(12) United States Patent
`Gano
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 8,039,627 B2
`Oct. 18, 2011
`
`USOO8039627B2
`
`(54) SUBSTITUTED
`3-ISOBUTYL-9,10-DIMETHOXY-1,3,4,6,7,11B
`HEXAHYDRO-zn-PYRIDO[2,1
`A]ISOQUINOLIN-2-OL COMPOUNDS AND
`METHODS RELATING THERETO
`
`(75) Inventor: Kyle W. Gano, San Diego, CA (US)
`
`(73) Assignee: Neurocrine Biosciences, Inc., San
`Diego, CA (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 698 days.
`
`(21) App1.No.: 11/937,445
`
`(22) Filed:
`
`Nov. 8, 2007
`
`(65)
`
`Prior Publication Data
`
`US 2008/0167337 A1
`
`Jul. 10, 2008
`
`Related US. Application Data
`
`(60) Provisional application No. 60/864,944, ?led on Nov.
`8, 2006.
`
`(51) Int. Cl.
`(2006.01)
`C07D 455/06
`(2006.01)
`A01N 43/42
`(52) US. Cl. ........................................ .. 546/95; 514/294
`(58) Field of Classi?cation Search .................. .. 546/95;
`5 14/294
`See application ?le for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`2,843,591 A
`7/1958 Brossiet al.
`2,852,518 A
`9/1958 Morgan
`3,209,005 A
`9/1965 Brossiet al.
`2003/0087803 A1
`5/2003 Latvin et a1.
`
`FOREIGN PATENT DOCUMENTS
`W091/16920 A1
`11/1991
`WO
`WO99/30561 A1
`6/1999
`WO
`WO W02005/077946 A1
`8/2005
`WO W02006/053067 A2
`5/2006
`WO W02007/005283 A2
`1/2007
`WO W02007/007105 A1
`1/2007
`WO
`W02007/017643 A1
`2/2007
`WO W02007/017654 A1
`2/2007
`
`OTHER PUBLICATIONS
`
`Pletscher, A. et a1, Benzoquinolizine Derivatives: A New Class of
`Monoamine Decreasing Drugs with Psychotropic Action, Interna
`tional Review of Neurobiology, 1962, 275-306.
`SchwarZ, D. E. et a1, Metabolice Studies of TetrabenaZine, A
`Psychotropic Drug in Animals and Man, Biochemical Pharmacology,
`1966, 645-655, 15.
`Pritsch, L. E. et a1, On the Pharmacology of a Benzoquinolizine
`Derivative: R0-1284, Prarmacology 1969, 113-123, 2.
`Mehvar, R. et a1, Direct Injection High-Performance Liquid Chro
`matography 0f Tetrabenazine and Its Metabolite in Plasma of
`Humans and Rats, Journal of Pharmaceutical Sciences, 1986, 1006
`1009, 75(10).
`Mehvar, R. et a1, Pharmacokinetics of Tetrabenazine and Is Major
`Metabolite in Man and Rat, Drug Metabolism and Disposition, 1987,
`250-255, 15(2).
`Aranda, G. et a1, Synthesis and biological activity of iodinated and
`photosensitive derivatives of tetrabenazine, European Journal of
`Medicinal Chemistry, 1990, 369-374, 25.
`Kilborn, M. et a1, Binding of alpha-dihydrotetrabenazine t0 the
`vesicular monoamine transporter is stereospeci?c, European Journal
`of Pharmacology, 1995, 249-252, 278.
`Lee, L. C., In Vitro and In Vivo Studies of Benzisoquinoline Ligands
`for the Brain Synaptic Vesicle Monoamine Transporter, Journal of
`Medicinal Chemistry, 1996, 191-196, 39.
`Kilborn, M.R. et a1, Absolute Con?guration of (+)-alpha
`Dihyrdotertabenazine, an Active Metabolite 0f Tetrabenazine.
`Chirality, 1997, 59-62, 9.
`Vig, B. S. et a1, Amino Acid Ester Prodrugs ofFloxuridine: Synthesis
`and Effects of Structure, Stereochemistry, and Site of Esteri?cation
`0n the Rate of Hydrolysis, 2003, 1381-1388, 20(9). Kim, I. et al, A
`Novel Nucleo side Prodrug-Activating Enzyme: Substrate Speci?city
`ofBiphenyl Hydrolase-like Protein, Molecular Pharmaceutics, 2004,
`117-127,1(2).
`Song, X., et a1, Amino Acid Ester Prodrugs 0f the Anticancer Agent
`Gemcitabine: Synthesis, Bioconversion, Metabolic Bioevasion, and
`hPEPTl-Mediated Transport, Molecular Pharmaceutics, 2005, 157
`167, 2(2).
`
`(Continued)
`
`Primary Examiner * Nizal Chandrakumar
`(74) Attorney, Agent, or Firm * Seed IP Law Group PLLC
`
`ABSTRACT
`(57)
`3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b
`Substituted
`hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol compounds are
`disclosed that are inhibitors of the vesicular monoamine
`transporter 2 (VMAT2). The compounds of this invention
`have the structure:
`
`Aranda et al. European Journal of Medicinal Chemistry, 25, 369-374,
`1990*
`Kilbourn et al. Chirality, 9, 59062, 1997.*
`Vig et a1. Pharmaceutical Research, 20 (9), 1381-1388, 2003*
`Cho et al., Annual Reports in Medicinal chemistry, 41, 395-407,
`2006*
`Communication pursuant to Article 94(3) (Form 2906) in EP App.
`No. 078641602 mailed Aug. 13, 2009.
`Stock, A. M. et a1, Structure and Tautomerism 0f the Esters of Several
`beta-Substituted Pyruvic Acids, Journal of Organic Chemistry, 1958,
`1840-1848, 23.
`Brossi, A. et a1, 2-Hydroxy-hydr0benzo[a]chin01iZine, Helvetica
`Chimica Acta1958, 1793-1806, 41.
`
`ORl
`
`wherein R1 is as de?ned herein, including stereoisomers and
`pharmaceutically acceptable salts and solvates thereof. Also
`disclosed are compositions containing a compound of this
`invention in combination with a pharmaceutically acceptable
`carrier, as well as methods relating to the use in a subject in
`need thereof.
`
`2 Claims, 3 Drawing Sheets
`
`Apotex Ex. 1007
`
`Apotex v. Auspex
`IPR2021-01507
`
`

`

`US 8,039,627 B2
`Page 2
`
`OTHER PUBLICATIONS
`Lorenzl, P. L. et a1, Amino Acid Ester Prodrugs of 2-Bromo-5,6
`dichloro-l-(beta-D-ribofuranosyl)benZimidazole Enhance Meta
`bolic Stability in Vitro and in Vivo, The Journal of Pharmacology and
`Experimental Therapeutics, 2005, 883-890, 314(2).
`Zheng, G. et al, Vesicular Monoamine Transporter 2: Role as a Novel
`Target for Drug Development, The AAPS Journal, 2006, 682-692,
`8(4).
`
`Cho, A., Recent Advances in Oral Prodrug Discovery, Annual
`Reports in Medicinal Chemistry, 2006, 395-407, 41.
`Zheng, F. et a1, Computational neural network analysis of the af?nity
`of lobeline and tetrabenaZine analogs for the vesicular monoamine
`transporter-2, Bioorganic and Medicinal Chemistry, 2007, 2975
`2992, 15.
`
`* cited by examiner
`
`Apotex Ex. 1007
`
`

`

`US. Patent
`
`0a. 18, 2011
`
`Sheet 1 013
`
`US 8,039,627 B2
`
`g 1.00
`3/
`2 0.50
`O
`u
`
`0.00
`
`Figure la
`
`TBZ in Human Hepatocytes (n=12
`+ TBZ
`+ HTBZ
`
`I
`
`0
`
`.
`20
`
`l
`40
`
`i
`60
`
`Time (min)
`
`Figure lb
`2-1 in Human Hepatocytes (n=3)
`
`+ 1d.1
`+ 2-1
`
`2 1000 '
`E
`5
`o- 500
`8
`o
`
`0
`
`Tlrne (min)
`
`Figure 10
`
`3-1 in Human Hepatocytes (n=12)
`
`—l
`
`+34
`+ ld.l
`—-l
`
`0
`
`I
`
`20
`
`1
`
`40
`
`9
`
`60
`
`Time (min)
`
`g 100
`3
`2 0150
`Q
`0
`
`0.00
`
`Apotex Ex. 1007
`
`

`

`US. Patent
`
`0a. 18, 2011
`
`Sheet 2 0f 3
`
`US 8,039,627 B2
`
`Figure 2a (rat)
`
`Figure 2b (rat)
`
`2.00 W
`A
`
`d 1.00
`o
`o
`
`3-1
`
`+101
`34
`+
`
`A 1.201
`E
`
`0'
`8 0.40
`0
`
`21
`
`+1d-1
`+ 2-1
`
`
`
`' ' ' 0
`
`
`
`. 20
`
`40
`
`Time (min)
`
`
`
`“‘"? 60 80
`
`
`
`
`
`Qm 0
`
`20
`
`40
`
`60
`
`80
`
`Time (min)
`
`Figure 20 (dog)
`
`Figure 2d (dog)
`
`I
`
`A 200 -
`v l
`g 1-00
`O ]
`
`3-1
`
`+101
`
`+34
`
`1.20 1
`
`24
`
`+1d-1
`2-1
`+
`
`g M
`a, 0.80
`‘5’ 0.40
`O
`
`000 ._ '
`0
`
`l
`20
`
`‘
`40
`Time (min)
`
`I
`60
`
`I
`80
`
`0.00
`
`0
`
`20
`
`40
`Time (min)
`
`,--——-?
`60
`80
`
`Figure 2e (human)
`
`Figure 2f (human)
`
`31
`
`175
`+3“
`
`2.1
`
`+1d.1
`1.201
`+24
`A
`2
`30.80 H\"\.\_
`d
`g 0.40
`
`g 2.00
`a
`g 100
`Q
`
`0,00
`
`0
`
`20
`
`40
`
`_
`_
`Tlme (mm)
`
`-% Q
`0.00 Tr° °
`60
`80
`
`0
`
`?
`
`20
`
`1 4
`1
`T
`
`1
`
`40
`Time
`
`60
`
`so
`
`Apotex Ex. 1007
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`

`

`US. Patent
`
`0a. 18, 2011
`
`Sheet 3 0f 3
`
`US 8,039,627 B2
`
`Figure 3a
`Plasma Concentration-Time Pro?le of
`10 mg/kg P0 of 3-] and IQ mg/kg P0
`of ld.| 10 male rals (N=3)
`
`10000
`+1d.1 @10mg/kg 3-1 PO
`---1d.1@10mg/kg1d.1PO
`
`1000
`
`
`
`
`
`Plasma (ng/ml) conc.
`
`Figure 3b
`Plasma Concentration-Time Pro?le
`of 10 mg/kg P0 of 2-1 to Male Rats
`(N=3)
`
`100
`
`+1d.1 @ 10mg/kg 2-1 PO
`+2-1 @10mglkg 2-1 PO
`
`
`
`
`
`Plasma conc. (ng/ml) 10
`
`l
`\
`NM. ‘__
`
`XA ' W
`
`10.
`
`.
`
`0 1
`
`.
`
`.
`
`.
`
`.
`
`v
`
`.
`
`2 3 4 5 6 7 8 9
`Time (hr)
`
`100
`
`1C
`0
`
`Figure 3c
`Plasma Concentration-Time Pro?le
`of 6.] mg/kg P0 of 3-1 to Male
`Dogs (N=3)
`
`Figure 3d
`Plasma Concentration-Ti me Pro?le
`of 10 mg/kg P0 of 2-1 to Male Dogs
`(N=3)
`
`0000
`1
`
`10000
`+3-1@6.1mg/kg 3-1PO
`-—1d.1@6.1mg/kg 3-1PO
`
`.4 O O
`
`
`
`
`
`Plasma (ng/ml) 8 Q conc.
`
`10
`
`10
`Time (hr)
`
`1000 +2-1@10mglkg PO
`-'—1d.1 from 2-1@10 mg/kg PO
`
`
`
`
`
`Plasma cone. (ng/ml)
`
`100
`
`1O
`
`1
`
`12
`
`2'4
`Time (hr)
`
`48
`
`Apotex Ex. 1007
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`

`

`US 8,039,627 B2
`
`1
`SUBSTITUTED
`3-ISOBUTYL-9,10-DIMETHOXY-1,3,4,6,7,11B
`HEXAHYDRO-ZH-PYRIDO[2,1
`A] ISOQUINOLIN-z-OL COMPOUNDS AND
`METHODS RELATING THERETO
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`This application claims the bene?t of US. Provisional
`Patent Application No. 60/864,944 ?led Nov. 8, 2006, which
`application is incorporated herein by reference in its entirety.
`
`FIELD OF THE INVENTION
`
`This invention relates generally to substituted 3-isobutyl
`9, l 0-dimethoxy- l ,3,4,6,7,1 lb-hexahydro-2H-pyrido[2, l -a]
`isoquinolin-2-ol compounds, their preparation and to meth
`ods of treating disorders by administration of such
`compounds to a warm-blooded animal in need thereof.
`
`BACKGROUND OF THE INVENTION
`
`3-Isobutyl-9,lO-dimethoxy-l,3,4,6,7,l lb-hexahydro-2H
`pyrido[2, l -a]isoquinolin-2-one, also known as tetrabenaZine
`(TBZ), has been used as a drug for decades. TetrabenaZine is
`a potent, reversible inhibitor of catecholamine uptake by
`vesicular monoamine transporter-2 (VMAT2) (IC50:3.2
`nM) (Scherman, et al, Proc. Natl. Acad. Sci. USA, (1983)
`80:584-8) and is currently used in the treatment of various
`hyperkinetic movement disorders. Side effects associated
`with TBZ include sedation, depression, akathi sia, and parkin
`sonism. Inhibition of VMAT2 by TBZ results in depletion of
`brain monoamines in vivo (Pettibone, D. J. et al., Eur. J.
`Pharmacol. (1984) 1021431-6). TBZ also inhibits presynaptic
`and postsynaptic dopamine receptors in rat brain (Login, I. S.,
`et al., (1982) Ann. Neurology 121257-62; Reches, et al, J.
`Pharmacol. Exp. Ther. (1983) 225:515-521). This off-target
`activity of TBZ may be responsible for some of the observed
`side effects.
`TBZ, which contains two chiral centers and is a racemic
`mix of two stereoisomers, is rapidly and extensively metabo
`lized in vivo to its reduced form, 3-isobutyl-9, l 0-dimethoxy
`l,3,4,6,7,l lb-hexahydro-2H-pyrido[2,l-a]isoquinolin-2-ol,
`also known as dihydrotetrabenaZine (HTBZ). HTBZ is
`thought to exist as four individual isomers: (1) alpha-HTBZ
`and (1) beta-HTBZ. The 2R, 3R, lle or (+) alpha-HTBZ is
`believed to be the ab solute con?guration of the active metabo
`lite (Chirality 1997 9:59-62). Despite its success in treating
`hyperkinetic disorders, tetrabenaZine has a fairly low and
`variable bioavailability. TetrabenaZine administration to
`humans is complicated by extensive ?rst pass metabolism and
`little or no tetrabenaZine is observed in the urine.
`There is a need in the art for analogs of tetrabenaZine that
`provide the advantageous properties of tetrabenaZine without
`exposing the body to all of stereoisomers of dihydrotetra
`benaZine. There is also a need for analogs of tetrabenaZine
`that exhibit a longer half-life than tetrabenaZine. There is
`likewise a need in the art for analogs of tetrabenaZine that
`exhibit greater selectivity forVMAT2 than tetrabenaZine. The
`present invention provides a tetrabenaZine analog that
`exposes the body to a single stereoisomer of dihydrotetra
`benaZine, exhibits greater selectivity for VMAT2 than tetra
`benaZine, exhibits a longer half-life than tetrabenaZine, and
`may exhibit lower variability in dose required from patient to
`patient.
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`BRIEF SUMMARY OF THE INVENTION
`
`In brief, this invention is generally directed to substituted
`3-isobutyl-9, l 0-dimethoxy- l ,3,4,6,7,1 lb-hexahydro-2H
`pyrido[2, l -a]isoquinolin-2-ol compounds, individual enanti
`omers thereof, as well as to methods for their preparation and
`use, and to pharmaceutical compositions containing the
`same. More speci?cally, the substituted 3-isobutyl-9,10
`dimethoxy-l ,3,4,6,7, l lb-hexahydro-2H-pyrido[2, l -a]iso
`quinolin-2-ol compounds of this invention have the following
`general structure (I):
`
`(I)
`
`ORl
`
`including stereoisomers and pharmaceutically acceptable
`salts and solvates thereof, wherein R1 is as de?ned below.
`The substituted 3-isobutyl-9,lO-dimethoxy-l ,3,4,6,7, 1 lb
`hexahydro-2H-pyrido[2,l-a]isoquinolin-2-ol compounds of
`this invention have utility over a wide range of therapeutic
`applications, and may be used to treat a variety of disorders
`including the family of hyperkinetic movement disorders.
`Additionally these compounds may prove useful in the treat
`ment of other disease states or conditions which are associ
`ated with inhibition of the vesicular monoamine transporter 2
`(V MAT2).
`The methods of this invention include administering an
`effective amount of a substituted 3-isobutyl-9, lO-dimethoxy
`l,3,4,6,7,l lb-hexahydro-2H-pyrido[2,l-a]isoquinolin-2-ol,
`preferably in the form of a pharmaceutical composition, to a
`mammal in need thereof. Thus, in still a further embodiment,
`pharmaceutical compositions are disclosed containing one or
`more substituted 3-isobutyl-9,lO-dimethoxy-l,3,4,6,7,l lb -
`hexahydro-2H-pyrido[2,l-a]isoquinolin-2-ol compounds of
`this invention in combination with a pharmaceutically accept
`able carrier and/or diluent.
`These and other aspects of the invention will be apparent
`upon reference to the following detailed description. To this
`end, various references are set forth herein which describe in
`more detail certain background information, procedures,
`compounds and/ or compositions, and are each hereby incor
`porated by reference in their entirety.
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`FIGS. 1a, 1b, and lc comprise three graphs showing the
`conversion of tetrabenaZine, compound 2-1 and compound
`3-1 to their respective metabolites in human hepatocytes.
`FIGS. 2a-2f comprise six graphs showing the stability pro
`?le of compounds 3-1 and 2-1 in rat, dog and human liver
`microsomes.
`FIGS. 3a-3d comprise four graphs showing the pharmaco
`kinetic properties of compounds 2-1 and 3-1 in dogs and rats
`and of ld.l in the rat.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`As mentioned above, the present invention is directed gen
`erally to substituted 3-isobutyl-9, l 0-dimethoxy- l ,3,4,6,7,
`
`Apotex Ex. 1007
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`

`US 8,039,627 B2
`
`3
`com
`l lb-hexahydro-2H-pyrido[2, l -a]isoquinolin-2-ol
`pounds. The compounds of this invention have the following
`structure (I):
`
`4
`In an embodiment, R1 of structure (I) is 4C(:O)O-alkyl
`as shown in structure (II) and in another embodiment, R1 of
`structure (I) is iC(:O)4C1_6alkanediyl -NH2 as shown in
`structure (III).
`
`(I)
`
`and stereoisomers, pharmaceutically acceptable salts and sol
`vates thereof,
`wherein:
`R1 is
`
`20
`
`(11)
`
`(111)
`
`O
`
`0
`
`In an embodiment, the 4Cl_6alkanediyl-NH2 of structure
`(III) is (S)- l -amino-2-methyl-propan- l -yl as shown in struc
`ture (IV). Structure (V) shows an embodiment of structure (I)
`where R1 is 4C(:O)iCl_6alkanediyl-NH2 and the C l_6al
`kanediyl is substituted with 4COOH.
`
`(1V)
`
`0/ \0 if O
`
`..
`
`NH2
`
`(V)
`
`COZH
`
`In additional embodiments, R1 of structure (I) is an amino
`acid residue as shown in structure (VI). Structure (VII) shows
`an embodiment of structure (VI) where the amino acid resi
`due is valine.
`
`25
`
`30
`
`35
`
`40
`
`45
`
`b) 4C(:O)4Cl_6alkanediyl-NH2,
`wherein said Cl_6alkanediyl is optionally substituted with a
`group selected from iNH4C(:NH)NH2, 4CO2H,
`iCO2Me, iSH, %(O)NH2, iNHz, iSCH3, phenyl,
`iOH, 4-hydroxy-phenyl, imidazolyl and indolyl.
`As used herein, the above terms have the following mean
`ing:
`“Alkyl” means a straight chain or branched, noncyclic or
`cyclic, unsaturated or saturated aliphatic hydrocarbon con
`taining from 1 to 10 carbon atoms, while the term “C 1_ 4alkyl”
`has the same meaning as alkyl but contains from 1 to 4 carbon
`atoms. “C1_6alkyl” has the same meaning as alkyl but con
`tains from 1 to 6 carbon atoms. Representative saturated
`straight chain alkyls include methyl, ethyl, n-propyl, n-butyl,
`n-pentyl, n-hexyl, and the like; while saturated branched
`alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, iso
`pentyl, and the like. Representative saturated cyclic alkyls
`include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
`iCHZ-cyclopropyl, 4CH2-cyclobutyl, iCHz-cyclopentyl,
`iCHz-cyclohexyl, and the like; while unsaturated cyclic
`alkyls include cyclopentenyl and cyclohexenyl, and the like.
`Cyclic alkyls include di- and poly-homocyclic rings such as
`decalin and adamantyl. Unsaturated alkyls contain at least
`one double or triple bond between adjacent carbon atoms
`(referred to as an “alkenyl” or “alkynyl”, respectively). Rep
`resentative straight chain and branched alkenyls include eth
`ylenyl, propylenyl, l-butenyl, 2-butenyl, isobutylenyl, l-pen
`tenyl, 2-pentenyl, 3-methyl-l-butenyl, 2-methyl-2-butenyl,
`2,3-dimethyl-2-butenyl, and the like; while representative
`straight chain and branched alkynyls include acetylenyl, pro
`pynyl, l-butynyl, 2-butynyl, l-pentynyl, 2-pentynyl, 3-me
`thyl-l butynyl, and the like.
`‘Cl_6alkanediyl” means a divalent Cl_6alkyl from which
`two hydrogen atoms are taken from the same carbon atom or
`from different carbon atoms, such as 4CH2i,
`iCHZCHzi, iCH(CH3)i iCHZCHzCHZi, %H
`(CH3)CH2CH2i, %H2C(CH3)2CH2i, and the like.
`“Amino acidresidue” means an amino acid structure which
`lacks the hydroxyl of the (x-carboxyl group. For example the
`alanine residue is iC(:O)4CH(NH2)CH3.
`
`50
`
`55
`
`60
`
`65
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`Apotex Ex. 1007
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`

`5
`
`US 8,039,627 B2
`
`6
`compounds of structure (I) above may be made by the fol
`lowing reaction schemes, wherein all substituents are as
`de?ned above unless indicated otherwise.
`
`(V1)
`
`0
`/
`
`\O
`
`0 /
`
`\O
`
`/O
`
`\O
`
`amino acid residue
`
`(VII)
`
`N
`
`0
`
`N
`
`ReactimlSchemel
`
`N
`
`O
`
`/O
`
`NaBH4
`—>
`MeOH, It
`
`N
`
`OH
`
`3.
`
`Reduction of a racemic mix of R,R and 8,8 tetrabenaZine
`with a borohydride reducing agent gives dihydrotetrabena
`Zine a. When the reducing agent is lithium tri-sec-butyl boro
`hydride (L-Selectride), predominantly the 2S, 3R, 11bR and
`2R, 3S, 11bS isomers are generated. Use of sodium borohy
`dride results in a mix of all 4 stereoisomers. The remaining
`stereoisomers may be synthesized by taking any or all of the
`previously generated stereoisomers and reacting them with a
`dehydrating agent such as phosphorous pentachloride to form
`the unsaturated compound which is then stereoselectively
`rehydrated by, for instance, a hydroboration procedure using
`borane-THF to form a borane complex which is oxidized to
`the appropriate dihydrotetrabenaZine with hydrogen perox
`ide (Clarke et al., WO2005077946). The racemic products
`can be further separated by chiral chromatography into the
`individual enantiomers by chiral chromatography.
`
`O—valine
`
`In an embodiment, compounds of the present invention
`may exist as the racemic mixture, as a diastereomeric pair or
`as the individual enantiomer or mix of enantiomers. Structure
`(VIII) shows the ring numbering for the substituted 3-isobu
`tyl-9, 1 O-dimethoxy- 1 ,3,4, 6,7,1 1b-hexahydro-2H-pyrido [2,
`1-a]isoquinolin-2-ol compounds of the invention. Stereo
`centers are located at the 2, 3, and 11b positions of the ring
`system. Compounds of the present invention include the 2R,
`3R, 11bR con?guration as well as the 2R, 3R, 11bS, the 2R,
`3S, 11bR, the 2S, 3R, 11bR, the 2R, 3S, 11bS, the 2S, 3R,
`11bS, the 2S, 3S, 11bR, and the 2S, 3S, 11bS. The 2R, 3R,
`11bR and 28, 3S, 11bS enantiomers are shown in structures
`(IX) and (X), respectively.
`
`(VIII)
`
`20
`
`25
`
`30
`
`35
`
`40
`
`Ollllll Z"
`
`45
`
`(1X)
`
`O /
`
`\O
`
`50
`
`(X)
`
`55
`
`60
`
`O /
`
`\
`O
`
`ReactionSchemeZ
`
`N
`
`OH
`
`a
`
`N
`
`0
`
`Cl
`
`I
`triphos gene
`
`CHZCIZ, rt
`
`alkyl-OH
`DMAP
`
`—>
`
`The compounds of the present invention may be prepared
`by known organic synthesis techniques, including the meth
`ods described in more detail in the Examples. In general, the
`
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`US 8,039,627 B2
`
`7
`-continued
`/0
`
`The chloroformate intermediate c may be generated by
`treating a with phosgene or triphosgene. Treatment of c with
`an alcohol in the presence of a base such as DMAP generates
`the carbonate product d. Alternatively, the carbonate d can be
`generated directly by treating the alcohol a with a pyrocar
`bonate under DMAP catalysis.
`
`20
`
`ReactionSchemel
`
`—>
`
`1) EDCI, DMAP
`2) TFAJCHZCIZ
`
`8
`times per day, certain compounds of this invention, such as,
`for example, compound 2-1, may be therapeutically effective
`when administered only once per day. Thus, because of the
`unexpectedly longer duration of action afforded by these
`compounds, once daily dosing may be attainable.
`Compounds of the present invention include the following
`esters:
`3-isobutyl-9,10
`acid
`(S)-2 -Amino-3-methyl-butyric
`dimethoxy- l ,3,4,6,7,l lb-hexahydro-ZH-pyrido[2, l -a]
`isoquinolin-2-yl ester
`Compounds of the present invention include the following
`carbonates:
`Carbonic acid ethyl ester 3-isobutyl-9, lO-dimethoxy- 1 ,3,4,6,
`7,1 lb-hexahydro-2H-pyrido[2,l-a]isoquinolin-2-yl ester;
`Carbonic acid butyl ester 3 -isobutyl-9, l O-dimethoxy- l ,3 ,4,6,
`7,1 lb-hexahydro-2H-pyrido[2,l-a]isoquinolin-2-yl ester;
`Carbonic acid pentyl ester 3-isobutyl-9, lO-dimethoxy-l ,3,4,
`6,7,1lb-hexahydro-2H-pyrido[2,l-a]isoquinolin-2-yl
`ester;
`Carbonic acid isobutyl ester 3-isobutyl-9, lO-dimethoxy-l ,3,
`4,6,7, 1 lb-hexahydro-2H-pyrido[2, l -a]isoquinolin-2-yl
`ester;
`Carbonic acid sec-butyl ester 3-isobutyl-9,lO-dimethoxy-l,
`3,4,6,7,1lb-hexahydro-ZH-pyrido[2,l-a]isoquinolin-2-yl
`ester;
`Carbonic acid 3-methyl-butyl ester 3-isobutyl-9,10
`dimethoxy- l ,3,4,6,7,l lb-hexahydro-ZH-pyrido[2, l -a]
`isoquinolin-2-yl ester; and
`Carbonic acid tert-butyl ester 3-isobutyl-9,lO-dimethoxy-l,
`3,4,6,7,1lb-hexahydro-ZH-pyrido[2,l-a]isoquinolin-2-yl
`ester.
`The compounds of the present invention may generally be
`utilized as the free acid or free base. Alternatively, the com
`pounds of this invention may be used in the form of acid or
`base addition salts. Acid addition salts of the free amino
`compounds of the present invention may be prepared by
`methods well known in the art, and may be formed from
`organic and inorganic acids. Suitable organic acids include
`maleic, fumaric, benzoic, ascorbic, succinic, methane
`sulfonic, acetic, tri?uoroacetic, oxalic, propionic, tartaric,
`salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspar
`tic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic
`acids. Suitable inorganic acids include hydrochloric, hydro
`bromic, sulfuric, phosphoric, and nitric acids. Base addition
`salts included those salts that form with the carboxylate anion
`and include salts formed with organic and inorganic cations
`such as those chosen from the alkali and alkaline earth metals
`(for example, lithium, sodium, potassium, magnesium,
`barium and calcium), as well as the ammonium ion and sub
`stituted derivatives thereof (for example, dibenzylammo
`nium, benzylammonium, 2-hydroxyethylammonium, and
`the like). Thus, the term “pharmaceutically acceptable salt” of
`structure (I) is intended to encompass any and all acceptable
`salt forms.
`With regard to stereoisomers, the compounds of structure
`(I) may have chiral centers and may occur as racemates,
`racemic mixtures and as individual enantiomers or diastere
`omers. All such isomeric forms are included within the
`present invention, including mixtures thereof. Furthermore,
`some of the crystalline forms of the compounds of structure
`(I) may exist as polymorphs, which are included in the present
`invention. In addition, some of the compounds of structure (I)
`may also form solvates with water or other organic solvents.
`Such solvates are similarly included within the scope of this
`invention.
`As mentioned above, the compounds of this invention and
`their salts may reduce the supply of monoamines in the cen
`
`o /
`
`\O
`
`N
`
`OH
`
`3.
`
`o /
`
`\O
`
`N
`
`o T O
`
`6
`
`DihydrotetrabenaZine a is condensed with a BOC pro
`tected amino acid using l-(3 -dimethylaminopropyl)-3 -ethyl
`carbodiimide hydrochloride (EDCI) and dimethylaminopy
`ridine (DMAP) in dimethylforrnamide and methylene
`chloride, followed by deprotection of the BOC functionality
`with, for instance, a 50/50 tri?uoroacetic acid/methylene
`chloride solution to give e. Alternatively, dihydrotetrabena
`Zine a may be condensed with a CBZ-protected amino acid
`using DCC (l,3-dicyclohexylcarbodiimide) followed by
`deprotection of the CBZ functionality by hydrogenation
`under appropriate conditions.
`Compounds of the present invention exhibit greater selec
`tivity for VMAT2 than tetrabenaZine. As a result, they may
`provide desirable properties of tetrabenaZine without all of
`the undesirable side effects. In addition, as shown in FIGS.
`3a-3d, certain compounds of this invention, such as, for
`example, compound 2-1, unexpectedly provide a longer dura
`tion of action than tetrabenaZine. This may be particularly
`bene?cial because it may allow an administration regimen
`that requires fewer doses per day than tetrabenaZine. For
`example, while tetrabenaZine is typically administered 2-3
`
`45
`
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`
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`
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`
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`US 8,039,627 B2
`
`tral nervous system by inhibiting the human monoamine
`transporter isoforrn 2 (VMAT2). As such, these compounds
`and their salts may have utility over a Wide range of thera
`peutic applications, and may be used to treat a variety of
`disorders Which are caused by or linked to inhibition of the
`human monoamine transporter isoform 2. These disorders
`include hyperkinetic disorders.
`In an embodiment, conditions Which may be treated by
`compounds of the current invention include, but are not lim
`ited to, treatment of hyperkinetic disorders such as Hunting
`ton’s disease, tardive dyskinesia, Tourette’s syndrome, and
`tics.
`In another embodiment of the invention, the compounds of
`this invention and their salts may be hydrolyzed in the body of
`a mammal to compounds that may inhibit the human
`monoamine transporter isoform 2. As such, these compounds
`and their salts may have additional utility in altering the in
`vivo properties of the metabolite in a mammal such as the
`maximum concentration or duration of action.
`In another embodiment of the invention, pharmaceutical
`compositions containing one or more monoamine re-uptake
`inhibitors are disclosed. For the purposes of administration,
`the compounds of the present invention may be formulated as
`pharmaceutical compositions. Pharmaceutical compositions
`of the present invention comprise a monoamine re-uptake
`inhibitor of the present invention and a pharmaceutically
`acceptable carrier and/or diluent. The VMAT2 inhibitor is
`present in the composition in an amount Which is effective to
`treat a particular disorderithat is, in an amount suf?cient to
`reduce the supply of monoamines in the central nervous sys
`tem, and preferably With acceptable toxicity to the patient.
`Appropriate concentrations and dosages can be readily deter
`mined by one skilled in the art.
`Pharrnaceutically acceptable carriers and/or diluents are
`familiar to those skilled in the art. For compositions formu
`lated as liquid solutions, acceptable carriers and/or diluents
`include saline and sterile water, and may optionally include
`antioxidants, buffers, bacteriostats and other common addi
`tives. The compositions can also be formulated as pills, cap
`sules, granules, or tablets Which contain, in addition to a
`VMAT2 inhibitor, diluents, dispersing and surface active
`agents, binders, and lubricants. One skilled in this art may
`further formulate the VMAT2 inhibitor in an appropriate
`manner, and in accordance With accepted practices, such as
`those disclosed in Remington ’s Pharmaceutical Sciences,
`Gennaro, Ed., Mack Publishing Co., Easton, Pa. 1990.
`In another embodiment, the present invention provides a
`method for treating disorders of the central or peripheral
`nervous system. Such methods include administering a com
`pound of the present invention to a warm-blooded animal in
`an amount suf?cient to treat the condition. In this context,
`“treat” includes prophylactic administration. Such methods
`include systemic administration of aVMAT2 inhibitor of this
`invention, preferably in the form of a pharmaceutical compo
`sition as discussed above. As used herein, systemic adminis
`tration includes oral and parenteral methods of administra
`tion. For oral administration, suitable pharmaceutical
`compositions include powders, granules, pills, tablets, and
`capsules as well as liquids, syrups, suspensions, and emul
`sions. These compositions may also include ?avorants, pre
`servatives, suspending, thickening and emulsifying agents,
`and other pharmaceutically acceptable additives. For parental
`administration, the compounds of the present invention can
`be prepared in aqueous injection solutions Which may con
`tain, in addition to the VMAT2 inhibitor, buffers, antioxi
`dants, bacterio stats, and other additives commonly employed
`in such solutions.
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`10
`EXAMPLES
`
`HPLC Methods for AnalyZing the Samples
`Retention time, t R, in minutes
`Analytical HPLC-MS Method 1
`Platform: Agilent 1 100 series: equipped With an auto-sam
`pler, an UV detector (220 nM and 254 nM), a MS detector
`(APCI);
`HPLC column: Phenomenex Synergi-Max RP 80A, 2.0x
`50 mm column;
`HPLC gradient: 1.0 mL/minute, from 10% acetonitrile in
`water to 90% acetonitrile in water in 2.5 minutes, maintaining
`90% for 1 minute. Both acetonitrile and water have 0.025%
`TFA.
`Analytical HPLC-MS Method 2
`Platform: Agilent 1 100 series: equipped With an auto-sam
`pler, an UV detector (220 nM and 254 nM), a MS detector
`(APCI);
`HPLC column: Phenomenex Synergi-Max RP 80A, 2.0x
`50 mm column;
`HPLC gradient: 1.0 mL/minute, from 5% acetonitrile in
`water to 95% acetonitrile in water in 13.5 minutes, maintain
`ing 95% for 2 minute. Both acetonitrile and water have
`0.025% TFA.
`Analytical HPLC-MS Method 3
`Platform: Gilson 215 Auto-sampler, Dionex Thermostat
`ted Column Compartment TCC-100 held at 30° C., Dionex
`PDA-100 Photodiode Array Detector (220 nm and 254 nm),
`Dionex P680 HPLC pump, Thermo Finnigan MSQ single
`quad Mass Spectrometer (APCI)
`HPLC column: Phenomenex Gemini 5p. C18 110A, 4.6><
`150 mm
`HPLC gradient: 2.5 mL/min, from 5% acetonitrile in water
`to 90% acetonitrile in water in 9.86 minutes, from 90% aceto
`nitrile in water to 95% acetonitrile in water in 0.1 minutes,
`hold at 95% for 1.19 minutes. Both acetonitrile and water
`have 0.04% NH4OH.
`Analytical HPLC-MS Method 4
`Platform: Gilson 215 Auto-sampler, Dionex Thermostat
`ted Column Compartment TCC-100 held at 30° C., Dionex
`PDA-100 Photodiode Array Detector (220 nm and 254 nm),
`Dionex P680 HPLC pump, Thermo Finnigan MSQ single
`quad Mass Spectrometer (APCI)
`HPLC column: Phenomenex Gemini 5p. C18 110A, 3.0x
`150 mm
`HPLC gradient: 1.5 mL/min, from 5% acetonitrile in water
`to 90% acetonitrile in water in 9.86 minutes, from 90% aceto
`nitrile in water to 95% acetonitrile in water in 0.1 minutes,
`hold at 95% for 1.19 minutes. Both acetonitrile and water
`have 0.04% NH4OH
`Chiral Supercritical Fluid Chromatography for Chiral Sepa
`ration Method 1
`Platform: Berger Multigram II SFC
`Autochem
`Column: Chiralcel OD-H, 2.1><25 cm, SFC column
`Modi?er: 20% methanol
`Flow rate: 60 mL/min
`Pressure: 100 bar
`Oven temperature: 35° C.
`Loading: approximately 14 mg/inj ection (methanol)
`Chiral Supercritical Fluid Chromatography for Chiral Sepa
`ration Method 2
`
`system from
`
`Apotex Ex. 1007
`
`

`

`US 8,039,627 B2
`
`system from
`
`11
`Platform: Berger Multigram 11 SEC
`Autochem
`Column: chiralpak AS-H, 2.l><25 cm, SEC column
`Modi?er: 20% methanol
`Flow rate: 60 mL/min
`Pressure: 100 bar
`Oven Temperature: 35° C.
`Loading: 40 mg/injection (MeOH)
`Chiral Supercritical Fluid Chromatography for Chiral Sepa
`ration Method 3
`Column: Chiralpak IA, 2.l><25 cm, SEC column
`Modi?er: 28% (Methanol/Acetone:7:3)
`Flow rate: 55 mL/min
`Pressure: 100 bar
`Oven Temperature: 35° C.
`Loading: 50 mg/injection
`The sample was dissolved in 1:1 mixture of Methanol/
`Acetone. The ?nal concentration was 50 mg/mL.
`
`EXAMPLE 1
`
`(2R,3R,11bR)-3 -isobutyl-9,10-dimethoxy-1,3,4,6,7,
`1 1b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol
`((2R,3R, 1 1bR)-dihydrotetrabenaZine)
`
`Step 1A: 3-Dimethylaminomethyl-5-methyl-hexan-2 -one
`Dimethylamine HCl (90 g, 1.1 mol), 5-methyl-2-hexanone
`(450 mL, 3.3 mol), and paraformaldehyde (50 g, 1.7 mol)
`were suspended in MeOH (80 mL) and concentrated HCl
`(200 uL) was added. The reaction mixture was heated to 80°
`C. for 12 hours. The mixture was allowed to cool to room
`temperature and 10% NaOH was added until basic. The entire
`mixture was extracted with Et2O (100 mL, 2><). The organic
`layer was dried over MgSO4 and concentrated. The crude
`reaction mixture was columned via ?ash column chromatog
`raphy (0.5:9.5 MeOH:CH2C12) to give 30 g (175 mmol) of
`3-dimethylamino