U.S. patent application number 11/952325 was filed with the patent office on 2011-08-25 for fluoroalkyl tetrabenazine carbinol compounds as imaging agents and probes.
This patent application is currently assigned to GENERAL ELECTRIC COMPANY. Invention is credited to Kande Kankanamalage Dayarathna Amarasinghe, Sean Richard Dinn, Bruce Fletcher Johnson, Michael James Rishel.
Application Number | 20110206609 11/952325 |
Document ID | / |
Family ID | 44476656 |
Filed Date | 2011-08-25 |
United States Patent
Application |
20110206609 |
Kind Code |
A1 |
Amarasinghe; Kande Kankanamalage
Dayarathna ; et al. |
August 25, 2011 |
FLUOROALKYL TETRABENAZINE CARBINOL COMPOUNDS AS IMAGING AGENTS AND
PROBES
Abstract
The present invention provides novel fluoroalkyl tetrabenazine
carbinol compounds having structure I ##STR00001## wherein R.sup.1
is a C.sub.1-C.sub.10 fluorinated aliphatic radical; R.sup.2 is a
C.sub.1-C.sub.10 aliphatic radical; R.sup.3 is hydrogen or a
C.sub.1-C.sub.10 aliphatic radical; R.sup.4 is hydrogen or a
C.sub.1-C.sub.10 aliphatic radical; and R.sup.5 is hydrogen, a
C.sub.1-C.sub.10 aliphatic radical, a C.sub.2-C.sub.10
cycloaliphatic radical, or a C.sub.2-C.sub.20 aromatic radical. In
a particular embodiment, --OR.sup.5 is an ester moiety. 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.
Inventors: |
Amarasinghe; Kande Kankanamalage
Dayarathna; (Latham, NY) ; Rishel; Michael James;
(Rensselaer, NY) ; Dinn; Sean Richard; (Delmar,
NY) ; Johnson; Bruce Fletcher; (Scotia, NY) |
Assignee: |
GENERAL ELECTRIC COMPANY
SCHENECTADY
NY
|
Family ID: |
44476656 |
Appl. No.: |
11/952325 |
Filed: |
December 7, 2007 |
Current U.S.
Class: |
424/9.1 ;
546/95 |
Current CPC
Class: |
C07D 455/02 20130101;
C07D 455/06 20130101; A61K 51/0455 20130101 |
Class at
Publication: |
424/9.1 ;
546/95 |
International
Class: |
A61K 49/00 20060101
A61K049/00; C07D 455/06 20060101 C07D455/06 |
Claims
1. A fluoroalkyl tetrabenazine compound having structure I
##STR00144## wherein R.sup.1 is a C.sub.1-C.sub.10 fluorinated
aliphatic radical; R.sup.2 is a C.sub.1-C.sub.10 aliphatic radical;
R.sup.3 is hydrogen or a C.sub.1-C.sub.10 aliphatic radical;
R.sup.4 is hydrogen or a C.sub.1-C.sub.10 aliphatic radical; and
R.sup.5 is hydrogen, a C.sub.1-C.sub.10 aliphatic radical, a
C.sub.2-C.sub.10 cycloaliphatic radical, or a C.sub.2-C.sub.20
aromatic radical.
2. The fluoroalkyl tetrabenazine compound according to claim 1,
comprising a fluorine-18 atom.
3. The fluoroalkyl tetrabenazine compound according to claim 1,
comprising a fluorine-19 atom.
4. The fluoroalkyl tetrabenazine compound according to claim 1,
wherein --OR.sup.5 is an ester moiety.
5. The fluoroalkyl tetrabenazine compound according to claim 1,
which is enantiomerically enriched.
6. The enantiomerically enriched fluoroalkyl tetrabenazine compound
according to claim 5 comprising a principal component enantiomer
having structure II ##STR00145## wherein R.sup.1 is a
C.sub.1-C.sub.10 fluorinated aliphatic radical; R.sup.2 is a
C.sub.1-C.sub.10 aliphatic radical; R.sup.3 is hydrogen or a
C.sub.1-C.sub.10 aliphatic radical; R.sup.4 is hydrogen or a
C.sub.1-C.sub.10 aliphatic radical; and R.sup.5 is hydrogen, a
C.sub.1-C.sub.10 aliphatic radical, a C.sub.2-C.sub.10
cycloaliphatic radical, or a C.sub.2-C.sub.20 aromatic radical.
7. The enantiomerically enriched fluoroalkyl tetrabenazine compound
according to claim 6, which is at least 80% enantiomerically
enriched.
8. The enantiomerically enriched fluoroalkyl tetrabenazine compound
according to claim 5, comprising a fluorine-18 atom.
9. The enantiomerically enriched fluoroalkyl tetrabenazine compound
according to claim 6, wherein --OR.sup.5 is an ester moiety.
10. The enantiomerically enriched fluoroalkyl tetrabenazine
compound according to claim 5 comprising a principal component
enantiomer having structure III ##STR00146## wherein R.sup.1 is a
C.sub.1-C.sub.10 fluorinated aliphatic radical; R.sup.2 is a
C.sub.1-C.sub.10 aliphatic radical; R.sup.3 is hydrogen or a
C.sub.1-C.sub.10 aliphatic radical; R.sup.4 is hydrogen or a
C.sub.1-C.sub.10 aliphatic radical; and R.sup.5 is hydrogen, a
C.sub.1-C.sub.10 aliphatic radical, a C.sub.2-C.sub.10
cycloaliphatic radical, or a C.sub.2-C.sub.20 aromatic radical.
11. The enantiomerically enriched fluoroalkyl tetrabenazine
compound according to claim 10, wherein --OR.sup.5 is an ester
moiety.
12. A PET imaging agent comprising a fluoroalkyl tetrabenazine
compound having structure I ##STR00147## wherein R.sup.1 is a
C.sub.1-C.sub.10 fluorinated aliphatic radical comprising at least
one fluorine-18 atom; R.sup.2 is a C.sub.1-C.sub.10 aliphatic
radical; R.sup.3 is hydrogen or a C.sub.1-C.sub.10 aliphatic
radical; R.sup.4 is hydrogen or a C.sub.1-C.sub.10 aliphatic
radical; and R.sup.5 is hydrogen, a C.sub.1-C.sub.10 aliphatic
radical, a C.sub.2-C.sub.10 cycloaliphatic radical, or a
C.sub.2-C.sub.20 aromatic radical.
13. The PET imaging agent of claim 12 further comprising a salt of
compound I.
14. The PET imaging agent of claim 12, wherein --OR.sup.5 is an
ester moiety.
15. A fluoroalkyl tetrabenazine carbinol compound having structure
IV ##STR00148## wherein R.sup.1 is a C.sub.1-C.sub.10 fluorinated
aliphatic radical; R.sup.2 is a C.sub.1-C.sub.10 aliphatic radical;
R.sup.3 is hydrogen or a C.sub.1-C.sub.10 aliphatic radical; and
R.sup.4 is hydrogen or a C.sub.1-C.sub.10 aliphatic radical.
16. The fluoroalkyl tetrabenazine carbinol compound according to
claim 15, comprising a fluorine-18 atom.
17. The fluoroalkyl tetrabenazine carbinol compound according to
claim 15, comprising a fluorine-19 atom.
18. The fluoroalkyl tetrabenazine carbinol compound according to
claim 15, which comprises a mixture of diastereomers.
19. The fluoroalkyl tetrabenazine carbinol compound according to
claim 15, which is enantiomerically enriched.
20. The enantiomerically enriched fluoroalkyl tetrabenazine
carbinol compound according to claim 19 comprising a principal
component enantiomer having structure V ##STR00149## wherein
R.sup.1 is a C.sub.1-C.sub.10 fluorinated aliphatic radical;
R.sup.2 is a C.sub.1-C.sub.10 aliphatic radical; R.sup.3 is
hydrogen or a C.sub.1-C.sub.10 aliphatic radical; and R.sup.4 is
hydrogen or a C.sub.1-C.sub.10 aliphatic radical.
21. The enantiomerically enriched fluoroalkyl tetrabenazine
carbinol compound according to claim 19 comprising a principal
component enantiomer having structure VI ##STR00150## wherein
R.sup.1 is a C.sub.1-C.sub.10 fluorinated aliphatic radical;
R.sup.2 is a C.sub.1-C.sub.10 aliphatic radical; R.sup.3 is
hydrogen or a C.sub.1-C.sub.10 aliphatic radical; and R.sup.4 is
hydrogen or a C.sub.1-C.sub.10 aliphatic radical.
22. The enantiomerically enriched fluoroalkyl tetrabenazine
carbinol compound according to claim 19, comprising a fluorine-18
atom.
23. The enantiomerically enriched fluoroalkyl tetrabenazine
carbinol compound according to claim 22, said compound being
comprised in a formulation suitable for use in PET imaging.
24. A PET imaging agent comprising a fluoroalkyl tetrabenazine
carbinol compound having structure IV ##STR00151## wherein R.sup.1
is a C.sub.1-C.sub.10 fluorinated aliphatic radical comprising at
least one fluorine-18 atom; R.sup.2 is a C.sub.1-C.sub.10 aliphatic
radical; R.sup.3 is hydrogen or a C.sub.1-C.sub.10 aliphatic
radical; and R.sup.4 is hydrogen or a C.sub.1-C.sub.10 aliphatic
radical.
25. The PET imaging agent of claim 24 further comprising a salt of
compound IV.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is related to U.S. patent applications Ser.
Nos. 11/760,359, and 11/760,372 filed Jun. 8, 2007, U.S. patent
applications Ser. Nos. 11/923,926 and 11/923,805 filed Oct. 25,
2007, and U.S. patent applications Ser. Nos. 11/947,215 and
11/947,275 filed Nov. 29, 2007.
BACKGROUND
[0002] This invention relates to carbinol compounds related to
tetrabenazine and intermediates useful in the preparation of such
fluoroalkyl tetrabenazine carbinol compounds
[0003] 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 A1), 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 [11C] dihydrotetrabenazine, J Cereb
Blood Flow Metab 19, 1376-1384).
[0004] 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.
[0005] 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
[0006] In one embodiment, the present invention provides a
fluoroalkyl tetrabenazine carbinol compound having structure I
##STR00002##
wherein R.sup.1 is a C.sub.1-C.sub.10 fluorinated aliphatic
radical; R.sup.2 is a C.sub.1-C.sub.10 aliphatic radical; R.sup.3
is hydrogen or a C.sub.1-C.sub.10 aliphatic radical; R.sup.4 is
hydrogen or a C.sub.1-C.sub.10 aliphatic radical; and R.sup.5 is
hydrogen, a C.sub.1-C.sub.10 aliphatic radical, a C.sub.2-C.sub.10
cycloaliphatic radical, or a C.sub.2-C.sub.20 aromatic radical.
[0007] In another embodiment, the present invention provides a PET
imaging agent comprising a fluoroalkyl tetrabenazine carbinol
compounds having structure I
##STR00003##
wherein R.sup.1 is a C.sub.1-C.sub.10 fluorinated aliphatic radical
comprising at least one fluorine-18 atom; R.sup.2 is a
C.sub.1-C.sub.10 aliphatic radical; R.sup.3 is hydrogen or a
C.sub.1-C.sub.10 aliphatic radical; R.sup.4 is hydrogen or a
C.sub.1-C.sub.10 aliphatic radical; and R.sup.5 is hydrogen, a
C.sub.1-C.sub.10 aliphatic radical, a C.sub.2-C.sub.10
cycloaliphatic radical, or a C.sub.2-C.sub.20 aromatic radical.
[0008] In yet another embodiment, the present invention provides
fluoroalkyl tetrabenazine carbinol compounds having structure
IV
##STR00004##
wherein R.sup.1 is a C.sub.1-C.sub.10 fluorinated aliphatic
radical; R.sup.2 is a C.sub.1-C.sub.10 aliphatic radical; R.sup.3
is hydrogen or a C.sub.1-C.sub.10 aliphatic radical; and R.sup.4 is
hydrogen or a C.sub.1-C.sub.10 aliphatic radical.
[0009] In yet another embodiment, the present invention provides a
PET imaging agent comprising a fluoroalkyl tetrabenazine carbinol
compounds having structure IV
##STR00005##
wherein R.sup.1 is a C.sub.1-C.sub.10 fluorinated aliphatic
radical; R.sup.2 is a C.sub.1-C.sub.10 aliphatic radical; R.sup.3
is hydrogen or a C.sub.1-C.sub.10 aliphatic radical; and R.sup.4 is
hydrogen or a C.sub.1-C.sub.10 aliphatic radical.
DETAILED DESCRIPTION
[0010] 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
[0011] The singular forms "a", "an" and "the" include plural
referents unless the context clearly dictates otherwise.
[0012] "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.
[0013] As used herein, the term "solvent" can refer to a single
solvent or a mixture of solvents.
[0014] 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.
[0015] 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 (C.sub.6H.sub.3) fused to a
nonaromatic component --(CH.sub.2).sub.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 4-methylphenyl radical is a
C.sub.7 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 C.sub.6 aromatic radical comprising a
nitro group, the nitro group being a functional group. Aromatic
radicals include halogenated aromatic radicals such as
4-trifluoromethylphenyl,
hexafluoroisopropylidenebis(4-phen-1-yloxy) (i.e.,
--OPhC(CF.sub.3).sub.2PhO--), 4-chloromethylphen-1-yl,
3-trifluorovinyl-2-thienyl, 3-trichloromethylphen-1-yl (i.e.,
3-CCl.sub.3Ph-), 4-(3-bromoprop-1-yl)phen-1-yl (i.e.,
4-BrCH.sub.2CH.sub.2CH.sub.2Ph-), and the like. Further examples of
aromatic radicals include 4-allyloxyphen-1-oxy, 4-aminophen-1-yl
(i.e., 4-H.sub.2NPh-), 3-aminocarbonylphen-1-yl (i.e.,
NH.sub.2COPh-), 4-benzoylphen-1-yl,
dicyanomethylidenebis(4-phen-1-yloxy) (i.e.,
--OPhC(CN).sub.2PhO--), 3-methylphen-1-yl,
methylenebis(4-phen-1-yloxy) (i.e., --OPhCH.sub.2PhO--),
2-ethylphen-1-yl, phenylethenyl, 3-formyl-2-thienyl,
2-hexyl-5-furanyl, hexamethylene-1,6-bis(4-phen-1-yloxy) (i.e.,
--OPh(CH.sub.2).sub.6PhO--), 4-hydroxymethylphen-1-yl (i.e.,
4-HOCH.sub.2Ph-), 4-mercaptomethylphen-1-yl (i.e.,
4-HSCH.sub.2Ph-), 4-methylthiophen-1-yl (i.e., 4-CH.sub.3SPh-),
3-methoxyphen-1-yl, 2-methoxycarbonylphen-1-yloxy (e.g., methyl
salicyl), 2-nitromethylphen-1-yl (i.e., 2-NO.sub.2CH.sub.2Ph),
3-trimethylsilylphen-1-yl, 4-t-butyldimethylsilylphenl-1-yl,
4-vinylphen-1-yl, vinylidenebis(phenyl), and the like. The term "a
C.sub.3-C.sub.10 aromatic radical" includes aromatic radicals
containing at least three but no more than 10 carbon atoms. The
aromatic radical 1-imidazolyl (C.sub.3H.sub.2N.sub.2--) represents
a C.sub.3 aromatic radical. The benzyl radical (C.sub.7H.sub.7--)
represents a C.sub.7 aromatic radical.
[0016] 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
(C.sub.6H.sub.11CH.sub.2--) 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-1-yl radical is a C.sub.6
cycloaliphatic radical comprising a methyl group, the methyl group
being a functional group which is an alkyl group. Similarly, the
2-nitrocyclobut-1-yl radical is a C.sub.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-1-yl, 4-bromodifluoromethylcyclooct-1-yl,
2-chlorodifluoromethylcyclohex-1-yl,
hexafluoroisopropylidene-2,2-bis (cyclohex-4-yl) (i.e.,
--C.sub.6H.sub.10C(CF.sub.3).sub.2C.sub.6H.sub.10--),
2-chloromethylcyclohex-1-yl, 3-difluoromethylenecyclohex-1-yl,
4-trichloromethylcyclohex-1-yloxy,
4-bromodichloromethylcyclohex-1-ylthio, 2-bromoethylcyclopent-1-yl,
2-bromopropylcyclohex-1-yloxy (e.g.,
CH.sub.3CHBrCH.sub.2C.sub.6H.sub.10O--), and the like. Further
examples of cycloaliphatic radicals include
4-allyloxycyclohex-1-yl, 4-aminocyclohex-1-yl (i.e.,
H.sub.2NC.sub.6H.sub.10--), 4-aminocarbonylcyclopent-1-yl (i.e.,
NH.sub.2COC.sub.5H.sub.8--), 4-acetyloxycyclohex-1-yl,
2,2-dicyanoisopropylidenebis(cyclohex-4-yloxy) (i.e.,
--OC.sub.6H.sub.10C(CN).sub.2C.sub.6H.sub.10O--),
3-methylcyclohex-1-yl, methylenebis(cyclohex-4-yloxy) (i.e.,
--OC.sub.6H.sub.10CH.sub.2C.sub.6H.sub.10O--),
1-ethylcyclobut-1-yl, cyclopropylethenyl,
3-formyl-2-terahydrofuranyl, 2-hexyl-5-tetrahydrofuranyl,
hexamethylene-1,6-bis(cyclohex-4-yloxy) (i.e.,
--OC.sub.6H.sub.10(CH.sub.2).sub.6C.sub.6H.sub.10O--),
4-hydroxymethylcyclohex-1-yl (i.e., 4-HOCH.sub.2C.sub.6H.sub.10--),
4-mercaptomethylcyclohex-1-yl (i.e.,
4-HSCH.sub.2C.sub.6H.sub.10--), 4-methylthiocyclohex-1-yl (i.e.,
4-CH.sub.3 SC.sub.6H.sub.10--), 4-methoxycyclohex-1-yl,
2-methoxycarbonylcyclohex-1-yloxy
(2-CH.sub.3OCOC.sub.6H.sub.10O--), 4-nitromethylcyclohex-1-yl
(i.e., NO.sub.2CH.sub.2C.sub.6H.sub.10--),
3-trimethylsilylcyclohex-1-yl,
2-t-butyldimethylsilylcyclopent-1-yl,
4-trimethoxysilylethylcyclohex-1-yl (e.g.,
(CH.sub.3O).sub.3SiCH.sub.2CH.sub.2C.sub.6H.sub.10--),
4-vinylcyclohexen-1-yl, vinylidenebis(cyclohexyl), and the like.
The term "a C.sub.3-C.sub.10 cycloaliphatic radical" includes
cycloaliphatic radicals containing at least three but no more than
10 carbon atoms. The cycloaliphatic radical 2-tetrahydrofuranyl
(C.sub.4H.sub.7O--) represents a C.sub.4 cycloaliphatic radical.
The cyclohexylmethyl radical (C.sub.6H.sub.11CH.sub.2--) represents
a C.sub.7 cycloaliphatic radical.
[0017] 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-1-yl radical is a C.sub.6 aliphatic radical comprising
a methyl group, the methyl group being a functional group which is
an alkyl group. Similarly, the 4-nitrobut-1-yl group is a C.sub.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.sub.2CHBrCH.sub.2--), and the like.
Further examples of aliphatic radicals include allyl, aminocarbonyl
(i.e., --CONH.sub.2), carbonyl, 2,2-dicyanoisopropylidene (i.e.,
--CH.sub.2C(CN).sub.2CH.sub.2--), methyl (i.e., --CH.sub.3),
methylene (i.e., --CH.sub.2--), ethyl, ethylene, formyl (i.e.,
--CHO), hexyl, hexamethylene, hydroxymethyl (i.e., --CH.sub.2OH),
mercaptomethyl (i.e., --CH.sub.2SH), methylthio (i.e.,
--SCH.sub.3), methylthiomethyl (i.e., --CH.sub.2SCH.sub.3),
methoxy, methoxycarbonyl (i.e., CH.sub.3OCO--), nitromethyl (i.e.,
--CH.sub.2NO.sub.2), thiocarbonyl, trimethylsilyl (i.e.,
(CH.sub.3).sub.3Si--), t-butyldimethylsilyl,
3-trimethyoxysilylpropyl (i.e.,
(CH.sub.3O).sub.3SiCH.sub.2CH.sub.2CH.sub.2--), vinyl, vinylidene,
and the like. By way of further example, a C.sub.1-C.sub.10
aliphatic radical contains at least one but no more than 10 carbon
atoms. A methyl group (i.e., CH.sub.3--) is an example of a C.sub.1
aliphatic radical. A decyl group (i.e., CH.sub.3(CH.sub.2).sub.9--)
is an example of a C.sub.10 aliphatic radical.
[0018] As noted, in one embodiment the present invention provides a
fluoroalkyl tetrabenazine carbinol compound having structure I
##STR00006##
wherein R.sup.1 is a C.sub.1-C.sub.10 fluorinated aliphatic
radical; R.sup.2 is a C.sub.1-C.sub.10 aliphatic radical; R.sup.3
is hydrogen or a C.sub.1-C.sub.10 aliphatic radical; R.sup.4 is
hydrogen or a C.sub.1-C.sub.10 aliphatic radical; and R.sup.5 is
hydrogen, a C.sub.1-C.sub.10 aliphatic radical, a C.sub.2-C.sub.10
cycloaliphatic radical, or a C.sub.2-C.sub.20 aromatic radical.
[0019] As noted, in another embodiment the present invention
provides a fluoroalkyl tetrabenazine carbinol compound having
structure IV
##STR00007##
wherein R.sup.1 is a C.sub.1-C.sub.10 fluorinated aliphatic
radical; R.sup.2 is a C.sub.1-C.sub.10 aliphatic radical; R.sup.3
is hydrogen or a C.sub.1-C.sub.10 aliphatic radical; and R.sup.4 is
hydrogen or a C.sub.1-C.sub.10 aliphatic radical.
[0020] 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 R.sup.5 is hydrogen (fluoroalkyl tetrabenazine
compounds having a tertiary hydroxy group at ring position-2), as
well as compounds in which R.sup.5 is a C.sub.1-C.sub.10 aliphatic
radical, a C.sub.2-C.sub.10 cycloaliphatic radical, or a
C.sub.2-C.sub.20 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".
[0021] 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 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.
[0022] 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 pathological conditions
related to diabetes. Positron emission tomography has become a
medical imaging technique of critical importance to human
health.
[0023] 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.
[0024] 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.
[0025] Fluoroalkyl tetrabenazine carbinol compounds having
structure I are illustrated in Table 1 below.
##STR00008##
TABLE-US-00001 TABLE 1 Examples Of Fluoroalkyl Tetrabenazine
Carbinol Compounds Having Structure I Ring Position* Entry R.sup.1
R.sup.2 R.sup.3 R.sup.4 R.sup.5 RP-2 RP-3 RP-12 1a ##STR00009##
##STR00010## CH.sub.3 CH.sub.3 Ac R/S R/S R/S 1b ##STR00011##
##STR00012## CH.sub.3 CH.sub.3 Ac R R R 1c ##STR00013##
##STR00014## CH.sub.3O CH.sub.3O Ph R/S R/S R/S 1d ##STR00015##
##STR00016## CH.sub.3O CH.sub.3O H S S S 1e ##STR00017##
##STR00018## EtO CH.sub.3O Ph R S R 1f ##STR00019## ##STR00020##
EtO EtO Ac S R S 1g ##STR00021## ##STR00022## CH.sub.3CH.sub.2
CH.sub.3 Ph R/S R/S R/S 1h ##STR00023## ##STR00024## CH.sub.3O
CH.sub.3O Ac R R R 1i ##STR00025## ##STR00026## CH.sub.3O CH.sub.3O
H R/S R/S R/S 1j ##STR00027## ##STR00028## CH.sub.3O CH.sub.3 Ac
R/S R/S R/S 1k ##STR00029## ##STR00030## CH.sub.3O H H R R R *RP-2
= Ring positon-2, RP-3 = Ring position-3, RP-12 = Ring
position-12
[0026] 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 1a (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 1b (Table 1) having the R configuration (absolute
stereochemistry) at ring positions-2, -3 and -12. In yet another
embodiment, structure I represents compound 1d (Table 1) having
absolute stereochemistry opposite that of compound 1b. 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.
[0027] 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 1a (Table 1), a
single enantiomer (e.g. compound 1b (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-US-00002 TABLE 2 Fluoroalkyl Tetrabenazine Carbinol Compounds
I Comprising A Principal Component Enantiomer And At Least One
Minor Component Enantiomer. Structure of Principal Component
Structure of Minor Component Entry Enantiomer Enantiomer 2a
##STR00031## ##STR00032## 2b ##STR00033## ##STR00034## 2c
##STR00035## ##STR00036##
[0028] In Table 2 the fluoroalkyl tetrabenazine carbinol
compositions comprise a principal 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.
[0029] 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.
[0030] 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.
[0031] 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
(--R.sup.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.sup.1) has a syn-configuration relative to the
hydrogen at ring position-12.
[0032] In one embodiment, the present invention provides an
enantiomerically enriched fluoroalkyl tetrabenazine carbinol
compound comprising a principal component enantiomer having
structure II
##STR00037##
wherein R.sup.1 is a C.sub.1-C.sub.10 fluorinated aliphatic
radical; R.sup.2 is a C.sub.1-C.sub.10 aliphatic radical; R.sup.3
is hydrogen or a C.sub.1-C.sub.10 aliphatic radical; R.sup.4 is
hydrogen or a C.sub.1-C.sub.10 aliphatic radical; and R.sup.5 is
hydrogen, a C.sub.1-C.sub.10 aliphatic radical, a C.sub.2-C.sub.10
cycloaliphatic radical, or a C.sub.2-C.sub.20 aromatic radical.
[0033] Principal component enantiomers having structure II are
illustrated in Table 3 below.
TABLE-US-00003 TABLE 3 Principal Component Enantiomers Having
Structure II Entry Structure 3a ##STR00038## 3b ##STR00039## 3c
##STR00040##
[0034] 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.
[0035] 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.
[0036] In one embodiment, the present invention provides an
enantiomerically enriched fluoroalkyl tetrabenazine carbinol
compound comprising a principal component enantiomer having
structure III
##STR00041##
wherein R.sup.1 is a C.sub.1-C.sub.10 fluorinated aliphatic
radical; R.sup.2 is a C.sub.1-C.sub.10 aliphatic radical; R.sup.3
is hydrogen or a C.sub.1-C.sub.10 aliphatic radical; R.sup.4 is
hydrogen or a C.sub.1-C.sub.10 aliphatic radical; and R.sup.5 is
hydrogen, a C.sub.1-C.sub.10 aliphatic radical, a C.sub.2-C.sub.10
cycloaliphatic radical, or a C.sub.2-C.sub.20 aromatic radical.
[0037] Principal component enantiomers having structure III are
illustrated in Table 4 below.
TABLE-US-00004 TABLE 4 Principal Component Enantiomers Having
Structure III En- try Structure 4a ##STR00042## 4b ##STR00043## 4c
##STR00044##
[0038] 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.
[0039] As noted, with respect to structures I, II, and III, in one
embodiment, the group --OR.sup.5 is not a hydroxy group and is
instead a C.sub.1-C.sub.10 aliphatic radical, a C.sub.2-C.sub.10
cycloaliphatic radical, or a C.sub.2-C.sub.20 aromatic radical.
Thus in one embodiment, the group --OR.sup.5 is an ester moiety,
for example an acetate group as exemplified by Entry 1a of Table 1,
or for example an aryl ether moiety, for example a phenoxy group as
exemplified by Entry 1g of Table 1. In one embodiment, the group
--OR.sup.5 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
--OR.sup.5 is a silyl ether moiety, for example
triethylsilyloxy.
[0040] 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.
##STR00045##
TABLE-US-00005 TABLE 5 Examples Of Fluorophilic Tetrabenazine
Carbinol Compound Having Structure IV Ring Position*
Stereochemistry Entry R.sup.1 R.sup.2 R.sup.3 R.sup.4 RP-2 RP-3
RP-12 5a ##STR00046## ##STR00047## CH.sub.3 CH.sub.3 R/S R/S R/S 5b
##STR00048## ##STR00049## CH.sub.3 CH.sub.3 R R R 5c ##STR00050##
##STR00051## CH.sub.3O CH.sub.3O R/S R/S R/S 5d ##STR00052##
##STR00053## CH.sub.3O CH.sub.3O S S S 5e ##STR00054## ##STR00055##
EtO CH.sub.3O R R R 5f ##STR00056## ##STR00057## EtO EtO S S S 5g
##STR00058## ##STR00059## CH.sub.3CH.sub.2 CH.sub.3CH.sub.2 R/S R/S
R/S 5h ##STR00060## ##STR00061## CH.sub.3O CH.sub.3O R R R 5i
##STR00062## ##STR00063## CH.sub.3O CH.sub.3O R/S R/S R/S 5j
##STR00064## ##STR00065## CH.sub.3O CH.sub.2CH.sub.3 R/S R/S R/S 5k
##STR00066## ##STR00067## CH.sub.3O H R R R
[0041] 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.
[0042] 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-US-00006 TABLE 6 Fluoroalkyl Tetrabenazine Carbinol Compounds
IV Comprising A Principal Component Enantiomer And At Least One
Minor Component Enantiomer. Structure of Principal Component
Structure of Minor Component Entry Enantiomer Enantiomer 6a
##STR00068## ##STR00069## 6b ##STR00070## ##STR00071## 6c
##STR00072## ##STR00073##
[0043] 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.
[0044] 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.
[0045] 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.
[0046] 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
(--R.sup.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.sup.1) has a syn-configuration relative to the
hydrogen at ring position-12.
[0047] In one embodiment, the present invention provides an
enantiomerically enriched fluoroalkyl tetrabenazine carbinol
compound comprising a principal component enantiomer having
structure V
##STR00074##
wherein R.sup.1 is a C.sub.1-C.sub.10 fluorinated aliphatic
radical; R.sup.2 is a C.sub.1-C.sub.10 aliphatic radical; R.sup.3
is hydrogen or a C.sub.1-C.sub.10 aliphatic radical; and R.sup.4 is
hydrogen or a C.sub.1-C.sub.10 aliphatic radical.
[0048] Principal component enantiomers having structure V are
illustrated in Table 7 below.
TABLE-US-00007 TABLE 7 Principal Component Enantiomers Having
Structure V Entry Structure 7a ##STR00075## 7b ##STR00076## 7c
##STR00077##
[0049] 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.
[0050] 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.
[0051] In one embodiment, the present invention provides an
enantiomerically enriched fluoroalkyl tetrabenazine carbinol
compound comprising a principal component enantiomer having
structure VI
##STR00078##
wherein R.sup.1 is a C.sub.1-C.sub.10 fluorinated aliphatic
radical; R.sup.2 is a C.sub.1-C.sub.10 aliphatic radical; R.sup.3
is hydrogen or a C.sub.1-C.sub.10 aliphatic radical; and R.sup.4 is
hydrogen or a C.sub.1-C.sub.10 aliphatic radical.
[0052] Principal component enantiomers having structure VI are
illustrated in Table 8 below.
TABLE-US-00008 TABLE 8 Principal Component Enantiomers Having
Structure VI En- try Structure 8a ##STR00079## 8b ##STR00080## 8c
##STR00081##
[0053] 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.
[0054] In another embodiment, the present invention provides an
enantiomerically enriched fluoroalkyl tetrabenazine carbinol
compound having structure IV, wherein R.sup.1 is a C.sub.1-C.sub.10
fluorinated aliphatic radical comprising at least one fluorine-18
atom; R.sup.2 is a C.sub.5-C.sub.10 aliphatic radical; and R.sup.3
and R.sup.4 are methoxy groups.
[0055] As will be clear to one of ordinary skill in the art, the
term "fluoroalkyl" refers to the group R.sup.1 of structures I-VI
which represents a C.sub.1-C.sub.10 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 C.sub.1-C.sub.10 fluorinated aliphatic radical at ring
position-2.
[0056] 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
--R.sup.1. 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
##STR00082##
wherein R.sup.1 is a C.sub.1-C.sub.10 fluorinated aliphatic radical
comprising at least one fluorine-18 atom; R.sup.2 is a
C.sub.1-C.sub.10 aliphatic radical; R.sup.3 is hydrogen or a
C.sub.1-C.sub.10 aliphatic radical; R.sup.4 is hydrogen or a
C.sub.1-C.sub.10 aliphatic radical; and R.sup.5 is hydrogen, a
C.sub.1-C.sub.10 aliphatic radical, a C.sub.2-C.sub.10
cycloaliphatic radical, or a C.sub.2-C.sub.20 aromatic radical.
[0057] 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
##STR00083##
wherein R.sup.1 is a C.sub.1-C.sub.10 fluorinated aliphatic radical
comprising at least one fluorine-18 atom; R.sup.2 is a
C.sub.1-C.sub.10 aliphatic radical; R.sup.3 is hydrogen or a
C.sub.1-C.sub.10 aliphatic radical; R.sup.4 is hydrogen or a
C.sub.1-C.sub.10 aliphatic radical; and R.sup.5 is hydrogen, a
C.sub.1-C.sub.10 aliphatic radical, a C.sub.2-C.sub.10
cycloaliphatic radical, or a C.sub.2-C.sub.20 aromatic radical.
[0058] 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
##STR00084##
wherein R.sup.1 is a C.sub.1-C.sub.10 fluorinated aliphatic radical
comprising at least one fluorine-18 atom; R.sup.2 is a
C.sub.1-C.sub.10 aliphatic radical; R.sup.3 is hydrogen or a
C.sub.1-C.sub.10 aliphatic radical; R.sup.4 is hydrogen or a
C.sub.1-C.sub.10 aliphatic radical; and R.sup.5 is hydrogen, a
C.sub.1-C.sub.10 aliphatic radical, a C.sub.2-C.sub.10
cycloaliphatic radical, or a C.sub.2-C.sub.20 aromatic radical.
[0059] In yet another embodiment, the present invention provides a
PET imaging agent comprising a fluoroalkyl tetrabenazine carbinol
compound having structure IV
##STR00085##
wherein R.sup.1 is a C.sub.1-C.sub.10 fluorinated aliphatic radical
comprising at least one fluorine-18 atom; R.sup.2 is a
C.sub.1-C.sub.10 aliphatic radical; R.sup.3 is hydrogen or a
C.sub.1-C.sub.10 aliphatic radical; and R.sup.4 is hydrogen or a
C.sub.1-C.sub.10 aliphatic radical.
[0060] 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
##STR00086##
wherein R.sup.1 is a C.sub.1-C.sub.10 fluorinated aliphatic radical
comprising at least one fluorine-18 atom; R.sup.2 is a
C.sub.1-C.sub.10 aliphatic radical; R.sup.3 is hydrogen or a
C.sub.1-C.sub.10 aliphatic radical; and R.sup.4 is hydrogen or a
C.sub.1-C.sub.10 aliphatic radical.
[0061] 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
##STR00087##
wherein R.sup.1 is a C.sub.1-C.sub.10 fluorinated aliphatic radical
comprising at least one fluorine-18 atom; R.sup.2 is a
C.sub.1-C.sub.10 aliphatic radical; R.sup.3 is hydrogen or a
C.sub.1-C.sub.10 aliphatic radical; and R.sup.4 is hydrogen or a
C.sub.1-C.sub.10 aliphatic radical.
[0062] In another embodiment, the present invention provides a PET
imaging agent comprising an enantiomerically enriched fluoroalkyl
tetrabenazine carbinol compound having structure IV, wherein
R.sup.1 is a C.sub.1-C.sub.10 fluorinated aliphatic radical
comprising at least one fluorine-18 atom; R.sup.2 is a
C.sub.5-C.sub.10 aliphatic radical; and R.sup.3 and R.sup.4 are
methoxy groups.
[0063] 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.
[0064] 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 imagining 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 imagining 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 imagining
agent may be administered to a patient as an aqueous formulation
comprising saline and the fluorine-18 labeled fluoroalkyl
tetrabenazine carbinol compound.
[0065] 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.
[0066] 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. For
example, 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.
[0067] 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
##STR00088##
wherein R.sup.1 is a C.sub.1-C.sub.20 aliphatic, a C.sub.2-C.sub.20
cycloaliphatic radical, or a C.sub.2-C.sub.20 aromatic radical
comprising at least one functional group susceptible to reaction
with nucleophilic fluoride ion or an electrophilic fluorinating
agent; R.sup.2 is a C.sub.1-C.sub.10 aliphatic radical; R.sup.3 is
hydrogen or a C.sub.1-C.sub.10 aliphatic radical; R.sup.4 is
hydrogen or a C.sub.1-C.sub.10 aliphatic radical; and R.sup.5 is
hydrogen, a C.sub.1-C.sub.10 aliphatic radical, a C.sub.2-C.sub.10
cycloaliphatic radical, or a C.sub.2-C.sub.20 aromatic radical.
[0068] 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-US-00009 TABLE 9 Examples Of Fluorophilic Tetrabenazine
Compounds Having Structure VII Ring Position* Stereochemistry Entry
R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 RP-2 RP-3 RP-12 9a
##STR00089## ##STR00090## CH.sub.3 CH.sub.3 Ac R/S R/S R/S 9b
##STR00091## ##STR00092## CH.sub.3 CH.sub.3 Ac R R R 9c
##STR00093## ##STR00094## CH.sub.3O CH.sub.3O Ph R/S R/S R/S 9d
##STR00095## ##STR00096## CH.sub.3O CH.sub.3O H S S S 9e
##STR00097## ##STR00098## EtO CH.sub.3O Ph R S R 9f ##STR00099##
##STR00100## EtO EtO Ac S R S 9g ##STR00101## ##STR00102##
CH.sub.3CH.sub.2 CH.sub.3CH.sub.2 Ph R/S R/S R/S 9h ##STR00103##
##STR00104## CH.sub.3O CH.sub.3O Ac R R R 9i ##STR00105##
##STR00106## CH.sub.3O CH.sub.2CH.sub.3 H R/S R/S R/S 9j
##STR00107## ##STR00108## CH.sub.3O H Ac R/S R/S R/S 9k
##STR00109## ##STR00110## CH.sub.3O CH.sub.3O H R R R 9l
##STR00111## ##STR00112## CH.sub.3O CH.sub.3O Ph R R R
[0069] As noted, in one embodiment, the present invention provides
a fluorophilic compound having structure VII, wherein R.sup.1 is a
C.sub.1-C.sub.20 aliphatic radical, a C.sub.2-C.sub.20
cycloaliphatic radical, or a C.sub.2-C.sub.20 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.
[0070] In one embodiment, the present invention provides a
fluorophilic compound having structure VII wherein the group
R.sup.1 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 R.sup.1 comprising the
tosylate group is also an aromatic radical. In the compound shown
in Entry 9a for example, the group R.sup.1 comprising the tosylate
group is a C.sub.9 aromatic radical which upon displacement with
fluoride ion becomes a C.sub.2 fluorinated aliphatic radical.
[0071] In an alternate embodiment, the present invention provides a
fluorophilic compound having structure VII wherein the group
R.sup.1 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 R.sup.1
comprising the mesylate group may be an aliphatic, a cycloaliphatic
or an aromatic radical depending on the overall structure of the
group R.sup.1. For example, in a fluorophilic compound having
structure VII in which R.sup.1 comprises both a mesylate group and
an epoxy group, the group R.sup.1 is a cycloaliphatic radical.
Alternatively, in a fluorophilic compound having structure VII in
which R.sup.1 comprises both a mesylate group and a tosylate group,
the group R.sup.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.
[0072] In an alternate embodiment, the present invention provides a
fluorophilic compound having structure VII wherein the group
R.sup.1 comprises at least one trifluoromethane sulfonate
(triflate) group susceptible to reaction with nucleophilic fluoride
ion. See for example Entry 9b of Table 9.
[0073] In an alternate embodiment, the present invention provides a
fluorophilic compound having structure VII wherein the group
R.sup.1 comprises at least one p-nitrobenzoate group susceptible to
reaction with nucleophilic fluoride ion. See for example Entry 9c
of Table 9.
[0074] In an alternate embodiment, the present invention provides a
fluorophilic compound having structure VII wherein the group
R.sup.1 comprises at least one methane sulfonate group susceptible
to reaction with nucleophilic fluoride ion. See for example Entry
9d of Table 9.
[0075] In an alternate embodiment, the present invention provides a
fluorophilic compound having structure VII wherein the group
R.sup.1 comprises at least one epoxy group susceptible to reaction
with nucleophilic fluoride ion. See for example Entry 9i of Table
9.
[0076] In yet another embodiment, the present invention provides a
fluorophilic compound having structure VII wherein the group
R.sup.1 comprises at least one cyclic sulfate group susceptible to
reaction with nucleophilic fluoride ion. See for example Entry 9l
of Table 9.
[0077] In one embodiment, the present invention provides a
fluorophilic compound having structure VII, wherein R.sup.1 is a
C.sub.2-C.sub.20 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.
[0078] 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 R.sup.1 comprises functional groups susceptible
to reaction with an electrophilic fluorinating agent (double bond)
and to reaction with nucleophilic fluoride ion (tosylate
group).
[0079] 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.
[0080] Thus, in one embodiment, the present invention provides an
enantiomerically enriched fluorophilic tetrabenazine carbinol
compound comprising a principal component enantiomer having
structure VIII
##STR00113##
wherein R.sup.1 is a C.sub.1-C.sub.10 aliphatic radical, a
C.sub.2-C.sub.20 cycloaliphatic radical, or a C.sub.2-C.sub.20
aromatic radical comprising at least one functional group
susceptible to reaction with nucleophilic fluoride ion or an
electrophilic fluorinating agent; R.sup.2 is a C.sub.1-C.sub.10
aliphatic radical; R.sup.3 is hydrogen or a C.sub.1-C.sub.10
aliphatic radical; R.sup.4 is hydrogen or a C.sub.1-C.sub.10
aliphatic radical; and R.sup.5 is hydrogen, a C.sub.1-C.sub.10
aliphatic radical, a C.sub.2-C.sub.10 cycloaliphatic radical, or a
C.sub.2-C.sub.20 aromatic radical. Principal component enantiomers
VIII are illustrated by Entries 9b, 9h, 9k, and 9l of Table 9.
[0081] In an alternate embodiment, the present invention provides
an enantiomerically enriched fluorophilic compound comprising a
principal component enantiomer having structure IX
##STR00114##
wherein R.sup.1 is a C.sub.1-C.sub.10 aliphatic radical, a
C.sub.2-C.sub.20 cycloaliphatic radical, or a C.sub.2-C.sub.20
aromatic radical comprising at least one functional group
susceptible to reaction with nucleophilic fluoride ion or an
electrophilic fluorinating agent; R.sup.2 is a C.sub.1-C.sub.10
aliphatic radical; R.sup.3 is hydrogen or a C.sub.1-C.sub.10
aliphatic radical; R.sup.4 is hydrogen or a C.sub.1-C.sub.10
aliphatic radical; and R.sup.5 is hydrogen, a C.sub.1-C.sub.10
aliphatic radical, a C.sub.2-C.sub.10 cycloaliphatic radical, or a
C.sub.2-C.sub.20 aromatic radical. Principal component enantiomers
IX are illustrated by Entry 9d of Table 9.
[0082] As noted, with respect to structures VII, VIII, and XI, in
one embodiment, the group --OR.sup.5 is not a hydroxy group and is
instead a C.sub.1-C.sub.10 aliphatic radical, a C.sub.2-C.sub.10
cycloaliphatic radical, or a C.sub.2-C.sub.20 aromatic radical.
Thus in one embodiment, the group --OR.sup.5 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.sup.5 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
--OR.sup.5 is a silyl ether moiety, for example
triethylsilyloxy.
[0083] Co-pending U.S. patent applications Ser. No. 11/760,359 and
Ser. No. 11/760,372 filed Jun. 8, 2007 disclose 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.
[0084] 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
##STR00115##
wherein R.sup.3 is hydrogen or a C.sub.1-C.sub.20 aliphatic
radical; R.sup.4 is hydrogen or a C.sub.1-C.sub.20 aliphatic
radical; and P.sup.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.
[0085] Representative aldehyde compounds encompassed by generic
formula X are given in Table 10.
TABLE-US-00010 TABLE 10 Representative Aldehyde Compounds
Encompassed By Formula X Ring Position* Compound Stereo- Entry Type
chemistry Structure 10a Single "R" enantiomer, "Boc" protecting
group P.sup.f RP-12 "R" ##STR00116## 10b Single "S" enantiomer,
"Boc" protection group P.sup.f RP-12 "S" ##STR00117## 10c
Enantiomeric ally enriched mixture of "R" and "S" enantiomers,
"alloc" protecting group P.sup.f RP-12 "R/S" ##STR00118## 10d
Racemic mixture of "R" and "S" enantiomers, "Fmoc" protecting group
P.sup.f RP-12 "R/S" ##STR00119## 10e Racemic mixture of "R" and "S"
enantiomers, "Cbz" protecting group P.sup.f RP-12 "R/S"
##STR00120## 10f Racemic mixture of "R" and "S" enantiomers, "Teoc"
protecting group P.sup.f RP-12 "R/S" ##STR00121## 10g Single "R"
enantiomer, "Boc" protecting group P.sup.f RP-12 "R"
##STR00122##
[0086] 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.
##STR00123##
[0087] 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.
[0088] 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.
[0089] 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.
[0090] 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
##STR00124##
[0092] The dihydroisoquinoline 1 (1.0 eq.) and Boc anhydride (1.5
eq.) were dissolved in CH.sub.2Cl.sub.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.degree. 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 .about.2.5.degree. C. 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 (Na.sub.2SO.sub.4), 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 SiO.sub.2
(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%:
[.alpha.].sup.26.sub.D-69.0 (c 0.21, CHCl.sub.3); .sup.1H NMR
(CDCl.sub.3) .delta. 0.81-1.02 (m, 6H), 1.06-1.17 (m, 6H),
1.23-1.38 (m, 9H), 2.51-2.63 (m, 1H), 2.64-2.77 (m, 1H), 3.20-3.29
(m, 0.6H), 3.32-3.41 (m, 0.4H), 3.51-3.58 (m, 1H), 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, 1H),
4.83-4.98 (m, 1H), 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, 1H), 6.77 (s, 0.6H),
6.81 (s, 0.4H); .sup.13C NMR (CDCl.sub.3) .delta. 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
##STR00125##
[0094] The starting material 2 was taken up in isopropanol to
provide a 0.2 M solution of 2. To this solution was added 1M
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.degree. C. for 22 min.
(timing was started when the temperature of the reaction mixture
temp exceeded 65.degree. C.). Following the allotted time the
reaction mixture was quickly cooled to 0.degree. C. The reaction
mixture carefully acidified with 2M aqueous HCl and extracted with
three portions of dichloromethane. The combined organic extracts
dried (Na.sub.2SO.sub.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.sub.2Cl.sub.2 and
was immediately purified by column chromatography on SiO.sub.2
(15-40% EtOAc-hexanes; 40%, the eluant was monitored at 284 nm).
The product 3 existed as a mixture of rotamers at room temperature
and was a colorless foam 79%: [.alpha.].sup.26.sub.D-82 (c 0.24,
CH.sub.2Cl.sub.2); .sup.1H NMR (CDCl.sub.3) .delta. 1.19-1.25 (m,
6H), 1.43-1.49 (m, 9H), 2.58-2.69 (m, 2H), 2.70-2.77 (m, 1H),
2.78-2.92 (m, 1H), 3.13-3.43 (m, 1H), 3.81-3.85 (m, 6H), 3.86-4.01
(m, 1H), 4.91-5.05 (m, 1H), 5.38-5.61 (m, 1H), 6.56-6.61 (m, 1H),
6.64-6.70 (s, 1H); .sup.13C NMR (CDCl.sub.3) .delta. 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 (C.sub.21H.sub.31NO.sub.6+H)
([M+H].sup.+ 394.22, found 394.16.
Method 3 Preparation of Aldehyde Compound 4
##STR00126##
[0096] To a 0.12 M solution of the starting monoester (3, 1.0 eq.)
in toluene at -78.degree. C. 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.degree. C. 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 (MgSO.sub.4), filtered, and concentrated
under reduced pressure. The crude product was subjected
purification on SiO.sub.2 (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%:
[.alpha.].sup.26.sub.D-116 (c 0.26, CH.sub.2Cl.sub.2); .sup.1H NMR
(CDCl.sub.3) .delta. 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, 1H), 3.78 (apparent s, 6H), 3.87-3.99 (m, 0.5H),
4.08-4.23 (m, 0.5H), 5.37-5.68 (m, 1H), 6.55 (s, 1H), 6.58 (s, 1H),
9.78 (s, 1H); .sup.13C NMR (CDCl.sub.3) .delta. 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
##STR00127##
[0097] 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% NiCl.sub.2 (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 14 h. 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 (MgSO.sub.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.sub.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.
Method 5 Oxidation of Allylic Alcohol 6 to Provide First
Intermediate 8
##STR00128##
[0099] To a 0.1 M solution of allylic alcohol 6 (1.0 eq) in
dichloromethane at 0.degree. C. 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
(MgSO.sub.4), filtered, and concentrated under reduced pressure.
The crude material was purified by column chromatography on
SiO.sub.2 (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.degree. C. as a 60:40 mixture
of rotamers in solution (66%): .sup.1H NMR (CDCl.sub.3) .delta.
0.82 (apparent t, J=7.6 Hz, 6H), 1.42 (s, 9H), 1.70 (apparent sept,
J=6.62 Hz, 1H), 2.08-2.15 (m, 1H), 2.15-2.24 (m, 1H), 2.62-2.70 (m,
1H), 2.75-2.91 (m, 1H), 2.93-3.07 (m, 1H), 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, 1H), 5.69 (s, 1H), 5.90 (s, 0.6H), 6.04 (s,
0.4H), 6.57 (s, 1H), 6.63 (s, 1H); .sup.13C NMR (CDCl.sub.3)
.delta. 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 (C.sub.24H.sub.35NO.sub.5)+H) ([M+H].sup.+ 418.2594, found
418.2590.
Method 5 Removal the Boc Protecting Group First Intermediate 8 and
Amino Cyclization Provide (+)-Tetrabenazine 9
##STR00129##
[0101] First intermediate 8 (1.0 eq) was dissolved in 10%
Me.sub.2S-dichloromethane to provide an 82 mM solution. The
solution was cooled to 0.degree. C. and triisopropylsilane (1.1
eq.) followed by TFA (precooled to 0.degree. C.) was added to the
reaction mixture to provide a final concentration of 41 mM. The
reaction mixture was permitted to stir at 0.degree. C. for 1 h.
Following the allotted time the reaction mixture was quenched at
0.degree. 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.sub.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. The resulting
colorless crystals were washed with hexanes to provide pure
(+)-tetrabenazine (9) 46%: mp 126.0.degree. C. (3.5% DME-hexanes)
(a crystal polymorph was observed at 116.degree. C.);
[.alpha.].sup.26.sub.D+37.2 (c 0.41, CH.sub.2Cl.sub.2); .sup.1H NMR
(CD.sub.2Cl.sub.2) .delta. 0.89 (apparent t, J=7.2 Hz, 6H), 0.98
(ddd, J=12, 6.0, 4.0 Hz, 1H), 1.59-1.68 (m, 1H), 1.74 (ddd, J=12,
5.9, 5.7 Hz, 1H), 2.32 (apparent t, J=11.7 Hz, 1H), 2.46 (apparent
t, J=12.3 Hz, 1H), 2.55 (ddd, J=12, 10.0, 3.8 Hz, 1H), 2.65-2.73
(m, 2H), 2.83 (dd, J=5.5, 2.8 Hz, 1H), 2.97-3.07 (m, 1H), 3.07-3.14
(m, 1H), 3.25 (dd, J=9.7, 6.3 Hz, 1H), 3.47 (apparent d, J=12 Hz,
1H), 3.75 (s, 3H), 3.77 (s, 3H), 6.55 (s, 1H), 6.60 (s, 1H)
.sup.13C NMR (CD.sub.2Cl.sub.2) .delta. 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 (C.sub.19H.sub.27NO.sub.3+H) ([M+H].sup.+ 318.2069, found
318.2082.
Example 1
Conversion of (+)-Tetrabenazine 9 into Tetrabenazine Carbinol
Compound 12
##STR00130##
[0103] To tert-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.degree.
C. 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.degree. C. for 1 h.
Following the allotted time the reaction mixture was quenched by
the addition of saturated ammonium chloride (NH.sub.4Cl). The
mixture was extracted with three portions of EtOAc, and the
combined organic extracts were washed with brine, dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated provide the
crude product. The crude product was chromatographed on SiO.sub.2
(12 g, 10% to 60% EtOAc in hexane) to provide 210 mg of the product
12 (diastereomeric mixture, dr=4:1) as a yellow solid (65%).
.sup.1H NMR (CDCl.sub.3) .delta. 6.64 (s, 1H), 6.54 (s, 1H), 4.40
(s, 2H), 3.84 (s, 6H), 3.46 (d, J=10.0 Hz, 1H), 3.06-3.13 (m, 1H),
2.99-3.02 (m, 1H), 2.95 (dd, J=15.0 & 5.0 Hz, 1H), 2.65 (d,
J=15.0 Hz, 1H), 2.49-2.58 (m, 3H), 2.28 (t, J=10.0 Hz, 1H),
1.90-1.96 (m, 1H), 1.77 (t, J=10.0 Hz, 1H), 1.63-1.70 (m, 1H),
1.49-1.54 (m, 1H), 1.21-1.27 (m, 1H), 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); .sup.13C NMR
(CDCl.sub.3) .delta. 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
##STR00131##
[0105] To a solution of
(2R,3R,11bR)-2-(3-(tert-Butyldimethylsilyloxy)prop-1-ynyl)-3-isobutyl-9,1-
0-dimethoxy-2,3
,4,6,7,11b-hexahydro-1-H-pyrido[2,1-a]isoquinolin-2-ol 12 (140 mg,
0.287 mmol) in CH.sub.2Cl.sub.2 (1 mL) (precooled to 0.degree. C.)
was added Ac.sub.2O (60 .mu.L, 0.631 mmol), Et.sub.3N (0.12 mL,
0.861 mmol and DMAP (4 mg, 0.03 mmol). The reaction mixture was
stirred for 14 h (0.degree. C. to RT). Following the allotted time
the reaction mixture was quenched with saturated sodium bicarbonate
(NaHCO.sub.3). The mixture was extracted with three portions of
CH.sub.2Cl.sub.2 and the combined organic extracts were washed with
brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated to provide the crude product. The crude product was
chromatographed on SiO.sub.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%). .sup.1H NMR (CDCl.sub.3) .delta. 6.66
(s, 1H), 6.57 (s, 1H), 4.42 (s, 2H), 3.85 (s, 3H), 3.83 (s, 3H),
3.50 (d, J=11.00 Hz, 1H), 3.39 (dd, J=12.47 & 2.16 Hz, 1H),
3.03-3.10 (m, 1H), 2.96-2.99 (m, 1H), 2.92 (dd, J=12.17 & 4.04
Hz, 1H), 2.65 (d, J=16.05 Hz, 1H), 2.53 (td, J=11.43 & 4.08 Hz,
1H), 2.44 (t, J=11.97 Hz, 1H), 2.12-2.16 (m, 1H), 2.04 (s, 3H),
1.65-1.70 (m, 2H), 1.49-1.55 (m, 1H), 1.20-1.25 (m, 1H), 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);
.sup.13C NMR (CDCl.sub.3) .delta. 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
##STR00132##
[0107] A solution of
(2R,3R,11bR)-2-(3-(tert-Butyldimethylsilyloxy)prop-1-ynyl)-3-isobutyl-9,1-
0-dimethoxy-2,3,4,6,7,11b-hexahydro-1-H-pyrido[2,1-a]isoquinolin-2-yl
acetate 13 (98 mg, 0.185 mmol) in THF (1 mL) was added dropwise a
solution of TBAF (0.56 mL, 1M in THF, 0.555 mmol) at 0.degree. C.
The reaction mixture was stirred (0.degree. C. to RT) for 2 h.
After the allotted time the reaction mixture was quenched with
saturated ammonium chloride (NH.sub.4Cl). The mixture was extracted
with three portions of EtOAc and the combined organic extracts were
washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated to provide the crude product. The crude product
was chromatographed on SiO.sub.2 (12 g, 10% to 50% EtOAc in hexane)
to produce 68 mg of the compound 14 as a slightly yellow solid
(88%). .sup.1H NMR (CDCl.sub.3) .delta. 6.67 (s, 1H), 6.57 (s, 1H),
4.35 (s, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 3.49 (d, J=12.00 Hz, 1H),
3.35 (d, J=11.24 Hz, 1H), 3.04-3.10 (m, 1H), 2.97-3.00 (m, 1H),
2.92 (dd, J=12.04 & 3.68 Hz, 1H), 2.75 (br s, 1H), 2.65 (d,
J=14.99 Hz, 1H), 2.49-2.54 (m, 1H), 2.39-2.44 (m, 1H), 2.10-2.16
(m, 1H), 2.05 (s, 3H), 1.63-1.70 (m, 2H), 1.50 (td, J=13.58 &
2.95 Hz, 1H), 1.16-1.21 (m, 1H), 0.95 (d, J=6.60 Hz, 3H), 0.93 (d,
J=6.60 Hz, 3H); .sup.13C NMR (CDCl.sub.3) .delta. 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
##STR00133##
[0109] To a 0.degree. C. solution of
(2R,3R,11bR)-2-(3-hydroxyprop-1-ynyl)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7-
,11b-hexahydro-1-H-pyrido[2,1-a]isoquinolin-2-yl acetate 14 (60 mg,
0.144 mmol) in CH.sub.2Cl.sub.2 (1.5 mL) was added dropwise
Et.sub.3N (61 .mu.L, 0.433 mmol) followed by methanesulfonyl
chloride (MsCl) (17 .mu.l, 0.216 mmol). The reaction mixture was
stirred at 0.degree. C. 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
CH.sub.2Cl.sub.2 and the combined organic extracts were dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue
was chromatographed on SiO.sub.2 (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
##STR00134##
[0111] A solution of
(2R,3R,11bR)-2-(3-hydroxyprop-1-ynyl)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7-
,11b-hexahydro-1-H-pyrido[2,1-a]isoquinolin-2-yl acetate 14 (10 mg,
0.024 mmol) in CH.sub.2Cl.sub.2 (0.5 mL) was cooled to -78.degree.
C. To this cooled solution was added dropwise a solution of
(diethylamino)sulfur trifluoride (DAST) (10 .mu.L, 0.072 mmol) in
CH.sub.2Cl.sub.2 (0.1 mL). The reaction mixture was stirred
(-78.degree. C. to RT) for 4 h. The reaction mixture was then
quenched with water and extracted with three portions of
CH.sub.2Cl.sub.2. The combined organic extracts were dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue
was chromatographed on SiO.sub.2 (0% to 10% MeOH in
CH.sub.2Cl.sub.2) to give 3 mg of the product 16 as a white solid
(30%). .sup.1H NMR (CDCl.sub.3) .delta. 6.68 (s, 1H), 6.60 (s, 1H),
5.10 (d, J=47.43 Hz, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.49 (d,
J=11.56 Hz, 1H), 3.40 (dd, J=12.40 & 2.36 Hz, 1H), 3.06-3.12
(m, 1H), 2.95-3.02 (m, 2H), 2.68 (d, J=15.12 Hz, 1H), 2.57 (td,
J=11.03 & 4.09 Hz, 1H), 2.44 (d, J=11.85 Hz, 1H), 2.10-2.21 (m,
1H), 2.09 (s, 3H), 1.70 (t, J=11.04, 2H), 1.51-1.56 (m, 1H),
1.20-1.25 (m, 1H), 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
##STR00135##
[0113] The starting fluoroalkyl tetrabenazine carbinol compound
(2R,3R,11bR)-2-(3-fluoroprop-1-ynyl)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,-
11b-hexahydro-1-H-pyrido[2,1-c]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 N.sub.2 and dissolved in
saturated ammonium chloride (NH.sub.4Cl). Following the allotted
time the mixture was extracted with three portions of
CH.sub.2Cl.sub.2 and the combined organic extracts were dried over
anhydrous Na.sub.2SO.sub.4, 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
##STR00136##
[0115] To a precooled (0.degree. C.) solution of tetrabenazine
carbinol compound, 12 (112 mg, 0.220 mmol) in 2 mL of THF, was
added dropwise a solution of TBAF (330 ml, 0.33 mmol, 1M 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 (NH.sub.4Cl). The mixture was extracted
with three portions of EtOAc, and the combined organic extracts
were washed with brine, dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated to provide a product. The product was
chromatographed on SiO.sub.2 (12 g, 0% to 10% MeOH in
CH.sub.2Cl.sub.2) to produce 49 mg of the tetrabenazine carbinol
compound, diol 18 as a slightly yellow solid (60%). .sup.1H NMR
(CDCl.sub.3) .delta. 6.67 (s, 1H), 6.57 (s, 1H), 3.42 (d, J=11.3
Hz, 1H), 3.14-3.21 (m, 1H), 2.94-3.00 (m, 2H), 2.62 (t, J=10.2 Hz,
2H), 2.50 (td, J=11.2 & 4.0 Hz, 1H), 2.17-2.26 (m, 2H), 2.08
(t, J=9.6 Hz, 1H), 1.61-1.72 (m, 2H), 1.21-1.29 (m, 1H), 1.02 (d,
J=6.6 Hz, 3H, 0.99 (d, J=6.6 Hz, 3H); .sup.13C NMR (CDCl.sub.3)
.delta. 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
##STR00137##
[0117] To a 0.degree. C. solution of diol 18 (1 equivalent) in
CH.sub.2Cl.sub.2 is added dropwise Et.sub.3N (3 equivalents)
followed by methanesulfonyl chloride (MsCl) (1.5 equivalents). The
reaction mixture is stirred at 0.degree. C. 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 CH.sub.2Cl.sub.2 and the combined
organic extracts are dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated. The residue may be chromatographed on
SiO.sub.2 (10% to 70% EtOAc in hexane) to provide the product
mesylate 19.
Example 9
Preparation of PET Imaging Agent 20
##STR00138##
[0119] 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.degree. 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.degree. 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 (3.times.) 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
##STR00139##
[0120] To a 0.11 M solution of (+)-TBZ (9) in ethanol at 0.degree.
C. was added NaBH.sub.4 (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
K.sub.2CO.sub.3. The aqueous washings were back extracted with two
portions of dichloromethane. The combined organic extracts were
dried (MgSO.sub.4), 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 SiO.sub.2 (2.5-5% MeOH-CH.sub.2Cl.sub.2,
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%:
[.alpha.].sup.26.sub.D+48 (c 0.30, CH.sub.2Cl.sub.2) .sup.1H NMR
(CD.sub.2Cl.sub.2) .delta. 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, 1H), 1.42 (dd, J=20.2,
11.4 Hz, 1H), 1.59 (ddd, J=13.7, 9.6, 3.3 Hz, 1H), 1.64-1.78 (m,
2H), 1.96 (apparent t, J=11.4 Hz, 1H), 2.27 (br s, 1H), 2.40-2.48
(m, 1H), 2.54 (ddd, J=12.3, 3.7, 2.3 Hz, 1H), 2.60-2.67 (m, 1H),
2.95-3.09 (m, 3H), 3.11 (apparent d, J=11.1 Hz, 1H), 3.35 (ddd,
J=10.4, 10.4, 4.5 Hz, 1H), 3.80-3.81 (m, 6H), 6.60 (s, 1H), 6.69
(s, 1H); .sup.13C NMR (CD.sub.2Cl.sub.2) .delta. 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 (C.sub.19H.sub.29NO.sub.3+H) [M+H].sup.+
320.2226, found 320.2242. The minor product 22 was a yellow oil 4%:
.sup.1H NMR (CD.sub.2Cl.sub.2) .delta. 0.94 (d, J=6.6 Hz, 3H), 0.96
(d, J=6.6 Hz, 3H), 1.13-1.20 (m, 1H), 1.24-1.34 (m, 2H), 1.60-1.77
(m, 2H), 1.89-2.00 (m, 1H) 2.36-2.44 (m, 2H), 2.53 (ddd, J=10.5,
10.5, 3.8 Hz, 1H), 2.58-2.70 (m, 2H), 2.91-2.98 (m, 1H), 2.98-3.09
(m, 1H), 3.48 (apparent d, J=11.6 Hz, 1H), 3.80-3.82 (apparent s,
6H), 4.07 (apparent d, J=3.1 Hz, 1H), 6.60 (s, 1H), 6.68 (s, 1H);
.sup.13C NMR (CD.sub.2Cl.sub.2) .delta. 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
[0121] 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, Md., 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
dihydrotetrabenazine (DTBZ) control (Comparative Example 2). 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-US-00011 TABLE 11 VMAT-2 Binding Affinity of Fluoroalkyl
Tetrabenazine Carbinol Compounds 16 and 17 Compound Ki Example No.
No. Structure (nM) Example 5 16 ##STR00140## 19 Example 6 17
##STR00141## 19 Comparative Example 1 Reserpine 23 ##STR00142##
162* Comparative Example 2 DTBZ 21 ##STR00143## 3 *Average of two
Ki values obatined for reserpine 70 nM and 254 nM
[0122] 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.
* * * * *