • R 2 is a C 1 -C 1 O aliphatic radical
  • R 3 is hydrogen or a C 1 -C 1 O aliphatic radical
  • R 4 is hydrogen or a C 1 -C 1 O aliphatic radical.
  • solvent can refer to a single solvent or a mixture of solvents.
  • Approximating language may be applied to modify any quantitative representation that could permissibly vary without resulting in a change in the basic function to which it is related. Accordingly, a value modified by a term or terms, such as "about”, is not to be limited to the precise value specified. In some instances, the approximating language may correspond to the precision of an instrument for measuring the value.
  • aromatic radical refers to an array of atoms having a valence of at least one comprising at least one aromatic group.
  • the array of atoms having a valence of at least one comprising at least one aromatic group may include heteroatoms such as nitrogen, sulfur, selenium, silicon and oxygen, or may be composed exclusively of carbon and hydrogen.
  • aromatic radical includes but is not limited to phenyl, pyridyl, furanyl, thienyl, naphthyl, phenylene, and biphenyl radicals.
  • the aromatic radical contains at least one aromatic group.
  • the aromatic radical may also include nonaromatic components.
  • a benzyl group is an aromatic radical, which comprises a phenyl ring (the aromatic group) and a methylene group (the nonaromatic component).
  • a tetrahydronaphthyl radical is an aromatic radical comprising an aromatic group (C O H 3 ) fused to a nonaromatic component -(CH 2 ) 4 -.
  • aromatic radical is defined herein to encompass a wide range of functional groups such as alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, haloaromatic groups, conjugated dienyl groups, alcohol groups, ether groups, aldehyde groups, ketone groups, carboxylic acid groups, acyl groups (for example carboxylic acid derivatives such as esters and amides), amine groups, nitro groups, and the like.
  • the A- methylphenyl radical is a C 7 aromatic radical comprising a methyl group, the methyl group being a functional group which is an alkyl group.
  • the 2-nitrophenyl group is a C 6 aromatic radical comprising a nitro group, the nitro group being a functional group.
  • Aromatic radicals include halogenated aromatic radicals such as A- trifluoromethylphenyl, hexafluoroisopropylidenebis(4-phen- 1-yloxy) (i.e.,
  • 3-trichloromethylphen-l-yl i.e., 3-CCl 3 Ph-
  • 4-(3-bromoprop-l-yl)phen-l-yl i.e., A- BrCH 2 CH 2 CH 2 Ph-
  • A- BrCH 2 CH 2 CH 2 Ph- 4-(3-bromoprop-l-yl)phen-l-yl
  • aromatic radicals include A- allyloxyphen-1-oxy, 4-aminophen-l-yl (i.e., 4-H 2 NPh-), 3-aminocarbonylphen-l-yl (i.e., NH 2 COPh-), 4-benzoylphen-l-yl, dicyanomethylidenebis(4-phen- 1-yloxy) (i.e., -OPhC(CN) 2 PhO-), 3-methylphen-l-yl, methylenebis(4-phen- 1-yloxy) (i.e., -OPhCH 2 PhO-), 2-ethylphen-l-yl, phenylethenyl, 3-formyl-2-thienyl, 2-hexyl-5- furanyl, hexamethylene-l,6-bis(4-phen- 1-yloxy) (i.e., -OPh(CH 2 ) 6 PhO-), A- hydroxymethylphen-1-yl (i.e., 4-
  • a C 3 - C 1O aromatic radical includes aromatic radicals containing at least three but no more than 10 carbon atoms.
  • the aromatic radical 1-imidazolyl (C 3 H 2 N 2 -) represents a C 3 aromatic radical.
  • the benzyl radical (C 7 H 7 -) represents a C 7 aromatic radical.
  • cycloaliphatic radical refers to a radical having a valence of at least one, and comprising an array of atoms which is cyclic but which is not aromatic. As defined herein a “cycloaliphatic radical” does not contain an aromatic group.
  • a "cycloaliphatic radical” may comprise one or more noncyclic components.
  • a cyclohexylmethyl group C O H 11 CH 2 -
  • a cycloaliphatic radical which comprises a cyclohexyl ring (the array of atoms which is cyclic but which is not aromatic) and a methylene group (the noncyclic component).
  • the cycloaliphatic radical may include heteroatoms such as nitrogen, sulfur, selenium, silicon and oxygen, or may be composed exclusively of carbon and hydrogen.
  • cycloaliphatic radical is defined herein to encompass a wide range of functional groups such as alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, conjugated dienyl groups, alcohol groups, ether groups, aldehyde groups, ketone groups, carboxylic acid groups, acyl groups (for example carboxylic acid derivatives such as esters and amides), amine groups, nitro groups, and the like.
  • the 4-methylcyclopent-l-yl radical is a C 6 cycloaliphatic radical comprising a methyl group, the methyl group being a functional group which is an alkyl group.
  • the 2-nitrocyclobut-l-yl radical is a C 4 cycloaliphatic radical comprising a nitro group, the nitro group being a functional group.
  • a cycloaliphatic radical may comprise one or more halogen atoms which may be the same or different. Halogen atoms include, for example; fluorine, chlorine, bromine, and iodine.
  • Cycloaliphatic radicals comprising one or more halogen atoms include 2-trifluoromethylcyclohex-l- yl, 4-bromodifluoromethylcyclooct- 1 -yl, 2-chlorodifluoromethylcyclohex- 1 -yl, hexafluoroisopropylidene-2,2-bis (cyclohex-4-yl) (i.e., -C 6 H 10 C(CF 3 ) 2 C 6 H 10 -), 2- chloromethylcyclohex-1-yl, 3- difluoromethylenecyclohex-1-yl, A- trichloromethylcyclohex- 1 -yloxy, 4-bromodichloromethylcyclohex- 1 -ylthio, 2- bromoethylcyclopent-1-yl, 2-bromopropylcyclohex- 1 -yloxy (e.g.,
  • cycloaliphatic radicals include 4-allyloxycyclohex-l-yl, 4-aminocyclohex-l-yl (i.e., H 2 NC 6 H 1 O-), A- aminocarbonylcyclopent-1-yl (i.e., NH 2 COCsH 8 -), 4-acetyloxycyclohex-l-yl, 2,2- dicyanoisopropylidenebis(cyclohex-4-yloxy) (i.e., -OC 6 H 10 C(CN) 2 C 6 H 10 O-), 3- methylcyclohex-1-yl, methylenebis(cyclohex-4-yloxy) (i.e., -OC O H 1O CH 2 C O H 1O O-), 1- ethylcyclobut-1-yl, cyclopropylethenyl, 3-formyl-2-terahydrofuranyl,
  • the terai "a C 3 - C 1 O cycloaliphatic radical” includes cycloaliphatic radicals containing at least three but no more than 10 carbon atoms.
  • the cycloaliphatic radical 2-tetrahydrofuranyl (C 4 H 7 O-) represents a C 4 cycloaliphatic radical.
  • the cyclohexylmethyl radical (C 6 H 11 CH 2 -) represents a C 7 cycloaliphatic radical.
  • aliphatic radical refers to an organic radical having a valence of at least one consisting of a linear or branched array of atoms, which is not cyclic. Aliphatic radicals are defined to comprise at least one carbon atom.
  • the array of atoms comprising the aliphatic radical may include heteroatoms such as nitrogen, sulfur, silicon, selenium and oxygen or may be composed exclusively of carbon and hydrogen.
  • aliphatic radical is defined herein to encompass, as part of the "linear or branched array of atoms which is not cyclic" a wide range of functional groups such as alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, conjugated dienyl groups, alcohol groups, ether groups, aldehyde groups, ketone groups, carboxylic acid groups, acyl groups (for example carboxylic acid derivatives such as esters and amides), amine groups, nitro groups, and the like.
  • the 4-methylpent-l-yl radical is a C 6 aliphatic radical comprising a methyl group, the methyl group being a functional group which is an alkyl group.
  • the 4-nitrobut-l-yl group is a C 4 aliphatic radical comprising a nitro group, the nitro group being a functional group.
  • An aliphatic radical may be a haloalkyl group which comprises one or more halogen atoms which may be the same or different.
  • Halogen atoms include, for example; fluorine, chlorine, bromine, and iodine.
  • Aliphatic radicals comprising one or more halogen atoms include the alkyl halides trifluoromethyl, bromodifluoromethyl, chlorodifluoromethyl, hexafluoroisopropylidene, chloromethyl, difluorovinylidene, trichloromethyl, bromodichloromethyl, bromoethyl, 2-bromotrimethylene (e.g., -CH 2 CHBrCH 2 -), and the like.
  • aliphatic radicals include allyl, aminocarbonyl (i.e., - CONH 2 ), carbonyl, 2,2-dicyanoisopropylidene (i.e., -CH 2 C(CN) 2 CH 2 -), methyl (i.e., - CH 3 ), methylene (i.e., -CH 2 -), ethyl, ethylene, formyl (i.e.,-CHO), hexyl, hexamethylene, hydroxymethyl (i.e.
  • a C 1 - C 1O aliphatic radical contains at least one but no more than 10 carbon atoms.
  • a methyl group i.e., CH 3 -
  • a decyl group i.e., CH 3 (CH 2 )cr
  • CH 3 (CH 2 )cr is an example of a C 1O aliphatic radical.
  • the present invention provides a fluoroalkyl tetrabenazine carbinol compound having structure I
  • R 1 is a C 1 -C 1 O fluorinated aliphatic radical
  • R 2 is a C 1 -C 1 O aliphatic radical
  • R 3 is hydrogen or a C 1 -C 1O aliphatic radical
  • R 4 is hydrogen or a C 1 -C 1O aliphatic radical
  • R is hydrogen, a C 1 -C 1O aliphatic radical, a C 2 -C 1O cycloaliphatic radical, or a C 2 - C 2 o aromatic radical.
  • the present invention provides a fluoroalkyl tetrabenazine carbinol compound having structure IV
  • R 1 is a C 1 -C 1O fluorinated aliphatic radical
  • R 2 is a C 1 -C 1O aliphatic radical
  • R 3 is hydrogen or a C 1 -C 1 O aliphatic radical
  • R 4 is hydrogen or a C 1 -C 1 O aliphatic radical.
  • fluoroalkyl tetrabenazine carbinol compound refers to compounds falling within the scope of generic structure I and includes compounds in which R 5 is hydrogen (fluoroalkyl tetrabenazine compounds having a tertiary hydroxy group at ring position-2), as well as compounds in which R 5 is a C 1 -C 1 O aliphatic radical, a C 2 -C 1 O cycloaliphatic radical, or a C 2 -C 2 O aromatic radical (fluoroalkyl tetrabenazine carbinol compounds incorporating a derivative of a tertiary hydroxy group at ring position-2).
  • compounds defined by generic structure I are referred to at times herein as "tetrabenazine carbinol compounds”.
  • R 1 is suitably selected from Ci- ⁇ fluoroalkyl, C 2 - ⁇ fluoroalkenyl, C 2 - ⁇ fluoroalkynyl C 1 - 6 fluoroalkoxy(C 1 _ 6 alkyl), Ci- ⁇ fluorohaloalkyl, Ci- ⁇ fluorohydroxyalkyl, and Ci- ⁇ fluoroalkylcarbony ⁇ Ci- ⁇ alkyl).
  • R 1 is C 2 . ⁇ fluoroalkynyl.
  • R 2 is suitably selected from Ci- ⁇ alkyl and C 3 -scycloalkyl and is more suitably C 1- ealkyl;
  • R 3 and R 4 are each suitably independently selected from C h alky! and C ⁇ ⁇ alkoxy.
  • R is suitably selected from hydrogen, (Ci- 6 alkyl)carbonyl, and phenyl.
  • R is hydrogen.
  • R 5 is (Ci_ 6 alkyl)carbonyl, more suitably CH 3 C(O)-.
  • fluoroalkyl tetrabenazine carbinol compounds provided by the present invention are shown herein to possess a high affinity for Type 2 Vesicular Monoamine
  • VMAT-2 Transporters (VMAT-2), a group of biomarkers, which correlate inter alia with diabetic activity in human patients.
  • VMAT-2 a group of biomarkers, which correlate inter alia with diabetic activity in human patients.
  • VMAT-2 biomarker VMAT-2 biomarker
  • the present invention provides radiolabeled fluoroalkyl tetrabenazine carbinol compounds falling within the scope of generic structure I comprising a fluorine- 18 atom.
  • the present invention provides radiolabeled fluoroalkyl tetrabenazine carbinol compounds falling within the scope of generic structure IV comprising a fluorine- 18 atom.
  • Fluorine- 18 labeled fluoroalkyl tetrabenazine carbinol compounds I and fluoroalkyl tetrabenazine carbinol compounds IV are suitable for use as imaging agents for positron emission tomography (PET) screening of human patients for example, for pathological conditions related to diabetes. Positron emission tomography has become a medical imaging technique of critical importance to human health.
  • the present invention provides fluoroalkyl tetrabenazine carbinol compounds falling within the scope of generic structure I and comprising a fluorine- 19 atom, a stable isotope of fluorine.
  • the fluoroalkyl tetrabenazine carbinol compounds comprising a fluorine- 19 atom are useful in binding studies which allow the identification of those fluoroalkyl tetrabenazine carbinol compounds possessing optimal affinity for a target biomarker, for example VMAT-2.
  • a substantial binding affinity of a given fluorine- 19 containing fluoroalkyl tetrabenazine carbinol compound for a target biomarker such as VMAT-2 is a reliable predictor of utility in PET imaging of the corresponding fluorine- 18 containing fluoroalkyl tetrabenazine carbinol compound.
  • fluoroalkyl tetrabenazine carbinol compounds I and IV show substantial binding affinity for the biomarker VMAT-2.
  • fluoroalkyl tetrabenazine carbinol compounds provided by the present invention are useful in the study and treatment of variety of human and animal diseases as imaging agents, as probes for the development of imaging agents, and as therapeutic agents.
  • Fluoroalkyl tetrabenazine carbinol compounds having structure I are illustrated in Table 1 below.
  • structure I depicts a fluoroalkyl tetrabenazine carbinol compound in which no absolute or relative stereochemistry is shown.
  • structure I is intended to represent a genus of fluoroalkyl tetrabenazine carbinol compounds which includes the racemic compound Ia (Table 1) having both the R configuration and S configuration at ring positions-2, -3 and -12.
  • structure I represents fluoroalkyl tetrabenazine carbinol compound Ib (Table 1) having the R configuration (absolute stereochemistry) at ring positions-2, -3 and -12.
  • structure I represents compound Id (Table 1) having absolute stereochemistry opposite that of compound Ib.
  • the present invention provides a fluoroalkyl tetrabenazine carbinol compound having structure I which may be a racemic mixture (e.g. compound Ia (Table 1), a single enantiomer (e.g. compound Ib (Table 1), or a composition enantiomerically enriched in a single principal component enantiomer.
  • Entries 2a-2c in Table 2 below illustrate fluoroalkyl tetrabenazine carbinol compounds I comprising a principal component enantiomer and at least one minor component enantiomer.
  • Entry 2a represents a fluoroalkyl tetrabenazine carbinol composition comprising 95 mole% of the R, R, R principal component enantiomer shown and a lesser amount of the S, S, S minor component enantiomer.
  • Entry 2c represents a fluoroalkyl tetrabenazine carbinol composition comprising 88 mole percent of the S, S, S principal component enantiomer having the structure shown and a lesser amount of the R, R, R minor component enantiomer.
  • the fluoroalkyl tetrabenazine carbinol compositions provided by the present invention may comprise a principal component enantiomer, a minor component enantiomer, and additional diastereomeric fluoroalkyl tetrabenazine carbinol components.
  • the present invention provides a fluoroalkyl tetrabenazine carbinol composition comprising a principal component enantiomer and related diastereomers.
  • the present invention provides a fluoroalkyl tetrabenazine carbinol composition having no principal component enantiomer and which is a diastereomeric mixture.
  • the present invention provides a fluoroalkyl tetrabenazine carbinol compound represented by structure I, which is enantiomerically enriched and is comprised of at least 95 mole percent (mole %) of an enantiomer having the R configuration at ring position- 12.
  • the present invention provides a fluoroalkyl tetrabenazine carbinol compound represented by structure I, which is enantiomerically enriched and is comprised of at least 95 mole percent (mole %) of an enantiomer having the R configuration at ring position-2.
  • the present invention provides a fluoroalkyl tetrabenazine carbinol compound having structure I in which the fluorinated aliphatic radical at ring position-2 (-R 1 ) has a syn-configuration relative to the hydrogen at ring position- 12.
  • the principal component enantiomers of Entries 2a-2b of Table 2 illustrate fluoroalkyl tetrabenazine carbinol compounds in which the fluorinated aliphatic moiety at ring position-2 (-R 1 ) has a syn-configuration relative to the hydrogen at ring position- 12.
  • the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising a principal component enantiomer having structure II
  • R 1 is a C 1 -C 1O fluorinated aliphatic radical
  • R 2 is a C 1 -C 1O aliphatic radical
  • R 3 is hydrogen or a C 1 -C 1 O aliphatic radical
  • R 4 is hydrogen or a C 1 -C 1 O aliphatic radical
  • R is hydrogen, a C 1 -C 1 O aliphatic radical, a C 2 -C 1 O cycloaliphatic radical, or a C 2 - C 2 o aromatic radical.
  • the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising at least 80 mole percent of an enantiomer having structure II, for example the composition comprising the compound of Entry 3a (Table 3) wherein the R, R, R enantiomer shown represents at least 80 mole percent relative to the amounts of all other fluoroalkyl tetrabenazine carbinol components in the composition.
  • the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound which is comprised of at least 95 mole % of an enantiomer having structure II, for example a fluoroalkyl tetrabenazine carbinol composition comprising the compound of Entry 3b (Table 3) wherein the enantiomer shown represents at least 95 mole percent relative to the amounts of all other fluoroalkyl tetrabenazine carbinol components in the composition.
  • the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising a principal component enantiomer having structure III
  • R 1 is a C 1 -C 1O fluorinated aliphatic radical
  • R 2 is a C 1 -C 1O aliphatic radical
  • R 3 is hydrogen or a C 1 -C 1O aliphatic radical
  • R 4 is hydrogen or a C 1 -C 1O aliphatic radical
  • R 5 is hydrogen, a C 1 -C 1 O aliphatic radical, a C 2 -C 1 O cycloaliphatic radical, or a C 2 - C 2 o aromatic radical.
  • the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising at least 80 mole percent of an enantiomer having structure III, for example a fluoroalkyl tetrabenazine carbinol composition comprising the compound of Entry 4a (Table 4) wherein the S, S, S enantiomer shown represents at least 80 mole percent relative to the amounts of all other fluoroalkyl tetrabenazine carbinol components in the composition.
  • a fluoroalkyl tetrabenazine carbinol composition comprising the compound of Entry 4a (Table 4) wherein the S, S, S enantiomer shown represents at least 80 mole percent relative to the amounts of all other fluoroalkyl tetrabenazine carbinol components in the composition.
  • the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising at least 95 mole percent of an enantiomer having structure III, for example a fluoroalkyl tetrabenazine carbinol composition comprising the compound of Entry 4b (Table 4) wherein the S, S, S enantiomer shown represents at least 95 mole percent relative to the amounts of all other fluoroalkyl tetrabenazine carbinol components in the composition.
  • the group -OR 5 is not a hydroxy group and is instead a C 1 -C 1O aliphatic radical, a C 2 -C 1O cycloaliphatic radical, or a C 2 -C 2O aromatic radical.
  • the group -OR 5 is an ester moiety, for example an acetate group as exemplified by Entry Ia of Table 1, or for example an aryl ether moiety, for example a phenoxy group as exemplified by Entry Ig of Table 1.
  • the group -OR 5 is an aliphatic ester moiety selected from the group consisting of formate, acetate, propanoate, butanoate, pentanoate, hexanoate, and heptanoate.
  • the group -OR 5 is a silyl ether moiety, for example triethylsilyloxy.
  • the present invention provides novel fluoroalkyl tetrabenazine carbinol compounds I and IV, and in certain embodiments, mixtures thereof.
  • Fluoroalkyl tetrabenazine carbinol compounds having structure IV are illustrated in Table 5 below.
  • Structure IV represents a genus of fluoroalkyl tetrabenazine carbinol compounds which includes the racemic compound 5a (Table 5) having both the R configuration and S configuration at ring positions-2, -3, and -12.
  • structure IV represents fluoroalkyl tetrabenazine carbinol compound 5b (Table 5) having the R configuration (absolute stereochemistry) at ring positions-2, -3, and -12.
  • structure IV represents compound 5d (Table 5) having absolute stereochemistry opposite that of compound 5b.
  • fluoroalkyl tetrabenazine carbinol compounds shown in Table 5 herein are illustrative of tetrabenazine carbinol derivatives falling within the scope of generic structure IV.
  • fluoroalkyl tetrabenazine carbinol compounds 5a, 5c, 5g, 5i and 5j represent racemic mixtures.
  • the present invention provides a fluoroalkyl tetrabenazine carbinol compound having structure IV which may be a racemic mixture (e.g. compound 5a (Table 5), a single enantiomer (e.g. compound 5b (Table 5), or a composition enantiomerically enriched in a single principal component enantiomer.
  • Entries 6a-6c in Table 6 below illustrate fluoroalkyl tetrabenazine carbinol compounds IV comprising a principal component enantiomer and at least one minor component enantiomer.
  • the fluoroalkyl tetrabenazine carbinol compositions comprise a principal component enantiomer and a minor component enantiomer.
  • the mole percentage of the principal component enantiomer is given as "mole%" and refers to the mole percentage of the principal component enantiomer having the structure shown relative to the amounts of all other fluoroalkyl tetrabenazine carbinol components in the composition.
  • a fluoroalkyl tetrabenazine carbinol is any compound falling within the scope of generic structure I.
  • Entry 6a represents a fluoroalkyl tetrabenazine carbinol composition comprising 98 mole% of the R, R, R principal component enantiomer shown and a lesser amount of the S, S, S minor component enantiomer.
  • Entry 6c represents a fluoroalkyl tetrabenazine carbinol composition comprising 88 mole percent of the S, S, S principal component enantiomer having the structure shown and a lesser amount of the R, R, R minor component enantiomer.
  • the present invention provides a fluoroalkyl tetrabenazine carbinol compound represented by structure IV, which is enantiomerically enriched and is comprised of at least 95 mole percent (mole %) of an enantiomer having the R configuration at ring position- 12.
  • the present invention provides a fluoroalkyl tetrabenazine carbinol compound represented by structure IV, which is enantiomerically enriched and is comprised of at least 95 mole percent (mole %) of an enantiomer having the R configuration at ring position-2.
  • the present invention provides a fluoroalkyl tetrabenazine carbinol compound having structure IV in which the fluorinated aliphatic radical at ring position-2 (-R 1 ) has a syn-configuration relative to the hydrogen at ring position- 12.
  • the principal component enantiomers of Entries 6a-6c of Table 6 illustrate fluoroalkyl tetrabenazine carbinol compounds in which the fluorinated aliphatic moiety at ring position-2 (-R 1 ) has a syn-configuration relative to the hydrogen at ring position- 12.
  • the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising a principal component enantiomer having structure V
  • R 1 is a C 1 -C 1O fluorinated aliphatic radical
  • R 2 is a C 1 -C 1O aliphatic radical
  • R 3 is hydrogen or a C 1 -C 1O aliphatic radical
  • R 4 is hydrogen or a C 1 -C 1O aliphatic radical.
  • the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising at least 80 mole percent of an enantiomer having structure V, for example the composition comprising the compound of Entry 7a (Table 7) wherein the R, R, R enantiomer shown represents at least 80 mole percent relative to the amounts of all other fluoroalkyl tetrabenazine carbinol components in the composition.
  • the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound, which is comprised of at least 95 mole % of an enantiomer having structure V, for example an fluoroalkyl tetrabenazine carbinol composition comprising the compound of Entry 7b (Table 7 wherein the R, R, R enantiomer shown represents at least 95 mole percent relative to the amounts of all other fluoroalkyl tetrabenazine carbinol components in the composition.
  • the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising a principal component enantiomer having structure VI
  • R 1 is a C 1 -C 1O aliphatic radical
  • R 3 is hydrogen or a C 1 -C 1 O aliphatic radical
  • R 4 is hydrogen or a C 1 -C 1 O aliphatic radical.
  • the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising at least 80 mole percent of an enantiomer having structure VI, for example a fluoroalkyl tetrabenazine carbinol composition comprising the compound of Entry 8a (Table 8) wherein the S, S, S enantiomer shown represents at least 80 mole percent relative to the amounts of all other fluoroalkyl tetrabenazine carbinol components in the composition.
  • the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising at least 95 mole percent of an enantiomer having structure VI, for example a fluoroalkyl tetrabenazine carbinol composition comprising the compound of Entry 8b (Table 8) wherein the S, S, S enantiomer shown represents at least 95 mole percent relative to the amounts of all other fluoroalkyl tetrabenazine carbinol components in the composition.
  • the present invention provides an enantiomeric ally enriched fluoroalkyl tetrabenazine carbinol compound having structure IV, wherein R 1 is a C 1 - C 1O fluorinated aliphatic radical comprising at least one fluorine- 18 atom; R is a C 5 - C 1O aliphatic radical; and R 3 and R 4 are methoxy groups.
  • fluoroalkyl refers to the group R 1 of structures I- VI which represents a C 1 -C 1O aliphatic radical and is not restricted to the ordinary meaning of the term “alkyl”.
  • fluoroalkyl tetrabenazine carbinol is used extensively herein for convenience and means a tetrabenazine compound falling within the scope of generic structure I and comprising a C 1 -C 1O fluorinated aliphatic radical at ring position-2.
  • the fluorine- 18 labeled compounds of formula (I), (II), (III), (IV), (V), and (VI) have use as PET imaging agents for the VMAT-2 biomarker. Therefore, according to a further aspect of the invention, there is provided a method for detection of VMAT-2 in a subject, comprising :
  • Such a method provides information and data having utility in the diagnosis and clinical research of VMAT-2 related disorders, for example by providing a method for determining beta cell mass.
  • the subject is a mammal, most suitably a human who has or is suspected of having a VMAT-2 related disorder.
  • a compound of formula (I), (II), (III), (IV), (V) or (VI) as defined above, or a salt thereof may also be used to image VMAT-2 in healthy human volunteers for example for clinical research purposes.
  • the imaging of VMAT-2 may be carried out quantitatively such that the amount or change in amount of VMAT-2 may be determined so as to diagnose or track progress of a disease. Alternatively the imaging of VMAT-2 may be used to locate VMAT-2.
  • VMAT-2 related disorder means a VMAT-2 related disease in the brain such as Huntington's, Parkinson's, or schizophrenia, or of the pancreas such as beta cell associated disorder including an insulinoma or other neuroendocrine tumour, or diabetes (for example type 1 diabetes, type 2 diabetes, or preclinical type 1 diabetes).
  • the VMAT-2 related disorder is diabetes.
  • the VMAT-2 related disorder is schizophrenia.
  • a fluorine- 18 labeled compound of formula (I), (II), (III), (IV), (V) or (VI) or a salt thereof in the manufacture of a radiopharmaceutical for the in vivo PET diagnosis or imaging of a VMAT-2 related disorder.
  • a fluorine- 18 labeled compound of formula (I), (II), (III), (IV), (V) or (VI) or a salt thereof for use in the in vivo PET diagnosis or imaging of a VMAT-2 related disorder.
  • a method for the in vivo diagnosis or imaging of a VMAT-2 related disorder in a subject comprising administration of a fluorine- 18 labeled compound of formula (I), (II), (III), (IV), (V) or (VI) or a salt thereof and detecting the uptake of said compound by an in vivo PET imaging technique.
  • the method is especially preferred for the in vivo diagnosis or imaging of diabetes.
  • the method comprises detecting the uptake of a fluorine- 18 labeled compound of formula (I), (II), (III), (IV), (V) or (VI) or a salt thereof by an in vivo PET imaging technique in a subject, preferably a human to whom said compound has been pre-administered.
  • the invention further provides a method of monitoring the effect of treatment of a subject, preferably a human with a drug to combat a VMAT-2 related disorder, said method comprising administering to said subject a fluorine- 18 labeled compound of formula (I), (II), (III), (IV), (V) or (VI) or a salt thereof and detecting the uptake of said compound by an in vivo PET imaging technique, said administration and detection optionally but preferably being effected repeatedly, e.g. before, during and after treatment with said drug.
  • a compound of formula (I), (II), (III), (IV), (V) or (VI) or a salt thereof is preferably administered for in vivo use in a pharmaceutical formulation comprising said compound and a pharmaceutically acceptable excipient, such formulations thus form a further aspect of the invention.
  • a "pharmaceutical formulation” is defined in the present invention as a formulation comprising an effective amount of a compound of formula (I), (II), (III), (IV), (V) or (VI) or a salt thereof in a form suitable for administration to a mammal, suitably a human.
  • the "pharmaceutically acceptable excipient” is a suitably a fluid, especially a liquid, in which the compound of formula (I), (II), (III), (IV), (V) or (VI) or a salt thereof can be suspended or dissolved, such that the formulation is physiologically tolerable, ie. can be administered to the mammalian body without toxicity or undue discomfort.
  • the pharmaceutically acceptable excipient is suitably an injectable carrier liquid such as sterile, pyrogen- free water for injection; an aqueous solution such as saline (which may advantageously be balanced so that the final formulation for injection is isotonic); an aqueous solution of one or more tonicity-adjusting substances (for example, salts of plasma cations with biocompatible counterions), sugars (for example, glucose or sucrose), sugar alcohols (for example, sorbitol or mannitol), glycols (for example. glycerol), or other non-ionic polyol materials (for example, polyethyleneglycols, propylene glycols and the like).
  • the pharmaceutically acceptable excipient is pyrogen-free water for injection or isotonic saline.
  • the pharmaceutical formulation may optionally contain additional excipients such as an antimicrobial preservative, pH-adjusting agent, filler, stabiliser or osmolality adjusting agent.
  • an antimicrobial preservative is meant an agent which inhibits the growth of potentially harmful micro-organisms such as bacteria, yeasts or moulds.
  • the antimicrobial preservative may also exhibit some bactericidal properties, depending on the dosage employed.
  • the main role of the antimicrobial preservative(s) of the present invention is to inhibit the growth of any such micro- organism in the pharmaceutical formulation.
  • the antimicrobial preservative may, however, also optionally be used to inhibit the growth of potentially harmful micro- organisms in one or more components of kits used to prepare said pharmaceutical formulation prior to administration.
  • Suitable antimicrobial preservative(s) include: the parabens, ie. methyl, ethyl, propyl or butyl paraben or mixtures thereof; benzyl alcohol; phenol; cresol; cetrimide and thiomersal.
  • Preferred antimicrobial preservative(s) are the parabens.
  • pH-adjusting agent means a compound or mixture of compounds useful to ensure that the pH of the pharmaceutical formulation is within acceptable limits (approximately pH 4.0 to 10.5) for human or mammalian administration. Suitable such pH-adjusting agents include pharmaceutically acceptable buffers, such as tricine, phosphate or TRIS [ie. r ⁇ s(hydroxymethyl)aminomethane], and pharmaceutically acceptable bases such as sodium carbonate, sodium bicarbonate or mixtures thereof.
  • the pH adjusting agent may optionally be provided in a separate vial or container, so that the user of the kit can adjust the pH as part of a multi-step procedure.
  • filler is meant a pharmaceutically acceptable bulking agent which may facilitate material handling during production and lyophilisation.
  • suitable fillers include inorganic salts such as sodium chloride, and water soluble sugars or sugar alcohols such as sucrose, maltose, mannitol or trehalose.
  • the pharmaceutical formulations of the invention are typically supplied in suitable vials or vessels which comprise a sealed container which permits maintenance of sterile integrity and/or radioactive safety, plus optionally an inert headspace gas (eg. nitrogen or argon), whilst permitting addition and withdrawal of solutions by syringe or cannula.
  • a sealed container which permits maintenance of sterile integrity and/or radioactive safety, plus optionally an inert headspace gas (eg. nitrogen or argon), whilst permitting addition and withdrawal of solutions by syringe or cannula.
  • a preferred such container is a septum- sealed vial, wherein the gas-tight closure is crimped on with an overseal (typically of aluminium).
  • the closure is suitable for single or multiple puncturing with a hypodermic needle (e.g. a crimped-on septum seal closure) whilst maintaining sterile integrity.
  • Such containers have the additional advantage that the closure can withstand vacuum if desired (eg.
  • Preferred multiple dose containers comprise a single bulk vial (e.g. of 10 to 30 cm 3 volume) which contains multiple patient doses, whereby single patient doses can thus be withdrawn into clinical grade syringes at various time intervals during the viable lifetime of the preparation to suit the clinical situation.
  • Pre-filled syringes are designed to contain a single human dose, or "unit dose” and are therefore preferably a disposable or other syringe suitable for clinical use.
  • the pharmaceutical formulations of the present invention preferably have a dosage suitable for a single patient and are provided in a suitable syringe or container, as described above.
  • the pharmaceutical formulations of the invention may be prepared under aseptic manufacture (ie. clean room) conditions to give the desired sterile, non-pyro genie product. It is preferred that the key components, especially the excipients plus those parts of the apparatus which come into contact with the pharmaceutical formulation (for example, vials) are sterile.
  • the components of the pharmaceutical formulation can be sterilised by methods known in the art, including: sterile filtration, terminal sterilisation using, for example, gamma-irradiation, autoclaving, dry heat or chemical treatment (for example, with ethylene oxide). It is preferred to sterilise some components in advance, so that the minimum number of manipulations needs to be carried out. As a precaution, however, it is preferred to include at least a sterile filtration step as the final step in the preparation of the pharmaceutical formulation.
  • an "effective amount" of a compound of formula (I), (II), (III), (IV), (V) or (VI) or a salt thereof means an amount which is effective for use in in vivo PET imaging or for use in therapy and will vary depending on the exact compound to be administered, the weight of the subject or patient, and other variables as would be apparent to a physician skilled in the art.
  • the fluorine- 18 labeled compounds of this invention may be administered to a subject for PET imaging in amounts sufficient to yield the desired signal, typical radionuclide dosages of 0.01 to 100 mCi, preferably 0.1 to 50 mCi will normally be sufficient per 70kg bodyweight.
  • the fluoroalkyl tetrabenazine carbinol compounds I, II, III, IV, V, and VI provided by the present invention may comprise a fluorine- 18 atom in the fluorinated aliphatic moiety -R 1 .
  • such fluoroalkyl tetrabenazine carbinol compounds comprising a fluorine- 18 atom are useful as PET imaging agents.
  • the present invention provides a PET imaging agent comprising a fluoroalkyl tetrabenazine carbinol compound having structure I
  • R 1 is a C 1 -C 1O fluorinated aliphatic radical comprising at least one fluorine- 18 atom
  • R 2 is a C 1 -C 1 O aliphatic radical
  • R 3 is hydrogen or a C 1 -C 1 O aliphatic radical
  • R 4 is hydrogen or a C 1 -C 1 O aliphatic radical
  • R 5 is hydrogen, a C 1 -C 1 O aliphatic radical, a C 2 -C 1O cycloaliphatic radical, or a C 2 -C 2O aromatic radical.
  • the present invention provides a PET imaging agent comprising an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising a principal component enantiomer having structure II
  • R 1 is a C 1 -C 1O fluorinated aliphatic radical comprising at least one fluorine- 18 atom
  • R 2 is a C 1 -C 1 O aliphatic radical
  • R 3 is hydrogen or a C 1 -C 1 O aliphatic radical
  • R 4 is hydrogen or a C 1 -C 1 O aliphatic radical
  • R 5 is hydrogen, a C 1 -C 1 O aliphatic radical, a C 2 -C 1 Q cycloaliphatic radical, or a C 2 -C 2 Q aromatic radical.
  • the present invention provides a PET imaging agent comprising an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising a principal component enantiomer having structure III
  • R 1 is a C 1 -C 1O fluorinated aliphatic radical comprising at least one fluorine- 18 atom
  • R 2 is a C 1 -C 1 O aliphatic radical
  • R 3 is hydrogen or a C 1 -C 1 O aliphatic radical
  • R 4 is hydrogen or a C 1 -C 1 O aliphatic radical
  • R is hydrogen, a C 1 -C 1 O aliphatic radical, a C 2 -C 1O cycloaliphatic radical, or a C 2 -C 2O aromatic radical.
  • the present invention provides a PET imaging agent comprising a fluoroalkyl tetrabenazine carbinol compound having structure IV
  • R 1 is a C 1 -C 1O fluorinated aliphatic radical comprising at least one fluorine- 18 aattoomm;; RR 22 iiss aa CC 11 --CC 11O Q aalliipphhaattiicc rraaddiiccaall;; RR 33 iiss ' . hydrogen or a C 1 -C 1 Q aliphatic radical; and R 4 is hydrogen or a C 1 -C 1 Q aliphatic radical.
  • the present invention provides a PET imaging agent comprising an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising a principal component enantiomer having structure V
  • R 1 is a C 1 -C 1O fluorinated aliphatic radical comprising at least one fluorine- 18 atom
  • R 2 is a C 1 -C 1O aliphatic radical
  • R 3 is hydrogen or a C 1 -C 1O aliphatic radical
  • R 4 is hydrogen or a C 1 -C 1 O aliphatic radical.
  • the present invention provides a PET imaging agent comprising an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising a principal component enantiomer having structure VI
  • R 1 is a C 1 -C 1O fluorinated aliphatic radical comprising at least one fluorine- 18 atom
  • R 2 is a C 1 -C 1O aliphatic radical
  • R 3 is hydrogen or a C 1 -C 1O aliphatic radical
  • R 4 is hydrogen or a C 1 -C 1 Q aliphatic radical.
  • the present invention provides a PET imaging agent comprising an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound having structure IV, wherein R 1 is a C 1 -C 1O fluorinated aliphatic radical comprising at least one fluorine- 18 atom; R 2 is a Cs-C 1O aliphatic radical; and R 3 and R 4 are methoxy groups.
  • PET imaging agent refers to a composition comprising a fluorine- 18 labeled fluoroalkyl tetrabenazine carbinol compound, which may be administered to a patient in order to perform a PET scan.
  • the imaging agent is presented to the patient in the form of an aqueous formulation containing a sufficient amount of fluorine- 18 labeled fluoroalkyl tetrabenazine carbinol compound to conduct the PET scan.
  • the amount of fluorine- 18 labeled fluoroalkyl tetrabenazine carbinol compound presented to a patient corresponds to a weight of the fluorine- 18 labeled fluoroalkyl tetrabenazine carbinol compound on the order of nanograms.
  • the PET imaging agent typically has a specific activity in a range from about 1 to about 99 percent. In one embodiment, the PET imaging agent has a specific activity in a range from about 10 to about 95 percent. In another embodiment, the PET imaging agent has a specific activity in a range from about 20 to about 90 percent.
  • the aqueous formulation containing the fluorine- 18 fluoroalkyl tetrabenazine carbinol compound is typically administered intravenously and may contain various agents, which promote the dispersal of the PET imaging agent in water.
  • the PET imaging agent may be administered to a patient in an aqueous formulation comprising ethanol and the fluorine- 18 labeled fluoroalkyl tetrabenazine carbinol compound.
  • the PET imaging agent may be administered to a patient as an aqueous formulation comprising dextrose and the fluorine- 18 labeled fluoroalkyl tetrabenazine carbinol compound.
  • the PET imaging agent may be administered to a patient as an aqueous formulation comprising saline and the fluorine- 18 labeled fluoroalkyl tetrabenazine carbinol compound.
  • a formulation may optionally contain further excipients as described above, more typically including one or more excipients 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 orp ⁇ ra-aminobenzoic acid.
  • the fluoroalkyl tetrabenazine carbinol compounds provided by the present invention are believed to possess therapeutic utility in the treatment of diseases such as schizophrenia and Huntington's disease.
  • the present invention provides a fluoroalkyl tetrabenazine carbinol compound having structure I, which is useful in treating a pathological condition in a patient.
  • the present invention provides a fluoroalkyl tetrabenazine carbinol compound having structure IV, which is useful in treating a pathological condition in a patient.
  • the present invention provides enantiomerically enriched fluoroalkyl tetrabenazine carbinol compounds II, III, V, and VI (and mixtures thereof), which are useful in treating a pathological condition in a patient.
  • the amount of amount of the fluoroalkyl tetrabenazine carbinol compound administered to a patient in a given dose is on the order of milligrams.
  • fluoroalkyl tetrabenazine carbinol compounds falling within the scope of generic structure I may under a variety of conditions form salts which are useful as PET imaging agents, probes for the discovery and development of imaging agents, and/or as therapeutic agents.
  • the present invention provides a host of novel and useful fluoroalkyl tetrabenazine carbinol compounds and their salts.
  • 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.
  • the present invention provides the hydrochloride salts of the hydroch
  • the fluoroalkyl tetrabenazine carbinol compounds of the present invention may be prepared by a variety of methods including those provided in the experimental section of this disclosure.
  • the fluoroalkyl tetrabenazine carbinol compound is prepared by reaction of nucleophilic fluoride ion or an electrophilic fluorinating agent with a fluorophilic tetrabenazine carbinol compound having structure VII
  • R 1 is a C 1 -C 2 O aliphatic, a C 2 -C 2 O cycloaliphatic radical, or a C 2 -C 2 O aromatic radical comprising at least one functional group susceptible to reaction with nucleophilic fluoride ion or an electrophilic fluorinating agent;
  • R 2 is a C 1 -C 1O aliphatic radical;
  • R 3 is hydrogen or a C 1 -C 1 O aliphatic radical;
  • R 4 is hydrogen or a C 1 -C 1 O aliphatic radical;
  • R is hydrogen, a C 1 -C 1 O aliphatic radical, a C 2 -C 1 O cycloaliphatic radical, or a C 2 -C 2 Q aromatic radical.
  • the present invention provides a fluorophilic tetrabenazine carbinol compound having structure VII. Fluorophilic tetrabenazine carbinol compounds having structure VII are illustrated in Table 9 below.
  • the present invention provides a fluorophilic compound having structure VII, wherein R 1 is a C 1 -C 2 O aliphatic radical, a C 2 -C 2 O cycloaliphatic radical, or a C 2 -C 2O aromatic radical comprising at least one functional group susceptible to reaction with nucleophilic fluoride ion.
  • the functional group susceptible to reaction with nucleophilic fluoride ion is an aromatic sulfonate ester (e.g. tosylate, benzenesulfonate, naphthalenesulfonate).
  • the functional group susceptible to reaction with nucleophilic fluoride ion is an aliphatic sulfonate ester (e.g. methane sulfonate, trifluoromethane sulfonate).
  • the functional group susceptible to reaction with nucleophilic fluoride ion is selected from the group consisting of tosylate, mesylate, and trifluoromethane sulfonate groups.
  • the present invention provides a fluorophilic compound having structure VII wherein the group R 1 comprises at least one tosylate group susceptible to reaction with nucleophilic fluoride ion.
  • the tosylate group is an aromatic radical and the group R 1 comprising the tosylate group is also an aromatic radical.
  • the group R 1 comprising the tosylate group is a C 9 aromatic radical which upon displacement with fluoride ion becomes a C 2 fluorinated aliphatic radical.
  • the present invention provides a fluorophilic compound having structure VII wherein the group R 1 comprises at least one mesylate group susceptible to reaction with nucleophilic fluoride ion.
  • the mesylate group is an aliphatic radical and the group R 1 comprising the mesylate group may be an aliphatic, a cycloaliphatic or an aromatic radical depending on the overall structure of the group R 1 .
  • the group R 1 is a cycloaliphatic radical.
  • the group R 1 is an aromatic radical. It is helpful to bear in mind that the definitions of aliphatic, cycloaliphatic and aromatic radicals provided in this disclosure establish a hierarchy in which aliphatic radicals (non-cyclic arrays of atom(s)) must be free of cycloaliphatic groups (a cyclic array of atoms which is not aromatic) and aromatic groups (a cyclic array of atoms which is aromatic), cycloaliphatic radicals must be free of aromatic groups, and aromatic radicals must simply comprise an aromatic group.
  • the present invention provides a fluorophilic compound having structure VII wherein the group R 1 comprises at least one trifluoromethane sulfonate (triflate) group susceptible to reaction with nucleophilic fluoride ion. See for example Entry 9b of Table 9.
  • the present invention provides a fluorophilic compound having structure VII wherein the group R 1 comprises at least one p-nitrobenzoate group susceptible to reaction with nucleophilic fluoride ion. See for example Entry 9c of Table 9.
  • the present invention provides a fluorophilic compound having structure VII wherein the group R 1 comprises at least one methane sulfonate group susceptible to reaction with nucleophilic fluoride ion. See for example Entry 9d of Table 9.
  • the present invention provides a fluorophilic compound having structure VII wherein the group R 1 comprises at least one epoxy group susceptible to reaction with nucleophilic fluoride ion. See for example Entry 9i of Table 9.
  • the present invention provides a fluorophilic compound having structure VII wherein the group R 1 comprises at least one cyclic sulfate group susceptible to reaction with nucleophilic fluoride ion. See for example Entry 91 of Table 9.
  • the present invention provides a fluorophilic compound having structure VII, wherein R 1 is a C 2 -C 2O aliphatic radical comprising at least one functional group susceptible to reaction with an electrophilic fluorinating agent, for example fluorine gas, perchloryl fluoride, mercuric fluoride, and phenyl selenenyl fluoride.
  • an electrophilic fluorinating agent for example fluorine gas, perchloryl fluoride, mercuric fluoride, and phenyl selenenyl fluoride.
  • the functional group susceptible to reaction with an electrophilic fluorinating agent is selected from the group consisting of carbon-carbon double bonds and carbon-carbon triple bonds.
  • Entries 9e, 9f, 9g, 9h and 9k of Table 9 illustrate compounds falling within the scope of generic structure VII, which are susceptible to reaction with an electrophilic fluorinating agent. Attention is called to Entry 9k wherein the group R 1 comprises functional groups susceptible to reaction with an electrophilic fluorinating agent (double bond) and to reaction with nucleophilic fluoride ion (tosylate group).
  • Fluorophilic tetrabenazine carbinol compounds VII may be prepared in enantiomerically enriched or racemic forms.
  • a fluorophilic tetrabenazine compound VII may be enriched in the R, R, R- enantiomer shown in Entry 9b of Table 9.
  • a fluorophilic tetrabenazine carbinol compound may be enriched in an enantiomer having absolute stereochemistry opposite that of Entry 9b of Table 9, for example the S, S, S-enantiomer of Entry 9d.
  • the present invention provides an enantiomerically enriched fluorophilic tetrabenazine carbinol compound comprising a principal component enantiomer having structure VIII
  • R 1 is a C 1 -C 1O aliphatic radical, a C 2 -C 2O cycloaliphatic radical, or a C 2 -C 2O aromatic radical comprising at least one functional group susceptible to reaction with nucleophilic fluoride ion or an electrophilic fluorinating agent;
  • R is a C 1 -C 1O aliphatic radical;
  • R 3 is hydrogen or a C 1 -C 1O aliphatic radical;
  • R 4 is hydrogen or a C 1 -C 1O aliphatic radical;
  • R 5 is hydrogen, a C 1 -C 1O aliphatic radical, a C 2 -C 1O cycloaliphatic radical, or a C 2 -C 2O aromatic radical.
  • Principal component enantiomers VIII are illustrated by Entries 9b, 9h, 9k, and 91 of Table 9.
  • the present invention provides an enantiomerically enriched fluorophilic compound comprising a principal component enantiomer having structure IX
  • R 1 is a C 1 -C 1 O aliphatic radical, a C 2 -C 2 O cycloaliphatic radical, or a C 2 -C 2 O aromatic radical comprising at least one functional group susceptible to reaction with nucleophilic fluoride ion or an electrophilic fluorinating agent;
  • R 2 is a C 1 -C 1O aliphatic radical;
  • R 3 is hydrogen or a C 1 -C 1 O aliphatic radical;
  • R 4 is hydrogen or a C 1 -C 1 O aliphatic radical;
  • R is hydrogen, a C 1 -C 1 O aliphatic radical, a C 2 -C 1 O cycloaliphatic radical, or a C 2 -C 2O aromatic radical.
  • Principal component enantiomers IX are illustrated by Entry 9d of Table 9.
  • the group - OR 5 is not a hydroxy group and is instead a C 1 -C 1 O aliphatic radical, a C 2 -C 1 O cycloaliphatic radical, or a C 2 -C 2O aromatic radical.
  • the group -OR 5 is an ester moiety, for example an acetate group as exemplified by Entry
  • the group -OR is an aliphatic ester moiety selected from the group consisting of formate, acetate, propanoate, butanoate, pentanoate, hexanoate, and heptanoate.
  • the group -OR 5 is a silyl ether moiety, for example triethylsilyloxy.
  • Co-pending International Patent Application PCT/US3008/065738 discloses methods for the preparation of racemic and enantiomerically enriched tetrabenazine compositions which may be used for the preparation of fluorophilic tetrabenazine carbinol compounds provided by the present invention.
  • the Examples Section of the present disclosure provides detailed experimental descriptions of the preparation and characterization of tetrabenazine carbinol compounds VII.
  • tetrabenazine carbinol compounds VII can be prepared from the corresponding tetrabenazine compound.
  • Tetrabenazine compounds may be prepared by reacting a nucleophilic alkenyl species with an aldehyde compound having structure X
  • R 3 is hydrogen or a C 1 -C 2 O aliphatic radical
  • R 4 is hydrogen or a C 1 -C 2 O aliphatic radical
  • P 1 is a protecting group, to provide an allylic alcohol (See Method 4 of the Examples section), which is then oxidized to provide an enone designated the "first intermediate" (See Example 1 of the Examples section), the protecting group of which is then removed and the resultant deprotected first intermediate undergoes an amino cyclization reaction to afford the corresponding tetrabenazine (TBZ) compound.
  • aldehyde compounds X may be prepared from intermediates prepared using methodology described by Sasamoto et al. (Journal of the American Chemical Society 128, 14010-14011, 2006).
  • Sasamoto et al. disclose the preparation of enantiomerically enriched tetrahydroquinoline malonate compounds, which may be converted to aldehyde compound X by selective hydrolysis of one of the ester moieties of the tetrahydroquinoline malonate and decarboxylation followed by reduction of the resultant tetrahydroisoquinoline monoester to aldehyde compound X as depicted in Scheme 1.
  • DM-SEGPHOS 2 mole percent DM-SEGPHOS shown in Scheme 1 represents a chiral catalyst responsible for the enantiomeric enrichment of the product aldehyde X, and further that the use of DM-SEGPHOS of opposite chirality as the chiral catalyst will afford a product aldehyde X enantiomerically enriched in the "S" enantiomer (aldehyde compound X having the S configuration at ring position- 12 (See for example Entry 10b of Table 10).
  • Suitable chiral catalysts include those disclosed by Sasamoto et al. (Journal of the American
  • racemic aldehyde compound X may be separated into its constituent enantiomers by high performance liquid chromatography (hplc) on a chiral hplc column.
  • a racemic fluoroalkyl tetrabenazine carbinol compound having structure I may be reacted with (- )-tartaric acid to form an adduct (ammonium tartarate salt) of the racemic fluoroalkyl tetrabenazine carbinol compound, said adduct comprising a mixture of diastereomeric ammonium tartarate salts which are then separated by fractional crystallization.
  • the dihydroisoquinoline 1 (1.0 eq.) and Boc anhydride (1.5 eq.) were dissolved in CH 2 Cl 2 at room temperature to provide a 1.5 M solution with respect to the dihydroisoquinoline.
  • the mixture was allowed to stir for 30 min. Following the allotted time, the reaction mixture was cooled to 0 0 C and then diisopropylmalonate (1.5 eq.) followed by a pre-chilled solution of the Pd catalyst (0.008 eq.) in dichloromethane were added successively to the reaction mixture to provide a final reaction concentration of 0.84 M with respect to the starting dihydroisoquinoline.
  • the reaction mixture was allowed to continue stirring at -2.5 0 C for 15 h.
  • the starting material 2 was taken up in isopropanol to provide a 0.2 M solution of 2. To this solution was added IM aqueous NaOH, bringing the final concentration of the reaction mixture to 0.1M with respect to the malonate 2. The reaction mixture was heated to and maintained 70 0 C for 22 min. (timing was started when the temperature of the reaction mixture temp exceeded 65 0 C). Following the allotted time the reaction mixture was quickly cooled to 0 0 C. The reaction mixture carefully acidified with 2M aqueous HCl and extracted with three portions of dichloromethane. The combined organic extracts dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure.
  • the isolated material was taken up in THF to provide a 0.1 M solution (based on the original quantity of 2 used in the reaction mixture) and triethylamine (1.0 eq) was added to the reaction mixture at room temperature.
  • the reaction mixture was heated to its reflux temperature and maintained at this temperature for 90 min.
  • the reaction mixture was concentrated under reduced pressure, dissolved in a minimal quantity of CH 2 Cl 2 and was immediately purified by column chromatography on SiO 2 (15-40% EtOAc-hexanes; 40%, the eluant was monitored at 284 nm).
  • the product 3 existed as a mixture of ro tamers at room temperature and was a colorless foam 79%: [ ⁇ ] 26 D -82 ( c 0.24, CH 2 Cl 2 ); 1 H NMR (CDCl 3 ) ⁇ 1.19-1.25 (m, 6H), 1.43-1.49 (m, 9H), 2.58-2.69 (m, 2H), 2.70-2.77 (m, IH), 2.78-2.92 (m, IH), 3.13-3.43 (m, IH), 3.81-3.85 (m, 6H), 3.86-4.01 (m, IH), 4.91-5.05 (m, IH), 5.38-5.61 (m, IH), 6.56-6.61 (m, IH), 6.64-6.70 (s, IH); 13 C NMR (CDCl 3 ) ⁇ 21.75, 21.90, 27.93, 28.08, 28.44, 37.53, 38.75, 42.22, 42.81, 51.11, 51.87, 55.92, 56
  • reaction mixture was diluted with 1:1 EtOAc-hexanes and an aqueous 0.5 M EDTA solution (pH 9) was added and the entire mixture was allowed to stir for 1.5 h.
  • aqueous layer was extracted with three portions of EtOAc, dried (MgSO 4 ), filtered, and the filtrate was concentrated under reduced pressure to provide a green oil.
  • the crude material was subjected to column chromatography on SiO 2 (35% EtOAc-hexanes; elution was observed at 285 nm and 228 nm).
  • the product allylic alcohol 6 was a pale yellow oil isolated in 53% yield as a mixture of diastereomers, which was taken on to the next step without additional characterization or analysis.
  • the crude material was purified by column chromatography on SiO 2 (10-30% EtOAc-hexanes, elution was observed at 285 nm and 228 nm).
  • First intermediate 8 (1.0 eq) was dissolved in 10% Me 2 S-dichloromethane to provide an 82 mM solution. The solution was cooled to 0 0 C and triisopropylsilane (1.1 eq.) followed by TFA (precooled to 0 0 C) was added to the reaction mixture to provide a final concentration of 41 mM. The reaction mixture was permitted to stir at 0 0 C for 1 h. Following the allotted time the reaction mixture was quenched at 0 0 C by the addition of saturated aqueous potassium carbonate solution and concentrated under reduced pressure to remove the majority of the dimethylsulfide.
  • the mixture was extracted with five portions of dichloromethane, and the combined organic extracts were washed with brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure to provide the crude product as a yellow solid.
  • the crude product was recrystallized from 3.5% dimethoxyethane in hexanes.
  • reaction mixture was stirred for 14 h (0 0 C to RT). Following the allotted time the reaction mixture was quenched with saturated sodium bicarbonate (NaHCO 3 ). The mixture was extracted with three portions of CH 2 Cl 2 and the combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to provide the crude product. The crude product was chromatographed on SiO 2 (12 g, 10% to 40% EtOAc in hexane) to provide 98 mg of the compound 13 (single diastereomer) as a slightly yellow solid (66%).
  • reaction mixture was poured into cold water and layers separated.
  • the reaction mixture was extracted with three portions of CH 2 Cl 2 and the combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered and concentrated.
  • the residue was chromato graphed on SiO 2 (12 g, 10% to 70% EtOAc in hexane) to give 38 mg of the product as a yellow solid of compound 15 (53%).
  • reaction mixture was stirred (-78 0 C to RT) for 4 h.
  • the reaction mixture was then quenched with water and extracted with three portions of CH 2 Cl 2 .
  • the combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered and concentrated.
  • the residue was chromatographed on SiO 2 (0% to 10% MeOH in CH 2 Cl 2 ) to give 3 mg of the product 16 as a white solid (30%).
  • a mixture of dimethyl formamide and acetonitrile (about 1 mL) containing the fluorophilic tetrabenazine carbinol compound, mesylate 20, (2 mg) is added and the vial is sealed.
  • the reaction mixture is stirred and heated at 100°C for 10 minutes and then is cooled to room temperature.
  • the product mixture comprising the starting mesylate 19 and the product F- 18 labeled fluoroalkyl tetrabenazine carbinol compound 20 is diluted with water (10 mL) and applied to a Sep-Pak cartridge. The cartridge is then washed with water (3x) to remove unreacted fluoride ion and other water soluble components of the product mixture.
  • radiolabled fluoroalkyl tetrabenazine carbinol compound 20 and starting mesylate 19 are then eluted from the cartridge with acetonitrile. Most of the acetonitrile is then evaporated and the residue is dissolved in aqueous acetonitrile and subjected to preparative reverse phase HPLC to afford an aqueous formulation comprising PET imaging agent 20.
  • VMAT-2 binding affinities were measured for fluoroalkyl tetrabenazine carbinol compounds 16 and 17 provided by the present invention.
  • VMAT-2 binding affinity measurements were carried out by Novascreen Biosciences Corporation (Hanover, Maryland, USA) using protocol Cat. No. 100-0751.
  • Novascreen, Inc. is a commercial provider of biological assays for the pharmaceutical industry. Binding affinity data are presented in Table 11 and illustrate very high binding affinity for the fluoroalkyl tetrabenazine carbinol compounds of the present invention (compounds 16 and 17) relative to a reserpine control (Comparative Example 1) and a dihydro tetrabenazine (DTBZ) control (Comparative Example X).
  • the data obtained for fluoroalkyl tetrabenazine carbinol compounds 16 and 17 reveal an unexpected tolerance of fluoroalkyl substitution at ring position-2, which combines a change in the size and lipophilicity of the group at ring position-2 with the uncertainty which arises whenever a hydrogen in a biologically active molecule is replaced by fluorine.
  • the binding constants Ki expressed in nano-molar (nM) concentration units indicate a very high affinity of the fluoroalkyl tetrabenazine carbinol compounds of the present invention for the VMAT-2 biomarker.
  • the word "comprises” and its grammatical variants logically also subtend and include phrases of varying and differing extent such as for example, but not limited thereto, “consisting essentially of” and “consisting of.” Where necessary, ranges have been supplied; those ranges are inclusive of all sub-ranges there between. It is to be expected that variations in these ranges will suggest themselves to a practitioner having ordinary skill in the art and where not already dedicated to the public, those variations should where possible be construed to be covered by the appended claims. It is also anticipated that advances in science and technology will make equivalents and substitutions possible that are not now contemplated by reason of the imprecision of language and these variations should also be construed where possible to be covered by the appended claims.

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Abstract

The present invention provides novel fluoroalkyl tetrabenazine carbinol compounds. The fluoroalkyl tetrabenazine carbinol compounds are provided in both racemic and enantiomerically enriched forms and may comprise either or both of fluorine-18 and fluorine 19. The fluoroalkyl tetrabenazine carbinol compounds are shown to possess high affinity for VMAT-2, a biomarker implicated in human diabetes. The fluoroalkyl tetrabenazine carbinol compounds comprising a fluorine-18 group are useful as PET imaging agents targeting the VMAT-2 biomarker. The non-radiolabled fluoroalkyl tetrabenazine carbinol compounds are useful as probes for the discovery of PET imaging agents.

Description

FLUOROALKYL TETRABENAZINE CARBINOL COMPOUNDS AS IMAGING
AGENTS AND PROBES
BACKGROUND
This invention relates to carbinol compounds related to tetrabenazine and intermediates useful in the preparation of such fluoroalkyl tetrabenazine carbinol compounds
Since first reported on in 1957 (Pletscher, A. (1957) Release of 5-hydroxytryptamine by benzoquinolizine derivatives with sedative action, Science 126, 507), tetrabenazine and structurally related compounds have been widely investigated, and a number of tetrabenazine (TBZ) compounds and derivatives of tetrabenazine have shown promise in the treatment of a variety of conditions affecting human health. For example, dihydrotetrabenazine has been identified as an agent for the treatment of schizophrenia and other psychoses (See for example WO 2007017654 Al), and tetrabenazine has shown promise as an agent in the treatment of Huntington's disease (Neurology (2006), 66(3), 366-372). Although most preparations used in biological studies of tetrabenazine and its derivatives have been carried out on racemates, in at least one instance the biological activity exhibited by enantiomers tested separately was highly differentiated (See Koeppe, R. A. et al. (1999) Assessment of extrastriatal vesicular monoamine transporter binding site density using stereoisomers of [HC] dihydrotetrabenazine, J Cereb Blood Flow Metab 19, 1376-1384).
More recently, derivatives of 9-desmethyl (±)-dihydrotetrabenazine incorporating a fluorine- 18 atom have been shown to be useful as PET imaging agents, Nuclear Medicine and Biology 33 (2006) 685-694. See also Nuclear Medicine and Biology 34 (2007) 239-246; and Nuclear Medicine and Biology 34 (2007) 233-237.
The present invention provides both a new class of fluorinated tetrabenazine derivatives and fluorinated tetrabenazine analogs, and discloses efficient synthetic methodology, which may be used to prepare such compounds in enantiomerically enriched or racemic forms. The fluoroalkyl tetrabenazine carbinol compounds provided by the present invention are useful as PET imaging agents, probes for the development of PET imaging agents, and therapeutic agents. In addition, the present invention provides novel synthetic intermediate compositions, which may be used to prepare either or both enantiomers of the subject tetrabenazine derivatives.
BRIEF DESCRIPTION
In one embodiment, the present invention provides a fluoroalkyl tetrabenazine carbinol compound having structure I
Figure imgf000003_0001
wherein R1 is a C1-C1O fluorinated aliphatic radical; R2 is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; R4 is hydrogen or a C1-C1O aliphatic radical; and R is hydrogen, a C1-C1O aliphatic radical, a C2-C1O cycloaliphatic radical, or a C2- C2o aromatic radical.
In another embodiment, the present invention provides a PET imaging agent comprising a fluoroalkyl tetrabenazine carbinol compounds having structure I
Figure imgf000003_0002
(D wherein R1 is a C1-C1O fluorinated aliphatic radical comprising at least one fluorine- 18 atom; R2 is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; R4 is hydrogen or a C1-C1O aliphatic radical; and R is hydrogen, a C1-C1O aliphatic radical, a C2-C1O cycloaliphatic radical, or a C2-C2O aromatic radical.
In yet another embodiment, the present invention provides fluoroalkyl tetrabenazine carbinol compounds having structure IV
Figure imgf000004_0001
wherein R1 is a C1-C1O fluorinated aliphatic radical; R2 is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; and R4 is hydrogen or a C1-C1O aliphatic radical.
In yet another embodiment, the present invention provides a PET imaging agent comprising a fluoroalkyl tetrabenazine carbinol compounds having structure IV
Figure imgf000004_0002
(IV) wherein R1 is a C1-C1O fluorinated aliphatic radical; R2 is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; and R4 is hydrogen or a C1-C1O aliphatic radical.
DETAILED DESCRIPTION
In the following specification and the claims, which follow, reference will be made to a number of terms, which shall be defined to have the following meanings.
The singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.
"Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
As used herein, the term "solvent" can refer to a single solvent or a mixture of solvents.
Approximating language, as used herein throughout the specification and claims, may be applied to modify any quantitative representation that could permissibly vary without resulting in a change in the basic function to which it is related. Accordingly, a value modified by a term or terms, such as "about", is not to be limited to the precise value specified. In some instances, the approximating language may correspond to the precision of an instrument for measuring the value.
As used herein, the term "aromatic radical" refers to an array of atoms having a valence of at least one comprising at least one aromatic group. The array of atoms having a valence of at least one comprising at least one aromatic group may include heteroatoms such as nitrogen, sulfur, selenium, silicon and oxygen, or may be composed exclusively of carbon and hydrogen. As used herein, the term "aromatic radical" includes but is not limited to phenyl, pyridyl, furanyl, thienyl, naphthyl, phenylene, and biphenyl radicals. As noted, the aromatic radical contains at least one aromatic group. The aromatic group is invariably a cyclic structure having 4n+2 "delocalized" electrons where "n" is an integer equal to 1 or greater, as illustrated by phenyl groups (n = 1), thienyl groups (n = 1), furanyl groups (n = 1), naphthyl groups (n = 2), azulenyl groups (n = 2), anthraceneyl groups (n = 3) and the like. The aromatic radical may also include nonaromatic components. For example, a benzyl group is an aromatic radical, which comprises a phenyl ring (the aromatic group) and a methylene group (the nonaromatic component). Similarly a tetrahydronaphthyl radical is an aromatic radical comprising an aromatic group (COH3) fused to a nonaromatic component -(CH2)4-. For convenience, the term "aromatic radical" is defined herein to encompass a wide range of functional groups such as alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, haloaromatic groups, conjugated dienyl groups, alcohol groups, ether groups, aldehyde groups, ketone groups, carboxylic acid groups, acyl groups (for example carboxylic acid derivatives such as esters and amides), amine groups, nitro groups, and the like. For example, the A- methylphenyl radical is a C7 aromatic radical comprising a methyl group, the methyl group being a functional group which is an alkyl group. Similarly, the 2-nitrophenyl group is a C6 aromatic radical comprising a nitro group, the nitro group being a functional group. Aromatic radicals include halogenated aromatic radicals such as A- trifluoromethylphenyl, hexafluoroisopropylidenebis(4-phen- 1-yloxy) (i.e.,
-OPhC(CF3)2PhO-), 4-chloromethylphen- 1-yl, 3-trifluorovinyl-2-thienyl,
3-trichloromethylphen-l-yl (i.e., 3-CCl3Ph-), 4-(3-bromoprop-l-yl)phen-l-yl (i.e., A- BrCH2CH2CH2Ph-), and the like. Further examples of aromatic radicals include A- allyloxyphen-1-oxy, 4-aminophen-l-yl (i.e., 4-H2NPh-), 3-aminocarbonylphen-l-yl (i.e., NH2COPh-), 4-benzoylphen-l-yl, dicyanomethylidenebis(4-phen- 1-yloxy) (i.e., -OPhC(CN)2PhO-), 3-methylphen-l-yl, methylenebis(4-phen- 1-yloxy) (i.e., -OPhCH2PhO-), 2-ethylphen-l-yl, phenylethenyl, 3-formyl-2-thienyl, 2-hexyl-5- furanyl, hexamethylene-l,6-bis(4-phen- 1-yloxy) (i.e., -OPh(CH2)6PhO-), A- hydroxymethylphen-1-yl (i.e., 4-HOCH2Ph-), 4-mercaptomethylphen-l-yl (i.e., A- HSCH2Ph-), 4-methylthiophen-l-yl (i.e., 4-CH3SPh-), 3-methoxyphen-l-yl, 2- methoxycarbonylphen- 1-yloxy (e.g., methyl salicyl), 2-nitromethylphen-l-yl (i.e., 2- NO2CH2Ph), 3-trimethylsilylphen-l-yl, 4-t-butyldimethylsilylphenl-l-yl, 4-vinylphen- 1-yl, vinylidenebis(phenyl), and the like. The term "a C3 - C1O aromatic radical" includes aromatic radicals containing at least three but no more than 10 carbon atoms. The aromatic radical 1-imidazolyl (C3H2N2-) represents a C3 aromatic radical. The benzyl radical (C7H7-) represents a C7 aromatic radical.
As used herein the term "cycloaliphatic radical" refers to a radical having a valence of at least one, and comprising an array of atoms which is cyclic but which is not aromatic. As defined herein a "cycloaliphatic radical" does not contain an aromatic group. A "cycloaliphatic radical" may comprise one or more noncyclic components. For example, a cyclohexylmethyl group (COH11CH2-) is a cycloaliphatic radical, which comprises a cyclohexyl ring (the array of atoms which is cyclic but which is not aromatic) and a methylene group (the noncyclic component). The cycloaliphatic radical may include heteroatoms such as nitrogen, sulfur, selenium, silicon and oxygen, or may be composed exclusively of carbon and hydrogen. For convenience, the term "cycloaliphatic radical" is defined herein to encompass a wide range of functional groups such as alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, conjugated dienyl groups, alcohol groups, ether groups, aldehyde groups, ketone groups, carboxylic acid groups, acyl groups (for example carboxylic acid derivatives such as esters and amides), amine groups, nitro groups, and the like. For example, the 4-methylcyclopent-l-yl radical is a C6 cycloaliphatic radical comprising a methyl group, the methyl group being a functional group which is an alkyl group. Similarly, the 2-nitrocyclobut-l-yl radical is a C4 cycloaliphatic radical comprising a nitro group, the nitro group being a functional group. A cycloaliphatic radical may comprise one or more halogen atoms which may be the same or different. Halogen atoms include, for example; fluorine, chlorine, bromine, and iodine. Cycloaliphatic radicals comprising one or more halogen atoms include 2-trifluoromethylcyclohex-l- yl, 4-bromodifluoromethylcyclooct- 1 -yl, 2-chlorodifluoromethylcyclohex- 1 -yl, hexafluoroisopropylidene-2,2-bis (cyclohex-4-yl) (i.e., -C6H10C(CF3)2 C6H10-), 2- chloromethylcyclohex-1-yl, 3- difluoromethylenecyclohex-1-yl, A- trichloromethylcyclohex- 1 -yloxy, 4-bromodichloromethylcyclohex- 1 -ylthio, 2- bromoethylcyclopent-1-yl, 2-bromopropylcyclohex- 1 -yloxy (e.g.,
CH3CHBrCH2C6H1OO-), and the like. Further examples of cycloaliphatic radicals include 4-allyloxycyclohex-l-yl, 4-aminocyclohex-l-yl (i.e., H2NC6H1O-), A- aminocarbonylcyclopent-1-yl (i.e., NH2COCsH8-), 4-acetyloxycyclohex-l-yl, 2,2- dicyanoisopropylidenebis(cyclohex-4-yloxy) (i.e., -OC6H10C(CN)2C6H10O-), 3- methylcyclohex-1-yl, methylenebis(cyclohex-4-yloxy) (i.e., -OCOH1OCH2COH1OO-), 1- ethylcyclobut-1-yl, cyclopropylethenyl, 3-formyl-2-terahydrofuranyl, 2-hexyl-5- tetrahydrofuranyl, hexamethylene-l,6-bis(cyclohex-4-yloxy) (i.e., -O
C6H1o(CH2)6C6H100-), 4-hydroxymethylcyclohex-l-yl (i.e., 4-HOCH2C6H10-), 4- mercaptomethylcyclohex-l-yl (i.e., 4-HSCH2COH1O-), 4-methylthiocyclohex-l-yl (i.e., 4-CH3SCOH1O-), 4-methoxycyclohex-l-yl, 2-methoxycarbonylcyclohex-l-yloxy (2- CH3OCOC6H10O-), 4-nitromethylcyclohex-l-yl (i.e., NO2CH2C6H10-), 3- trimethylsilylcyclohex- 1 -yl, 2-t-butyldimethylsilylcyclopent- 1 -yl, 4- trimethoxysilylethylcyclohex-1-yl (e.g., (CH3O)3SiCH2CH2C6H10-), 4- vinylcyclohexen-1-yl, vinylidenebis(cyclohexyl), and the like. The terai "a C3 - C1O cycloaliphatic radical" includes cycloaliphatic radicals containing at least three but no more than 10 carbon atoms. The cycloaliphatic radical 2-tetrahydrofuranyl (C4H7O-) represents a C4 cycloaliphatic radical. The cyclohexylmethyl radical (C6H11CH2-) represents a C7 cycloaliphatic radical.
As used herein the term "aliphatic radical" refers to an organic radical having a valence of at least one consisting of a linear or branched array of atoms, which is not cyclic. Aliphatic radicals are defined to comprise at least one carbon atom. The array of atoms comprising the aliphatic radical may include heteroatoms such as nitrogen, sulfur, silicon, selenium and oxygen or may be composed exclusively of carbon and hydrogen. For convenience, the term "aliphatic radical" is defined herein to encompass, as part of the "linear or branched array of atoms which is not cyclic" a wide range of functional groups such as alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, conjugated dienyl groups, alcohol groups, ether groups, aldehyde groups, ketone groups, carboxylic acid groups, acyl groups (for example carboxylic acid derivatives such as esters and amides), amine groups, nitro groups, and the like. For example, the 4-methylpent-l-yl radical is a C6 aliphatic radical comprising a methyl group, the methyl group being a functional group which is an alkyl group. Similarly, the 4-nitrobut-l-yl group is a C4 aliphatic radical comprising a nitro group, the nitro group being a functional group. An aliphatic radical may be a haloalkyl group which comprises one or more halogen atoms which may be the same or different. Halogen atoms include, for example; fluorine, chlorine, bromine, and iodine. Aliphatic radicals comprising one or more halogen atoms include the alkyl halides trifluoromethyl, bromodifluoromethyl, chlorodifluoromethyl, hexafluoroisopropylidene, chloromethyl, difluorovinylidene, trichloromethyl, bromodichloromethyl, bromoethyl, 2-bromotrimethylene (e.g., -CH2CHBrCH2-), and the like. Further examples of aliphatic radicals include allyl, aminocarbonyl (i.e., - CONH2), carbonyl, 2,2-dicyanoisopropylidene (i.e., -CH2C(CN)2CH2-), methyl (i.e., - CH3), methylene (i.e., -CH2-), ethyl, ethylene, formyl (i.e.,-CHO), hexyl, hexamethylene, hydroxymethyl (i.e. ,-CH2OH), mercaptomethyl (i.e., -CH2SH), methylthio (i.e., -SCH3), methylthiomethyl (i.e., -CH2SCH3), methoxy, methoxycarbonyl (i.e., CH3OCO-) , nitromethyl (i.e., -CH2NO2), thiocarbonyl, trimethylsilyl ( i.e., (CH3)3Si-), t-butyldimethylsilyl, 3-trimethyoxysilylpropyl (i.e., (CH3O)3SiCH2CH2CH2-), vinyl, vinylidene, and the like. By way of further example, a C1 - C1O aliphatic radical contains at least one but no more than 10 carbon atoms. A methyl group (i.e., CH3-) is an example of a C1 aliphatic radical. A decyl group (i.e., CH3(CH2)cr) is an example of a C1O aliphatic radical.
As noted, in one embodiment the present invention provides a fluoroalkyl tetrabenazine carbinol compound having structure I
Figure imgf000009_0001
wherein R1 is a C1-C1O fluorinated aliphatic radical; R2 is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; R4 is hydrogen or a C1-C1O aliphatic radical; and R is hydrogen, a C1-C1O aliphatic radical, a C2-C1O cycloaliphatic radical, or a C2- C2o aromatic radical.
As noted, in another embodiment the present invention provides a fluoroalkyl tetrabenazine carbinol compound having structure IV
Figure imgf000010_0001
wherein R1 is a C1-C1O fluorinated aliphatic radical; R2 is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; and R4 is hydrogen or a C1-C1O aliphatic radical.
Those skilled in the art will appreciate that the term "fluoroalkyl tetrabenazine carbinol compound" refers to compounds falling within the scope of generic structure I and includes compounds in which R5 is hydrogen (fluoroalkyl tetrabenazine compounds having a tertiary hydroxy group at ring position-2), as well as compounds in which R5 is a C1-C1O aliphatic radical, a C2-C1O cycloaliphatic radical, or a C2-C2O aromatic radical (fluoroalkyl tetrabenazine carbinol compounds incorporating a derivative of a tertiary hydroxy group at ring position-2). For convenience, compounds defined by generic structure I are referred to at times herein as "tetrabenazine carbinol compounds".
In the compounds of formulae (I) and (IV) and in other aspects of the invention below:
R1 is suitably selected from Ci-όfluoroalkyl, C2-όfluoroalkenyl, C2-όfluoroalkynyl C1-6fluoroalkoxy(C1_6alkyl), Ci-όfluorohaloalkyl, Ci-όfluorohydroxyalkyl, and Ci-όfluoroalkylcarbony^Ci-όalkyl). In one aspect of the invention R1 is C2. όfluoroalkynyl.
R2 is suitably selected from Ci-όalkyl and C3-scycloalkyl and is more suitably C1- ealkyl;
R3 and R4 are each suitably independently selected from Chalky! and Cμόalkoxy. In the compounds of formula (I) and in related aspects of the invention below, R is suitably selected from hydrogen, (Ci-6alkyl)carbonyl, and phenyl. In one aspect R is hydrogen. In a separate aspect R5 is (Ci_6alkyl)carbonyl, more suitably CH3C(O)-.
The fluoroalkyl tetrabenazine carbinol compounds provided by the present invention are shown herein to possess a high affinity for Type 2 Vesicular Monoamine
Transporters (VMAT-2), a group of biomarkers, which correlate inter alia with diabetic activity in human patients. The discovery that substitution at ring position-2 of the tetrabenazine structure by an aliphatic radical comprising a fluorine atom is tolerated with respect to VMAT-2 binding in this series of novel fluoroalkyl tetrabenazine carbinol compounds enables the compounds of present invention to be used as positron emission tomography (PET) imaging agents in studies targeting the
VMAT-2 biomarker.
Thus, in one embodiment, the present invention provides radiolabeled fluoroalkyl tetrabenazine carbinol compounds falling within the scope of generic structure I comprising a fluorine- 18 atom. In an alternate embodiment, the present invention provides radiolabeled fluoroalkyl tetrabenazine carbinol compounds falling within the scope of generic structure IV comprising a fluorine- 18 atom. Fluorine- 18 labeled fluoroalkyl tetrabenazine carbinol compounds I and fluoroalkyl tetrabenazine carbinol compounds IV are suitable for use as imaging agents for positron emission tomography (PET) screening of human patients for example, for pathological conditions related to diabetes. Positron emission tomography has become a medical imaging technique of critical importance to human health.
In an alternate embodiment, the present invention provides fluoroalkyl tetrabenazine carbinol compounds falling within the scope of generic structure I and comprising a fluorine- 19 atom, a stable isotope of fluorine. The fluoroalkyl tetrabenazine carbinol compounds comprising a fluorine- 19 atom are useful in binding studies which allow the identification of those fluoroalkyl tetrabenazine carbinol compounds possessing optimal affinity for a target biomarker, for example VMAT-2. A substantial binding affinity of a given fluorine- 19 containing fluoroalkyl tetrabenazine carbinol compound for a target biomarker such as VMAT-2 is a reliable predictor of utility in PET imaging of the corresponding fluorine- 18 containing fluoroalkyl tetrabenazine carbinol compound. As is disclosed herein, fluoroalkyl tetrabenazine carbinol compounds I and IV show substantial binding affinity for the biomarker VMAT-2.
Although throughout this disclosure there is considerable focus on human health, the fluoroalkyl tetrabenazine carbinol compounds provided by the present invention are useful in the study and treatment of variety of human and animal diseases as imaging agents, as probes for the development of imaging agents, and as therapeutic agents.
Fluoroalkyl tetrabenazine carbinol compounds having structure I are illustrated in Table 1 below.
Figure imgf000012_0001
Table 1 Examples Of Fluoroalkyl Tetrabenazine Carbinol Compounds Having Structure I
Figure imgf000012_0002
Figure imgf000013_0001
* RP-2 = Ring position-2, RP-3 = Ring position-3, RP- 12 = Ring position-12
In general, and throughout this disclosure, where no absolute or relative stereochemistry is shown for a structure, as in for example structure I, the structure is intended to encompass all possible absolute and relative stereochemical configurations. Thus, structure I depicts a fluoroalkyl tetrabenazine carbinol compound in which no absolute or relative stereochemistry is shown. As such, structure I is intended to represent a genus of fluoroalkyl tetrabenazine carbinol compounds which includes the racemic compound Ia (Table 1) having both the R configuration and S configuration at ring positions-2, -3 and -12. In another embodiment, structure I represents fluoroalkyl tetrabenazine carbinol compound Ib (Table 1) having the R configuration (absolute stereochemistry) at ring positions-2, -3 and -12. In yet another embodiment, structure I represents compound Id (Table 1) having absolute stereochemistry opposite that of compound Ib. Those having ordinary skill in the art will appreciate that the individual fluoroalkyl tetrabenazine carbinol compounds shown in Table 1 herein are illustrative of tetrabenazine (TBZ) derivatives falling within the scope of generic structure I.
As noted, in one embodiment, the present invention provides a fluoroalkyl tetrabenazine carbinol compound having structure I which may be a racemic mixture (e.g. compound Ia (Table 1), a single enantiomer (e.g. compound Ib (Table 1), or a composition enantiomerically enriched in a single principal component enantiomer. Entries 2a-2c in Table 2 below illustrate fluoroalkyl tetrabenazine carbinol compounds I comprising a principal component enantiomer and at least one minor component enantiomer.
Table 2 Fluoroalkyl Tetrabenazine Carbinol Compounds I Comprising A Principal Component Enantiomer And At Least One Minor Component Enantiomer.
Figure imgf000015_0001
component enantiomer (the structures appearing under the title heading "Structure of Principal Component Enantiomer") and a "Minor Component Enantiomer". In the fluoroalkyl tetrabenazine carbinol compositions illustrated in Table 2 the mole percentage of the principal component enantiomer is given as "mole%" and refers to the mole percentage of the principal component enantiomer having the structure shown relative to the amounts of all other fluoroalkyl tetrabenazine carbinol components in the composition. For the purposes of this discussion a fluoroalkyl tetrabenazine carbinol is any compound falling within the scope of generic structure I. Entry 2a represents a fluoroalkyl tetrabenazine carbinol composition comprising 95 mole% of the R, R, R principal component enantiomer shown and a lesser amount of the S, S, S minor component enantiomer. Entry 2c represents a fluoroalkyl tetrabenazine carbinol composition comprising 88 mole percent of the S, S, S principal component enantiomer having the structure shown and a lesser amount of the R, R, R minor component enantiomer. Those skilled in the art will appreciate that the fluoroalkyl tetrabenazine carbinol compositions provided by the present invention may comprise a principal component enantiomer, a minor component enantiomer, and additional diastereomeric fluoroalkyl tetrabenazine carbinol components. In one embodiment, the present invention provides a fluoroalkyl tetrabenazine carbinol composition comprising a principal component enantiomer and related diastereomers. In an alternate embodiment, the present invention provides a fluoroalkyl tetrabenazine carbinol composition having no principal component enantiomer and which is a diastereomeric mixture.
In one embodiment, the present invention provides a fluoroalkyl tetrabenazine carbinol compound represented by structure I, which is enantiomerically enriched and is comprised of at least 95 mole percent (mole %) of an enantiomer having the R configuration at ring position- 12.
In an alternate embodiment, the present invention provides a fluoroalkyl tetrabenazine carbinol compound represented by structure I, which is enantiomerically enriched and is comprised of at least 95 mole percent (mole %) of an enantiomer having the R configuration at ring position-2.
In one embodiment, the present invention provides a fluoroalkyl tetrabenazine carbinol compound having structure I in which the fluorinated aliphatic radical at ring position-2 (-R1) has a syn-configuration relative to the hydrogen at ring position- 12. The principal component enantiomers of Entries 2a-2b of Table 2 illustrate fluoroalkyl tetrabenazine carbinol compounds in which the fluorinated aliphatic moiety at ring position-2 (-R1) has a syn-configuration relative to the hydrogen at ring position- 12. In one embodiment, the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising a principal component enantiomer having structure II
Figure imgf000017_0001
wherein R1 is a C1-C1O fluorinated aliphatic radical; R2 is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; R4 is hydrogen or a C1-C1O aliphatic radical; and R is hydrogen, a C1-C1O aliphatic radical, a C2-C1O cycloaliphatic radical, or a C2- C2o aromatic radical.
Principal component enantiomers having structure II are illustrated in Table 3 below.
Table 3 Principal Component Enantiomers Having Structure II
Figure imgf000017_0002
In one embodiment, the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising at least 80 mole percent of an enantiomer having structure II, for example the composition comprising the compound of Entry 3a (Table 3) wherein the R, R, R enantiomer shown represents at least 80 mole percent relative to the amounts of all other fluoroalkyl tetrabenazine carbinol components in the composition.
In an alternate embodiment, the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound which is comprised of at least 95 mole % of an enantiomer having structure II, for example a fluoroalkyl tetrabenazine carbinol composition comprising the compound of Entry 3b (Table 3) wherein the enantiomer shown represents at least 95 mole percent relative to the amounts of all other fluoroalkyl tetrabenazine carbinol components in the composition.
In one embodiment, the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising a principal component enantiomer having structure III
Figure imgf000018_0001
wherein R1 is a C1-C1O fluorinated aliphatic radical; R2 is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; R4 is hydrogen or a C1-C1O aliphatic radical; and R5 is hydrogen, a C1-C1O aliphatic radical, a C2-C1O cycloaliphatic radical, or a C2- C2o aromatic radical.
Principal component enantiomers having structure III are illustrated in Table 4 below. Table 4 Principal Component Enantiomers Having Structure III
Figure imgf000019_0001
In one embodiment, the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising at least 80 mole percent of an enantiomer having structure III, for example a fluoroalkyl tetrabenazine carbinol composition comprising the compound of Entry 4a (Table 4) wherein the S, S, S enantiomer shown represents at least 80 mole percent relative to the amounts of all other fluoroalkyl tetrabenazine carbinol components in the composition. In another embodiment, the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising at least 95 mole percent of an enantiomer having structure III, for example a fluoroalkyl tetrabenazine carbinol composition comprising the compound of Entry 4b (Table 4) wherein the S, S, S enantiomer shown represents at least 95 mole percent relative to the amounts of all other fluoroalkyl tetrabenazine carbinol components in the composition.
As noted, with respect to structures I, II, and III, in one embodiment, the group -OR5 is not a hydroxy group and is instead a C1-C1O aliphatic radical, a C2-C1O cycloaliphatic radical, or a C2-C2O aromatic radical. Thus in one embodiment, the group -OR5 is an ester moiety, for example an acetate group as exemplified by Entry Ia of Table 1, or for example an aryl ether moiety, for example a phenoxy group as exemplified by Entry Ig of Table 1. In one embodiment, the group -OR5 is an aliphatic ester moiety selected from the group consisting of formate, acetate, propanoate, butanoate, pentanoate, hexanoate, and heptanoate. In an alternate embodiment, the group -OR5 is a silyl ether moiety, for example triethylsilyloxy.
As noted, the present invention provides novel fluoroalkyl tetrabenazine carbinol compounds I and IV, and in certain embodiments, mixtures thereof. Fluoroalkyl tetrabenazine carbinol compounds having structure IV are illustrated in Table 5 below.
Figure imgf000020_0001
Table 5 Examples Of Fluorophilic Tetrabenazine Carbinol Compound Having Structure IV
Figure imgf000020_0002
Figure imgf000021_0001
Structure IV represents a genus of fluoroalkyl tetrabenazine carbinol compounds which includes the racemic compound 5a (Table 5) having both the R configuration and S configuration at ring positions-2, -3, and -12. In another embodiment, structure IV represents fluoroalkyl tetrabenazine carbinol compound 5b (Table 5) having the R configuration (absolute stereochemistry) at ring positions-2, -3, and -12. In yet another embodiment, structure IV represents compound 5d (Table 5) having absolute stereochemistry opposite that of compound 5b. Those having ordinary skill in the art will appreciate that the individual fluoroalkyl tetrabenazine carbinol compounds shown in Table 5 herein are illustrative of tetrabenazine carbinol derivatives falling within the scope of generic structure IV. Those skilled in the art will appreciate as well that fluoroalkyl tetrabenazine carbinol compounds 5a, 5c, 5g, 5i and 5j represent racemic mixtures.
As noted, in one embodiment, the present invention provides a fluoroalkyl tetrabenazine carbinol compound having structure IV which may be a racemic mixture (e.g. compound 5a (Table 5), a single enantiomer (e.g. compound 5b (Table 5), or a composition enantiomerically enriched in a single principal component enantiomer. Entries 6a-6c in Table 6 below illustrate fluoroalkyl tetrabenazine carbinol compounds IV comprising a principal component enantiomer and at least one minor component enantiomer.
Table 6 Fluoroalkyl Tetrabenazine Carbinol Compounds IV Comprising A Principal Component Enantiomer And At Least One Minor Component Enantiomer.
Figure imgf000022_0001
Figure imgf000023_0001
In Table 6 the fluoroalkyl tetrabenazine carbinol compositions comprise a principal component enantiomer and a minor component enantiomer. In the fluoroalkyl tetrabenazine carbinol compositions illustrated in Table 6 the mole percentage of the principal component enantiomer is given as "mole%" and refers to the mole percentage of the principal component enantiomer having the structure shown relative to the amounts of all other fluoroalkyl tetrabenazine carbinol components in the composition. For the purposes of this discussion a fluoroalkyl tetrabenazine carbinol is any compound falling within the scope of generic structure I. Those skilled in the art will appreciate that all compounds falling within the scope of generic structure IV also fall within the scope of generic structure I. Entry 6a represents a fluoroalkyl tetrabenazine carbinol composition comprising 98 mole% of the R, R, R principal component enantiomer shown and a lesser amount of the S, S, S minor component enantiomer. Entry 6c represents a fluoroalkyl tetrabenazine carbinol composition comprising 88 mole percent of the S, S, S principal component enantiomer having the structure shown and a lesser amount of the R, R, R minor component enantiomer.
In one embodiment, the present invention provides a fluoroalkyl tetrabenazine carbinol compound represented by structure IV, which is enantiomerically enriched and is comprised of at least 95 mole percent (mole %) of an enantiomer having the R configuration at ring position- 12.
In an alternate embodiment, the present invention provides a fluoroalkyl tetrabenazine carbinol compound represented by structure IV, which is enantiomerically enriched and is comprised of at least 95 mole percent (mole %) of an enantiomer having the R configuration at ring position-2.
In one embodiment, the present invention provides a fluoroalkyl tetrabenazine carbinol compound having structure IV in which the fluorinated aliphatic radical at ring position-2 (-R1) has a syn-configuration relative to the hydrogen at ring position- 12. The principal component enantiomers of Entries 6a-6c of Table 6 illustrate fluoroalkyl tetrabenazine carbinol compounds in which the fluorinated aliphatic moiety at ring position-2 (-R1) has a syn-configuration relative to the hydrogen at ring position- 12.
In one embodiment, the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising a principal component enantiomer having structure V
Figure imgf000024_0001
OH (V)
wherein R1 is a C1-C1O fluorinated aliphatic radical; R2 is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; and R4 is hydrogen or a C1-C1O aliphatic radical.
Principal component enantiomers having structure V are illustrated in Table 7 below.
Table 7 Principal Component Enantiomers Having Structure V
Entry Structure
Figure imgf000025_0001
In one embodiment, the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising at least 80 mole percent of an enantiomer having structure V, for example the composition comprising the compound of Entry 7a (Table 7) wherein the R, R, R enantiomer shown represents at least 80 mole percent relative to the amounts of all other fluoroalkyl tetrabenazine carbinol components in the composition.
In an alternate embodiment, the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound, which is comprised of at least 95 mole % of an enantiomer having structure V, for example an fluoroalkyl tetrabenazine carbinol composition comprising the compound of Entry 7b (Table 7 wherein the R, R, R enantiomer shown represents at least 95 mole percent relative to the amounts of all other fluoroalkyl tetrabenazine carbinol components in the composition.
In one embodiment, the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising a principal component enantiomer having structure VI
wherein R1 is a C1-C1O
Figure imgf000026_0001
aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; and R4 is hydrogen or a C1-C1O aliphatic radical.
Principal component enantiomers having structure VI are illustrated in Table 8 below.
Table 8 Principal Component Enantiomers Having Structure VI
Structure
Figure imgf000027_0001
In one embodiment, the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising at least 80 mole percent of an enantiomer having structure VI, for example a fluoroalkyl tetrabenazine carbinol composition comprising the compound of Entry 8a (Table 8) wherein the S, S, S enantiomer shown represents at least 80 mole percent relative to the amounts of all other fluoroalkyl tetrabenazine carbinol components in the composition. In another embodiment, the present invention provides an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising at least 95 mole percent of an enantiomer having structure VI, for example a fluoroalkyl tetrabenazine carbinol composition comprising the compound of Entry 8b (Table 8) wherein the S, S, S enantiomer shown represents at least 95 mole percent relative to the amounts of all other fluoroalkyl tetrabenazine carbinol components in the composition.
In another embodiment, the present invention provides an enantiomeric ally enriched fluoroalkyl tetrabenazine carbinol compound having structure IV, wherein R1 is a C1- C1O fluorinated aliphatic radical comprising at least one fluorine- 18 atom; R is a C5- C1O aliphatic radical; and R3 and R4 are methoxy groups.
As will be clear to one of ordinary skill in the art, the term "fluoroalkyl " refers to the group R1 of structures I- VI which represents a C1-C1O aliphatic radical and is not restricted to the ordinary meaning of the term "alkyl". Thus although the term fluoroalkyl tetrabenazine carbinol is used extensively herein for convenience and means a tetrabenazine compound falling within the scope of generic structure I and comprising a C1-C1O fluorinated aliphatic radical at ring position-2.
As demonstrated below, the fluorine- 18 labeled compounds of formula (I), (II), (III), (IV), (V), and (VI) have use as PET imaging agents for the VMAT-2 biomarker. Therefore, according to a further aspect of the invention, there is provided a method for detection of VMAT-2 in a subject, comprising :
(i) administration of a fluorine- 18 labeled compound of formula (I), (II), (III), (IV), (V) or (VI) as defined above, or a salt thereof to said subject;
(ii) detecting uptake of said fluorine- 18 labeled compound by in vivo PET imaging.
Such a method provides information and data having utility in the diagnosis and clinical research of VMAT-2 related disorders, for example by providing a method for determining beta cell mass. The subject is a mammal, most suitably a human who has or is suspected of having a VMAT-2 related disorder. In an alternative aspect, a compound of formula (I), (II), (III), (IV), (V) or (VI) as defined above, or a salt thereof may also be used to image VMAT-2 in healthy human volunteers for example for clinical research purposes. The imaging of VMAT-2 may be carried out quantitatively such that the amount or change in amount of VMAT-2 may be determined so as to diagnose or track progress of a disease. Alternatively the imaging of VMAT-2 may be used to locate VMAT-2.
The term "VMAT-2 related disorder" means a VMAT-2 related disease in the brain such as Huntington's, Parkinson's, or schizophrenia, or of the pancreas such as beta cell associated disorder including an insulinoma or other neuroendocrine tumour, or diabetes (for example type 1 diabetes, type 2 diabetes, or preclinical type 1 diabetes). In one aspect of the invention, the VMAT-2 related disorder is diabetes. In an alternative aspect of the invention, the VMAT-2 related disorder is schizophrenia.
Accordingly, there is further provided use of a fluorine- 18 labeled compound of formula (I), (II), (III), (IV), (V) or (VI) or a salt thereof in the manufacture of a radiopharmaceutical for the in vivo PET diagnosis or imaging of a VMAT-2 related disorder. In the alternative, there is provided a fluorine- 18 labeled compound of formula (I), (II), (III), (IV), (V) or (VI) or a salt thereof for use in the in vivo PET diagnosis or imaging of a VMAT-2 related disorder.
In a further aspect, there is provided a method for the in vivo diagnosis or imaging of a VMAT-2 related disorder in a subject, preferably a human, comprising administration of a fluorine- 18 labeled compound of formula (I), (II), (III), (IV), (V) or (VI) or a salt thereof and detecting the uptake of said compound by an in vivo PET imaging technique. The method is especially preferred for the in vivo diagnosis or imaging of diabetes. In one aspect of the invention, the method comprises detecting the uptake of a fluorine- 18 labeled compound of formula (I), (II), (III), (IV), (V) or (VI) or a salt thereof by an in vivo PET imaging technique in a subject, preferably a human to whom said compound has been pre-administered.
The invention further provides a method of monitoring the effect of treatment of a subject, preferably a human with a drug to combat a VMAT-2 related disorder, said method comprising administering to said subject a fluorine- 18 labeled compound of formula (I), (II), (III), (IV), (V) or (VI) or a salt thereof and detecting the uptake of said compound by an in vivo PET imaging technique, said administration and detection optionally but preferably being effected repeatedly, e.g. before, during and after treatment with said drug.
A compound of formula (I), (II), (III), (IV), (V) or (VI) or a salt thereof is preferably administered for in vivo use in a pharmaceutical formulation comprising said compound and a pharmaceutically acceptable excipient, such formulations thus form a further aspect of the invention. A "pharmaceutical formulation" is defined in the present invention as a formulation comprising an effective amount of a compound of formula (I), (II), (III), (IV), (V) or (VI) or a salt thereof in a form suitable for administration to a mammal, suitably a human. The "pharmaceutically acceptable excipient" is a suitably a fluid, especially a liquid, in which the compound of formula (I), (II), (III), (IV), (V) or (VI) or a salt thereof can be suspended or dissolved, such that the formulation is physiologically tolerable, ie. can be administered to the mammalian body without toxicity or undue discomfort. The pharmaceutically acceptable excipient is suitably an injectable carrier liquid such as sterile, pyrogen- free water for injection; an aqueous solution such as saline (which may advantageously be balanced so that the final formulation for injection is isotonic); an aqueous solution of one or more tonicity-adjusting substances (for example, salts of plasma cations with biocompatible counterions), sugars (for example, glucose or sucrose), sugar alcohols (for example, sorbitol or mannitol), glycols (for example. glycerol), or other non-ionic polyol materials (for example, polyethyleneglycols, propylene glycols and the like). Preferably the pharmaceutically acceptable excipient is pyrogen-free water for injection or isotonic saline.
The pharmaceutical formulation may optionally contain additional excipients such as an antimicrobial preservative, pH-adjusting agent, filler, stabiliser or osmolality adjusting agent. By the term "antimicrobial preservative" is meant an agent which inhibits the growth of potentially harmful micro-organisms such as bacteria, yeasts or moulds. The antimicrobial preservative may also exhibit some bactericidal properties, depending on the dosage employed. The main role of the antimicrobial preservative(s) of the present invention is to inhibit the growth of any such micro- organism in the pharmaceutical formulation. The antimicrobial preservative may, however, also optionally be used to inhibit the growth of potentially harmful micro- organisms in one or more components of kits used to prepare said pharmaceutical formulation prior to administration. Suitable antimicrobial preservative(s) include: the parabens, ie. methyl, ethyl, propyl or butyl paraben or mixtures thereof; benzyl alcohol; phenol; cresol; cetrimide and thiomersal. Preferred antimicrobial preservative(s) are the parabens.
The term "pH-adjusting agent" means a compound or mixture of compounds useful to ensure that the pH of the pharmaceutical formulation is within acceptable limits (approximately pH 4.0 to 10.5) for human or mammalian administration. Suitable such pH-adjusting agents include pharmaceutically acceptable buffers, such as tricine, phosphate or TRIS [ie. rπs(hydroxymethyl)aminomethane], and pharmaceutically acceptable bases such as sodium carbonate, sodium bicarbonate or mixtures thereof. When the pharamceutical formulation is employed in kit form, the pH adjusting agent may optionally be provided in a separate vial or container, so that the user of the kit can adjust the pH as part of a multi-step procedure.
By the term "filler" is meant a pharmaceutically acceptable bulking agent which may facilitate material handling during production and lyophilisation. Suitable fillers include inorganic salts such as sodium chloride, and water soluble sugars or sugar alcohols such as sucrose, maltose, mannitol or trehalose.
The pharmaceutical formulations of the invention are typically supplied in suitable vials or vessels which comprise a sealed container which permits maintenance of sterile integrity and/or radioactive safety, plus optionally an inert headspace gas (eg. nitrogen or argon), whilst permitting addition and withdrawal of solutions by syringe or cannula. A preferred such container is a septum- sealed vial, wherein the gas-tight closure is crimped on with an overseal (typically of aluminium). The closure is suitable for single or multiple puncturing with a hypodermic needle (e.g. a crimped-on septum seal closure) whilst maintaining sterile integrity. Such containers have the additional advantage that the closure can withstand vacuum if desired (eg. to change the headspace gas or degas solutions), and withstand pressure changes such as reductions in pressure without permitting ingress of external atmospheric gases, such as oxygen or water vapour. Preferred multiple dose containers comprise a single bulk vial (e.g. of 10 to 30 cm3 volume) which contains multiple patient doses, whereby single patient doses can thus be withdrawn into clinical grade syringes at various time intervals during the viable lifetime of the preparation to suit the clinical situation. Pre-filled syringes are designed to contain a single human dose, or "unit dose" and are therefore preferably a disposable or other syringe suitable for clinical use. The pharmaceutical formulations of the present invention preferably have a dosage suitable for a single patient and are provided in a suitable syringe or container, as described above.
The pharmaceutical formulations of the invention may be prepared under aseptic manufacture (ie. clean room) conditions to give the desired sterile, non-pyro genie product. It is preferred that the key components, especially the excipients plus those parts of the apparatus which come into contact with the pharmaceutical formulation (for example, vials) are sterile. The components of the pharmaceutical formulation can be sterilised by methods known in the art, including: sterile filtration, terminal sterilisation using, for example, gamma-irradiation, autoclaving, dry heat or chemical treatment (for example, with ethylene oxide). It is preferred to sterilise some components in advance, so that the minimum number of manipulations needs to be carried out. As a precaution, however, it is preferred to include at least a sterile filtration step as the final step in the preparation of the pharmaceutical formulation.
An "effective amount" of a compound of formula (I), (II), (III), (IV), (V) or (VI) or a salt thereof means an amount which is effective for use in in vivo PET imaging or for use in therapy and will vary depending on the exact compound to be administered, the weight of the subject or patient, and other variables as would be apparent to a physician skilled in the art. The fluorine- 18 labeled compounds of this invention may be administered to a subject for PET imaging in amounts sufficient to yield the desired signal, typical radionuclide dosages of 0.01 to 100 mCi, preferably 0.1 to 50 mCi will normally be sufficient per 70kg bodyweight.
As noted, the fluoroalkyl tetrabenazine carbinol compounds I, II, III, IV, V, and VI provided by the present invention may comprise a fluorine- 18 atom in the fluorinated aliphatic moiety -R1. In various embodiments such fluoroalkyl tetrabenazine carbinol compounds comprising a fluorine- 18 atom are useful as PET imaging agents. Thus, in one embodiment, the present invention provides a PET imaging agent comprising a fluoroalkyl tetrabenazine carbinol compound having structure I
Figure imgf000033_0001
wherein R1 is a C1-C1O fluorinated aliphatic radical comprising at least one fluorine- 18 atom; R2 is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; R4 is hydrogen or a C1-C1O aliphatic radical; and R5 is hydrogen, a C1-C1O aliphatic radical, a C2-C1O cycloaliphatic radical, or a C2-C2O aromatic radical.
In another embodiment, the present invention provides a PET imaging agent comprising an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising a principal component enantiomer having structure II
Figure imgf000033_0002
wherein R1 is a C1-C1O fluorinated aliphatic radical comprising at least one fluorine- 18 atom; R2 is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; R4 is hydrogen or a C1-C1O aliphatic radical; and R5 is hydrogen, a C1-C1O aliphatic radical, a C2-C1Q cycloaliphatic radical, or a C2-C2Q aromatic radical. In yet another embodiment, the present invention provides a PET imaging agent comprising an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising a principal component enantiomer having structure III
Figure imgf000034_0001
wherein R1 is a C1-C1O fluorinated aliphatic radical comprising at least one fluorine- 18 atom; R2 is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; R4 is hydrogen or a C1-C1O aliphatic radical; and R is hydrogen, a C1-C1O aliphatic radical, a C2-C1O cycloaliphatic radical, or a C2-C2O aromatic radical.
In yet another embodiment, the present invention provides a PET imaging agent comprising a fluoroalkyl tetrabenazine carbinol compound having structure IV
Figure imgf000034_0002
wherein R1 is a C1-C1O fluorinated aliphatic radical comprising at least one fluorine- 18 aattoomm;; RR22 iiss aa CC11--CC11OQ aalliipphhaattiicc rraaddiiccaall;; RR33 iiss '. hydrogen or a C1-C1Q aliphatic radical; and R4 is hydrogen or a C1-C1Q aliphatic radical. In another embodiment, the present invention provides a PET imaging agent comprising an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising a principal component enantiomer having structure V
Figure imgf000035_0001
(V) wherein R1 is a C1-C1O fluorinated aliphatic radical comprising at least one fluorine- 18 atom; R2 is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; and R4 is hydrogen or a C1-C1O aliphatic radical.
In yet another embodiment, the present invention provides a PET imaging agent comprising an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound comprising a principal component enantiomer having structure VI
Figure imgf000035_0002
wherein R1 is a C1-C1O fluorinated aliphatic radical comprising at least one fluorine- 18 atom; R2 is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; and R4 is hydrogen or a C1-C1Q aliphatic radical. In another embodiment, the present invention provides a PET imaging agent comprising an enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound having structure IV, wherein R1 is a C1-C1O fluorinated aliphatic radical comprising at least one fluorine- 18 atom; R2 is a Cs-C1O aliphatic radical; and R3 and R4 are methoxy groups.
The term "PET imaging agent" as used herein refers to a composition comprising a fluorine- 18 labeled fluoroalkyl tetrabenazine carbinol compound, which may be administered to a patient in order to perform a PET scan. Typically, the imaging agent is presented to the patient in the form of an aqueous formulation containing a sufficient amount of fluorine- 18 labeled fluoroalkyl tetrabenazine carbinol compound to conduct the PET scan. Typically, the amount of fluorine- 18 labeled fluoroalkyl tetrabenazine carbinol compound presented to a patient corresponds to a weight of the fluorine- 18 labeled fluoroalkyl tetrabenazine carbinol compound on the order of nanograms. In reference to the relative amounts of non-radioactive fluorine- 19 containing fluoroalkyl tetrabenazine carbinol compound present in the PET imaging agent presented to a patient, the PET imaging agent typically has a specific activity in a range from about 1 to about 99 percent. In one embodiment, the PET imaging agent has a specific activity in a range from about 10 to about 95 percent. In another embodiment, the PET imaging agent has a specific activity in a range from about 20 to about 90 percent.
The aqueous formulation containing the fluorine- 18 fluoroalkyl tetrabenazine carbinol compound is typically administered intravenously and may contain various agents, which promote the dispersal of the PET imaging agent in water. In one embodiment, the PET imaging agent may be administered to a patient in an aqueous formulation comprising ethanol and the fluorine- 18 labeled fluoroalkyl tetrabenazine carbinol compound. In an alternate embodiment, the PET imaging agent may be administered to a patient as an aqueous formulation comprising dextrose and the fluorine- 18 labeled fluoroalkyl tetrabenazine carbinol compound. In yet another embodiment, the PET imaging agent may be administered to a patient as an aqueous formulation comprising saline and the fluorine- 18 labeled fluoroalkyl tetrabenazine carbinol compound. Such a formulation may optionally contain further excipients as described above, more typically including one or more excipients 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 orpαra-aminobenzoic acid.
In addition to being useful as PET imaging agents and as probes for determining the suitability of a given fluoroalkyl tetrabenazine carbinol compound for use as a PET imaging agent, the fluoroalkyl tetrabenazine carbinol compounds provided by the present invention are believed to possess therapeutic utility in the treatment of diseases such as schizophrenia and Huntington's disease. Thus, in one embodiment, the present invention provides a fluoroalkyl tetrabenazine carbinol compound having structure I, which is useful in treating a pathological condition in a patient. In an alternate embodiment, the present invention provides a fluoroalkyl tetrabenazine carbinol compound having structure IV, which is useful in treating a pathological condition in a patient. In various other embodiments, the present invention provides enantiomerically enriched fluoroalkyl tetrabenazine carbinol compounds II, III, V, and VI (and mixtures thereof), which are useful in treating a pathological condition in a patient. Typically the amount of amount of the fluoroalkyl tetrabenazine carbinol compound administered to a patient in a given dose is on the order of milligrams.
Those skilled in the art will appreciate that fluoroalkyl tetrabenazine carbinol compounds falling within the scope of generic structure I may under a variety of conditions form salts which are useful as PET imaging agents, probes for the discovery and development of imaging agents, and/or as therapeutic agents. Thus, the present invention provides a host of novel and useful fluoroalkyl tetrabenazine carbinol compounds and their salts.
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. In one particular embodiment, the present invention provides the hydrochloride salts of the novel fluoroalkyl tetrabenazine carbinol compounds, for example the hydrochloride salt of the compound of Entry 4a of Table 4.
In a further aspect of the invention, there is provided a compound of formula (I), (II), (III), (IV), (V), or (VI) or a salt thereof, for use in medicine.
The fluoroalkyl tetrabenazine carbinol compounds of the present invention may be prepared by a variety of methods including those provided in the experimental section of this disclosure. In one embodiment, the fluoroalkyl tetrabenazine carbinol compound is prepared by reaction of nucleophilic fluoride ion or an electrophilic fluorinating agent with a fluorophilic tetrabenazine carbinol compound having structure VII
Figure imgf000038_0001
wherein R1 is a C1-C2O aliphatic, a C2-C2O cycloaliphatic radical, or a C2-C2O aromatic radical comprising at least one functional group susceptible to reaction with nucleophilic fluoride ion or an electrophilic fluorinating agent; R2 is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; R4 is hydrogen or a C1-C1O aliphatic radical; and R is hydrogen, a C1-C1O aliphatic radical, a C2-C1O cycloaliphatic radical, or a C2-C2Q aromatic radical. Thus in one embodiment, the present invention provides a fluorophilic tetrabenazine carbinol compound having structure VII. Fluorophilic tetrabenazine carbinol compounds having structure VII are illustrated in Table 9 below.
Table 9 Examples Of Fluorophilic Tetrabenazine Compounds Having Structure VII
Figure imgf000039_0001
Figure imgf000040_0001
As noted, in one embodiment, the present invention provides a fluorophilic compound having structure VII, wherein R1 is a C1-C2O aliphatic radical, a C2-C2O cycloaliphatic radical, or a C2-C2O aromatic radical comprising at least one functional group susceptible to reaction with nucleophilic fluoride ion. In one embodiment, the functional group susceptible to reaction with nucleophilic fluoride ion is an aromatic sulfonate ester (e.g. tosylate, benzenesulfonate, naphthalenesulfonate). In an alternate embodiment, the functional group susceptible to reaction with nucleophilic fluoride ion is an aliphatic sulfonate ester (e.g. methane sulfonate, trifluoromethane sulfonate). In one embodiment, the functional group susceptible to reaction with nucleophilic fluoride ion is selected from the group consisting of tosylate, mesylate, and trifluoromethane sulfonate groups.
In one embodiment, the present invention provides a fluorophilic compound having structure VII wherein the group R1 comprises at least one tosylate group susceptible to reaction with nucleophilic fluoride ion. See for example the Entries 9a, 9j and 9k of Table 9. As defined herein, the tosylate group is an aromatic radical and the group R1 comprising the tosylate group is also an aromatic radical. In the compound shown in Entry 9a for example, the group R1 comprising the tosylate group is a C9 aromatic radical which upon displacement with fluoride ion becomes a C2 fluorinated aliphatic radical.
In an alternate embodiment, the present invention provides a fluorophilic compound having structure VII wherein the group R1 comprises at least one mesylate group susceptible to reaction with nucleophilic fluoride ion. As defined herein, the mesylate group is an aliphatic radical and the group R1 comprising the mesylate group may be an aliphatic, a cycloaliphatic or an aromatic radical depending on the overall structure of the group R1. For example, in a fluorophilic compound having structure VII in which R1 comprises both a mesylate group and an epoxy group, the group R1 is a cycloaliphatic radical. Alternatively, in a fluorophilic compound having structure VII in which R1 comprises both a mesylate group and a tosylate group, the group R1 is an aromatic radical. It is helpful to bear in mind that the definitions of aliphatic, cycloaliphatic and aromatic radicals provided in this disclosure establish a hierarchy in which aliphatic radicals (non-cyclic arrays of atom(s)) must be free of cycloaliphatic groups (a cyclic array of atoms which is not aromatic) and aromatic groups (a cyclic array of atoms which is aromatic), cycloaliphatic radicals must be free of aromatic groups, and aromatic radicals must simply comprise an aromatic group.
In an alternate embodiment, the present invention provides a fluorophilic compound having structure VII wherein the group R1 comprises at least one trifluoromethane sulfonate (triflate) group susceptible to reaction with nucleophilic fluoride ion. See for example Entry 9b of Table 9.
In an alternate embodiment, the present invention provides a fluorophilic compound having structure VII wherein the group R1 comprises at least one p-nitrobenzoate group susceptible to reaction with nucleophilic fluoride ion. See for example Entry 9c of Table 9.
In an alternate embodiment, the present invention provides a fluorophilic compound having structure VII wherein the group R1 comprises at least one methane sulfonate group susceptible to reaction with nucleophilic fluoride ion. See for example Entry 9d of Table 9.
In an alternate embodiment, the present invention provides a fluorophilic compound having structure VII wherein the group R1 comprises at least one epoxy group susceptible to reaction with nucleophilic fluoride ion. See for example Entry 9i of Table 9.
In yet another embodiment, the present invention provides a fluorophilic compound having structure VII wherein the group R1 comprises at least one cyclic sulfate group susceptible to reaction with nucleophilic fluoride ion. See for example Entry 91 of Table 9.
In one embodiment, the present invention provides a fluorophilic compound having structure VII, wherein R1 is a C2-C2O aliphatic radical comprising at least one functional group susceptible to reaction with an electrophilic fluorinating agent, for example fluorine gas, perchloryl fluoride, mercuric fluoride, and phenyl selenenyl fluoride.
Thus in one embodiment, the functional group susceptible to reaction with an electrophilic fluorinating agent is selected from the group consisting of carbon-carbon double bonds and carbon-carbon triple bonds. Entries 9e, 9f, 9g, 9h and 9k of Table 9 illustrate compounds falling within the scope of generic structure VII, which are susceptible to reaction with an electrophilic fluorinating agent. Attention is called to Entry 9k wherein the group R1 comprises functional groups susceptible to reaction with an electrophilic fluorinating agent (double bond) and to reaction with nucleophilic fluoride ion (tosylate group).
Fluorophilic tetrabenazine carbinol compounds VII may be prepared in enantiomerically enriched or racemic forms. For example, a fluorophilic tetrabenazine compound VII may be enriched in the R, R, R- enantiomer shown in Entry 9b of Table 9. Alternatively, a fluorophilic tetrabenazine carbinol compound may be enriched in an enantiomer having absolute stereochemistry opposite that of Entry 9b of Table 9, for example the S, S, S-enantiomer of Entry 9d.
Thus, in one embodiment, the present invention provides an enantiomerically enriched fluorophilic tetrabenazine carbinol compound comprising a principal component enantiomer having structure VIII
Figure imgf000043_0001
wherein R1 is a C1-C1O aliphatic radical, a C2-C2O cycloaliphatic radical, or a C2-C2O aromatic radical comprising at least one functional group susceptible to reaction with nucleophilic fluoride ion or an electrophilic fluorinating agent; R is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; R4 is hydrogen or a C1-C1O aliphatic radical; and R5 is hydrogen, a C1-C1O aliphatic radical, a C2-C1O cycloaliphatic radical, or a C2-C2O aromatic radical. Principal component enantiomers VIII are illustrated by Entries 9b, 9h, 9k, and 91 of Table 9.
In an alternate embodiment, the present invention provides an enantiomerically enriched fluorophilic compound comprising a principal component enantiomer having structure IX
Figure imgf000043_0002
wherein R1 is a C1-C1O aliphatic radical, a C2-C2O cycloaliphatic radical, or a C2-C2O aromatic radical comprising at least one functional group susceptible to reaction with nucleophilic fluoride ion or an electrophilic fluorinating agent; R2 is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; R4 is hydrogen or a C1-C1O aliphatic radical; and R is hydrogen, a C1-C1O aliphatic radical, a C2-C1O cycloaliphatic radical, or a C2-C2O aromatic radical. Principal component enantiomers IX are illustrated by Entry 9d of Table 9.
As noted, with respect to structures VII, VIII, and XI, in one embodiment, the group - OR5 is not a hydroxy group and is instead a C1-C1O aliphatic radical, a C2-C1O cycloaliphatic radical, or a C2-C2O aromatic radical. Thus in one embodiment, the group -OR5 is an ester moiety, for example an acetate group as exemplified by Entry
9a of Table 9, or for example an aryl ether moiety, for example a phenoxy group as exemplified by Entry 9c of Table 9. In one embodiment, the group -OR is an aliphatic ester moiety selected from the group consisting of formate, acetate, propanoate, butanoate, pentanoate, hexanoate, and heptanoate. In an alternate embodiment, the group -OR5 is a silyl ether moiety, for example triethylsilyloxy.
Co-pending International Patent Application PCT/US3008/065738 discloses methods for the preparation of racemic and enantiomerically enriched tetrabenazine compositions which may be used for the preparation of fluorophilic tetrabenazine carbinol compounds provided by the present invention. In addition, the Examples Section of the present disclosure provides detailed experimental descriptions of the preparation and characterization of tetrabenazine carbinol compounds VII.
In general, tetrabenazine carbinol compounds VII can be prepared from the corresponding tetrabenazine compound. Tetrabenazine compounds may be prepared by reacting a nucleophilic alkenyl species with an aldehyde compound having structure X
Figure imgf000044_0001
wherein R3 is hydrogen or a C1-C2O aliphatic radical; R4 is hydrogen or a C1-C2O aliphatic radical; and P1 is a protecting group, to provide an allylic alcohol (See Method 4 of the Examples section), which is then oxidized to provide an enone designated the "first intermediate" (See Example 1 of the Examples section), the protecting group of which is then removed and the resultant deprotected first intermediate undergoes an amino cyclization reaction to afford the corresponding tetrabenazine (TBZ) compound.
Representative aldehyde compounds encompassed by generic formula X are given in Table 10.
Table 10 Representative Aldehyde Compounds Encompassed By Formula X
Figure imgf000046_0001
The preparation of the aldehyde compound featured in Entry 10a of Table 10 is described in the Examples section of this disclosure (Methods 1-3). In general, the class of aldehyde compounds represented by structure X may be prepared by art recognized methods, for example using the methodology depicted in Scheme 1.
Figure imgf000047_0001
Figure imgf000047_0002
Scheme 1
Thus, aldehyde compounds X may be prepared from intermediates prepared using methodology described by Sasamoto et al. (Journal of the American Chemical Society 128, 14010-14011, 2006). Sasamoto et al. disclose the preparation of enantiomerically enriched tetrahydroquinoline malonate compounds, which may be converted to aldehyde compound X by selective hydrolysis of one of the ester moieties of the tetrahydroquinoline malonate and decarboxylation followed by reduction of the resultant tetrahydroisoquinoline monoester to aldehyde compound X as depicted in Scheme 1.
One of ordinary skill in the art will appreciate that the 2 mole percent DM-SEGPHOS shown in Scheme 1 represents a chiral catalyst responsible for the enantiomeric enrichment of the product aldehyde X, and further that the use of DM-SEGPHOS of opposite chirality as the chiral catalyst will afford a product aldehyde X enantiomerically enriched in the "S" enantiomer (aldehyde compound X having the S configuration at ring position- 12 (See for example Entry 10b of Table 10). Suitable chiral catalysts include those disclosed by Sasamoto et al. (Journal of the American
Chemical Society 128, 14010-14011, 2006), for example (S)-Binap, (R)-Binap, (S)- DM-Binap, (R)-DM-Binap, (S)-DM-SEGPHOS, and (R)-DM-SEGPHOS. Typically use of a catalyst consisting of a ligand possessing a single, for example "S", configuration produces stereochemically enriched malonate adducts of the opposite "R" configuration and vice versa.
In addition to the use of a chiral catalyst to generate aldehyde compounds X enriched in a single configuration at ring position- 12, there are available a wide variety of methods for the separation of racemic aldehyde X into its constituent enantiomers. For example, racemic aldehyde compound X may be separated into its constituent enantiomers by high performance liquid chromatography (hplc) on a chiral hplc column.
Other methods for producing enantiomerically enriched compositions provided by the present invention include conversion of a racemic fluoroalkyl tetrabenazine carbinol compound having structure I into an adduct comprising a mixture of diastereomers which are then separated by fractional crystallization. For example, a racemic fluoroalkyl tetrabenazine carbinol compound having structure I may be reacted with (- )-tartaric acid to form an adduct (ammonium tartarate salt) of the racemic fluoroalkyl tetrabenazine carbinol compound, said adduct comprising a mixture of diastereomeric ammonium tartarate salts which are then separated by fractional crystallization.
EXAMPLES
Method 1 Preparation of Protected Diester 2
Figure imgf000048_0001
The dihydroisoquinoline 1 (1.0 eq.) and Boc anhydride (1.5 eq.) were dissolved in CH2Cl2 at room temperature to provide a 1.5 M solution with respect to the dihydroisoquinoline. The mixture was allowed to stir for 30 min. Following the allotted time, the reaction mixture was cooled to 0 0C and then diisopropylmalonate (1.5 eq.) followed by a pre-chilled solution of the Pd catalyst (0.008 eq.) in dichloromethane were added successively to the reaction mixture to provide a final reaction concentration of 0.84 M with respect to the starting dihydroisoquinoline. The reaction mixture was allowed to continue stirring at -2.5 0C for 15 h. Following this time EtOAc and brine were added to the reaction mixture. The aqueous layer was extracted with three portions of EtOAc and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the crude product. The crude material was dissolved in a minimal amount of dichloromethane and purified by flash chromatography on SiO2 (15-30% EtOAc-hexanes, elution was observed at 285 nm and 228 nm). The product 2 was a colorless solid that existed as a mixture of rotamers in solution at room temperature 94%: [α] D -69.0 ( c 0.21, CHCl3); 1H NMR (CDCl3) δ 0.81-1.02 (m, 6H), 1.06-1.17 (m, 6H), 1.23-1.38 (m, 9H), 2.51-2.63 (m, IH), 2.64-2.77 (m, IH), 3.20-3.29 (m, 0.6H), 3.32-3.41 (m, 0.4H), 3.51-3.58 (m, IH), 3.62-3.70 (m, 6H), 3.70-3.76 (m, 0.4H), 3.91-4.01 (m, 0.6H), 4.65-4.82 (m, IH), 4.83-4.98 (m, IH), 5.71 (apparent d, J = 5.7 Hz, 0.6H), 5.78 (apparent d, J = 7.9 Hz, 0.4H), 6.42-6.49 (m, IH), 6.77 (s, 0.6H), 6.81 (s, 0.4H); 13C NMR (CDCl3) δ 21.02, 21.09, 21.18, 21.32, 27.24, 27.95, 28.02, 37.60, 39.34, 52.11, 52.83, 55.48, 55.52, 59.28, 60.08, 68.58, 68.76, 68.82, 79.46, 80.03, 110.09, 110.73, 111.13, 126.11, 126.18, 126.37, 127.07, 146.81, 146.87, 147.93, 153.86, 154.30, 166.29, 166.78, 166.94, 167.06.
Method 2 Selective Hydrolysis and Decarboxylation of Protected Ester 3
Figure imgf000049_0001
The starting material 2 was taken up in isopropanol to provide a 0.2 M solution of 2. To this solution was added IM aqueous NaOH, bringing the final concentration of the reaction mixture to 0.1M with respect to the malonate 2. The reaction mixture was heated to and maintained 70 0C for 22 min. (timing was started when the temperature of the reaction mixture temp exceeded 65 0C). Following the allotted time the reaction mixture was quickly cooled to 0 0C. The reaction mixture carefully acidified with 2M aqueous HCl and extracted with three portions of dichloromethane. The combined organic extracts dried (Na2SO4), filtered and concentrated under reduced pressure. The isolated material was taken up in THF to provide a 0.1 M solution (based on the original quantity of 2 used in the reaction mixture) and triethylamine (1.0 eq) was added to the reaction mixture at room temperature. The reaction mixture was heated to its reflux temperature and maintained at this temperature for 90 min. The reaction mixture was concentrated under reduced pressure, dissolved in a minimal quantity of CH2Cl2 and was immediately purified by column chromatography on SiO2 (15-40% EtOAc-hexanes; 40%, the eluant was monitored at 284 nm). The product 3 existed as a mixture of ro tamers at room temperature and was a colorless foam 79%: [α]26 D -82 ( c 0.24, CH2Cl2); 1H NMR (CDCl3) δ 1.19-1.25 (m, 6H), 1.43-1.49 (m, 9H), 2.58-2.69 (m, 2H), 2.70-2.77 (m, IH), 2.78-2.92 (m, IH), 3.13-3.43 (m, IH), 3.81-3.85 (m, 6H), 3.86-4.01 (m, IH), 4.91-5.05 (m, IH), 5.38-5.61 (m, IH), 6.56-6.61 (m, IH), 6.64-6.70 (s, IH); 13C NMR (CDCl3) δ 21.75, 21.90, 27.93, 28.08, 28.44, 37.53, 38.75, 42.22, 42.81, 51.11, 51.87, 55.92, 56.02, 68.08, 79.74, 80.21, 109.60, 109.99, 111.44, 111.54, 126.28, 126.48, 128.54, 128.76, 147.51, 147.97, 154.39, 154.51, 170.36, 170.59; LRMS- (ESI+) calcd for (C21H31NO6 + H) ([M+H]+ 394.22, found 394.16.
Method 3 Preparation of Aldehyde Compound 4
Figure imgf000050_0001
To a 0.12 M solution of the starting monoester (3, 1.0 eq.) in toluene at -78 0C was added a 1.5 M solution of DiBAl-H in hexanes (1.5 eq.) dropwise via a syringe pump. Following the addition the reaction mixture was stirred at -78 0C for 2 h. The reaction mixture was quenched by the addition of EtOAc and was then acidified with saturated aqueous citric acid solution. The reaction mixture was allowed to warm to room temperature and continue stirring for 30 min. The phases were separated, and the aqueous layer extracted with three portions of EtOAc. The combined organic extracts were washed with two portions of 2 M aqueous HCl solution, brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was subjected purification on SiO2 (15-35% EtOAc-hexanes; Elution was observed at 285 nm and 228 nm). The isolated product, aldehyde compound 4, was a colorless foam. The product existed as a 1:1 mixture of rotamers at room temperature 76%: [α]26o -116 ( c 0.26,CH2Cl2); 1H NMR (CDCl3) δ 1.40 (s, 9H), 2.58 (apparent t, J = 3.8 Hz, 0.5H), 2.61 (apparent t, J = 3.5 Hz, 0.5H), 2.68-2.88 (m, 3H), 3.02-3.27 (m, IH), 3.78 (apparent s, 6H), 3.87-3.99 (m, 0.5H), 4.08-4.23 (m, 0.5H), 5.37-5.68 (m, IH), 6.55 (s, IH), 6.58 (s, IH), 9.78 (s, IH); 13C NMR (CDCl3) δ 20.90, 28.02, 28.27, 37.23, 38.65, 49.29, 49.93, 51.12, 55.83, 55.96, 80.13, 80.64, 109.42, 109.52, 111.52, 126.34, 126.51, 127.78, 127.82, 147.72, 147.97, 153.85, 154.62, 200.08, 200.33.
Method 4 Reaction Of Aldehyde Compound 4 With Nucleophilic Alkenyl Species Derived From Alkenyl Iodide 5 With To Provide Allylic Alcohol 6
Figure imgf000051_0001
To a neat mixture of the alkenyl iodide 5 (1.0 eq) and the aldehyde compound 4 (1.0 eq.) at room temperature was added 2.65 eq. of chromium chloride doped with 0.5% NiCl2 (w/w). The mixture was vortexed for about 2 min. to provide a homogeneous, green/grey paste and then stirred under nitrogen for an additional 10 min. after which time anhydrous DMF was added to bring the final reaction concentration to 0.36 M. The reaction mixture was deep green in color and was permitted to continue stirring at room temperature for 14h. Following the allotted time, the reaction mixture was diluted with 1:1 EtOAc-hexanes and an aqueous 0.5 M EDTA solution (pH 9) was added and the entire mixture was allowed to stir for 1.5 h. The aqueous layer was extracted with three portions of EtOAc, dried (MgSO4), filtered, and the filtrate was concentrated under reduced pressure to provide a green oil. The crude material was subjected to column chromatography on SiO2 (35% EtOAc-hexanes; elution was observed at 285 nm and 228 nm). The product allylic alcohol 6 was a pale yellow oil isolated in 53% yield as a mixture of diastereomers, which was taken on to the next step without additional characterization or analysis.
Method 5 Oxidation Of Allylic Alcohol 6 To Provide First Intermediate 8
Figure imgf000052_0001
To a 0.1 M solution of allylic alcohol 6 (1.0 eq) in dichloromethane at 0 0C was added 1.1 eq. of the Dess-Martin reagent 7. The reaction mixture was allowed to stir, slowly warming to room temperature over 2.5 h. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution and diluted with ethyl acetate. The organic and aqueous layers were partitioned and separated and the aqueous layer extracted with three additional portions of ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on SiO2 (10-30% EtOAc-hexanes, elution was observed at 285 nm and 228 nm). The product first intermediate 8 was a colorless, foul-smelling oil that existed at 26 0C as a 60:40 mixture of rotamers in solution (66%): 1H NMR (CDCl3) δ 0.82 (apparent t, J = 7.6 Hz, 6H), 1.42 (s, 9H), 1.70 (apparent sept, J = 6.62 Hz, IH), 2.08-2.15 (m, IH), 2.15-2.24 (m, IH), 2.62-2.70 (m, IH), 2.75-2.91 (m, IH), 2.93-3.07 (m, IH), 3.07- 3.29 (m, 1.6H), 3.30-3.43 (m, 0.4H), 3.79 (s, 3H), 3.81 (s, 3.4H), 4.04-4.16 (m, 0.6H), 5.52-5.62 (m, IH), 5.69 (s, IH), 5.90 (s, 0.6H), 6.04 (s, 0.4H), 6.57 (s, IH), 6.63 (s, IH); 13C NMR (CDCl3) δ 22.45, 27.04, 27.25, 28.11, 28.41, 38.01, 39.33, 40.39, 45.20, 45.90, 51.62, 55.92, 55.98, 79.75, 80.23, 109.85, 110.25, 110.28, 111.41, 125.65, 125.72, 126.26, 129.25, 147.57, 147.87, 148.16, 148.29, 148.35, 154.40, 154.51, 199.53; HRMS-(ESI+) calcd for (C24H35NO5) + H) ([M+H]+ 418.2594, found 418.2590.
Method 5 Removal The Boc Protecting Group First Intermediate 8 And Amino Cyclization Provide (+)-Tetrabenazine 9
Figure imgf000053_0001
First intermediate 8 (1.0 eq) was dissolved in 10% Me2S-dichloromethane to provide an 82 mM solution. The solution was cooled to 0 0C and triisopropylsilane (1.1 eq.) followed by TFA (precooled to 0 0C) was added to the reaction mixture to provide a final concentration of 41 mM. The reaction mixture was permitted to stir at 0 0C for 1 h. Following the allotted time the reaction mixture was quenched at 0 0C by the addition of saturated aqueous potassium carbonate solution and concentrated under reduced pressure to remove the majority of the dimethylsulfide. The mixture was extracted with five portions of dichloromethane, and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to provide the crude product as a yellow solid. The crude product was recrystallized from 3.5% dimethoxyethane in hexanes. The resulting colorless crystals were washed with hexanes to provide pure (+)-tetrabenazine (9) 46%: mp 126.0 0C (3.5% DME-hexanes) (a crystal polymorph was observed at 116 0C); [α]26 D +37.2 (c 0.41, CH2Cl2); 1H NMR (CD2Cl2) δ 0.89 (apparent t, J = 7.2 Hz, 6H), 0.98 (ddd, J = 12, 6.0, 4.0 Hz, IH), 1.59-1.68 (m, IH), 1.74 (ddd, J = 12, 5.9, 5.7 Hz, IH), 2.32 (apparent t, J = 11.7 Hz, IH), 2.46 (apparent t, J = 12.3 Hz, IH), 2.55 (ddd, J = 12, 10.0, 3.8 Hz, IH), 2.65-2.73 (m, 2H), 2.83 (dd, J = 5.5, 2.8Hz, IH), 2.97-3.07 (m, IH), 3.07-3.14 (m, IH), 3.25 (dd, J =9.7, 6.3 Hz, IH), 3.47 (apparent d, J = 12Hz, IH), 3.75 (s, 3H), 3.77 (s, 3H), 6.55 (s, IH), 6.60 (s, IH) 13C NMR (CD2Cl2) δ 21.98, 23.02, 25.51, 29.46, 35.16, 47.47, 47.63, 50.47, 55.87, 56.01, 61.47, 62.46, 108.46, 111.72, 126.37, 128.96, 147.65, 147.98, 209.72; HRMS-(ESI+) calcd for (C19H27NO3 + H) ([M+H]+ 318.2069, found 318.2082.
Example 1 Conversion of (+)-Tetrabenazine 9 into Tetrabenazine Carbinol Compound 12
Figure imgf000054_0001
To te/t-butyldimethyl(prop-2-ynaloxy)silane 10 (0.27 mL, 1.323 mmol) in THF (4 mL) was added nBuLi 11 (0.53 mL, 2.5 M in hexane, 1.323 mmol) dropwise. The mixture was stirred at 0 0C for 0.5 h. To the above reaction mixture tetrabenazine 9 (210 mg, 0.660 mmol) in THF (4 mL) was added dropwise over a period of 10 min. The reaction mixture was stirred at 0 0C for Ih. Following the allotted time the reaction mixture was quenched by the addition of saturated ammonium chloride (NH4Cl). The mixture was extracted with three portions of EtOAc, and the combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated provide the crude product. The crude product was chromato graphed on SiO2 (12g, 10% to 60% EtOAc in hexane) to provide 210 mg of the product 12 (diastereomeric mixture, dr = 4:1) as a yellow solid (65%). 1H NMR (CDCl3) δ 6.64 (s, IH), 6.54 (s, IH), 4.40 (s, 2H), 3.84 (s, 6H), 3.46 (d, J = 10.0 Hz, IH), 3.06-3.13 (m, IH), 2.99-3.02 (m, IH), 2.95 (dd, J = 15.0 & 5.0 Hz, IH), 2.65 (d, J = 15.0 Hz, IH), 2.49-2.58 (m, 3H), 2.28 (t, J = 10.0 Hz, IH), 1.90-1.96 (m, IH), 1.77 (t, J = 10.0 Hz, IH), 1.63-1.70 (m, IH), 1.49-1.54 (m, IH), 1.21-1.27 (m, IH), 0.95 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 0.91 (s, 9 H), 0.14 (s, 6H); 13C NMR (CDCl3) δ 147.41, 147.10, 129.03, 126.48, 111.47, 107.82, 86.25, 85.11, 72.18, 59.71, 58.54, 55.91, 55.82, 51.76, 51.48, 45.57, 43.92, 37.17, 29.15, 25.80, 25.58, 24.10, 21.84, 18.27. Example 2 Esterification of Tetrabenazine Carbinol Compound 12 to Provide Acetate 13
Ac2O, Et3N, catDMAP
Figure imgf000055_0001
Figure imgf000055_0002
To a solution of (2R, 3R, l lbi?)-2-(3-(tert-Butyldimethylsilyloxy)prop-l-ynyl)-3- isobutyl-9,10-dimethoxy-2,3,4,6,7,l lb-hexahydro-l-H-pyrido[2,l-α]isoquinolin-2-ol 12 (140 mg, 0.287 mmol) in CH2Cl2 (1 mL) (precooled to 0 0C) was added Ac2O (60 μL, 0.631 mmol), Et3N (0.12 mL, 0.861 mmol and DMAP (4 mg, 0.03 mmol). The reaction mixture was stirred for 14 h (0 0C to RT). Following the allotted time the reaction mixture was quenched with saturated sodium bicarbonate (NaHCO3). The mixture was extracted with three portions of CH2Cl2 and the combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to provide the crude product. The crude product was chromatographed on SiO2 (12 g, 10% to 40% EtOAc in hexane) to provide 98 mg of the compound 13 (single diastereomer) as a slightly yellow solid (66%). 1H NMR (CDCl3) δ 6.66 (s, IH), 6.57 (s, IH), 4.42 (s, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.50 (d, J = 11.00 Hz, IH), 3.39 (dd, J = 12.47 & 2.16 Hz, IH), 3.03-3.10 (m, IH), 2.96-2.99 (m, IH), 2.92 (dd, J = 12.17 & 4.04 Hz, IH), 2.65 (d, J = 16.05 Hz, IH), 2.53 (td, J = 11.43 & 4.08 Hz, IH), 2.44 (t, J = 11.97 Hz, IH), 2.12-2.16 (m, IH), 2.04 (s, 3H), 1.65-1.70 (m, 2H), 1.49-1.55 (m, IH), 1.20-1.25 (m, IH), 0.95 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 0.91 (s, 9 H), 0.14 (s, 6H); 13C NMR (CDCl3) δ 169.76, 147.89, 147.61, 129.31, 126.96, 111.88, 108.56, 88.11, 81.61, 79.27, 59.50, 58.31, 56.52, 56.19, 52.16, 51.79, 42.78, 41.59, 37.80, 29.61, 26.15, 26.09, 24.28, 22.44, 18.59, 4.61, 4.71.
Example 3 Deprotection of Acetate 13 to Tetrabenazine Carbinol Compound 14
Figure imgf000056_0001
A solution of (2R, 3R, l lbi?)-2-(3-(tert-Butyldimethylsilyloxy)prop-l-ynyl)-3- isobutyl-9,10-dimethoxy-2,3,4,6,7,l lb-hexahydro-l-H-pyrido[2,l-α]isoquinolin-2-yl acetate 13 (98 mg, 0.185 mmol) in TΗF (1 niL) was added dropwise a solution of TBAF ( 0.56 niL, IM in TΗF, 0.555 mmol) at 0 0C. The reaction mixture was stirred (0 0C to RT) for 2 h. After the allotted time the reaction mixture was quenched with saturated ammonium chloride (NH4Cl). The mixture was extracted with three portions of EtOAc and the combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to provide the crude product. The crude product was chromatographed on SiO2 (12 g, 10% to 50% EtOAc in hexane) to produce 68 mg of the compound 14 as a slightly yellow solid (88%). 1H NMR (CDCl3) δ 6.67 (s, IH), 6.57 (s, IH), 4.35 (s, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 3.49 (d, J = 12.00 Hz, IH), 3.35 (d, J = 11.24 Hz, IH), 3.04-3.10 (m, IH), 2.97-3.00 (m, IH), 2.92 (dd, J = 12.04 & 3.68 Hz, IH), 2.75 (br s, IH), 2.65 (d, J = 14.99 Hz, IH), 2.49- 2.54 (m, IH), 2.39-2.44 (m, IH), 2.10-2.16 (m, IH), 2.05 (s, 3H), 1.63-1.70 (m, 2H), 1.50 (td, J = 13.58 & 2.95 Hz, IH), 1.16-1.21 (m, IH), 0.95 (d, J = 6.60 Hz, 3H), 0.93 (d, J = 6.60 Hz, 3H); 13C NMR (CDCl3) δ 170.20, 147.99, 147.64, 129.03, 126.86, 111.92, 108.65, 88.42, 82.15, 79.31, 59.40, 58.22, 56.58, 56.20, 51.62, 51.31, 42.59, 41.49, 37.62, 29.49, 26.11, 26.05, 24.49, 22.42.
Example 4 Preparation of Fluorophilic Tetrabenazine Carbinol Compound, Mesylate 15
Figure imgf000057_0001
15
To a 0 °C solution of (2R, 3R, llbi?)-2-(3-hydroxyprop-l-ynyl)-3-isobutyl-9,10- dimethoxy-2,3,4,6,7,l lb-hexahydro-l-H-pyrido[2,l-α]isoquinolin-2-yl acetate 14 (60 mg, 0.144 mmol) in CH2Cl2 (1.5 niL) was added dropwise Et3N (61 μL, 0.433 mmol) followed by methanesulfonyl chloride (MsCl) (17 μl, 0.216 mmol). The reaction mixture was stirred at 0 0C for about 2 h. After the allotted time the reaction mixture was poured into cold water and layers separated. The reaction mixture was extracted with three portions of CH2Cl2 and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated. The residue was chromato graphed on SiO2 (12 g, 10% to 70% EtOAc in hexane) to give 38 mg of the product as a yellow solid of compound 15 (53%).
Example 5 Preparation of Fluoroalkyl Tetrabenazine Carbinol Compound 16
Figure imgf000057_0002
A solution of (2R, 3R, l lbi?)-2-(3-hydroxyprop-l-ynyl)-3-isobutyl-9,10-dimethoxy- 2,3,4,6,7,1 lb-hexahydro-l-H-pyrido[2,l-α]isoquinolin-2-yl acetate 14 (10 mg, 0.024 mmol) in CH2Cl2 (0.5 mL) was cooled to -78 0C. To this cooled solution was added dropwise a solution of (diethylamino) sulfur trifluoride (DAST) (10 μL, 0.072 mmol) in CH2Cl2 (0.1 mL). The reaction mixture was stirred (-78 0C to RT) for 4 h. The reaction mixture was then quenched with water and extracted with three portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated. The residue was chromatographed on SiO2 (0% to 10% MeOH in CH2Cl2) to give 3 mg of the product 16 as a white solid (30%). 1H NMR (CDCl3) δ 6.68 (s, IH), 6.60 (s, IH), 5.10 (d, J = 47.43 Hz, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.49 (d, J = 11.56 Hz, IH), 3.40 (dd, J = 12.40 & 2.36 Hz, IH), 3.06-3.12 (m, IH), 2.95- 3.02 (m, 2H), 2.68 (d, J = 15.12 Hz, IH), 2.57 (td, J = 11.03 & 4.09 Hz, IH), 2.44 (d, J = 11.85 Hz, IH), 2.10-2.21 (m, IH), 2.09 (s, 3H), 1.70 (t, J = 11.04, 2H), 1.51-1.56 (m, IH), 1.20-1.25 (m, IH), 0.99 (d, J = 6.62 Hz, 3H), 0.95 (d, J = 6.62 Hz, 3H).
Example 6 Preparation of Fluoroalkyl Tetrabenazine Carbinol Compound 17
NaOMe / MeOH
Figure imgf000058_0001
Figure imgf000058_0002
The starting fluoroalkyl tetrabenazine carbinol compound (2R, 3R, 1 lbi?)-2-(3- fluoroprop-l-ynyl)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,l lb-hexahydro-l-H- pyrido[2,l-α]isoquinolin-2-yl acetate 16 (1.8 mg, 0.0043 mmol) was added to 1 mL of a solution prepared by dissolution of freshly cut sodium (1 mg, 0.043 mmol) in cold MeOH (10 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated under a stream of N2 and dissolved in saturated ammonium chloride (NH4Cl). Following the allotted time the mixture was extracted with three portions of CH2Cl2 and the combined organic extracts were dried over anhydrous Na2SO4, filtered, concentrated and dried under vacuum to give 1.5 mg of the product as a white solid 17 which was > 95% pure by HPLC analysis (92%). HRMS calcd. for (M+H) 376.2288, found 376.2290.
Example 7 Preparation of Tetrabenazine Carbinol Compound, Diol 18
Figure imgf000059_0001
To a precooled (0 0C) solution of tetrabenazine carbinol compound, 12 (112 mg, 0.220 mmol) in 2 niL of THF, was added dropwise a solution of TBAF (330 ml, 0.33 mmol, IM in THF). The mixture is stirred at room temperature for 12 h. Following the allotted time the reaction mixture was quenched by the addition of saturated ammonium chloride (NH4Cl). The mixture was extracted with three portions of EtOAc, and the combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to provide a product. The product was chromatographed on SiO2 (12 g, 0% to 10% MeOH in CH2Cl2) to produce 49 mg of the tetrabenazine carbinol compound, diol 18 as a slightly yellow solid (60%). 1H NMR (CDCl3) δ 6.67 (s, IH), 6.57 (s, IH), 3.42 (d, J = 11.3 Hz, IH), 3.14-3.21 (m, IH), 2.94-3.00 (m, 2H), 2.62 (t, J = 10.2 Hz, 2H), 2.50 (td, J = 11.2 & 4.0 Hz , IH), 2.17-2.26 (m, 2H), 2.08 (t, J = 9.6 Hz, IH), 1.61-1.72 (m, 2H), 1.21-1.29 (m, IH), 1.02 (d, J = 6.6 Hz, 3H, 0.99 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3) δ 148.1, 147.59, 128.67, 123.63, 111.85,108.43, 88.70, 84.75, 72,31, 60.64, 58.64, 56.55, 56.05, 52.36, 50.36, 44.19, 37.01, 28.73, 25.89, 24.64, 22.50.
Example 8 Preparation of Fluorophilic Tetrabenazine Carbinol Compound, Mesylate 19
Figure imgf000059_0002
To a 0 0C solution of diol 18 (1 equivalent) in CH2Cl2 is added dropwise Et3N (3 equivalents) followed by methanesulfonyl chloride (MsCl) (1.5 equivalents). The reaction mixture is stirred at 0 0C for about 2 h. After the allotted time the reaction mixture is poured into cold water and layers are separated. The quenched reaction mixture is extracted with three portions of CH2Cl2 and the combined organic extracts are dried over anhydrous Na2SO4, filtered and concentrated. The residue may be chromato graphed on SiO2 (10% to 70% EtOAc in hexane) to provide the product mesylate 19.
Example 9 Preparation of PET Imaging Agent 20
Figure imgf000060_0001
19 20
To a Teflon-lined reaction vial contained in a shielded hood and fitted with a nitrogen purge inlet and magnetic spin bar, is added about 1 milliliter of an aqueous acetonitrile solution F- 18 fluoride ion, potassium carbonate (about 1 mg), and Kryptofix 221 (about 10 mg). The vial is heated at 100°C under a stream of nitrogen to effect the azeotropic removal of water. Additional dry acetonitrile (1 mL) is added and evaporated. This azeotropic drying protocol is repeated three times. After the final evaporation step a mixture of dimethyl formamide and acetonitrile (about 1 mL) containing the fluorophilic tetrabenazine carbinol compound, mesylate 20, (2 mg) is added and the vial is sealed. The reaction mixture is stirred and heated at 100°C for 10 minutes and then is cooled to room temperature. The product mixture comprising the starting mesylate 19 and the product F- 18 labeled fluoroalkyl tetrabenazine carbinol compound 20 is diluted with water (10 mL) and applied to a Sep-Pak cartridge. The cartridge is then washed with water (3x) to remove unreacted fluoride ion and other water soluble components of the product mixture. The radiolabled fluoroalkyl tetrabenazine carbinol compound 20 and starting mesylate 19 are then eluted from the cartridge with acetonitrile. Most of the acetonitrile is then evaporated and the residue is dissolved in aqueous acetonitrile and subjected to preparative reverse phase HPLC to afford an aqueous formulation comprising PET imaging agent 20.
Method 6 Reduction of (+)-tetrabenazine 9 To a Diasteromeric Mixture of Dihydrotetrabenazine Compounds 21 and 22
Figure imgf000061_0001
To a 0.11 M solution of (+)-TBZ (9) in ethanol at 0 0C was added NaBH4 (2.85 eq). The reaction mixture was allowed to stir for 60 min. at room temperature. The solvent was carefully removed under reduced pressure, and the residue was taken up in dichloromethane and washed with three portions of saturated aqueous K2CO3. The aqueous washings were back extracted with two portions of dichloromethane. The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to provide a colorless oil that crystallized on standing under high vacuum. Purification of the crude product was achieved by chromatography on SiO2 (2.5-5% MeOH-CH2Cl2, elution was observed at 285 nm) UV active fractions were reanalyzed by TLC. Two products, 21 and 22, were isolated from this procedure. The major product 21 was a colorless solid 74%: [α]26 D +48 (c 0.30, CH2Cl2) 1H NMR (CD2Cl2) δ 0.93 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H), 1.04 (ddd, J = 14.6, 8.7, 4.3 Hz, IH), 1.42 (dd, J = 20.2, 11.4 Hz, IH), 1.59 (ddd, J = 13.7, 9.6, 3.3 Hz, IH), 1.64-1.78 (m, 2H), 1.96 (apparent t, J = 11.4 Hz, IH), 2.27 (br s, IH), 2.40-2.48 (m, IH), 2.54 (ddd, J = 12.3, 3.7, 2.3 Hz, IH), 2.60-2.67 (m, IH), 2.95-3.09 (m, 3H), 3.11 (apparent d, J = 11.1 Hz, IH), 3.35 (ddd, J = 10.4, 10.4, 4.5 Hz, IH), 3.80-3.81 (m, 6H), 6.60 (s, IH), 6.69 (s, IH); 13C NMR (CD2Cl2) δ 21.61, 24.02, 25.33, 29.30, 39.68, 40.81, 41.58, 51.83, 55.74, 55.91, 60.02, 60.92, 74.32, 108.42, 111.73, 126.68, 129.76, 147.35, 147.61; HRMS-(ESI+) calcd for (C19H29NO3 + H) [M+H]+ 320.2226, found 320.2242. The minor product 22 was a yellow oil 4%: 1H NMR (CD2Cl2) δ 0.94 (d, J = 6.6 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H), 1.13-1.20 (m, IH), 1.24-1.34 (m, 2H), 1.60-1.77 (m, 2H), 1.89-2.00 (m, IH) 2.36-2.44 (m, 2H), 2.53 (ddd, J = 10.5, 10.5, 3.8 Hz, IH), 2.58-2.70 (m, 2H), 2.91-2.98 (m, IH), 2.98-3.09 (m, IH), 3.48 (apparent d, J = 11.6 Hz, IH), 3.80-3.82 (apparent s, 6H), 4.07 (apparent d, J = 3.1Hz, IH), 6.60 (s, IH), 6.68 (s, IH); 13C NMR (CD2Cl2) δ 22.74, 22.81, 24.87, 29.30, 37.83, 38.87, 39.42, 52.44, 55.76, 55.96, 56.32, 56.43, 67.88, 108.45, 111.78, 127.18, 130.38, 147.30, 147.54.
Measurement of Binding Affinity of Fluoroalkyl Tetrabenazine Carbinol Compounds to VMAT-2
VMAT-2 binding affinities were measured for fluoroalkyl tetrabenazine carbinol compounds 16 and 17 provided by the present invention. VMAT-2 binding affinity measurements were carried out by Novascreen Biosciences Corporation (Hanover, Maryland, USA) using protocol Cat. No. 100-0751. Novascreen, Inc. is a commercial provider of biological assays for the pharmaceutical industry. Binding affinity data are presented in Table 11 and illustrate very high binding affinity for the fluoroalkyl tetrabenazine carbinol compounds of the present invention (compounds 16 and 17) relative to a reserpine control (Comparative Example 1) and a dihydro tetrabenazine (DTBZ) control (Comparative Example X). The data obtained for fluoroalkyl tetrabenazine carbinol compounds 16 and 17 reveal an unexpected tolerance of fluoroalkyl substitution at ring position-2, which combines a change in the size and lipophilicity of the group at ring position-2 with the uncertainty which arises whenever a hydrogen in a biologically active molecule is replaced by fluorine. In addition, the binding constants Ki expressed in nano-molar (nM) concentration units indicate a very high affinity of the fluoroalkyl tetrabenazine carbinol compounds of the present invention for the VMAT-2 biomarker.
Table 11 VMAT-2 Binding Affinity of Fluoroalkyl Tetrabenazine Carbinol Compounds 16 and 17
Figure imgf000062_0001
Figure imgf000063_0001
The foregoing examples are merely illustrative, serving to illustrate only some of the features of the invention. The appended claims are intended to claim the invention as broadly as it has been conceived and the examples herein presented are illustrative of selected embodiments from a manifold of all possible embodiments. Accordingly, it is the Applicants' intention that the appended claims are not to be limited by the choice of examples utilized to illustrate features of the present invention. As used in the claims, the word "comprises" and its grammatical variants logically also subtend and include phrases of varying and differing extent such as for example, but not limited thereto, "consisting essentially of" and "consisting of." Where necessary, ranges have been supplied; those ranges are inclusive of all sub-ranges there between. It is to be expected that variations in these ranges will suggest themselves to a practitioner having ordinary skill in the art and where not already dedicated to the public, those variations should where possible be construed to be covered by the appended claims. It is also anticipated that advances in science and technology will make equivalents and substitutions possible that are not now contemplated by reason of the imprecision of language and these variations should also be construed where possible to be covered by the appended claims.

Claims

What is claimed is:
1. A fluoroalkyl tetrabenazine carbinol compound having structure I
Figure imgf000065_0001
wherein R1 is a C1-C1O fluorinated aliphatic radical; R2 is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; R4 is hydrogen or a C1-C1O aliphatic radical; and R5 is hydrogen, a C1-C1O aliphatic radical, a C2-C1O cycloaliphatic radical, or a C2- C2o aromatic radical.
2. The fluoroalkyl tetrabenazine carbinol compound according to claim 1, which is enantiomerically enriched.
3. The enantiomerically enriched fluoroalkyl tetrabenazine carbinol compound according to claim 2 comprising a principal component enantiomer having structure II
wherein R1 is a C1-C1O
Figure imgf000065_0002
aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; R4 is hydrogen or a C1-C1O aliphatic radical; and R .5 i •s hydrogen, a C1-C1O aliphatic radical, a C2-C1O cycloaliphatic radical, or a C2- C2o aromatic radical.
A fluoroalkyl tetrabenazine carbinol compound having structure IV
Figure imgf000066_0001
wherein R1 is a C1-C1O fluorinated aliphatic radical; R2 is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; and R4 is hydrogen or a C1-C1O aliphatic radical.
5. A fluoroalkyl tetrabenazine carbinol compound according to claim 4 comprising a principal component enantiomer having structure V
Figure imgf000066_0002
(V) wherein R1 is a C1-C1O fluorinated aliphatic radical; R2 is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; and R4 is hydrogen or a C1-C1O aliphatic radical.
6. The enantiomerically enriched tluoroalkyl tetrabenazine carbinol compound according to claim 3 or 5, which is at least 80 % enantiomerically enriched.
7. A compound according to any of Claims 1 to 6 wherein
R1 is selected from Ci-όfluoroalkyl, C2-όfluoroalkenyl, C2-όfluoroalkynyl C1_6fluoroalkoxy(C1_6alkyl), Ci-όfluorohaloalkyl, Ci-όfluorohydroxyalkyl, and Ci-όfluoroalkylcarbony^Ci-όalkyl), and is suitably C2-όfluoroalkynyl;
R2 is selected from Ci-όalkyi and C3-scycloalkyl, and is suitably Ci-όalkyi;
R3 and R4 are each independently selected from Ci-όalkyi and Ci_6alkoxy;
R5 is selected from hydrogen, (Ci_6alkyl)carbonyl, and phenyl.
8. A compound according to any of claims 1 to 3 wherein -OR5 is an ester moiety.
9. A compound according to any of claims 1 to 3 having structure:
Figure imgf000067_0001
10. A compound according to any of claims 1 to 3 having structure:
Figure imgf000067_0002
11. A compound according to any of claims 1 to 10, comprising a fluorine- 18 atom.
12. A salt of a compound according to any of claims 1 to 11.
13. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 12 and a pharmaceutically acceptable excipient.
14. A compound according to any one of claims 1 to 12 for use in medicine.
15. A method for detection of VMAT-2 in a subject, comprising :
(i) administration of a fluorine- 18 labeled compound according to claim 11 , or a salt thereof to said subject;
(ii) detecting uptake of said fluorine- 18 labeled compound by in vivo PET
16. A method for the in vivo diagnosis or imaging of a VMAT-2 related disorder in a subject, preferably a human, comprising administration of a fluorine- 18 labeled compound according to claim 11 or a salt thereof and detecting the uptake of said compound by an in vivo PET imaging technique.
17. A method according to claim 16 wherein the VMAT-2 related disorder is diabetes.
18. A compound according to claim 11 or a salt thereof, for use in a method according to any one of claims 15 to 17.
19. A fluorophilic compound having structure VII
Figure imgf000069_0001
wherein R1 is a C1-C2O aliphatic radical, a C2-C2O cycloaliphatic radical, or a C2-C2O aromatic radical comprising at least one functional group susceptible to reaction with nucleophilic fluoride ion or an electrophilic fluorinating agent; R2 is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; R4 is hydrogen or a C1-C1O aliphatic radical; and R is hydrogen, a C1-C1O aliphatic radical, a C2-C1O cycloaliphatic radical, or a C2-C2O aromatic radical.
20. The fluorophilic compound according to claim 19, wherein R1 comprises at least one functional group susceptible to reaction with nucleophilic fluoride ion.
21. The fluorophilic compound according to claim 19 or 20, which is enantiomerically enriched.
22. The fluorophilic compound according to any one of claims 19 to 21, which is comprised of at least 95 mole % of an enantiomer having the R configuration at ring position- 12.
23. The fluorophilic compound according to any one of claims 19 to 22, which is comprised of at least 95 mole % of an enantiomer having the R configuration at ring position-2.
24. The fluorophilic compound according to any one of claims 19 to 23, in which the group R1 at ring position-2 has a syn configuration relative to the hydrogen at ring position- 12.
25. The fluorophilic compound according to any one of claims 19 to 24, wherein -OR is an ester moiety.
26. The fluorophilic compound according to any one of claims 19 to 25, wherein R1 comprises at least one aromatic or aliphatic sulfonate ester group.
27. An enantiomerically enriched fluorophilic compound comprising a principal component enantiomer having structure VIII
Figure imgf000070_0001
wherein R1 is a C1-C1O aliphatic radical, a C2-C2O cycloaliphatic radical, or a C2-C2O aromatic radical comprising at least one functional group susceptible to reaction with nucleophilic fluoride ion or an electrophilic fluorinating agent; R2 is a C1-C1O aliphatic radical; R3 is hydrogen or a C1-C1O aliphatic radical; R4 is hydrogen or a C1-C1O aliphatic radical; and R is hydrogen, a C1-C1O aliphatic radical, a C2-C1O cycloaliphatic, or a C2-C2O aromatic radical.
28. The enantiomerically enriched fluorophilic compound according to claim
27, which is comprised of at least 80 mole % of an enantiomer having structure VIII.
29. The enantiomerically enriched fluorophilic compound according to claim
27, which is comprised of at least 95 mole % of an enantiomer having structure VIII.
30. The enantiomerically enriched fhiorophilic compound according to claim
27, wherein R1 comprises at least one functional group susceptible to reaction with nucleophilic fluoride ion.
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JP5597835B2 (en) 2014-10-01
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