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United States Patent
i 10)
Munoz et al.
(45)
1541 llYDROXYBE.'IlZOATE SALTS OF
META.'IlICOTr"E COMPOU~DS
(is',
Inventors:
Julio A. Munoz, Walnut Cove. NC (US):
John Genus. Winston-Salem. NC (US):
James R. Moore, Newark, DE (US)
(~:;)
.\ssig.nce:
Targaccpt,
Inc., Winston·Salem.
NC
(US)
( .)
Notice:
Ill)
AppJ. No,: 111270,018
Subject to any disclaimer, the term afthis
patent is e),,1ended or adjusted under 35
USe. 154(b) by 274 days,
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ABSTRACT
Patients susccptibie 10 or suftering from conuitious aDd ci,orders, such as ccntral nervous sy,tem disorders, arc trcake!
by :Idministering to n patiem in need thereof compositini1s
thaI are hydroxybenzoate salts of [-metanicoline-type
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tanicotine compounds is also useful in purifying the E-mclanicotine compounds, as the hydroxybenzoate
salts lend 10
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compounds, and compounds where the double bond h,lS
migrated. in solution, If desired, the hydroxybenzoatc sailS
('ail be convened
to either the free base (the E-metar,icolinc)
or to another phamlliceutically acceptable salt fom],
Vernier et ~~.
Dull
2000. vol. !1'7. pp
11' 7001273213, Daiicbi Sciyal:u Co,
Acheson. R \1, et aL. .. rransfc'rmations invoh ing the Pyrrolidine
Ring of '\icoiinC:' J Gem, Sac.. 1: ';79·';85 (1980\.
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1'1989
12'1992
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7,1992
4/1994
A2
WO
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"'"'''',,,'''
of Classification
0297858
0516409Bl
2295387
WO 92. 12122
WO 94.;08992
WO 9921S14
WO
5l4'349
PATENT DOCUJvlENTS
WO
\\'0
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(2006,01 )
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10loo5
2 '2002
5,2002
42003
3'2004
4/2004
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FOREIGN
E1'
US 7,459,469 B2
Patent No.:
Date of Patent:
6,958,399
2002'0016460
2002'0052497
200Y0069272
2004'0044023
2004'0067974
2005'0203 130
2006012:238
2006'0 I59768
2007.0265314
11111111
2 Claims,
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Drawings
US 7A59,469 B2
Pag.e 2
OTHER PUBLICATIONS
Harsing.
LG .. .Ir.. et a1.. "Dopamine
Cnronic
Arncric.
peutic
$ .. et al.. "Choiinergic
stralegy
channel
for .-\lzheimer's
Exp. Opin. lm"CSl. Drug.\.
disease."
Hayes.
5Ur ~9·IOO (:996)
Americ.
S ..
C{
Alzheimer's
Pharmacology
Chlll1nel Activalm
of A13T-4 18: A Proto·
for the Potential
Pyridyl,l-L4-dihydropyridine
Pharm.
Analgesic
Xicotinic
Acetykh(>-
.·\ctivity by Sel"ctive \1()dulation of :\curonal
line Rccep10rs." Sciellce. 279: 77-81 (1998).
T. Roc
Bencherif.
\1.. an<1 J.D. Schmitt.
A Path to Xcw 'Therapies:'
"Targeting
l':euronal
M ..
Sclecti\'ity
I In \'itro Characterization,"
pemiC5. 279(3):
1413-1421
RF .. "Reductive
Borch.
hrioDi. .rD.
(1
Ch,tnne1
with Sodium
with C,S
Expel'. The~a-
and \"01'e1
.\1odulai('r~.M Adv. Phllrm,,{"()!.. 37: 153·214
S.X..
ai.
('I
"5·{?\-Oxya/1l)-7-substituled·!A-
d;hydIOquinoxalllle·2.3-diones:
Broad SpecUlnn
1\o\'el.
.\m<tgonists
ale R¢ccpl'.>rs." J .\fed.
Systemically
for \"MDA:glycine.
Ci/<'>II1.. 40(22):
(K,; and the Concentration
C0nstanr
Ceni
(1,..)
inhihition
(,f
an
ofInhibiror"'ruch
2~(23). 3{)99-:~lO~ (1973).
i< .. et 31.. "Sex Differences
in Clwliner!;ic
'0 PCI
BioclwlIl
j»)Ul/""'l.u.'(J.
(,hiari.
SlIrrkmenlal
.,iologl.
\iCC'lini, \1echanism
,) i(~):i44: -145~ (1999).
DL..
C·Jnuns.
Direct"d
and \1.0
Killpack.
by n-Amino
in "onnal
"Lithiation
I: ..\
Analges'"
( i990j.
F. el aLl..
Dlillackef.
Xc;iw:fol'"ch .. :;4b: 172')-ji,6
Dilmaj. er aL "-\nalgesic
[jnie AgoDisl."
-\clivily of\1elanic01ine.
Sociely.f..r,r :Velllv.H·ience,
\-t!. el al.. "Antinocieepl
\1ctanic:>lillc.
a Selcclive
ive and Ph;mnacological
Nicotinic
Effects of
L,I'.
riler .. 291(1 1:390-:;% (1999.1
P.
D"cina.
\:r al.. "Cq!a1L1re
P:llkins .. nism:·
Dubey,
Smoking
BIOi. hy,hicmy.
and
indiul!
(,Iwm
1
..
~~l-~_~.~ (19;NJ.
!.lwoSkiD, L.P .. et :11.. "ReLent
dt,velopmenls
acetylcholine
v
,,,,,ept(!r antagonists.
in neuronal
niLOlinie
Lrp. Opill. l1Jer. Palell/.l.
lO( 10 ,.
! '-r, \·1 -'Xl (2000i
hank. W.c.. et a!.. "PaliaJium-Catai)-7edVinylic
Substitution
RellClions \lith lletcrocyclic
Hromides:'
.I. Org U/CIT/.. 43( 1.'1 2947·
2')49 (1971\).
hissen
...
\.E.
Intramolecular
Diels-Alder
Reactions.
1'"
of p)Tilllldines
Svnthesis
(>f .\nndated
Tr.7!'ail~dr(J/I.45(3j: 803-812 (19R9.i
Pyridines:'
(jibson.
et al.. "Ring·Transfonmtions
S .. et a1.. "Principle
.-\Cli\'ities and \·1olecular
Components
Diversity
Descrihing
of Heterocyclic
Bio\ogical
Aromatic
Rinc:
J. Med. Olem .• 39: 4065-407: (1996).
Grc(·o. C\" .. and !.\i. Hunsberger. "Synthesis
of Some Substituted
P;Tidylsydnonc,:'
J !J(,/cl'ocyclic Cltelll .. 7: 761-'66 (197(J).
Hall. G.n .. and D.M. '1umer. "Efiecb of \'i"orin~ un th~ Release (,j"
';)J-"oradrenaline
from the Hypothalamus:'
Biochcflllcd Plranno::%g;". 21. UQ9- I ~3~ 119'72).
Ha.mon. \1"."?\cllrophatmat'Olo~'y
of anxiety perspectives and PF)Sp,-cts." liPS 15 3(,-19 (1994).
I'rltgments:'
,4(36)
5,77·5780
Carboxylic
~ew
HOllloallyl
Re<:eptors
4169-4194
Acid
Esters
COD\'enient
and
Acce~s
to
l.eller".
1i.'lrcJledT'OIl
A!coh0is:'
(1993).
A. .. et al .. "Synthesis
Organopalladium
Chemistry.
i SJ-lcaralcn0ne."}
()rg
of B·Resorcylie
Application
Chcm,
\1acmlides
the 'Iotal
10
56: 288.1-2894
via
Synthesis
of
(1991)
V .. and S Schna1ter('r. "Chemisiry of3-i1ydrox;:pyridine
Part
2. Symhcsis of 5.6 -Dihalo-3-hydroxypyridines:'
.~1'I1iiJe"is.499-50 I
'1'.. el al.
Kubo:;.
i\lcohois
trom
"Facile
Klihkr.
-rC.
Synlhesis
Tritllloroacetald~hyde
drOll !.el1el"\. 3~(!O1
of" ex-Tritlllolomethvl;tled
Ethyl
r;rahe-
Hemiacelal.'·
135\·1:;,41199:',
el ai.. "StJlIC!w·e-Acri\·ir.y
En .... lhe
pyle'l i
Preparation
tivcs ,)fp)'ridine:'
JAm.
La\·and'homme.
P.
Rciatic>nshlP (If Omepfli/olc
t: .-ease
'md Properties
.I. M("d.
lnhibilo":'
of"Sollle \,C\\. Deril'a-
c.'hem. Soc .. '0 2477-24:0;3 (19:'~).
and lC
Eisenach.
Ana1g.csia II: Dif1ering
"Sex
.'vfecharlisms
Ditrerences
in
in Two ModeL
01
Alle.Ili1e.<iulogl·.
91('): 1455·1461 ( !99'i).
E.D .. and .-\.H. Rez\'ani. ""Icotinielreatment
for Cognitive
Dysfimction."
CWTe.'ll Drug fargezs: C;\,S alia Seurological Disorders. 1(4): 423-431 (2002i.
.
c"s
l.ippiello.
P.\1. el al.. "RJR·2403:
A :\icolinic Agonist with
Sclecti\'ity II. In Vivo Characterilat.ion."
J. Phal'll/awl. Exp. ])'el' ..
2"'9(,') 1422-1429 (199(')
h.. and S Kober. ('ltelli. Ber .. ~" 3431·343:'-; !,I909.1
l.()ftkr.
8: Spc..:tia of ~-:\IJ...-·yl· l\
n-BfPrro<>alkyl-l H-imid.ii/olb)ryndin~·s:'
ltiB(6)"
\eurokpti,-lnJuceJ
2X(6): S02-S0X (1'190).
P.R., .uld C \" KalJ1am. "Syntn~is
I'hm·nracol.,
Arch
Lel'in,
266.9
.i. Pharmacal.
Agonist:'
in Ral
.-\liodynia:'
A Selecri,",' "i<:o-
:;9<;71
Damaj.
Pcrfilloro
,,-PeIlluoroalkylated
Chulinergic
(1979)
23: 669 AbstraC!
from
Hydride.
LaForge.
of\kthoxypyndwes
J. Org Ci/e!'/. . '5( 1) 69-~3
Alkoxides:'
Deri\'ed
;,nd ,\na!c'gu,-"s as lIclic"bactcr
(hem., 38: 4906-4916 (l995i.
Allesihe·
r~maks."
'H-5-
Receptors
, 19(0).
the Inhihiti(>n
Causes
Reaction."
Synthetized
hoch.
iI99~).
Bet"ecn
Enzymatic
and
,'.MPA. and "-ain·
3679-368('
Cheng. \. C .. and WHo PIlI>olf. "Relalionship
Acti\"(,
;\'al/l1)'II-Scltmiedebl'rgs
Diisohutylaluminum
Kali_relenos,
! :99~1
Cai.
of:\ewly
and Musnlfinic
1431-1432
Hughe5 . .T., "S 40 ~icoline and ?\europsychiatric
Disorders," Session
6. in lnterllariollal Symposium on Xicorine: The E!Tects ofNicotilleon
Biological Systems 1/, (BirkhiiuserVerlag
Publi~hers, 1994).
Ishihara. 1., ct al., "Zinc Bromide Promoted Allylatin of Aluminum
Acctals
Cyanoborohydride:
0f (--i-\'Icmine
of the Release
21:
(I (93).
Org Syn., 52: 124-127 (1974).
al. "The Phannaeology
Collision-
(1997).
Nicotinic
Agonist
J. Pharmd:ol.
from
Hoyer, D .. and H.W.G.M. Boddeke. "PaniaJ agonists. full agonists.
antagonists:
dilemmas
of definition:'
nps Review", 14: 270-275
(1996).
Amination
'-'. "--Dimethykyclohexyl."
Cholinergic
\"icotinic
of Dibydrogen
Ions in the Gas Phase. A.Jl Ab initio and
hy Nicotinic
Slices."
J
.
.
Holladay. M. W.. et al .. "!\ellronal ~icotinic Acetylcholine
as '!argets for Drug Discovery," 1. Med. Cltem .. 40(26):
Current Drug Tar~ets. [(4):
A
el al .. "RJR-2403:
"Conlfol
After
2\16: 91-9, (1977).
(2002)
Bcncherif.
F., et aL.
Striatum
Desensitizarion:'
.7. Chelll. Soc. Commull ..
Study:'
Hypothalamic
eil"m .. 41: 729-741 (1976).
Receptors:
Effect
"Elimination
~egative
HydJo.\)1rypta.mine
Buli.
!\on-Opioid
.-\!koxide
Isotope
(984).
Hery.
Calcium Anlagc>of 4-(SlIbstirllred
Olem.
Derivatives."
AW .. et al .. "Broad-Spectnun.
349-357
of
(1990)
'1'('1:;: 2446-2451'
Balkowski.
Treatment
eNS D11lg Rev., 1(1): 1-26 ( ]')95).
Disease."
.\shimori.
A .. ct al .. "1\o\'d 1.4-Dihydrop:ndine
nist"
I. Symhesis and Hypotensive
Activity
Bannon.
R.?\' .. et aL
actil'ated
a!.. "Preclinical
Iypical Cholinergic
from
Evidence
for AUloreceot.or
i'ieu.rochem .. 59( I): 4g-54 (19921.'
as a novel ther,,·
modulators
Effiux
~cotine:
".F.
\olalei.. \..1 .. and
01"(
innarnyia.mi.nes:'.J.
\1oonnann.
"j'alladium-(
'"t:tlv/ed S\'nlhes"
(jrg Chern .. ~-;: 5~9)-';;~~)"'7 :19S2).~
.\1ichae\. T. ('I al.. SyntheSIS of Functional,zed
Cyclopenranes.
Cydohexanes
and Cyclohepranes
by a Silicon-induced
Domine'
Reacl iOIl. Licbigs .41111 .. I J; J X! l-lt21
Y..
\lorisawll.
aI..
ct
4-Deoxypyridoxol
1:~-,-1281 (197')
\'icmine
R"vcf'es
MJ .. el aI .• "The Role OfSellf('I1al
in Acme lInd Chronic
7mgels.
C\'S aJld ."·iL1irulugh"I
Paulder.
W.W.
Synthesis
and T-K Chen.
of 1.2.4-Triazine~
cr-rJt"'ydi{' Chem ..
7·
Age-Associ;ued
and Al1xi\:ly in Ra1s." Life 5cienccs.
.
193-202 (199:\ I.
R"ceplors
~icotinic
A.cer\'kholine
\'eurodeg~neration:'
lJi.wrder.<. 1(4).199-411
1.2.4-TrialinC5.
and their Covalent
C/IJ'I~entDmg
(2002 I..
III A Convenient
.. J Hei-
Hydration
:0-"7-7!'I n9iO).
O.F.. et al.. "The Effects (lfCJ!~aret1~ Smoking
and Anxiety." Addictive Beltaviol".\. 'I: 265-~~ I (1984).
Pomerleau.
Pullan.
Colitis:'
R.D .. et al. ''Transdcrmal
_"'ell
oJ
'-Position
.
E.S .. el al. "Chronic
incrcases in 'I ail-Flick l.atency
O·\'eiil.
at
A:.;r Bioi. O"'m .. ,9(6:
and f,·'·\'orp}1ido.wl:'
Onai<'i,
5~(3):
(j9%1
"Modification
Ellglalld
\'icotine
for Active
J. M<.>d.. 3,0( 121 Sll-Sl5
0994:,
('11
Pain
Ukerallve
LS 7,459,469 B2
Page 3
Rapier. ct aL. "Slerooselectivc
Sicotine-Induced
Release of
Dopamine from Striatal Synaprosomes: Concentration Dependence
and Repetitive Stimulation." J Xellrochem., 50(4): i ID-I DO
(19SSI.
Rondahl.
L.. "Synthetic analogues of nicotine \"1." ACTe
Pharmaceutica Sueciea, 14(2): 113-118 (1977).
Rowell. P.P. and Donald L 'WInkler. "~icotinic Stimulalion of f 11]
Acetylcholine
Release
from
Mouse
Cerebral
Cortical
SynaplOsomes." .J Neurodlem .. 43(6): 1593-1598 (19M).
Sanherg. P.R.. el al .. "\"icotine Potentiation of Haloperidol-Induced
CaUllcpsy: Striatal '-1echanisms:' Pharlllacol. Biochem. & Behavior.
4(" 303-,07 (IW3J.
Sandor. \1.1.. el al. "Effect of nicotine on dopamincrgic-cholincrglC
interaction in the striatum:' Brain Res .. 567: 313-316 (1991).
Sjak-Shie. \" \ .. and E.\1 Meyer. "Effects of chronic nicotine and
pilocarpine administration on neocortocal neuronal density and
3
1 1J1GABA uplake in nucleus basalis lesionedrats:'
Brail! Res .• 624:
295-298 (1993).
Schmlt1. J.D .• and Merouane Bencherif. "Chapter 5. Targeting \'icc'tinic Acetylcholine Receptors: Advances in Molecular Design and
Therapies." AnI!. RC'p. Afed. ChC'm., 35: 41-51 (2000),
Taylor. Fe. et al.. "Intramolecular Diels-Alder Reactions of 1.2.4Triazines. A General Synthesis of Furo[2.3-Q]Pyridines.
2,3Dihydro-pyranof2.3-Q]J»Tidines,
and Pyrrolo[2.3-b]J»'fidines,"
TeTrahedron. 43(21): 5145-5158 (1987).
·l<>lh. F .. el •.1 .. "Fffeci of ~icoti.ne of E:\1racellular l.evels of
1\eur"IJaIlsmiilers
Assessed by !\1icmdialysis in Various Brain
Regic'ns Role of Glutamic Acid." NC'Urochem. Res .. 1;(3): 265-270
(; 99.~).
Trip"'hi. !.j L.. ct a1.. "1\icotine-IndIKedAnrinc'eiception
of RJ.ls Rnd
\lh:e Correlation with :\icolinc Brain Lcvels:' J Pharmacal. Exp
71,('/".221(1) 91-96(1'182!
\·Iau.-i. \1C. et al, "SJnUlesis of 6-SlIhsuluted 2-Phenyloxaz<iI(.j45-b]pyridines:'
He1e',()'~1ell's. 41(12). 2799-2g09 (1995)\·i7i. F.S ..".-\celylcholine re!e;L<;efrom guincl!-pig ileum byparasymI'arr.etlc ganglion srimlllallls and gastrin-like poIYflCptides." BI J.
Phi2'-m{;[' .. 'fi 7(i5-777 (IY~3).
Wagner. H.. el a!.. "[)(,es Smoking Reduce the Risk of \ellrolepltc'
l'iulins,m,)i,L,·'." Pharmllcapsychial.,
21: 302-303 (I%X,IWillmms, \1.. eI aL, "\ellfOn:t1 \icolinic Acetylcholine Receptors:'
I)n,g .\",., p,·,·sf'cc .. ~(4). 205-223 (1994).
Yoshikawa.. T., et al.. "Synthesis of 3-PyridinoIs II Reaction ',if
4·\'1ethyl()~az()Je with Dienophiles" Chem. Pharm. Bull. 13(7): X7.'·
XiX rl9651
l'oln,al Inlernari"nal Se,lfch Report (I'('T1;S2005 '0406'iO . dated
Va) 5. ~O()61
de Costa et aI.. "Synthesis and biological evaluation of conformationally restricted 2-( l-pyrrolidinyJ)-\" -[2 -(3 .4-dichlorophenyl )ethyl]\-metlrylelhylenediam
ines as sigma receptor ligands. 1. J»TfOlidine,
piperidine. homopiperidine.
and tetrahydroisoquinoline
classes," J
rnec Chern (1992\ 35(23):4334-4343.
Koller et aI., "The Preparation of Substituted HydroxyphenyIpyridyl-ethanols and -l1ydro:\'yphenyl--methylpyridineethanols
by
the Condensation of 2- ..3-. or 4-Picolyllithium ""ith Select Hydroxybenzaldehydes and 4-Hydroxyacefophenone."
Synthetic COHununications U995) 25(19):2963-2974.
:\otice o[Allov.-ance daled Apr. 8.2008 cited in copending 1..' .S. Appl.
\0 IL270.753.
\otice of copending applications.
Bastin et al.. "Salt selection and optimization for pharmaceutical new
chemical entitie.s." Organic Process Research and Developmenl
(2000) 4(5)427-435.
Habennan "Nicotinic receptor agonist~ for treat ing diseases of cognitive dysfunction:' Spectnun (2007) pp. 1t-I 1011-19.
Lel'in et aI.. "Nicotine-haloperidoal
interactions and cognitive perfonnance in schiwphrenics."
NeW'opsychopharmacology
(1996)
15(5)430-436.
Geerts "Ispronicline Targacept:' Current Opinion in Investigational
DllIgs (2006) 7(1).60-69.
Buccafusco "Neuronal nicntinic receplor subtypes: defining therapetnic targels:' \lolecliJar Interventions (2(04) 4 (5):285-295.
InlemationaJ Search Report (pcr CS2005t140650
dated Aug. 29.
2(06)
Int;~rnational Se,!J'ch Report rPCT'l.:S2005'040588
.' dated Ocr. 10.
20()6)
Hen,'g. IUD., et al.. "The Reactivity of Bromine Atoms in
Bwminatc-o Pyridlnes:" Reel. Trm·: Chin! Pa):I'-Ba.\, 67(7:X): .,,7737'} (194~).
Bihliographic prinlolll hom DL...LO,j rc;car.:h
sponding 10 Japane>c Pal "i(, ;00E7}2)
wmp.-my (.corre-
killk2wa
et "I.. ··..\typical
anlip>y~h('IIC dru!!s. queliapin,·.
i1operidone. ;m<1meiperone. preleremially in(re~_,e dopamine and
i1(~ry1cholirlc relea,e in ral medial prefronlal COI1<:.": role ot" 5-1IT i.\
!C"(CplOf
ag.oni~m:· Brain Res~arch (2002) Y5(j.349<~57.
Sh('emaker et al. "Quetiapine produces a prolonged reversal of the
scnsOlimotor galing-dis11lptive eJk'Cts of basolalcml amygdala
lesions in rats:' BehaviNaJ \'eul'Oscience (200}) 1170):136-143.
lnternalional Search Repolt dated Sep. ~. 2008 for International
AppliGllion \"('. pcr 1.;S07'~8466
• cited
1:>y examiner
CS 7.459.469 B2
1
2
HYDROXYBE!\ZOATE SALTS OF
:\ITTA..'\ICOn'\'E COMPOU~DS
have therapeutic propenies. See. for example, Bencherif and
Schmitt. Current Drug Targels: CVS and Neurological Disorders 1(4): 349-357 (2002), Levin and Rezvani. Current
Drug Targets: CII.'S and Neurological Disorders 1(4): 423431 (2002). O'Neill, et aI., Current Drug Targets: CNS and
]":eurologicul Disorders 1(4): 399-41 I (2002). U.S. Pat. Nos.
5.187.1 66to Kikuchi et al .. 5.672.601 to CignareIla, PeT \\'0
99'2 1834 and PCT WO 97/40049, UK l'atentApplication GB
2295387 and European Patent Application 297,858.
eNS disorders 3re a type of neurological disorder. CNS
disorders can be drug-induced; can be attributed to genetic
predisposition. infection or trauma: or can be of unknown
etiology. eNS disorders comprise neuropsychiatric disorders. neumlogical disl,ases, and mental illnesses. ,md include
neurodegenenllive diseases, behavioral disorders, cognitive
disorders. and cognitive affective disorders. There are severdl
CNS disorders whose clinical manifestations have b(:en
attributed to CNS dysfunction (i.e., disorders resulting. from
inappropriate levels of neurotransmitter release, inappropriate properties ofneurotransminer
receptors, and/or inappropriate intemclion between neurotmnsmilters and neurotransmitter receptors). Several eNS disorders can be attributed to
a deficiency 0f acetylcholine. dopamine. norepinephrine.
and/or serotonin.
Relatively common CNS disorders include pre-senile
dementia (early-onset Alzheimer's disease), senile dementia
I dementia of the .\!Lheimer·s type). micro-infarct dementia.
\IDS-rdated dementia, vascular dementia. Crcutzfdd-Jakob
disease. Pick's disease. Parkinsonism including Parkinson' s
disease, Ltwy body dementia. prog.ressive supranuckar
pal sy. Huntington's chorea. tardiw dyskinesia. hyperkinesia.
epilepsy, mania. allemion deficit disorder, anxiety. dyslexia.
schizophrenia. depression, \)bsessive-compulsive disorders.
<Iudlourene's syudmme.
Subtypes l,f n:\ChRs arc preselli ill both the central and
pc:.ipheral nerVOllSsystems ..hutlhe distribution of sub[~'pes is
heterogeneous. For instance, the sUhtypes which are predominant in vel1ehrate brain arc u4B2. u7. and 0.3B2.
whereas those which predominate llt the autonomic ganglia
arc u3f)4 and those of n<:uromuscular jWlction are 0.1 ~ I?I)'
and (111110E (see j()r instance Dwoskin et al., ElIJ. Opin. 771('1:
l'menJs 10: 1561 (2000): and Schmitt and Bencherif Annual
Reporl.i in Med. Chem. 35: 41 (2000)).
A.limitation of some nicotinic compounds is that they elicit
various wldcsirable pharnlacolog..ical effects because ('ftheir
interactinl1 with n.\CbRs in peripheral tissues (fur example.
by ,timulating musclt' and ganglionic n.-\( ~hR suhtypes). it is
:herdi)[c desirable 10 have compounds. compositions, and
!1ldhods hir preventing andior treating various cunditions l)r
disurders (e.g .. CNS disorders). including. alleviating the
s\'mptoms of these disorders. where the compounds exhibit
Ilicl"inic ph,U1llaco]ogy with a benefici,lle1Tecl l1l1the CNS
n.-\ChR.s (e.g., upon the functioning ofL'Je eNS l. hut without
signiflcant associated elJl."'Cts on the peripheral n:\CbRs
(compounds specitic 1\)r CNS nAChRs). It is also highly
desirable to have compoundS. compo'itions. and methods
that affect CNS function without significantly aflL"'Ctingthose
receptor subtypes which have the potcutial 10 induce undeslrdble side effects (e.g., appreciable activit)' at cardio\ascu,
1ar and skeletal musc!c siles).
Method:; for treating and/or preventing the above-dc;.cribeJ conditions anu disorders by administering E·metanicmine compounds. particularly those which maximi/e the
cfkx:t on eNS nrnction with0Ul sigl:.ificamiy affecting those
f(.'ceptor subtypes which havc the potential to i.ndUCl' unde·
sirdhle side effects, have been described in the a.1 Represenwtive [-Illetanicotine compounds for use in treating andior
This application claims benefit ofD.S. Provisional Patent
Application No. 60/626.751. filed Nov. 10,2004. the contents
of which are fully incorporated herein by re1erence.
FIELD OF THE INVENTION
Tbe present i.nvention relates to processes for preparing 1"
nicotinic compounds 3nd phamJaceutically acceptable salts
thereof 3Swell as pharn13ccutical compositions and methods
for treating a wide variety of conditions and disorders associaled with dysfunction of the centrdl and autonomic nervous
systems.
I;
B.\CKGROlJ1\'D
OF THE I!\]vB"rrION
Nicotine has been proposed to have a number of ph arm acological effects. See. for example, Pullan et al .. :V Engi. J. ~[,
Med. 330:811 -815 (1994). Certain of those effects can be
related to eflects upon neurotransmitter release. Release of
acetylcholine. dopamine. norepinephrine,
serotonin. and
glmamate upon administration of nicotine has been reported
(R.oweIJ et a!.. 1. Neuroehem. 43:1593 (1984): R.apier et al.. 1. c;
,Vel/menem.
50: 1 12j (J 988): Sandor et al.. Brain Res. 567:
3P (1<j9!):\"izi.Br J. PharJIw{'ol. 47:765 (107:;): Halletal..
JJiochem Pharmacul. 21. I829 (1972): Bel)' ~t al.. Arch. InT.
Fh<1rl1la,"oJm. Ther. 29(,:91 (] 977): and loth ~t aI., SeuTO·
,'hem Res. !7:265 11992)). Confimlatory rep()rts and addi· 01'
tional recellt slUdies have included the modulation in the
Central Nervous System (CNS) of glutamate. nitric oxide.
(;AB.-\. takykinins. cytokines, and peptides (r~ icv.'cd in
Hri('ni et al...4d,: l'i7l1rt//{)(o/. :'7.!~:' (19');.il.ln addition.
nicmine repl)rtedlv potenTiates the pharmacological hehavior:,
of c~rtajn pharmaceutical compositions used 10 treat certain
disorders. See, for example, S:mbcrg et aI., l'hannacol. Hio,
('hem. 8.:. 8ehavior 4(dfn (1993): Ilarsing et ai .. .J .1I.'euro"hem. 59:48 (1993): and Hughes, Proceedings /;")//1 /nll.
S,·mp. Nil'. 540 (1994). Furthermore. the neuroprotective
4(;
dT.xts of nicotine ha\'c bcen proposed. see, for example,
Sjak-shie el al.. Brain Res. 624:295 (19931. \'arious other
beneficia! pharmacolugical dIects have also been proposed.
Sec. f(.Jr (:xample. Decina et a1., BioI. i'sl'chill1rv 2R:502
I i990'l: Wag.ner et ,11.. l'h<lrmacopsychiatry
21 :301 (198S): 45
I'umerle:1ll (:t al.. .4ddini,>e Hehal'iors 9:265 (984): Onai\'i et
;iI. Lite .\;,..i. ~4(::;): 193 (J <}()4): Tripathi et a!.. .!. Phamw(fi!.
f. 'F. Till'r ::] :9! (j 982 r and Hamon. Trend.' in Pham/(J('ui.
Hc's, 15:.~6 11 \jl}4 j.
\;lriO!J; compounds that largctlLt.,ChRs (nicotinic acetyl· '"
chulinergic rcceptnr<i !:<1\e heen reported as being useflll fl)r
lre:ll ing " \\ ide varicly llf cl.'nditions and di,urders. Sec. !()r
example. Williams ..:t ai .. f):\,&f' 7(4):205 (,1994): :\mcric el
,Ii. C\S Drug, N!.'I 11 I): I \ j 995): .\meric el a!.. Exp. Of/in.
[men Drugs 5( I ):79 (19'l6): 8encherif et al...1. Pharmllcol. ~,
FIJI. Ill!.'!: :'79:141.; (199(,L l.ippiello et al...!. Phart/wm/.
1:":!I. lner 279:1 4~:(1996): Damaj etal...J. Phllrllwcol. E.rp.
171i?1:
~9 1:~<)O (19991: Chiari el al.. AneslhesiologJ' I) I: 1447
(1999:: [,a\'and'homme
and Eisenbach, Anesthesiolugy
<)! J 455 (1999): Holladay cl aL J Aid ('helll. 40(28): 41 (,9 ,)"
I 1997i:
Bannon et aL .\·ciel1ce 279: 77 (1998}: PCT WO
(4'OWi92: 1'(T WO 9(i:; 1475: PCT \VA 9640682: and FS
!'a'.. Nos. 5.SKU 40 to Bcncherif et al.: 5.59~.919 to DuB et
al.. 5.f,04.2:'1 to Smith el al.: and 5.852.041 TO Cosford el al.
Nicotinic compmmds arc r"'P0rted as being particularly USl~- "
ful for treating a wide \miety of eNS disorders. Indeed. ;)
wide variety of nicotinic compounds have been reponed to
US 7.459,469 82
4
3
pri.'venting the above-described disorders are disclosed. for
example. in U.S. Pat. No. 5.:12.188 to Caldwell et a1.. ::-.S.
Pat. No. 5.604.23 J to Smith el aL. U.s. P'dt. No. 5,616.707 to
Crooks et al.: U.S. Pat. No. 5.616.716 to Dull et al.. U.S. Pat.
No. 5.663.356 to Ruecroft et al.. U.S. Pat. No. 5.726.316 to
Crooks et aI., U.S. PaL No. 5.81 1.442 to Bencherifet aL U.S.
Pat. No. 5,861.423 to C.aldwell et aL PCT WO 97/40011:
PCT WO 99/65876 PCT WO 00/007600: and U.S. patent
application Ser. No. 09/391,747. filed on Sep. 8.1999, the
contents of each of which are hereby incorporJtcd by reference.
The syntheses described in the art for fonning E-metanicotines typically involve performing a Heck reaction between
a halogenated heteroaryl ring. such as a halo-pyridine or
halo-pyrimidine. and a double bond-containing compound.
The double bond-eontaining compolmd typically includes
either a hydroxy group, which is couverted to an amiue group
to form the E-metacicotine, or includes a pro!t.."<.1edami.ne
group, which is dcprotectcd following the Heck reaction to
foml the E-metacicotine. A limitation of the Heck coupling
chemistry is that. while the major reaction product is the
desired E-metanicotinc. there are minor reaction products.
including the Z-mct ..micotine, a metanicotine compound
where the double bond has migrated from the position adjacenl to the beteroaryl (such as pyridine or pyrimidine) ring
(i.e., a nOll-conjugated double bond), and a compound in
which tbe hetemaryl group is attached at the secondary (as
oppased to primary) alkene carbon (i.e., a methylene comP:HIl1J ,)[ '\:xe'" double bond). l! can be diilJcuit to remove
these minor reaction products. particularly on scale-up.
1; wuu Id be advamagcnus to provide new melllOds of prep,l"ing purified E-l1lelanicotine compounds substantially free
1'[',>111 tbe abo\'e-descriht'd
minor reaction products. It would
also be ac!\',1Il1age0llSh; pro\·ide new salt {i)flllS!,fthese drugs
10 impnwc their hi"a\·ailability. anei'M to as,ist in preparing
1:lrge quan:ilies of these compounds in a commercially reasonabie m~llllCr. TIle pr,~scnt invention provides such new
s:.nthesi s meUKlds ;Uid new salt forms
ment of the ary] group to the aIkeue chain is at the secondary
double bond carbon) in solution. This improvement makes it
relatively easy to reIDove these minor reaction products. particularly on scale-up.
In one embodimcn~ the synthesis of the E-metanicotines
involves forming an amine-protected 4-penten-2-amine intermedia1e. and coupling this intermediate via a Heck reaction
with a lu"llog.enated heteroaryl ring. The choice ofheteroaryl
riug is not essential to the success of the Heck coupling
to reaction.. although pyridine aud pyrimidllle rings can be prefelTed. (2S)-( 4E )-N -methyl-5-[3-(5-isopropoxypyridin)yl)]4-pCDten-2-amine is a representative E-metanicotine. p-hydroxybenzoate is a rt..-presentative hydroxyben7.03te salt, and
(25 l-( 4E)-N -methy 1-5-[3-( 5-isopropoxypyridin )yl )J-4\ 5 penten-2-amine p-hydroxybenzoate
is a representative E-metanicotiue hydmxybenzoate salt.
A..Il exemplary reaction is shown below'
~,)
(CH3HtBcx:~
~)
,I;
;,
4('
Nev. methods of syntbesizing E-metacicotine compolillds
described herei.n. as well as new pharmaceutically acceptaJ1c salt forms of L-llletanicotllle compounds. Pharmaceutic,,, coInp0sitions including the new salt fonns. and methods
uf'treatl1leUl amh'r pre\ention using the new S~jit{,")fIllS. are
also di,dosed.
'n)e methods t0r synthesizing. the E-mel:Jnicotine com<,('unds typically include the step of pcrlorming. a Heck rcac(Hill bctween a Iwil'genated
hetemaryl ring. such as a halopyridine or halo-pynmidine. and a double bond-containing
c;:Hnpound The double bc)nd-containing compolmd typically
includes either a hydf(n:y group. which is subsequemly con\·~:rted tn an amine group to limn tbe F-metanico1ine COlll:->lHUld.
or includes a prutccted amine group. which is depm\ccled foJllm ing the lleck reaelion to form the
F-me1i1uicotine compound.
.\I'rer the Heck reaction and J!.lmwtion of an E-mdanicC'line with a free amine group (whether by conversion of a
nydl'l'xy group nr derrotL'ctioll of a protecll'd amine group).
the next step inyo lves brming a hydroxybenloate salt (If the
L-metanicotiul' compound. Unden:eI1ain conditions. one can
precipitate Oil! the hydmxybenzoa1e salt of the F.-melanic()tine compound wlule ie,l\'ing the minor impwi.ties (7-c;ewaicotine and/Of the iSl'mers of the E-ml'tanieOline compound
wherein the doubie bond has mign:ned to a posilion othe than
dired~· adjacent Ii) lhe hetcroaryl ring or wherein the anac];-
Cy· Hal+CH2~·H---{:"H2CHiCH3)~(CE,I(lBoc):E lC'y-{'H=CH--·CH2CH(CH,)N(CH,ytB,,,,).;.
(Z !Cy-CH=-eH---{:"H2CH(CH;)~(CH ,)
IlBoc'+iE!l.nj'oI Z)Cy-CH2CH=CliCII(CII;)N
(CH"itBoc: Cy-C~CH2;---{:"H2C!-i;C!l,}~
a:'L'
4~
,
'.'
<,L
c'
where Cy is a five or six membered beteroary1 ring.
In ~lI1otberembodiment. tbe Heck coupling reaction takes
place using: a hydroxy-alkene. such as 4-penten-2-01. and the
hydroxy group is converteJ to an amine group alier the I leek
cilupling: reaction takes place. TIle conversion can be elTcc1eJ.
ti,r example. by converting the hydroxy group to a 1osylate.
and displacing the lOsylale with a suitable amine, sllch as
metbylamine. III this emhodiment. the Heck coupling re,\ctiell] still forms the same major and minor products, except
thar tbey include a hydroxy group rather than a prOJected
amine g.rollp. h,lIc)wing formation llj' the aminc-{:olEaining
compound (i.e .. tlJ~ (E)-met:micotine). if the impurities lie ..
the minor pmduch of the Beck coupling. reaction) Jre not
already removed. the chemistry involved in fimning the
hydroxyben/.Llate salts is substantially 1he same.
Aiier deprotectiug the amine group (in the first embodiIDent), or l!.)rming the amine group (in the sec~)nd embodi·
ment). one can f!.lflll a hydroxybellZoate salt of the E-metanicotine by reaction witb a bydroxybenzoic acid as described
herein. TIle hydroxybenzoate salts of the major product (the
(E)-melanicotine) and ofthe minor products wi]] form. However. under certain conditions, the hydroxybellzoate salt of
the JlJajor reaction product, the (E)-metaniwtine hydroxyben/oate salt. will precipitate out of sol lition in relatively pure
f'.mn. lea\'ing behind a mother liquor enriched in tll" mill:);
uupurities. This result cnmprises a significant advance in the
,ynthesis and puri!lcation of (I:)-me,alucotllles.
In one embodiment. the hydroxybenloale salts arc i~olated
and then used a, in1eDnediates 10 form different salt forms bv
reaction with different phannaceU!ically acceptable acids or
salts thert..'of. However. in another embodiment. the E-met~nicotine h\'droxybenzoa!e salts are used as active phanllaceutical ingredients (AP]"s). 111e hydroxyben1.oate salts can be
used directly. or included in phiU1n;Jceutical compositions t-y
cLlmbining tbem with a pharmaceutically acceptable excipieni. The hydroxybenzoale salts and/or pharmaceutical eOIllpllsitions can be used to treat and/or pre\·ent a wide variety of
c'lllditions or disorders. 'nle disorders are particularly those
disorders characterized by dysli.mctiun of nicotinic cholinergic nellfotrallsmission. including disorders invoh'ing nellrmuodularion of ncurotnlllsmiller release, such as dopanune
release. The compounds can he used inmetnods for treatment
andior prophylaxis of di:"nrders, such as centra] nervous system (eNS) disorders, which arc characterized by an altcration
LS 7.459,469 B2
5
6
in n;Jrma] neurotransmitter release. Tne compounds can also
be used to treat certain conditions (e.g... a method for alle-.·iating pain). The meth,lds involve administering to a subject an
effective amount of a E -rnetanicotine hydroxybenzoate salt.
or pharmaceutical composition including a E-metanicotine
hydrm;ybenzoa1e salt, as described herein.
The pharmaceutical compositions. when employed in
elfective amounts. can intemet with rele-.'ant nicotinic receptor site, in a patient. and act as therapeutic and/or prophylactic agents in connection with a wide variety of conditions and ! r,
disorders. particularly CNS disorders charaucrizcd by an
alter,l1ion it: normal neurotransmitter release. The phamlaccutieal COllll)(),itions can provide therapeutic benefit to individuals suHi::ring from such disorders and exhibiting clinical
nJallifestations of such disorders in that the compounds 15
within tllose compositions. when employed in effective
amounts, can (i) exhibit nicotinic phannacology and affect
rdevant nicotinic receptors sites (e.g., activate nicotinic
receptors). and (il) modulate neurotransmitter secretion, and
hence prevent and suppress the symptoms associated with ~"
thosc disorders. ln addition. the compounds can (i) increase
the number of nicotinic cholinergic receptors of the brain of
the patiell1. (ii) exhibit neuroproteetive effects and (iii) when
e:nployed in effective amounts can exhibit relatively lo\\'
levels of adverse side elIects (e.g .. significant increascs in "
bl,)od pressure and heart rale. significant negative eHects
U;->LJIl the gastro-intestin'il
tracL and significant effects upon
skelcwlmuscle).
·nle foregoing and (.ther aspL"Ctsof the prl'sent in\·ention
:.ire expbincd in de!:.iil in the delailed descriplion and
,'xamples set fonh be1<,\\.
As used herein, "aromatic group-containing species" refer
to moieties that are or include an aromatic group. Accordlllg.ly. phenyl and benzyl moieties are included iuthis definition. as both are or include an aromatic group.
As used herein. "aryl" refers to aromatic radicals having
six to ten carbon atoms, such as phenyl. naphthy!. and the like:
"su bstimted ary I" refers to ar)' Iradicals further bearing one or
more substiment groups as defined herein.
:\s used herein, "alJ.:ylaryl" refers to alkyl-substituted aryl
mdicals: "subs1ituted alkylaryr· refers to all...ylaryl rJdicals
Jllrther bearing one or more substituent groups as defin(.'(}
herein: "arylalkyl'· refers to aryl-substituted alkyl radicals:
and "substituted arylalkyl" refers to arylall..yl radicals further
bearing one or more substituent gmups as delined herein.
As used herein. C 6 alkyl mdicals (lower alkyl radicals)
contain from I to G carbon atoms in a straight or bmnehed
chain. and also include (3-6 cycloalk·yl moieties and alk·yl
rddicals that contain C3.6 cycloalkyl moieties.
..'\s used herein, "alkenyl" refers to straight chain or
branched hydrocarbon radicals including C 1.8' preferably
C " and having at least one earboll-carbon double bond: "substituted alkenyl" refers to alkeny! radicals further bearing one
or more substituent groups as defined herein.
As used herein. C 1.6 alkoxy radicals comain Irom I to 6
carbon atoms in a straight or branched chain. and also inc lude
(,.,
cycloalkyl and alkoxy· mdicals that contain C_~
cydoalkyl moieties.
- .
As used herein, aryl radicals are selected from phenyl.
naphthyl. and indenyl.
As used herein. cycloalkyl mdicals are saturated or lUlsaturated cyclic ring-containing radicals containing three to
eig.ht carbou atoms, preferably three to six carbon atoms:
··substituted
cycl()alk~]"' rete::; 10 cycloan,-yl radicals further
I )l'TAILbD DESCRIPTION OF TIlL IN\"ENTiUN
bearing. Due or mort' sJbstituent g.roups as detlned ~ercin.
As llsed herein. halog.en is chl()rine. iodine. lluorine. or
ille hydroxybenwale
salts described herein. which ,v·l'
bromine.
derived Irom F-l11etanicotillt.» and hydmxybenzoic acids.
..\s used herein. heleroaryl radic;iJ, contain ii·Olll :; to 10
il<lvea Humber of advantages over otlwr s:.ills derived frum
members, prcfc."fably 5 or G members. including one or more
E-metanicotines and other acids. In general. the hydroxybenheteroatoms sel<xted hum OXVl1.en.sulfur. and nitp,)l1.en.
zoic acid salts ofE-mewnicotines arew·aler-soluble materials
4,
Examples of suitable 5-membe~;d ring heteroaryl moi~iie"
that teud to be hig.h!y crystalline and Jess hygmscc'pic in
include fury], pyrrolyL imidazolyl. oxazolyl. thiazolyL thienature :han other salts. For example, the p-hydroxybenzoate
nyL tetrazalyl. and pynlw]y!. Examples of slliwble 6-memsalt of (2S )-( 4E)-N-mcthyl-5-[3-(5-isopropoxypyridin)yi)
Jbered ring. heleroary] moieties include pyridinyl. pyrimidinyl.
4.pell1en-2-amine i, physically and chemically stahle. freeand pyraziny!. of which pyridinyl and pyrimidinyl are preIlLlwi.ll:? crystalline powder. Such properties are definite
~~ ferred.
:.idvall1ages for pharmaceutical fonnulalioll development and
As llsed herein. "heteroeyclyr· refers to saturated or unsatpharmaceutical manubcturing. If ncces,ary. this salt can be
urated cydic radicals containing. one or more helt'r;latoms
mi ikd \(> an acceplahk panicle size raniLefor phann:,ccutic;.:1
(e.g... 0, N. S) as part of the ring structure and having lWO tel
Noce:;siug. Tlk' salt is compatible with a wide range "I
sevcn carho;} atoms in tlle ring: ·',ubstitllted helerocyc!vi'·
t'"'cipients thai mig.ht be chosen Jar the manufacture of solid
5' rcfers 10 beterocyclyl rJdicals further bearing one or morc
ural dosage forms. ·;lli, is especially so for those exicipiellts.
substituent groups as defined herein. Examples of suitable
sllch as polysaccharide derivatives, that are pharmaceuticallY
hctcwcyc]yl moieties includc. bUl are not limited to. pipcrididdind hydrdles and lhosc with only loosely bound sllrJi,cc
nyL morpholinyL pyrrolidinyL imidazolidinyl. pyrazo1idiny1.
water. As an iilustration. salls derived [rom certain F-mewisolhia/didillyL
thiazolidinyL isoxazo!idinyL oxazolidinyl.
nicotines. such a, E-melanicotine and fumaric acid are prone
,; piperaz.inyL tetrahydropyranyl. aud letrahydrllfuranyl
ll' tllC !,)nnation of impurities v.·ithin the salt. For ex..uuple.
:\s used herein. polycycloalkyl rJdicals arc tllscd cyclic
impwities arise fwm the Michael addition reaclion of lhe
ring stmctnres. Representative
polycycloalkyl
radicals
secondary amine in E-metanicotine to the olefin in tlllnaric
include. bUI are not limiled 10. adamanty!. bomanyl. mr,Kid. These impurities lower lhe cht'mical purit~, oj the salt
bomanyL bomenyl. and llorbomenyl. Polycycloalkyl rJdicals
and adversely uJTcct the chemical integrity of the salt upiln
",. can also inciude one or more heteroaloms, such as N. O. or s.
IonfC-term slt1rage
As used herein. cycloalkyl mdicals contain from:; t,) 8
The synthetic methods described herein wil1 be bener
carbon atoms. Examples of suilablc cycloalkyl radicals
understood with reference to the following preferred embodiinclude. but are nOllimiled t(,. cyc!opropyi. cyc!ubutyi. cvclome!Jls. The j(·,lkm ing definitions will be usehll ir: defining tlle
penty!. cyclohexyL cyclobeptyL and cyclooctyL
scope of the invention:
,..
As used herein. the term "substilU\(xj" as uscG with an'· 0:
.\s used herein. "aromatic" reier:, te) :; 10 10, preferably 5
Ihe aho\ie tenIls, ~efers to the presence of onc, two or tl~re,
and (,·mcmbcn ..'\.l ring aromatic and hClcmaromatic rings
substituents such as alkyl, substinlled aU..yL aIkeny\. substi·
,I
,';
j•
US 7.459,469 B2
7
8
nlled alkeny!. heterocycl~'1. substituted
heterocycJyL
cycloaU •.-yLsubstituted cycloall.:yl. aryl. substituted aryl, aJk:laryl. substituted aU:ylary!. arylalkyl. substituted arylall.:yl. F.
Cl, 13r, 1. NR'R", CF" CN. NO!, C2R', SIL SCH3, N3,
SOFH.'. OR'. (CR'R")qOR'. O---{CR'R")qC2R'. SR', C(=O)
NR'R". !'I"R'C(=O)R". C(=O)R', C(-O)oR',
OC(=O)R'.
(CR'R")PCHzC2R',
(CR'R")qC(=O)R',
(CR'R")qG
(CHCH3 lOR', O(CR'R")qC(=O)OR'.
(CR'R")qC(---':'0)
NR'R". (CR'R")ql\!R'R", CH:c::C"HR',OC(--:.,{)l\"R'R", and
N"R'C(":::::())()RIf y\-here q is an integer from 1 10 6 and R' and 1:)
R" are irldividually hydrogen, or all,;}l (e.g" CJ•JO alkyl. prde:-:ibly C 1.5 all-.:y!.and more preferably methyl. ethyl. isopropyl. tertiarybutyl or isobmyl). cycloalkyl (e.g., cyclopropyl
cyclobutyL cyc1opemyl, cyclohexyL cycloheptyl, and adaI)lantyJ). a nnn-arOJnatic heterocyclic ring v.·hercin the het- 15
eroatom of the heterocyclic moiety is separated from any
other nitrogen, oxygen or sulfur atom by at least two carbon
atoms (e.g., quinuclidinyl, pyrollidinyl, and piperidinyl), an
ammatic group-containing species (e.g .. pyridinyl, quinolinyl~pyrilnid.inyl~ furanyl. phenyl, and benzyl where any of the
fOrL'gDing can be suitably substituted wiu1 at least one substituent group, such as alkyL hydroxyl, alkOl,:y!, halo, or
amino substituents).
As used herein. neurotransmitters whose release is mediated by the compounds described herein include, but are not
limited to. acetylcholine. dopamine. norepineph.riJle, serotonin. and glutamate, and the compounds dL'Scrihed herein
function as agoni!>ts or partial agonists at one or more of the
Central Nervous Sys1CmlCNS) n.o\CbRs.
I. Compounds
'Ibc compounds described herein arc hydroxy benzoate
salts of (E)-metanicotine-type
compounds.
A. Hydroxyben:lOic Acids
Ibc hydwxybenzoic acids that can be used to prepare the
hydroxybenzoate salts of the (E)-mcranicotine-iype
compounds have the following general formula:
~~.!
~s \\·here the hydroxy group can be present in a position ortbo,
meta or para to the carboxylic acid group. Z represents a
irs binding partner. typically a receptor. Stimul,i\ion is defincd
A;, used herein. an ·'ag.onist'· is a substance that stimulates
nOll-hydrogen substituent. and j is a number jrom zero to
in lhe contexl of the particular assay, or may be apparent in the
thrc'C. representing the number of Z substituents that can be
lilcfdlure fnJm a ciisClls"ion herein thaTmakes a comparison 18
present on the ling. Fxamples of suitahle I suhsliments
,i JilClllr or substance thill is accepted as an "agonist'· or an
"am'Jgonist" of the particular binding panner under subslan- },> include alkyl. substituted all..:l alken~·l. substituted alkeuyJ.
ti,ilh· similar circumstances as appreciated hy those of skili in
helerocyc1yl. substituted heterocyclyl. cycloall-..-yl. substithe art. Stimulation may be defined with respect to an increase
nned cycloalJ,,-yl. aryl. suhstinned aryl. aJkylaryL substituted
ill a panicnlar efrtx:t or fum.1ionihat is induced by illleracrio:l
~ill,-ylaryl.arylall-.:yl. substituted arylall..~'l. F. Cl. Br. 1. NR'R".
"fthe agonist or ranial agonisr with a binding partner and can
CF,. eN. NO,. CR'. STI.SOl,. N,. SO,CH" OR'. (CRW'!.
include allo;,teric cJleC1s
;5 OR'. O-(CR~R"V··:R'·
SR', C\,O)NIZ'W: NR'C(, O)R'::
.\s used herein. an "all1agonist" is a substance that inhibits
C(.O)R'.
C( .....OjOR'. OCC·'O JR'. (CR'R" ),.eX] l2C:lZ'.
its hinding partner typically a receptor. inhibition is defined
(Ct{'l('\C2( .. J))R', (CR'R")/'(ClICll,,)OR',
O(Cl{'R")/-:
in the contextofthc particularassay. or maybe apparent in the
(=0 lOR'.
(CR'R" JqC(c-:.oO)NR'R".
(CR'R'\NR'R".
Iilerdture rrmna discussion herein that makes a comparison to
C! 1--,-0 IR', (X~(--,-O)NR'R", and NR'C(=O)OR" whereq is
a 1;,ctor or substance that is accepted as an "agonist" or an ,i'J an integer from 1 to 6 and R' and R" are individually hydro.
"antagonist" ofthc p~U1icularbinding partner w1der substallgen. or~dkyl (e.g .. C:.>o alk'yJ. prefembly C 1.5 all-.:yl,and lUorc
tially similar circwllStances as appreciated by those of skill in
preferably methyl. ethyl. isopropyl, tertiarybutyl or isobutyl).
the art. Inhibirion may be defined witl1 respc'Ct to a decrease in
cycloalkyll e.g .. eyclopropyl cyclobutyl. cyc1opcntyl. cycloa particulareifect or function that is induced by intemction c,f
hexyL cycloheptyL and adamantyl), a non-aromatic heterolhc antagonist witb a binding partner, and can include aDm- ~5 cye! ic ~ing whereiu the heteroatom oflhe hetcrocyclic moiety
!eric effects.
is separated from any other nitrogen. L1xygelJor sul fur atom
by at leasttW(1 carbon atOln> (e.g., 4uinue!iJinyL pyroJlidinyl.
\; used herein. a "partial agonist" is a snbstance thaI
alld piperiJillylj. an ar(][n,i1ic g.ruup-cllntaining species (e.g.,
pF'\ides ,1 k\·d c,f sliIllu!atwn to it, binding partner that is
py,idinyL 4uiIJ01inyL pyrimidinyl. fUrill1yl. phellYI. and beninkr!ll.:.'{liate between that ora ti.JIJ or Cl)mplele antag.onist and
an :Ig.onist ddined by any accepted S[llndard for agonl~t act i\'- ....~. zyl where any of the j(lreguing can be suitabl!' subslitllled
with at least one substituent group. such as aLk'yLhydroxyl.
ity. 11 will be recognized that stimulation, and hence. inhibialkoxyl. halo. or amino suhsri wents l. Other represemative
tillll is defined intrinsically Jilr any substance or category of
arommi(~ ring systems are set forth in Gibson et a1.. J :\11'd.
subswnces t(l he defined as agonists. antagonists. or partial
Cherll. 39:4()('5 (l (,ll)(i). R' and R" can he straight chain or
a):(onisls.. \; llsed herein. "inlrinsic activity". llf "elllcacy.'·
,'elates tu some :neasure of biological efrectivenes~ of the :'; bmfIched allyl, or R' and R" and the ill1ervening atoms can
c,.,mbine to form a ring structure (e.g., cyclopropyl cyclobuhinding partner comp Icx. With regard to recq)tor phannacoltyl. ;:yclopentyl, cyclohexyl. cycloheptyl. adamanty] or quiogy UK' context in which intrinsic activity or e1iicacy shollid
nuc1idinyl). The hydroxybenzoic acids can ()ptionally be subhe defined will depend on Ihe COllteXl of the biDding partner
stinned I'iith a chiral functional group. which can assist in
'e.g .. receptor'ligand) complex and the considemtion or an
al:[ivit~, relevant to a particular biok)gical outcome. For r", purifving E-metanicotines which contain a cluml carbon. by
forming diasterc'omers.
example. in some circumstances, intrinsic activity may va,y
Representative benzoic acid, tllat can be used include salielL-pending Oil the particular second messenger system
ill\'ojved. See Hoyer. D. and Rnddeke. 1·1., Trends I'hurmuu)i
cylic acid. me1<l-hydrcxyhenzoic acid. pard-hydroxyhenzoic
acid, vanillic acid. isonUlilJic acid. gentisic acid, gaUit, acid.
S, ',. j 4(",::7(j·5 (l Y(3). Where such cOll1extually specific
e-.'aluati(,ns are relevant. and how they might be relevant ill the ,,; ~··aIllinosalicyjic acid. >yringic acid, 4-methylsalicylic acid.
~-chloro-4-hydroxyhenzA')ic acid, and 5-hydroxyisophthalic
Cllll1e),1of the prescl!1 invention, wi]] he apparcll1 to one (,f
acid.
\.miina!y skill in the art.
9
10
[3. 1.: ~!vh:~tanic:Gtines
Tl;~ i -meliJnicc\line cC'lnpcH.lnd5 include compc)llnds
.
0: !1,e
S,l.:i:abk' n(n:-h~·Cr~)g.cnsubstinl~nl spL"Cic~arc as defined
'Jh:'\ i.: witb respcc: 1(' L
In ~nOlher emh,)diment. Cy i, a 5-memberee nng heter, ~:.iryl {'f tbe- fi~..,n(\\:..·icg ft·HT.:1ula:
/"
_~_,~_
,c':-",:___
[
-.---
"/.
\\ li(r~in:
\..h...:rc Y ~l])dy" ar ....
~ indl\'ldualJy
ni1rogen. nilrogcf; l){'ndcd In
h':"h.::rot1J)'l ring.
;-,'.uhslitucnt spt'::il's. OX~'l':'.L'n,sulfur 0:- carbon handed to 8
i·· :-~ndF indi\'idual1:,: n:prL·~eni hydrog.l?n. alkyl. substituted
::;U~Si1tlli ..'nt species. ~uld )~!'iild ""HI arc nitrogen
or carbon
:likyL h;,]n suhstinnd
alkyl. cycJmdj,cyl. subqiwtd
b, I!idl'j \(1 a "ub,linl,'nr >pecil's_ The dashed jine" indicate l11a:
~'y..:!oi.1H~)Lh(:lerocyz.':)L :-;nnstituied heterocyclyl. ;]~'l: suhthe ~j,'nds (be1\\i.~enY ,md Y' and betwccn Y' and '(" ) can he
S;i!iilcJ a:-yi. iill-.-yLryl. ,uhs!iwted
:ilky]aryJ. aryblkyJ LX>L1bt'E:ief sing.1e or (bub]e bonds. However. when Ihe hond
s!innd aryla!kyl:
bel\\L~nYalljY is a single bond, the hond het\\"ce:1 1"' and'}'''
/. and I" indi\'idually n:prc>cnt hydrL'gen (:r alkyl (includ.'.\
nll!:::!be a d{)ubl~ hond and vice \ ('rsa. 1n ca~(~ in which"'y' or
ing cycb:.Jikyl). and prckrahly
at leas! one Pi" 7' and T' i"
Y" :s eXVQ.e:1 ()[ sul fi.~r. onl\' ooe 0!)' and \'" is either oX\"l!.cn
h~ (:rl)g~~L and 1110St pref{:r.:·lbl:: /' is. hydrngcn ~ll1d z,· i:-(I, sulfll;.~-\l1easl
onc of!:. Y. \''', and \~" mU$1 be cx):g"ct:.
;1"H_':hyl: ii;temativC'ly Z', Z". 3:1.:l the a~so('ialeci njt;(lg~n aleX'll
:--l:]li.lL nitrngcr:. (I; niln.-,gen hl"lnded h) a suh:-tti1uc.~mspecies, 11
~';.:ii1.t~·H·::1a ring. ::.:tnll't:1.:""C .";Ul:h~s 31.iridlcyL ~:7cLldln.'·L r-yr, <:' !':-l'j~rrL,j tlE:l ;1" mure th:m three (J'( \". Y". and Y'" be
Ld;!JyL p;pcridinyL ripr..·r<L~inyL 11lurpholiDyi. :Hld
\
;\:·~('n. ~\1ihJr. nilftigelL or nitrngen honded h~a substiluent
~A'ih 1· gn)up::-. ~)n lh ....
, l.k\il1,:"k b~)nd ~:ri...'
prcferah!: hydr('),Sl':J.
(y ::;.~~
:'- i.'!f (i·elcn1hi..'rcJ
'r'l· ....
:i~5: ~~:'
;,::l'J
:i
'~n','1;:(' 1'J.:10()uill1L":')i.
:;:kli,r-:ef
~i~i'::
F
aud~:
i·:ydJ(!g~L. ~1!v..: ::j
are
".'!"nDt:)diniClll. ~.i:j{~dSl njh.~ uf E (Il" F'
~s alkyl
an(:
!~h:"
:·:':'·:l~::jjr!f! f-" ~lnd r-~'~;r~'hyd!\l~ef1. In? prcfcrr:.:\i emb('ldinJe~l!.
I" ~~:~:j~:lky; g.:nilp. ~rcj,';--~l1jlya 111dhyl
.
.
;~,'·l~'lt.'rs. nlIx:l1re:-...
.
:i)\...·L'. ·.1~~1~iLTl'~.\i~I~;·'::'
:;l(:i~l(:l.i~g raCCITlJi.:
]\h·.li
1':"1(:':--C\1Pl'
m:\Lli\:~.
L~11;'1:.:~·
:'(.ljl~;
ni" r!w : n"·t.'nli,'lll.
r'i:l~l hCH..T~';"t-~·i
n!l~':'~ containing,
hl.il not linl1tcd 1(". C'lh't·~.
L...
.'~:,d.;tnl:t.~i.:. kCh}nl'. 1~l('ICIk·. JiJct:.irn. c art"\:'llli: Ill', ~:r
.:!.....
;~ hllh·11,.'lj~~ll]:::·:,
. )LT'L·Il..lI;I~ Uf',l:l lhe i,ieniil.\'
F ~\·r.aln
.., ,J:!:.:] :. ;llEI
: I·.~
if. ,.;);.'"('mbt'I(:i;,·n· ..'L~.(.:' :>~: ~lx-L:iemhc;L',:
..J~'ril·;t~d C.S fldiows·
n(") Inure
hCkr~.H::,cli-:.·
~l;"
::~,-'r..·\;1. ~l;c .. ~
Plh:~. hUi
:'uh:<iTllt..l1t
SPt·i.·iL~S on \:. X', X". X'!'. X"". Y. Y'. Y". <Exl
";" :h..,]".: ~'i·:!.id~·Ln:.C~:!.~"l
,..\.'llTlbinl' lu fi..'lnn one or J1F,n.,·salli:·;Il~~(:('If l.InS;j;lJr~lic'.:.I. ~uhstiLU,-~j
or u:1:.;ub:-:lirUlcd ca;-}l,.K.:yciic
;)\.,'l;;\'
.
,. .
.
~.!.:·t:,,: ::,!~)h.)rnersc1 t:lt:>:,,' l"':.1ll.r~,nJJH..!:-.
.,\,:]1 il:\ "dl~!;::laCL'Ulj(..~::j:: :h..'l·Cpwbk
\1.,
~:-~I;jr
.
,.
fU:-!:i(~r pre·ien·ed thill a~ lea~l
:lli ~h..rt.:'t·. (,f'';'. \". Y", ~!!Jd yn. be r:~t:\~g.t.'n.
..
llll' CdI1)PUlJlld
can
:z '~lrS ':"·("n!'ig.lIr~~li{lll;-"L
and pusiti()nii1~
h([\ (' \.Hk'
C~iJ.1
bl,.~'..
:lH..' pr~sent in',t::111ioll
:~.:lL l:'lL\l Ufc·S l.' f :-- :J~:hc~\rnr()llnd\
,d·t~;I\.:i1 il1(ji-
'rliu!ily ac!:\ l.~
Uf !1'l()rCchiral ;':CIl1l~r.:;. \\'i:h
l\)lnp(ll1nd~
<1:'
\\·c'!l
rclal.L\~ 1~:~
ral:C~
~i:-; ~illt:
le ell~ull()nl::..~r
~'(~m?()\I1Id.:>.
(')~' r~lJ1i("ub:· ~:l1L~resi are aryi
~",.,':il.id....~,flh('
sllh~liltll('d
<UJJHh:
COHi·
J~\:'!;;~l~a:
I
-,I
....... (.:.:./. "/'.
\(; :'\Y~,~ll (e.t- .. (l~·l \·.,\\lde or \" -.(j
ur ~·:~;-t)(i1·;t'undt.:'d h.' I; \.)1 ;1 li.~)n-bydn\gcn
",lh:~!iiih..'ni :,rl('(:ic~; \ .....
il\:.ln.: lh'lil1hrcc >Jr\.. \~. \!'. \'" ;,;H~;
\ .... :~:-\.' niln ..1gt:r: ~l[ nitr.I~,i..·E hundcd 1('1 (';}..:'~;.~rL all..:! it 1:-;·,:\..I'i..·:T:""~:lha~ nl1~:· ;':!h:'J!W ~:·r\.X'. \". ~\~", all\..1 X· ..· 'In.:
I;ilr~"g~~n\I;' nilf(lyclJ b~)!'l\..L:cl 1() (\\.y~ell. lr~ ,i~jdililln,1: ;~
::\~'~hj~·
;"'t:-ckrrcJ lh~'lln~~l:~lnr\"'lhall un~ nL\. \!, Xl!, X~". ~il"I(;
\" .. b nitr','lger: bi.\ldL>c~ i;' ,:\ygeri. an': i~i....
r,:·~~k-rrc.'dl[~;'Jt :(
~,:j;.
:':11!\'~l'n bl:udt\!
11K1i'.':,1.:dn:
l.
Inc ..'.rlll~·'''l~ :--;pl'l'it·~ i:-: n..Lf(Ig:.'n
..·It.~~1S \'l!.
:)u[ldcd
~vlost rr,.:<C'r~~h1::.X~l~ i:,
l\: ,\),:ygCll,
nitrCl~~L'll
In
Ih~L :"f1:...".
ccrl:'liI;
pr,,'-
,::T('(: ,~·i:-::::lllY::-;1ancc:..;, r,.:~:jl ~\.. a:i';'} ~". e:irc =1ltr·.1i-c:.1. 'r:T\i'_'~jl::
\. \'!. a:l.i X"" ;11'(.' c;.!rb~H! h:H)(ied h~a >tlh:..::ilu('~ln ~:rc·~ic:--.
. ::l,i ]'.::-:. :Yrj~;.tllL:;l l~·l'_' :'·.lbslilUci1: :-;pc:.:.:i,,~~, ;11 X ..X!!. all~: \!~"
;:".:: :1\ :ir\'g.en.
l'nr Ccn~:l;i\·'tl'ier pn:i'e:-:·'CG ~·;'.lI;r.'nlh:...''-'.':11..'[";.'
\". i~:'::JdX'l1 ri.ll"ll..lcd L' il :,;ub~;~iiLlcnl sri.:~\.:i.....
:; suel1 ~b by.:.i~., .
g(~::. :. ~~!)\l ~. ;ir":".' b,,<L ~.litrc'g.cli.. in Ci.:~i~i:n (lllK~:- rrL'kTn:":1
~;()mp;)un(L; \\ here \. l:- ~:UdX\li hun,j:.:"d 1\ :: ~l.:bqilUt.'I:; ~ll~.
~"h::-:sue!: ;.~~Ly(in,'~,eli.. :\ ~!nd X'"
(H1.:
h(l[11 llitr<!~Ln
\, ~k':·'~·\'.
\ .. \'
L
i'
;jrl·~i ;\"
/'
a:';.,'
/'!. and
I11:-H:..:
I:~,,(ln'gen
dr
as d('fineJ bl~!Tinl)l'krf\.:. ;:n,.1
;1 ~u~~titUC'Il!
,p~"cit's /. ;!~
k~jil1~\.l~,dlln·c \\ ilil fl'~rl,.·(,'t h': the :1: jr<·lxybl~rv()il'
:H.:ids PiL'l'-\.T~ihl';. ;l;! !: ~,:r;.,·!'l:~jr~~~L'l:
~j:1d i'-I is alkyl. pn,:'·kr;tb\y fncILyl
:·)rckr;inj:~'. ;. > l:yJr,~g.cn ;:Il~:7." i\, hydr-~)gcI1 ~)r n1ctl~y;.
:lrci'lTibJ>·. 11.!, 1 ()f:.
; .\,.::nr:ar.\ :\,~",~:-- I'aryl ~u:-·:-:tian('(~ ;l!l1i;1t.~ UH1,:r~·'tlnJ~.d:·L'
;i·I~,.~t·
tilt: l:"~lC :-:c: i:"H111ii. 1.~.S. I'm. \(~s. ~.:~:.~~h
\' .
t 'ai.:.Jwd] l'; a:. :~./,04 .;:. 110 Smith ct al.: ::'.6"1 (\ 70: 1(', (, 'nH"li\,~
i.'~ ~tl
.. ~.(16.'""7:·> l(~ D~jl] e: a1 . 5,(1(3,;:'6 1(' Ruecf(,ft e1 ~l1..
~',""'::(.:;}(-l:. (ro\)k:-. ct al.: ~,S.1I"+.:1:
1~" r~i..'nci-lerif e: ~i:.
:::-.:v,;: .~:3 it~ (,·:ilJv,,·\.'11 l"'t ~,.d.: {;.~~....,..~~ i In 1)i111 (~1 aL: \\'C)
;, -: ,l( ,(, i ~.\\·C/ ;
an:! \\'Ci ((l'(P(J"":' 600. Tbf 1(~!""(·g.()iD~
:·l'(('r .....
·il~(':; "rL' i!1c;)rrUnHl~d her-eifl 1;y r~.fc-n..·i"j(.\: 111 :.:1\..'::'~':i11r,-~:yhl;- pu;p~ ':->L'~o~·pn·,\·iding. di:,c illSUrc.' "f rcpresenl:.Jtl\"l:
,::..:jl"!!-.~)uncis 11.;:...'fu! ir carr:'inf:
{1U: the: prcs:""1i! il1"cntir li.
I,'
or
j{)
(,~~-
(:
1
US 7,459,469 B2
11
12
Exemplary compounds useful in accordance with the
present invention include metanicotine-type
compounds.
Representative preferred compounds include (E)-metanicotine.
(3E)· N -methyl-4-( 5-ethoxy· 3-pyridiny Ii- 3-bmen-lamine_
(25 )-( 4E)-N-methyl-5-(3-pyridiny1)-4-pentcu-2amine,
(2R )-(4£)- N-methyl-5-(3-pyridinyl
)-4-penten- 2amine,
(2Sf-( 4E )-N -methyl-5-( 5-meL.1:loxy·3-pyridinyl)-4penten-2 -amine.
(2R)-( 4E)-N-methyl-5-(5-methoxy-3pyridinyl H-penten- 2-amine,
(2S )-( 4E)- N-metl]yl- 5-( 5isopropoxy- 3·pyridiny I)-4-penten- 2-amine,
(2R)-( 4E)- Nmethyl-5-( 5-i sopropoxy- 3-pyridinyl )-4- penten- 2-amine.
(3 E)-N -mcthy 1-4-(5-nitro-(i-amino- 3-pyridiny l)- 3-buten -1amin.... (3E)- N-metbyl-4-(5-(N- henzylcarboxamido)- 3-pyridiny 1)-3-butcn- J -.uuinc. (2S)-( 4E)-N -methyl-5-(5-pyrimidinyl )-4-penten-2-amine.
(2R)-( 4E)-N-methyl-5-(5pyrimidinyl )-4 -penteo -2-aminc, (4E)-N -methyl- 5-(2-amino5-pyrimidinyl)-4-pemen- 2-mnine,
(4E)- N-metby 1-5-( 5amino- 3-pyridiny I)-4-penten- 2-amine. (2S )-(4 E)- N -methy 15-( 5-isopropoxy·l-oxo- 3-pyridiny 1)-4-penten- 2-aminc,
(3E)-N -methyl-4-( 5-isobutoxy- 3-pyridinyl)- 3-buten-lamme.
(3E)-N"-methyl-4-(I-oxo-3-pyridiny1)-3-buten-lamine,
(4E)-N-methyl-5-( 1-oxo-3-pyridiny1)-4-penten-2amine. (3E)- N-methy 1-4-(5-cthy Ithio- 3 -pyridiny 1)-3-butenI-amine. i4E )-N-methyi-5-i5-triftuoromethyl-3-pyridinyl)4-pel1tcu-2-amine,
(4E )-N- mcthyl-5-( 5-«(carblJxymcthyl)
oxy}-:; -pyridiny 1)-4- renten- 2-amine, (4 E)- 5-( 5-isopropoxy.:;-pyricEJ1yJ)-4-jltTlten-2-aminc.
and (4E)-N-mcthyl-5-(5llydroxy -3-rYlidinyl)-4-penlen-2-amine.
Additional
,eprc,en131iw examples include (2S )-(4E)-N-mcthyl-5-1.5cyrlohexylnxy-3-pyridinyl
)-4-pcntcn- 2-arninc.
(2R)-(4F)]'oJ -mel hy j-:' -( 5-cyclobexyloxy -3-pyridiny1 )-4-pcnten- 2.;nDlllC,
(2S :'-(4E )-N-metbyl-5-(5-phcnoxy- 3-pyridiny 1)-4pcnlcn-: -amine.
CR)-( 4 [i-N -methyl-5-i 5-phenoxy- 3jly:idinyl)-4-p ...nkn-2-arn ine, (2S )-14Ei-N-methy 1-5-( 5-(4fluor('phe!loxy)- 3-pyridinyl)-4-penten-2-3mine,
(2Rl-(4E)t\'-mel hy i- 5-(:i -(4- tluornphcnoxy)- 3 -pyridinyl )-4-ren tcn -2:mllnc _
(2S )-(4E)-N-mctbyl-5-(5-( 4-chJornphclloxy)-3pyriJinyj)-4-penten- 2-amine. (2R)-( 4El-N-methyl-5-(5-( 4c!1Iorophenoxy)-3-pyridinyl)-4-pcnten-2-amine.
(2S )-( 4E)'\"-!TIcthy 1-5-( 5-(3 -cyanophenoxy)- 3-pyridinyl )-4-pentcn- 2amine_
(2R)-( 4E )-N -methyl-5-1 5-(3-cyanopbclloxy)- 3pyridil1yl)-4-penten-2-<Uuinc,
(2S )-(4E)-N-methy 1-5-(5-( 5indolyJcxYI-3-pyridinyl )-4-pelllen-2-amine. and (2R)-( 4E)t\'-lllet hy]- 5-i 5 -(5-i nJo ly loxy)- 3-pyridiny1 )-4 -pcmen -2-
"I)'picaU)', the types of procedures set forth ill Frank ei aL 1.
Org. Chem.. 43: 2947-2949 (1978) and Malek et a1., 1. Org.
Chem_, 47: 5395-5397 (1982) involving a palladium-catalyzed coupling of an olefin and an aromatic halide are used.
The olefinic alcohol optionally can be protected as a t-butyldimethylsilyl ether prior to the coupling. Desilylation then
pmduces the olefinic alcohol. The alcohol condensation pmduei then is convened to an amine using the type of procedures
set forth in dL'C.o5ta et aI., 1. Org. Oem., 35: 4334-4343
(1 (92). Typically, the alcohol condensation product is conVCI1L-'d to the a0'1 substituted olefinic amine by activation of
thc alcohol using l1lelhanesulfony1 chloridc or p-tolucnesu!f()J]yl chloride, followed by l11esyl3tc or t05y1atc displaccment using ammonia. or a primary or secondary amine. TI1Us,
whcn the anline is ammonia. an aryl substituted olefinic primary .unine compound is provided; when the amine is a
primary amine such 3S methylamine or cydobutylamine,
an
aryl substituted olcfinic secondary amine compound is provided: and when thc amine is a secondary aminc such as
dimethyJamine or pyrrolidine, an aryl substituted olefinic
tertiary amine compound is pnwided. Other representative
olefinic alcohols
include 4-penten-l-oL
5-hexen-2-o1,
5-hexcn-3-oL 3-mcthyl-3-butcn-l -01. 2-mcthyl-3-butcn- 101. 4-methyl-4-penten-l-01.
4-methy-4-penten-2-o1.
l-octen4-01. 5-methyl-l-heptcn-4-ol.
4-mcthyl-S-bcxcn-2-oL
S-mcthy:-5-hexen-2-oL S-hexen-2-o1 and 5-methyl-5-hexcn-3-ol.
Trii1uonnelhy1-substiluteu
olefinic alcohols, such as I). 1trii'luoro-4-pcmen-2-o1. can bc prcpared from 1-cthoxy-2,2.
2-trit1uoro-ethanol ,md allyltrimcihylsi1anc using. thc proccdures of Kubota et a!.. Tetrahedron Letter.'. 33( 10): 1351l354 (J 992), or from triftuoroacetic acid cthyl ester and
all::1tributylstannane using the procedures ofIshihara et a!..
Telral7l'dro!1 Lena.'. 34(56): 5777-57RO (i 993). Ceri,lin olei1nic alcohol> arc optically activc_ and can be used a, enantioJlleric lllixnlres or as pure enantiulllers in order to provide
the co,re,p<lllding optically active t(lrmS of aryl ,ubstilUllJd
olefinic ,~Dline compound,. Whcn an olefinic allylic alcobol.
such as mcthallyl ablhoL is rcacted with an aromatic halide.
an aryl substitlJted olefinic aldehyde is produced; and the
resulting aldchyde can be convcned to an a0'1 substituted
old1Ilic amine compound by reductivc amination (e.g .. by
treatment using 3n a 11-..·y 1 amine and sodium cyanoborohydridej. Preferred aromatic halides are 3-broll1opyridine-type
compounds and 3-iodopyridinc-type
compounds. Typically,
substiwent gIoups of such 3-halopyridine-type
compounds
are such that 1110segroups cml survive contact with those
chemicals It' g., tosylchloride and mdhyJaminc) alld 111ereaction conditions expenmced during ihc preparation of the aryl
,ul1;;:illlteJ olefinic amine comp('Uni.1. .\llernative!y. sub"l.iruellt, such as -DB_ ·---NH: and ---··SH can be protected as
cofre,ponding
acyl compounds. or substitucnts such as
···N!J. caD be protccted as a phthalimidelllJlctionality.
In \hc
case of a dihaJoarnmatic, sequential palladiurr.-cilta]yzcd
(Heck-type) coupling> to lwo differt'n1 (,Idinit: ,ide chains arc
pll,sible.
III one cmbodimenL thc (E)-mctanicotillc-typc compounds
pos,;css a branched side chain. such 3S (4E)-N-methyl-5-(5isopropoxy-3-pyridiEyl)-4-penteu-2-amine.
By using one
synthetic approach, the latler compound can be synthesized in
a C(JllVcrgcnt manDer, in which thc side chain. N-methyl-!,,(ler!-butoxycaroonyl)-4-pentcn-2-aminc
is coupled with the
3-,lIb,tituted 5-halo-substituted pyridine, 5-bromo-3-isopropox~'pyridine. under fleck reaction conditions. fo]]cmed by
n:n](lval of the tel1-bmoxyea.rbonyl protccting group_ Typicall\', the typcs of procedures sct fortb in W. C. Frank ct 31.. J.
Olg. Chem 43:29-"7 (1978) and K J. Malek e1 aL 1. Org.
Cln'lII. 47:5395 (J 9S2:, involving a palladium-catalyzed
cou-
a.i11Ull~.
C ,),npound Preparation
The fIJ(~Jll1t~r in \\·hich the' (E,)-ruelmlicotine-Iype
CO!T);"'UlI(!s de,cribed herein are ,ynthelical!y producL'\l can \"L,.,.·.
h.,r c:o..'!lllpic. the compounus can be prcpared by the palla-",
dium-cawlylt:d coupling. reaction of an aromatic halide and a
tenninal olelJn t:onlaining a protectecl amine substituent.
rCnlt al of the pr,,)1ective group 10 obtain a primary: or sec~)ndar\" aminc and optional alkylaiionlO pml'.ide a scconda0
Jr te:olary amine. In panicular.
cenain mctanicotine-typt'
:()!np()und, can be pr('pared by subjecting a 3-haJo-substiruted. optionally 5-substimred. pyridine compound or H
5-!wb-sub,linned
pyrimidine compound to a pa1ladiumc3Iaiyzed coupling re;ictioll using an olefin pos,essing a protected amine fuucli,HlaJity iC.g. .. such ;w olefin provided by
,he reacrion of a phthalimide salt with 3-halo-J -propcnc.
4-hak'-1-butene, 5-halo-l-pentene or 6-halo-l-hexene j. S'-'e.
Frank e1 a1.. J Org Chem. 4:'>(15i:2947·2949 (1l)7~j: and
1vbiek e' 31.. J Or'!. Ciu:m. -f':5:\95-5397 (19fCL
5
I'.>
lo
:?ll
20
:iU
:"
""',
40
j].
l\
In aucllhcr embodimcnt. the compounds arc synthcsized by
~'()nden"jng an olefinic akobo:. such a, 4-penten-2-ol. witb an
aromatic halide. such as :'>-bmmopyridinc Of 3-iodopyridinc.
'0
0('
GO
uS 7,459,469 82
14
13
pIing of an olefin and an aromatic halide are used. lbe
required
N -methyl -N -(tcrt -butoxycarbonyl }-4-penten- 2iUl1ine can be synthesized as follows: (i) commercially available 4-penten-2-01 (Aldrich C1lemical Company. Lancaster
Synthesis Inc.) can be treated with p-toluenesulfony! chloride
in pyridine to yield 4-penten-2-o1 p-toluenesulfonate.
pre\'iously described by 1. Michel. et al .. Liebigs Ann. 11: 18]]
(1996); (ii) the resulting tosylate can be heated witb excess
metbylamine to yield N-methyl-4-penten-2-amine:
(iii) the
resulting amine. such as previously mentioned by A. Viola et i"
al.. J Chelll. Soc .. Chem. Cmnmlln. 21: 1429 (1984). can bc
al1()\\ed to react with 1.2 molar equivalents of di-tcrt-butyl
dicarbonatc in c!r:' tetrdbydrotiJran to yield the side chain.
N-mdhy l-N -(tert-butoxycarbonyl )-4-peoten-2-mnine.
TIle
halo-substituted pyridine (e.g., 5-bromo-3-isopropoxypyri1,>
dine). can be synthesized by at least two different roUles. In
one preparation. 3,5-dibromopyridille is heated at 140 C. for
14 hours with 2 molar equivalents of potassium isopropoxide
in dry isopropanol in the prescnce of coppcrpowder (5%, wi,\,
of the 3.5-dibromopyridine)
in a sealed glass tube to yield ""
5-bmmo-:'\-isopmpoxypyridine.
A second preparation of
5-bromo-3-isopropoxypyridine
from 5-bromonicotinic acid
can bc p~rfon11l:d as follows: (i) 5-J3romon.icotinic acid is
converted to 5-bromonicotinmnide by treatment with thiony!
chhlridc. followed bv re:lCtion of the interrnt,.diatc acid Ch.1l1- _)
ride with aqueous a~llnonia. (ii) "Ine resulting: 5-bromonicutinamidc. prc\'iously described by C. Y Greco et a\., 1. /lel('o(:"c!ic Chem. 7(4):761 (j (70). is subjt-'Cted to Bollnaml
deg:r<ldalillD by treatment with sodium hydroxide and a 70'~";,
so!ution llfcalcium hypochlorite. (iii) The resulling3-amino-',;
5-hromopyridine, prel'ions!y described by C. V. Greco e1 al..
.! Jil'1eo,:n'!ic Chem. 7(4I: 761 (1970), C,Ul be converted to
5-brol1lo-:;-isopropoxypyndine
by dia70tization
with
I,u,lmylnitrik under acidic conditions. j(lJlowed hy tre<l1ment
cftlle imermediatc diazonium salt with isoprop:U1olw yield ,5-brt'mo- :'I-isopropoxypyridine.
Tne pal ladi um-cata]Y7.ed
cuupling of 5-brolllo-:;-j~opropoxypyridine
and N-nJl'tbyl!\-(ten-butoxycarbonyl)-4-penten-2-amine
is carried Dut in
acetonitrile-triethylamine
(2:1. v. v) using. a catalyst consisting ('1' 1 mole '!,o palladium(JI"l acetatc 'U1d 4 nde % tn-D" 4(
tellylpho'phine. -nle rcaction can be carried out by heating. the
components at 80" C. for 20 hours to yield (4E)-N-methyl\ -( ten -bUillxycarbonyl)- 5-( S - isopropoxy -:'\-pyridiny 1)-4p~nten-2-aminc. Remo\,:!] ofthetert-bulCxycarbonyl
protecting gfllllp can bc accomplished hy treatment with 30 1110!<i1' ~
equi\'alellts nftrifluomacetic acid in anisole al 0" C. w "ff()!"d
! 41· ;-!"-m£"thy!-5-C5-isoprupoxy-3-pyridinyJ
H-pellten-:~l~li!Je. .\ .-ariety (>f ~-methyl-S-15-alkoxy
e)r 5-ar:kxv-3·
ryr;dinyl)-4-rcnlen-~<U11ine:,
are available frt'ln1 3.~-dihrc\ll10pyridine using this lype oftechnolog:y (i.e .. treatment with ';,
sodium nr potassium alkoxides or aryJoxides and subsequenl
Ikck cDupling and c!cprulectioll).
in another emhodimenL a compound such as (4E:,-!--i-m::th\"I-5-15-rndlmxy-:;-p:,ridinyl)-4-pent<:n-2-amine
can bc
synthesi7.ed by coupling a halo-substituted
py riJine.
5-brol11o-3-mctboxypyriJine
with an olcfln containing a secondary aicohol fUllctionality. 4-penten-2-oL under Heck reaclilln conditions: and lhe resulting pyridinyl alcohol intermediate can be converted to its p-tolllenesu!f(lnate
ester,
f()\lowed hy treatment with mctbylam ine Typically. th:: lyres
ofprocedurcs set forth in W. C. Frank et al..J. Org. Chem 43:
2947 (1978\ and!"\. J. !\;lalek ct al., 1. Org. Oem. 4': 50.95
(1 %:' invohing ~ipalladium-catalyzed
coupling of <]:1 nieli)]
and an aromalic halide are used. 'Ille halo-substituted pyridine, 5-brol1lo-3-illethm,'ypyridinc is synthesized usiug.rlldh- 0<
odoh)gy similano that described by H . .L den Bertl'g el al..
Reci. Ti-a,: ChillI. Pm's-BlIs (,7:377 (I94R). namely hy healing
0
f"
3.5-dibromopyridinc
with 2.5 molar equivalents of sodium
methoxide in c!r:' methanol in the presence of copper powder
(5%. w/v, of the 3.5-dibromoP:Tidine)
in a sealed glass tube
at 150" c:. for 14 bours to produce 5-bmmo-3-mcthoxypyridine. -I11e resulting 5-bromo-3-methoxypyridine.
previously
described by D. L. Comins. et aI., J Org. Chcm. 55: 69
(1990). can be coupled with 4-pemen-2-ol in acetonitriletriethylamine (1: I. v!v) using a catalyst consisting of J mole
'% palladium(Iri acetate and 4 mole % tri-o-lOlylphosphine.
The reaction is carried out by heating the components in a
scaled glass tube at 140 C. for 14 hours to yield (4E)-Nmethyl-5-( 5-11lctho~,.y-3-pyridinyl
.
H-pentcn-2-oL
'Ille
resulting alcohol is treated with 2 molar equivalents ()fp-toluenesulfonyl chloride in dry pyridine at 0° C. to produce (4E)N -methy 1-5-( 5-methoxy- 3-pyridiny l)-4-penten- 2-0 I p-lOlucm:ulfonate. The lDSylate intemJediate is treated with 120molar equi\"alents of methylamine as a 40% aqueous solution.
containing a small amount of ethanol as a co-solvent to produce (4E)-N-methyl-5-( 5-methoxy-3-pyridinyl
)-4-penten-2aminc. When 3,5-dibromopyridine
is submined 10 Heck coupling with N-methyl-N-(ten-butoxycarbonyl)-4-penten-2amine, under conditions described above. N-methyl-N-(tertbU10Xycarhonyl )-5-( 5-bromo- 3- pyridi nylH- pcmen -2amine is produced. 111is CillJbe coupled in a subs"quent Beck
reactinn v.ith styrene and deprotccted (removal of the tenbutoxycarbonyl group), as described pre\"iuusly. to give (4E)'\ -ll1dhy 1-5- [3-( 5 -trans-beta-stYr:' lpyridin)y 1]-4-pen ten- 2;\mine. Similar second coupling with ethynylhenzene. and
suhsequent depmtection, will give (4E)-N-methy!-5-[3-(5rhenylelhynylpyridin
)ylj-4-penten- ~-amine,
0
Opnca])y active Janus of certain aryl substituted uletJnic
i111,inecompotlllds. such as OS)-(4E,-N-methyl-5-i3-pyridinyi)-4-penkn-:-amilK
can he proiideJ
In (me synthetic
i'ppro~H:h. tbe !aTter type of compound is symhes!zc'd hy COll"ling a halo-substituted pyridine. 3.bromnpy;-idinc. with an
olefin possessing a chiraL secondary aicohol fum:tionality,
I)R)-4-penten-2-o1.
wlder Heck reaction conditions. 111e
r,·suIting. chiral pyridinyl alcohol inlemlediak. (2R)-( 4E)-5n-pyridinyl H-penten-2-ol
is converted to it, corresponding
p-to]uenesulfonate
ester. which is subsequently trc3ted with
lllethylamine, res-ulting ill tosylate displacement with inversion of cOllligur.nion. Typically, the types of procedures s<:t
f(mh in \\i. C. Frank et aLl. Orx. ("hem. 43: 2947 (1978) and
~. J. Malek d aL.f. Org. C/1('/II 47· 5:'195(1982) invoh'ing, a
palladium-catalyzed
coupling of an aromatic halide and an
"Ienn ~IrellS'-'d. T1-lechiral side Ch:lID. (2Rl-4·pcnten-2-o] can
b:: prepared by treatment of the chiral epoxidc. (RH+ l-prop}'lcne OXIde icol'lmercially avaibhk Ii-o:n 1-'iuk;, Uwmic.d
Cl1mpiilly') with vinylmagnesiull1 bromide ,I,1d copper(]"
Iodide in tetmhydrofurdlJ at low temperatures (-25 [0 -10"
c.'! using the general synthetic metl1l1dl1!ogy ell" A.
Killivretenos . .I. K. Stille. and L.. S. I kgedt.:s . .!. Org. Cht!1II
56: 2883 (J 99J:i. to alTord (2R H-penten-2-ol.
The resulting
chira] alcohoi is subjected to a IJeck reaction with :;-hr;)l110pyridine in acetonitrile-triethylamine
(!: i. Vi\) w,ing a
calaly;;t consisting of 1 mole % palladium(ll\ acetale and 4
nH'lc 'Yo tri-o-rolyiphosphine. '11K' reactioll is done by be<lting
the components at 140" C. for 14 hours in a ;;e:iled glass tube.
\() pmJuce the lIeck reactiun proJuct. i)R i-( 4F )-5-(3-pYliJinyJ)-4-pCnlcn-2-ol. 'J1w resulting chiral pyridiny] alcohol is
treated \\ ilh :\ molar equivalents of p-tuluenesulfonyl chlDride in dry pyridine at or, C _,to aflora the to,yJatein1ermediate. The r-lCJluellesulfonatc eSll'r is heated with 82 molar
equi\'alenb ()f mcthylamine a, " -+(~,+aqueous 'olminn. cu,Wining. if small mJ10um ofcthalJ(il as" co-slllvent. to produce
(2 S)-(4 Fl-!' -methy 1-5-(3 -pyridiny 1)-4-penten- 2-amine
CS 7,459,469 B2
15
16
In a similar manner. the corresponding aryl substituted
pen teD- : -amine, Toe requisite bromo- imidazopyridine.
)Iefin.ic amine el1amiomer, such as (2R)-( 4E)-N-methyl-5-(36-bromo-2-methy]-lH-im.idazo[4.5-b]pyridine
ean be preoyridinyl)-4-pemen-2-amine.
can be synthesized by the Heck
pared in 8~% yield by heating. 2,3-diamino-5-bromopyridine
:::mpli.ng of 3-bromopyridine and (2S)-4-pemen-2-o1. The
with acetic acid in polyphosphoric acid according. to the
3.,'sulting intermediatc. (25 H4E)-5-{3-pyridinyl)-4-pentenmethods described by P. K. Dubey et a1.. Indian J. Chern.
2-01, is converted to its p-to]uel1esulfonate, which is subjected
168(6):531 -533 (1978). 2,3-Diamino-5-bromopyridine
can
·CC) methylamine
displacement. The chiral alcohoL (25)-4be prepared in 97% yield hy heating. 2-amino-5-bromo-3oenten-2-o1. is prepared from (5)-(- )-propyJene oxide (comnitropyridine (commercially available from Aldrich Chemi:nerciaJJy availa ble from Aldrich Chemical C0mpany) using a
cal Company and Lancaster Synthesis, 1nc) with tin(H) dllo'oTOcedure analog.ous to that described for the preparation of 10 ride dihydmte in boiling ethanol according to the techniques
)R)-4-penten-2·01 from (R)-( + )-propylene oxide as repOr1ed
dt:.'Scribed by S. X. Cai et a1. J. !lied. Chern. 40(22): 3679'Jy:\. Kalivretenos, 1. K. Stille. and L. S. Hegedus, .I. Org.
3686 (1 \197).
Chem. 5(, 28:-;3 (1991).
111,mother example. a bromo fused-ring heterocycle, such
In another approach, such compounds as (3El-N-methylas 6-bmmo-l.3-dioxolo[4,5-b]pyridine
can be coupled \\ith
'H:I-(6-aminopyridin)yl)-3-buten-l-am.ine
can be prepared J5 the previously menlioned olefinic amine side chain, N-me'oy subjecting a 3-halo-substinned pyridine such as 2-am.inothyl-N-(lert-butoxycarbonyl)-4-penten-2-amine
using the
5-bromopyridinc (Aldrich Chemical Company) to a pallaHeck reaction. The resulting. Sac-protected intem1ediate can
dium-catalyZL'd coupling reaction with an olefIn possessing a
be depmtectt'd with a strong acid such as trifiuoroacetic acid
:Jn1lected aminc functionality, such as N-methyl-N-(3-butento produce (4E)-N-methyl-5-(6-(
l.3-dioxolo[ 4,5-b ]pyridin)
l-yJ)benrdmide. The benzoyl-protecting
group from the ~o yl)-4-penten-2-amine.
llJe requisite bromo compound.
:'em1ting Heck reaction product can be removed by heating
6-bromo-1.3-dioxo1014,5-b]pyridine
can be synthesized
with aqueous acid to give (3E)-N-methyl-4-(3-(6-aminopyfrom 5-bromo-2,3-dihydmxypyridine.
also known as
ridin)yl)-3-buten-l-amine.
The olefinic starling materiaL
5-brorno-3-hydroxy-2(l H)-pyridinone. via a methylenation
\'-methy]-N'-(3-buten-l-yl)be117..3J1lide, can be prepared by
procedure using bromochloromethane,
in the presence of
"C3cting 4-bromo-l-butene
with an excess of condensed c'i pOlassium carbonate and N.N-di.melhyl1i:Jrmmnide according
methylamine in N,N-dimethylfonnamide
in the presence of
to the methodology of F. Dallacker et a1.. Z Nalur{orsch. 34
J';'ltassiull1 carbomJte to give N-mdhyl-3-bulen-j -amine.
h: 17':29-]736 (J 979). 5-Bromo-2,3-dihydroxypyridine
can be
Treatment of the laner compound with benzoyl chloride in
prepared from f1.lrfuraJ (2-furaldehyde, commercia]])' availdichlommcthanc containing tricthylamine afJ(lrds thc oleahle Irolll Aldrich Chemical Company and I,ancasler Synihe:Inic side ch<lin. N-methyl-N-(3-buten·l-yl)bcn:r.amide.
)I) sis, Iuc.) using the methods described in F. DaJlacker el a1. 7..
]11e compounds described herein Gill contain a pyrdzine or
:Valul{vrsch. 34 b: 1729- I 736 (1979). A..ltematively, 5-bmmo:wridazine ring. Using procedures reported M. Hasegaw'a, et
2.3-dihydroxypyridille can be prepared according to the l,-'eh;J!. (Furopean Patent ~(). 05] 6 409 HI). 2-methylpyrazine
ur
niques described in F1' OORI745 to D. Rose and N Maak.
:;-llli'thylpyrich'Yi11e (both :I\ailable from Aldrich Chemical
In anotlk'r example ofa compollud rhal pllssesses a fllscd':·ompany) can be condell;;ed with N-merhyl-N-(krt-butoxy.;, ring heterocycle. the hromo componnd. 7-bromo-2.3-dihy('arbony! :'-3-aminoburanal to give (4F)-I\'-methyl-N-(tert-hudm-1.4-djoxinoI2.3-hJpyridine
(also knpwn as ,-hromo-5.;,xycarbonyl)-)-(2-pymzinyl)-4-penlen-2-amine
and (4E)aza-.1-oxachromane) call be condensed witl1 the pre\'iou;;iy
:\ -met hy 1-1\'-( ter1-butoxycarbonyl)- 5-(3 -pyridazi ny1)-4mentioned olefInic amine side chain. N-methyl-\'-(tcrt-bupenten-2-am.inc.
respectively.
Rcmoval of the terttoxycarbonyl)-4-pemen-2-amine
using the Heck reaction.
'Jutoxycarhonyl group with triHlloroacetic acid will produce 4') The resulting Boc-prok'Cted compound can be deprotected
,4L)-N-methyl-5-(2-pyrazinyl)-4-penten-2-amine
and (4E)with strong acid such as trifluoroacetic acid to produce (4L)S -met hy J-5-(3 -py ridaziny J )-4-pent en- 2-amine. resp<Xtively,
N-methyl-5-(7 -(23-dihydro-l.4-dioxino[
2.3-b Jpyridin)yI11w requisik
N-lllethyJ-~-(lert-buroxycarbnnyl)-3-alUi4-penten-2-amine. 'Ioe bromo compound. 7-bromo-2.3-di:'I~)but,Ulalcan;,e produced from the corresponding alcohol
hydro-1.4-dioxino[2.3-b ]pyridine, can be prepared by
\litb L2-dibmmo:Jsing techJliques described by M. Adamczyk and Y. Y. Chen ,5 treating 5-bromo-2.3-dihydroxypyridine
1I !'CT International Application WO 9212122, 111ealcohol.
eth,me and potassitun carbonate in N.N-dimethylformamide
'-methy]-N-(tert-butoxycarbonyi
)-3-;Ullino-.1-butanol. can
accordin~ to the methodoh)gy ofF. DalJacker et aLl. :\'alurle made from wmnlercially a\'ailabk 4-hydroxy-2-butanol1e
iursch 34 b: 172()-] 736 (1979). 5-Bromo-2,3-dihydmxypyLancaster SYl1lhcsis.lnc.) by ~l'qllential reductive alnination
rioint' ~1Il be prepared from tilrlimil as described ahu\'e.
Other polycyclic aromatic compounds call be prepared by
'\\ lIh melhybJ11ine anG ;;(Klium cyanoboruhydride.
using'"
the Heck reaction. Thus. cer1ain compe,unds <:an be synthe;:ilemi;lry rerurted by R. r Borch in Org. S:"I1.. :52:124
sizcd by the palladium-catalyzed coupling of a bmmo fuscd: 1 y~ j I' and prolC'Ction with di-tert-bulyl dicarbonate.
-fllL';kck CLlupling reaction described ab0ve is also u,efuJ
ring hetcrocycle, such as 6-hli.lmo-1 l{-imidazo[4.5-b]pyridine-2-tbio] with the previously mentioned oieiinic amine
;11 preparing compounds
that pos"'"-'ssceria in fu;;ed-ring hetsidt' chain. N-methyi-N'-(tert-buloxycarbony1)-4-penten-2.:rt\Cycks. Such compounds can be synthesized by the pallaamine. The Boc-protectcd intermediatc. resulting jj-OJl1 the
Jiul11-cawlyzed coupling ofa hmmo heterocyclic compOlUld.
!leek reaction. can be subjected to trealment with a stmng
'L1chas 6-bromo-2-methyl-11-J-imidazo[ 4.5-bJpyridine with
acid. such as lrit1uoroacetic acid to pmdllce (4E)-N-methyl:he pre\'iously mentioned oldlnic amine side chain. N-meellyi-N-(lert- h\lloxycarbon~'])-4-penten- 2-am ine. Typica lly.
S-( 6-(2-thio- I H-imidaz0[ 4.5-bJpyridin)yl H-penten-2the lyP('S of procedures set forth in W. C. Frank ct a1.. J. Or!? ,," amine. -11K requisite bromo compound. 6-bromo-lH-imi('hem 4~ 2947 (1978) and N J. Malek et al.. J. Org. Chem
dazo[ 4.5-b !pyridine-2-thi01 can be prepared by treating
(,-bromo-m-imidazo[4.5-b]pyridillt:
with sulfur at 2:;0-260"
~~: S~;'5 (] 9821 involving a palladium-catalyzed coupling of
C. according. to the methods described in}'. M, Yur:lov. Khilll.
'l:, olefin and a:l aromatic halide are used for the coupling
(jelerolsikJ
Dvcdin. 6: 799-R04 (1988). ('-Bromo-1H-imir<2action.!lle resu.lting tert -bll1oxycarbonyl-proK'Cted (Bocrrotcc1Cd:1 ime.-mediare can be subjectt.-d to treatment with a c' d.azo[4.5-b jpyridlllC can be obtained from Sig.ma-Aldrich
Chemical Company. Alternatively, 6-bronw 1l-j-imdazo[ 4.5strung acid, such as tritiuoroacetic acid to pruduce (4E)-Nmethy; -:5-{ H2-mclhyl- j H-imidazol-t5-h]pyridiu)yl)-4bjpyridinc can be prepared hy treating 2.:;-diamino-5-broI
US 7,459,469 82
17
J1lopyridine with formic acid in polyphosphoric acid using
methodolog)' similar to that described by P. K. Dubey et a!..
,'ndianJ. Chem. 16B(6):531-533 (1978). 23-Diamino-5-broJ1lopyridine can be prepared in 97% yield by heating 2-aminoS-bromo-3-nitropyridine
(commercially available from .AJdlich Chemical Company and Lancaster S)11thesis, Inc) with
tin(Jl) chloride dihydrate in boiling ethanol according to the
techniques described by S. X. Cai et al.. 1. Jfed. Chem ..
.10(221: 3679-3686 (1997). Alternatively. 6-broillo-1H-imidazo[4,5-b ]pyridine-2-thio! can be prepared by healing 2.3- l!)
diami.no-5-bromopyridine
with K+- SCSOEt in agU<..'(Jus
'.':hanol using methodology similar to that described by 1. C.
Kuhler et aL J. Med Chem. 3R(25): 4906-4916 (J 995). 2.:\])iamino-5-bromopyridine
C,ill be pr\.-i'ared from 2-amino-5hro!llo-3-nitropyridine as described above.
15
In a related example. 6-bromo-2-phenylmethylthio-JHimidazo[4.5-b]pyridine
can be coupled via Heck reaction
'~ilb the previously mentioned olefinic amine side chain.
:\1-methy1- N -(teJ1-butoxycarbonyl )-4-pcmen-2 -alninc. The
:'csuhing Boc-protected intennediate can be subjected to ell
treatment with a strong acid, such as uitluoroacetic acid to
produce (4E)-·N-met11yl-5-( 6-(2-phenylmethylthio-l
B -imiddYo[4,5-b]pyridin)yl)-4-pentcn-2-amine.
Thc hfllmo comxilmd. 6-bromo· 2-phenylmetbylthio-l H -iIllidazo[ 4,5- bJpy:-idinc can be prepared by a1kyiating the previously described ~)
()-bmmo-l B-imidazo[4.5-b ]pyridine·2-thiol
""ith benzyl
)fo!Dide in the presence of potassium carblmatc and N,Ndimcth ylformamide.
In anothcr example. o-hmllJooxazolo[4.5-h]pyridinc.
":hen submit1e:l sequentially 10 palladiwu catalyzed coupling 3'.'
:0 N -mcthyl-N-(teJ1-butoxycarbonyI )-4-pcntcn-2-amine
and
.leproteclion \\ ith trifluoroacetic acid. gives (4F)-N-methyl'-(6-C\ahllo[ 4,5-h]pyridinyl)-4-penten-2-amine.
The requiiik (,-hmmooxazolo[4.5-hJp:.-ridine
can be produced from
2-amilk'-5-bromo-3-pyridinol
by condensation with jemnic ."
acid or a trialkyl orthofimllate. lIsing methodology similar to
lh~,tof ~1-C. \-iaud et a1.. Hell'l'O(:;-r:!es 4 j: 2799-2809 (j (95).
ne use nf other carboxylic acids produces 2-s11bstituted-obrcllm)oxaz",,]o[4.5-b ]pyridinc:;, which are also substrates for
the IJeek reaction. The synthesis of 2-amino-5-bromo-3-py4t;
ridilwl procet·ds from f11ffllrylamine (.-\ldricb Chemical
Company). "TItus. 5-bromo-3-pyridinol (produced from furfury!amine according to U.S. Pat. No. 4.192.(46) can be
chlorinakd. using methods described by \". Koch et a!.. S:rnthesis. 499 l I 990). to give 2-chloro-5-bromc'- 3-pyridinol. "-5
\\'hich in tum can he convened 10 2-amino-5-bronw-3-pyridinf.'l t··y lreatJl.1Cnt with an]n1\..mi~1.
5-~lro!Jlo(!x;jz.o]oI5A-bjryridine. isomeric by orientation
"j'ring jmioE \() the previously Jescribed (l-hrollh)OXazu]ul·t
S-b Ip~:ridifle. ,~an a1sl' he used in the Beck coupling with ,,'
N- metilY:' N -(ten-buiux:.!carbol1yl )-4-pellten-2 -amine. Sub~eqllelit remc'\al 01" the ten-hutoxycarbonyl pro!L'cting group
['ro\" ide,
14 F )-N -methyl- 5-( 5-ox~7.0lo[ 5.4-b ]pyridiny 1)-4N~Ilh:n-2·amine The S-bmnloo\azo!oi
5.4-b ]ryridinc can be
,yntht·si/.eC lrnm 3-amino-5-bromo-2-p\'ridino]
(3-amino-5- 5'
hrum(i-2-pyridone) by condensation with formic acid (m ~;
deri\·ative then_'of) as described above. 3·.\mino-5-bromo-2pyridillol can be made by brominarion (using techniqucs
described by 1. Batkowski. Roc:::. Gem. 41: 729-'741 (1967\)
and subsequent tin(ll"; chloride reduction (according to the 6\'
:J)eth,'d described by S. X. Cai et a!...! Med. Chem. 40(22):
367S:-:;6~6 (l997)) of wmmcrcially available 3-nitro-2-pyriJino: (Aldrich Chemical Company.l.
06cr polycyclic aromatic compounds of tile present
invention can be prcpared by the Heck reaction. 11ms both (5
5-hronIofuro[ 2.3-h ]pyridine and 5-bromo-1 H-)'yrrolo[ 2.3-b I
['yridine ;;an undergo paliadium catalyzed coupling with the
18
pre\'iously described olefinic amine side chain. ~-methyl-N(tert-butm:ycarbonyl)-4-penten-2-amine,
to give (4E)-N-metilyl-N -(ter1-butoxycarbonyl)- 5-( 5- furor 2.3-b ]pyridiny 1)-4pentcn-2-amine
and
(4E)-N-methyl-N-(tcJ1buto>,:ycarbony 1)-5-(5-1 H1 r·J-pyrrolo[2,3-b ]pyridillyl)-4penten-2-amine respectively. Subsequent removal of the tertbutoxycarbonyl group with uifluoroacetic acid will provide
(4 E)- N -metilY]- 5-( 5-fino[ 2.3-b ]pyridillyl )-4-pcnlen-2amine and (4E)- N-methyl·5-(5- I l-I-pyrrolo[ 2.3-b ]pyridinyl)4-penten-2-amine. '111ereguisiLC 5-bromofuro[2.3- b]pyridine
and 5-broJno-II'l-pyrrolo[2.3-b]pyridine
can be made from
2J-c1ihydrofuro[2.3-b]pyridine
and 2.3-dihydropyrrolol.2.3b]pyridine respectively. by bromination (hromine and sodium
bicarbonate in methanl,l) and dehydrogenation (2.3-dichloro5.6-dicyano- J.4-benzoquinone), using chemistry described
by E. C. Taylor et a!.. TeTrahedron 43: 5145-5158 (987)
2,3-Dihydrofllro[2,3-b lpyridille and 2.3-dihydropyrroloI2,3b ]pyridine are. in turn, made from 2-chlllfupyrimidine (Aldrich C1lcmical Company). as described by A. E. Frissenet al.,
TeTrahedron 45: 803-812 (1989), by nucleophilic displacement of the chloride (with the sodium salt of3-butYll-l -01 or
with 4-amino-l-bUlyne)
and subsequent intramolecular
Diels-.\ldcr reaction. Using similar chemistry, 2,3-dihydrofuror B-b ]pyridine and 2,3-dihydropyrrolol2.3-b]pyridine
arc a1>o pmduced from 3-methylth.io- L2.4-uiazene (E. C.
Taylor et aL TeTrahedron 43: 5145-5158 (1987)), which in
turn i, m"dc from glyoxal and S-mcthylthioscmicarbaljdc
(W. l'audlereta1..JHeterr)(:l'ciicChem.
7: 767-771 (1970)).
Brominatcd
dihydrofurllpyridines,
dibydropyrrolllpyridiucs. and dihydropyranopyridilles
arc also substrates for
the palladium catalyzd
courling. For instance. both
5-bromo-2.3-dihydrofuroI2.3-b]pyridine
and 5-bromo-2.3dihydmpyrroloi2.3-b'lryridinC'
(irom brominatioll of 2.3-dihydwfuw! 2.3-b !ryridine and 2,3-dihydmpyrrolClI2.3-b ]pyridille. as described above I can be coupled witb the pre\'inusly
mentioned olef1nic amine side chain in a I-leek process. Subs~'queIl1 depmtL'Ction gives the corresponding (4F)-N-mc.
thyl-5-(S-(2,3-dihydwfllro[
2.3-b ]pyidin)yl )-4-petJten-2amine and (4E)-N-methyl-5-(5-(2,3-dihydropyrrolo[2,3-b]
pyridin)yl)-4-penten-2<uninc.
Similar treatment of (i-bromo2.3-c1ihydrofuroI3J-b ]pyridine (isumeric at the ring fusion
"ith the [2.3-b] system) will provide (4E)-N-lllelhyl-S-(6-(2.
3-dihydrofuroI3.2-b ]pyridn.ly1)-4-penten-2-amine.
'I1Je requisite 6-bromo-2.3-dihydrofuro[3.2-b
Jpyridine can be made
from 5-hromo-2-Illl'1llyl-3-pyridinol
by sequcnti<J1 treatmenl
with two equivalents \)1' lithium diisopwpylamide i,to general\: the 2-metbylenyl. :"-(\\y dianion) and one equi\'alent of
dibromolJ]elh~U1e.. \iternativc!y. llsing chemistry SImilar \\)
thai described b~ '1'1. U Koller el a1.. -"l'mh. COfllllllin .~5:
2%3-74 (1995). the silyl-protected pyridinol(5-hruIllo-2-metJJyl-3-1rimcthylsily]oxypyridine)
can bc treated ~equentially
\\ ith one equi\alel1ll'fJithiul11 c1iisopropylamidc and ,l!1 alkyl
or aryl aldehyde 10 produce a 2-(2-(1-a1kyl- or l-a[)'I-l -h)'uroxy )dhyl)-5-hromo- 3-(trimdhylsilyJuxy )pyridine. Such
materials can be clJl1vened, b\' IllL'1hods (such as acid catalyzed ~ycJi/.ation or thl~Williamson synthesis.l kuo\vn to those
skilled in the al1, into the c(mespClnding cyclic ethers
C·alky]or
:-aryl-6-bromo-2.3-dihydrofuru[3.2-blpyridines).Simiiar chemistry. in which epoxides (instead of
allkhydes) are used in reaction with the pyridinylmethyl carbanion. lC<Jdsto 2-al1:yl- and 2-aryl-7-bmmo-2.3-dihydropyranu[3J-b jpyric1incs. These 2-substitll1ed. brominated dihydn,furo- and dihydropyranopyridines
are also substrates for
tbt· Heck reaction. F,)r instance, o-brorn(~-2.3-dihyd.ro-2-pheuylfuro[3.2-h'lpyridiuc can be coupled, in a palladium catalyz.ed process. with N-methyl-N-(tert-bU1oxycarbony])-4pentcn-2-aminc.
and the coupling product treated with
US 7,459,469 B2
19
trifluoroacetic acid (to remove the tert-huto:>.ycarbonyJ
group). to give (4E)-N-methyl-5-( 6-(2,3-dihydro-'::-phenylfllrol3.2 -b ]pyridin)y 1)-4-pentcn- 2-amine.
20
Formation of E-metanicotille Hydroxybenzoates
'I11e (E)-metanieotine
hydro~ ..ybenzoates are formed by
reacting the E-metanicotinc-type
compounds
described
above with hvdroxybcnzoic acids. The stoichiometrv of the
]hc 5-bromo-2-methyl-3-pyridinol,
used to ::ynthesize the
individual co~pon~nts (E-metanicotine and hYdroxybenzoic
brominated dihydrofuro- and dihydropyranopyridines.
is
acid)
used to prepare the salts can vary. It is typical that the
produced by standard tr.msformations of commercially availmolar ratio ofhydroxyben7l.1ic acid to base (E-metanicotine)
able materials. Thus. 2-methyinicotinic acid (Aldrich Chemiis typically 2:1 to 1:2, more typically 2:1 or 1:1, but other
cal Company) can be converted, by sequential treatment with
ratios (such as 3:2) are possible. It is preferred that the molar
thion;l chloride. bromine. and ammonia (methodology
I')
ralic) of acid to base is 1: 1. Depending upon the manner by
described by C. V. Greco el a1., J. Heterocyclic Chem. 7:
\\·hich the salts of the present invention are formed, those S<Jlts
761-7()(i (1970)). into 5-bromo-2-methylnicotinamide.llof·
may have crystal structures that may occlude soh'ems thai arc
maIUl rearrangement of 5-bromo-2-methylnicotinamide
with
present during salt formation.TIlus, salts of the pre,ent invenhypochlorite will give 3-amino-5-bromo-2-methylpyridine.
tion can occur as hydrates and other soh'ates of varying sto\\'hich can be converted to 5-bromo-2-methyl-3-pyridinol
by i5 ichiometry of ,olvent relative to aryl substituted amine.
diazotization v,'ith sodium nitrite in aqueous sulfuric acid.
'111emethod for providing compounds ofthe present inveno'I.lternative1y, alanine ethyl ester (Aldrich Chcmical Comtion can \"ary. For instance, the preparation of (2S)-(4E)-Npanyi is converkd (using ethyl fomlate) into its N-formyl
methyl-5-(5-isopropoxy-3-pyridinyl)-4-penten-2-amine
in a
derivative, which is then converted to 5-cthoxy-4-methyloxp-hydroxybenzoate form can involve (i) adding a solution of
azoIc using phosphorous pentoxide (N. Takco et aI., Japan 211 suitably pure compound dissolved in ethanol to a solution of
p-hydroxybenzoic
acid (J.1 equivalents) in ethanol, heatl.'d
Patent No. 45.012.732). Diels-Alder reaction of 5-ethoxy-4under reflux, to foml a precipitate, (ii) applying heat andior
:nethyloxazole with acrylonitrile gives 5-hydroxy-6-methwater and ethanol (water nolto exceed 10%) to dissolve the
yinicotinonitrile (T. Yoshikawa et aI., Che1l1. Pharm. Bull. 13:
precipitate. (iii) cooling the resulting solution if necessary to
8f:; (1965)). which is converted to 5-amino-2-methyl-3-pyrldinol by hydration llild Hofi113nn rearrangenlcnt
(Y 2:' cau>c preci pi talion of Ihe salt and (iv) ftltering and collecting
the salt. The stoichiometry, solvent mix, solute concentration
Mori,><lw:let al .. A.g7: Bioi. Chem. :'9: 1275- I 2X1 (1975)). "llJe
and temper,HUTe emp1<'yed call vary. but thc fonmnion ofihl'
5-amlnc)-2-methyl-:'-pyridinol
can then be converted, by diasalt> is within the level of skill of those of skill in the art.
zotlz3tio!l inlhe presence of cuprous bromide. to the desired
Formation of Other Sah FonllS
5-hromo-2-methyl- 3-pyriJiIll)l.
If desired. once the hydroxybenzoate
,alts are isolated.
'lllese methods each pro\lde the (E)-metanicotine-type
other salt f~mns can he fonned. for example, by Jinx:! reaccllmpounds as the major pmduct. but also produce a minm
tioll with ~Ulotherpharmaceutically acceptable acid or by !in;t
amount of the corresponding (Z)-metanicotine-type
COllii,;olating the free ba,;e (by reaction with strong. base and
Pl'tUlds and Ol~ler isolllt:rs. as beli)rc described. These minor
eXiraction into an appropriate solvent) and then ret.lclion WiTh
reaction products C<lll be relUO\'l:xJusing couventional tech- 1;
anNher pharm~lceutjcally acceptable acid. Such procedures
niques_ if desired .. '\lternati\·ely. as described in more detail
arc bown It' those of skill in the art.
bel()\\, the (l'i'IMtanicotine-1Ypc
compOllllds can be isolawd
II I. Pharmaceutical Compo,itions
tiS the hydroxy benzoate salts. which can precipitate out in
substantially pure limll from a reaction mixture including
The phannaceu!ical compositions ofthe present invenlion
hydroxybenzDate s..1ltS of the (Z)-metanicotine-type
com- 4" include the hydroxy-benzoates described herein. in the pure
pmUlds and other minor reaction products.
state or in the fonn of a composition in which the compounds
are combined with any other phanuaceutiCtllly compatible
Other methods beside the Heck coupling reaction can be
pmdUl"L which can be inert or physiologically active. Such
used 10 provide the compoul1l.ls. For example. the (E)-metacompositions can be administered,
fix example. orally,
niCl,tine-type compounds can be prepared using the techniques set forth by Loftler 1.'1 al.. Chem. Bel:. 42::'4:'1-343R "5 pan:n\erally. recta lIy, or topically.
Lxamples of solid compositions for mal administrati\1n
I. I <)0'11 and L;)forge . .!..4.C.S 50:'::477 (1928) from substiinclude. bUI are not limited to, tablets. pills. powders (gelatin
1tnC'd nicotine-lype compounds. Certain 6-subslituted metacapsules. cachels I. and g.rJIltiles. ln Ihese cnmposilions. Ibe
nicolille-l:'Pe COmp(lIUld, C<lllbe pr"'pared from the cone,leI:\'(' compound i, mixed ~i[h one or more inert diluents,
,p(Hllung (i-,uhstinIled nicolin.:-Iype compound, u,ing the
~eneral method, of A.cheson eI al.. J. Chem. So(". Perkill i,. such as stDfI,;h.cellulose. sucrosc, laclOsc, or silica: idc;)!ly,
under a stream of an inert gas such as argon.
hans. 1(2):579-585 i:9XO).Tile requisite precursor, for sucb
The compositions can also include substances other than
comp'.llmds. (i··,;ubstituted nicotine-type compoullds. can be
diluen:s. f,'r example. ,me or more lubricants such as magnesynthesizcd from 6-sutJstinned nicotinic acid esters using the
,iuIT, Slear.lie or laic. a colOI~mL<l coating t:coateJ tablets). or
g:enlTdi methods discl\lsOO by Rondahl. ACTa Phanll. Slice.
141 i 3-11 g (1977). Prcpararion of certain 5-substitll1ed -,1 a \'amish.
Example,; of liquid compositions for ('ral admini,trll1ion
lllClanico!inc·t\'pe compound, can be accomplished filml thc
include. bm are not limited to, solutions. suspensions. emulcorresponding 5-substinned nicotine-type cnmpounds using.
sions. syrups, and elixirs that are phannac.eutically acceptable
ihe general method taught by .-\cheson d a1.. J. ChClIl. Soc.
and typica]]y contairJ inen diJuents such as water. ethanol.
j'erkili Trails. ] (2): 579·5R5 i 1980). TIle 5-haltH'ub,tiruted
~lic()tine-tY'Pe compounds (c.g .. f1uoro- and bromo-,ubsti('l' glyCi.:nll. vegetab1c nils, or liquid paraffin. TIlese wmpnsitioes can comprise substances other th,lIl 1be diluents, for
HnC(] lliwline-type cOmp01111GS)alld the 5-amino nicoline·
cXampic, wening agents. sweeteners. thickeners. flavors. and
lype wmplHmds can he pn:pared using the generai procestabilizer:.;.
dures disclosed by Ronda.l]!, ..lei. Phanll. Suet:. 14: 1n-11 R
1.1(':") The 5-triiiuoromethylllicotine-type
wmpowlds can
Sterile composilioas
for parenteral administmtion can
be prepared using the techniques and llwterials set forth in '" include, filr example. agm.·olls or nonaqueous solutions. sn~Asb..im:1Det a I.. Chell!. !'hI/I'm. BII!i .. :'8(9):2~46-2458 (1990)
pensiO!L~. ,:nd emuhiolls. Examples of suitable S(>!venl, and
,1;-lC !\Dndahl. ACio j)harm. Suec.. 14: 113-1! R (1977).
vehicies include. bm are not limited 10 aqueous solutions.
US 7,459.469 B2
21
22
:Jreferably buffered aqueous solutions, propylene glycol, a
genetic predisposJlIOn, infection or trauma: or can be of
JolyetltyJene glycol, vegetable oils. especially olive oiL
unknown etiology. CNS disorders comprise neuropsychiatric
injectable organic esters. for example ..'thyl oleate. and other
disorders. neurological diseases. and mental illnesses, and
include neurodegenerative
diseases, behavloral disorders,
appropriate organic solvents. These compositions can also
cognitive disorders. and cognitive affective disorders. There
include adjuvants. especially wetting agents, isotonicity
agent~. emulsifiers. dispersants, and stabiIi7.ers. Such sterile
are st."verdlCNS disorders whose clinical manifestations have
::ompositions can he sterilized in a number of ways. for
been arrributed to eNS dysfunction (i.e .. disorders resulting
from inappropriate levels of neurotransmitter release, inapexample, by asepticizing filtration, by incorporating sterilizpropriate properties of neurotransmitter receptors. andlor
ing-agellts into the composition, by irradiation and by heating.
·nley can also be prepared in the form of sterile solid compo- l!> in<lppropriate interdction between neurotmllsminers and neusitions ","hich can be dissolved at the time of use in sterile
rotr"Jnsmil1cr receptors). Several CNS disorders can be attribwater or any other s1eri]c injt.'Ctable medium.
uted to a deficiency of choline. dopamine. norepinephrine.
andior serotonin.
Examples of compositions
for rectal administration
include. but are not limited to, suppositories and rectal capExamples of CNS disorders that can be treated using the
sules that. in addition Il1 the active product, can include 15 E-l1letanicotine compounds
and hydroxybenzoate
saIlS
excipiclllS such as cocoa butter, semi-synthetic glycerides.
described herein, and phannaceutical composilions including
and polyethylene glycols.
the~ compounds and salts, include pre-senile dementia
Compositions for topical admillistration can, for example.
(early onset Alzheilller's disease). senile dementia (dementia
be creams, lotions, eyewashes. collutoria, nasal drops or aeroc" 0 f the AI weimer's type ), Lewy Body dementia. micro-infarct
sols.
dementia. AIDS-related dementia. IUY-dementia, multiple
The plmnnacemical compositions also can include various
cerebral infarcts, Parkinsonism including Parkinson· s disother components as additives or adjuncts. Exemplary phareasc. Pick·s disease. progrcssive supranuclear palsy, Hunmaceutically acceptable components or adjuncts which ar\;,
ting.lOn's chorea. tardive dyskinesia. hyperkinesia, epilcpsy.
employed in relevant circumstances include antioxidants.
free radical scavenging agents, peptides, gro~1h lactors. anti- :' mania. attention deficit disorder. anxiety, depression, dysbiotics, bacteriostatic agents, inununosuppressives,
anticolexia. schizophrenia depression. obsessive-compulsive disoragulants. buffering agcnts, <lnti-inl1alllmatory agents, iillliders. TL)urelle's syndrome, mild cognitiw impaim1t~lll (Mel).
pyretics. time release hinders, anesthetics. stemids. and
age-associated memory impaimlent L\AMl). prematllre
corticosteroids. Such components can provide additionai
amnesic ,md cognitive disorders which are age-related or a
therapeutic benefit. act to affect the therapeutic action Oftil\;, ,I,
consequence of alcoholism. or imnnm,)deficicncy syndrome.
pharmaceutical comp,)sition. l1r act tov.ards preventing. any
or are associated with vascular disorders, with genetic alterpotcmial side ellects \\'bich may he posed as a result of
ilti,'ns (such as. fur exanlple, trisomy 21) l1r with anentioll
administration oftbe phannacelltical composition. In certain
d\;'liciencies or learning deficiencies. acute or cllJ\.\Oic neumcircumsull1ces. a compound of the present invention call b,'
c:l1plnycd as ?dr1 ora pharmaceutical cOlnposilion with olhl:[ "'.., deg.enerative conditions such as amyotrophic lateral sclem,is. multiple sclemsis, peripheralneur\Jlrophies,
and cerebral
compounds intended to prevent or treat a particular disorder.
Dr spinal traumas. In addition, the compouncb can be lIseu 10
1\. Methods ~)fTreatlJ1ent
trem nicotine addiction andior oUler behavioral disorders
TIle hydroxyhcl1loate salts descrihed herein arc useful for
related to substances that lead to dependency (e.g .. alcohol.
treating those types of conditions and disorders for which 4"
c(leaine.
heroin iU1d opiates, psychostimulams. benzodiazother types (If nicotinic compounds have been proposed as
epines. and barbiturates). and to treat obesity. '111ecompounds
thefJpeutics. See. for example, Williams et aL ]);\"&1' 7( 4):
C,Ul also be used to treat pathologies exhibiting ffil inflamma:205-227 (1994): Americ et a1.. C;\,S Drug RC1: I (l): J -26
torv character within tile gas1rointestinal system such as
(1995): :\rneric et a1.. E.\j!. Opin. lINest. Dnlgs 5(1 ):79·1 00
(199(i1: Benchcrif et a1.. .!. P!la17l1a,'o!. Exp. Ther. 279: 14 J 3 ~-' en'Ilm's disease. irritable bowel syndrome and ulceratiH'
i 19'i(i): l.ipriel1o et al.. .J. j-'harmo("o! .. f."J.p. ll1er: :279: 142'::
colitis. and diarrheas.
(19'}(;): ])am;~i "t al.. S"liroscience (1997): Holladay et aL..l.
'ihc manner in which the hydroxybenzoatc sa]ts ;Jr,' admin.\1,,) ("hem. 40(2gl: 4169-4194 (1997): BaW1ll11 et al.. S('iisterl'u can \·a,y. 111e salts can he admillistcred by inh,datiun
ellcL'
279: -;-7-80 r,J<)98i: peT WO 94fOS99:2: PCT we>
(c .g. .. in the form nLm aerosol either nasally or llsing. delivery
%~ 1475: and 1..:.S. Pal. Nos. 5.583,140 to 13encherifet al.: "
articles
ur the lype set forth in U.S. Pat. No. 4.922.901 10
5.5')1.91 <) 1<: Dull et a1.: and 5,604.231 Il1 Smith et al.
Brook.>
et
aLl: topically (e.g., in lotion form): orally (e.g... in
'[hc ,a Its Lan also be med as adjmct therapy in combinaliljuid
fonn
within a solvent such as an aqueous or nOIltion with eXJsting therapies in the managemcnt of the a fore:aqueous liquid. or within" solid carrier): intravenously (e.g...
menUllnt..u typt.'S of disease'S and disorders. In slich situations.
within a dextrose or s;:dine solution): as an .infusion or injecit is prcferabiy to administer the active ingredients in a man-"
ner that minimizes djects upon nAChR subtypes such as
tiull (c.g .. as ,1 suspension or as an emulsion in·a pharmaccul1h)SeUJatare associated with muscle and ganglia. This can he
tically acceptable iiquid or mixtme of iiquids), intrathecally:
a~complished hy targeted dmg delivery and/or by adjustlllg
lll1racercbroventlicnlarly:
or transdermally (e.g .. using a
the dosRge such that a desired effect is obtained without
transdcnnal patchl ...\lthoug,h it is possihle to administer the
meeting the threshold dDsage required 10 cause signifi~ant ""
salts in the form of a bulk aClive chemical. il is preferred to
side effi.v..;ts.The pharmaceutical compositions can bc usd to
present each salts in t11eform of a phamlaceut ical composiameliorale ,my oi'thc symplollls associated with lhose ronji:i"n or formulation f(lr efficient and elE~ctive administration.
'linn:).diseases. and disorders.
txempl:lry methods for administering such salls will be
r:xamples of conditions imd disorders lhm C<Jll be treated
include neurulogical disorders. neurodegenerativc disorde:-s. ,,,. apparent to the skilled artisan Fm example. the salts can be
adminiskred in the form of a tabiet. ;; [lard g.elatin capsule or
in panicnlar. Cl\S disorders, and inflammalory disorders.
as a lime-release capsule. As another<:xample. the salts can be
eNS dis(lrdcrs can be dmg induced: can bc anributed \()
., ...
--'
US 7,459,469 B2
24
of the salts of the present invention against !hose n..-\ChRs
delivered transdermally using the types of patch technologies
responsible for cardiovascular side effects is demonSlrdted by
available from Novartis and Alza Corporation.. The adminisa lack of the abil ity of those salts to activate nicotinic function
tration of the pharmaceutical compositions of the present
of adrenal chromaffin tissue. As such, s"Uchsalts have poor
invention can be intermiUent, or at a gradual. continuous.
ability to cause isotopic rubidium ion flux through n..-\ChRs in
constant or controlled rate to a warm-blooded animal. (e.g .. a
cell preparations derived from the adrenal gland. Generally,
mammal such as a mouse. rat cat rabbit, dog, pig. cow. or
typical preferred salts useful in carrying out the present invenmonkey): but, advantageously, the compOlUlds are preferably
tion maximally activate isotopic rubidium ion flux by less
administered to a htilllan being. In addition, the time of day
and the number of times per day that the phannaceUlical II; than 10 percent often by less than 5 percent of that maximally provided by S( -) nicotine.
formulation is administered can vary. Administration preferably is such that the activc ingredients of the pharmaceutical
"llle salts are dlective towards providing some degn..'C of
Ji.lflllulation interact with f(.'t:eptor sites ",ithin the body of the
prevention of the progression of CNS disorders. amcl iorating
subject that affect the functioning of the eNS or of the gasthe symptoms of CNS disorders, and anleJiordting to some
trointestinal ((iI) tract. More specifically. in treating a eNS j 5 degree the recurrence ofCNS disorders. However. such effecdisorder administration preferably is such so as to optimize
tive amolUlts of those salts are not sufficient to elicit any
the effect upon those relevant receptor subtypes which ha\"e
appreciable undesired nicotinic effects. as is demonstrated by
an e[fect upon the functioning of the CNS. while minimi7jng
decreased effects on preparations believed to reflect effects on
thc effects upon muscle-type receptor subtypes. Other suit- 20 !he cardiovascular system, or effects to skelt:tal muscle. As
able methods for administering the salts arc described in U.S.
such, administration of salts of the present invention provides
Pal. No. 5.604.23 I to Smith et a!., the disclosure of which is
a therapeutic window in whieh treatment of certain CNS
incorporated herein by reference in its entirety.
disorders is provided. and undesired peripheral nicotinic
effects/side effects are avoided. 'lbat is. an efiective dose of a
'Jne appropriate dose ofthe salts is that amount effective to
prevent occurrence of the symptoms of the disorder or to treat 2:- compound of the present invention is sufficient to provide the
some symptoms of the disorder from which the patient sufdesired efiects upon the eNS, but is insufficient (i.c .. is nOI at
fers. By "effective amotmt:' "therapeutic atllount," or "effeca hig.h enough level) to provide undesirable side eJfects. Preftive dose" is meant that amount su fficient to elicit the desired
erably. effective administration ofa compound ofuw present
pharmacological or U1erapeutic effects. !hus resulting in
invention resulting in treatment of eNS disorders occurs
dlective prevention or lreatnlent of the disorder. 1l1US. when .)!.i
up,m administratioI1 of less than 1,/,. frequently less than 'A,
treating a eNS disorder. an ellecrive amount ofthe hydroxyand often. less than lilO. that amount suflicient to cause allY
benzoate salts is an amount reqnired to deher. across the
side effects to a signific1Ult degree.
blood-brain barrier of the su~iect. a sufiiciern amount of the
The following synlhetic and analytical examples arc prcfree base drug. 10 bind to rele\"ant receptor sites in the brain d
\idc-d
10 illustrdte the preselll invention. and ,1ll1uld not be
the ~ubject~ and to Iuodulate relevant nicntinic receptor sub- -,~
wllStmed as limiting th..:reof. In these exmnplcs, all pans and
types (e .g .. provide neurotransmitter secretion. thus resnltlllg
percentages arc by ",eight. unless othef\,'ise noted. Reaction
in effective prevention ortreatment of the disorder). Prl'venyields are reported iI1mole percentages.
ti'lIt oftbe disorder is manifested by at least delaying the onset
urthe symptoms oft be disorder or reducing the severity of the .
symptoms. Treatment of the disorder is manifested b~' ~I 4"
EXAMPLE 1
decrease in !he symptoms associated with the disorder or an
amelioration of the recurrence of t11esymptoms of the disorSynthesis of (1S)-(4EJ-N-methyl-5-(5-isopropoxy-3dl:r.
p) Tidinyl )-4-penten -2 -am ine p-bydroxybenzoate
I1te effective dose can vary, dl'pending upon lilctOrs such L<
a, the condition of the patient. the severity of the ,ylUptoms of
(2S )-(41-')-N -mctbyl-5-(5-isopropcxy- 3-pyridinyl )-4the disorder. and the lllatlIler in ,vhich the phannaceU!ical
penkn-2-aminc p-hydrnxyhenzU3te
cnmp,'sitidn is administered for buman patienls, the df,'clive dose of typical sailS generally require'S administerins the
1'-1Iydwxybenzl'ic acid 12.62 g. 19.0 nUllo!.' was added in
salts in:ill amount sutlicient to modula1e rde\';Jnt receptors j(1
" portions to a sHrred solution C2S)-(4i:)-1\-mdhyl-5-(5-iso,11fect neurolTansminer (e.g .. dopamine) release hU1 the
propoxy-3-pyridinyl )-4-pentcn-1-amine (4.79 g 01"93% pure.
amount should be insufficient to induce ellens on skeletal
19.0mmol) in isopn'pyl acetate (50mL) During theaddilion.
lIlu,cJes and gang.lia to any significant degree. 'n1e effective
crystallization nfsalt was evident.. A-Jier complete addition oj"
dose oflhe hydroxyhenzoate salts will of course Llilfer Ir-om
patient to patient but in general includes amounts ;;tar,ing '.' the p-hydroxyhcnzoic acid. tll<:sllspcnsion was hC3tcd near
its boiling point as isopropanol was slowly added. Alier 15
where eNS effL'Ctsor tlther desired therapeutic effects ('ccur.
!I~Lofisnprnpanol had been added. complete dis,o]ution was
hut belm, the amount where muscular em,'cts are ohsen ed.
('blained. Cooling of the solution to ,unbient temperature
'nte dt'ses depend on the desired effect. the duration nf
i overnight) re,l1lted in deposition of a crystall ine mass, ,,--hlCh
treatment and the administration route used: they are generally be~'een (l.OS mg and 100 Ill!, of active subs1ance per day I" was collected by suction filtration and air dried (4.03 g). A
,econd crop (O.R2 g) was isolated from thc (;oncentmted Iil('rally for an adult. Generally speaking. a medical doctor will
trate, by addition of acetone. 'J11Ctwo crops of cryslLlls were
detem1ine the appropriate dosage as a fimction of the age.
combined and rc'Crystallized from acetone (50 mL). 'J11esolid
weig.hl and all the other facton; specific to the patient.
\\'as collected by suction filtration and dried in the vacuum
The salts of !he presen: invention. when emplc>yed in effece
tive 2mounts in aCCl\rJance with the method of the present ,,' (wen 150 C.) IClr ISh. TI1is left 4.24 g (60.0"';;) of v,.-hile
cryslO!S
(98+%
pure hy both G-CMS and LCMS: m.p 99-1010
invention. otien lack the ability 10 elicit acti,'ation of human
C.).
ganglion n:\ChRs to any significant degr<'C. '111isselccti\ity
,.
-~
US 7.459,469 B2
26
EXAlv'..PLE 2
(2S )-(4E )-N -Methyl- 5-( 5-isopropoxy -3-pyridinyl )-4penten-2-amine p-hydroxybenzoate
Synthesis of (2S )-(4E)-N-methyl-5-\ 5-isopropoxy-3pyridinyl )-4-pentcn-2-amine (via the IIeck reaction
with (S)- N- MethyJ-N -(tert-butoxycarbony 1)-4pentcn-2-amine) and the use ofthc p-hydroxybenzaate salt to facilitate isolation and purification of
(2S )-(4 E)- N -methy1- 5-( 5-isopropoxy- 3-pyridinyl)-4penten- 2-amine
3-Broroo-5-isopropoxypyridinc
:\ 72 L reactor was charged successively with sodium
tcrt-pemoxide (2.2 kg. 20 mol) and 1-methyl-2-pyrrolidinolle
(17.6 L). TIlls nllxture was stirred for 1 h. and then :2-propano 1
(12 L) was added over a period of2 h. 3,5-Dibromopyridin.:
(3.0 kg. 13 mol) was then added to the reactor. and the nllxturc
was heated at 75° C. for 12 h under a nitrogen atmosphere.
The mixture was theu cooled.. diluted with toluene (15 L). aud
waslu.'Ii with water (30 I..). 'nle aqueous phase was eXlrdcled
with toluene (15 L), and the combined toluene phases were
washed with waTer (15 L) and concentrated under reduced
pressure, to give 2.5 kg of dark oil. TIlis was combined an
equal sized batch of material from a second nm and vacuum
disTilJed (b.p. 65° C at 0.3 mm), to yield :\.1 kg: (57%) of
3-bmmo-5-isopropoxypyridine
as a pak yellow oil.
(2R)-4-Pentcn-2-ol
(2R)-.t-Pentcn-2-ol WaSprepared in 82.5% yield lrom (R)(+"!-propylcne oxide according to procedures sel10l1h in A
l\.ali\Tet<'lllls . .1_ K. Stille. and L. S. Heg.edus . .1. Org. Chen!.
56 :::883 (1 \i~ll).
(S)- N-Melhyl-N-(H:I1-bliloxycarhonyl
mnine
A mixture of 3-bromo-5-isopropoxypyridine
(21.0 g, 97.2
mmol). (S )-N- Methyl -N -(ter1-butoxycarbonyl )-4-penten- 2amine (24.0 g, 120 mmol), DMF (53 mL). K2CO:; (22 g, 159
mmol), paJladium(II) acetate (0.22 g. 0.98 mmol) and tri-otolylphosphine (0.57 g. 1.9 lunlol) was degassed and placed
\I' under a nitrogen atmosphere.
'J11e stirred mixture was then
heatcd at 13(f' C. for 2.5 h. To remove palladium salts.
Smopex 1M (20 g) and ethyl acetate (100 mL) were added. 'n1e
stirred mixture was heated at 50° C. for 5 h and at ambient
temperature for 16 h and then filtered. The filtrate was conL';
centrated llllder reduced pressure, and the residue (83 g) was
dissolved in methanol (25 mL), cooled in a cold water bath
«5° C) and treated drop-wise with 6 M Hel (100 mL). 111is
mixture was stirred 3 h at ambient temperature, and the
c,~ met11ano1 was removed by concentration under vaCUlllll. The
remaining aqueous mixture was washed with dich1oromethane (100 mI.), made basic by careful (wiih cooling)
addition of 3 M NaOH. and cxtracted (2x200 mL) with
dich1orDmethBne. 111ese Jailer extracts were washed wit1)
::s saturated. aqueous NaCI and concentmted under vacuum. The
residue was dissolved in acetone (150 mL). and p-hydroxybeilloic acid (14.0 g. 1Ollnmol) was added, After complete
dissolution of the p-hydroxybenzoic
acid. the solution was
"" kept at ambient temperature, as a large amount of solid
f(,rmed (several hours). After several hours of cooling. at-15°
c. the mixture was ,uction filtered. The resulting solid (24.8
g) \\a5 recrystallized from acetone (240 mI.) to give 2~3 g
(6] ()",o) of off·v,hitc cry,wl, (97+%, pure by GeMS and
LeMS).
)-4-pell1en-2-
.-\ mixture of(R)-4-penten-2-01 (7.62 g, 88.5 Olmol), pyri- oj"
dine 115 m!.), and dry (distilled Irom calcium hydride)
dichlurometll<lne (30 mL) was stirred in an ice baTh as p-toluencsulfonyl chloride (18.6 g. 97.4 mmol) was added over a 3
min period. The mixture was stirred 20 mill at 0" C. and 16 h
ai ,Ullbicnt temp<:raturc. as a heavy precipitate formed. San,- ;,
,at cd aqucuus s(Jdiulll hicarbonate (75 mL) was added. and
;lie hiphasic mixture was slirred \'igorous!y for :; h. TiJc
dicl'lorumcthdnc pl.wsc and two Jicbh)folllethaJlc extrdcts (50
mi. e(Kh) 0;" the aqueo\ls phase were c,)mbined, dri"d
:'(:
(l\a2S0~). and concentr<lk'd by rota!)' e\·:Jpuratioll. Hig.h
\·<lcuum treatmentlefi 187 g. of ]ight yellow oil. w-hich was
c, ,;:j.,iJled \\'ith dimethyl1<.mmunidc (DIv1f:) (3S mi.) and 40".;.
aqueous methylamine (35 m, ). This solution was stirred at
;mibient temperaturef()r 48 h and then poured into ;J 11lixtur~ ';
:1f saruratd "qm.'ous sodium chlllridc (;00 mf) and 2.5 M
sodium hydroxide (50 illL). This mixture was cxtracted ",it]]
ether 15x250 mL L and the eTher extracts were dried (Nn :SC\)
and concentrated hy rotary ~vaporation (from an ice cookd
hath: to a \'ulume of about 250 mL. '111eremaining solution 6,
was combined with di-Ier1-butyl dicarbon<tle (: (1.9 g. 77.4
nuno]) and THF (] 00 IllI l. and the mixture \'.-a, stirred at
ambient tcmperJmre for 16 11. 'I11e volatiles were evaporated
by rota!)· e\ aporJtion. and the residue was vacuum distilled at C'
~ mn: pressure (bp 79-8e C. ',. to gi\·e 7.74 12(43.9% yield) of
c]car, colorless Equid
LX.\Ml'LE :;
Synthesis of (2S )-( 4E)-N-Illethyl-5-(5-111ethoxy-~py ridi ny 1)-4-pent en- 2-amine;>,5 -di hydroxybellzo<lte
(g.entisate)
(2S)-( 4E )-N -Methyl -5-( 5-metboxy- 3-pyridinyl)-4penkn-2·aminc 2.5·dihvdroxybenlOate
\ hot s\'lutiol1 ,,1 2.5-dihydroxybenmic
acid (gcnti,ic
acidi 10582 g. 3."f; lllllltllj in ahS(llll1f' ethan~ll (] mi.) was
added to a warm s\llUlioll of (2S)-14Ei-N-methyl-5-(5-methoxy-3-pyridinyl)-4-penten·2-amine
(l.OO g. 4.85 mmo!.
g(,!".,) E isomer hy (;C-FJDI in absolute ethanol (] mL).
using additiPl1al etkmol (2 mL) in tlw lr:msJ"'r. 'nle resulting
mix lUre was c()ncent~ated \"iu rotary e\"aporati:)[), leaving 1.5
mL pl"ethano I jf) the solutioll. With stining 'Uld heating to near
re11lix. c!)·stallizatTllIl occurred. The resulting. he)t mixmre
was treated drop-wise with ethyl acelaTe (5.5 mI). A.1ter
woling to room temperature. the nllxture was ftU1her cooled
at 5" C. for 48 h. The resulting solids were filtered, washed
wnh ethyl acetait' (2.><5LUL)and dried al 50" C to give 1.24 g
(9, c'(oJ of an o1T-\\hitc powder (98.0{~/;,E i~omer by GC-FlD
for the free base). 10 remove the color from the sample. lhe
malerial was n.'C!)·,tallizcd from ethanoj,"isopropanol (3.5
111L:5_5mi.) to give 1.03 g (83% n.'cove!)·) of an ol'f-\,·hite
powder ,md subsequently recrystallized from ethanoJlethyl
aceme (3 mL: 12 mL) TClgive 0.90 g. (87% recovery) of a
white. crystallinc j'ov.der, mp 166-167' C
US 7,459,469 B2
27
28
EXAJv'.J'LE 4
temperanlIe and further cooling at 5°
the oD-"'hite solids
were fiitered., washed with isopropyl acetate and dried to give
0.505 g (51.8%) of waxy. tan flakes, mp 160-161.5° C. JI-l
Nl\1R (D20):
mono-salt
stoichiometry.
Caled.
for
CH>II;..N2,C7H60~.0.15I-l20:
C. 64.00";0; R 6.41%: N.
8.78%. Found: C, 64.03. 64.02%: H, 638, 6.38%: N, 8.80,
8.76%.
Synthesis of E-metanicotine
c..
2,s-dihydroxybenzoote
E-Metanicotine 2.5-dihydroxybenzoate
5
2.5-Dihydroxybenzoic
acid (geniisic acid) (0.475 g. 3.08
mmol) was added to a solution of E-metanicotine (0,s00 g.
ANAI'l:'TlCAL EXAMPLES
3.08mmolj in ethyl acetate (3 InL)and isopropanol (2.5 mL),
and the resulting mixture Was gently heated until all solids )(;
EXAMPLE 6
dissolw ..-d. Upon cooling, a white gra.l1ular precipitate was
deposited_ and the mixture was cooled at y' C. 'l1le solids
Iktemlinatio.l1 of Binding to Relevant Receptor Sites
\\ere filtered, washed with cold isopropanol ('\x2 mI.) and
dried under vacuum at 40° C. for 4 h to giveO.58 g (29.7%) 01"
"TIleinteraction of the hydroxybenzoate salts with relevant
a lig.ht-yellow. f1al:y solid, mp 90-91.5° C. IH NMR (DP):
l'
receptor sites can be determined in accordance 'with the techmono-salt
stoichiometry.
Caled.
for
niques described in U.S. Pat. No. 5,597.919 to Dull et al.
ClQIlJ4N2.C,Hp4.0.l5HP:
C. 64.00%: H, 6.41~:6: N.
Inhibition constants (Ki values), reported in nM, can be cal8.78~'O. FOlUJd C. 63.92. 64.00%: H, 6.33. 6.34%: N, 8.79.
culated from the I C 50 values using the method of Cheng et al.,
8.84°6.
2l' Biochem. Pharmacol. 22:3099 (1973). Low binding, constants indicate that the components of the salts descrih(;.'{]
EXAMPLE 5
herein exhibit good high affinity binding to certain CNS nicoiinic receptors.
Synthesis of E-metanicOline 3.5-dihydroxybenzoate
The foregoing is illustrative of the present invent ion and is
25 not 10 be cOllstmed as limiting thereof. The invention is
E-\1etanicotine 3.5-dihydm)o,:ybenzoate
defined by the following claims. with equivalents of the
clain~s to he includt'{] therein.
3.5-Dihydroxyhcnzoic
acid (OA75 g. 3.OX mmol) wa,
What is claimed is:
added to a warm solution of E-metanicotine (0.500 g. 3.08
1...\ compound denote<l (2S)-(4E)-;\"-mcthyl-5-(S-isnprommolj in isopropanol (1] mJ.) and methanol (4.5 mI.). CPOIl
ht:ating to near reflux to dissulve the resulting gUill, the lig.ht- ,U pllxy-3-pyridinyl )-4-pentt:n-2-amine p-hydroxylx-nzoate.
2 . .'\ phamlaceUlical composition comprising the comydk,\\ solution was con]ed 10 room temperature and further
pnund llfclaim 1 and!l pharmaceutically acceptahle carrier.
co\)k'C1 at 5" C. The resulting dark-yellow gum that was
deposited was dissolved in isopropyl acetate r:- mL) and
melhanol (4 mL). assisted k heating. Aller co\'Jing {(1 room