Note: Descriptions are shown in the official language in which they were submitted.
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- 1 -
PIPERIDINE AND TETRAHYDROPYRIDINE DERIVATIVES
The present invention relates to a class of substituted piperidine
and tetrahydropyridine derivatives which act on 5-hydroxytrypt~mine
5 (5-HT) receptors, being selective agonists of so-called "5-HTl-like"
receptors. They are there~ore useful in the treatment of t.linic~l con-1iti-~nc:for which a selective agonist of these receptors is indicated.
It has been known for some time that 5-HTl-like receptor agonists
which exhibit selective vasoconstrictor activity are of use in the treatment
of migraine (see, for example, A. Doenicke et al., The Lancet, 1988, Vol. 1,
1309-11; and W. Feniuk and P.P.A. Humphrey, Drug Deuelopment
Research, 1992, 26, 235-240).
The human 5-HTl-like or 5-HTln receptor has recently been shown
by molecular cloning techniques to exist in two distinct subtypes. These
subtypes have been termed 5-HTlDa (or 5-HTlD l) and 5-HTlD~ (or
5-ETlD 2), and their amino acid sequences are disclosed and claimed in
WO-A-91/17174.
The 5-HTlDa receptor subtype in humans is believed to reside on
sensory termin~ in the dura mater. Stimulation of the 5-HTlDa subtype
inhibits the release of infl:~mm~tory neuropeptides which are thought to
contribute to the headache pain of migraine. The human 5-HTlD~ receptor
subtype, meanwhile, is located predominantly on the blood vessels and in
the brain, and hence may play a part in me~i~ting constriction of cerebral
and coronary arteries, as well as CNS efl~ects.
~tlmini.stration of the plotol,y~ical 5-HTlD agonist sumatriptan
(GR43175~ to humans is known to give rise at therapeutic doses to certain
adverse cardiovascular events (see, for example, F. Willett et al., Br. Med.
J., 1992, 304, 1415; J.P. Ottervanger et al., The Lancet, 1993, 341, 861-2;
and D.N. Batem~n, The Lancet, 1993, 341, 221-4). Since sumatriptan
barely discriminates between the human 5-HTlDa and 5-HTlD~ receptor
subtypes (cf. WO-A-91/17174, Table 1~, and since it is the blood vessels
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with which the 5-HTlD~ subtype is most closely associated, it is believed
that the cardiovascular side-effects observed with sumatriptan can be
attributed to stimulation of the 5-HTlD~ receptor subtype. It is accordingly
considered (c~ G.W. Rebeck et al., Proc. Natl. Acad. Sci. US~l, 1994, 91,
3666-9) that compounds which can interact selectively with the 5-HTlD"
receptor subtype, whilst having a less pronounced action at the 5-HTlD~
subtype, might be free from, or at any rate less prone to, the undesirable
cardiovascular and other side-effects associated with non-subtype-selective
5-HTm receptor agonists, whilst at the same time m~int~ininF a benet;ci~l
10 level of anti-~nigraine activity.
The compounds of the present invention, being selective 5-HTl-like
receptor agonists, are accordingly of benefit in the treatment of migraine
and associated con-lition~, e.g. cluster headache, chronic paroxysmal
hemicrania, headache associated with vascular disorders, tension
15 headache and paediatric migraine. In particular, the compounds
according to this invention are potent agonists of the human 5-HT1Da
receptor subtype. Moreover, the compounds in accordance with this
invention have been found to possess at least a 10-fold selective af~lnity for
the 5-HTlD~ receptor subtype relative to the 5-HTlD~ subtype, and they can
20 therefore be expected to mzlnif?st fewer side-effects than those associated
with non-subtype-selective ~-HTlD receptor agonists.
Several distinct classes of substituted five-membered
heteroaromatic compounds are described in published European patent
applications 0438230, 0494774 and 0497512, and published International
25 patent applications 93/18029, 94/02477 and 94/03446. The compounds
described therein are stated to be agonists of 5-HTl-like receptors, and
accordingly to be of particular use in the treatment of migraine and
associated conditions. None of these publications, however, discloses nor
even suggests the substituted piperidine and tetrahydropyridine
30 derivatives provided by the present invention.
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In EP-A-0548813 is described a serie~ of alko~y~ ridin-4-yl and
alkoxypyrimi-lin-4-yl derivatives of indol-3-ylalkylpiperazines which are
alleged to provide treatment of vascular or vascular-related headaches,
including migraine. There is, however, no disclosure nor any suggestion in
~i EP-A-0548813 of replacing the substituted piperazine moiety with a
differently substituted piperidine or tetrahydropyridine moiety.
WO-A-91/18~97 describes a class of trypt~min~ derivatives
substituted by various five-membered rings, which are stated to be specific
to a particular type of "5-HTl-like" receptor and thus to be efEective agents
for the treatment of elini~.~l conditions, particularly migraine, requiring
this activity. A further class of tryp~mine derivatives with alleged anti-
migraine activity is disclosed in WO-A-94/0~460. However, neither
WO-A-91/18897 nor WO-A-94/02460 discloses or suggests the substituted
piperidlne and tetrahydropyridine derivatives provided by the present
invention.
Moreover, nowhere in the prior art mentioned above is there any
disclosure of a subtype-selective 5-HTlv receptor agonist having a 5-HTlDa
receptor binding af~mity (IC50) below 50 nM and at least a 10-fold selective
affinity for the 5-HTlna receptor subtype relative to the 5-HTlD~ subtype.
The compounds according to the present invention are subtype-
selective 5-HT1D receptor agonists having a human 5-HTlDa receptor
binding affinity (IC~o) below 100 nM, typically below 50 nM, suitably
below 10 nM and preferably below 1 nM; and at least a 10-fold selective
affinity, typically at least a 50-fold selective affinity and preferably at
least a 100-fold selective affinity, for the human 5-HTlD,~ receptor subtype
relative to the 5-HTlD~ subtype. Moreover, the compounds in accordance
with this invention possess interesting properties in terms of their efficacy
and/or bioavailability.
The present invention provides a compound of formula I, or a salt or
prodrugthereof:
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- 4-
Q - F~ ~ N -
U
T
wherein
Z represents hydrogen, halogen, cyano, nitro, tri~luoromethyl, -OR5,
-OCOR5, -OCONR5RG, -OC~I2CN, -OCH2CONR~R6, -SR5, -SOR5, -SO2R5,
-SO2NR5R~, -NR5RG, -NR5COR6, -NR5CO2R6, -NR5SO2R6, -COR~, -CO2R5,
-CONR5RG, or a group of ~ormula (Za), (Zb), (Zc) or (Zd):
Y~ R4 y~ R4 y
~\N X ~ R4 - N ~ N
(Za) (Zh) (Zc) (Zd~
in which the asterisk * denotes a chiral centre; or
~; rcpresents an optionally substituted five-membered
heteroaromatic ring selected from furan, thiophene, pyrrole, oxazole,
thiazole, isoxazole, isothiazole, imirl~ole, pyrazole, oxadiazole,
thiadiazole, triazole and tetrazole;
X represents oxygen, sulphur, -NH- or methylene;
Y represents oxygen or sulphur;
E represents a chemical bond or a straight or branched alkylene
chain cont~ining from 1 to 4 carbon atoms;
Q represents a straight or branched alkylene chain cont~ining from
1 to 6 carbon atoms, optionally substituted in any position by one or more
substituents selected from fluoro and hydroxy, or by an oxo moiety;
T represents nitrogen or CH;
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U represents nitrogen or C-R2;
V represents oxygen, sulphur or N-R3;
-F-G- represents -CM-CH2- or -C=CH-;
M represents hydrogen, halogen or Cl 6 alkoxy;
Rl represents C3-6 alkyl, C3-6 alkenyl, C3 6 alkynyl, C3-7
cycloalkyl(Cl 6)alkyl, aryl(Cl 6)alkyl or heteroaryl(Cl 6)alkyl, any of which
groups may be optionally substituted;
R2, R3 and R4 independently represent hydrogen or Cl 6 alkyl; and
R5 and R6 independently represent hydrogen, Cl 6 alkyl,
10 trifluoromethyl, phenyl, methylphenyl, or an optionally substituted
aryl(Cl 6)alkyl or heteroaryl(Cl 6)alkyl group; or R~ and R6, when linked
through a nitrogen atom, together represent the residue of an optionally
substituted azetidine, pyrrolidine, piperidine, morpholine or piperazine
ring.
The present invention also provides compounds of formula I as
defined above, and salts and prodrugs thereof, wherein Q represents a
straight or branched alkylene chain conts~ining from 1 to 6 carbon atoms,
optionally substituted in any position by one or more substituents selected
from fluoro and hydroxy.
Where Z in the compounds of formula 1 above represents a five-
membered heteroaromatic ring, this ring may be optionally substituted by
one or, where possible, two substituents. As will be appreciated, where Z
represents an oxadiazole, thiadiazole or tetrazole ring, only one
substituent will be possible; otherwise, one or two optional substituents
26 may be accommodated around the five-membered heteroaromatic ring Z.
mples o~ suitable substituents on the five-membered heteroaromatic
~ ring Z include Cl 6 alkyl, C2 6 alkenyl, C2-6 alkynyl, C3 7 cycloalkyl, aryl,
aryl(Cl 6)alkyl, C3-7 heterocycloalkyl, heteroaryl, heteroaryl(Cl 6)alkyl, Cl-~
alkoxy, Cl 6 alkylthio, amino, Cl 6 alkylamino, di(Cl 6)alkylamino, halogen,
30 cyano and trifluoromethyl.
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The group R1 may be optionally substituted by one or more
substituents, as also may the groups R5 or R6 where these represent
aryl(C1 6)alkyl or heteroaryl(Cl 6)alkyl. Where Rl, R5 or R6 represents
aryl(Cl 6)alkyl or heteroaryl(Cl.6)alkyl, any optional substitution will
~i suitably be on the aryl or heteroaryl moiety thereof, although substitution
on the alkyl moiety thereof is an alternative possibility. li,'x~3mple~ of
optional substituents thereon include halogen, cyano, trifluoromethyl,
triazolyl, tetrazolyl, C1-6 alkyl-tetrazolyl, hydroxy, keto, C1 6 alkoxy, C1 6
alkylthio, C~6 alkoxycarbonyl, C2 6 alkylcarbonyl, C1 G alkylsulphonyl,
10 arylsulphonyl, amino, C1 6 alkylamino, di(Cl 6)alkylamino,
di(C1-6)alkylaminomethyl, C2 6 alkylcarbonylamino, arylcarbonyl~mino,
C2 6 alkoxycarbonyl~min~-, N-(Cl G)alkyl-N-(C2 6)alkoxycarbonylamino, Cl 6
alkylsulphonylz~minl, arylsulphonyl~min~, Cl 6
alkylsulphonyl~minomethyl, aminocarbonyl~mino, C1 G
1~ alkylaminocarbonylamino, di(Cl 6)alkylz~minocarbonyl~minn, mono- or
diarylaminocarbonyl ~ m i n 1~, pyrrolidinylcarbonylamino,
piperidinylcarbonyl~mino, aminocarbonyl, Cl 6 alkyl.qminncarbonyl,
di(Cl 6)alkyl:~minocarbonyl, aminosulphonyl, Cl 6 alkyl~minosulphonyl,
di(C1 G)alkylaminosulphonyl, aminosulphonylmethyl, C1 G
20 alkylaminosulphonylmethyl and di(Cl G)alkylaminosulphonylmethyl.
When R5 and RG, when linked through a nitrogen atom, together
represent the residue of an azetidine, pyrrolidine, piperidine, morpholine
or piperazine ring, this ring may be unsubstituted or substituted by one or
more substituents. Examples of suitable substituents include C1.G alkyl,
2~ aryl(Cl 6)alkyl, Cl 6 alkoxy, C2 6 alkoxycarbonyl and C1-G
alkylaminocarbonyl. Typical substituents include methyl, benzyl,
methoxy, methoxycarbonyl, ethoxycarbonyl and methylaminocarbonyl. In
particular, where R5 and RG together represent the residue of a piperazine
ring, this ring is preferably substituted on the distal nitrogen atom by a
30 C2.G alkoxycarbonyl moiety such as methoxycarbonyl or ethoxycarbonyl.
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- 7-
As used herein, the expression "C~.6 alkyl" includes methyl and
ethyl groups, and straight-chained or branched propyl, butyl, pentyl and
hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl,
isopropyl and tert-butyl. Derived expressions such as "C1-6 alkoxy", "C1 6
5 alkylthio" and "Cl 6 alkylamino" are to be construed accordingly.
The expression ''c~2-6 alkenyl" as used herein refers to straight-
chained and branched alkenyl groups corlt~ining from 2 to 6 carbon atoms.
Typical examples include vinyl, allyl, dimethylallyl and butenyl groups.
The expression ''C2-6 alkynyr' as used herein re~ers to straight-
10 chained and branched alkynyl groups cont~inin~ ~rom 2 to 6 carbon atoms.Typical examples include ethynyl and propargyl groups.
Typical C3-7 cycloalkyl groups include cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl.
Typical C3-7cycloaLkyl(cl.6)alkylgroups include cyclopropylmethyl
15 and cyclohexylmethyl.
Typical aryl groups include phenyl and naphthyl.
The expression "aryl(Cl 6)alkyl" as used herein includes benzyl,
phenylethyl, phenylpropyl and naphthylmethyl.
Suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl,
20 piperidinyl, piperazinyl and morpholinyl groups.
Suitable heteroaryl groups include pyridinyl, qui~olinyl,
isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl,
benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl,
indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,
26 benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.
The expression "heteroaryl((~l 6)alkyl" as used herein includes
furylmethyl, furylethyl, thienylmethyl, thienylethyl, thienylpropyl,
oxazolylmethyl, oxazolylethyl, thiazolylmethyl, thiazolylethyl,
thiazolylpropyl, pyrazolylpropyl, imi~ 701ylmethyl, imidazolylethyl,
imi~1~ 7 olylpropyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl,
thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl,
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-8-
tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridinylpropyl,
pyridazinylpropyl, pyrimi-linylmethyl, pyrimi(linylpropyl,
pyrazinylmethyl, pyrazinylpropyl, quinolinylmethyl and
isoquinolinylmethyl.
The term "halogen" as used herein includes fluorine, chlorine,
bromine and iodine, especially fluorine.
For use in medicine, the salts of the compounds of formula I will be
pharmaceutically acceptable salts. Other salts may, however, be useful in
the preparation of the compounds according to the invention or of their
10 pharmaceutically acceptable salts. Suitable pharmaceutically acceptable
salts of the compounds of this invention include acid addition salts which
may, for example, be formed by mi~cing a solution of the compound
according to the invention with a solution of a pharmaceutically acceptable
acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid,
15 fumaric acid, m~leic acid, succinic acid, acetic acid, benzoic acid, oxalic
acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
Furthermore, where the compounds of the invention carry an acidic
moiety, suitable pharmaceutically acceptable salts thereof may include
alkali metal salts, e.g. sodium or potassium salts; ~lk~line earth metal
20 salts, e.g. calcium or magnesium salts; and salts formed with suitable
organic ligands, e.g. quaternary ammonium salts.
The present invention includes within its scope prodrugs of the
compounds of formula I above. In general, such prodrugs will be
functional derivatives of the compounds of formula I which are readily
25 convertible i77, uivo into the required compound of formula I. ~onventional
procedures for the selection and preparation of suitable prodrug
derivatives are described, for example, in Design of Prodrugs, ed. H.
B~ln-1g~rd, Elsevier, 1985.
Where the compounds according to the invention have at least one
30 asymmetric centre, they may accordingly exist as enantiomers. Where the
compounds according to the invention possess two or more asymmetric
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g
centres, they may additionally exist as diastereoisomers. For example, the
compounds of formula I above wherein Z represents a group of formula
(Zb~ or (Zc) have a chiral centre denoted by the asterisk *, which may
accordingly be in the (R) or (S~ configuration. It is to be understood that
5 all such isomers and mixtures thereof in any proportion are encompassed
within the scope of the present invention.
Where E and Q, which may be the same or different, represent
straight or branched al3~ylene chains, these may be, for example,
methylene, ethylene, 1-methylethylene, propylene, 2-methylpropylene or
butylene. In addition, the alkylene chain Q may be substituted in any
position by one or more substituents selected from fluoro and hydroxy
giving rise, for example, to a 2-hydroxypropylene, 2-hyd. o~yll.ethyl-
propylene, 2-:l~luoropropylene or 2-fluoromethyl-propylene chain Q.
Moreover, Q may represent a 1-hydroxypropylene linkage or be
substituted in any position by an oxo moiety giving rise, for example, to a
2-oxopropylene chain Q. Furthermore, E may represent a chemical bond
such that the moiety Z is attached directly to the central fused bicyclic
heteroaromatic ring system cont~ininF the variables T, U and V.
Suitably, E represents a ~h~mic~l bond or a methylene linkage.
Representative alkylene chains for Q include propylene, butylene, 2-
hydroxypropylene, 2-hydroxymethyl-propylene, 2-fluoropropylene and 2-
~luoromethyl-propylene, especially propylene.
The compound of formula I in accordance with the present invention
is suitably an indole, benzofuran or benzthiophene derivative of formula
IA, an indazole derivative of formula IB, or a pyrrolo[2,3-c]pyridine
derivative of formula I(~:
.
Q - F N - Rl
R~ ~A)
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- 10 -
Q - F N - Rl
N ~B)
R3
Q - F N - Rl
~ (IC)
N N
R3
wherein Z, E, Q, V, F, G, Rl, R2 and R3 are as defined above. Preferably,
the compounds according to the invention are indole or
5 pyrrolo[2,3-c]pyridine derivatives of formula ID:
Q - F N - Rl
Z-E ~ R5 (ID)
\3
wherein Z, E, Q, T, F, G, Rl, R2 and R3 are as defïned above, in particular
10 wherein R2 and R3 are both hydrogen.
Suitably, -F-G- represents -CM-CH2-.
Suitably, M represents hydrogen, fluoro or methoxy, especially
hydrogen or fluoro, and particularly hydrogen.
Suitable values for the substituent Rl include 3,3-dimethylbutyl,
15 allyl, dimethylallyl, butenyl, propargyl, cyclohexylmethyl, benzyl,
phenylethyl, phenylpropyl, furylmethyl, thienylmethyl, thienylpropyl,
thiazolylpropyl, pyrazolylpropyl, imidazolylmethyl, itni(l:~701ylpropyl,
pyridinylmethyl, pyridinylpropyl, pyridazinylpropyl, pyrimidinylpropyl
and pyrazinylpropyl, any of which groups may be optionally substituted.
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- 11 -
Selected values of Rl include 3,3-dimethylbutyl, allyl, dimethylallyl,
butenyl, propargyl, cyclohexylmethyl, benzyl, phenylethyl, phenylpropyl,
furylmethyl, thienylmethyl, imi~ .olylmethyl and pyridinylmethyl, any of
which groups may be optionally substituted. Typical substituents on the
group R1 include halogen, cyano, tri~Luoromethyl, triazolyl, tetrazolyl, Cl-6
alkyl-tetrazolyl, hydroxy, keto, Cl 6 alkoxy, amino, di(Cl 6)alkyl~mino,
di(C16)alkyl~minQmethyl, ~2-6 alkylcarbonyl~mino, ~2-6
alkoxycarbonyl~minn, N-(Cl 6~alkyl-N-(C~ 6)alkoxycarbonyl~mino, Cl 6
alkylsulphonylamino, aminocarbonylamino, aminocarbonyl, Cl 6
10 al~ylaminocarbonyl, di(Cl 6)alkyl~min-)carbonyl, aminosulphonyl and ~1-6
~ alkylaminosulphonylmethyl, especially halogen, tri~uoronlethyl, hydroxy,
Cl 6 alkoxy, Cl 6 alkyl~minncarbonyl and aminosulphonyl.
Particular values of R1 include 3,3-dimethylbutyl, allyl,
dimethylallyl, butenyl, propargyl, cyclohexylmethyl, benzyl, ~1uorobenzyl,
15 difluorobenzyl, cyanobenzyl, tetrazolyl-benzyl, methyltetrazolyl-benzyl,
methoxybenzyl, aminobenzyl, dimethyl~minomethyl-benzyl, acetylz~min-)-
benzyl, aminocarbonyl-benzyl, methyl~min-)carbonyl-benzyl,
dimethylaminocarbonyl-benzyl, aminosulphonyl-benzyl, phenylethyl,
fluoro-phenylethyl, dii~uoro-phenylethyl, cyano-phenylethyl,
20 trifluoromethyl-phenylethyl, triazolyl-phenylethyl, 2-hydroxy-1-
phenylethyl, phenylcarbonylmethyl, amino-phenylethyl, dimethylamino-
phenylethyl, acetyl~mino-phenylethyl, methoxycarbonyl~mino-
phenylethyl, (N-methyl-N-methoxycarbonyl)amino-phenylethyl,
aminocarbonyl z3 m i n o-phenylethyl, 2-phenylpropyl, 3 -phenylpropyl, 2-
2~ (~luorophenyl)propyl, 2-(chlorophenyl)propyl, 2-(dichlorophenyl)propyl, 2-
(trii~uoromethylphenyVpropyl, 2-~(chloro)(tri~Luoromethyl)phenyl]propyl,
~ 2-hydroxy-2-phenylpropyl, 2-(methoxyphenyl)propyl, 2-
(aminosulphonylphenyl)propyl, furylmethyl, thienylmethyl, 2-
(thienyl)propyl, 2-(thiazolyl)propyl, 2-(pyrazolyl)propyl, imi~olyl_ethyl,
30 2-(imidazolyl)propyl, pyridinylmethyl, 2-(pyridinyl)propyl, 2-
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- 12 -
(_ethoxypyridinyl)propyl, 2-(pyri~azinyl)propyl, 2-(pyrimidinyVpropyl and
2- (pyrazinyl)propyl.
Particular values of Rl include 3,3-dimethylbutyl, benzyl,
methyl~minocarbonyl-benzyl, phenylethyl, fluoro-phenylethyl, difluoro-
5 phenylethyl, trifluoromethyl-phenylethyl, 2-hydro~y-1-phenylethyl, 2-
phenylpropyl, 3-phenylpropyl, 2-(fluorophenyVpropyl, 2-
(chlorophenyl)propyl, 2-(dichlorophenyl)propyl, 2-
(trifluoromethylphenyVpropyl, 2-[(chloro)(trifluoromethyl)phenyl]propyl,
2-hydroxy-2-phenylpropyl, 2-(methoxyphenyl)propyl, 2-
10 (aminosulphonylphenyVpropyl, 2-(thienyl)propyl, 2-(thiazolyl)propyl, 2-
(pyrazolyl)propyl, 2-(imirl~ lyl)propyl, 2-(pyridinyl)propyl, 2-
(methoxypyridinyl)propyl, 2-(pyridazinyl)propyl, 2-(pyrimidinyl)propyl and
2-(pyrazinyVpropyl.
An especial value of R1 is 2-phenylpropyl.
Suitably, R2 and R3 independently represent hydrogen or methyl,
especially hydrogen.
Suitably, R4 represents hydrogen or methyl.
Suitably, Rs and R6 are independently selected from hydrogen,
methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl,
20 phenyl~ methylphenyl (especially 4-methylphenyl), benzyl and phenethyl.
~ uitably, the substituent Z ~epresents hydrogen, fluoro, cyano,
hydroxy, methoxy, ethoxy, benzyloxy, rnethylamino-carbonyloxy, cyal:3o-
methoxy, aminocarbonyl-methoxy, methylsulphonyl, aminosulphonyl, N-
methylamino-sulphonyl, N,N-dimethylslmin-~-sulphonyl, amino,
25 formylamino, acetyl~mino, trifluoromethyl-carbonylamino, benzyloxy-
carbonylzlminn, methyl-sulphonylamino, ethyl-sulphonylamino,
methylphenyl-sulphonyl~min~, N-methyl-(N-methylsulphonyl)-amino,
N-methyl-(N-ethylsulphonyl)-amino, N-methyl-(N-
tri uoromethylsulphonyl)-amino, N-ethyl-(N-methylsulphonyV-amino, N-
3() benzyl-(N-methylsulphonyl)-amino, N-benzyl-(N-ethylsulphonyl)-amino,
acetyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl,
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methyl~minncarbonyl, et~yl~minocarbonyl, propyl~minocarbonyl,
butylaminocarbonyl, benzylaminocarbonyl or phenethyl-aminocarbonyl; or
a group of formula (Za), (Zb), (Zc) or (Zd) as defined above; or an optionally
substituted five-membered heteroaromatic ring as specified above.
~i In a particular embodiment, ~ represents -SO2NR~R6 in which R~
and RG are as defined above. In a subset of this embodiment, R5 and R6
independently represent hydrogen or Cl 6 alkyl, especially hydrogen or
methyl. Particular values of Z in this context include aminosulphonyl, N-
methyl~qminn-sulphonyl and N,N-dimethy~mino-sulphonyl, especially N-
methyl~mino-sulphonyl.
In another embodiment, Z represents a group of formula (Zb) in
which R4 is hydrogen or methyl. In a subset of this embodiment, X and Y
~oth represent oxygen. In a particular aspect of this subset, t~e chiral
centre denoted by the asterisk * is in the (S) configuration.
1~ When the group Z represents an optionally substituted five-
membered heteroaromatic ring, this is suitably a 1,3-oxazole, 1,3-thiazole,
imi(lzl7.vle, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thi~ 7.ole, 1,3,4-
thiadiazole, 1,2,3-triazole, 1,2,4-triazole or tetrazole ring. Preferably, the
ring is a 1,3-oxazole, 1,3-thiazole, imidazole, 1,2,4-oxadiazole, 1,2,4-
thiadiazole or 1,2,4-triazole ring, typically an irnirl~70l-1-yl, 1,2,4-triazol-1-
yl or 1,2,4-triazol-4-yl moiety, and in particular a 1,2,4-triazol-1-yl or
1,2,4-triazol-4-yl moiety.
Suitably, the five-membered heteroaromatic ring Z is unsubstituted.
mples of optional substituents which may typically be attached to the
2~ moiety Z include methyl, ethyl, benzyl and amino, especially ethyl.
A particular sub-class of compounds according to the invention is
represented by the compounds of formula IIA, and salts and prodrugs
thereof:
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- 14-
:R.7
A B~N (CH2)m \ ~ l ~ N - (CH2)p
T N
(IIA)
wherein
m is zero, 1, 2 or 3, preferably zero or 1;
p is zero, 1 or 2;
Ql represents a straight or branched alkylene chain cont~ining from
2 to 5 carbon atoms, optionally substituted in any position by one or more
substituents selected *om fluoro and hydroxy;
T represents nitrogen or CE~;
A represents nitrogen or CE;
B represents nitrogen or C-R8;
R7 and R8 independently represent hydrogen, C1 G alkyl, C2 G
alkenyl, C3 7 cycloalkyl, aryl, aryl(Cl.6)alkyl, C3 7 heterocycloalkyl,
heteroaryl, heteroaryl~Cl 6)alkyl, C16 alkoxy, C1 G alkylthio, amino, C1 6
alkylamino, di(Cl 6)alkylamino, halogen, cyano or trifluoromethyl;
W represents tert-butyl, cyclohexyl, phenyl, thienyl, thiazolyl,
pyrazolyl, imitlfl7.olyl, pyridinyl, pyridazinyl, pyrimidinyl or pyridazinyl,
any of which groups may be unsubstituted or substituted by one or more
groups selected from halogen, cyano, trifluoromethyl, triazolyl, tetrazolyl,
C1 6 alkyl-tetrazolyl, Cl 6 alkoxy, C2 6 alkylcarbonyl, amino, C1 G
alkylamino, di(Cl 6)alkylamino, di(Cl 6)alkylaminomethyl, C2 G
alkylcarbonyl~mino, C16 alkylsulphonylamino, aminocarbonyl~m;no, C1 G
aIkyl~minocarbonyl, aminosulphonyl and Cl-6 alkyl~minnsulphonylmethyl;
and
Rl~ represents hydrogen, C1-3 alkyl, hydroxy(Cl 3)alkyl or C1 G
alkylaminocarbonyl .
CA 02236834 1998-05-06
W O 97/19073 PCTtGB96/02795
F.~3m~les of selected substituents on the moiety W include halogen
(especially ~uoro or chloro), trifluoromethyl, hydroxy, C~1-6 a~oxy
(especially methoxy) and aminosulphonyl.
In a particular aspect, W represents tert-butyl, cyclohexyl or a group
5 of formula (Wa), (Wb) or (VVc):
R9~ ~ R9
~a) ~b) ~c)
in which
Wl represents CH or nitrogen;
W2 represents oxygen, sulphur, NH or N-methyl; and
R9 represents hydrogen, halogen, cyano, tri~1uoromethyl, triazolyl,
tetrazolyl, Cl 6 alkyl-tetrazolyl, C1-6 alkoxy, C2-6 alkylcarbonyl, amino, C1 G
alkylamino, di(Cl 6)alkylamino, di(Cl.6)alkylaminomethyl, C2 6
alkylcarbonyl~mino, C1-G alkylsulphonylamino, aminocarbonylamino, C1 G
alkylaminocarbonyl, aminosulphonyl or C1 G alkylaminosulphonylmethyl.
Suitably, Ql represents a straight or branched 3 or 4 carbon
alkylene chain, optionally substituted in any position by one or more
substituents selected from fluoro and hydroxy. Particular alkylene chains
for Ql include propylene, butylene, 2-hydroxypropylene, 2-
(hydroxymethyl)-propylene, 2-fluoropropylene and 2-(fluoromethyl)-
propylene, especially propylene.
Particular values of R7 and R8 include hydrogen, methyl, ethyl,
benzyl and amino, typically hydrogen or ethyl, and especially hydrogen.
Particular values of R9 include hydrogen, fluoro, chloro, cyano,
trifluoromethyl, triazolyl, tetrazolyl, methyl-tetrazolyl, methoxy, amino,
dimethyl~min-~methyl, acetyl~min--, aminocarbonyl~mino,
methylaminocarbonyl and aminosulphonyl, typically hydrogen, fluoro,
_ _ _ _ _ _
CA 02236834 l998-0=,-06
PCT/GB96/02795
W O 97/19073
- 16-
chloro, trifluoromethyl, methoxy or an~inosulphonyl, and especially
hydrogen, ~luoro or trifluoromethyl.
Particular values of Rl~ include hydrogen, methyl, hydroxymethyl
and methylaminocarbonyl, especially hydrogen or methyl.
Another sub-class of compounds according to the invention is
represented by the compounds of formula IIB, and salts and prodrugs
thereof:
R
~r, Q ~ N - (CH2)p ~
N~ / (CHa~m ~ ~ ~ W
a~B)
wherein
m, p, Ql, T, W and Rl~ are as defined with reference to formula IIA
above; and
R5 and RG are as defined with reference to formula 1 above.
Particular values of R5 and RG in relation to formula IIB above
include hydrogen and Cl 6 alkyl, especially hydrogen or methyl. Suitably,
one of R5 and R~; represents hydrogen and the other represents hydrogen or
methyl.
A further sub-class of compounds according to the invention is
represented by the compounds of formula IIC, and salts and prodrugs
thereof:
CA 02236834 1998-0~-06
W O 97/19073 PCT/GB96/02795
-17-
N ~ (CH~ ~ / ~ N (CHz~
aI(:~)
wherein the asterisk * denotes a chiral centre;
m, p, Ql, T, W and Rl~ are as dehned with reference to formula IIA
5 above; and
R4 and Y are as de~med with reference to formula I above.
Particular values of R4 in relation to formula IIC include hydrogen
and methyl, especially hydrogen.
Preferably, Y in formula IIC is oxygen.
Preferably, the chiral centre denoted by the asterisk * in formula
IIC is in the (S) configuration.
Speci~lc compounds within the scope of the present invention
include:
l-benzyl-4-[3-(5-(1,2,4-triazol-4-yV-lH-indol-3-yl)propyl]piperidine;
1-(3,3-dimethylbutyl)-4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-
yl)propyl]piperidine;
1-(2-phenylethyl3-4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-
yl)propyl]piperidine;
l-cyclohexylmethyl-4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-
yl)propyl]piperidine;
1-(3-phenylpropyl)-4-r3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-
yl)propyl]piperidine;
1-[2-(3-fluorophenyl)ethyl]-4-[3-(5-(1,2,4-triazol-4-yl~-lH-indol-3-
yl~propyl]piperidine;
1-[2-(4-trifluoromethylphenyl)ethyl]-4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-
yl)propyl]piperidine;
CA 02236834 1998-0~-06
W ~ 97119073 PCT/GB96/02795 - 18-
1-[2-(3,4-di~1uorophenyl)ethyl] -4-[3-(5-(1,2,4-triazol-4-yl)- lH-indol-3-
Yvpropyl]piperidine;
N-methyl-2-phenyl-2-[4-(3-(5-(1,2,4-triazol-4-yV-lH-indol-3-
yl)propyl)piperidin-l-yl]acet~mi~
1-(2-oxo-2-phenylethyl)-4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-
YVpropyllpiperidine;
1-(2-phenylpropyl)-4-[3-(5-(1,2,4-triazol-4-yV-lH-indol-3-
yl)propyl]piperidine;
1-(2-hydroxy- 1-phenylethyl)-4- [3-(5-(1,2,4-triazol-4-yV- 1~-indol-3-
10 yl)propyl]piperidine;1-[2-(2-fluorophenyl)ethyl]-4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-
yl)propyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yV-lH-indol-3-yVpropyl]-1-~2-(2-
chlorophenyVpropyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yV-lH-indol-3-yl)propyl]-1-[2-(2-
tri:Eluoromethylphenyl)propyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-1-[2-(4-
chlorophenyVpropyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yV-lH-indol-3-yVpropyl]-1-[2-(4-
20 methoxyphenyl~propyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-1-[2-(2,6-
dichlorophenyl)propyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-1-[2-(3-
methoxyphenyl)propyl3piperidine;
2~ 4-~3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-1-[2-(2-
methoxyphenyVpropyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yV-lH-indol-3-yl)propyl]-1-[2-(3-
chlorophenyl)propyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yVpropyl]-1-[2-(3-
30 aminosulphonylphenyVpropyl]piperidine;
CA 02236834 1998-0~-06
W O 97/19073 PCT/GB96/02795
- 19 -
4-~3-(6-(1,2,4-triazol-4-yV-lH-indol-3-yl)propyl]-1-[2-(pyrimidin-2-
yl)propyl]piperidine;
4-~3-(5-(1,2,4-triazol-4-yV-lH-indol-3-yl)propyl]-1-[2-(thiazol-2-
Yvpropyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-1-[2-(pyrazin-2-
Yvpropyllpiperazine;
4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yVpropyl]-1-[2-(imi~ 7.ol-l-
Yvpropyl]piperazine;
4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yVpropyl]-1-[2-(pyrazol-1-
10 yl)propyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yVpropyl]-1-[2-(pyridin-2-
Yvpropyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yVpropyl]-1-[2-(pyridin-3-
yl)propyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yVpropyl]-1-[2-(pyridin-4-
yl)propyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yV-lH-indol-3-yl)propyl]-1-[2-(pyridazin-3-
Yvpropyl]piperidine;
4-~Luoro-4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-1-~2-(pyridin-3-
yl)propyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yVpropyl]-1-[2-(thien-3-
yl)propyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-1-[2-(2-methoxypyridin-3-
yl)propyl~piperidine;
4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-1-[2-(4-methoxypyridin-3-
yl)propyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yVpropyl]-l-[(R)-2-(pyridin-3-
yl)propyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-1-[(S)-2-(pyridin-3-
yl)propyl]piperidine;
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W O 97/19073 PCT/GB96/02795
-20-
4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yVpropyl3-1-[(S)-(2-
phenylpropyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yVpropyl]-l-[(R)-2-
phenylpropyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yVpropyl]-1-[2-(2-
fluorophenyl)propyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yV-lH-indol-3-yVpropyl]-1-[2-(3-
fluorophenyl)propyl]piperidine;
4-~3-(5-(1,2,4-triazol-4-yV-lH-indol-3-yl)propyl]-1-[2-(4-
10 :E~uorophenyl)propyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yl)-1~-indol-3-yVpropyl]-1-[2-(2-chloro-5-
(trifluoromethyVphenyl)propyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yVpropyl]-l-[(S)-2-(4-
fLuorophenyVpropyl]piperidine;
4-[3-(5-(1,2,4-triazol-4-yV-lH-indol-3-yl)propyl]-1-(2-hydroxy-2-
phenylpropyl)piperidine;
4-[3-(5-(N-(methyVaminosulphonylmethyl)-lH-indol-3-yl)propyll-1-(2-
phenylpropyVpiperidine;
4-t3-(5-(N-(methyl)aminosulphonylethyl)-lH-indol-3-yl)propyl]-1-(2-
20 phenylpropyl)piperidine;4-[3-(5-(2-ethylimi-1~7.ol-l-yl)-lH-indol-3-yl)propyl]-1-(2-
phenylpropyl)piperidine;
4-[3-(5-((5~-2-oxo-1,3-oxazolidin-4-ylmethyl)-lH-indol-3-yl)propyl]-1-(2-
phenylpropyl)piperidine;
4-fluoro-4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-1-(2-
phenylpropyl)piperidine;
4-[2-fluoro-3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-1-(2-
phenylpropyl)piperidine;
4-t3-(5-(1,2,4-triazol-4-yV-lH-indol-3-yl)-2-hydroxypropyl]-1-(2-
30 phenylpropyl)piperidine;
CA 02236834 1998-0~-06
W O 97/19073 PCT/GB96/02795 -21-
4-[3-(~-(1,2,4-triazol-4-yV-lH-indol-3-yV-2-oxopropyl~-1-(2-
phenylpropyVpiperidine;
4-[3-~5-(1,2,4-triazol-4-yl)-lH-indol-3-yl)-1-hydlo~y~ropyl~ (2-
phenylpropyl)piperidine;
5 and salts and prodrugs thereof.
The invention also provides pharmaceutical compositions
comprising one or more compounds of this invention in asso~i~t.ion with a
pharmaceutically acceptable carrier. Preferably these compositions are in
unit dosage forms such as tablets, pills, capsules, powders, granules,
10 sterile parenteral solutions or suspensions, metered aerosol or liquid
sprays, drops, ampoules, auto-injector devices or suppositories; for oral,
parenteral, intr~n~.qS~l, sublingual or rectal ~lmini.~tration, or for
a-lmini~tration by inhalation or insl~ffl~inn. For preparing solid
compositions such as tablets, the principal active ingredient is ~ixed with
15 a pharmaceutical carrier, e.g. conventional tableting ingredients such as
corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium
stearate, dicalcium phosphate or gums, and other pharmaceutical
diluents, e.g. water, to form a solid preformulation composition conts3ining
a homogeneous mixture of a compound of the present invention, or a
20 pharmaceutically acceptable salt thereof. When referring to these
preformulation compositions as homogeneous, it is meant that the active
ingredient is dispersed evenly throughout the composition so that the
composition may be readily subdivided into equally effective unit dosage
forms such as tablets, pills and capsules. This solid preformulation
25 composition is then subdivided into unit dosage forms of the type described
above cont~ining from 0.1 to about 500 mg of the active ingredient of the
~ present invention. Typical unit dosage forms contain fi~om 1 to 100 mg, for
example 1, 2, ~, 10, 25, 50 or 100 mg, of the active ingredient. The tablets
or pills of the novel composition can be coated or otherwise compounded to
30 provide a dosage form affording the advantage of prolonged action. For
example, the tablet or pill can comprise an inner dosage and an outer
CA 02236834 1998-0~-06
W O 97/19073 PCT/GB~6/02795
-22-
dosage component, the latter being in the form of an envelope over the
former. The two components can be separated by an enteric layer which
serves to resist disintegration in the stom~(~h and permits the inner
component to pass intact into the duodenum or to be delayed in release. A
5 variety of materials can be used for such enteric layers or coatings, such
materials including a number of polymeric acids and mixtures of polymeric
acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present
invention may be incorporated for ~lmini~tration orally or by injection
10 include aqueous solutions, suitably flavoured syrups, aqueous or oil
suspensions, and flavoured em~ ion.q with edible oils such as cottonseed
oil, sesame oil, coconut oil or peanut oil, as well as elixirs and .qirnil~t
pharmaceutical vehicles. Suitable dispersing or suspending agents for
aqueous suspensions include synthetic and natural gums such as
15 tragacanth, acacia, ~lgin~qte, dextran, sodium carboxymethylcellulose,
methylcellulose, polyvinyl-pyrrolidone or gelatin.
In the treatment of migraine, a suitable dosage level is about 0.01 to
250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and
especially about 0.05 to 5 mg/kg per day. The compounds may be
20 a~ ini~tered on a regimen of 1 to 4 times per day.
The compounds according to the invention may be prepared by a
process which comprises attachment of the Rl moiety to a compou~d of
formula III:
G~
Q--F N--H
T V
(III)
CA 02236834 1998-0~-06
W O 97/19073 PCT/GB96/02795 -23-
wherein Z, E, Q, T, U, V, F and G are as defined above; by conventional
means including N-alkylation.
Att~hment of the Rl moiety to the compounds of formula III may
conveniently be effected by standard alkylation techniques. One example
5 thereof comprises treatment with an alkenyl halide such as 4-bromobut-1-
ene, 4-bromo-2-methylbut-2-ene or allyl bromide, an alkynyl halide such
as propargyl bromide, or an aryl(Cl 6)all~yl or heteroaryl(Cl 6)alkyl halide
such as benzyl iodide, typically under basic conditions, e.g. sodium hydride
in N,N-dimethylform~mi(le, or potassium carbonate in isopropanol.
10 Another example compri~es treatment of the compound of formula III with
an aryl~Cl 6)alkyl or heteroaryl(C1 6)alkyl mesylate such as 2-(thiazol-2-
yVpropyl methanesulphonate, ideally in the presence of a base such as
sodium carbonate, in a suitable solvent such as 2-propanol, typically at the
reflux temperature of the solvent. A further example, for the preparation
1~ of a compound of formula I in which R1 is substituted with hydroxy,
comprises treating the requisite compound of formula III with an epoxide
derivative such as a-methylstyrene epoxide, typically in a solvent such as
methanol in a sealed tube at an elevated temperature.
Alternatively, the Rl moiety may conveniently be attached by
20 reductive alkylation, which may be accomplished in a single step, or as a
two-step procedure. The single-step approach suitably comprises treating
the required compound of formula III as defined above with the
appropriate aldehyde, e.g. benzaldehyde, pyridine carboxaldehyde,
furfuraldehyde or thiophene carboxaldehyde, in the presence of a reducing
25 agent such as sodium cyanoborohydride. In a typical two-step procedure,
for the preparation of a compound of formula I wherein Rl corresponds to a
group of formula -CH2Rll, a carboxylic acid derivative of formula Rll-CO2~I
is condensed with the required compound of formula III, suitably in the
presence of 1-(3-dirnethyl~minopropyl)-3-ethylcarbodiimide hydrochloride
30 and l-hydroxybenzotriazole hydrate, to afford a compound corresponding
to formula I wherein Rl represents -CORll; the carbonyl group thereof can
CA 02236834 1998-0~-06
W O 97/19073 PCT/G~61~2~9S
- ~4-
then be reduced, for example by treatment with diisobutylaluminium
hydride, and the required compound of formula I thereby obtained.
The compounds of formula III above wherein T represents ~H, U
represents C-R2 and V represents N-R3, corresponding to the indole
6 derivatives of formula ID as defined above wherein T represents CEI and
Rl is hydrogen, may be prepared by a process which comprises reacting a
compound of formula IV:
Z~
~ NH - ~H
(IV)
wherein Z and E are as defined above; with a compound of formula V, or a
carbonyl-protected form thereof:
O G~
R2 ~ Q--F N - RP
wherein Q, F, C~ and R2 are as defined above, and RP represents an amino-
protecting group; followed, where required, by N-alkylation by standard
methods to introduce the moiety R3; with subsequent removal of the
amino-protecting group RF.
The reaction between compounds IV and V, which is an exanlple of
the well-known Fischer indole synthesis, is suitably carried out by heating
the reagents together under mildly acidic conditions, e.g. 4% sulphuric
acid at reflux.
Suitable carbonyl-protected forms of the compounds of formula V
25 include the dimethyl acetal or ketal derivatives.
CA 02236834 1998-05-06
W O 97/19073 PCT/GB96/02795 -25-
The protecting group RP in the compounds of formula V is suitably a
carbamoyl moiety such as tert-butoxycarbonyl (BOC), which can
conveniently be removed as necessary by treatment under mildly acidic
conditions. Indeed, the acidic conditions of the Fischer indole synthesis
5 reaction will generally suffice to remove the BOC group.
The Fischer reaction between compounds IV and V may be carried
out in a single step, or may proceed via an initial non-cyclising step at a
lower temperature to give an intermediate of formula VI:
Z--E~ ~Q--F N_~D
~)
wherein Z, E, Q, F, G, R2 and RP are as defined above; followed by
cyclisation using a suitable reagent, e.g. a polyphosphate ester.
The compounds according to the invention wherein T represents
15 CH, U represents C-R2 and V represents N-R3 - i.e. the indole derivatives
of formula ID as defined above wherein T represents CH - may
alternat*ely be prepared by a process which comprises reacting a
compound of formula IV as defined above with a compound of formula VII,
or a carbonyl-protected form thereof:
~ Q - F N - Rl
wherein Q, F, G, Rl and R2 are as de~ined above; under conditions
analogous to those described above for the reaction between compounds IV
CA 02236834 1998-0~-06
W O 97/19073 PCT/GB96/02795 - 26-
and V; followed, w~ere required, by N-alkylation by standard methods to
introduce the moiety R3.
As for the compounds of formula V, suitable carbonyl-protected
forms of the compounds of formula VII include the dimethyl acetal or ketal
derivatives. Where the alkylene chain Q is substituted by a hydroxy
group, this group may condense with the carbonyl moiety in compounds V
and VII, whereby the carbonyl moiety is protected in the form of a cyclic
hemiacetal.
As with that between compounds IV and V, the Fischer reaction
10 between compounds IV and VII may be carried out in a single step, or may
proceed via an initial non-cyclising step at a lower temperature to give an
intermediate of formula VIII:
z--E~ Q--F N--R
wherein Z, E, Q, F, (~, Rl and R2 are as defined above; followed by
cyclisation using a suitable reagent, e.g. a polyphosphate ester.
In a further procedure, the compounds of formula III above wherein
T represents CH, U represents nitrogen and V represents N-R3,
20 corresponding to the indazole derivatives of formula IB as defined above
wherein Rl is hydrogen, may be prepared by a process which comprises
cyclising a compound of formula IX:
CA 02236834 1998-05-06
W O 97/19073 PCT/GB96/0279
- 27-
~ ~ P
~Q--F N--R
N~I2 N--D
(IX)
wherein Z, E, Q, F, G and ~P are as defined above, and Dl represents a
readily displaceable group; followed, where required, by N-alkylation by
standard methods to introduce the moiety R3; with subsequent removal of
5 the amino-protecting group RP.
Similarly, the compounds of formula I wherein T represents CH, U
represents nitrogen and V represents N-R3 - i.e. the indazole derivatives of
formula IB as defined above - may be prepared by a process which
comprises cyclising a compound of formula X:
~0
E
G
N~2 N -D
~ )
in which ~, E, Q, F, ~, Rl and Dl are as defined above; followed, where
required, by N-alkylation by standard methods to introduce the moiety R3.
The cyclisation of compounds IX and X is conveniently achieved in a
15 suitable organic solvent at an elevated temperature, for example in a
mixture of m-xylene and 2,6-lutidine at a temperature in the region of
140~C.
The readily displaceable group Dl in the compounds of formula IX
and X suitably represents a Cl4 alkanoyloxy group, preferably acetoxy.
20 Where Dl represents acetoxy, the desired compound of formula IX or X
CA 02236834 1998-05-06
W O 97/19073 PCT/GB96/02795 - 28-
may be conveniently prepared by treating a carbonyl compound of formula
XI:
~G ~
Q--F N--R
NH2 ~
~gI)
wherein Z, :E, Q, F and G are as defined above, and Rx corresponds to the
group Rl as defined above, or Rx represents an amino-protecting group as
de~ined for RP; or a protected derivative thereof, preferably the N-formyl
protected derivative; with hy(l~oxyls~min~ hydrochloride, advantageously
10 in pyridine at the reflux temperature of the solvent; followed by
acetylation with acetic anhydride, advantageously in the presence of a
catalytic ~uantity of 4-dimethyl~minopyridine, in dichloromethane at
room temperature.
The N-formyl protected derivatives of the intermediates of formula
15 XI may conveniently be prepared by ozonolysis of the corresponding indole
derivative of formula XII:
Q--F~ ~N_ Rx
Z--E ~
N
(XII)
20 wherein Z, E, Q, F, G and Rx are as defined above; followed by a reductive
work-up, advantageously using dimethylsulphide.
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-29-
The indole derivatives of formula XII may be prepared by methods
analogous to those described in the accompanying F',~mples, or by
procedures well known from the art.
In a still further procedure, the compound~ of formula III above
wherein T represents CH, U represents C-R2 and V represents oxygen or
sulphur, corresponding to the benzofilran or benzthiophene derivatives of
formula IA wherein V is oxygen or sulphur respectively and Rl is
hydrogen, may be prepared by a process which comprises cyclising a
compound of formula XIII:
G ~
Z - E ~ O ~ Q - F N - RP
vl R2
~III)
wherein Z, E, Q, F, G, R2 and RP are as defined above, and V1 represents
oxygen or sulphur; followed by removal of the amino-protecting group RP.
1~ Similarly, the compounds of formula I wherein T represents CH, U
represents C-R2 and V represents oxygen or sulphur - i.e. the benzofuran
or benzthiophene derivatives of formula IA above - may be prepared by a
process which comprises cyclising a compound of formula XIV:
Z - E ~ O ~ Q - E N - R
~r~
wherein Z, E, Q, F, G, R1, R2 and Vl are as defined above.
CA 02236834 1998-0~-06
W O 97/19073 PCT/GB96/02795 -30 -
The cyclisation of compounds XIII and XIV is conveniently effected
by using polyphosphoric acid or a polyphosphate ester, advantageously at
an elevated temperature.
The compounds of formula XIII and XIV may be prepared by
5 reacting a compound of formula XV with a compound of formula XVI:
G~
Z - E ~ Vl- H ~ ~ F ~ N - R
~ V) ~VI~
wherein Z, E, Q, F, G, R2, Vl and Rx are as defined above, and Hal
represents a halogen atom.
The reaction is conveniently effected in the presence of a base such
as sodium hydroxide.
The hydroxy and mercapto derivatives of formula ~I may be
prepared by a variety of methods which will be readily apparent to those
skilled in the art. One such method is described in EP-A-0497512.
The hydrazine derivatives of formula IV above may be prepared by
methods analogous to those described in EP-A-0438230, EP-A-0497512,
EP-A-0548813 and WO-A-91/18897.
Where they are not commercially available, the starting materials
~s of formula V, VII and XVI may be prepared by methods analogous to those
20 described in the accompanying Examples, or by standard procedures well
known from the art.
It will be understood that any compound of formula I init.i~311y
obtained from any of the above processes may, where appropriate,
subsequently be elaborated into a further compound of formula I by
25 techniques known from the art. For example, a compound of formula I
wherein -F-G- represents -C=CH- init.iz~lly obtained may be readily
converted into the corresponding compound wherein -F-G- represents
CA 02236834 1998-0~-06
W O 97/19073 PCT/~5~ i95
- 31-
-CH-~H2- by conventional catalytic hydrogenation procedures. A
compound of formula I initi~lly obtained wherein Q is substituted by
hydroxy may be converted into the corresponlling compound wherein Q is
substituted by an oxo moiety by treatment with an o~ri(li~ing agent,
5 suitably sulphur t.rio~i~le-pyridine complex. In ~ition, a compound of
formula I wherein Rl is benzyl initi~lly obtained may be converted by
catalytic hydrogenation to the corresponding compound of formula III,
which in turn may be converted into a further compound of formula I
using standard N-aIkylation techniques as described above. Furthermore,
10 a compound of formula I init.i~lly obtained wherein the Rl moiety is
substituted by nitro or cyano may be converted by catalytic hydrogenation
to the corresponding amino- or ~minnmethyl-substituted compound
respectively. AdrlitioI~lly, a compound of formula I wherein the Rl moiety
is substituted by hydroxymethyl may be obtained by lithium aluminium
16 hydride reduction of a precursor alkoxycarbonyl derivative; the resulting
hydroxy compound may then be be mesylated under standard conditions,
and the mesyl group subsequently displaced by an amino moiety by
treatment with the desired amine in a sealed tube at an elevated
temperature. The amine derivative resulting from any of these procedures
20 may then, for example, be N-acylated using the appropriate acyl halide,
e.g. acetyl chloride; or aminocarbonylated, using potassium isocyanate, to
the corresponding urea derivative; or converted to a 1,2,4-triazol-4-yl
derivative using N,N-dimethylform~mi~e azine; or reductively alkylated
by treatment with the appropriate aldehydLe or ketone in the presence of
25 sodium cyanoborohydride. If desired, the amine derivative may also be
carbamoylated by treatment with the requisite alkyl chloroformate. A
compound of formula I init.is~lly obtained wherein the Rl moiety is
substituted by cyano may be converted, by treatment with sodium azide,
to the corresponding tetrazole derivative, which in turn may be alkylated
30 on the tetrazole ring by treatment with an alkyl halide under standard
conditions. By way of additional illustration, a compound of formula I
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-32-
initially obtained wherein the Rl moiety is substituted by an
alkoxycarbonyl moiety may be saponified, by treatment with an alkali
metal hydroxide, to the corresponding carboxy-substituted compound,
which in turn may be converted to an amide derivative by treatment with
5 the appropriate amine, advantageously in the presence of 1-(3-
~imethyl~minopropyl)-3-ethylcarbodiimide hydrochloride and 1-
hydroxybenzotriazole. Alternatively, a compound of formula I init.i~lly
obtained wherein the Rl moiety is substituted by an alkoxycarbonyl
moiety may be converted directly to an amide derivative by treatment
lO with the appropriate amine in a sealed tube at an elevated temperature,
or in the presence of trimethylaluminium. Moreover, a compound of
formula I wherein R3 is hydrogen initially obtained may be converted into
a compound of formula I wherein R3 represents Cl 6 alkyl by standard
alkylation techniques, for example by treatment with an alkyl iodide, e.g.
15 methyl iodide, typically under basic conditions, e.g. sodium hydride in
dimethylform~mi(le, or triethyl~mine in acetonitrile.
Where the above-described processes for the preparation of the
compounds according to the invention give rise to mixtures of
stereoisomers, these isomers may be separated by conventional techniques
20 such as preparative chromatography. The novel compounds may be
prepared in racemic form, or individual enantiomers may be prepared
either by enantiospecific synthesis or by resolution. The novel compounds
may, for example, be resolved into their component enantiomers by
standard techniques such as preparative HPLC, or the formation of
2~ diastereomeric pairs by salt formation with an optically active acid, such
as (-~-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid,
followed by fractional crystallization and regeneration of the free base.
The novel co~npounds may also be resolved by formation of diastereomeric
esters or amides, followed by chromatographic separation and removal of
30 the chiral auxiliary.
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During any of the above synthetic sequences it may be necessary
and/or desirable to protect sensitive or reactive groups on any of the
molecules concerned. This may be achieved by means of convention~l
protecting groups, such as those described in Protective Groups in Organic
Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene &
P.G.M Wuts, Protectiue Groups in Organic Synthesis, ~ohn Wiley & Sons,
1991. The protecting groups may be removed at a convenient subsequent
stage using methods known from the art.
The following F,~mples illustrate the preparation of compounds
10 according to the invention.
The compounds in accordance with the present invention potently
and selectively bind to the 5-HTlDa receptor subtype, inhibit forskolin-
stimulated adenylyl cyclase activity, and stimulate ~35S]-GTP~S binding to
membranes from clonal cell lines expressing human cloned receptors.
5-HTlDC,/5-HTlD~ Radioligand Binding
Chinese hamster ovary (CHO) clonal cell lines expressing the
human 5-HTlDC, and 5-HTlD~ receptors were harvested in PBS and
20 homogenised in ice cold 50 mM Tris-HCl (pH 7.7 at room temperature)
with a Kinematica polytron and centrifuged at 48,000g at 4~C for ll min.
The pellet was then resuspended in 50 mM Tris-HCl followed by a 10 min
incubation at 37~C. Finally the tissue was recentrifuged at 48,000g, 4~C
for 11 min and the pellet resuspended, in assay buffer (composition in mM:
25 Tris-HCl 50, pargyline 0.01, CaCl2 4; ascorbate 0.1%; pH 7.7 at room
temperature) to give the required volume immediately prior to use (0.2 mg
protein/ml). Incubations were carried out for 30 min at 37~C in the
presence of 0 02-150 nM [3Hl-5-HT for saturation studies or ~-5 nM [3H]-5-
HT for displacement studies. The final assay volume was 1 ml. 5-HT (10
30 ~LM) was used to define non-specific binding. The reaction was initiated by
the addition of membrane and was terminated by rapid ~ltration through
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Whatman GF/B filters (presoaked in 0.3% Pl~I/ 0.5% Triton X) followed by
2 x 4 ml w~hin~.~ with 50 mM Tris-HCl. The radioactive filters were then
counted on a LKB beta or a Wallac beta plate counter. Binding
parameters were determined by non-linear, least squares regression
5 analysis using an iterative curve fitting routine, from which ICso (the
molar concentration of compound necessary to inhibit binding by 50%)
values could be calculated for each test compound. The ICso values for
binding to the 5-HTlDa receptor subtype obtained fox the compounds of the
accompanying Examples were below 100 nM in each case. Furthermore,
10 the compounds of the accompanying F',~ mples were all found to possess a
selective affinity for the 5-HTlDo~ receptor subtype of at least 10-fold
relative to the 5-HTlD,~ subtype.
5-HTlDa/5-HTlD~ Adenylyl Cyclase Assay
~ ~ =
Studies were performed essentially as described in J. Pharmacol.
Exp. Ther., 1986, 238, 248. CHO clonal cell ~ines expressing the human
cloned 5-HTlDo~ and 5-HTlD~ receptors were harvested in PBS and
homogenised, using a motor driven teflon/glass homogeniser, in ice cold
~0 Tris HCl-EGTA buffer (composition in mM: Tris HCl 10, EGTA 1, pH 8.0
at room temperature) and incubated on ice for 30-60 min. The tissue was
then centrifuged at 20,000g for 20 min at 4~C, the supernatant discarded
and the pellet resuspended in Tris HCl-EDTA buffer (composition in mM:
Tris HCl 50, EDTA 5, pH 7.6 at room temperature) just prior to assay.
The adenylyl cyclase activity was determined by measuring the conversion
of ~ 33P~-ATP to [33P]-cyclic AMP. A lû ~1 aliquot of the membrane
suspension was incubated, for 10-15 min, in a final volume of 50 ,ul, at
30~C, with or without forskolin (10 ~lM~, in the presence or absence of test
compound. The incubation buffer consisted of 50 mM Tris HCl ~H 7.6 at
room temperature), 100 mM NaCl, 30 ,uM GTP, 50 ,uM cyclic AMP, 1 mM
dithiothreitol, 1 mM ATP, 5 mM MgCl2, 1 mM EGTA, 1 mM 3-isobutyl-1-
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methyl~r~n~l~ine, 3.5 mM creatinine phosphate, 0.2 mg/ml creatine
phosphokinase, 0.5-1 ~LCi oc-[33P]-ATP and 1 nCi [3EI~-cyclic AMP. The
incubation was initiated by the ~ ition of membrane, following a 5 min
preincubation at 30~C, and was terminated by the addition of 100 ~ll SDS
~; (composition in mM: sodium lauryl sulphate 2%, ATP 46, cyclic AMP 1.3,
pH 7.5 at room temperature). The ATP and cyclic AMP were separated on
a double column chromatography system (~nal. Biochem., 1974, 58, 541).
Functional parameters were determined using a least squares curve
fitting programme ALLFIT (Am. J. Physiol., 1978, 235, 1397) from which
Emax (m~imz~l effect) and ECso (the molar concentration of compound
necessary to inhibit the ms~rim~l effect by 50%) values were obtained for
each test compound. Of those compounds which were tested in this assay,
the E C50 values for the 5-HTlDa receptor obtained for the compounds of the
accompanying F.~r~mples were below ~00 nM in each case. Moreover, the
compounds of the accompanying l~ mples which were tested were all
found to possess at least a 10-ffild selectivity for the 5-HTlD~ receptor
subtype relative to the 5-HTlD~ subtype.
5-HT1Da/5-HTlD~ GTP~yS Binding
Studies were performed essentially as described in Br. J.
Pharmacol., 1993, 109, 1120. CHO clonal cell lines expressing the human
cloned 5-HTlDo, and 5-HTlD~ receptors were harvested in PBS and
homogenised using a Kinematica polytron in ice cold 20 mM HEPES
cont~inin~ 10 mM EDTA, pH 7.4 at room temperature. The membranes
were then centrifuged at 40,000g, 4~C for 15 min. The pellet was then
resuspended in ice cold 20 mM HEPES cont~ining 0.1 mM EDTA, pH 7.4
at room temperature and recentrifuged at 40,000g, 4~C for 15-25 minutes.
The membranes were then resuspended in assay buf~er (composition in
mM: HEPES 20, NaCl 100, MgCl2 10, pargyline 0.01; ascorbate 0.1%; pH
7.4 at room temperature~ at a concentration of 40 ~g protein/ml for the
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- 36-
5-HTlDa receptor transfected cells and 40-60 ~Lg protein/ml for the 5-HTlD~
receptor transfected cells. The membrane suspension was then incubated,
in a volu_e of 1 ml, with GDP (100 ,uM for 5-HTlDa receptor transfected
cells, 30 ~LM for the 5-HTlD~ receptor transfected cells) and test compound
at 30~C for 20 min and then transferred to ice for a further 15 min.
~35S]-GTPyS was then added at a final concentration of 100 pM and the
samples incubated for 30 min at 30~C. The reaction was initiated by the
addition of membrane and was terminated by rapid filtration through
Wh~tm~n GF/B filters and washed with 5 ml water. The radioactive
filters were then counted on a LKB beta counter. Functional parameters
were determined by a non-linear, least squares regression analysis using
an iterative curve fitting routine, fro_ which l~max (m~im~l effect) and
ECso (the molar concentration of compound necessary to inhibit the
m~im~l effect by 50%) values were obtained for each test compound. Of
those compounds which were tested in this assay, the ECso values for the
5-HTlDa receptor obtained for the compounds of the accompanying
~ mples were below 500 nM in each case. Moreover, the compounds of
the accompanying F,~mples which were tested were all found to possess
at least a 10-fold selectivity for the 5-HTlDa receptor subtype relative to
the 5-HTlD~ subtype.
DESCRIPTION 1
4-~1,2~4-Triazol-4-yl)phenylhvdrazine
Prepared as described in WO 94/03446, F'.~mple 1.
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DESCRIPTION 2
4-r3-(5-(1,2.4-Triazol-4-yl~-lH-indol-3-Yl)propvllPiperidine
5 a) 5-(4-PYridvl)pent-4-yn-1-ol
4-Bromopyridine hydrochloride (5g, 0.031mol) was partitioned
between 2N NaOH (50mV and ethyl acetate (250mV. The organic layer
was collected, dried over MgS04 and evaporated in vacuo. The resulting
oil was dissolved in triethylamine (10mV and degassed with nitrogen.
Pent-4-yn-1-ol (3g, 0.035moV was added, followed by
bis(triphenylphosphine)palladium (II) chloride (200mg) and copper iodide
(lOOmg). The reaction was heated to reflux and stirred for 15min. The
reaction was partitioned between ethyl acetate (250ml) and water (50mV.
The organic layer was collected, dried over MgSO4 and evaporated. The
residue was chromatographed on silica eluting with ethyl acetate to afford
the title compound as a yellow solid (3.14g). lH NMR (250MHz, CDCl3)
1.8 (lH, br s), 1.87 (2H, q), 2.57 (2H, t), 3.81 (2H, br t), 7.24 (2H, dd), 8.78(2H, dd).
b) 5-(4-Pvridvl)- 1-Pentanol
~-(4-PyridyVpent-4-yn-l-ol (3.41g) prepared according to the
procedure described above was dissolved in ethanol (30ml) and
hydrogenated over palladium hydroxide catalyst (0.300g) at 45psi for 3h.
The catalyst was filtered and the ethanol evaporated in vcl,cuo to yield the
title product as a colourless oil (3.2g~. lH NMR (250MHz, CDCl3~ ~ 1.40-
1.45 (2H, m), 1.47-1.80 (4H, m), 2.00 (lH br s), 2.62 (2H, t), 3.64 (2H, t),
7.10 (2H, d), 8.45 (2H, d).
c) ~ (N-BenzYl)- 1~ 2 . 5 . 6-tetrahYdroPvridin-4-yn - l -pentanol
The alcohol from above was dissolved in acetone (150ml) and benz~yl
bromide added. The reaction was heated to reflux for 3h, cooled, hexane
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W O 97/19073 PCT/GB96/02795 - 38-
(50mV added, and the solid :Eiltered. The white solid was washed with
hexane, air dried and re-dissolved in 100ml of 80% MeOH/H20. The
reaction mixture was cooled to 0~C and sodium borohydride (1.4g) added,
portionwise, and stirred at 0~C for 15min and then at reflux for 16h. The
methanol was removed i71 vacuo, the residue partitioned between EtOAc
(250ml) and water (50ml), and the organic layer collected. The ethyl
acetate layer was dried (MgSO4) and filtered, and removed in vacuo to
yield 4.5g of the title compound as a colourless oil (91% yield). IH NMR
(250MHz, CDCl3) S 1.30-1.59 (6H, m), 1.97 (2H, br t), 2.06 (2H, m), 2.54
10 (2H, t), 2.95 (2H, m), 2.57 (2H, s), 3.63 (2H, t), 5.35 (lH, br m), 7.22-7.37 (5H, m3.
d) 5-(N-tert-ButoxYcarbonvl-4-piperidinvl)-1-~entanol
5-[1-(N-Benzyl)-1,2,5,6-tetrahydru~ idin-4-yl]-1-pentanol
15 (Description 2c) (48.7g, 0.19mol) was dissolved in methanol (300ml) and
purged with nitrogen. Palladium hydroxide on carbon (4g) was added
followed by ammonium formate (50g) and the reaction stirred at reffux for
lh. The reaction was filtered through Celite and concentrated in vacuo.
The residue was redissolved in dichloromethane (250ml) and txeated with
20 di-tert-butyldicarbonate (45.61g). After 1 hour the reaction was
concentrated i71 uacuo and purified on silica eluting with 50-80%
EtOAc/hexane to yield 40.6g (79%) of the title compound as a colourless
oil. lH NMR (250MEz, CDCl3) ~ 1.45 (9H, s), 1.99 (lH, m), 1.26-1.3 (6H,
m), 1.37-1.70 (6H, m), 2.66 ~2H, dt), 3.64 (2H, t), 4.08 (2H, br d).
e) 5-(N-tert-Butoxvcarbonvl-4-~iperidinYl)- 1-pentanal
The alcohol (1.59g, 0.0055mol) from Description 2d was dissolved in
anhydrous DMSO (20ml) and triethylamine (3.8ml, 0.027mol) added.
Sulfurtrioxide pyridine complex (1.32g,1).0083mol) was added portionwise
30 and the reaction stirred for 0.5h. The reaction was diluted with EtOAc
(70ml) and poured into water (30ml). The organic layer was collected and
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W O 97/19073 PCT/GB96/02795 - 39-
washed with water (3X30mV, dried over MgSO4, and the solvent removed
in uacuo. The residue was used directly in l~escxiption 2e without further
purification.
f) 4-r3-(6-(1~2,4-Triazol-4-yl)-lH-indol-3-yl)~ropvl~piperidine
A 4% H2SO4 solution (25ml) was heated to 50~C for 30min while
bubbling N2 through the solution. 4-(1,2,4-Triazol-4-yl)phenylhydrazine
(Description 1) (1.06g, 0.0061mol) was added to the acid solution followed
by a solution of the aldehyde from Description 2e (1.5g, 0.005mol) in
10 dichloromethane. The reaction was heated to reflux using an air-cooled
condenser and a N2 bubbler for 2h. The reaction was cooled to 0~C and
aqueous N H3 added till pH>8. The product was extracted into ethyl
acetate (3xlOOml), dried over MgSO4 and the solvent removed in v~cuo.
The residue was chromatographed on alumina eluting with CH2C12~1-5%
MeOH/CH2Cl2 and finally 5:1:94 MeOH/NH3/CH2C~12. The title compound
was obtained as a pale yellow foam (0.630g~. 1~ NMR (250MHz, CDCl3) o
1.1 (lH, m), 1.23-1.28 (3H, m), 1.68-1.79 (5H, m), 2.57 (2H, dt, J=1.5Hz),
2.74 (2H, t, J=3Hz), 3.05 (2H, br d, J=5Hz), 7.14 (2H, m, indole-H), 7.47
(lH, d, J=2Hz, indole-H), 7.54 (lH, d, indole-H), 8.46 (s, Ar-H (triazole)),
8.60 (br s, NH (indole)), MS: m/z 3Q9 ~M+1).
EXAM~PLE 1
4-~3-(5-(1.2~4-Triazol-4-vl~-lH-indol-3-yl~uropvl]-1-r2-(2-
2Ej fluorophenyl)ethvllpiperidine. Bis ~IYdrochloride
The product of Description 2 (0.2g, 0.65mmol), potassium carbonate
(0.270g, 1.95mmol) and 2-fluorophenethyl bromide (0.131g, 0.65mmol)
were dis~olved in propan-2-ol (5mV and heated to reflux for 16 hours. The
solvent was removed and the residue was dissolved in ethyl
30 acetate/methanol and washed with saturated potas~ium carbonate soln.
The organic extract was dried (MgSO4), filtered and evaporated to yield
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W O 97/19073 PCT/GB96/02795 - 40 -
the crude product which was purified on silica using 1-3%
meth~n--Vdichloromethane with 0.1% ammonium hydroxide. The
resulting oil was treated with excess meth~noli~ hydrochloric acid to yield
the title product (0.09g). 'H NM~ (360MHz, d4 MeOH) ~ 9.82 (2H, s), 7.70
(lH, s), 7.58 (lH, d, J=8.5Hz), 7.26-7.17 (4H, m), 7.09-6.98 (2H, m), 2.99
(2H, bd, J=10.8Hz), 2.86-2.74 (4H, m), 2.56-2.51 (2H, m), 2.08-2.02 (2H,
m), 1.74-1.71 (4H, m), 1.35-1.22 (5H, m), MS (ES+) 432 (M+H)+. Found: C,
57.35; H, 6.80; N, 12.41. C26H2sFNs. 2HCl. 2.35H20 requires C, 57.10; H,
6.77; N, 12.81%.
EXAMPLE 2
4-r3-(5-(1,2,4-Triazol-4-vl)-lH-indol-3-yl)propyll-l-r2-(3
~luorophenyl)ethyn~iperidine
Prepared according to the method of F'.~mple 1 using 2-(3-
~uorophenyl)ethyl bromide.
lH NMR (360MHz, d4 MeOH) ~ 8.46 (2H, s~, 8.35 (lH, s), 7.54 (lH,
d, J=2Hz), 7.47 (lH, d, J=8.5Hz), 7.26-7.13 (3H, m), 6.98-6.86 (3H, m),
3.15-2.90 (2H, m), 2.85-2.79 (2H, m), 2.75 (2H, t, J=7.6Hz), 2.54-2.68 (2H,
20 m), 1.97-2.12 (2H, m), 1.82-1.65 (4H, m), 1.24-1.45 (5H, m), MS (ES+) 432
(M+H)+. Found: C, 72.04; H, 7.11; N, 15.48. C2GH30FNs requires C, 73.36;
H, 7.00; N, 16.23%.
EXAMPLE 3
4-[3-(5-(1~2,4-Triazol-4-vl)-lH-indol-3-~l)ProPYn-l-r2-(4
(trifluoromethyl)~henyl)ethvnpiperidine
Prepared according to the method of l~ le 1 using 2-[4-
(tri~luoromethyl)phenylJethyl bromide.
NMR (250MHz, CDCl3) ~ 8.47 (2H, s), 8.31 (lH, s), 7.55-7.46 (4H,
m), 7.33-7.26 (lH, s), 7.17-7.14 (2H, m), 3.20-2.88 (4H, m), 2.88-2 60 (4H,
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W O 97/19073 PCT/GB96/02795 - 41-
m), 2.20-2.00 (2H, m), 1.85-1.18 (9H, m), MS (ES+) 482 (M~ . Found: C,
66.91; H, 6.20; N, 14.06. C27H30F3Ns. (0.25)H20 re~uires C, 66.72; H, 6.32;
N, 14.41%.
EXAMPLE 4
4- r3-(5-(1.2,4-Triazol-4-vl)- lH-indol-3-vl)propvll - 1- r3-
(phenvl~propynpiperidine
The product of Description 2 (0.2g, 0.65mmoV and
hydror.innzlm~lflehyde (0.09ml, 0.66mmoV were stirred together in
methanol (5ml). Acetic acid (1mV and sodium cyanoborohydride (0.041g,
0.66mmol) were added and the reaction was stirred for 16 hours. The
solvent was removed and the residue was partitioned between ethyl
acetate/butanol and potassium carbonate solution. The organic layer was
concentrated and the residue was purified by column chromatography on
silica using 1-3% methanol/dichloromethane with 0.1% ammoniu_
hydroxide to yield the title compound as a white solid (0.089g). lH NMR
(250MHz, CDCl3) ~ 8.48 (lH, s), 8.46 (2H, s), 7.53 (lH, d, J=2Hz), 7.47 (lH,
d, J=8.5Hz), 7.30-7.12 (6H, m), 3.04-2.92 (2H, m), 2.98-2.68 (2~I, m), 2.68-
2.58 (2H, m), 2.45-2.34 (2H, rn), 2.02-1.68 (4H, m), 1.42-1.20 (5H, m), MS
(ES+) 428 (M+H)+. Found: C, 76.17; H, 7.85; N, 15.52. C27H33Ns requires C,
75.84; H, 7.78; N, 15.52%.
EXAMPLE 5
~)-4-~3-(5-(1~2,4-Triazol-4-vl)-lH-indol-3-Yl)-~ropYl]-l-r2-(~henvl)-
pro~Yllpiperidine. Bis Oxalate
Prepared according to the method of ~,~mple 4 using the compound
from Description 2 and 2-phenylpropionaldehyde.
lH NMR (250MHz, d6-DMSO) ~ 11.18 (lH, s), 9.15 (2H, s), 7.89 (lH,
d, J=2Hz), 7.59 (lH, d, J=8.3Hz), 7.44-7.28 (6H, m), 3.04-2.77 (4H, m),
_
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W O 97/19073 PCT/GB96/0279S - 42 -
2.46-2.43 (2H, m), 2.01-1.70 (6H, m), 1.48-1.12 (5H, m), 1.28 (3H, d,
J=6.8Hz), MS (ES~ 428 (M+H)+. Found: C, 58.40; H, 6.35; N, 10.60.
C27H33N~. 2(CO2H)2. 1.7~;(H20) requires C, 58.25; H, 6.39; N, 10.9~%.
EXAMPLE 6
4-r3-(5-(1.2~4-Triazol-4-vl)-lH-indol-3-vl)propvl~ r2-(3,4
diiluorol~henvl)ethvnPiperidine
Prepared according to the method of Example 4 using the compound
from Description 2 and 3,4-diiluorophenylacetaldehyde.
NMR (360MHz, d6 DMSO) ~ 11.18 (lH, s), 9.55 (2H, s), 7.88 (lH, d,
J=2Hz), 7.54-7.13 (6H, m), 3.55-3.43 (2H, m), 3.28-3.07 (2H, m), 3.07-2.84
(4H, m), 2.78-2.68 (2H, m), 1.96-1.82 (2H, m), 1.76-1.24 (7H, m), MS (ES+)
450 (M~1)+.
EXAMPLE 7
4-r3-(5-(1,2~4-Triazol-4-Yl)-lH-indol-3-Yl)proPYl~-l-benzYlpiperidine
Prepared according to the method described for Example 4 using the
compound from Description 2 and benzaldehyde. MS (ES) 400 (M+1). IH
NMR ~250MHz, CDCl3) ~ 1.25-1.36 (4H, m), 1.68 (5H, m~, 1.92 (2H, br t),
2.73 (2H, t, J=3Hz), 2.87 (2H, d, J=5Hz), 3.47 (2H, s), 7.13 (2H, m), 7.26
(5H, m), 7.46 (lH, d, J=4Hz), 7.53 (lH, d), 8.37 (br s, NH (indole)), 8.46
(2H, s, Ar(H) triazole). Oxalate salt: C2sH2sNs. 1.6(COOH)2 calculated for:
2~ C, 62.30; H, 5.97; N, 12.88%; found C, 62.23; H, 6.07; N, 12.82%.
EXAMPLE 8
4-r3-(5-(1,2,4-Triazol-4-Yl)-lH-indol-3-yl)proPvl~ (2-tert-butylethyl)-
30 piPeridiIle
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Prepared according to the method described for Example 4 using the
compound from Description 2 and 3,3-dimethylbutyraldehyde. MS (ES)
394 (M+l). lH ~MR (250MHz, CDCl3) ~ 0.88 (9H, s), 1.13-1.43 (7H, m),
1.66-1.91 (6H, m), 2.26-~.33 (2H, m), 2.74 (2H, t, J=3Hz), 2.93 (2H, bd,
J=4Hz), 7.13 (2H, m), 7.47 (lH, d, J=2Hz), 7.54 (lH, d, J=lHz), 8.47 (2H, s,
Ar(H) triazole), 8.64 (br s, NH (indole)). Oxalate salt C24H3sNs. C2H204
calculated for C, 58.53; H, 7.25; N, 12.50; found C, 58.78; H, 7.05; N,
12.51%.
EXAMPI,E 9
4-r3-(5-(1.2.4-Triazol-4-vl)-lH-indol-3-vl)propvn-4-(2-phenvlethyl)-
piperidine
Prepared according to the method described for F.x~mple 4 using the
compound from Description 2 and phenylacetaldehyde. MS (ES) 414
(M+l). lH NMR (250MHz, CDCl3) ~ 1.28-1.39 ~5H, m), 1.72 (4H, m), 1.98
~2H, br t), 2.53-2.59 (2H, m), 2.72-2.84 (4H, m), 3.0 (2H, br d, J=3Hz), 7.12-
7.30 (7H, m), 7.47 (lH, d, J=3Hz), 7.54 (lH, d, J=3Hz), 7.54 (lH, d,
J=lHz), 8.47 (2H, s, ArH (triazole)), 8.48 (br s, indole (NH)). Oxalate salt
C26H3~Ns. C2H204 calculated for C, 60.81; H, 6.13; N, 11.98; found C,
60.77; H, 6.05; N, 12.38%.
DESCRIPTION 3
4-~3-(5-(1.2.4-Triazol-4-yl)-lH-indol-3-vl)propyll-l-(a-
methoxvcarbonvlbenzvl)PiPeridine
4-L3-(5-~1,2,4-Triazol-4-yV-lH-indol-3-yl)propyl]piperidine
(Description 2, 0.800g, 0.0026mol) was dissolved in anhydrous DMF
(lQmV, under N2, and potassium carbonate (0.540g, 0.0039mol) added
followed by (+)-methyl a-bromophenylacetate (Aldrich, 0.5ml, 0.0031mol).
The reaction was stirred at 25~C for 16h, then poured into ethyl acetate
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- 44 -
(lOOml) and H20 (30ml). The organic layer was collected, washed with
H20 (3x30m1), dried over MgS04 and evaporated with 1-5% MeOH/CH2Cl2
to obtain the title compound as a colourless oil. lH NMR 1.23-1.33 (6H,
m), 1.66 (5H, m), 2.04 (lH, br m), 2.72 (2H, t, J=3Hz), 2.96 (lH, bm), 3.69
(3H, s), 3.98 (lH, br s), 7.11 (lH, d, J=lHz), 7.14 (lH, d, J=2Hz), 7.33 (3H,
m), 7.43-7.48 (2H, m), 7.50 (lH, d, J=3Hz), 7.51 (lH, d, J=l~Iz), 8.07 (br s,
indole (NH)), 8.45 (2H, s, Ar (triazole)).
13XAMPLE 10
N-MethYl-2-PhenYl-2-r4-(3-(5-(l.2~4-triazol-4-vl~-lH-indol-3
yl)proPyl)PiPeridin- 1 -vn acetamide
The compound from Description 3 (0.530g) was dissolved in a
solution of methyl~min~ in methanol (~GM, lOml) and heated at 70~C in a
sealed tube for 24h. The tube was cooled, and the contents evaporated.
The residue was chromatographed on silica gel eluting with 1-5%
MeOH/CH2Cl2 to obtain the title compound as a colourless oil (0.220g).
MS (ES) 456 (M+l). lH NMR (250MHz, CDCl3) ~ 1.23-1.28 ~6H, m), 1.69
(5H, m), 2.06 (lH, br m), 2.72 (2H, t, J=3H~;), 2.85 (3H, d, J=2Hz), 2.96
(lH, br m), 3.85 (lH, br s), 7.11 (lH, dt, J=lHz), 7.13 (lH, J=lHz), 7.27
(5H, m~, 7.46 (lH, d, J=3Hz), 7.51 (lH, d, J=lHz), 8.46 ~3H, s, ArH
(triz~7ol~ + indole (NH)).
EXAMPLE 11
4-~3-(5-(1,2,4-Triazol-4-Yl)-lH-indol-3-vl)~ropYn-l-(l-~henvl-2-
hydroxvethyl)piperidine
The compound *om Description 3 (0.800g, 0.00175mol) was
dissolved in anhydrous THF (lOml) and lithium aluminium hydride (0.5M
in DME, 2.3ml, 0.0023mol) added dropwise at 0~C. The reaction was
stirred at 0~C for 20min, and quenched by the slow addition of cold
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saturated NH4Cl solution. The reaction was poured into EtOAc
(50mV/NE4Cl (20mV, the organic layer collected, dried over MgSO4 and
evaporated. The residue was purif;ed on silica eluting with 5% MeOH/1%
NH3/94% CH2Cl2 to obtain the title compound as a colourless oil (0.720g).
MS (ES) 430 ~M+l). lH NMR (250MHz, CDCl3) ~ 1.18-1.28 (4H, m), 1.43
(4H, m), 2.05 (2H, br t), 2.70 (2H, t, J=3~Iz), 2.87 (2H, br d), 3.54-3.75 (2H,
m), 4.00 (lH, t, J=4Hz), 7.12-7.19 (4H, m), 7.26 (3H, m), 7.46 (lEI, d,
J=3Hz), 7.50 (lH, d, J=lHz), 8.39 (br s, indole-NH), 8.47 (2H, s, ArH
(triazole)) oxalate salt.
EXAMPLE 12
4-r3-(5-(1.2~4-Triazol-4-Yl)-lH-indol-3-yl)pro~yll-1-~2-(2-
chlorophenyl)prol?Yll~iperidine
Step 1: 2-(2-Chlorophenvl)-l-methoxvPropene
To a stirred solution of methoxymethyl triphenylphosphonium
chloride (16.6 g, 0.0484 moV in THF (120 ml) at -78~C, was added n-butyl
lithium (26 ml of a 1.6 M solution in hexanes, 0.042 mol) dropwise. The
20 mixture was stirred at -78~C for 30 min then at -20~C for 30 min. The
solution was cooled to -78~C and a solution of 2-chloroacetophenone (5.0 g,
0.032 moV in THF (10 ml) was added dropwise. After addition the mixture
was allowed to warm to room temperature then stirred overnight. The
undissolved solid was removed by ~lltration and the filtrate washed with
25 water (100 ml). The organic layer was separated, dried (Na2SO4) and
evaporated. The residue was chromatographed on silica, using
petrol:ether (25:1) as the eluant, to give the (E)- and (Z)-enol ethers (1.5 g,
26%) as a colourless oil. lH NMR (250MHz, CDCl3) ~ 1.87 and 1.95 (3H, 2
x d, J=1.5 and 1.4Hz respectively), 3.52 and 3.70 (3H, 2 x s), 6.04 (lH, m),
30 7.14-7.40 (4H, m).
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Step 2: 2-(2-ChlorophenYl)ProPanal ~ ~
To a solution of 2-(2-chlorophenyl)-1-methoxy~ ene (712 mg~ 3.9
mmol) in ether (8 ml) at 0~C was added perchloric acid (70%, 3 ml). After
stirring for 1 h the solution was diluted with ether (8 ml) and washed with
water (2 x 20 ml). The organic phase was separated, dried (Na2SO4) and
evaporated. ~he crude 2-(2-chlorophenyl)propanal was isolated as a
colourless oil and used without further purific~ n.
Ste~ 3: 4-r3-(5-(1,2,4-Triazol-4-Yl)-lH-indol-3-vl)proPyll-l-r2-(2-
chlorophenvl)propYnpiperidine
Prepared according to the method of ~.~mI)le 4, using the
compound from Description 2 and 2-(2-chlorophenyl)propanal. lE NMR
(360MHz, CDCl3) ~ 1.20-1.40 (8H, m), 1.55-1.77 (4H, m), 1.90-2.10 (2H, m),
2.38-2.60 (2H, m), 2.73 (2H, t, J=7.5Hz), 2.80-2.92 (lH, m), 2.96-3.10 (lH,
m~, 3.46-3.60 (lH, m), 7.07-7.13 (3H, m), 7.15-7.27 (2H, m), 7.32 (lH, d,
J=7.9Hz), 7.46 (lH, d, J=8.5Hz), 7.53 (lH, s), 8.31 (lH, br s), 8.46 ~2H, s).
MS (ES+) 462/464 (M+1)+. Found: C, 67.58; H, 6.61; N, 14.56%.
C27H32N5Cl. 0.9 (H2O) re~uires: C, 67.81; ~, 7.12; N, 14.64%.
EXAMPLE 13
4-r3-(5-(1,2,4-Triazol-4-yl)-lH-indol-3-~l~prop~ l-r2-(2-
trifluoromethyl~henvl)~ropvllpi~eridine Oxalate
Step 1: 1-Methoxv-2-(2-trifluoromethvlPhenYl)ProPene
Prepared according to the method of ~,~iqmple 12, Step 1 using
2-trifluoromethylacetophenone. lH N~R (250MHz, CDCl3) ~ 1.86 and 1.92
(3H, 2 x d, J=1.5 and 1.4Hz respectively), 3.49 and 3.66 (3H, 2 x s), 5.90
and 5.98-6.00 (lH, br s and m respectively), 7.02-7.38 (2H, m), 7.44-7.54
(lH, m), 7.62-7.68 (lH, m).
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Step 2: 2-(2-Trifiuoromethylphenyl)propanal
Prepared acco~ g to the method of ~.~zlm~le 12, Step 2, using 1-
methoxy-2-(2-~rifluoromethylphenyVpropene. The crude product was used
directly without further purifi~ tinn. lH NMR (25UMHz, CDCl3) o 1.4~
(3H, d, J=7.0Hz), 4.09 (lH, q, J=7.0Hz), 7.22 (lH, d, J=7.8Hz), 7.41 (lH, t,
J=7.7Hz), 7.57 (lH, t, J=7.6Hz), 7.73 (lH, d, J=7.5Hz), 8.71 (lH, s).
SteP 3: 4-r3-(5-(1.2.4-Triazol-4-vl)-lH-indol-3-vl~propvll-1-r2-~2-
trifluoromethvl~henvl)PropvllPiPeridine Oxalate
Prepared according to the method of l~ mple 4, using the
compound from Description 2 and 2-(2-trifLuoromethylphenyl)propanal.
lH NMR (360MHz, dG-DMSO) o 1.24-1.50 (8H, m), 1.60-1.81 (4H, m), 2.69
(2H, t, J=7.5Hz), 3.04-3.30 (2H, m), 3.38-3.51 (lH, m), 3.60-3.80 (4H, m),
7.26-7.32 (2H, m~, 7.46-7.50 (2H, m), 7.68-7.72 (3H, m), 7.76 (lH, s), 9 01
(2H, s), 11.07 (lH, ~r s). MS (ES~) 496 (M+l)+. Found: C, 59.51; H, 5.90;
N, 11.11%. C2gH32NsF3. 1.4(C2H204) requires: C, 59.51; H, 5.64; N, 11.27%.
EXAMPLl~ 14 =
4- ~3-(5-(1,2 4-Triazol-4-vl)- lH-indol-3-yl)propyll - 1 - r2-(4-
chloroPhenvl)~roPyllpiperidine. Oxalate
Step 1: 1-Methoxv-2-(4-chlorophenvvpropene
Prepared accordirlg to the method of Example 12, Step 1, using
4-chloroacetophenone. lH NMR (360MHz, CDCl3) â 1.89 and 1.95 (3H, 2 x
d, J=1.3Hz each), 3.67 and 3.71 (3H, 2 x s), 6.10-6.14 and 6.38-6.40 (lH, 2
x m), 7.17-7.29 (3~, m), 7.'-,3-7.56 (lH, m).
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Step 2: 2-(4-ChlorophenYllpropanal
Prepared according to the method of F'.~ ple 12, Step 2, using 1-
methoxy-2-(4-chlorophenyVpropene. The crude aldehyde was used directly
without further purification.
Step 3: 4-r3-(5-(1,2,4-Triazol-4-vl~-lH-indol-3-vl)pro~yll-1-~2-(4-
chlorophenYl)propvllPiperidine. Oxalate
Prepared according to the method of Example 4, using the
compound from Description 2 and 2-(4-chlorophenyl)propanal. lH NMR
(360MHz, d~-DMSO) ~ 1.20-1.56 (8H, m), 1.61-1.84 (4H, m), 2.61-2.88 (4H,
m), 3.16-3.36 (5H, m), 7.25-7.32 (2H, m), 7.36-7.42 (4~I, m), 7.47 (lH, d,
J=8.6Hz), 7.76 (lH, s), 9.01 (2H, s), 11.09 (lH, br s). MS (ES+) 462 (M+l)~.
Found: C, 60.14; H, 6.44; N, 11.80%. C~7H32NsCl. 1.3(C2H204). 0.~ (H2)
requires: C, 60.45; H, 6.10; N, 11.91%.
:~~AMPLE 15
4-r3-(s-(l~2~4-triazol-4-vl)-lH-indol-3-yl)propyll-l-r2-(4
methoxyphenvl)propvllPiperidine. Oxalate
steP 1: 1-Methoxv-2-(4-methoxyphenYl)Propene
Prepared according to the method of ~ mple 12, Step 1 using 4-
methoxyacetophenone. lH NMR (250MHz, CDCl3) ~ 1.90 and 2.00 (3H, 2 x
d, J=1.3Hz each), 3.66 and 3.70 (3H, 2 x s), 3.80 and 3.81 (3H, 2 x s), 6.04-
6.07 and 6.30-6.34 (lH, 2 x m), 6.83-6.90 (2H, m), 7.19-7.28 (lH, m), 7.51-
7.59 (lH, m).
SteP 2: 2-(4-MethoxY~henY~propanal
Prepared according to the method of F~ mple 12, Step 2 using 1-
methoxy-2-(4-methoxyphenyl)propene. The crude aldehyde was used
directly without further purification.
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- 4~-
Step 3: 4- r3 - (5 - ~ 1,2.4-Triazol-4-vl~ - 1 H-indol- 3 -Yl~Pro~Y~ - r2- (4-
methoxvPhenvl)Propv31Piperidine. Oxalate
Prepared according to the method of F'.~s~mple 4, using the
compound ~rom Description 2 arld 2-(4-methoxyphenyl)propanal. lH NMR
(360MHz, d6-DMSO) ~ 1.17-~.59 (7H, m), 1.60-1.76 (5H, m), 2.42-2.90 (5H,
m), 3.12-3.44 (4H, m), 3.74 (3H, s), 6.91 (2H, d, J--8Hz), 7.20-7.34 (4H, m),
7.48 (lH, d, J=8.2Hz), 7.77 (lH, s), 9.01 (2H, s), 11.09 (lH, br s). MS (ES~
458 (M~l)+. P'ound: C, 61.08; H, 6.56; N, 10.78%. (~2sH3sNsO. l.9(C2H2O4)
requires: C, 60.75; H, 6.22; N, 11.14%.
E~AMPLE 16
4-r3-(5-(1,2~4-Triazol-4-vl)-lH-indol-3-vl)~ropvll-1-r2-(2,6-
dichloroPhenYl)Pro~ynpiperidine
l~i
Ste~ 1: Ethvl (2.6-dichloroPhenvl)acetate
To a solution of 2,6-dichlorophenyl acetic acid (6.7 g, 0.033 mol) in
dichloromethane (170 ml) was added triethylamine (5.9 ml, 0.043 mol), 1-
ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.1 g, 0.043
mol) and 4-pyrrolidinopyridine (0.58 g, 0.004 n3ol). Ethanol (2.5 ml, 0.043
mol) was added dropwise and the solution stirred overnight at room
temperature. After this time the mixture was washed with water (2 x 100
ml), lM HCl (2 x 100 ml), aq. K2CO3 (sat.; 2 x 100 ml) and brine (100 ml).
The organic phase was separated, dried (Na2SO4) and evaporated. The
residue was chromatographed on silica, using petrol:ether (10:1) as the
eluant, to give the ester (7.2 g, 94%) as a colourless oil which solidified on
st~n(ling at 0~C. lH NMR (360MHz, d6-DMSO) ~ 1.26 (3H, t, ~=7.1Hz),
4.01 (2H, s), 4.18 (2H, q, J=7.1Hz), 7.15 (lH, t, J=8.6Hz), 7.32 (2H, d,
J=8.6Hz).
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Step 2: Ethvl 2-(2.6-dichlorophenYl)pro~anoate
To a solution of diisopropylamine (1.3 ml, 9.4 mmol) in THF (20 ml)
at 0~C was added n-butyl lithium (5.9 ml of a 1.6M solution in hexane, 9.4
mmol) dropwise. The solution was stirred at 0~C for 30 min then cooled to
-78~C. A solution of ethyl (2,6-dichlorophenyVacetate (2.0 g, 8.6 mmol) in
TH~ (20 ml) was added dropwise and the solution stirred at -78~C for lh.
Iodomethane (0.59 ml, 9.4 mmol) was then added and the solution stirred
at -78~C for 15 min before the cooling was removed. The solution was
allowed to warm to room temperature then NH4Cl (sat., 20 ml) was added.
The organic phase was separated and washed with lM HCl (2 x 20 ml)
followed by water (20 ml). The organic layer was separated, dried
(Na2SO4) and evaporated. The residue was chromatographed on silica,
using petrol:ether (15:1) as the eluant, to give the ester (0.66 g, 31%) as a
colourless oil. lH NMR (360MHz, CDCl3) o 1.21 (3H, t, ~=7.~Ez), 1.53 (3H,
d, 3=7.1~Iz), 4.01-4.24 (2H, m), 4.46 (lH, ~, J=7.1Hz), 7.12 (lH, t,
J=7.9Hz), 7.29 (2H, d, J=8.1Hz).
Step 3: 2-(2,6-Dichlorophenvl~Pro~an-1-ol
To a solution of ethyl 2-(2,6-dichlorophenyl)propanoate (0.66 g, 2.7
mmol) in THF (30 ml) at 0~C~ was added diisobutylaluminium hydride (6.
ml of a 1.0M solution in THF, 6.6 mmol) dropwise. The cooling bath was
removed and the mixture stirred at room temperature for 45 min. More
diisobutylaluminium hydride (3 ml of a 1.0M solution in THF, 3.0 mmol)
was added and the solution stirred for a further 45 min. ~fter this time
more diisobutylaluminium hydride (3 ml of a 1.0M solution in TEF, 3.0
mmol) was added and the solution stirred for lh. NH4Cl (sat., 10 ml) was
added and the mixture stirred at room temperature for lh. The organic
layer was decanted off and the gelatinous precipitate partitioned between
ether (30 ml) and lM HCl (30 ml). The organic layers were combined,
dried (Na2SO4~ and evaporated. The residue was chromatographed on
silica, eluting with petrol:EtOAc (3:1), to afford the alcohol (546 mg, 100%)
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as a colourless oil. lH NMR (250MHz, CDCl3) ~ 1.41 (3H, d, J=6.7Hz),
3.94-4.01 (2H, m), 4.13-4.23 (lH, m), 7.08 (lH, t, J=7.9Hz), 7.20-7.40 (2H,
m).
Step 4: 2-(2.6-Dichlorophenvl)Pro~anal
To a stirred solution of 2-(2,6-dichlorophenyl)propan-1-ol (278 mg,
1.4 mmol) in DMSO (6 ml) was added triethylamine (1.1 ml, 8.1 mmol)
followed by pyridine-sulphur tri~ (322 mg, 2.0 mmoV. After lh more
pyridine-sulphur tri-~irle (161 mg, 1.0 mmol) was added and the mixture
10 stirred for a further lh. The mixture was partitioned between EtOAc (3 x
20 ml) and water (20 ml). The combined organic layers were washed with
brine (20 ml) then separated and dried (Na2SO4). The solvent was
evaporated and the residue azeotroped with toluene (2 x 20 ml). The
aldehyde was used directly without further purification. lH NMR
15 (250MHz, CDCl3) ~ 1 (3H, d, J=7.0Hz), 4.17 (lH, q, J=7.0Hz), 7.20 (lH,
t, J=8.0Hz), 7.33 (2H, d, J=8.5Hz).
Ste~ 5: 4-r3-~5-(1.2.4-Triazol-4-vl)-lH-indol-3-Yl)propY1~ 2-(2,6-
dichlorol)henvl)propyllpi~eridine
Prepared according to the method of :Example 4, using the
compound fro~n Description 2 and 2-~2,6-(lirhlnrophenyl)propanal.
H NMR (360MHz, CDCl3) ~ 1.02-1.28 (5H, m), 1.32 (3H, d, J=7.2Hz), 1.48-
1.70 (4H, m), 1.82-2.00 (2H, m), 2.65 (2H, t, J=7.5Hz), 2.67-2.80 (lH, m),
2.81-2.90 (3H, m), 3.79-3.89 (lH, m), 6.95 (lH, t, J=8.0Hz), 7.01-7.06 (2H,
25 m), 7.13-7.22 (2H, m), 7.39 (lH, d, J=8.5Hz), 7.45 (lH, d, J=1.9Hz), 8.39
(3H, s). MS (ES+) 496/498 (M+l)+. Found: C, 64.60; H, 6.37; N, 13.84%.
C27H3lN5C12. 0.3(H20) requires: C, 64.62; H, 6.35; N, 13.95%.
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EXAMPLE 17
4-r3-(5-(1~2,4-Triazol-4-vl)-lH-indol-3-vl3propvn-1-~2-(3
methoxy~henYl~pronvllpiperidine. Oxalate
steP 1: 1-Methoxy-2-(3-methoxyphenyl)~ropene
Prepared according to the method of ~,~r~m~le 12, Step 1, using 3-
methoxyacetophenone. lH NMR (360MHz, CDCls) ~ 1.91 and 1.97 (3H, 2 x
d, J=1.3Hz), 3.67 and 3.71 (3H, 2 x s), 3.81 (3H, s), 6.11-6.12 and 6.42-6.43
(lH, 2 x m), 6.72-6.92 (2H, m), 7.16-7.27 (2H, m).
SteP 2: 2-(3-Methoxvphenvl)propanal
Prepared according to the method of l~ mple 12, Step 12 using 1-
methoxy-2-(3-methoxyphenyl)propene. The crude aldehyde was used
directly without further puri~ tinn.
~teP 3: 4-r3-~5-(1,2,4-Triazol-4-vl)-lH-indol-3-vl)proPvll-l-r2-(3-
methoxvphenvl)pro~vllPi~eridine. Oxalate
Prepared according to the method of ~xample 4, using the
compound from Description 2 and 2-(3-methoxyphenyl)propanal. lH NMR
(360MHz, d6-DMSO) ~ 1.07-1.50 (8H, m), 1.60-1.80 (4H, m), 2.60-2.76 (4H,
m), 3.04-3.34 (5H, m), 3.75 (3H, s), 6.80-6.84 (lH, m), 6.86-6.90 (2H, m),
7.22-7.30 (3H, m), 7.47 (lH, d, J=8.6Hz), 7.75 (lH, d, J=1.9Hz), 9.00 (2H,
s), 11.09 (lH, br s). MS (ES+) 458 (M+l)+. Found: C, 64.91; H, 6.98; N,
12.55%. C2g~I3sNsO. (CO2H)2. 0.5(H20) requires: C~ 64.73; H, 6.88; N,
12.58%.
EXAMPLl~ 18
4- r3 - (5 - (1.2,4-Triazol-4-vl) - lH-indol- 3 -vl)ProPYll - 1 - ~2- (2 -
methoxvphenyl)propyllpiperidine. Oxalate
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Ste~ Methoxy-2-(2-methoxv~henvl)~ro~ene
Prepared according to the method of ~ mI~le 12, Step 1 using 2-
methoxyacetophenone. lH NMR (360MHz, CDCl3) ~ 1.87 and 1.96 (3H, 2 x
d, J=1.4Hz), 3.54 and 3.68 (3H, 2 x s), 3.82 and 3.83 (2H, 2 x s), 6.02-6.05
and 6.20-6.22 (lH, 2 x m), 6.85-6.96 (2H, m), 7.11-7.26 (2H, m).
Step 2: 2-(2-MethoxvphenYl)propanal
Prepared according the method of F~mI~le 12, Step 2 using 1-
methoxy-2-(2-methoxyphenyl)propene. The crude aldehyde was u~ed
directly without further purification. lH NMR (360MHz, CDCl3) ~ 1.39
(3H, d, 3=7.1Hz), 3.83 (3H, s), 3.86 (lH, q, J=7.0Hz), 6.92 (lH, d, J=8.0Hz),
6.97 (lH, t, J=7.5Hz), 7.11 (lH, dd, J=7.5 and 1.6Hz), 7.26-7.31 (lH, m),
9.67 (l~I, s).
Step 3: 4-r3-(5-(1.2.4-Triazol-4-vl)-lH-indol-3-vl3propvl~ 2-(2-
methoxv~henvl)Propyllpiperidine. Oxalate
Prepared according to the method of Example 4, using the
compound from Description 2 and 2-(2-methoxyphenyl)propanal. lH NMR
(360MHz, d6-DMSO) ~ 1.12-1.54 (8H, m), 1.64-1.84 (4H, m), 2.62-2.90 (4H,
m), 3.08-3.20 (2H, m), 3.28-3.42 (2H, m), 3.48-3.66 (lH, m), 3.81 (3H, s),
6.95 (lH, t, J=7.3Hz), 6.99 (lH, d, J=8.1Hz), 7.23-7.32 (4H, m), 7.48 (lH, d,
J=8.6Hz), 7.77 (lH, d, J-1.9Hz), 9.02 (2H, s), 11.10 (lH, br s). MS (ES+)
458 (M~l)+. Found: C, 63.95; H, 6.99; N, 12.26%. C2sEl3GNsO. (C02H)2.
H20 requires: C, 63.70; H, 6.95; N, 12.38%.
EXA3~tPLE 19
4-~3-~5-(1,2.4-Triazol-4-vl~-lH-indol-3-vl)prol~yll-1-r2-(3-
30 chlorophenvl)prol)vll~iperidine. Oxalate.
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SteP 1: 2-(3-Chlorophenvl)-l-methoxY,propene
Prepared according to the method of Example 12, Step 1, using
3-chloroacetophenone. lEI NMR (360MHz, CDCl3) ~ 1.89 and 1.96 (3H, 2 x
d, J=1.3Hz), 3.69 and 3.73 (3H, 2 x s), 6.14 and 6.43 (lH, 2 x d, J=1.2 and
1.3Hz respectively), 7.10-7.62 (4H, m).
SteP 2: 2-(3-Chlorophenvl~propanal
Prepared according to the method of F',~:~mI~le 12, Step 2, using 2-(3-
chlorophenyl)-l-methoxypropene. The crude product was used directly
10 without further purification.
SteP 3: 4-r3-~5-(1,2.4-Triazol-4-vl)-lH-indol-3-Yl)prop~l~-l-r2-~3-
chlorophenyl)proPvllPiPeridine. Oxalate
Prepared according to the method of F'.~r~m~le 4, using the
15 compound from Description 2 and 2-(3-chlorophenyl)propanal. lH NMR
(360MHz, d6-DMSO) o 1.22-1.72 (8H, m), 1.60-1.80 (4H, m), 2.60-2.80 (4H,
m), 3.08-3.34 (5H, m), 7.25-7.49 (7H, m), 7.76 (lH, d, J=2.0Hz), 9.00 (2H,
s), 11.08 (lH, br s). MS (ES+) 462 (M+1)+. Found C, 61.62; H, 6.49; N,
11.77%. C27H32NsCl. 1.25(CO2H)2. 0.25(H20) requires: C, 61.19; ~, 6.09; N,
~2.09%.
EXAMPLE 20
4-r3~ 2~4-Triazol-4-v~ H-indol-3-yl)propyl~ 2-(3
aminosulPhonvlphenvl)proPYllpiperidine. Oxalate
Step 1: 3-AminosulPhonvlacetophenone
To a stirred solution of 3-acetylbenzene sulphonyl fluoride (0.~ g, 2.5
mmol) in THF (l ml) at ambient temperature was added a solution of
ammonia in water (25%, 1.35 ml), and the mixture stirred for 2 hours.
The mixture was diluted with ethyl acetate (25 ml) and water (25 ml).
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The two layers were separated and the a~ueous extracted with ethyl
acetate (25 ml). The combined organic phases were dried (I\!~g~ O4) and
evaporated. The residue was chromatographed on silica using
hexane:ethyl acetate (1:1), followed by ethyl acetate as the eluant, to give
the title compound (0.31g, 63%) as a colourless solid. lH NMR (360MHz,
d~-DMS0) ~ 2.65 (3H, s), 7.50 (2H, br s), 7.75 (lH, t, J=7.5Hz), 8.06-8.08
(lH, m), 8.18-8.20 (lH, m), 8.35-8.36 (lH, m).
SteP 2: 2-(3-Aminosulphonylpheny~ -methoxvpropene
To a stirred solution of methoxymethyl triphenylphosphonium
chloride (25.8 g, 75.4mmol) in THF (150 ml) under nitrogen at -78~C was
added n-butyl lithium (37.7 ml of a 1.6M solution in he~ s, 60.3 mmol)
dropwise. The mi~ture was stirred at -78~C for 10 min and then at 0~C for
45 min. The solution was cooled to -78~C and a solution of 3-
15 aminosulphonylacetophenone (5 g, 25.1m mol) in THF (50 ml) was added
dropwise. After addition the mixture was stirred at -78~C for lh and then
the mixture was allowed to warm to ambient temperature, then stirred for
16h. NH4Cl solution (sat., 100 ml) was added to the mixture and the two
phases separated. The aqueous phase was extracted with ether (100 ml)
20 and the combined organic phases were dried (Na2SO4) and evaporated.
The residue was chromatographed on silica with hexane:ethyl acetate
(20:7) followed by hexane:ethyl acetate (1:1) to afford the title compound
(2.47 g, 43%) as a colourless solid. lH NMR (360MHz, CDCl3) ~ 1.94 and
1.99 (3H, 2 x d, J=1.3Hz), 3.72 and 3.76 (3H, 2 x s), 4.83 and 4.86 (2H, 2 x
25 br s), 6.20-6.22 and 6.50-6.52 (lH, 2 x m), 7.39-7.84 (3H, m), 7.86-7.86 and
8.17-8.18 (lH, 2 x m).
Step 3: 2-(3-Aminosul~honylphenvl)~ropanal
Prepared according to the method of ~3xample 12, Step 2 using 2-(3-
30 aminosulphonylphenyV-1-methoxypropene. The crude product was used
directly without further purification.
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Step 4: 4-r3-(~-tl.2.4-Triazol-4-Yl)-lH-indol-3-vl~proPYl~-l-r2-(3-
aminosulPhonYlphenvl)prop~ iPeridine oxalate
Prepared according to the method of F'.~mple 4, using the
compound from Description 2 and 2-(3-aminosulphonylphenyVpropanal.
lH NMR (360MHz, d6-DMSO) ~ 1.20-1.52 (8H, m), 1.80-1.92 (4H, m), 2.64-
2.82 (4H"n), 3.10-3.42 (5H, m), 7.24-7.37 (4H, m), 7.48 (lH, d, J=8.7Hz),
7.50-7.~i8 (2H, m), 7.70-7.80 (3H, m), 9.01 (2H, s), 11.09 (lH, br s~. MS
(ES+) 507 (M+l)+. Found: C~, 54.86; H, 6.35; N, 12.82%. C27H34N~02S.
1.4(CO2H)2. H20 requires: C, 55.00; H, 6.01; N, 12.91%.
E~AMPLE 21
4-r3-(5-(1.2.4-Triazol-4-vl)-lH-indol-3-~rl)pro~Y1~ 2-(pyrimi-lin-2-
vl)~ropvllPiperidine. Oxalate
Step 1: Diethvl 2-(~yrimidin-2-yl)malonate
To a solution of sodium hydride (4.4 g of a 60% dispersion ~n oil,
0.11 mol) in DMF (200 ml) was added diethyl malonate (16 ml, 0.11 mol)
in DMF (50 rnl) dropwise at room temperature. After 30 min 2-
bromopyrimidine (8.0 g, 0.05 mol) was added portionwise and the solution
heated at 100~C for 3h. The solution was cooled to room temperature,
water (100 rnl) was added and the mixture extracted with EtOAc (3 x 60
mV. The combined organic layers were dried (MgSO4) and evaporated.
The residue was chromatographed on silica, using he~:~ne:EtOAc (3:1) as
the eluant, to afford the ester (5.9 g, 49%) as a pale yellow oil which
solidified on standing at 0~C. lH NMR (360MHz, CDCl3) ~ 1.29 (6H, t,
J=7.1Hz), 4.29 (4H, q, J=7.1Hz), 5.10 (lH, s), 7.26 (lH, t, J=4.9Hz), 8.74
(2H, d, J=4.9Hz).
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Step 2: Ethvl (pvrimi~lin-2-yl)acetate
A solution of diethyl 2-(pyrimitlin-2-yVmalonate (1.0 g, 4.2 mmol)
and sodium chloride (491 mg, 8.4 mmoV in DMSO (6 ml) and water (151
,ul, 8.4 mmol) was heated at 180~C for 20 min. The mixture was cooled to
5 room temperature, water (12 ml) was added, and the solution extracted
with l~tOAc (2 x 20 mV. The combined organic layers were dried (M gSO4)
and evaporated. The residue was chromatographed on silica, eluting with
hexane:EtOAc (2:1), to afford the ester (434 mg, 62%) as a pale yellow oil.
lH NMR (250MHz, CDCl3) ~ 1.27 (3H, t, J=7.1Hz), 4.04 (2H, s), 4.23 (2H,
q, J=7.1Hz), 7.22 (lH, t, J=5.3Hz), 8.72 (2H, d, J=5.3Hz).
Ste~ 3: Ethvl 2-(pvrimidin-2-vl)~ropanoate
To a solution of diisopropyl~min~ (2.2 ml, 0.015 moV in THF (60 ml)
at 0~C, was added butyl lithium (9.6 ml of a 1.6 M solution in hexane,
16 0.015 moV dropwise. The solution was stirred at 0~C for 30 min then
cooled to -78~C and iodomethane (960 ,ul, 0.015 mol) added dropwise. The
solution was stirred at -78~C for 10 min, -50~C for 30 min then at room
temperature for 20 min. After this time NH4Cl (sat., 30 ml) was added
and the mixture stirred at room temperature ~or 10 min. Water (lOQ ml)
20 was added and the mixture was extracted with EtOAc (2 x 100 ml). The
combined organic layers were dried (Na2SO4) and evaporated. The residue
was chromatographed on silica, eluting with hexane:EtOAc (2:1), to give
the ester (1.8 g, 71%) as a yellow oil. lH NMR (250ME~z, CDCl3) ~ 1.22
(3H, t, J=7.2Hz), 1.62 (3H, d, J=7.2Hz), 4.12 (lH, q, J=7.2Hz), 4.22 (2H, q,
25 J=7.2Hz), 7.19 (lH, t, J=4.9Hz), 8.74 (2H, d, J=4.9Hz).
Step 4: 2-(Pvrimidin-2-vl)~ro~an-1-ol
~ To a solution of ethyl 2-(pyrimidin-2-yl)propanoate (1.7 g, 9.4 mmol)
in THF (100 ml) at 0~C, was added diisobutylaluminium hydride (23.6 ml
30 of a 1.0 M solution in THF, 23.6 mmol) dropwise. After 3h NH4Cl (sat., 30
ml) was added and the mixture stirred at room temperature for 30 min.
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EtOAc (100 ml) was added and the mixture filtered. The filtrate was dried
(Na2SO4) and evaporated. The residue was chromatographed on silica,
eluting with CH2Cl2:MeOH (95:5), to give the alcohol (562 mg, 43%) as a
pale yellow oil. lH NMR (360MHz, CDCls) ~ 1.38 (3H, d, J=7.2Hz), 3.22-
3.31 (lH, m), 3.65 (lH, br s), 3.80-4.05 (2H, m), 7.18 (lH, t, J=4.9Hz), 8.72
(2H, d, J=4.9Hz).
Step 5: 2-(PYrimidin-2-yl)propanal
Prepared according to the method of F.~s~mple 16, Step 4, using 2-
(pyrimi~in-2-yVpropan-1-ol. The aldehyde was used directly without
further purification.
Step 6: 4-r3-(5-(l~2~4-Triazol-4-vl)-lH-indol-3-yl)propvl~-l-r2
~Pvrimidin-2-vl)proPYllpiperidine. Oxalate
Prepared according to the method of F,~mple 4, using the
cornpound ~rom Description 2 and 2-Gpyrimidin-2-yVpropanal. lH NMR
(360MHz, dG-DMSO) ~ 1 16-1.56 (8H, m), 1.61-1.83 (4H, m), 2.54-2.67 (4H~
m), 3.00-3 10 (lH, m), 3.12-3.21 (lH, m), 3.23-3.60 (3H, m), 7.21-7.26 (2H,
m), 7.34 (lH, t, J=4.8Hz), 7.46 (lH, d, J=8.5Hz), 7.69 (lH, s), 8.70 (2H, d,
J=4.8Hz3, 8.86 (2H, s), 10.84 (lH, br s). MS (ES+) 430 (M+l)+. Found: C,
58.76; H, 6.56; N, 16.97%. C23H31N7. 1.3(C2H204). H20 requires: C, 58.71;
H, 6.36; N, 17.37%.
EX~PLE 22
4-r3-(5-(1.2,4-Triazol-4-yl)-lH-indol-3-vl)propyn-1-r2-~thiazol 2
Yl)Propyllpiperidine
Step 1: EthYl 2-(thiazol-2-vl)acetate
Prepared according to the method of F~m~le 21, Step 2 using
diethyl 2-(thiazol-2-yl)malonate. IH NMR (360MHz, CDCl3) ~ 1.29 (3H, t,
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_ ~9
J=7.3Hz), 4.09 (2H, s), 4.22 (2H, q, J=7.3Hz), 7.32 (lH, d, J=3.5Hz), 7.75
(lH, d, J=3.5Hz~. MS (FS+) 172 (M+1)~.
Step 2: Ethvl 2-(thiazol-2-Yl)uroPanoate
Prepared according to the method of F'.~mple 21, Step 3 using ethyl
2-(thiazol-2-yl)acetate. lH NMR (360MHz, CDCl3) ~ 1.29 (3H, t, J=7.1Hz),
1.67 (3H, d, J=7.2Hz), 4.17-4.24 (3H, m), 7.29 (lH, d, J=3.3Hz), 7.73 (lH,
d, 3=3.3Hz). MS (ES+) 186 ~M~1)+.
10 Step 3: 2-(Thiazol-2-vl~propan-1-ol
To a stirred solution of ethyl 2-(thiazol-2-yl)propanoate (418 mg, 2 3
mmol) in ether (15 mV at -10~C was added LiAlH4 (2.2 ml of a l.OM
solution in ether, 2.2 mmol) dropwise. After 2h at -10~C more LiAlH4 (0.5
ml of a l.OM solution in ether, 0.5 mmol) was added. After a further lh
15 more LiAlH4 (0.5 ml of a l.OM solution in ether, 0.5 mmoV was added.
Stirring was continued for lh then Na2SO4 (sat., 3 mV was added and the
mixture stirred at room temperature for 10 min. The mixture was filtered
and the filtrate evaporated. The residue was chromatographed on silica,
eluting with CH2Cl2:MeOH ~95:5), to give the alcohol (266 mg, 82%) as a
20 colourless oil. lH NMR (250MHz, CDCls) ~ 1.42 (3H, d, J=7.1Hz), 3.31-
3.44 (lH, m), 3.64 (lH, br s), 3.80-3.93 (2H, m), 7.25 (lH, d, J--3.3Hz), 7.70
(lH, d, J=3.3Hz).
Step 4: 4-~3-(~-(1,2~4-Triazol-4-yl)-lH-indol-3-vl)Pro1?Yl~-1-[2-(thiazol-
25 2-vl)nropYll~iperidine
To a solution of 2-(thiazol-2-yl)propan-1-ol (304 mg, 2.1 mmol) in
THF (7 ml) at 0~(~, was added triethyl~mine (319 ~11, 2.3 mmol) followed by
methanesulphonyl chloride (181 ~Ll, 2.3 mmol). The solution was stirred at
0~C for lh then the mixture was filtered and the filtrate evaporated. The
30 crude mesylate was used directly without further purification.
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To a solution of the compound *om Description 2 (100 mg, 0.32
n~mol) in isopropanol was added the mesylate prepared above (144 mg,
0.66 mmol) and K2CO3 (67 mg, 0.48 mmol). The mixture was heated at
re~lux for 6h, after which time more mesylate (144 mg, 10.65 mmol) was
5 added. Heating was continued for a further 6h after which time the
601ution was cooled to room temperature and filtered. The filtrate was
diluted with CH2Cl2 (20 ml) and washed with water (20 ml). The organic
layer was separated and the aqueous phase washed with CH2Cl2 (20 mV.
The combined organic layers were dried (Na2SO4) and evaporated. The
10 residue was chromatographed on silica, eluting with CH2Cl2:MeOH:NH3
(90:10:1), to give the product (28 mg, 20%) as a colourless gum. lH NMR
(360MHz, CDCls) ~ 1.17-1.40 (5H, m), 1.40 (3H, d, J=7.0Hz), 1.60-1.77 (4H,
m), 1.85-2.12 (2H, m), 2.53-2.77 (4H, m), 2.80-2.98 (2H, m), 3.33-3.48 (lH,
m), 7.10-7.14 (2H, m), 7.22 (lH, d, J=3.2Hz), 7.46 (lH, d, J=8.3Hz), 7.53
(lH, d, J=2.0Hz), 7.66 (lH, d, J=3.3Hz), 8.48 (2H, s). MS (ES+) 435 (M+1)+.
Found: C, 64.34; H, 6.76; N, 18.48%. C24H30N6S. 0.7(H20) requires: C,
64.46; H, 7.08; N, 18.79%.
E~AMPLE 23
4-~3-(5-(1,2,4-Triazol-4-Yl)-lH-indol-3-Yl)pro~Yl~ 2-(nYrazin-2
Yl)propvllpinerazine Oxalate
Step 1: 1-Methoxv-2-(pyrazin-2-vl)propene
Prepared according to the method of Example 12, Step 1 using
2-acetylpyrazine. lH NMR (250MHz, CDCl3) ~ 2.02 (3H, d, J=1.4Hz), 3.84
(3H, s), 7.22-7.25 (lH, m), 8.29 (lH, d, J=2.5Hz), 8.37-8.40 ~lH, m), 8.48-
8.52 (lH, m).
,
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Step 2: 2-(Pvrazin-2-vl)~ropanal
Prepared according to the method of F,~3m~le 12, Step 2, using
l-methoxy-2-(pyrazin-2-yl)propene. The aldehyde was used directly
without further purification.
Ste~ 3: 4-r3-(5-(1.2~4-Triazol-4-vl)-lH-indol-3-vl)~ro~vll-1-[2-~Pvrazin-
2-yl)~ropvnpi~erazine Oxalate
Prepared according to the method of F'.~mple 4, using the
compound from Description 2 and 2-(pyra~in-2-yVpropanal. lE~ NMR
(360MHz, dG-DMSO) ~1.24-1.~8 (8H, m), 1.61-1.71 (2H, m), 1.72-1.84 (2H,
m), 2.64-2.91 (4H, m), 3.18-3.59 (5H, m), 7.25 (lH, s), 7.29 (lH, d,
J=8.6Hz), 7.47 (lH, d, J=8.6Hz), 7.75 (lH, s), 8.56 (lH, s), 8.61 ~lH, s),
8.68 (lH, s), 9.00 (2H, s), 11.07 (lH, br s). MS (ES+) 430 (M+l)+. Found C,
56.12; H, 6.~0; N, 15.07%. C2sH3lN7. 2.2(C2H204). 0.3(H2O). 0.3(Et2O)
requires: C, 56.09; H, 6.00; N, 14.96%.
EX~M~PLE 24
4-r3-(5-(1,2.4-Triazol-4-Yl~-lH-indol-3-yl)~ropyl~-l-r2-fim
20 yl)propvlll)iperazine Oxalate
Ste~ 1: Ethvl 2-(imidazol-1-yl)~ropanoate
A solution of imidazole (5.0 g, 0.074 mol), ethyl 2-bromopropanoate
(7.6 ml, 0.06 mol) and K2CO3 (11.2 g, 0.08 mol) in DMF (120 ml) was
25 heated at 90~C for 2h. After this time the solution was cooled to room
temperature, ~lltered and the fïltrate diluted with EtOAc (200 ml). The
mixture was washed with water (2 x 20 mV and the organic phase
separated. The combined aqueous layers were washed with EtOAc (200
ml) and the combined organic layers washed with brine (200 ml). The
30 organic layer was separated, dried (Na2SO4) and evaporated. The residue
was chromatographed on silica, eluting with CH2Cl2:MeOH (95:Ei), to
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afford the ester (1.1 g, 9%) as a pale yellow oil. lH NM~ (250MHz, CDCl3)
1.26 (3H, t, J=7.1Hz), 1.75 (3H, d, J=7.3Hz), 4.20 (2H, q, J=7.1Hz), 4.85
(lH, q, J=7.3Hz), 7.02-7.04 (lH, m), 7.08-7.10 (lH, m), 7.58 (lH, s).
Step 2: 2-(Tmi-1~7-~1-l-yl)propan-l-ol
Prepared according to the method of ~ mple 22, Step 3, using
ethyl 2-(imi~7ol-l-yl)propanoate. lH NMR (250MHz, CDCl3) ~ 1.47 (3E,
d, J=7.0Hz), 3.30 (lH, br s), 3.66-3.83 (2H, m), 4.18-4.31 (lH, m), 6.90-6.94
(2H, m), 7.41 (lH, s).
Step 3: 4-r3-(5-(1,2.4-Triazol-4-vl)-lH-indol-3-vl)proPvll-l-r2-
(imidazol-l-vl)Propvllpiperidine. Oxalate
Prepared according to the method of Example 22, Step 4, using
2-(imirl~7Ol-l-yl)-propan-l-ol. lH NMR (360MHz, d6-DMSO) ~ 1.07-1.20
(2H, m), 1.21-1.38 (3H, m), 1.41 (3H, d, J=6.7Hz), 2.18-2.38 (2H, m), 2.64-
2.78 (3H, m), 2.79-2.91 (lH, m), 2.93-3.10 (2H, m), 4.66-4.77 (lH, m), 7 20-
7.27 (2H, m), 7.29 (lH, dd, J=8.5 and 2.1Hz), 7.47 (lH, d, J=8.6Hz), 7.53
(lH, s), 7.75 (lH, d, J=1.9Hz), 8.34 (lH, s), 9.00 (2H, s), 11.07 (lH, br s).
MS (ES+) 418 (M+l)+. Found: C, 55.49; H, 6.48; N, 16.68%.
C24Hsl~7.1.8(C2H2O4). 0.9(H20) requires: C, 55.64; H, 6.16; N, 16.46%.
EXAMPLE 25
4-r3-(5-(1,2~4-Triazol-4-vl)-lH-indol-3-yl)propyll-1-r2-(pyrazol-1-
Yl~proPyl3piperidine
SteP 1: EthYl 2-(pyrazol-1-yl)propanoate
Prepared according to the method of l~ mple 24, Step 1, using
pyrazole. lH NMR (250MHz, CDCl3) ~ 1.25 (3H, t, J=7.2Hz), 1.79 (3H, d,
J=7.3Hz), 4.23 (2H, q, J=7.2Hz), 5.10 (lH, q, J=7.3Hz), 6.32 (lH, t,
J=2.1Hz), 7.55 (2H, d, J=2.1Hz). MS (ES+) 169 (M+l)+.
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-63-
Step 2: 2-(Pvrazol-l-~l)prop an-l-ol
Prepared according to the method of F.~r~mple 21, Step 4, using
ethyl 2-(pyrazol-1-yVpropanoate. lH NMR (250MHz, CDCl3) ~ 1.51 (3H, d,
J=6.8HZ), 3.17 (l H, br s3, 3.83-3.92 (2 H, m), 4.37-4.46 (lH, m), 6.27 (lH, t,
J-2.0Hz), 7.46 (l H, d, J=2.1 H z), 7.53 (l H, d, J=1.4Hz).
SteP 3: 2-(Pvrazol-l-yl)propanal
Prepared according to the method of F'.~r~mple 16, Step 4, using 2-
(pyrazol-l-yVpropan-l-ol. The aldehyde was used directly without further
puril;cation.
SteP 4: 4-r3-(5-(1,2~4-Triazol-4-vl)-lH-indol-3-yl3propyll-1-[2-(pyrazol-
1 -Yl)ProT)vllpiPeridine
Prepared according to the method of Example 4, using the
compound of Description 2 and 2-(pyrazol-1-yVpropanal. lH NMR
(360MHz, CDCl3) ~ 1.08-1.37 (4H, m), 1.49 (3H, d, J=6.7Hz), 1.54-1.78 (5H,
m), 1.91-2.03 (2H, m), 2.55-2.65 (2H, m), 2.68-2.78 (4H, m), 4.40-4.50 (lH,
m), 6.21 (lH, t, J=2.0Hz), 7.08-7.16 (2H, m), 7.43 (lH, d, J=2.0Hz), 7.46
(lH, d, J=8.5Hz), 7.49 (lH, d, J=1.5Hz), 7.53 (lH, d, J=1.8Hz~, 8.36 (lH, br
s), 8.46 (2H, s). MS (ES+) 418 (M+l)+. Found: C, 68.54; H, 7.30; N, 23.33%.
C~4H31N7. 0.1(H20) requires: C, 68.74; H, 7.50; N, 23.38%.
EXAMPLE 26
4-r3-(5-(l~2~4-Triazol-4-yl)-lH-indol-3-vl)propyll-l-r2-(pyridin-2
Yl)propyllpiperidine. Oxalate
Prepared according to the method of Example 22, Step 4 using the
compound from Description 2 and 2-(~yridin-2-yl)propanol. lH NMR
(360MHz, d~-DMSO) ~ 1.10-1.56 (8H, m), 1.60-1.74 (2H, m), 1.76-1.84 (2H,
m), 2.70 (2H, t, J=7.4Hz), 2.76-2.96 (2H, m), 3.22-3.56 (5H, m), 7.26-7.32
(3H, m), 7.40 (lH, d, J=7.8Hz), 7.47 (lH, d, J=8.6Hz), 7.76-7.82 (2H, m),
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8.52-8.56 (lH, m), 9.01 (2H, ~), 11.09 (lH, br s). MS (ES+) 429 (M+l)+.
Found: C, 57.16; H, 5.98; N, 13.22%. C26H32N6. 2.1(C02H)2. 0.9(H2O)
requires: C, 57.23; H, 6.04; N, 13.26%.
EXAMPLE 27
4-r3-(5-~l~2~4-Triazol-4-y~ H-indol-3-yl)propyn-l-[2-(pvridin-3
~l)propvllPiperidine Oxalate
10 SteP 1: Eth~l 2-(p~ridin-3-vl)propanoate
Prepared according to the method of ~.~mI)le 21, Step 3 using ethyl
3-pyridylacetate. lH NMR (250MHz, CDCl3) ~ 1.21 (3H, t, J=10.3Hz) , 1.53
(3H, d, J--10.4Hz), 3.74 (lH, q, J=10.4Hz), 4.04-4.23 (2H, m), 7.24-7.29
(lH, m~, 7.63-7.69 (lH, m), 8.48-8.57 (2H, m).
Step 2: 2-(Pvridin-3-Yl)Pro~anol
Prepared according to the method of Example 22, Step 3 using ethyl
2-(pyridin-3-yl)propanoate. lH NMR (250MHz, CDCl3) ~ 1.31 (3H, d,
J=10.lHz), 2.05 (lH, br s), 2.91-3.05 ~lH, m), 3.75 (2H, d, J=9.6Hz), 7.25
20 (lH, dd, J=11.3 and 6.9Hz), 7.55-7.60 {lH, m), 8.42-8.50 (2H, m).
Step 3: 4-[3-(5-(1,2,4-Triazol-4-vl)-lH-indol-3-vl)~ropYll-l-L2-(pyridin-
3-yllPro~vllPiperidine Oxalate
Prepared according to the method of Example 22, Step 4 using the
25 compound from Description 2 and 2-(pyridin-3-yl)propanoL lH NMR
(360MHz, d6-DMSO) ~ 1.20-1.54 (8H, m~, 1.60-1.82 (4H, m), 2.64-2.90 (4H,
m), 3.22-3.42 (5H, m), 7.24-7.32 (2H, m), 7.36-7.40 (lH, m), 7.47 (lH, d,
J-8.6Hz), 7.72-7.78 (2H, m), 8.46-8.48 (lH, m), 8.55-8.59 (lH, m), 9.00
(2H, s), 11.08 (lH, br s). MS (ES+) 429 (M+l)~. Found C, 57.07; H, 6.01;
30 N, 12.82%. C26H32N6. 2.2(CO2H)2. 0.8(H20) requires: C, 56.96; H, 5.98; N,
13.1~%.
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EXAMPLE 28
4-~3-(5-(1.2,4-Triazol-4-vl)-lH-indol-3-Yl)Propvn-l-r2-(Pvridin-4
vl)~ropYll~i~eridine Oxalate
Prepared according to the method of ~m~le 22, Step 4, using the
compound from Description 2 and 2-~pyridin-4-yVpropanol. lH NMR
(360MHz, d6-DMSO) o 1.10-1.~i2 (8H, m), 1.60-1.82 (4H, m~, 2.64-2.90 (4H,
m), 3.20-3.40 (5H, m), 7.24-7.32 (2H, m), 7.36-7.39 (2H, m), 7.47 (lH, d,
J=8.6Hz), 7.84-7.86 (lH, m), 8.50-8.54 (2H, m), 9.00 (2H, s), 11.07 (lH, br
s). MS (:~St) 429 ~M fl)+. Found: C, 56.56; H, 6.15; N, 13.00%. C2~H32N6.
2(CO2H)2. 1.5(H20) requires: C, 56.68; H, 6.18; N, 13.22%.
EXAMPLE 29
4-r3-(5-(l~2.4-Triazol-4-vl)-lH-indol-3-~ll)pro~yll-l-r2-(pvridazin-3
~l)Prop~ iperidine Oxalate
Step 1: 1-Methoxv-2-(PYridazin-3-vl)propene
Prepared according to the method of Example 12, Step 1, using 3-
acetylpyridazine. lH NMR (360MHz, CDCl3) ~ 2.15 (3H, d, J--1.3Hz), 3.78
(3H, s), 6.49 (lH, d, J=1.2Hz), 7.33 (lH, dd, J=8.8 and 4.8Hz), 8.16 (lH, dd,
J=8.8 and 1.6Hz), 8.95 (lH, dd, J--4.8 and 1.6Hz).
Step 2: 2-(Pyridazin-3-vl)ProPanal
To a solution of l-methoxy-2-~yridazin-3-yVpropene (0.26 g, 1.72
~ mmol) in THF (50 ml) and water (10 ml) under nitrogen at ambient
temperature was added mercury(II)acetate (1.66 g, 5.2mmol). This
mixture was stirred at room temperature for 2 hours, and was then pourcd
3(~ onto potassium iodide solution (7%, 350 mV and extracted with toluene (2
x 50 mV. The combined organic phases were washed with potassium
_
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iodide (7%, 140 ml) and brine (90 mV, dried (N~a2SO4) and evaporated to
give the title compound (54 mg, 23%), as an orange gum. The crude
aldehyde was used directly without further purification.
Step 3: 4-r3-(5-(1.2 4-Triazol-4-vl)-lH-indol-3-vl~r,ropyn-l-~2
(pyridazin-3-vl)pro~vllPir7eridine Oxalate
Prepared according to the method of F',~rrple 4 using the compound
from Description 2 and 2-(pyridazin-3-yl~propanal. lH NMR (360MHz, d6-
DMSO) ~ 1.20-1.56 (8~3, m), 1.62-1.84 (4H, m), 2.64-2.94 (4H, m), 3.30-3 50
(3H, m), 3.60-3.72 (2H, m), 7.24-7.34 (2H, m), 7.48 (lH, d, J=8.6Hz), 7.68-
7.78 (3H, m), 9.01 (2H, s), 9.14-9.18 (lH, m), 11.10 (lH, br s). MS (ES+)
430 (M+1)+. Found: C, 54.23; H, 5.87; N, 15.42%. C2sH3lN7. 2.1(C02H)2.
1.5(H20) requires: C, 54.32; H, 5.96; N, 15.19%.
DESCRIPTION 4
4-Fluoro-4-~3-(5-(1,2,4-triazol-4-vl)-lH-indol-3-Yl)propvnriperidine
a) 4-(HYdroxY)-4'-(l-tert-butvldimethYlsilYloxy-4-rentyn-5-yl~-N-(tert-
butoxYcarbonYl)riPeridine
1-tert-Butyldimethylsilyl-4-pentyn-1-ol (4.6 g, 0.028 mmol) was
placed in a dry three-neck flask under N2 and charged with
tetrahydrofuran (40 ml) and cooled to -78~C. n-Butyllithium (1.6M in
hexanes, 18.8 ml, 0.030 mol) was added dropwise and the solution stirred
at -78~C for 0.5h. N-tert-Butyloxycarbonyl-4-piperidone (4.0 g, 0.0184 mol~
was dissolved in tetrahydrofuran (10 ml) and added dropwise to the lithio
anion and the reaction mixture stirred at -78~C for 0.5h, and then at 0~C
for another 0.5h. The reaction was quenched by the slow ~lrlitic)n of
saturated NH4Cl (40 ml) and extracted with ethyl acetate (3 x 20 ml). The
organic layers were combined, dried over MgSO4 and evaporated. The
residue was chromatographed on silica using petroleum ether-ethyl
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acetate as eluent (9:1~7:3) to give the product as a colourless oil (6.2 g).
H NMR (250MHz, CDCl3) ~ -0.012 (6H, s), 0.84 (9H, s), 1.40 (9H, s), 1.48-
1.82 (6H, m), 2.25 (2H, t), 3.16 (2H, m), 3.60-3.77 ~4H).
b) 4-Fluoro-4'-(1-tert-butYldimeth~lsil~loxY-4-~entYn-5-Yl)-N-(tert
butoxvcarbonyl~piperidine
The alcohol from step a (1.6 g, 3.6 mmol) was dissolved in
dichloromethane (20 ml) and cooled to -78~C under N2.
Diethyl~rninosulfur trifluoride (DAST, 1.05 ml, 0.0079 mol) was added
10 dropwise over 10 minutes. The reaction was stirred at -78~C for 0.5h and
warmed to 0~C for 20 min. The reaction was slowly poured into cold
saturated NaHCO3 (40 ml) and extracted with ethyl acetate (2 x 20 mV.
The organic layers were combined and dried over MgSO4 and evaporated.
Thc residue was chromatographed on silica eluting with petrol:ether
16 (20:1~10:1) to yield the fluoroalkyne as a colourless oil (0.81 g). lH NMR
(250MHz, CDCl3) ~ 0.00 (6H, s), 0.83 (9H, s), 1.40 (9H, s), 1.66 (2H, m),
1.61-1.91 (4H, m), 2.28 (2H, m), 3.35-3.55 (4H, m), 3.62 (2H, t).
c) 4-Fluoro-4'-(5-hvdroxypentanYl~-N-tert-butoxvcarbonylpiperidine
The fluoroalkyne from step b (0.800 g) was dissolved in EtOH (10
ml) and hydrogenated over 10% palladium on carbon at 50 psi for 3h. The
catalyst was filtered and the ethanol removed in vacuo. The residue was
dissolved in THF (10 ml) and treated with tetrabutylammonium fluoride
(l.OM solution in THF, 9.6 ml) for 16h. The solvents were removed
25 in vacuo and the residue partitioned between ethyl acetate (40 ml) and
H20 (20 ml). The organic layer was dried over MgSO4 and evaporated.
The residue was chromatographed on silica eluting with petrol:ethyl
acetate (7:30) to yield the alcohol as a colourless oil (0.48 g, 86% yield). lH
NMR (250MHz, CDCl3) ~ 1.37-1.46 (6H, m), 1.46 (9H, s), 1.60-1.62 (6H,
30 m), 1.78 (2H, m), 3.06 (2H, m), 3.64 (2H, t), 3.89 (2H, m).
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d) 4-Fluoro-4-r3-(5-(1,2.4-triazol-4-vl)-lH-indol-3-vl)proPyllPiperidine
The alcohol from step c (1.5 g, 0.0052 mol) was dissolved in
hloromethane (20 ml) and 4A molecular sieves (2.5 g) was added,
followed by N-methylmorpholine-N-oxide (0.913 g, 0.0078 mol) and
tetrapropyl~mm-)nium perruthenate (0.913 g, 0.26 mmol). The reaction
was stirred under N2 for 0.5h and diluted with ethyl acetate and filtered
through a 3" plug of silica. The filtrate was collected and the solvent
evaporated in vacuo. The residue was reacted with 4-(1,2,4-triazol-4-
yVphenylhydrazine according to the procedure outlined in Description 2
(step f) to yield 4-fluoro-4-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-
yl)propyl3piperidine as a colourless foam. lH NMR (250MHz, CDCl3) ~
1.42-1.92 (8H, m), 2.79 (2H, t), 2.88-2.98 (4H, m), 7.13 (lH, d), 7.16 (2H, d),
7.48 (lH, d), 7.54 (lH, d), 8.37 (2H, s), 8.47 (lH, br s). MS (ES+) (328,
M+1).
EXAMPLE 30
4-Fluoro-4-~3-(5-(1.2~4-triazol-4-Yl)-lH-indol-3-Yl)proPyll-l-r2-(pyridin-3
yl)propvllpiperidine Oxalate
Prepared according to the method of Example 22, Step 4 using the
compound from Description 4 and 2-(pyridin-3-yl)propanol (Example 27,
Step 3). lH NMR (360MHz, d6-DMSO) ~ 1.24 (3H, d, J=6.8Hz), 1.60-1.90
(8H, m), 2.64-2.78 (4H, m), 2.98-3.26 (5H, m), 7.26-7.38 (3H, m), 7.48 (lH,
d, J=8.7Hz), 7.70-7.80 (2H, m), 8.42-8.46 (lH, m), 8.50-8.54 (lH, m), 9.01
(2H, s), 11.10 (lH, br s). MS (ESt) 447 (M+l)+. Found C, 57.54; H, 6.29;
N, 14.13%.
EXAMPLE 31
4-r3-(5-(1,2,4-Triazol-4-Yl~-lH-indol-3-yl)Pro1?yIl-l-r2-(thien-3- ==
yl)propyllpiPeridine Oxalate
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Ste~ 1: EthYl 2-(thien-3-yl)propanoate
Prepared according to the method of Example 21, Step 3 using ethyl
3-thienylacetate. lH NMR (360MHz, CDCl3) o 1.24 (3H, t, J=7.2Hz), 1.51
(3H, d, J=7.1Hz), 3.82 (lH, q, J=7.1Hz), 4.08-4.19 (2H, m), 7.07 (lH, dd,
J=5.1 and l lHz), 7.11-7.13 (lH, m3, 7.27 (lH, dd, J=5.0 and 3.1Hz).
Ste~ 2: 2-~I'hien-3-yl)propanol
Prepared according to the method of ~ mple 22, Step 3 using ethyl
2-(thien-3-yl)propanoate. lH NMR (360MHz, CDCl3) ~ 1.29 (3H, d,
J=7.0Hz), 3.04-3.12 (lH, m), 3.62-3.72 (2H, m), 7.02 (lH, dd, J=5.0 and
1.3Hz), 7.04-7.07 (lH, m), 7.31 (lH, dd, J=5.0 and 2.9Hz).
Step 3: 2-(Thien-3-vl)propanal
Prepared according to the method of Example 16, Step 4, using 2-
(thien-3-yVpropanol. lH NMR (360MHz, CDCl3) ~ 1.46 (3H, d, J=7.1Hz),
3.70-3.78 (lH, m), 6.99 (lH, dd, J=5.0 and 1.2Hz), 7.10-7.13 (lH, m), 7.36
(lH, dd, J=4.9 and 3.0Hz), 9.65 (lH, d, J=1.7Hz).
SteP 4: 4-~3-(5-(1~2.4-Triazol-4-vl)-lH-indol-3-vl)propvll-1-r2-(thien-3-
yl)pro~vllpiperidine Oxalate
Prepared according to the method of ~,~mple 4, using the
compound from Description 2 and 2-(thiophen-3-yl)propanal. IH NMR
(360MHz, d6-DMSO) ~ 1.10-1.56 (8H, m), 1.62-1.82 (4H, m), 2.64-2.90 (4H,
2~i m), 3.10-3.42 (5H, m), 7.13 (lH, d, J=5.0Hz), 7.24-7.80 (3H, m), 7.46-7.66
(2H, m), 7.74-7.76 (lH, m), 9.00 (2H, s), 11.08 (lH, br s).MS (ES+) 434
(M+l)+. Found: C, 58.76; H, 6.46; N, 11.82%. C2sH3lNsS. 1.4(C02H)2.
0.6(H20). 0.3(Et20) requires C, 58.93; H, 6.72; N, 11.49%.
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EXAMPLE 32
4-~3-(5-(1.2~4-Triazol-4-vl)-lH-illdol-3-vl3pro~vn-l-r2-(2-methoxYPvridin-3-
vl)pro~YllPiperidine Oxalate
Ste~ 1: 1-Methoxv-2-(2-metho~y~"~ridin-3-vl)propene
Prepared according to the method of F.2~m~1e 12, Step 1 using 3-
acetyl-2-methoxypyridine. lH NMR (250MEz, CDCl3) ~ 1.86 (3H, d,
J=1.3Hz), 3.72 (3E, s), 3.97 (3H, s), 6.44-6.46 (lH, m), 6.83 (lH, dd, J=7.3
and 5.1Hz), 7.39 (lH, dd, J=7.3 and 1.8Hz), 8.01 (lH, dd, J=5.0 and
1.8Hz).
SteP 2: 2-(2-Methoxvpyridin-3-vl)l~ropanal
Prepared according to the method of li',~m~le 12, Step 2 using 1-
methoxy-2-(2-methoxypyridin-3-yl)propene. The crude aldehyde was used
directly without further puri~lcation.
~ Step 3: 4-r3-(5-~1.2.4-Triazol-4-Yl)-lH-indol-3-Yl)pro~vll-l-r2-(2-
methoxvnvridin-3-Yl)pro,~Yl~piPeridine Oxalate
Prepared according to the method of Example 4, using the
compound from Description 2 and 2-(2-methoxypyridin-3-yl)propanal. lH
NMR (360MHz, d6-DMSO) ~ 1.20-1.52 (8H, m), 1.60-1.82 (4H, m~, 2.60-
2.82 (4H, m), 3.00-3.44 (6H, m), 3.89 (3H, s), 6.96-7.01 (lH, m), 7.24-7.32
(2H, m), 7.48 (lH, d, J=8.5Hz), 7.64-7.70 (lH, m), 7.74-7.78 (lH, m), 8.04-
8.10 (lH, m), 9.00 (2H, s), 11.08 (lH, br s). MS (ES+) 459 (M~l)+. ~ound:
C, 60.61; H, 6.74; N, 14.37%. C27H34N60 1.3(CO2H)2. 0.5(H20) requires: C,
60.81; H, 6.48; N, 14.37%.
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EXAMPLE 33
4-r3-(~-(1.2,4-q'riazol-4-yl)-lH-indol-3-Yl)~roPvll-l-r2-(4-methoxvpyridin-3-
vl)propYllPiPeridine Oxalate
.
Ste~ 1: 3-Acetvl-4-methoxv~vridine
A solution of 3-acetyl-4-chloropyridine (0.75 g, 4.8 mmoV in sodium
methoxide solution (0.5M in methanol, 10.6 ml, 5.3 mmoV was heated at
reElux for 1 hour. After cooling water (10 ml) was added and the solvents
10 evaporated. The residue was partitioned between dichloromethane (4 x 50
ml) and water (50 ml), the combined organic phases dried (M gSO4) and
evaporated to afford the title compound (0.58 g, 80%) as a yellow solid.
lH NMR (360MHz, CDCl3) ~ 2.62 (3H, s), 3.98 (3H, s), 6.90 (lE~, d,
J=5.8Hz), 8.57 (lH, d, J=5.7Hz), 8.81 (lH, s).
16
Step 2: 1-Methoxv-2-(4-methoxypvridin-3-yl)pro~ene
Prepared according to the method of h'.~r~mple 12, Step 1 using 3-
acetyl-4-methoxypyridine. lH NMR (250MHz, CDCl3) ~ 1.86 and 1.94 (3H,
2 x d, J=1.5Hz), 3.56 and 3.71 (3H, 2 x s), 3.88 (3H, s), 6.10-6.11 and 6.22-
20 6.23 (lH, 2 x m), 6.77 and 6.81 (lH, 2 x d, J=5.8Hz), 8.23 and 8.31 (lH, 2 x
s), 8.35-8.38 (lH, m).
Step 3: 2-(4-Methoxvpvridin-3-vl)propanal
Prepared according to the method of Example 12, Step 2 using 1-
25 methoxy-2-(4-methoxy~yridin-3-yl)propene. lH NMR (250MHz, CDCl3)
1.45 (3H, d, J=7.1Hz), 3.77 (lH, q, J-7.2Hz)) 3.88 (3H, s), 6.85 (lH, d,
J--5.7Hz), 8.28 (lH, s), 8.46-8.50 (lH, m), 9.69 (lH, s).
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Ste~ 4: 4-~3-(5-~1~2.4-Triazol-4-vl)-lH-indol-3-vl)propYll-l-r2-(4-
methoxvPvridin-3-vl)propYll~iperidine Oxalate
Prepared according to the method of F"r~mple 4, using the
compound from Description 2 and 2-(4-methoxypyridin-3-yVpropanal. lH
6 NMR (360MHz, d6-DMSO) ~ 1.18-1.56 (8H, m), 1.60-1.82 (4H, m), 2.60-
2.86 (4H, m), 3.10-3.50 (5H, m), 3.87 (3H, s), 7.05 (lH, d, J=2.0Hz), 7.25-
7.32 (2H, m), 7.47 (lH, d, J=5.7Hz), 7.76 (lH, d, J=8.6Hz), 8.35-8.39 (2H,
m), 9.01 (2H, s), 11.08 (lH, br s). MS (ES+) 459 (M~l)+. Found: C, 56.78;
H, 6.82; N, 12.99%. C27H34N60. 1.6(C02H)2. 2(H20) requires: C, 56.79; H,
10 6.50; N, 13.15%.
EX~MPLE 34
Chiral seParation of the enantiomers of 4-r3-(5-(1.2~4-triazol-4-vl)-lH-
15 illdol-3-Yl)~ro~vll-l-r2-(l3vridin-3-Yl)Pro~yllpiperidine
4-[3-(5-(1,2,4-Triazol-4-yV-lH-indol-3-yl)propyl]-1-~2-(pyridin-3-
yVpropyl]piperidine (100 mg, 0.23 mmol) was dissolved in 20% EtOH in
hexane (12 mglml~. 50 ~Ll of solution was injected onto a Chiralpak AS
column (250 x 4.6 mm i.d., 10NM:) per run, using 20% EtOH in hexane as
20 the mobile phase. Using a flow rate of 2.5 ml/min and W detection at 235
nm, the two enantiomers were ef~lciently separated. The fractions
cont~inin~ each separate enantiomer were combined and evaporated
i71 vacuo.
Peak A (25 mg): Retention time 27.8 min. mp=89~C (dec.).
2~ Purity A:B >99.5:0.5
Peak B (27 mg): Retention time 17.8 min. mp=92~C (dec.).
Purity B:A >99.5:0.5.
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EXAMPI,E 35
(S)-4-~3-(5-(1,2,4-Triazol-4-vl)-lH-indol-3-Yl)prop~11-1-(2-
phenylpro~Yl)piperidine. Bis Hvdrochloride
a) 5-(N-tert-Butoxvcarbonvl-4-PiPeridinvl)pent-1-Yl benzoate
The alcohol from Description 2d (116 g, 448 mmol) wa~ dissolved in
dry pyridine (11) and cooled to 0~C. Benzoyl chloride (96 g, 80 ml), 683
mmol) was added, m~int~ininE the internal temperature of the reaction at
below 5~C. The reaction was stirred for 16 hours and
3-dimethyl~minnpropylamine (48 g, 60 ml, 470 mmol) was added and the
reaction was stirred for a further 0.5h, before diluting with ethyl acetate.
The organic layer was washed with 10% citric acid solution until the
w~Rhing~q were acidic and then the organic layer was washed with brine,
saturated aqueous sodium bicarbonate solution, dried (M gso4),flltered
and evaporated to yield an oil which crystallised on st~n(1ing (168 g). lH
NMR (250MHz, CDCls) o 1.46 (9H, s), 0.98-1.84 (13H, m), 2.65 (2H, dt,
J=13 and 2.6Hz), 4.04-4.09 (2H, m), 4.32 (2H, t, J=7.5Hz), 7.27-7.59 (3H,
m), 8.02-8.06 (2H, m).
b) 5-(4-Piperidinvl)-1-pentvl benzoate
The foregoing product (25 g, 67 mmol) was added to trifluoroacetic
acid (200 ml) portionwise, at 0~C. The reaction was stirred for one hour
and the solution was evaporated and the residue was taken up into ethyl
acetate and washed with saturated aqueous sodium bicarbonate until the
aqueous w~ ingq were z~lks~line. The organic extract was dried (MgSO4),
filtered and evaporated to yield an oil (18.33 g). lH NMR (360MHz,
CDCl3) o 1.34-1.49 (9H, m), 1.73-1.81 (2E, m), 1.85-1.88 (2H, m), 2.80-2.84
(2H, m), 3.30-3.40 (2H, m), 4.31 (2H, t, J=6.6Hz), 7.44 (2H, t, J=6.5Hz),
7.53-7.58 (lH, m), 8.02-8.04 (2H, m).
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c) ~s)-~-rl -(2-Phenylpropvl)piperidin-4-yl~ entanol
The foregoing product (17.4 g, 66.7 mmol) and (S)-2-phen~lpropionic
acid (10 g, 66.7 mmol) were dissolved in dichloromethane and cooled to
0~C. Triethyl~minP~ (185 ml, 133 mmol) and bis(2-oxo-2-
~i oxazolidinyl)phosphinic chloride ~17 g, 66.7 mmol) were added and the
reaction mi}~ture was stirred for 16 hours. The solvent was removed and
the residue was taken up into ethyl acetate and washed with potassium
carbonate solution, 10% citric acid solution, water, saturated aqueous
sodium bicarbonate solution, and then dried (M gSO4), filtered and
evaporated to yield an oil (16.5 g) which was dissolved in borane THF
complex (400 ml of a lM solution in tetrahydrofuran) and heated to re~lux
for 16 hours. The reaction was cooled, and the solvent was removed. The
residue was taken up into acetone (~00 ml), 2N hydrochloric acid solution
(100 ml) was added and the reaction was stirred for one hour. The acetone
was evaporated and the aqueous solution was washed with ethyl acetate,
basified with ammonium hydroxide solution and then extracted to dryness
to yield an oil which was purified by column chromatography on silica
using 10% methanoVdichloromethane as eluant to yield an oil (9.1 g). lH
NMR (250MHz, CDCl3) ~ 1.27 (3H, d, J=7Hz), 1.06-2.00 (14H, m~, 2.35-
2.51 92H, m), 2.81-3.03 (4H, m), 3.62 (2H, t, J=7.5Hz), 7.14-7.37 (~H, m).
d) (S)-4-r3-(5-(1,2,4-Triazol-4-vl)-lH-indol-3-Yl)-prop~l3-1-(2-
phenvlpropyl)piperidine. Bis Hydrochloride ~
The foregoing product was dissolved in dry dimethylsulfoxide (11
ml) and triethylamine (74.5 g) was added and the reaction mixture was
stirred vigorously while adding sulfurtrioxide pyridine in portions for one
hour. The mixture was then poured into ice/water and extracted with ethyl
acetate. The organic extract was washed with water (3x), dried ~M gSO4),
filtered and evaporated to yield an oil which was dissolved in ethanol (100
mV and was added dropwise to a solution of 4-(1,2,4-triazol-4-
yl)phenylhydrazine hydrochloride (Description 1) (~.0 g) in 200 ml of 4%
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sulphuric acid solution at 70~C over a period of one hour. The reaction
was then heated to reflux and was stirred for 16 hours. The reaction was
cooled and basffled with ammonium hydroxide and extracted with butanol.
The organic extract was washed with water and evaporated to yield an oil
5 which was purified by column chromatography on s~lica eluting with 5%
methanol-~if hloromethane to give an oil which was converted to the
hydrochloride salt. 98.6% e.e. by hplc using a Chiralpak Ad column (250 x
4.6 mm i.d.) at 40~(~ eluting with 6% ethanol in hexane with 0.1%
diethylz~min~ at a flow rate of 1 ml/min. lH NMR (250MHz, DMS03 â 1.29
10(3H, d, J=6.7Hz), 1.28-1.72 (lOH, m), 2.62-3.41 (8H, m), 7.23-7.42 (8H, m),
7.54 (lH, d, J=8.6Hz), 7.93 (lH, d, J=2Hz), 9.82 (2H, s), 10.28 (lH, bs),
11.33 (lH, s), MS (ES+) 428 ~ . Found: C, 59.93; H, 7.30; N, 12.85;
C27H33Ns. 2~ICl. 2.25(H20) requires: C, 59.94; H, 7.36; N, 12.94%.
15EXAMPLE 36
(R~-4-r3-(5-(1,2.4-Triazol-4-vl)-lH-indol-3-Yl)pro~Yll-1-(2-
phenvlpropyl)piperidine. Bis Hvdrochloride
Prepared according to the method of Example 35 using (R)-2-
20 phenylpropionic acid. 98 2% e.e. by h.plc using the methods described inExample 35. MS (ES+) 428 (M+l)+. Found: C, 60.33; H. 7.42; N, 12.99;
C27H33Ns. 2HCl. 2H20 requires C, 60.44; H, 7.33; N, 13.05%.
EXAMPLE 37
2l;
4-~3-(5-(1.2,4-Triazol-4-vl)-lH-indol-3-vl)pronYll-l-r2-(2-
fluorophenyl~propYll~iperidine. Bis Hvdrochloride
Prepared from 2-fluoroacetophenone according to the method of
mple 4. IH NMR (360MHz, DMSO) ~ 1.33 (3H, d, J=7Hz), 1.28-1.75
30(lOH, m), 2.8~-3.61 (8H, m), 7.17-7.53 (7H, m), 7.88 (lH, d, J=2.2Hz), 8.24
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(lH, s), 8.49 (2H, s); MS (ES~) 446 (M+l~+. Found: C, 56.64; H, 7.04; N,
12.23; C27H32NsF. 2HCl. 3H20 requires C, 56.93; H, 6.84; N, 12.07%.
EXAMPL:~3 38
4-r3-(5-(1.2.4-Triazol-4-vl)-lH-indol-3-vl)propyll-1-[2-(3-
fluoroPhenvl)proPYllPiperidine. Bis HYdrochloride
Prepared from 3-fluoroacetophenone according to the method of
~.~r~mple 4. lH NMR (250MHz, DMSO) ~ 1.16 (3H, d, J=6.8Hz), 1.00-2.01
(lOH, m), 2.20-3.10 (8H, m), 6.90-7.08 (3H, m), 7.20-7.33 (3H, m), 7.46 (lH,
d, J=8.5Hz), 7.76 (lH, d, J=2Hz), 9.02 (2H, s), 11.06 (lH, s); MS (ES+) 446
(M+l)+. Found: C, 56.74; H, 5;87; N, 10.62; C27H32NsF. 2(CO2H)2. 1.5(H20)
requires: C, 57.03; H, 6.03; N, 10.73%.
EXAMPLE 39
4-[3-(5-(1,2,4-Triazol-4-vl)-lH-indol-3-vl)proPvll-l-r2-(4-
fluorophenyl)propvll~iperidine. Bis HYdrochloride
Prepared from 4-fluoroacetophenone according to the method of
Example 4. lH NMR (360MHz, DMSO) â 1.27 (3H, d, J--6.9Hz), 1.28-1.80
(lOH, m), 2.60-3.45 (8H, m), 7.15-7.20 (2H, m), 7.20 (lH, d, J=lHz), 7.35-
7.~2 (3H, m), 7.52 (lH, d, 8.6Hz), 7.86 (l~I, d, J=lHz), 9.55 (2H, s), 11.22
(lH, s); MS (ES+) 446 (M+l)+. Found: C, 55.39; H, 6.89; N, 12.04;
C27H32NsF. 2HCl. 3l/2H20 requires: C, 55.84; H, 7.12; N, 12.07%.
EXAMPLE 40
4-r3-(5-(1.2~4-Triazol-4-Yl)-lH-indol-3-yl)pronY1~ 2-(2-chloro-5-
(trifluoromethvl)phenYl)propYllPiPeridine~ Bis ~Ivdrochloride
Prepared from 2-chloro-5-(trifluorolnethyl)acetophenone according
to the method of Example 4 lH NMR (360MHz, CDC13) ~ 1.27 (3H, d,
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J=6.8Hz), 1.05-1.38 (6H, m), 1.60-1.80 (3H, m), 1.90-2.06 (2H, m), 2.40-
2.58 (2H, m), 2.73 (2H, t, J=7.5Hz), 2.70-2.84 (lH, m), 2.96-3.00 (l~I, m),
3.52-3.60 (lH, m); MS (ES+) 531 (M+l)+.
DESCRIPTION 5
(S)-2-(4-FluoroPhenvl)pro~ionic acid
a) (R)-4-BenzYl-(R and S~-3-r2-(4-fluoronhenvl)Propionzlmi(1Ol-2-
oxazolidinone
(R)-(~)-4-benzyl-2-oxazolidinone (9.0 g, 50.8 mmoV in dry
tetrahydrofuran (250 ml) was cooled to -78~C and butylithium (32 ml of
1.6M in hexane, 50.8 mmol) was added dropwise to the solution
maintaining the temperature below -70DC. After 0.~ hours (R,S)-2-(4-
fluorophenyl)propionyl chloride (8.6 g, 46.2 mmol) in tetrahydrofuran (10
ml) was added below -70~C and the reaction was stirred for 0.5 h.
Saturated ammonium chloride was added and the reaction was extracted
with ethyl acetate, dried (M gSO4),filtered and evaporated. The two
diastereomers were separated by column chromatography on silica using
ethyl acetate/hexane (1:4) to yield the less polar diastereomer tentatively
assigned as (R)-4-benzyl-(R)-3-[2-(4-fluorophenyl)propion:~mi(l- ]-2-
oxazolidinone (7.5 g); and the more polar isomer, tentatively assigned as
(R)-4-benzyl-(S)-3-[2-(4-fluorophenyl)propions~mi~1O]-2-oxazolidinone (6.5
g)-
b) (S)-2-(4-Fluorol~henvl)~ropionic acid
The more polar diastereomer obtained from step a (silica, ethyl
acetatefhexane (1:4)) (6.5 g, 19.2 mmol) was dissolved in
tetrahydrofuran/water (4:1) (100 mV and cooled to 0~C. Hydrogen
peroxide (30% aqueous solution, 7.9 ml, 77 mmol) was added dropwise
below 5~C, ~ollowed by lithium hydroxide (0.74 g, 31.0 mmol). The
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reaction was allowed to warm to 20~C over 1.5 hours and then quenched
with sodium sulfite (12.6 g) in water (75 ml). The reaction was washed
with dichloromethane ~x3) and the aqueous was acidified to pH 1 at 0~C
with hydrochloric acid and then extracted with ethyl acetate (3x) and the
5 organic extract was dried (M gSO4), filtered, and evaporated to yield an oil,
which crystallised on st~n(lin~ (3.11 g). lH NMR (250MHz, DMSO) ~ 1.35
(3H, d, J=7.1Hz), 3.70 (lH, q, J=7.1Hz), 7.10-7.19 (2H, m), 7.29-7.36 (2H,
m); [a]20D CHCl3 (C=1.2) = +~7.1~
EXAMPLE 41
(S~-4-r3-(5-(1.2,4-Triazol-4-vl)-lH-indol-3-Yl~propyl]-l-r2-(4-
fluoronhenvl)propvll~iperidine. Bis ~IYdrochloride
Prepared according to the method of F.~r~mple 35 Step c using (S)-2-
(4-fluorophenyl)propionic acid. Obtained in >99.5% e.e. by hplc.
lH NMR (360MHz7 DMSO) ~ 1.28 (3H, d, J=6.8Hz), 1.29-1.80 (~H, m),
2.60-3.45 (8H, m), 7.16-7.20 (2H, m), 7.20 (lH, d, J=lHz), 7.36-7.41 (3H,
m), 7.53 (lH, d, d=8.8Hz), 7.88 (lH, d, J=lHz), 9.59 (2H, s), 9.99 (lH, bs),
11.23 (lH, s); MS (ES+) 446 (M+1)+.
EXAMPLE 42
4-~3-(5-(1.2.4-Triazol-4-vl)-lH-indol-3-~ roPY11-1-(2-hvdroxY-2-
Phenvl~roPyl)piperidine
a-Methyl styrene epoxide (Org. Prep. Proced. I7lt.~ 1989, 757-761)
(0.26 g, 2 mmol) and the product of Description 2 (0.309 g, 1 mmol) were
heated to 100~C in methanol (5 ml) in a sealed tube for 16 hours. The
solvent was removed and the residue was purified by silica
chromatography eluting with 2-propanoV-lichl-)romethane (1:20) with 0.1%
ammonium hydroxide. The pure fractions were converted to the
hydrochloride salt (0.065 g). lH NMR (250MHz, DMSO) â 1.63 (3H, s),
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1.20-1.80 (9H, m), 2.69-3.62 (8H, m), 7.25-7.59 (8H, m), 7.95 (lH, d,
J=2Hz~, 9.95 (2H, s), 11.39 (lH, s); MS (ES+) 444 (M~1)+. Found: C, 54.56;
H, 6.81; N, 11.55; C27H33NsO. 3HCl. 2.5(H20) requires: C, 54.34; H, 6.93;
N, 11.74%.
F'XAMPLE 43
4-~3-(~-(N-~Methvl)aminosulphonvlmethYl)-lH-indol-3-vl)propvll-1-(2-
phenylProP~l)~i~eridine Hvdrochloride
Prepared fiom 4-(N-(methyVaminosulphonylmethyl)-
phenylhydrazine hydrochloride (DE 3320521) using the method of
Description 2f. lH NMR (250MHz, DMSO) o 1.28 (3H, d, J=6.3Hz), 1.26-
1.76 (lOH, m), 2.52 (3H, d, J=6Hz), 2.62-3.60 (8H, m), 4.34 (2H, s), 6.78-
6.84 (lH, m), 7.04-7.36 (8H, m), 7.48 (lH, s), 9.60-9.80 (lH, bs), 10.86 (lH,
s), MS (ES+) 468 ~M+l)+. Found: C, 62.58; H, 7.66; N, 8.22. C27H37N302S.
HCl. 0.75(H20) requires: C, 62.58; H, 7.69; N, 8.12%.
EXAMPLE 44
4-r3-~5-(N-(Meth~l)aminosul~honylethyl)-lH-indol-3-yl)~ropvll-1-(2-
Phenvl~ropYl)~iperidine Hydrochloride
Prepared from 4-(N-(methyl)aminosulphonylethyl)phenylhydrazine
hydrochloride using the method of Description 2~ lH NMR (250MHz,
DMSO) ~ 1.28 (3H, d, J=6.4Hz), 1.27-1.78 (lOH, m), 2.61 (3H, d, J=5Hz),
2.60-3.42 (12H, m), 6.94-7.36 (lOH, m), 9.65-9.75 (lH, bs), 10.72 (lH, s);
MS (ES+) 482 (M+l)+. Found: C, 63.46; H, 7.92; N, 7.87; C2sH3sN302S. HCl.
V.75(H20) requires C, 63.26; H, 7.87; N, 7.90%.
_
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EXAMPL13 45
4-r3-(5-(2-Ethvlirni(1~7,ol-l-Yl)-lH-indol-3-Yl)Propyn-l-(2
phenYlpropYl)~iperidine Hvdrochloride
5Prepared from 4-(2-ethylimifl~7ol-1-yl)phenylhydrazine using the
method of Description 2f which was in turn prepared from 4-(2-
ethylimidazol-1-yl)~nilinP (BE 880020) using the method of Description
l(d). lH Nl~R (500MHz, DMSO + trifluoroacetic acid~ ~ 1.17 (3H, t,
J=7.6Hz), 1.26 (3H, d, J=5.5Hz), 1.15-1.78 (10~1, m), 2.67 (2H, t, J=7.2Hz),
2.83 (2H, q, J=7.5Hz), 2.74-3.46 (6H, m),7.19-7.26 (2H, m),7.33 (lH, s),
7.78 (lH, s), 7.82 (lH, d, J=2Hz), 11.28 (lH, s); MS (ES+~ 455 (M+1)~;
Found: C, 64.11; H, 7.73; N, 9.96. C30H3sN4. 2H Cl.2H2O requires C, 63.93;
H, 7.87; N, 9.94%.
EXAMPL:~ 46
4-~3-(6-((S)-2-Oxo-1,3-oxazolidin-4-Ylmethvl)-lH-indol-3-yl)propyn-1-(2-
phenvlpropyl~piperidine HYdrochloride
a) 4-r3-(5-((S)-2-Oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-
vl)pro~YllPiperidine HYdrochloride
(S)-4-(4-Hydrazinobenzyl~-1,3-oxazolid-2-one hydrochloride (J. Med.
Chem., 1995, 38(18), 3566-3580) (0.8 g) and the product of Description 2(e)
(1 g) were dissolved in acetic acid (10 ml), water (30 ml) and cthanol (15
25 ml) and heated at 60~C for one hour and then at reflux for 16 hours. The
reaction was cooled and then evaporated and the residue basified with
ammonium hydroxide and extracted with butanol. The organic phase was
washed with water and evaporated and used unpurified for the next step.
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- 81-
b) 4-r3-(5-((S)-2-Oxo-1.3-oxazolidin-4-vl~methvl)-lH-indol-3-vl)nroPvl~-l-
r(R,S)-2-phenylpropynpiperidine Hvdrochloride
~ Prepared from the foregoing product using the method of Example
4. lH NMR (250MHz, DMSO) ~ 1.28 (3H, d, J=6.3Hz~, 1.29-1.80 (lOH, m),
2.50-2.86 and 3.27-3.60 (lOH, m), 3.98-4.15 (2H, m), 4.16-4.28 (lH, m),
6.92 (lH, dd, J=2 and 7.5Hz), 7.05 (lH, d, J=2Hz), 7.24 (lH, d, J=8Hz),
7.23-7.37 (5H, m), 7.79 (lH, s), 9.50-9.65 (lH, bs), 10.71 (lH, s); MS (ES~)
460 (M+l)+. Found: C, 66.73; H, 7.65; N, 7.97. C2sH37N30. HCl. 1.5(H20)
requires: C, 66.58; H, 7.90; N, 8.03%.
EXA~MPLE 47
4-Fluoro-4-r3-(5-(1,2,4-Triazol-4-vl)-lH-indol-3-yl)propyl]-1-(2-
phenvlpropYl)piPeridine oxalate
Prepared according to the method of F',~mple 4 using the compound
from Description 4 and (+)-2-phenylpropionaldehyde. lH NMR (DMSO,
360MHz) ~ 1.28 (3H, d), 1.66-1.70 (4H, m), 1.94 (4H, m), 2.73 (2H, t), 2.97
(2H, m), 3.32 (2H, m), 7.24-7.35 (7H), 7.47 (lH, d), 7.78 (lH, d), 9.01 (2H,
s), 11.12 (lH, br s). MS (ES+) (446, M+l).
EXAMPLE 48
4- ~2-Fluoro-3-(5-(1,2 ~ 4-triazol-4-Yl)- lH-indol-3-vl)ProPYll - 1 -(2-
phenylpropyl)piperidine oxalate
a) 3-rN-r(tert-butvloxY)carbonYllpiperidinyl-4-yll-1.2-~ropylene oxide
To sodium hydride (1.2 g, 0.03 mol of a 60% dispersion in oiV and
trimethylsulfoxonium iodide (6.6 g, 0.03 mol) at 0~C under N~ was added
anhydrous DMSO dropwise. The ice-bath was removed after complete
addition and the reaction stirred at 25~C for 30 min. The reaction was
then cooled to 0~C, and a solution of 2-~N-[(tert-
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butyloxy)carbonyl]piperidin-4-yl]ethyl aldehyde ~prepared according to J.
Med. Chem., 1994, 37, 2537-2551) (6.8 g, 0.03 mol) was added in a steady
stre~m as a solution in anhydrous DMSO (15 ml). The ice-bath was
removed, the reaction stirred at 25~C for 15 min and then at 50~C for lh.
The reaction mixture was cooled, quenched with HzO (40 mV then poured
into H20 (100 ml) and ethyl acetate (50 ml). The reaction mixture was
extracted with ethyl acetate (2 x) and the organic layer washed with H20
(3 x 20ml). The combined organic extracts were dried over MgSO4,
evaporated and the residue chromatographed on silica eluting with ethyl
10 acetate: petrol (10:90 to 20:80) to obtain the epoxide as a colourless oil (4.7
g, 49% yield). lH NMR (250MHz, CDCl3) ~ 1.14-1.28 (3H, m), 1.45 (9H, s),
1.63-1.78 (4H, m), 2.44 (lH, dd), 2.71 (2H, t), 2.77 (lH, t), 2.95 (lH, m),
4.12 (~H, m).
15 b) (+)-5-rN-(tert-ButvloxYcarbonvl~piperidin-4-vll-4-hvdroxy-1-
triethvlsilvl- l-pentyne
A dry flask under N~ was charged with THF (50 ml) and n-
butyllithium (13 ml, 0.021 mol, 1.6 M solution in hexanes) and cooled to
-78~C. Triethylsilylacetylene (3.0 ml, 0.021 mol) was added dropwise and
20 the reaction stirred for 0.5h. Distilled boron trifluoride etherate (3.03 ml,0.025 mol) was then added and the reaction stirred at -78~C for a further
10 min. The epoxide (step a) was then added as a solution in THF (20 ml)
and the reaction stirred for 0.75h. The reaction was quenched by the
addition of saturated NH4Cl and extracted into ethyl acetate. The organic
25 layer was dried over MgSO4 and evaporated in vc~cuo. The residue was
taken up in dioxane:water (1:1, 100 mV and triethylamine (2.0 ml, 0.0145
mol) added followed by tert-butyldicarbonate (3.0 g, 0.0145 mol). The
reaction was stirred for lh, the dioxane evaporated and the residue
partitioned between ethyl acetate and saturated NH4~1. The organic layer
30 was collected, dried over Mg~04 and evaporatea. The residue was
chrotnatographed on silica eluting with ethyl acetate:hexanes (1:9 ~ 2:8) to
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- 83 -
obtain the alcohol as a colourless oil (2.4 g, 49%). IH NMR (250MHz,
CDCl3) ~ 0.58 (6H, q), 0.95 (9H, t), 1.08-1.16 (3H, m), 1.45 (9H, s), 1.59-
1.78 (4H, m), 2.35 (lH, dd), 2.47 (lH, dd), 2.73 (2H, t), 4.12 (3H, m).
c) ~~)-5-rN-(tert-Butyloxycarbonyl~iperidin-4-vll-4-fluoro-1-
triethylsilvl- l-pent~ne
The alcohol from step b (1.0 g, 0.003 mol) was dissolved in CH2C12
and cooled to -78~C. Diethyl~minl3sulLu. l,rifluoride (0.8 ml, 0.0057 moV
was added dropwise and the reaction was stirred at -78~C for 15 min and
warmed to 0~C over 0.5h. The reaction was quenched by pouring into cold
saturated NaHCO3 (20 ml) and extracted into ethyl acetate (2 x 20 ml).
The organic layers were combined, washed with brine, dried over MgSO4
and evaporated. The residue was chromatographed on silica eluting with
petroleum ether:ether (20:1) to obtain the fluoride as a colourless oil (0.250
g, 22%). IH NMR (250MHz, CDCl3) ~ 0.59 (6H, q), 0.96 (9H, t), 1.08-1.28
(3H, m), 1.64-1.78 (4H, m), 2.47-2.75 (4H, m), 4.12 (2H, m), 4.60 (0.5H, m),
4.81 (0.5H, m).
d) (+)-4-r2-Fluoro-3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yl)propyll-N (tert
butvloxYcarbonYl)Piperidine
The fluoroalkyne from step c (0.250 g, 0.652 mmol) was dissolved in
anhydrous DMF (10 ml) and 2-iodo-4-(1,2,4-triazol-4-yl)aniline (0.186 g,
0.652 mmol) was added, together with sodium carbonate (0.276 g, 2.6
mmol), magnesium sulfate (0.090 g, 0.72 mmol) and anhydrous lithium
chloride (0.028 g, 0.652 mmol). The reaction mixture was de-gassed using
a stream of N2 for 10 min and palladium acetate (0.016 g, 0.071 mmol)
added. After de-gassing the reaction for a further 5 min, the reaction was
heated at 105~C for 16h. The reaction mixture was cooled, the DMF
removed in vacuo and the residue partitioned between butanol/water. The
organic layer was collected, dried over MgSO4 and evaporated. The crude
residue was dissolved in MeOH (10 ml) and 5M HCl (6 ml) and the
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reaction stirred at 25~C for 72h. The solvents were removed in vacuo and
the residue dissolved in dioxane:water (1:1, 10 ml) and basified to pH 9
with solid K2CO3. Di-tert-butyldicarbonate (0.285 g, 1.3 mmol) was then
added and the reaction stirred for 12h. The reaction mi~ture was
5 partitioned between 5% MeOH/EtOAc and H20, the organic layer
collected, dried over MgSO4 and evaporated. The residue was
chromatographed on silica eluting with a gradient consisting of CH2C12
then 1-5% MeOH:(~H2Cl2 to obtain the product as a colourless oil (0.120 g,
43%). lH NMR (250MHz, CDCl3) ~ 1.09-1.16 (3H, m), 1.44 (9H, s), 1.63-
1.74 (4H, m), 2.70 (2H, m), 3.02 (lH, t3, 3.09 (lH, d), 4.12 (2H, m~, 4.79
(0.5H, m), 4.94 ~0.5H, m), 7.15 (lH, dd), 7.25 (2H, d), 7.50 (lH, d), 7.58
(lH, s), 8.48 (2H, s), 8.63 (lH, br s).
e) 4-~2-Fluoro-3-(5-~1,2,4-triazol-4-vl)-lH-indol-3-vl)propvll-1-(2-
15 phenYlpro~Yl)piperidine oxalate
The compound from step d (0.120 g) was treated with triflLuoroacetic
acid (3 mV and the excess acid removed i77, vacuo. The residue was
dissolved in MeOH (5 ml) and sodium methoxide (0.165 g) added. The
resulting amine was reacted with (_)-2-phenylpropionaldchyde according
20 to the procedure described for h',x~mple 4 to obtain the title compound as a
pale yellow solid. lH NMR (free base, 250MHz, CDCl3) ~ 1.26 (3H, d),
1.30-2.20 (lOH, m), 2.49 (2H, d), 2.90-3.00 (3H, m), 3.08 (lH, d), 4.73
(0.5H, m), 4.93 (0.5H, m), 7.13-7.31 (7H, m), 7.48 (lH, d), 7.56 (lH, d), 8.34
(2H, s), 8.46 (lH, br s). Oxalate salt MS (ES+) (446, M+l).
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- 85 -
EXAMPLE 49
4-r3-(5-(1,2,4-Triazol-4-yl)-lH-indol-3-Yl)-2-hYdroxYPropyll-l-(2
phenvlpropvl)Piperidine oxalate
a) 4-r3-(5-(1,2,4-Triazol-4-vl)-lH-indol-3-vl)-2-hYdroxYPro~Pvll-N-(tert
hutYloxYcarbonvl)piPeridine
Prepared according to the procedure described for ~ mple 49 step
d, using (+) 5- [N-(tert-butyloxycarbonyl)piperidin-4-yl] -4-hydroxy- 1 -
triethylsilyl-l-pentyne (Example 49, step b) and 2-iodo-4-(1,2,4-triazol-4-
yl)aniline. lH NMR (250MHz, CDCl3) o 1.04-1.19 (3H, m), 1.44 (9H, s),
1.68 (4H, m), 2.69 (2H, bt), 2.82 (IH, dd), 3.0 (lH, dd), 4.08 (3H, m), 7.17
(lH, dd), 7.25 (2H, m), 7.50 (lH, d), 7.59 (lH, d), 8.44 (2H, s), 8.46 (lH, s).
b) 4-r3-(5-(l~2~4-Triazol-4-vl)-lH-indol-3-yl)-2-hydroxypropyll-l-(2
Phenvlpro~vl)piperidine oxalate
Prepared accoldi.lg to the procedure described for Example 48, step
e, using the product from step a, and (~)-2-phenylpropionaldehyde. lH
NMR (360MHz, DMSO) ~ 1.26 (3H, d), 1.27-1.44 (4H, m), 1.74 (3H, m),
2.68 (2H, m), 2.80 (2H, d), 3.07-3.20 (5H, m3, 3.86 (lH, m), 7.24-7.35 (7H,
m), 7.47 (lH, d), 7.74 (lH, d), 8.85 (2H, s), 10.89 ~lH, br s). MS (ES~) (444,
M+1) Found: C, 58.98%; H, 6.35%; N, 11.16%. C27H34NsO. 2(C2H204).
0.5H20 requires C, 58.78%; H, 6.20%; N, 11.0~%.
EXAMPLE 50
4-~3-(5-(1,2~4-Triazol-4-vl~-lH-indol-3-vl)-2-oxopropY11-1-(2-
Phenylprop~rl)piperidine hvdrochloride
Prepared according to the procedure described in Description 2, step
30 e, using the compound from Example 49, step b, and sulfur trioxide
pyridine complex. l~ NM~ (free base, 250MHz, CDC13) ~ 1.23 (3H, d),
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1.58 (3H, d), 1.83-1.88 (4H, m), 2.42 (5H, m), 2.78-3.00 (2H, m), 3.81 (2H,
s), 7.17-7.30 (7H, m), 7.48 (lH, d), 7.52 (lH, d), 8.46 (2H, s), 8.70 (lH, br s).
l~XAMPLE 51
4- r3-(s-~l ~ 2 4 Triazol-4-Yl)- lH-indol-3-vl)- l-hvdrox~rpropvn -1-(2-
pherlvlDropvl)piperidine hydrochloride
a) (N-tert-ButoxYcarbonYlPiPeridin4-yl)-4-ket
diethvlmethYlphosphonate
Diethylmethylphosphonate (4.96 g, 32.6 mmol) was dissolved in
tetrahydrofuran (60 ml) and cooled to -78~C. n-BuLi (1.6M solution in
hexanes, 20.3 ml, 32.6 mmol) was added dropwise and the reaction stirred
under N2 for lh. Ethyl (N-tert-butoxycarbonyl)isonipecotate (3 g, 13.0
mmol3 in THF (2 ml) was added dropwise and the reaction stirred at -78~C
for 0.5h. The reaction was quenched with saturated NH4Cl and extracted
with ethyl acetate (3x). The combined organic layers were dried over
MgS04 and concentrated i71, vacuo. The residue was chromatographed on
silica eluting with ethyl acetate:hexanes (1:1) to obtain the product as a
colourless oil (0.530 g). lH NMR (250MHz, CDCl3) ~ 1.33 (6H, t), 1.44 (9H,
s), 1.51 (4H, m), 1.70 (2H, m), 2.70-2.82 (3H, m), 3.13 (2EI, d), 4.02-4.20
(4H, m).
b) 4-r3-(5-(1,2~4-Triazol-4-Yl~-lH-indol-3-Yl)-l-hvdroxvPropvll-N-(tert-
butox~carbonvl)ni~eridine
(i) Sodium hydride (0.084 g, 2.083 mmoI, 60% dispersion in oil)
was dissolved in anhydrous DMF (5 ml) under N2 and cooled to 0~C. (N-
tert-Butoxycarbonylpiperidin-4-yl)-4-keto-diethylmethylphosphonate (step
a, 0.530 g, 1.5 mmol) in DMF (3 ml) was added dropwise and the reaction
stirred for lh. 5-(1,2,4-Triazol-4-yl)-1-(N-p-toluenesulfonyl)-indole-3-
carboxaldehyde (0.500 g, 1.37 mmol) in hot DMF (5 ml) was then added
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and the reaction stirred at 25~C for 16h. The reaction was quenched by
the f.~l(litlon of water (30 mV and extracted with ethyl acetate (2x). The
organic layer was washed with water (3x) and dried over MgSO4 and
concentrated ~n vacuo. The residue was purified on silica eluting with
CH2C~12, then 1-3% MeOH/CH2Cl2 to give 0.300 g of a colourless oil.
(ii) The compound from above was hydrogenated over freshly
prepared Wilkinson's catalyst (0.025 g) in 5 ml of ethyl acetate for 16h.
The solvent was removed and the residue dissolved in ethanol (10 ml) and
cooled to 0~C. Sodium borohydride (0.0368 g) was added and the reaction
10 stirred at 0~C for lh. The solvent was removed and the reaction
partitioned between n-butanol/water. The organic layer was evaporated
and the residue chromatographed on silica eluting with CH2Cl2, then l-
10% MeOH/CH2Cl2 to obtain 0.212 g of a colourless oil.
15 c) 4-~3-(5-(1,2,4-Triazol-4-vl)-lH-indol-3-vl)-1-hvdroxqpropvl:1-1-(2-
~henvlPropvl~iperidine hvdrochloride
Prepared according to the method described for ~ mI)le 48, step e
using the cornpound from above (step b) and (~)-2-phenylpropionaldehyde.
The resulting compound was refluxed with KOH (0.034 g) in MeOH (5 ml)
20 for 16h. The compound was purified by preparative thin layer
chromatography. lH NMR (360MHz, DMSO) ~ 1.27 (3E~, d), 1.40 (lH, m),
1.42-1.90 (9H, m), 2.73 (2H, m), 2.87 (2H, m), 3.26 (2H, m), 3.38 (lH, m).
MS (ES+) (445, M+l).
