JP5663309B2 - Fluorinated dihydrotetrabenazine ether imaging agents and probes - Google Patents

Description

  The present invention relates to fluorinated ether compounds related to dihydrotetrabenazine and intermediates useful in the preparation of such fluorinated ether compounds.

Since the first time been reported in 1957 (Pletscher, A. (1957) Release of 5-hydroxytryptamine by benzoquinolizine derivatives with sedative action, Science 126, 507), a compound that tetrabenazine and structurally related has been widely investigated, some of TBZ It has been shown that compounds and tetrabenazine derivatives are promising for treating various conditions affecting human health. For example, dihydrotetrabenazine has been identified as a drug for the treatment of schizophrenia and other psychoses (see, eg, WO 2007/017654), and tetrabenazine is for the treatment of Huntington's disease. It has been shown to be promising as a drug (Neurology (2006), 66 (3), 366-372). Although most of the processes used in the biological studies of tetrabenazine and its derivatives have been carried out on racemates, in at least one case the biological activity exhibited by the separately tested enantiomers is significantly different. (Koeppe, R. A. et al. (1999) Assessment of extrastructural vegetative monoaxial transporter binding b ine 19 b)

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 Nucleic Medicine and Biology 34 (2007) 239-246 and Nucleic Medicine and Biology 34 (2007) 233-237.

  The present invention provides a new class of fluorinated dihydrotetrabenazine derivatives and fluorinated dihydrotetrabenazine analogs and to produce such fluorinated ether compounds in enantiomerically enriched or racemic forms. An efficient synthesis method that can be used is disclosed. The fluorinated ether compounds provided by the present invention are useful as PET imaging agents, probes for developing PET imaging agents, and therapeutic agents. In addition, the present invention provides novel synthetic intermediate compositions that can be used to make enantiomers of one or both of the subject dihydrotetrabenazine derivatives and dihydrotetrabenazine analogs.

International Publication No. 2007/130365 Pamphlet

  In one embodiment, the present invention provides a fluorinated ether compound having the following structure I:

In the formula, R ¹ is a C _{2 to} C ₁₀ fluorinated aliphatic group, R ² is a C _{1 to} C ₁₀ aliphatic group or a C _{3 to} C ₁₀ alicyclic group, and R ³ is hydrogen or C _1. -C a ₁₀ aliphatic group, R ⁴ is hydrogen or C ₁ -C ₁₀ aliphatic group.

  In another embodiment, the present invention provides an enantiomerically enriched fluorinated ether compound comprising a principal component enantiomer having the following structure II:

In the formula, R ¹ is a C _{2 to} C ₁₀ fluorinated aliphatic group, R ² is a C _{1 to} C ₁₀ aliphatic group or a C _{3 to} C ₁₀ alicyclic group, and R ³ is hydrogen or C _1. -C a ₁₀ aliphatic group, R ⁴ is hydrogen or C ₁ -C ₁₀ aliphatic group.

  In yet another embodiment, the present invention provides an enantiomerically enriched fluorinated ether compound comprising a principal component enantiomer having the following structure III:

In the formula, R ¹ is a C _{2 to} C ₁₀ fluorinated aliphatic group, R ² is a C _{1 to} C ₁₀ aliphatic group or a C _{3 to} C ₁₀ alicyclic group, and R ³ is hydrogen or C _1. -C a ₁₀ aliphatic group, R ⁴ is hydrogen or C ₁ -C ₁₀ aliphatic group.

  In yet another embodiment, the present invention provides a PET imaging agent comprising a fluorinated ether compound having the following structure I:

Wherein R ¹ is a C ₂ -C ₁₀ fluorinated aliphatic group containing one or more fluorine-18 atoms, and R ² is a C ₁ -C ₁₀ aliphatic group or a C ₃ -C ₁₀ alicyclic group. Yes, R ³ is hydrogen or a C ₁ -C ₁₀ aliphatic group, and R ⁴ is hydrogen or a C ₁ -C ₁₀ aliphatic group.

  A number of terms are used throughout the specification and claims, which are defined to have the following meanings:

  Even in the singular form, it includes plural cases unless it is clear from the context.

  The term “optional” or “optionally” means that the event or situation described following the term may or may not occur, and such a description may be used when the event occurs. Includes cases that do not occur.

  As used herein, the term “solvent” can mean a single solvent or a mixture of solvents.

  Roughly expressed terms used throughout the specification and claims can be applied to modify any quantity expression that is allowed to vary without causing a change in the underlying function to which it relates. . Thus, a value modified with a term such as “about” should not be limited to the exact value specified. In some cases, the summary terminology may correspond to the accuracy of the instrument for measuring the value.

As used herein, the term “aromatic group” refers to an atomic arrangement having a valence of at least one comprising at least one aromatic group. The atomic arrangement of one or more valences containing one or more aromatic groups may contain heteroatoms such as nitrogen, sulfur, selenium, silicon and oxygen, or may be composed solely of carbon and hydrogen. Good. The term “aromatic group” as used herein is not particularly limited, but includes phenyl group, pyridyl group, furanyl group, thienyl group, naphthyl group, phenylene group and biphenyl group. As described above, the aromatic group contains one or more aromatic groups. The aromatic group is always a cyclic structure having “delocalized” electrons of 4n + 2 (where “n” is an integer of 1 or more), a phenyl group (n = 1), a thienyl group (n = 1), furanyl group (n = 1), naphthyl group (n = 2), azulenyl group (n = 2), anthracenyl group (n = 3) and the like. The aromatic group may also contain non-aromatic components. For example, a benzyl group is an aromatic group composed of a phenyl ring (aromatic atomic group) and a methylene group (non-aromatic component). Similarly, the tetrahydronaphthyl group is an aromatic group formed by condensing an aromatic group (C ₆ H ₃ ) with a non-aromatic component — (CH ₂ ) ₄ —. For convenience, the term “aromatic group” in this specification refers to an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a haloaromatic group, a conjugated dienyl group, an alcohol group, an ether group, an aldehyde group, a ketone group, It is defined to include a wide range of functional groups such as acid groups, acyl groups (for example, carboxylic acid derivatives such as esters and amides), amine groups, and nitro groups. For example, the 4-methylphenyl radical is a C 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 ₆ aromatic group containing a nitro group, and the nitro group is a functional group. Aromatic groups include 4-trifluoromethylphenyl, hexafluoroisopropylidenebis (4-phen-1-yloxy) (ie —OPhC (CF ₃ ) ₂ PhO—), 4-chloromethylphen-1-yl, trifluorovinyl-2-thienyl, 3-trichloromethylphen-1-yl _{(i.e., 3-CCl 3 Ph -)} , 4- (3- bromoprop-1-yl) phen-1-yl (i.e., 4 A halogenated aromatic group such as —BrCH ₂ CH ₂ CH ₂ Ph—). Still other examples of aromatic groups include 4-allyloxyphen-1-oxy, 4-aminophen-1-yl (ie, 4-H ₂ NPh-), 3-aminocarbonylphen-1-yl ( That, NH ₂ COPh -), 4-benzoyl 1-yl, dicyanomethylidene bis (4-phen-1-yloxy) _{(i.e., -OPhC (CN) 2 PhO -} ), 3- methyl phen-1- yl, methylenebis (4-phen-1-yloxy) (i.e., -OPhCH ₂ PhO -), 2- Echirufen-1-yl, phenylethenyl, 3-formyl-2-thienyl, 2-hexyl-5-furanyl, Hexamethylene-1,6-bis (4-phen-1-yloxy) (ie, —OPh (CH ₂ ) ₆ PhO—), 4-hydroxymethylphen-1-yl (ie, 4-HOCH) ₂ Ph-), 4-mercaptomethylphen-1-yl (ie 4-HSCH ₂ Ph-), 4-methylthiophen-1-yl (ie 4-CH ₃ SPh-), 3-methoxyphen-1 -Yl, 2-methoxycarbonylphen-1-yloxy (eg methyl salicyl), 2-nitromethylphen-1-yl (ie 2-NO ₂ CH ₂ Ph), 3-trimethylsilylphen-1-yl, 4 -T-butyldimethylsilylphen-1-yl, 4-vinylphen-1-yl, vinylidenebis (phenyl) and the like. The term “C ₃ -C ₁₀ aromatic group” encompasses aromatic groups containing 3 to 10 carbon atoms. The aromatic group 1-imidazolyl (C ₃ H ₂ N ₂ —) represents a C ₃ aromatic group. Benzyl radical (C ₇ H ₇ -) represents a C ₇ aromatic radical.

As used herein, the term “alicyclic group” refers to a group having a valence of at least one comprising a cyclic but non-aromatic atomic arrangement. An “alicyclic group” as defined herein does not contain an aromatic group. An “alicyclic group” may contain one or more acyclic components. For example, a cyclohexylmethyl group (C ₆ H ₁₁ CH ₂ —) is an alicyclic group composed of a cyclohexyl ring (a cyclic but non-aromatic atomic arrangement) and a methylene group (acyclic component). The alicyclic group may contain heteroatoms such as nitrogen, sulfur, selenium, silicon and oxygen, or may consist solely of carbon and hydrogen. For convenience, the term “alicyclic group” in this specification refers to an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a conjugated dienyl group, an alcohol group, an ether group, an aldehyde group, a ketone group, a carboxylic acid group, an acyl group. Defined as containing a wide range of functional groups such as groups (eg carboxylic acid derivatives such as esters and amides), amine groups, nitro groups and the like. For example, a 4-methylcyclopent-1-yl group is a C ₆ alicyclic group containing a methyl group, and the methyl group is a functional group that is an alkyl group. Similarly, the 2-nitrocyclobut-1-yl group is a C ₄ alicyclic group containing a nitro group, and the nitro group is a functional group. The alicyclic group may contain one or more halogen atoms which may be the same or different. Halogen atoms include, for example, fluorine, chlorine, bromine and iodine. Alicyclic groups containing one or more halogen atoms include 2-trifluoromethylcyclohex-1-yl, 4-bromodifluoromethylcyclooct-1-yl, 2-chlorodifluoromethylcyclohex-1-yl, hexafluoro-2,2-bis (cyclohex-4-yl) _{(i.e., -C 6 H 10 C (CF} 3) 2 C 6 H 10 -), 2- chloromethyl-cyclohex-1-yl, 3-difluoromethylenecyclohex-1-yl, 4-trichloromethylcyclohex-1-yloxy, 4-bromodichloromethylcyclohex-1-ylthio, 2-bromoethylcyclopent-1-yl, 2-bromopropylcyclohex Su-1-yloxy (for example, CH ₃ CHBrCH ₂ C ₆ H ₁₀ O—) and the like. Still other examples of alicyclic groups include 4-allyloxycyclohex-1-yl, 4-aminocyclohex-1-yl (ie, H ₂ NC ₆ H ₁₀ —), 4-aminocarbonylcyclopent 1-yl _{(i.e., NH 2 COC 5 H 8 -} ), 4- acetyloxy cyclohex-1-yl, 2,2-dicyano isopropylidene bis (cyclohex-4-yloxy) (i.e., -OC ₆ H ₁₀ C (CN) ₂ C ₆ H ₁₀ O—), 3-methylcyclohex-1-yl, methylenebis (cyclohex-4-yloxy) (ie —OC ₆ H ₁₀ CH ₂ C ₆ H ₁₀ O—) 1-ethylcyclobut-1-yl, cyclopropylethenyl, 3-formyl-2-tetrahydrofuranyl, 2-hexyl-5-tetrahydrofuranyl, hexamethylene-1,6-bis (cyclohex-4 Yloxy) _{(i.e., -OC 6 H 10 (CH 2} ) 6 C 6 H 10 O -), 4- hydroxymethyl-cyclohex-1-yl _{(i.e., 4-HOCH 2 C 6 H} 10 -), 4- mercapto methyl cyclohex-1-yl _{(i.e., 4-HSCH 2 C 6 H} 10 -), 4- methylthiophenyl cyclohex-1-yl _{(i.e., 4-CH 3 SC 6 H} 10 -), 4- methoxy cyclohex - 1- yl, 2-methoxycarbonyl-cyclohex-1-yloxy _{(2-CH 3 OCOC 6 H} 10 O -), 4- nitro-methyl cyclohex-1 -yl _{(i.e., NO 2 CH 2 C 6 H} 10 -) , 3-trimethylsilyl cyclohex-1-yl, 2-t-butyldimethylsilyl-cyclopent-1-yl, 4-trimethoxysilylethyl cyclohex-1-yl _{(e.g., (CH 3 O) 3 SiCH} 2 C ₂ C ₆ H ₁₀ -), and the like 4-vinylcyclohexene-1-yl, vinylidene bis (cyclohexyl). The term “C ₃ -C ₁₀ alicyclic group” includes alicyclic groups containing 3 to 10 carbon atoms. The alicyclic group 2-tetrahydrofuranyl (C ₄ H ₇ O—) represents a C ₄ alicyclic group. The cyclohexylmethyl group (C ₆ H ₁₁ CH ₂ —) represents a C ₇ alicyclic group.

As used herein, the term “aliphatic group” refers to an organic group having a valence of at least one consisting of a linear or branched array of atoms that is not cyclic. An aliphatic group is defined as containing one or more carbon atoms. The atomic arrangement forming the aliphatic group may contain heteroatoms such as nitrogen, sulfur, silicon, selenium and oxygen, or may be composed only of carbon and hydrogen. For convenience, the term “aliphatic group” as used herein refers to an alkyl group, alkenyl group, alkynyl group, haloalkyl group, conjugated dienyl group, alcohol as part of a “non-cyclic linear or branched atom array”. It is defined to include a wide range of functional groups such as groups, ether groups, aldehyde groups, ketone groups, carboxylic acid groups, acyl groups (eg carboxylic acid derivatives such as esters and amides), amine groups and nitro groups. For example, a 4-methylpent-1-yl group is a C ₆ aliphatic group containing a methyl group, and the methyl group is a functional group that is an alkyl group. Similarly, the 4-nitrobut-1-yl group is a C ₄ aliphatic group containing a nitro group, and the nitro group is a functional group. An aliphatic group can be a haloalkyl group containing one or more halogen atoms, which can be the same or different. Halogen atoms include, for example, fluorine, chlorine, bromine and iodine. Aliphatic groups containing one or more halogen atoms include alkyl halides trifluoromethyl, bromodifluoromethyl, chlorodifluoromethyl, hexafluoroisopropylidene, chloromethyl, difluorovinylidene, trichloromethyl, bromodichloromethyl, bromoethyl, 2-bromotrimethylene (eg, —CH ₂ CHBrCH ₂ —) and the like. Still other examples of aliphatic groups include allyl, aminocarbonyl (ie, —CONH ₂ ), carbonyl, 2,2-dicyanoisopropylidene (ie, —CH ₂ C (CN) ₂ CH ₂ —), methyl ( That is, —CH ₃ ), methylene (ie, —CH ₂ —), ethyl, ethylene, formyl (ie, —CHO), hexyl, hexamethylene, hydroxymethyl (ie, —CH ₂ OH), mercaptomethyl (ie, -CH ₂ SH), methylthio (i.e., -SCH _3), methylthiomethyl (i.e., -CH ₂ SCH _3), methoxy, methoxycarbonyl (i.e., CH ₃ OCO-), nitromethyl (i.e., -CH ₂ NO ₂₎ , thiocarbonyl, trimethylsilyl _{(i.e., (CH 3) 3 Si -} ), t- butyldimethylsilyl, 3-trimethoxysilylpropyl (i.e., (C _{3 O) 3 SiCH 2 CH 2} CH 2 -), vinyl, vinylidene, and the like. As yet another example, the C ₁ -C ₁₀ aliphatic group contains 1 or more and 10 or less carbon atoms. A methyl group (ie, CH ₃ —) is an example of a C ₁ aliphatic group. A decyl group (ie, CH ₃ (CH ₂ ) ₉ —) is an example of a C ₁₀ aliphatic group.

  As described above, in one embodiment, the present invention provides a fluorinated ether compound having the following structure I:

In the formula, R ¹ is a C _{2 to} C ₁₀ fluorinated aliphatic group, R ² is a C _{1 to} C ₁₀ aliphatic group or a C _{3 to} C ₁₀ alicyclic group, and R ³ is hydrogen or C _1. -C a ₁₀ aliphatic group, R ⁴ is hydrogen or C ₁ -C ₁₀ aliphatic group.

In compounds of formula (I) as well as other aspects of the invention described below,
R ¹ is preferably C _2-6 fluoroalkyl, C _1-6 fluoroalkoxy (C _1-6 alkyl), C _2-6 fluorohaloalkyl and C _1-6 fluoroalkylcarbonyl (C _1-6 alkyl). Selected
R ² is preferably selected from C _1-6 alkyl and C _3-8 cycloalkyl,
R ³ and R ⁴ are each independently selected from C _1-6 alkyl and C _1-6 alkoxy.

  The fluorinated ether compounds provided by the present invention have high affinity for type 2 vesicle monoamine transporter (VMAT-2), a group of biomarkers believed to correlate with diabetic activity, particularly in human patients. It is shown herein that With the discovery that fluorine substitution in this series of new fluorinated ether compounds is permissible with respect to VMAT-2 binding, the compounds of the present invention can be used for positron emission tomography (PET) in studies targeting VMAT-2 biomarkers. ) For use as an imaging agent.

  Thus, in one embodiment, the present invention provides a radiolabeled fluorinated ether compound within the general structure I comprising a fluorine-18 atom that is a radioactive positron emitting isotope of fluorine. Such radiolabeled fluorinated ether compounds are suitable for use as imaging agents for conducting positron emission tomography (PET) screening of human patients for pathological conditions associated with, for example, diabetes. Positron emission tomography has become a critically important medical imaging technique for human health.

  In another embodiment, the present invention provides fluorinated ether compounds within the general structure I comprising the fluorine-19 atom which is a stable fluorine isotope. Fluorinated ether compounds containing a fluorine-19 atom are useful in binding tests that allow identification of fluorinated ether compounds with optimal affinity for a target biomarker (eg, VMAT-2). The substantial binding affinity of a given fluorine-19-containing fluorinated ether compound for a target biomarker such as VMAT-2 is a reliable predictor of the usefulness of the corresponding fluorine-18-containing fluorinated ether compound in PET imaging It is. As disclosed herein, the fluorinated ether compound having structure I exhibits substantial binding affinity for VMAT-2.

  Although the focus of interest throughout this specification is primarily directed to human health, the fluorinated ether compounds provided by the present invention are useful as imaging agents in the examination and treatment of various human and animal diseases. It is useful as a probe for development and as a therapeutic agent.

  The fluorinated ether compounds having structure I are illustrated in Table 1 below.

  In general, and throughout this specification, absolute or relative stereochemistry for a structure is not shown, for example, as seen in structure I, but the structure is intended to encompass all possible absolute and relative stereochemical configurations. To do. That is, Structure I represents a fluorinated ether compound that has no absolute or relative stereochemistry. Thus, structure I represents a group of fluorinated ether compounds, including racemic fluorinated ether compounds 1a (Table 1) having both R and S configurations at ring positions 2, 3 and 12. In another embodiment, structure I represents a fluorinated ether compound 1b (Table 1) having an R configuration (absolute stereochemistry) at ring positions 2, 3 and 12. In yet another embodiment, structure I represents a fluorinated ether compound 1d (Table 1) having an absolute stereochemistry opposite to that of the fluorinated ether compound 1b. Those skilled in the art will readily understand that the individual fluorinated ether compounds shown in Table 1 herein exemplify dihydrotetrabenazine (DTBZ) ether derivatives within the scope of general structure I. Like.

  As described above, in one embodiment, the invention provides a racemic mixture (eg, fluorinated ether compound 1a (Table 1)), a single enantiomer (eg, fluorinated ether compound 1b (Table 1)), or Provided is a fluorinated ether compound of structure I that can be an enantiomerically enriched composition for a single principal component enantiomer. The numbers 2a-2c in Table 2 below exemplify fluorinated ether compounds containing the main component enantiomer and one or more minor component enantiomers.

  Table 2, fluorinated ether compositions contain principal component enantiomers (the structure of which is shown in the "Structure of principal component enantiomers" column) and one or more "trace component enantiomers" . In the fluorinated ether compositions illustrated in Table 2, the mole percentage of the major component enantiomer is shown as “mol%”, which is an indication relative to the amount of all other fluorinated ether components of the composition. Is the mole percentage of the major component enantiomer of the structure. For the purposes of this discussion, a dihydrotetrabenazine ether derivative is any compound that falls within the scope of general structure I. Number 2a represents a fluorinated ether composition comprising 96 mole% of the indicated R, R, R principal component enantiomer and lesser amounts of S, S, S minor component enantiomer. Number 2c represents a fluorinated ether composition comprising a major component enantiomer having the indicated structure and three minor components having the indicated structure. Those skilled in the art will readily understand that the crude product illustrated in Table 2 number 2c represents an example of a diastereomeric mixture.

  In one embodiment, the present invention provides 95 mole percent (mol%) of a fluorinated ether compound of structure I that is enantiomerically enriched and has an R configuration at ring position 12. ) Provide what includes the above.

  In another embodiment, the present invention provides a fluorinated ether compound of structure I that is enantiomerically enriched and contains 95 mole percent (moles) of the enantiomer having the R configuration at ring position 3. %) Or more.

In one embodiment, the present invention is a fluorinated ether compound having structure I, wherein the fluorinated ether moiety at ring position 2 (—O—R ¹ ) is reversed with respect to the R ² group at ring position 3 The thing which has is provided. The main component enantiomers of numbers 2a to 2c in Table 2 are fluorinated ether compounds in which the fluorinated ether moiety at the ring position 2 (—O—R ¹ ) has an opposite arrangement to the R ² group at the ring position 3. Is illustrated. Number 1a in Table 1 is a racemic fluorinated ether compound, each of the component enantiomers having an inverse relationship between the fluorinated ether moiety at ring position ² and the R ² group at ring position 3. It represents what is characterized by.

  In one embodiment, the present invention provides an enantiomerically enriched fluorinated ether compound comprising a principal component enantiomer having the following structure II:

In the formula, R ¹ is a C _{2 to} C ₁₀ fluorinated aliphatic group, R ² is a C _{1 to} C ₁₀ aliphatic group or a C _{3 to} C ₁₀ alicyclic group, and R ³ is hydrogen or C _1. -C a ₁₀ aliphatic group, R ⁴ is hydrogen or C ₁ -C ₁₀ aliphatic group.

  Principal component enantiomers having structure II are illustrated in Table 3 below.

  In one embodiment, the present invention provides a fluorinated ether composition comprising an enantiomerically enriched fluorinated ether compound comprising 80 mol% or more of the enantiomer having structure II, for example the compound of number 3a (Table 3). Wherein the indicated R, R, R enantiomer accounts for 80 mol% or more relative to the amount of all other dihydrotetrabenazine ether components of the composition.

  In another embodiment, the present invention provides an enantiomerically enriched fluorinated ether compound comprising 95 mol% or more of the enantiomer having structure II, for example a fluorinated ether comprising a compound of number 3b (Table 3). A composition is provided wherein the indicated R, R, R enantiomer accounts for 95 mol% or more based on the amount of all other dihydrotetrabenazine ether components of the composition.

In one embodiment, the invention provides a principal component mirror image having structure II where R ¹ is a C ₂ -C ₁₀ fluorinated aliphatic group, R ² is isobutyl, and R ³ and R ⁴ are methoxy groups. Enantiomerically enriched fluorinated ether compounds containing isomers are provided, and such principal component enantiomers are illustrated in Table 4 below.

  In one embodiment, the present invention provides an enantiomerically enriched fluorinated ether compound comprising a principal component enantiomer having the following structure III:

In the formula, R ¹ is a C _{2 to} C ₁₀ fluorinated aliphatic group, R ² is a C _{1 to} C ₁₀ aliphatic group or a C _{3 to} C ₁₀ alicyclic group, and R ³ is hydrogen or C _1. -C a ₁₀ aliphatic group, R ⁴ is hydrogen or C ₁ -C ₁₀ aliphatic group.

  Principal component enantiomers having structure III are illustrated in Table 5 below.

  In one embodiment, the present invention provides a fluorinated ether composition comprising an enantiomerically enriched fluorinated ether compound comprising at least 80 mol% of the enantiomer having structure III, for example the compound of number 5a (Table 5). Wherein the indicated S, S, S enantiomer accounts for 80 mol% or more relative to the amount of all other dihydrotetrabenazine ether components of the composition. In another embodiment, the present invention provides an enantiomerically enriched fluorinated ether compound comprising 95 mol% or more of the enantiomer having structure III, such as a fluorinated ether comprising a compound of number 5b (Table 5). Compositions are provided wherein the indicated S, S, S enantiomer accounts for 95 mol% or more relative to the amount of all other dihydrotetrabenazine ether components of the composition.

In another embodiment, the present invention provides a main component having structure III where R ¹ is a C ₂ -C ₁₀ fluorinated aliphatic group, R ² is isobutyl, and R ³ and R ⁴ are methoxy groups. Enantiomerically enriched fluorinated ether compounds containing enantiomers are provided, and such principal component enantiomers are illustrated in Table 6 below.

As demonstrated below, the fluorine-18 labeled compounds of formulas (I), (II), and (III) are useful as PET imaging agents for VMAT-2 biomarkers. Thus, according to yet another aspect of the invention, there is a method for detecting VMAT-2 in a subject comprising
(I) administering to the subject a fluorine-18 labeled compound of formula (I), (II) or (III) or a salt thereof as defined above; and (ii) said fluorine--by in vivo PET imaging. A method is provided comprising detecting the uptake of 18-labeled compound.

  Such methods provide information and data that have utility in the diagnosis and clinical research of VMAT-2 related diseases, for example, by providing a method of measuring beta cell mass. The subject is a mammal, most preferably a human, having or suspected of having a VMAT-2 related disease. In another aspect, a compound of formula (I), (II) or (III) or a salt thereof as defined above also images VMAT-2 in healthy human volunteers, eg for clinical research purposes Can also be used. Imaging of VMAT-2 can be performed quantitatively, so that the amount of VMAT-2 or a change in the amount can be measured to diagnose a disease or follow its progression. Alternatively, VMAT-2 imaging can also be used to locate VMAT-2.

  The term “VMAT-2 related disease” refers to brain VMAT-2 related diseases such as Huntington's disease, Parkinson's disease or schizophrenia, or β-cell related diseases or diabetes, including insulinomas and other neuroendocrine tumors (eg, It means a VMAT-2 related disease of the pancreas such as type 1 diabetes, type 2 diabetes or type 1 diabetes before onset of symptoms). In one aspect of the invention, the VMAT-2 related disease is diabetes. In another aspect of the invention, the VMAT-2 related disorder is schizophrenia.

  Accordingly, further provided is the use of a fluorine-18 labeled compound of formula (I), (II) or (III) or a salt thereof in the manufacture of a radiopharmaceutical for in vivo PET diagnosis or imaging of a VMAT-2 related disease. . In another aspect, there is provided a fluorine-18 labeled compound of formula (I), (II) or (III) or a salt thereof for use in in vivo PET diagnosis or imaging of a VMAT-2 related disease.

  In yet another aspect, a method for in vivo diagnosis or imaging of a VMAT-2 related disease in a subject (preferably a human) comprising a fluorine-18 labeled compound of formula (I), (II) or (III) or a salt thereof And a method comprising detecting uptake of said compound by in vivo PET imaging techniques. This method is particularly preferred for in vivo diagnosis or imaging of diabetes. In one aspect of the invention, the method is performed by in vivo PET imaging techniques in a subject (preferably a human) previously administered a fluorine-18 labeled compound of formula (I), (II) or (III) or a salt thereof. Detecting the uptake of said compound.

  The present invention further provides a method for monitoring the therapeutic effect of a subject (preferably a human) with a drug for combating a VMAT-2 related disease, comprising a fluorine-- of formula (I), (II) or (III) Administering an 18-labeled compound or salt thereof to the subject and detecting uptake of the compound by in vivo PET imaging techniques, wherein the administration and detection is optional but preferably (eg, treatment with the drug Methods are provided that are performed repeatedly (before, during and after treatment).

  The compound of formula (I), (II) or (III) or salt thereof is preferably administered as a pharmaceutical formulation comprising said compound and a pharmaceutically acceptable excipient for use in vivo, Such formulations thus constitute a further aspect of the present invention. “Pharmaceutical formulation” as used herein includes an effective amount of a compound of formula (I), (II) or (III) or a salt thereof in a form suitable for administration to a mammal (preferably a human). Is defined as “Pharmaceutically acceptable excipients” are preferably formulated so that the formulation is physiologically acceptable (ie, can be administered to a mammalian body without toxicity or intolerable discomfort). A fluid (especially liquid) capable of suspending or dissolving the compound of I), (II) or (III) or a salt thereof. The pharmaceutically acceptable excipient is preferably an aqueous solution such as sterile pyrogen-free water for injection, saline (which can advantageously be balanced so that the final formulation for injection is isotonic), Alternatively, one or more tonicity adjusting substances (eg, salts of plasma cations and biocompatible counterions), sugars (eg, glucose or sucrose), sugar alcohols (eg, sorbitol or mannitol), glycols (eg, glycerol ) Or other non-ionic polyol materials (eg, polyethylene glycol, propylene glycol, etc.) in an injectable carrier liquid. Preferably, the pharmaceutically acceptable excipient is pyrogen-free water for injection or isotonic saline.

  The pharmaceutical formulation can optionally include additional excipients such as antimicrobial preservatives, pH adjusters, fillers, stabilizers or osmolality adjusters. The term “antimicrobial preservative” means an agent that inhibits the growth of potentially harmful microorganisms (eg, bacteria, yeast or mold). Antimicrobial preservatives may also exhibit some bactericidal properties depending on the dose used. The main role of the antimicrobial preservative of the present invention is to inhibit the growth of such microorganisms in pharmaceutical formulations. However, antimicrobial preservatives can optionally also be used to inhibit the growth of potentially harmful microorganisms in one or more components of the kit used to prepare the pharmaceutical formulation prior to administration. Suitable antimicrobial preservatives include parabens (ie, methyl, ethyl, propyl or butyl paraben or mixtures thereof), benzyl alcohol, phenol, cresol, cetrimide and thiomersal. Preferred antimicrobial preservatives are parabens.

  The term “pH adjuster” is a compound useful for ensuring that the pH of a pharmaceutical formulation is within an acceptable range for administration to humans or mammals (approximately pH 4.0-10.5). Or a mixture of compounds. Suitable such pH adjusting agents include pharmaceutically acceptable buffers such as tricine, phosphate or TRIS [ie, tris (hydroxylmethyl) aminomethane], and sodium carbonate, sodium bicarbonate or mixtures thereof. There are pharmaceutically acceptable bases such as When using pharmaceutical formulations in the form of kits, the pH adjuster can optionally be supplied in a separate vial or container so that the kit user can adjust the pH as part of a multi-stage operation. can do.

  The term “filler” means a pharmaceutically acceptable bulking agent that can facilitate handling of the material during manufacture and lyophilization. Suitable fillers include inorganic salts such as sodium chloride and water soluble sugars or sugar alcohols such as sucrose, maltose, mannitol or trehalose.

  The pharmaceutical formulations of the present invention typically maintain sterile health and / or radioactivity safety while allowing addition and withdrawal of the solution via a syringe or cannula, and optionally an inert headspace gas (eg, nitrogen or argon). ) In a suitable vial or container consisting of a sealed container that enables maintenance of A preferred such container is a septum-sealed vial crimped with an overseal (typically made of aluminum). The closure is suitable for one or several punctures with a hypodermic needle while maintaining aseptic integrity (eg, a crimped septum-sealed closure). Such containers can withstand vacuum when desired (eg, for headspace gas changes or solution degassing) and do not allow entry of external atmospheric gases such as oxygen or water vapor. It has the additional advantage of being able to withstand pressure changes such as reduced pressure.

A preferred multi-dose container consists of a single bulk vial containing multiple patient doses (eg, 10-30 cm ³ in volume), and therefore, once at various time intervals during the useful life of the formulation to suit the clinical situation. Patient doses can be withdrawn into clinical grade syringes. The prefilled syringe is designed to contain a single human dose or “unit dose” and is therefore preferably a disposable or other syringe suitable for clinical use. The pharmaceutical formulations of the present invention preferably have a dosage suitable for one patient and are supplied in a suitable syringe or container as described above.

  The pharmaceutical formulations of the present invention can be manufactured under aseptic manufacturing conditions (ie, in a clean room) to obtain the desired sterile and non-pyrogenic product. It is preferred that the basic components, especially the device parts (eg vials) that come into contact with excipients and pharmaceutical formulations, are sterile. The components of the pharmaceutical formulation can be sterilized by methods known in the art, including sterile filtration or terminal sterilization (eg, using gamma irradiation, autoclaving, dry heat or chemical treatment (eg, with ethylene oxide)). . It is preferable to sterilize some components in advance because a minimum number of operations can be performed. However, as a precaution, it is preferred to include at least a sterile filtration step as the final step in the manufacture of the pharmaceutical formulation.

  By “effective amount” of a compound of formula (I), (II) or (III) or salt thereof is meant an amount effective for use in in vivo PET imaging or for therapeutic use, and the exact amount to be administered. Depending on the particular compound, the weight of the subject or patient, and other variables that are obvious to a skilled physician in the art. The fluorine-18 labeled compound of the present invention may be administered to a subject in an amount sufficient to produce the desired signal for PET imaging. Usually a typical radionuclide dosage of 0.01-100 mCi, preferably 0.1-50 mCi per 70 kg body weight will be sufficient.

As mentioned above, the fluorinated ether compounds I, II and III provided by the present invention may contain a fluorine-18 atom in the fluorinated ether moiety —OR ¹ . In various embodiments, such fluorinated ether compounds containing fluorine-18 atoms are useful as PET imaging agents. Thus, in one embodiment, the present invention provides a PET imaging agent comprising a fluorinated ether compound having the following structure I:

Wherein R ¹ is a C ₂ -C ₁₀ fluorinated aliphatic group containing one or more fluorine-18 atoms, and R ² is a C ₁ -C ₁₀ aliphatic group or a C ₃ -C ₁₀ alicyclic group. Yes, R ³ is hydrogen or a C ₁ -C ₁₀ aliphatic group, and R ⁴ is hydrogen or a C ₁ -C ₁₀ aliphatic group.

  In another embodiment, the present invention provides a PET imaging agent comprising an enantiomerically enriched fluorinated ether compound comprising a main component enantiomer having the following structure II:

Wherein R ¹ is a C ₂ -C ₁₀ fluorinated aliphatic group containing one or more fluorine-18 atoms, and R ² is a C ₁ -C ₁₀ aliphatic group or a C ₃ -C ₁₀ alicyclic group. Yes, R ³ is hydrogen or a C ₁ -C ₁₀ aliphatic group, and R ⁴ is hydrogen or a C ₁ -C ₁₀ aliphatic group.

  In yet another embodiment, the present invention provides a PET imaging agent comprising an enantiomerically enriched fluorinated ether compound comprising a principal component enantiomer having the following structure III:

Wherein R ¹ is a C ₂ -C ₁₀ fluorinated aliphatic group containing one or more fluorine-18 atoms, and R ² is a C ₁ -C ₁₀ aliphatic group or a C ₃ -C ₁₀ alicyclic group. Yes, R ³ is hydrogen or a C ₁ -C ₁₀ aliphatic group, and R ⁴ is hydrogen or a C ₁ -C ₁₀ aliphatic group.

  As used herein, the term “PET imaging agent” refers to a composition comprising a fluorine-18 labeled fluorinated ether compound that can be administered to a patient to perform a PET scan. Typically, the imaging agent is administered to the patient in the form of an aqueous formulation that contains an amount of a fluorine-18 labeled fluorinated ether compound sufficient to perform a PET scan. Typically, the amount of fluorine-18 labeled fluorinated ether compound administered to a patient corresponds to the order of nanograms as the weight of the fluorine-18 labeled fluorinated ether compound. With respect to the relative amount of non-radioactive fluorine-19 containing fluorinated ether compound present in a PET imaging agent administered to a patient, the PET imaging agent typically has a specific activity within the range of about 1 to about 99%. . In one embodiment, the PET imaging agent has a specific activity within the range of about 10 to about 95%. In another embodiment, the PET imaging agent has a specific activity within the range of about 20 to about 90%.

  Aqueous formulations comprising a fluorine-18 fluorinated ether compound are typically administered intravenously and may contain various agents that facilitate the dispersion of the PET imaging agent in water. In one embodiment, the PET imaging agent can be administered to a patient as an aqueous formulation comprising ethanol and a fluorine-18 labeled fluorinated ether compound. In another embodiment, the PET imaging agent can be administered to the patient as an aqueous formulation comprising dextrose and a fluorine-18 labeled fluorinated ether compound. In yet another embodiment, the PET imaging agent can be administered to the patient as an aqueous formulation comprising saline and a fluorine-18 labeled fluorinated ether compound. Such formulations may optionally contain still other excipients as described above. Such excipients more typically include buffers, pharmaceutically acceptable solubilizers (eg, surfactants such as cyclodextrins or Pluronics, Tweens or phospholipids). And one or more excipients such as pharmaceutically acceptable stabilizers or antioxidants (eg, ascorbic acid, gentisic acid or p-aminobenzoic acid).

  In one embodiment, the present invention provides a PET imaging agent comprising a fluorinated ether compound having the structure [18F] IV:

  In addition to being useful as a PET imaging agent and as a probe for determining the suitability of a given fluorinated ether compound for use as a PET imaging agent, the fluorinated ether compounds provided by the present invention are useful for schizophrenia. And is believed to have therapeutic utility in the treatment of diseases such as Huntington's disease. Thus, in one embodiment, the present invention provides a fluorinated ether compound having structure I useful for treating a pathological condition in a patient. In another embodiment, the present invention provides an enantiomerically enriched fluorinated ether compound having structure II that is useful for treating a pathological condition in a patient. In yet another embodiment, the present invention provides an enantiomerically enriched fluorinated ether compound having structure III that is useful for treating a pathological condition in a patient. Typically, the amount of fluorinated ether compound administered to a patient is on the order of milligrams.

  Fluorinated ether compounds, such as fluorinated ether compounds within the scope of General Structure I or General Structure II or III, as PET imaging agents under various conditions, as probes for the discovery and development of imaging agents, It will be readily appreciated by those skilled in the art that salts useful as therapeutic agents may be formed. Accordingly, the present invention provides a new and useful host of fluorinated ether compounds and salts thereof.

  Suitable salts according to the invention include (i) those derived from mineral acids (eg hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid) and organic acids (eg tartaric acid, trifluoroacetic acid). Physiologically acceptable acid addition salts, such as those derived from citric acid, malic acid, lactic acid, fumaric acid, benzoic acid, glycolic acid, gluconic acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid) And (ii) ammonium salts, alkali metal salts (eg, sodium and potassium salts), alkaline earth metal salts (eg, calcium salts and magnesium salts), organic bases (eg, triethanolamine, N-methyl-D) -Salts with glucamine, piperidine, pyridine, piperazine and morpholine) and salts with amino acids (eg arginine and lysine) Una, physiologically it is acceptable base salts. In one particular embodiment, the present invention provides a novel fluorinated ether compound hydrochloride having structure IV.

  In yet another aspect of the invention, there is provided a compound of formula (I), (II) or (III) or a salt thereof for use in medicine.

The fluorinated ether compounds of the present invention can be made by a variety of methods, including those shown in the experimental section of this specification.
In one embodiment, the fluorinated ether compound is prepared by forming a first intermediate dihydrotetrabenazine compound by reaction of a dihydrotetrabenazine having the following structure V with a bifunctional electrophile. .

In the formula, R ² is a C _{1 to} C ₁₀ aliphatic group or a C _{3 to} C ₁₀ alicyclic group, R ³ is hydrogen or a C _{1 to} C ₁₀ aliphatic group, and R ⁴ is hydrogen or C _1. ~C ₁₀ aliphatic group. Said first intermediate can itself react with a nucleophilic fluoride ion or an electrophilic fluorinating agent, or by one or more chemical steps, a nucleophilic fluoride ion or an electrophilic fluorinating agent To a second intermediate dihydrotetrabenazine compound capable of reacting with.

  Thus, in one embodiment, the present invention provides a fluorinated compound having structure VI.

Wherein R ¹ is a C ₂ -C ₂₀ aliphatic group, C ₃ -C ₂₀ alicyclic group or C 1 containing one or more functional groups capable of reacting with a nucleophilic fluoride ion or an electrophilic fluorinating agent. a ₃ -C ₂₀ aromatic radical, R ² is C ₁ -C ₁₀ aliphatic group or C ₃ -C ₁₀ cycloaliphatic radical, R ³ is hydrogen or C ₁ -C ₁₀ aliphatic group, R ⁴ is hydrogen or a C ₁ -C ₁₀ aliphatic group.

  The fluorinated compounds having structure VI are illustrated in Table 7 below.

  Fluorophilic compounds provided by the present invention include racemic mixtures (eg, compositions of numbers 7a, 7c, 7g, 7i and 7j) and enantiomerically enriched compositions (eg, shown in number 7b). And a composition comprising a major component enantiomer having a different structure).

In an embodiment, the present invention is, C ₂ -C ₂₀ aliphatic group containing one or more functional groups R ¹ are susceptible to reaction with nucleophilic fluoride ion, C ₃ -C ₂₀ cycloaliphatic radical or a C ₃ It provides a fluorophilic compound having structure VI is a -C ₂₀ aromatic group. In one embodiment, the functional group capable of reacting with a nucleophilic fluoride ion is an aromatic sulfonate group (eg, tosylate, benzene sulfonate, naphthalene sulfonate). In another embodiment, the functional group capable of reacting with a nucleophilic fluoride ion is an aliphatic sulfonate group (eg, methanesulfonate, trifluoromethanesulfonate). In one embodiment, the functional group capable of reacting with a nucleophilic fluoride ion is selected from the group consisting of a tosylate group, a mesylate group, a trifluoromethanesulfonate group and a p-nitrobenzoate group.

In one embodiment, the present invention provides a fluorinated compound having structure VI wherein the R ¹ group includes one or more tosylate groups that can react with a nucleophilic fluoride ion. For example, see Table 7 numbers 7a, 7j and 7k. As defined herein, a tosylate group is an aromatic group and an R ¹ group containing a tosylate group is also an aromatic group. For example, in the compound shown in No. 7a, the R ¹ group containing a tosylate group is a C ₉ aromatic group, which becomes a C ₂ fluorinated aliphatic group when substituted with a fluoride ion.

In another embodiment, the present invention provides a fluorinated compound having structure VI wherein the R ¹ group includes one or more mesylate groups that can react with a nucleophilic fluoride ion. As defined herein, the mesylate group is an aliphatic group, and the R ¹ group containing the mesylate group is an aliphatic group, an alicyclic group or an aromatic group depending on the overall structure of the R ¹ group. obtain. For example, in the fluorinated compound having the structure VI in which R ¹ includes a mesylate group and an epoxy group, the R ¹ group is an alicyclic group. Alternatively, in the fluorinated compound having structure VI where R ¹ includes a mesylate group and a tosylate group, the R ¹ group is an aromatic group. According to the definition of aliphatic group, alicyclic group and aromatic group shown in this specification, an aliphatic group (non-cyclic atomic arrangement) is an alicyclic group (non-aromatic cyclic atomic arrangement) and aromatic. Must not contain an aromatic group (a cyclic atomic arrangement that is aromatic), an alicyclic group must not contain an aromatic group, and an aromatic group must contain only aromatic groups. It is useful to keep in mind that a hierarchical structure must be established.

In another embodiment, the present invention provides a fluorinated compound having structure VI, wherein the R ¹ group comprises one or more trifluoromethanesulfonate (triflate) groups that can react with nucleophilic fluoride ions. For example, see Table 7 number 7b.

In another embodiment, the present invention provides a fluorinated compound having structure VI wherein the R ¹ group includes one or more p-nitrobenzoate groups that can react with a nucleophilic fluoride ion. See, for example, number 7c in Table 7.

In another embodiment, the present invention provides a fluorinated compound having structure VI, wherein the R ¹ group includes one or more methanesulfonate groups that can react with a nucleophilic fluoride ion. For example, see number 7d in Table 7.

In another embodiment, the present invention provides a fluorinated compound having structure VI, wherein the R ¹ group includes one or more epoxy groups that can react with nucleophilic fluoride ions. See, for example, number 7i in Table 7.

In yet another embodiment, the present invention provides a fluorinated compound having structure VI, wherein the R ¹ group includes one or more cyclic sulfate groups that can react with a nucleophilic fluoride ion. See, for example, number 7l in Table 7.

In one embodiment, the present invention provides one or more functionalities wherein R ¹ can react with an electrophilic fluorinating agent (eg, fluorine gas, perchloryl fluoride, mercuric fluoride and phenyl selenenyl fluoride). It provides a fluorophilic compound having structure VI is a C ₂ -C ₂₀ aliphatic group containing a group.

  Thus, in one embodiment, the functional group capable of reacting with the electrophilic fluorinating agent is selected from the group consisting of a carbon-carbon double bond and a carbon-carbon triple bond. Numbers 7e, 7f, 7g, and 7h in Table 7 illustrate compounds that are within the scope of the general structure VI that can react with the electrophilic fluorinating agent.

  The fluorinated tetrabenazine compound VI can be prepared in an enantiomerically enriched form or in a racemic form. For example, the fluorinated tetrabenazine compound VI can be enriched with the R, R, R-enantiomer shown in Table 7, number 7b. Alternatively, the fluorinated tetrabenazine compound may be enriched with an enantiomer (eg, S, S, S-enantiomer number 7d) having the absolute stereochemistry opposite to number 7b in Table 7. it can.

  Thus, in one embodiment, the present invention provides an enantiomerically enriched fluorophilic compound comprising a principal component enantiomer having the following structure VII:

Wherein R ¹ is a C ₂ -C ₂₀ aliphatic group, C ₃ -C ₂₀ alicyclic group or C 1 containing one or more functional groups capable of reacting with a nucleophilic fluoride ion or an electrophilic fluorinating agent. a ₃ -C ₂₀ aromatic radical, R ² is C ₁ -C ₁₀ aliphatic group or C ₃ -C ₁₀ cycloaliphatic radical, R ³ is hydrogen or C ₁ -C ₁₀ aliphatic group, R ⁴ is hydrogen or a C ₁ -C ₁₀ aliphatic group. Principal component enantiomer VII is exemplified by numbers 7b, 7e, 7h, 7k and 7l in Table 7.

  In another embodiment, the present invention provides an enantiomerically enriched fluorophilic compound comprising a principal component enantiomer having the following structure VIII:

Wherein R ¹ is a C ₂ -C ₂₀ aliphatic group, C ₃ -C ₂₀ alicyclic group or C 1 containing one or more functional groups capable of reacting with a nucleophilic fluoride ion or an electrophilic fluorinating agent. a ₃ -C ₂₀ aromatic radical, R ² is C ₁ -C ₁₀ aliphatic group or C ₃ -C ₁₀ cycloaliphatic radical, R ³ is hydrogen or C ₁ -C ₁₀ aliphatic group, R ⁴ is hydrogen or a C ₁ -C ₁₀ aliphatic group. Principal component enantiomer VIII is illustrated by number 7d in Table 7.

  A dihydrotetrabenazine compound having structure V is readily prepared from the corresponding tetrabenazine (TBZ) having the following structure IX.

In the formula, R ² is a C _{1 to} C ₁₀ aliphatic group or a C _{3 to} C ₁₀ alicyclic group, R ³ is hydrogen or a C _{1 to} C ₁₀ aliphatic group, and R ⁴ is hydrogen or C _1. ~C ₁₀ aliphatic group. For example, dihydrotetrabenazine V can be obtained by reducing the carbonyl group at ring position 2 with sodium borohydride in ethanol.

  Tetrabenazine compounds having structure IX are known in the chemical literature and describe the preparation of both racemic tetrabenazine and dihydrotetrabenazine compositions and enantiomerically enriched tetrabenazine and dihydrotetrabenazine compositions. ing. Co-pending International Patent Application No. PCT / US2008 / 065738 discloses a process for the preparation of racemic tetrabenazine compositions and enantiomerically enriched tetrabenazine compositions. In addition, the Examples section of this specification provides a detailed experimental description of the preparation and characterization of tetrabenazine compound IX and dihydrotetrabenazine compound V.

  In general, to produce the tetrabenazine compound IX, an allylic alcohol is obtained by reacting a nucleophilic alkenyl species with an aldehyde compound having the following structure X (see Methods 4, 5 and 6 in the Examples section): See).

In the formula, R ³ is hydrogen or a C ₁ -C ₂₀ aliphatic group, R ⁴ is hydrogen or a C ₁ -C ₂₀ aliphatic group, and P ¹ is a protecting group. The allylic alcohol is then oxidized to give the enone called “first intermediate” (see methods 7, 8 and 9 in the Examples section). The protecting group is then removed and the deprotected first intermediate is subjected to an amino cyclization reaction to give the corresponding TBZ compound.

  Representative aldehyde compounds encompassed by general formula X are shown in Table 8 below.

  The preparation of the aldehyde compound shown in Table 8 number 8a is described in the Examples section (Methods 1-3) herein. In general, a class of aldehyde compounds represented by Structure X can be prepared by art recognized methods using, for example, the methodology shown in Scheme 1 below.

Thus, the aldehyde compound X is prepared according to Sasamoto et al. (Journal of the American Chemical Society 128 , 14010-140111, 2006). Sasamoto et al. Discloses a process for the preparation of enantiomerically enriched tetrahydroquinoline malonate compounds. Such compounds, as shown herein, are aldehyde compounds from the selective hydrolysis and decarboxylation of one ester moiety of tetrahydroquinoline malonate as illustrated in Scheme 1 and then the resulting tetrahydroisoquinoline monoester. Can be converted to aldehyde compound X by reduction to X.

If 2 mol% of DM-SEGPHOS shown in Scheme 1 is the chiral catalyst responsible for the enantiomeric enrichment of the product aldehyde X, and if the opposite chirality of DM-SEGPHOS is used as the chiral catalyst The product aldehyde X enriched for the "S" enantiomer (aldehyde compound X having the S configuration at ring position 12 (see, eg, number 8b in Table 8)). Will be readily understood by those skilled in the art. Suitable chiral catalysts include 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, There are (S) -DM-SEGPHOS and (R) -DM-SEGPHOS. Typically, the use of a catalyst consisting of a ligand having a single configuration (eg, “S” configuration) yields a stereochemically enriched malonate adduct of the reverse “R” configuration, and vice versa. correct.

  In addition to producing a single configuration-enriched aldehyde compound X at ring position 12 using a chiral catalyst, a wide variety of methods for separating racemic aldehyde X into its component enantiomers Is available. For example, racemic aldehyde compound X can be separated into its component enantiomers by high performance liquid chromatography (hplc) on a chiral hplc column.

  Another method for preparing the enantiomerically enriched composition provided by the present invention is the conversion of a racemic fluorinated ether compound having structure I into an adduct consisting of a mixture of diastereomers. And then separated by fractional crystallization. For example, by reacting a racemic fluorinated ether compound having structure I with (+)-tartaric acid, an adduct (ammonium tartrate salt) of the racemic fluorinated ether compound can be produced. The adduct consists of a mixture of diastereomers of ammonium tartrate, which can then be separated by fractional crystallization.

  The following examples are merely illustrative of methods and embodiments according to the present invention and therefore should not be construed as limiting the scope of the claims.

Method for producing dihydrotetrabenazine (DTBZ) starting material
Method 1 Preparation of protected diester 2

Dihydroisoquinoline 1 (1.0 eq.) And Boc anhydride (1.5 eq.) Were dissolved in room temperature CH ₂ Cl ₂ to give a 1.5 M solution for dihydroisoquinoline. The mixture was stirred for 30 minutes. After a predetermined time, the reaction mixture is cooled to 0 ° C., and then a pre-cooled dichloromethane solution of diisopropyl malonate (1.5 eq.) And Pd catalyst (0.008 eq.) Is added to the reaction mixture in turn, to give the starting dihydro A final reaction concentration of 0.84M was obtained for isoquinoline. The reaction mixture was kept stirring at about 2.5 ° C. for 15 hours. After 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 ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the crude product. The crude material was dissolved in a minimum amount of dichloromethane and purified by flash chromatography on SiO ₂ (15-30% EtOAc-hexanes, elution was observed at 285 nm and 228 nm). Product 2 was a colorless solid (94%) present as a mixture of rotamers in solution at room temperature. [Α] ²⁶ _D -69.0 (c0.21, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ 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); 13} C NMR (CDCl 3) δ21.02,21.09,21.18,21.32,27.24,27.95,28.02,37.60,39. 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 2

Starting material 2 was dissolved in isopropanol to give a 0.2M solution of 2 . To this solution was added 1M aqueous NaOH to bring the final concentration of the reaction mixture to 0.1M with respect to malonate 2 . The reaction mixture was heated to 70 ° C. and kept at this temperature for 22 minutes (time started when the temperature of the reaction mixture exceeded 65 ° C.). After a predetermined time, the reaction mixture was rapidly cooled to 0 ° C. The reaction mixture was carefully acidified with 2M aqueous HCl and extracted with three portions of dichloromethane. The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The isolated material was dissolved in THF (based on the initial amount of 2 used in the reaction mixture) to give a 0.1 M solution and triethylamine (1.0 eq) was added to the reaction mixture at room temperature. The reaction mixture was heated to its reflux temperature and kept at this temperature for 90 minutes. The reaction mixture was concentrated under reduced pressure, dissolved in minimum amount of CH ₂ Cl _2, (monitored 15 to 40% EtOAc-hexane, the eluate with 40% 284 nm) immediately column chromatography on SiO ₂ Purified by Product 3 existed as a mixture of rotamers at room temperature and was a colorless foam (79%). [Α] ²⁶ _D -82 (c0.24, CH ₂ Cl ₂ ); ¹ H NMR (CDCl ₃ ) δ 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); ¹³ C NMR (CDCl ₃ ) δ 21.75, 21.90, 27.93, 28.08, 28.44, 37.53, 38.75, 42.22, 42.81, 51.11, 51.87, 55.92, 56.02, 68.08, 79.74, 80 21, 109.60, 109.99, 111.44, 111.54, 126.28, 126.48, 128.54, 128.76, 147.51, 147.97, 154.39, 154.51, 170.36,170.59; LRMS- (ESI +) ( C 21 H 31 NO 6 + H) [M + H] + calculated for 394.22, found 394.16.

Method 3 Production of aldehyde compound 4

A 1.5M hexane solution of DiBAl-H (1.5 eq.) Was added dropwise to a 0.12M solution obtained by dissolving the starting monoester ( 3 , 1.0 eq.) In toluene at −78 ° C. with a syringe pump. After the addition, the reaction mixture was stirred at −78 ° C. for 2 hours. The reaction mixture was quenched by the addition of EtOAc and then acidified with saturated aqueous citric acid. The reaction mixture was allowed to warm to room temperature and kept stirring for 30 minutes. The phases were separated and the aqueous phase was extracted with 3 portions of EtOAc. The combined organic extracts were washed with two portions of 2M aqueous HCl, washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The crude product was subjected to purification on SiO ₂ (15~35% EtOAc- hexanes, elution was observed at 285nm and 228 nm). The isolated product, aldehyde compound 4, was a colorless foam (76%). The product was present as a 1: 1 mixture of rotamers at room temperature. [Α] ²⁶ _D −116 (c 0.26, CH ₂ Cl ₂ ); ¹ H NMR (CDCl ₃ ) δ 1.40 (s, 9H), 2.58 (apparent t, J = 3.8 Hz, 0. 5H), 2.61 (apparent t, J = 3.5 Hz, 0.5H), 2.68-2.88 (m, 3H), 3.02-3.27 (m, 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); ¹³ C NMR (CDCl ₃ ) δ 20.90, 28.02, 28.27, 37. 23, 38.65, 49.29, 49.93, 51.12, 55.83, 55.96, 80.13, 80.64, 109.42, 109.52, 111. 2,126.34,126.51,127.78,127.82,147.72,147.97,153.85,154.62,200.08,200.33.

Method 4 Production of allyl alcohol 6 by reaction of aldehyde compound 4 with nucleophilic alkenyl species derived from alkenyl iodide 5

A neat mixture of room temperature consisting of alkenyl iodide 5 (1.0 eq) and aldehyde compound 4 (1.0 eq.) Was doped with 0.5% NiCl ₂ (w / w) 2.65 eq. Was added. The mixture was vortexed for about 2 minutes to give a homogeneous green-gray paste and then stirred for an additional 10 minutes under nitrogen before anhydrous DMF was added to a final reaction concentration of 0.36M. The reaction mixture was dark green and continued to stir at room temperature for 14 hours. After a predetermined time, the reaction mixture was diluted with 1: 1 EtOAc-hexane, 0.5 M aqueous EDTA solution (pH 9) was added, and the whole mixture was stirred for 1.5 hours. The aqueous layer was extracted with three portions of EtOAc, dried (MgSO ₄ ), filtered, and the filtrate was concentrated under reduced pressure to give a green oil. The crude material was subjected to column chromatography on SiO ₂ (35% EtOAc- hexane, elution was observed at 285nm and 228 nm). The product, allylic alcohol 6 , was a pale yellow oil isolated in 53% yield as a mixture of diastereomers, which was subjected to the next step without further characterization or analysis. did.

Method 5 Preparation of allyl alcohol 8 by reaction of aldehyde compound 4 with a nucleophilic alkenyl species derived from alkenyl iodide 7

A neat mixture of room temperature consisting of alkenyl iodide 7 (1.0 eq) and aldehyde compound 4 (1.25 eq.) Was doped with 0.5% NiCl ₂ (w / w), 2.5 eq. Was added. The mixture was vortexed for about 2 minutes to give a homogeneous green-gray paste and then stirred for an additional 10 minutes under nitrogen before anhydrous DMF was added to a final reaction concentration of 0.36M. The reaction mixture was dark green and continued to stir at room temperature for 14 hours. After a predetermined time, the reaction mixture was diluted with 1: 1 EtOAc-hexane, 0.5 M aqueous EDTA solution (pH 9) was added, and the whole mixture was stirred for 1.5 hours. The aqueous layer was extracted with three portions of EtOAc, dried (MgSO ₄ ), filtered, and the filtrate was concentrated under reduced pressure to give a green oil. The crude material was subjected to column chromatography on SiO ₂ (20% EtOAc- hexanes to 35% EtOAc-hexane, elution was observed at 285nm and 228 nm). The product, allylic alcohol 8 , was a pale yellow oil isolated in 54% yield as a mixture of diastereomers, which was subjected to the next step without further characterization or analysis. did.

Method 6 Production of an allylic alcohol 10 by reaction of an aldehyde compound 4 with a nucleophilic alkenyl species derived from alkenyl iodide 9

A room-temperature neat mixture consisting of alkenyl iodide 9 (1.5 eq) and aldehyde 4 (1.0 eq.) Was added with 0.5% NiCl ₂ (w / w) doped chromium chloride 2.5 eq. Was added. The mixture was vortexed for about 2 minutes to give a homogeneous green-gray paste and then stirred for an additional 10 minutes under nitrogen before anhydrous DMF was added to a final reaction concentration of 0.36M. The reaction mixture was dark green and continued to stir at room temperature for 14 hours. After a predetermined time, the reaction mixture was diluted with 1: 1 EtOAc-hexane, 0.5 M aqueous EDTA solution (pH 9) was added, and the whole mixture was stirred for 1.5 hours. The aqueous layer was extracted with three portions of EtOAc, dried (MgSO ₄ ), filtered, and the filtrate was concentrated under reduced pressure to give a green oil. The crude material was subjected to column chromatography on SiO ₂ (40% EtOAc-hexane, elution was observed at 285 nm and 228 nm) to give the product allylic alcohol 10 as a 1: 1 mixture of diastereomers. Obtained as a pale yellow oil (47%) present. ¹ H NMR (CD ₂ Cl ₂ ) δ 0.94-1.00 (m, 6H), 1.13-1.16 (m, 9H), 1.54-1.57 (m, 9H), 67-1.74 (m, 2H), 1.79-1.86 (m, 0.5H), 1.87-1.94 (m, 1H), 1.96-2.05 (m, 0) .5H), 2.09-2.24 (m, 2H), 2.66-2.77 (m, 1H), 2.85-2.99 (m, 1H), 3.16-3.22. (M, 0.5H), 3.36-3.44 (m, 0.5H), 3.80-3.92 (m, 8H), 4.01-4.08 (m, 0.5H) 4.12-4.17 (m, 0.5H), 4.30-4.38 (m, 0.5H), 4.66-4.77 (m, 0.5H), 4.86- 4.96 (m, 1H), 5.23-5.30 (m, 0.5 ) 5.34-5.39 (m, 1H), 5.39-5.43 (m, 0.5H), 6.68-6.72 (m, 1H), 6.73-6.77 (M, 0.5H), 6.77-6.81 (m, 0.5H), 7.43-7.52 (m, 6H), 7.75-7.82 (m, 4H); ¹³ C NMR (CD ₂ Cl ₂ ) δ 19.12, 26.83, 27.33, 27.45, 27.54, 27.59, 28.29, 28.41, 33.46, 33.48, 38. 30, 39.45, 43.64, 43.82, 44.93, 45.05, 45.48, 45.95, 50.95, 52.25, 55.89, 55.99, 56.01, 61.14, 69.99, 73.06, 80.03, 80.49, 110.21, 110.56, 111.87, 112.00, 11 .02, 112.39, 125.92, 126.32, 126.35, 127.77, 129.57, 129.69, 130.17, 134.15, 135.68, 147.85, 147.88 147.999, 148.11, 148.71, 149.59, 149.61, 155.79, 156.39.

Method 7 Production of first intermediate 12 by oxidation of allylic alcohol 6

To a 0.1 M solution of allylic alcohol 6 (1.0 eq) dissolved in dichloromethane at 0 ° C., 1.1 eq. Of Dess-Martin reagent 11 was added. The reaction mixture was allowed to warm slowly to room temperature over 2.5 hours with stirring. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate and diluted with ethyl acetate. The organic and aqueous layers were separated and separated, and the aqueous layer was extracted with three more portions of ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on SiO ₂ (10~30% EtOAc- hexanes, elution was observed at 285nm and 228 nm) was purified by. The product, first intermediate 12, was a colorless, malodorous oil (66%) that was present in solution as a 60:40 mixture of rotamers at 26 ° C. ¹ H NMR (CDCl ₃ ) δ 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, 0.6 H), 6.04 (s, 0.4 H), 6.57 (s, 1 H), 6.63 (s, 1 H); ¹³ C NMR (CDCl ₃ ) δ22 .45, 27.04, 2 .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 +) ( C 24 H 35 NO 5) + H) [M + H] + calculated for 418.2594, found 418.2590.

Method 8 Production of First Intermediate 13 by Oxidation of Allyl Alcohol 8

8 (1.0 eq) in 0.1 M solution in dichloromethane at 0 ° C., 1.1 eq. Of Dess-Martin reagent 11 was added. The reaction mixture was allowed to warm slowly to room temperature over 2.5 hours with stirring. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate and diluted with dichloromethane. The organic and aqueous layers were separated and separated, and the aqueous layer was extracted with three more portions of dichloromethane. The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on SiO ₂ (10~50% EtOAc- hexanes, elution was observed at 285nm and 228 nm) was purified by. The product, first intermediate 13, was a colorless oil (82%) present at 26 ° C. as a 50:50 mixture of rotamers in solution. ¹ H NMR (CD ₂ Cl ₂ ) δ 1.19 (s, 9H), 1.55 (s, 9H), 1.63-1.83 (m, 5H), 2.34-2.57 (m, 2H), 2.70-2.85 (m, 1H), 2.85-3.05 (m, 1H), 3.05-3.41 (m, 2.5H), 3.41-3. 56 (m, 0.5H), 3.81-3.83 (m, 1H), 3.84 (s, 3H), 3.86 (s, 3H), 3.97-4.08 (m, 0.5H), 4.20-4.35 (m, 0.5H), 5.68 (apparent t, J = 6.6 Hz, 1H), 5.87 (s, 1H), 6.09 ( s, 0.5H), 6.19 (s, 0.5H), 6.71 (s, 1H), 6.76 (s, 1H), 7.45-7.60 (m, 6H), 7 .77-7.95 (m, 4H); ¹³ C NMR (CD ₂ Cl ₂ ) δ 19.19, 24.66, 24.75, 26.83, 28.06, 28.28, 30.57, 32.43, 37.75, 39.20, 45.16, 45.66 63.84, 79.46, 79.77, 110.21, 110.49, 111.81, 124.37, 124.67, 126.45, 127.76, 129.19, 129.68, 134 .13,135.61,147.79,148.19,149.20,154.09,154.41,199.15,199.27; HRMS- (ESI +) ( C 40 H 53 NO 6 Si + H) [ Calculated value 672.3720 for M + H] ⁺ , measured value 672.3715.

Method 9 Production of First Intermediate 14 by Oxidation of Allyl Alcohol 10

To a 0.1 M solution of allyl alcohol 10 (1.0 eq) dissolved in dichloromethane at 0 ° C., 1.1 eq. Of Dess-Martin reagent 11 was added. The reaction mixture was allowed to warm slowly to room temperature over 5 hours with stirring. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate and diluted with dichloromethane. The organic and aqueous layers were separated and separated, and the aqueous layer was extracted with three more portions of dichloromethane. The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on SiO ₂ (10~50% EtOAc- hexanes, elution was observed at 285nm and 228 nm) was purified by. The product, first intermediate 14, was a yellow foam (93%) present at 26 ° C. as a 50:50 mixture of rotamers in solution. ¹ H NMR (CD ₂ Cl ₂ ) δ 0.85 (s, 6H), 1.14 (s, 9H), 1.48-1.57 (m, 9H), 1.65 (t, J = 7. 3Hz, 2H), 2.30-2.50 (m, 2H), 2.70-2.80 (m, 1H), 2.85-2.98 (m, 1H), 3.07-3. 17 (m, 1H), 3.22-3.37 (m, 1.5H), 3.38-3.50 (m, 0.5H), 3.81 (s, 3H), 3.85 ( s, 3H), 3.85-3.92 (m, 2H), 3.94-4.02 (m, 0.5H), 4.18-4.25 (m, 0.5H), 5. 65-5.72 (m, 1H), 5.74 (s, 1H), 6.07 (s, 0.5H), 6.14 (s, 0.5H), 6.69 (s, 1H) , 6.76 (s, 1H), 7.45-7.54 (m, 6 ), 7.77-7.82 (m, 4H) ; 13 C NMR (CD 2 Cl 2) δ19.09,26.80,26.92,26.97,28.13,28.22,28. 28, 33.22, 37.94, 39.39, 41.79, 41.87, 44.49, 45.33, 46.02, 51.16, 51.44, 55.79, 55.83, 61.05, 79.47, 79.76, 110.18, 110.51, 111.74, 126.40, 127.26, 127.36, 127.76, 129.48, 129.69, 134. 09,135.66,146.93,147.06,147.78,148.10,154.16,154.47,199.36; HRMS- (ESI +) ( C 42 H 57 NO 6 Si-C 5 H ₉ O ₂ (Boc) + H) [M-Boc Calculated value for + H] ⁺ 600.3509, measured value 600.3496.

Method 10 Preparation of (+)-Tetrabenazine 15 by Removal of Boc Protecting Group from First Intermediate 12 and Amino Cyclization

The first intermediate 12 (1.0 eq) was dissolved in 10% Me ₂ S-dichloromethane to obtain an 82 mM solution. The solution was cooled to 0 ° C. and triisopropylsilane (1.1 eq.) Followed by TFA (precooled to 0 ° C.) was added to the reaction mixture to give a final concentration of 41 mM. The reaction mixture was stirred at 0 ° C. for 1 hour. After a predetermined time, the reaction mixture was quenched at 0 ° C. by addition of saturated aqueous potassium carbonate solution and concentrated under reduced pressure to remove most of the dimethyl sulfide. The mixture was extracted with five portions of dichloromethane and the combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give the crude product as a yellow solid. The crude product was recrystallized from 3.5% dimethoxyethane in hexane. The obtained colorless crystals were washed with hexane to obtain pure (+)-tetrabenazine ( 15 ) (46%). mp126.0 ° C. (3.5% DME-hexane) (crystalline polymorph was observed at 116 ° C.); [α] ²⁶ _D +37.2 (c0.41, CH ₂ Cl ₂ ); ¹ H NMR (CD ₂ Cl ₂ ) δ 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 = .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); ¹³ C NMR (CD ₂ Cl ₂ ) δ 21.98, 23.02, 25.51, 29.46, 35.16, 47.47, 47.63, 50. 47, 55.87, 56.01, 61.47, 62.46, 108.46, 111.72, 126.37, 128.96, 147.65, 147.98, 209.72; HRMS- (ESI + _{) (C 19 H 27 NO 3} + H) [M + H] + calculated for 318.2069, found 318.2082.

Method 11 Preparation of (+)-TBZ Compound 16 by Removal of Boc Protecting Group from First Intermediate 13 and Amino Cyclization

The first intermediate starting material 13 (1.0 eq) was dissolved in 10% Me ₂ S-dichloromethane to obtain a 26 mM solution. The solution was cooled to 0 ° C. and triisopropylsilane (1.1 eq.) Followed by TFA (precooled to 0 ° C.) was added to the reaction mixture to give a final concentration of 13 mM. The reaction mixture was stirred at 0 ° C. for 1 hour. After a predetermined time, the reaction mixture was quenched at 0 ° C. by addition of saturated aqueous potassium carbonate solution and concentrated under reduced pressure to remove most of the dimethyl sulfide. The mixture was extracted with five portions of dichloromethane and the combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give an orange oil. Isolated material immediately flash chromatography on SiO ₂ (20~30% EtOAc- hexanes, elution was observed at 285nm and 228 nm) was purified by. The semi-pure product (present as a mixture of diastereomers rich in the desired product) was crystallized from 3.5% dimethoxyethane in hexane over several days. The obtained colorless crystals were washed with hexane to obtain (+)-TBZ compound 16 as a single diastereomer (42%). [Α] ²⁶ _D +40.1 (c 0.63, CH ₂ Cl ₂ ); ¹ H NMR (CD ₂ Cl ₂ ) δ 1.14 (s, 9H), 1.18-1.30 (m, 1H), 1.45 to 1.56 (m, 2H), 1.60 to 1.75 (m, 2H), 1.86 to 1.98 (m, 1H), 2.41 (apparent t, J = 11 .4 Hz, 1H), 2.47 (apparent t, J = 12.6 Hz, 1H), 2.59-2.82 (m, 3H), 2.93 (dd, J = 13.1, 2. 8 Hz, 1 H), 3.06-3.20 (m, 2 H), 3.34 (dd, J = 9.6, 6.1 Hz, 1 H), 3.55 (apparent d, J = 11.6 Hz) , 1H), 3.78 (apparent t, J = 6.3 Hz, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 6.64 (s, 1H), 6. 69 (s, 1H) 7.40-7.53 (m, 6H), 7.70-7.81 (m, 4H); 13 C NMR (CD 2 Cl 2) δ19.14,23.43,25.98,26.74 29.47, 32.77, 47.55, 49.42, 50.44, 55.74, 55.86, 61.06, 62.36, 63.81, 108.31, 111.68, 126 .31,127.68,128.91,129.60,134.15,135.59,147.59,147.90,209.36; HRMS- (ESI +) ( C 35 H 45 NO 4 Si + H) [ Calculated value 572.3196 for M + H] ⁺ , found value 5723187.

Method 12 Preparation of (+)-TBZ Compound 17 by Removal of Boc Protecting Group from First Intermediate 14 and Amino Cyclization

Starting material 14 (1.0 eq) was dissolved in 10% Me ₂ S-dichloromethane to obtain a 176 mM solution of the starting material. The solution was cooled to 0 ° C. and triisopropylsilane (1.1 eq.) Followed by TFA (precooled to 0 ° C.) was added to the reaction mixture to give a final concentration of 88 mM. The reaction mixture was stirred at 0 ° C. for 1 hour. After a predetermined time, the reaction mixture was quenched at 0 ° C. by addition of saturated aqueous potassium carbonate solution and concentrated under reduced pressure to remove most of the dimethyl sulfide. The mixture was extracted with five portions of dichloromethane and the combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give a yellow foam. The crude product was purified by flash chromatography on SiO ₂ (0.2% triethylamine -10% EtOAc-89.8% Hexane 0.2% triethylamine -50% EtOAc-49.8% Hexane, elution 285nm and 228nm Was observed). The product (+)-TBZ compound 17 was a colorless foam (73%) consisting only of the desired diastereomer. ¹ H NMR (CD ₂ Cl ₂ ) δ 0.79 (dd, J = 13.8, 3.8 Hz, 1H), 0.92 (s, 6H), 1.14 (s, 9H), 1.59− 1.72 (m, 2H), 2.27 (dd, J = 13.2, 5.1 Hz, 1H), 2.52-2.65 (m, 2H), 2.68-2.82 (m , 2H), 2.94 (dd, J = 13.0, 3.0 Hz, 1H), 3.06-3.18 (m, 2H), 3.25 (dd, J = 9.8, 6. 3 Hz), 3.55 (dd, J = 11.6, 1.8 Hz, 1H), 3.83-3.88 (m, 8H), 6.65 (s, 1H), 6.69 (s, 1H), 7.44-7.53 (m, 6H), 7.74-7.82 (m, 4H); ¹³ C NMR (CD ₂ Cl ₂ ) δ 19.09, 26.79, 27.10, 29.48, 32.3 36.90, 44.38, 46.02, 47.45, 50.15, 55.77, 55.91, 61.09, 62.53, 63.50, 108.38, 111.75, 126 .30,127.74,128.93,129.67,134.13,135.65,147.66,147.98,208.73; HRMS- (ESI +) ( C 37 H 49 NO 4 Si + H) [ Calculated value 600.3509 for M + H] ⁺ , found 600.3499.

Method 13 Preparation of Diastereomeric Mixtures of Dihydrotetrabenazine Compounds 18 and 19 by Reduction of (+)-Tetrabenazine 15

NaBH ₄ (2.85 eq) was added to a 0.11 M solution in which (+)-TBZ ( 15 ) was dissolved in ethanol at 0 ° C. The reaction mixture was stirred at room temperature for 60 minutes. The solvent was carefully removed under reduced pressure and the residue was dissolved in dichloromethane and washed with 3 portions of saturated aqueous K ₂ CO ₃ . The aqueous washes were back extracted with two portions of dichloromethane. The combined organic extracts were dried (MgSO ₄ ), filtered, and concentrated under reduced pressure to give a colorless oil that crystallized upon standing under high vacuum. Purification of the crude product was achieved by chromatography on SiO ₂ (2.5-5% MeOH—CH ₂ Cl ₂ , elution was observed at 285 nm). The UV active fraction was reanalyzed by TLC. Two products 18 and 19 were isolated by this procedure. The main product 18 was a colorless solid (74%). [Α] ²⁶ _D +48 (c 0.30, CH ₂ Cl ₂ ); ¹ H NMR (CD ₂ Cl ₂ ) δ 0.93 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6 .6 Hz, 3H), 1.04 (ddd, J = 14.6, 8.7, 4.3 Hz, 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 (brs, 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. 4,1 .4,4.5Hz, 1H), 3.80-3.81 (m , 6H), 6.60 (s, 1H), 6.69 (s, 1H); 13 C NMR (CD 2 Cl 2) δ 21.61, 24.02, 25.33, 29.30, 39.68, 40.81, 41.58, 51.83, 55.74, 55.91, 60.02, 60.92, 74. 32,108.42,111.73,126.68,129.76,147.35,147.61; HRMS- (ESI +) ( C 19 H 29 NO 3 + H) [M + H] + calculated for 320.2226 Actual value 320.2242. Byproduct 19 was a yellow oil (4%). ¹ H NMR (CD ₂ Cl ₂ ) δ 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). 07 (apparent d, J = 3.1 Hz, 1H), 6.60 (s, 1H), 6.68 (s, 1H); ¹³ C NMR (CD ₂ Cl ₂ ) δ 22.74, 22.81, 24.87, 2 .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.

General procedure for the preparation of ether compounds derived from DTBZ having structure V A mixture (0.1 M) of DTBZ compound having structure V (1 eq) and NaH (5.0 eq) dissolved in DMF at 60 ° C. Heat for 3 hours. The mixture is cooled to 0 ° C., a suitable alkylating agent (eg, fluoroalkyl tosylate, allyl halide or benzyloxyalkyl tosylate) is added and the mixture is allowed to warm to room temperature (RT). The reaction mixture is then heated at 60 ° C. for 14 hours and cooled to RT. The reaction mixture is quenched by the addition of water and extracted three times with an organic solvent (eg, EtOAc, toluene, diethyl ether). The combined organic extracts are washed sequentially with water and brine, dried over a desiccant (eg, Na ₂ SO ₄ , MgSO ₄ , CaCl ₂ ), filtered and concentrated. By purifying the residue by chromatography, the product ether compound can be obtained.

Method 14 Preparation of 2-fluoroethyl 4-methylbenzenesulfonate 20

Tosyl chloride (6.5 g, 34.1 mmol) was added over 30 minutes to a 0 ° C. solution of 2-fluoroethanol (1.0 g, 15.6 mmol) in pyridine (15 mL). The reaction mixture was stirred at 0 ° C. for 4 h and quenched by the addition of ice cold water and EtOAc. The layers were separated and the organic layer was washed sequentially with water, 1M HCl (5 ×), saturated Na ₂ CO ₃ and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (12 g) using 5-40% EtOAc in hexane as eluent to give fluorotosylate 20 (3.2 g, 95%) as a slightly yellow oil. Obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.83 (d, J = 10.0 Hz, 1 H), 7.38 (d, J = 10.0 Hz, 2 H), 4.59 (dt, J = 50.0 & 5 .0Hz, 2H), 4.28 (dt, J = 30.0 & 5.0Hz, 2H), 2.47 (s, 3H).

Method 15 Preparation of 3-fluoropropyl 4-methylbenzenesulfonate 21

A mixture of 3-chloropropanol (2.5 mL, 30 mmol), KF (3.5 g, 60 mmol) and NaI (50 mg, 0.33 mmol) dissolved in ethylene glycol (10 mL) was attached to a short path distillation condenser. Placed in bottom flask. The mixture was heated at 130 ° C. and the resulting 3-fluoropropanol was collected as a colorless liquid. Tosyl chloride (3.2 g, 16.78 mmol) was added over 30 minutes to a 0 ° C. solution of 3-fluoroethanol (600 mg, 7.68 mmol) in pyridine (8 mL). The reaction mixture was stirred at 0 ° C. for 4 h and quenched by the addition of ice cold water and EtOAc. The product fluorotosylate was purified as described in Method 14 above to give Compound 21 (1.2 g, 67%) as a slightly yellow oil. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.83 (d, J = 10.0 Hz, 1 H), 7.38 (d, J = 10.0 Hz, 2 H), 4.59 (dt, J = 50.0 & 5.0 Hz, 2H), 4.28 (dt, J = 30.0 & 5.0 Hz, 2H), 2.47 (s, 3H).

Example 1 Production of fluorinated ether compound 22

A general procedure for preparing ether compounds derived from DTBZ having structure V was used. That, DTBZ (18) (10mg, 0.031mmol), NaH (4mg, 0.155mmol) and 2-fluoroethyl 4-methylbenzenesulfonate (7 mg, 0.031 mmol) from, CH ₂ Cl ₂ in 1-2% After flash chromatography on silica gel (4 g) using MeOH as the eluent, 3 mg (27%) of the product fluorinated ether compound 22 with the indicated 2R, 3R, 12R absolute stereochemistry was obtained as a yellow solid. It was. ¹ H NMR (500 MHz, CDCl ₃ ) δ 6.69 (s, 1H), 6.61 (s, 1H), 4.65 (t, J = 4.0 Hz, 1H), 4.56 (t, J = 4.0 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.07-3.18 (m, 3H), 3.01-3.04 (m, 1H) 2.59-2.69 (m, 2H), 2.48 (t, J = 9.6 Hz, 1H), 2.01 (t, J =, 1H), 1.93-1.86 (m , 1H), 1.64-1.74 (m, 4H), 1.50 (q, J = 9.0 Hz, 1H), 1.03 (ddd, J = 14.6, 8.7 & 4.). 3 Hz, 1H), 0.95 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H). High resolution mass spectrometry (HRMS) (ESI +) C 21 H 32 FNO 3 [M + H] + Calculated for 366.2444, found 366.2441.

Example 2 Production of fluorinated ether compound 23

A general procedure for preparing ether compounds derived from DTBZ having structure V was used. That is, from DTBZ ( 18 ) (23 mg, 0.072 mmol), NaH (18 mg, 0.72 mmol) and 3-fluoropropyl 4-methylbenzenesulfonate (17 mg, 0.072 mmol), after purification by preparative HPLC, 0.5 mg (2%) of the product fluorinated ether compound 23 having 2R, 3R, 12R absolute stereochemistry was obtained as a yellow solid. _{HRMS (ESI +) C 22 H} 35 FNO 3 [M] + Calculated for 380.2601, found 380.2568.

Method 16 Preparation of benzyloxypropyl DTBZ ether 24

A mixture of DTBZ ( 18 ) (1 eq) and NaH (5.0 eq) dissolved in DMF is heated at 60 ° C. for 3 h. The mixture is then cooled to 0 ° C., treated with 3-benzyloxypropyl tosylate and allowed to warm to room temperature. The reaction mixture is then heated at 60 ° C. for 14 hours and cooled to ambient temperature. The reaction mixture is quenched by the addition of water and the mixture is extracted 3 times with Et ₂ O (3 ×). The combined organic extracts are washed sequentially with water and brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue is purified by chromatography to give a DTBZ ether compound having structure 24 .

Method 17 Preparation of Hydroxypropyl DTBZ Ether 25

A solution of 100 mg of benzyloxypropyl DTBZ ether 24 in ethanol (50 mL) in a Parr bottle is first purged with argon gas and 5 wt% palladium on carbon (Pd / C) (10 mg) is added. The Parr bottle is then attached to the Parr hydrogenator and purged again with argon and then with hydrogen gas. Gently shake the Parr bottle while keeping the hydrogen pressure slightly above atmospheric pressure. The hydrogenolysis mixture is monitored periodically by thin layer chromatography (tlc). When tlc indicates complete removal of the benzyl group, the hydrocracking mixture is filtered through diatomaceous earth and the filtrate is concentrated under reduced pressure on a rotary evaporator to give hydroxypropyl DTBZ ether 25 .

Example 3 Preparation of Fluorophilic DTBZ Ether Tosylate 26

Toluenesulfonyl chloride (tosyl chloride, 1.5 eq) was added to a solution of 3-hydroxypropyl DTBZ ether derivative 25 (50 mg) in pyridine (1 mL) and the mixture was stirred at 0 ° C. and periodically with tlc. Monitor. When tlc shows complete consumption of the starting 3-hydroxypropyl DTBZ ether, the reaction mixture is quenched by the addition of ice cold water and EtOAc. The organic layer is washed sequentially with water, 1M HCl (5 ×), saturated Na ₂ CO ₃ and brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is chromatographed on silica gel to give the fluorinated DTBZ ether tosylate 26 .

Example 4 Production of PET Imaging Agent 27

A Teflon-lined reaction vial housed in a shielded hood and equipped with a nitrogen purge inlet and a magnetic rotating rod was charged with F-18 fluoride ion, potassium carbonate (about 1 mg) and Kryptofix 221 (about 10 mg). About 1 milliliter of an aqueous acetonitrile solution containing The vial is heated to 100 ° C. under a stream of nitrogen to effect azeotropic removal of water. Add additional dry acetonitrile (1 mL) and evaporate. This azeotropic drying protocol is repeated three times. After the final evaporation step, a mixture of dimethylformamide and acetonitrile (about 1 mL) containing DTBZ ether tosylate 26 (2 mg) is added and the vial is sealed. The reaction mixture is heated with stirring at 100 ° C. for 10 minutes and then cooled to room temperature. The product mixture containing the starting tosylate ether 26 and the product F-18 fluorinated ether compound 27 is diluted with water (10 mL) and passed through a Sep-Pak cartridge. The cartridge is then washed with water (3 ×) to remove unreacted fluoride ions and other water soluble components of the product mixture. Radiolabeled fluorinated ether compound 27 and starting tosylate 26 are then eluted from the cartridge with acetonitrile. The majority of acetonitrile is then evaporated and the residue is dissolved in aqueous acetonitrile and subjected to preparative reverse phase HPLC to obtain an aqueous formulation containing PET imaging agent 27 .

Method 18 Preparation of hydroxyethyl DTBZ ether 28

A mixture of DTBZ ( 18 ) (1 eq) and NaH (5.0 eq) dissolved in DMF is heated at 60 ° C. for 3 h. The mixture is then cooled to 0 ° C. and a solution containing ethylene oxide in tetrahydrofuran is added and allowed to warm to room temperature. The reaction mixture is then heated at 60 ° C. for 24 hours and cooled to ambient temperature. The reaction mixture is quenched by the addition of water and the mixture is extracted 3 times with Et ₂ O (3 ×). The combined organic extracts are washed sequentially with water and brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue is purified by chromatography to give a hydroxyethyl DTBZ ether compound having structure 28 .

Example 5 Production of Fluorophilic DTBZ Ether Tosylate 29

Toluenesulfonyl chloride (tosyl chloride, 1.5 eq) was added to a solution of 2-hydroxyethyl DTBZ ether derivative 28 (100 mg) in pyridine (2 mL) and the mixture was stirred at 0 ° C. and periodically with tlc. Monitor. When tlc shows complete consumption of the starting 2-hydroxyethyl DTBZ ether, the reaction mixture is quenched by the addition of ice cold water and EtOAc. The organic layer is washed sequentially with water, 1M HCl (5 ×), saturated Na ₂ CO ₃ and brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is chromatographed on silica gel to give the fluorinated DTBZ ether tosylate 29, which can be further purified by recrystallization.

Example 6 Production of PET Imaging Agent 30

A Teflon-lined reaction vial housed in a shielded hood and equipped with a nitrogen purge inlet and a magnetic rotating rod contains F-18 fluoride ions, potassium carbonate (about 1 mg) and cryptofix 221 (about 10 mg). Add about 1 milliliter of aqueous acetonitrile solution. The vial is heated to 100 ° C. under a stream of nitrogen to effect azeotropic removal of water. Add additional dry acetonitrile (1 mL) and evaporate. This azeotropic drying protocol is repeated three times. After the final evaporation step, a mixture of dimethylformamide and acetonitrile (about 1 mL) containing DTBZ ether tosylate 29 (2 mg) is added and the vial is sealed. The reaction mixture is heated with stirring at 100 ° C. for 10 minutes and then cooled to room temperature. The product mixture containing the starting tosylate ether 29 and the product F-18 fluorinated ether compound 30 is diluted with water (10 mL) and passed through a Sep-Pak cartridge. The cartridge is then washed with water (3 ×) to remove unreacted fluoride ions and other water soluble components of the product mixture. The radiolabeled fluorinated ether compound 30 and starting tosylate 29 are then eluted from the cartridge with acetonitrile. The majority of acetonitrile is then evaporated and the residue is dissolved in aqueous acetonitrile and subjected to preparative reverse phase HPLC to obtain an aqueous formulation containing PET imaging agent 30 .

Method 19 Production of PET Imaging Agent 30 by Alternative Method

A Teflon-lined reaction vial housed in a shielded hood and equipped with a nitrogen purge inlet and a magnetic rotating rod contains F-18 fluoride ions, potassium carbonate (about 1 mg) and cryptofix 221 (about 10 mg). Add about 1 milliliter of aqueous acetonitrile solution. The vial is heated to 100 ° C. under a stream of nitrogen to effect azeotropic removal of water. Add additional dry acetonitrile (1 mL) and evaporate. This azeotropic drying protocol is repeated three times. After the final evaporation step, a mixture of dimethylformamide and acetonitrile (about 1 mL) containing ethylene glycol bistosylate (2 mg) is added and the vial is sealed. The reaction mixture is heated with stirring at 100 ° C. for 10 minutes and then cooled to room temperature. The product mixture containing the starting vistosylate and the product F-18 fluorinated monotosylate is diluted with water (10 mL) and passed through a Sep-Pak cartridge. The cartridge is then washed with water (3 ×) to remove unreacted fluoride ions and other water soluble components of the product mixture. The radiolabeled fluorinated monotosylate and starting bistosylate 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 give purified F-18 fluorinated monotosylate. Purified F-18 fluorinated monotosylate is dried by azeotropic removal of water and acetonitrile. The dried F-18 fluorinated monotosylate is then reacted with about 2 mg of DTBZ sodium salt at 60 ° C. A product mixture containing the radiolabeled fluorinated ether compound 30 and DTBZ sodium salt is quenched with an aqueous ammonium chloride solution and subjected to preparative HPLC, whereby an aqueous preparation containing the PET imaging agent 30 is obtained. Alternatively, F-18 fluorinated monotosylate is described in J. Org. Label. Compd. Radiopharm. 2006, 49: pp 177-195.

Method 20 Alternative Preparation of Hydroxypropyl DTBZ Ether 25

Following the general procedure, DTBZ (18) is reacted with sodium hydride and allyl bromide in dimethylformamide (DMF) to give DTBZ allyl ether 31 as a synthetic intermediate (see method 21 below for structure) Which is purified by column chromatography. The intermediate DTBZ allyl ether is treated overnight with 1/3 equivalent of 1 mol borane (BH ₃ ) in THF in tetrahydrofuran at room temperature. Then 3 equivalents of sodium perborate in a 1: 1 mixture of THF: water is added and the mixture is stirred overnight at room temperature. The reaction mixture is quenched by addition of water and extracted 3 times with Et ₂ O (3 ×). The combined organic extracts are washed sequentially with water and brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue is purified by chromatography to give a 3-hydroxypropyl DTBZ ether compound having structure 25 .

Method 21 Alternative Preparation of Hydroxyethylene DTBZ Ether 28

DTBZ allyl ether 31 (500 mg) is reacted with excess ozone for 1 hour in methylene chloride (CH ₂ Cl ₂ ) at 0 ° C. The reaction mixture is quenched at 0 ° C. by the addition of aqueous sodium borohydride followed by the addition of methanol with an equal volume of methylene chloride. The reaction mixture is allowed to warm to room temperature and methanol and methylene chloride are removed on a rotary evaporator. The crude product is dissolved in ethyl acetate (EtOAc), washed with saturated ammonium chloride solution, water and brine, then dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure to give hydroxyethyl DTBZ ether 28 , which can be purified by chromatography on silica gel.

Example 7 Production of PET Imaging Agent 33

A Teflon-lined reaction vial housed in a shielded hood and equipped with a nitrogen purge inlet and a magnetic rotating rod contains F-18 fluoride ions, potassium carbonate (about 1 mg) and cryptofix 221 (about 10 mg). Add about 1 milliliter of aqueous acetonitrile solution. The vial is heated to 100 ° C. under a stream of nitrogen to effect azeotropic removal of water. Add additional dry acetonitrile (1 mL) and evaporate. This azeotropic drying protocol is repeated three times. After the final evaporation step, a mixture of dimethylformamide and acetonitrile (about 1 mL) containing ether tosylate 32 (2 mg) (prepared as compound 29 ) is added and the vial is sealed. The reaction mixture is heated with stirring at 100 ° C. for 10 minutes and then cooled to room temperature. The product mixture containing the starting tosylate 32 and the product F-18 fluorinated ether compound 33 was then treated with octadecylamine 5 mg and potassium carbonate (2 mg) at 60 ° C. for 5 minutes to give unreacted ether tosylate. The rate is converted to the corresponding octadecylamine 34 . The product mixture is then diluted with water (10 mL) and passed through a Sep-Pak cartridge. The cartridge is then washed with water (3 ×) to remove unreacted fluoride ions and other water soluble components of the product mixture. The radiolabeled fluorinated ether compound 33 and the corresponding octadecylamine adduct 34 are then eluted from the cartridge with acetonitrile. The majority of acetonitrile is then evaporated and the residue is dissolved in aqueous acetonitrile and subjected to preparative reverse phase HPLC to yield purified PET imaging agent 33 .

Example 8 Production of PET Imaging Agent 36

A Teflon-lined reaction vial housed in a shielded hood and equipped with a nitrogen purge inlet and a magnetic rotating rod contains F-18 fluoride ions, potassium carbonate (about 1 mg) and cryptofix 221 (about 10 mg). Add about 1 milliliter of aqueous acetonitrile solution. The vial is heated to 100 ° C. under a stream of nitrogen to effect azeotropic removal of water. Add additional dry acetonitrile (1 mL) and evaporate. This azeotropic drying protocol is repeated three times. After the final evaporation step, a mixture of dimethylformamide and acetonitrile (about 1 mL) containing ether tosylate 35 (2 mg) (prepared as compound 29 ) is added and the vial is sealed. The reaction mixture is heated with stirring at 100 ° C. for 10 minutes and then cooled to room temperature. To the product mixture is added an amount of aminopropyl functionalized silica containing about 10 equivalents of primary amine groups based on the number of moles of starting tosylate 35 . The mixture is warmed to react the aminopropyl functionalized silica with unreacted tosylate 35 and then filtered through a layer of diatomaceous earth. The diatomaceous earth layer is rinsed with additional acetonitrile and the combined column effluent is concentrated to dryness in a sample preparation vial. An aqueous formulation of PET imaging agent 36 is obtained by adding ethanol and water to the vial. An aqueous formulation containing compound 36 is assayed by HPLC using a gamma ray detector capable of detecting fluorine-18 radio decay.

Measurement of Binding Affinity of Fluorinated Ether Compound to VMAT-2 VMAT-2 binding affinity was measured for the fluorinated DTBZ ether compounds 22 and 23 provided by the present invention. Measurement of VMAT-2 binding affinity is performed using the protocol Cat. No. Performed by Novascreen Biosciences Corporation (Hannover, MD) using 100-0751. Novascreen, Inc. Is a commercial provider of biological assays for the pharmaceutical industry. The binding affinity data is shown in Table 9 below, which shows that the fluorinated ether compounds of the present invention (compounds 22 and 23 ) have a very high binding affinity compared to the DTBZ control (Comparative Example 1). Illustrated. The data obtained for the fluorinated ether compounds 22 and 23 show that the substitution of the hydroxyl group at ring position 2 with a fluoroaliphatic group (this is an uncertainty that occurs whenever the biologically active molecule hydrogen is replaced with fluorine). Is a structural change that combines changes in the size and lipophilicity of the group at the ring position 2 of DTBZ). In addition, the binding constant Ki expressed in nanomolar (nM) concentration units represents the very high affinity of the fluorinated ether compounds of the present invention for the VMAT-2 biomarker.

  The above examples are exemplary only and serve to illustrate only some features of the invention. The following claims are intended to claim the invention to the fullest extent possible, and the examples set forth herein illustrate embodiments selected from a wide variety of all possible embodiments. ing. Accordingly, it is Applicants' intention that the appended claims should not be limited by the choice of examples utilized to illustrate features of the present invention. The term “including” and its grammatical variants used in the claims is logically defined in various ways, such as, but not limited to, “consisting essentially of” and “consisting of” It also includes words with different ranges. Ranges are indicated where necessary, but these ranges include all subranges contained therein. Variations within these ranges will be obvious to those skilled in the art, and it should be understood that these variations are covered by the appended claims if possible, even if not yet published. In addition, scientific and technological advances are expected to allow equivalents and substitutions not currently envisaged due to language inaccuracies. It should be understood that it is covered by the claims.

Claims (10)

An enantiomerically enriched fluorinated ether compound comprising a main component enantiomer having the structure II:
(Wherein R ¹ is a C _2-6 fluoroalkyl group containing a fluorine-18 atom , R ² is isobutyl , and R ³ and R ⁴ are methoxy groups .) Having the following Structures IV, a compound according to claim 1.
(In the formulas, Me Ri methyl der, F is including fluorine-18 atom.) Having the following structure The compound of claim 1, wherein.
(In the formulas, Me Ri methyl der, F is including fluorine-18 atom.) A salt of the compound according to any one of claims 1 to 3 . A pharmaceutical preparation comprising the compound according to any one of claims 1 to 4 and a pharmaceutically acceptable excipient. 5. A compound according to any one of claims 1 to 4 for use in medicine. The compound or a salt thereof according to any one of claims 1 to 4 , for use in the detection of VMAT-2 in a subject or an in vivo diagnosis or imaging method for a QVMAT-2-related disease. An enantiomerically enriched fluorophilic compound comprising a main component enantiomer having the following structure VII:
Wherein R ¹ is a C ₂ -C ₂₀ aliphatic group or aromatic group containing a functional group that reacts with a nucleophilic fluoride ion to form a C _2-6 fluoroalkyl group, Is selected from the group consisting of aliphatic sulfonic acid ester groups and aromatic sulfonic acid ester groups, R ² is isobutyl , and R ³ and R ⁴ are methoxy groups .) 9. The enantiomerically enriched fluorophilic compound of claim 8 , comprising at least 80 mol% of the enantiomer having structure VII. 9. The enantiomerically enriched fluorophilic compound of claim 8 , comprising at least 95 mol% of the enantiomer having structure VII.