Note: Descriptions are shown in the official language in which they were submitted.
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5-Heteroaryl substituted indoles
The present invention relates to novel 5-heteroaryl substituted indoles having
high affinity for al-
adrenoceptors. Accordingly, the compounds of the invention are considered
useful for the
treatment of diseases or disorders responsive to al-adrenoceptor antagonists.
Further, as some of
the compounds are selective ccl-adrenoceptor ligands they may be particularly
useful as PET or
SPECT ligands.
Background
US patent No. 4,710,500 discloses, in general, optionally 5-substituted indole
derivatives having
the general formula:
R~ ~~',, N-Rz
~N
R
The compounds may be substituted in position 5 with a substituent selected
from halogen, lower
alkyl, lower allcoxy, hydroxy, cyano, nitro, lower alkylthio, CF3, lower
alkylsulphonyl, amino,
lower alkylamino and lower di-allcyamino. The compounds are claimed to be
potent and long-
lasting dopamine antagonists, and accordingly useful for the treatment of
psychoses, and
additionally to be strong 5-HT antagonists indicating effects in the treatment
of negative
symptoms of schizophrenia and depression and for the treatment of
cardiovascular diseases.
The use of sertindole having the formula
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2
0
N~NH
as an antipsychotic is specifically claimed in EP-A2-0 392 959.
This type of compounds has also been shown to be useful for the treatment of a
range of other
disorders including anxiety (WO 92/00070), cognitive disorders (WO 92/15303),
abuse (WO
92/15302) and hypertension (WO 92/15301).
WO 92/15301 discloses compounds having affinity for the al-adrenoceptor,
however, the
compounds disclosed herein are not selective for the ocl-adrenoceptor.
15
WO 99/46259 and WO 01/21614 relate to al-adrenoceptor antagonists related to
the compounds
of the invention which, however, have very different substituents on the
piperazine, piperidine
and tetrahydropyridine ring. The compounds of WO 01/21614 are not substituted
in position 5 of
the indole ring with a heteroaryl group.
Interest in the development of a,l-adrenoceptor antagonists has primarily
focused on therapeutics
for the treatment of cardiovascular diseases (Hieble et al., Exp. Opin.
Invest. Drugs, 1997, 6,
3657). Prazosin is the prototype of an ocl-adrenoceptor antagonist which has
very potent
peripherally effects. Prazosin has also in some animal models indicated
effects in the central
nervous system, although prazosin is considered to have poor CNS penetration.
Evidence exists indicating that blockade of al-adrenoceptor neurotransmission
could be beneficial
in the treatment of psychoses. Most classical antipsychotics including
clozapine bind potently to
a1-adrenoceptors labelled with [3H]prazosin or [3H]WB-4101. Some studies seem
to indicate a
central role of the ocl-component for the atypical profile of clozapine. (
Baldessarini, et al., Br°. J.
PsyclZiatjy, 1992, 160, 12-16 and Prinssen, et al., Eur. J. Plaarmacol., 1994,
262, 167-170).
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Several lines of evidence indicate that blockade of a,l-adrenoceptor
neurotransmission alone could
be beneficial in the treatment of schizophrenia. Metabolic and post-mortem
studies indicate
hyperactivity of the noradrenergic system in psychotic patients (R.J.
Baldessarini, D. Huston-
Lyons, A. Campbell, E. Marsh, B.M. Cohen, Br JPsychiatry Suppl 12 (1992)). The
firing pattern
of midbrain dopamine neurons in rats is modulated by prazosin administration
(J. Grenhoff, T.H.
Svensson, Euf° J Pharniacol 233, 79 (1993)) and by electrical
stimulation of noradrenergic
neurons in the locus coeruleus (J. Grenhoff, M. Nisell, S. Ferre, G. Aston-
Jones, T.H. Svensson, J
NeuYal Trarasrn Gesz. Sect 93, 11 (1993)). In addition, prazosin reversed the
disruption of prepulse
inhibition of acoustic startle response in rats induced by phencyclidine (PCP)
(V.P. Bakshi, M.A.
Geyer, J Plaarrnacol Exp Ther 283, 666 (1997) and B.S. Carasso, V.P. Balcshi,
M.A. Geyer,
Neuroplzarnaacology 37, 401 (1998)).
Further, repeated co-administration of prazosin and haloperidol was found to
reduce the effect of
haloperidol on the firing of dopamine neurons in nigrostriatal areas,
suggesting that the
combination would be effective as antipsychotic treatment without producing
extrapyramidal side
effects (EPS) (Chiodo, et al., J. Neunosci. 1985, 3, 2539-2544).
Co-administration of sub-threshold doses of the dopamine DZ antagonist
raclopride and the al-
adrenoceptor antagonist prazosin caused significantly enhanced suppression of
conditioned
avoidance behaviour in rats without inducing catalepsy (M.L. Wadenberg, et al,
JNeunal Transna
107, 1229 (2000)). It was suggested that al adrenoceptor blockade in the
presence of a low Dz
receptor occupancy might improve antipsychotic efficacy and thereby improve
the therapeutic
window with regard to extrapyramidal side effects.
It has also been suggested that centrally acting a,l-adrenoceptor antagonists
will have antimanic
effects while corresponding agonists would be beneficial for the treatment of
depression
(Lipinslcy, et al., Life Sciences, 1987, 40, 1947-1963).
Centrally acting a,l-adrenoceptor antagonists may also have effect against
Post Traumatic Stress
Disorder (Raslcind, M.A.; Dobie, D.J.; I~anter, E.D.; Petrie, E.C.; Thompson,
C.E.; Peskind, E.R.,
J. Clin. Psychiatry, 2000, 61, 129-133 and Taylor, F.; Raslcind, M.A., J. Clin
Psychopharmacol.
2002, 22, 82-85)
Labelled compounds of the present invention are considered to be valuable PET
(positron
emission tomography) ligands and SPECT ligands due to their selectivity for
cci-adrenoceptors.
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Finally, it is well established that al-adrenoceptor antagonists acting
peripherally are useful for
the treatment of benign prostatic hyperplacia, hypertension and cardiac
arrhytmias and for the
reduction of infra ocular pressure.
Tlie invention
According to the present invention novel compounds having the formula
/ (CH2)~ (CHZ)m X-Y
Het
R3
wherein
Het is a five- or six-membered aromatic, heterocyclic ring containing at least
one nitrogen atom as
a ring member, and optionally substituted with Cl_6-alkyl;
nis0orl;
G is N, C or CH; the dotted line meaning a bond when G is C, and the dotted
line meaning no
bond when G is CH or N;
Ar is phenyl optionally substituted with one or more substituents
independently selected from
halogen, Cl_~-alkyl, CI_~-allcoxy, hydroxy, trifluoromethyl and cyano, or Ar
is 2-thienyl, 3-thienyl,
2-furanyl, 3-furanyl, 2-thiazolyl, 2-oxazolyl, 2-imidazolyl, 2-pyridyl, 3-
pyridyl, or 4-pyridyl;
R2, R3, R4 and RS are independently selected from hydrogen, Cl_~-allcyl, Cl_~-
allcoxy, hydroxy,
halogen, trifluoromethyl, nitro, cyano, amino, CI_~-alkylamino and Cl_6-
diallcylamino;
m is 1, 2 or 3;
X is a bond, -CHZ-, -O-, -S-, -NH-, -NHCO- or -CONH-; and
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Y is cyano, Cl_~-alleyloxy, Cl_~-allcyl substituted with hydroxy, Cl_~-
allcoxy, or Cl_~-
allcylcarbonyloxy or Y is phenyl which may optionally be substituted one or
more times with
substituents selected from halogen, CI_~-alkyl, trifluoromethyl, hydroxy, Cl_~-
alkoxy, C1_~-
allcylcarbonyloxy, nitro, cyano, amino, CI_~-allcylamino, CI_~-diallcylamino,
methylenedioxy and
5 ethylenedioxy, or Y is an aromatic mono- or bicyclic heterocyclic ring
containing only one
heteroatom which may optionally be substituted one or more times with
substituents selected from
halogen, CI_~-alkyl, trifluoromethyl, hydroxy, Cl_6-allcoxy, Cl_~-
allcylcarbonyloxy, nitro, cyano,
amino, C~_~-allcylamino and Cl_~-dialleylamino; provided Y is not cyano when X
is O, S, NH,
NHCO or CONH; and Y is not Cl_~-alkoxy when X is O, S or NH;
or pharmaceutically acceptable acid addition salts thereof, is provided.
In a particular embodiment of the invention, Het is optionally substituted
triazolyl, pyrazolyl,
pyrimidyl, pyridinyl or imidazolyl. Suitably, Het is 1-methyl-1H 1,2,4-triazol-
3-yl,
2-methyl-2H 1,2,4-triazol-3-yl, 3-methyl-3H 1,2,3-triazol-4-yl, 1-methyl-1H
pyrazol-4-yl,
2-methyl-2H pyrazol-3-yl, 1-methyl-1H imidazol-2-yl, pyrimidin-2-yl or pyridin-
3-yl.
In another embodiment, the invention relates to compounds of fornmla (~
wherein Y is cyano, CI_
~-allcyl substituted with hydroxy, Cl_6-alkoxy, or Cl_~-alkylcarbonyloxy or Y
is optionally
substituted phenyl, in particular the group of compounds wherein Y is Cl_~-
alkyl substituted with
hydroxy, Cl_~-alkoxy, or Cl_~-alkylcarbonyloxy or Y is optionally substituted
phenyl
In a third embodiment, X is a bond , -CHZ-, O or S, preferably O or S.
In a fourth embodiment, Y is an optionally substituted, aromatic bicyclic
heterocyclic ring
containing only one heteroatom, such as for example optionally substituted
indolyl, benzofuranyl
or dihydro-1,4-benzodioxinyl.
In a fifth embodiment, X is -NHCO- or -CONH-.
In a sixth embodiment, Y is optionally substituted phenyl.
In a seventh embodiment, the invention relates to compounds wherein Y is Cl_6-
alkyl substituted
with hydroxy, Cl_~-alkoxy or Gl_6-alkylcarbonyloxy
Finally, the invention relates to the group of compounds wherein Y is cyano.
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The compounds of the invention are potent ccl-adrenoceptor antagonists and the
compounds are
therefore useful for the treatment of disorders or diseases responsive to
antagonism of the al-
adrenoceptor.
Some of the compounds of the invention have stronger affinity to the ocla
adrenoceptor than the
alv-adrenoceptor and the ald-adrenoceptor.
Thus, in another aspect, the present invention relates to a pharnlaceutical
composition comprising
at least one compound of formula I as defined above or a pharmaceutically
acceptable acid
0 addition salt thereof and optionally a second pharmaceutically active
ingredient in combination
with one or more pharmaceutically acceptable carriers or diluents.
In a further aspect, the present invention relates to the use of a compound of
formula I as defined
above or an acid addition salt thereof and optionally a second
pharmaceutically active ingredient
l5 for the manufacture of a pharmaceutical medicament for the treatment of a
disorder or disease
responsive to antagonism of a1-adrenoceptor.
Thus, in still another aspect, the present invention relates to the use of a
compound of formula I as
above and optionally a second agent having antipsychotic activity for the
preparation of a
20 medicament for the treatment of psychosis.
30
Diseases and disorders responsive to antagonism of al-adrenoceptors includes
psychosis, mania,
benign prostatic hyperplacia, hypertension, post traumatic stress disorder and
cardiac arrhytmias.
Antagonists of a,l-adrenoceptors are also useful for the reduction of infra
ocular pressure.
In a further aspect, the invention relates to a method for the treatment of a
disorder or disease
responsive to antagonism of al-adrenoceptors in a mammal comprising
administering a
compound of formula I as above and optionally a second pharmaceutically active
ingredient to
said manvnal.
In still another aspect, the present invention relates to a method for the
treatment of psychosis in a
mammal comprising administering a compound of formula I as above and
optionally a second
agent having antipsychotic activity to said mammal.
The above mentioned second pharmaceutically active ingredient may be another
agent having
antipsychotic activity, for example an agent having dopamine DZ antagonistic
effect. As
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mentioned above, evidence exists which indicate that such combinations may be
advantageous for
treatment of psychoses without causing extrapyramidal effects.
Finally, the present invention relates to radio-labelled compounds of formula
I and the use thereof
in various biological assays and PET- or SPECT studies.
Detailed Description of the Invention
When used herein halogen means fluoro, chloro, bromo or iodo.
The ternz C1_~ alkyl refers to a branched or unbranched alkyl group having
from one to six carbon
atoms inclusive, including groups such as methyl, ethyl, 1-propyl, 2-propyl, 1-
butyl, 2-butyl, 2-
methyl-2-propyl and 2-methyl-1-propyl.
The terms Cl_~-allcoxy, Cl_6-alkylamino, Cl_6-dialkylamino etc. designate such
groups in which Cl_
~ alkyl is as defined above.
Het meaning a five-membered aromatic heterocyclic ring containing at least one
nitrogen as a ring
member, includes, but are not limited to, heterocyclic rings selected from
pyrrol-1-yl, pyrrol-2-yl,
pyrrol-3-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, pyrazol-1-yl,
pyrazol-3-yl, pyrazol-4-yl,
1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-1-
yl, 1,2,4-triazol-3-yl, 1,2,4-
triazol-5-yl, tetrazol-1-yl, tetrazol-2-yl, tetrazol-5-yl, oxazol-2-yl, oxazol-
4-yl, oxazol-5-yl,
isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, , thiazol-4-yl,
thiazol-5-yl, isothiazol-3-
yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-
yl, 1,2,4-oxadiazol-3-
yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,3-
thiadiazol-4-yl, 1,2,3-
thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-
thiadiazol-2-yl, 1,3,4-thiadiazol-
5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-thiadiazol-3-yl, oxatriazol-4-yl and
thiatriazol-4-yl.
Het meaning a six-membered aromatic heterocyclic ring containing at least one
nitrogen as a ring
member, includes, but are not limited to, pyridin-2-yl, pyridin-3-yl, pyridin-
4-yl, pyrimidin-2-yl,
pyrimidin-4-yl and pyrimidin-5-yl.
Y meaning an aromatic mono- or bicyclic heterocyclic ring containing only one
heteroatom
includes, but are not limited to, rings such as pyridin-2-yl, pyridin-3-yl,
pyridin-4-yl, furan-2-yl,
furan-3-yl, 2-thienyl, 3-thienyl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, indol-
1-yl, indol-2-yl, indol-
3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, benzofuran-2-yl,
benzofuran-3-yl, benzofuran-
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4-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, isobenzofuran-1-yl,
isobenzofuran-3-yl,
isobenzofuran-4-yl, isobenzofuran-5-yl, isobenzofuran-6-yl, isobenzofuran-7-
yl, benzothien-2-yl,
benzothien-3-yl, benzothien-4-yl, benzothien-5-yl, benzothien-6-yl, benzothien-
7-yl,
isobenzothien-1-yl, isobenzothien-3-yl, isobenzothien-4-yl, isobenzothien-5-
yl, isobensothien-6-
yl, isobenzothien-7-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-
5-yl, quinolin-6-yk,
quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-
4-yl, isoquinolin-5-yl,
isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8-yk.
The acid addition salts of the compounds of the invention are pharmaceutically
acceptable salts
formed with non-toxic acids. Exemplary of such organic salts are those with
malefic, fumaric,
benzoic, ascorbic, succinic, oxalic, bis-methylenesakicylic, methanesukfonic,
ethanedisulfonic,
acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic,
mandelic, cinnamic, citraconic,
aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic,
benzenesukfonic, and
theophylline acetic acids, as well as the 8-hakotheophyllines, for example 8-
bromotheophylline.
Exemplary of such inorganic salts are those with hydrochloric, hydrobromic,
sulfuric, sulfamic,
phosphoric, and nitric acids.
The selectivity of the compounds of the invention for the al-adrenoceptor
makes them
particularly useful for the development of radiolabelled ligands useful in
various biological assays
and in PET and SPECT studies.
The compounds of the invention "can be labelled by reacting the unlabelled
precursor molecules
with [1'C] methyl iodide, ['1C] methyl triflate, or other [1'C] labelled
reagents derived from [11C]
carbon dioxide. The compounds may also be labelled with 18F,'z3I or'zSI.
Radiolabeling of compounds of the present invention may be performed according
to
radiolabeling methods known and used in the prior art. For example, as stated
in the
specification, compounds can be labelled by reaction of the appropriate
precursors with radio-
labelled reagents, including 1'C-labelled reagents such as [1'C]methyl iodide
and [lIC]methyl
triflate.
It is also within the knowledge of a person skilled in the art of
radiopharmaceuticaks to label
compounds with 18F or lzsl. Compounds of the present invention radiolabelled
with'8F may be
prepared by aromatic nucleophikic substitution of a precursor molecule
containing an appropriate
leaving group (such as nitro, bromo, iodo or triflate) by reaction with [18F]F-
. For example,
compounds of the present invention may be radiolabelled with'8F in the 4-
position of the phenyl
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group attached to the indole N-1. The compounds may be prepared by aromatic
nucleophilic
substitution of a precursor molecule containing an appropriate leaving group
(such as nitro,
bromo, iodo or triflate) by reaction with [I8F]F-. After appropriate
activation of the aromatic ring
with one or two electron withdrawing groups, such as forniyl group(s). The
formyl groups may
easily be removed after radioflourination by reaction with Willcinson's
catalyst in dioxane at
elevated temperature (Sobrio, F.; Amolchtari, M.; Gourand, F.; Dhilly, M.;
Dauphin, F.; Barre, L.,
Bioorg. Med. Chern. 2000, 8, 2511-2518).
Radiolabelling with'ZSI or'''3I may be performed by halodemetalation of the
corresponding tin
substituted (organotin) precursors, for example by treatment of an ethanolic
solution of the
organotin precursor with Na'Z3I or Nal2sl in the presence of chloramine-T and
aqueous
hydrochloric acid analogously to the procedure described by Foged et al
(Foged, C.; Halldin, C.;
Hiltunen, J.; Braestrup, C.; Thomsen, C.; Hansen, H.C.; Suhara, T.; Pauli, S.;
Swahn, C.-G.;
I~arlsson, P.; Larsson, S. and Farde, L., Nucl. Med. Biol. 1996, 23, 201-209).
The organotin precursors of the compounds of the invention can be readily
prepared from 1-(4-
bromophenyl) or 1-(4-iodophenyl) substituted 5-heteroaryl-indoles by reaction
with n-
butyllithium or tert-butyllithium in THF at low temperature, followed by
reaction with a
triallyltin halide such as trimethyltin chloride or tributyltin chloride.
Magnesium metalated
internzediates may also be used in place of lithium. Alternatively, palladium
catalyzed reaction
with hexaallcyldistannanes may also give the corresponding organotin
precursors. (Ali, H.; Johan,
and van Lier, J.E., Synthesis 1996, 423-445)
Alternatively, 4-[igF]flouroiodobenzene may be prepared as described in the
literature (Shah, A.;
Widdowson, D. A.; Pilce, V. W., J.Labelled Cofnpd.Radiopharna. 1997, 40, 65-
67), and reacted
with N-unsubstituted indole to give the final radiolabelled compounds.
The compounds of the present invention can be prepared according to the
procedures described
below:
a) Reacting an indole derivative of the following formula
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Het/
(
wherein RZ, R3, R4, R5, Ar, Het and n are as defined above, with a 4-
piperidone of the formula
p N (CHz)m X-Y
(III)
5
wherein m, X and Y are as defined above, A is an oxygen atom or a -O-(CHz)q O-
chain, wherein
qis2or3;
b) reducing the tetrahydropyridine double bond in a compound of the formula
~ (CHZ)"
Het
R
/ (CHZ)m X-Y
(N)
wherein R2, R3, R4, R5, m, X, Y, Ar, Het and n are as defined above;
c) reacting a compound of the formula
(CHZ)m X-Y
~CHz)
He /t
(V)
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wherein R2, R3, Rø, R5, m, X, Y, G, the dotted line, Het and n are as defined
above, with a
compound of the formula Ar-hal wherein Ar is as defined above and "hal" is
halogen, in the
presence of a metal catalyst,
d) reacting a compound of the formula
IH
(CHz)n
Het
R
(VI)
wherein RZ, R3, R4, R5, G, the dotted line, Ar, Het and n are as defined
above, with a reagent of
formula L-(CHZ)n,-X-Y wherein m, X, and Y are defined above and L is halogen,
mesylate or
tosylate
e) reducing the carbonyl group of a compound of the formula
0
R8
(CHZ)n
Het
R
(VII)
wherein R2, R3, R4, R5, G, the dotted line, Ar, Het and n are as defined above
and R8 is
(CHz)~In-i>-X-Y, wherein m, X, and Y are defined above
f) decarboxylating a compound of the formula
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/ (cH2>"
Het
R
(VIII)
wherein RZ, R3, R4, Ar, Het and n are as defined above, followed by reaction
with a piperazine of
the formula
X-Y
HN"N (CH2)m
\\~ // (IX)
wherein m, X and Y is as defined above;
g) allcylating the group Het in a compound of formula I wherein Het is
unsubstituted on at least
one pyrrole-lilce nitrogen atom with an alkylating reagent, such as Cl_~-alkyl-
L, wherein L is
chloro, bromo, iodo, mesylate or tosylate.
Method g) may accordingly be used to introduce radiolabelled alkyl groups,
such as ['1C]methyl
iodide, ["C]methyl triflate, etc.
Methods for the preparation of the starting materials used in the above
processes are described in
US patent No. 4,710,500, WO 92/00070, WO 99/46259 and in Perregaard et al.,
J.Med.Cl2ern.
1992 (35), 1092-1101, or can be prepared analogously to the procedures
described herein.
Starting materials wherein the group Het is tetrazol-5-yl may be prepared by
reacting the
corresponding 5-cyano-indole with azide.
Starting materials wherein the group Het-(CHZ)" is tetrazol-5-ylmethyl may
likewise be prepared
from the corresponding indole containing a 5-cyanomethyl group by reaction
with azide. The 5-
cyanomethyl-indoles may be prepared by hydrolysis of the corresponding 5-cyano-
indole,
reduction of the carboxylic acid functionality obtained to hydroxymethyl,
reaction with
methanesulphonyl chloride to form the corresponding 5-chloromethyl-indoles
followed by
reaction with a cyanide to form the 5-cyanomethyl-indole.
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N Boc-protected 5-bromo-1-Ar-3-piperidinyl-1H indole is prepared in three
steps from 5-bromo-
1-Ar-1H indole. Reaction of 4-piperidin-2-one hydrochloride, hydrate with 5-
bromo-Ar-
fluorophenyl)-1H indole using acidic conditions followed by catalytic
hydrogenation analogously
to published procedures (Perregaard, et al. JMed Claena 1992, 35, 1092)
results in the
unsubstituted piperidyl compound. Finally, reaction with boc-anhydride affords
the desired
starting material.
Introduction of heteroaryl groups in the 5-positions in the N Boc-protected 5-
bromo-1-Ar-3-
piperidinyl-1H indole is accomplished by two alternative methods A and B.
In Method A, the N boc-protected 5-bromo-1-Ar-3-piperidinyl-1H indole is
treated with ya-
butyllithium followed by transmetalation to the corresponding zinc chloride.
Addition of the
appropriate heteroaryl halide and 5 mol%
tetralcis(triphenylphosphine)palladium(0) affords the
corresponding heteroaryl substituted intermediates. In the reverse method B
deprotonation of the
heteroaryl derivatives or halogen/metal exchange of heteroaryl halides
followed by
transmetalation to the corresponding zinc chlorides and
tetralcis(triphenylphosphine)palladium(0)
catalysed cross-coupling with the N boc-protected 5-bromo-1-Ar-3-piperidinyl-
1H indole results
in the corresponding 5-heteroaryl-indoles.
The boc-protected derivatives obtained by Methods A and B is deprotected and
used as starting
materials for method d) described below.
Starting materials for methods a), b), c) and e) may be prepared analogously
using properly
protected starting materials.
In method a), the reaction is performed under strong acidic conditions by
heating. Trifluoroacetic
acid or HCl in ethanol are preferred as acidic catalysts.
In method b), the reduction is preferably carried out at low hydrogen
pressures (3 Ato.) in the
presence of platinum or palladium on carbon black.
In method c), the arylation is preferably carned out at about 160-210
°C in aprotic polar solvents
such as N-methyl-2-pyrrolodine or hexamethylphosphoric triamide with I~ZC03 as
base and
copper as a catalyst.
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In method d), the allcylations are performed in a an aprotic solvent such as
dimethylformamide or
acetonitrile using an appropriate base such as potassium carbonate or
diisopropyl ethyl amine at
elevated temperatures (50-120 °C).
In method e), the reduction is preferably carried out with LiALH4 in THF or
diethylether or with
diborane in THF.
Method f), is a two step procedure in which compound VIII is first
decarboxylated in the presence
of an inorganic salt as e.g. LiCI or MgClz in a polar solvent as e.g. diglyme,
hexamethylphosphoric triamide or N-methyl-2-pyrolidone at elevated
temperatures (120-150 °C).
Finally, the appropriate piperazine is added and the temperature raised to
about 200 °C and lcept
there until the corresponding indoxyle has disappeared according to TCL
analysis. The
compounds of Formula VIII are conveniently prepared according to the
procedures reported by
Unangst et al., .l. Hete~ocyclic Gheyn. 1954, 21, 709.
In method g), the allcylation with alkyl iodides or bromides is performed by
in aprotic solvents
such as acetone or dimethylformamide using an appropriate base such as
potassium carbonate or
diisopropyl ethyl amine at elevated temperatures (40-90 °C).
In the following, the invention is further illustrated by way of examples
that, however, may not be
construed as limiting.
Examples
General. All reactions were carried out under a positive pressure of nitrogen
or argon. Glassware
for water sensitive reactions was dried in an oven at 150 °C over
night. THF was freshly distilled
from sodium/benzophenone. DMF was sequentially dried and stored over 3 A
molecular sieves.
ZnClz was flame dried in vacuo and dissolved to 1.0 M in dry THF after cooling
to room
temperature. Acetone and CH3CN for alkylation reactions were HPLC-grade.
Saturated
HCl/MeOH solutions were prepared by saturation of MeOH with HCl gas. For flash
chromatography either silica gel of type I~ieselgel 60, 230-400 mesh ASTM or
Biotage Flash40
(50 or 100 g columns) were used. 'H NMR spectra were recorded of all novel
compounds at 250
MHz on a Brulcer AC 250 or at 500 MHz on a Bruker Avance DRX500 instrument.
Deuterated
chloroform (99.8%D) or DMSO-d~ (99.9%D) were used as solvents. TMS was used as
internal
reference standard. Chemical shift values are expressed in ppm-values. The
following
abbreviations are used for multiplicity of NMR signals: s=singlet, d=doublet,
t=triplet, q=quartet,
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dd=double doublet, dt=double triplet, tt=triplet of triplets, m=multiplet. NMR
signals
corresponding to acidic protons are generally omitted. Melting points are
reported uncorrected.
Solvent residuals in elemental analysis samples were measured by Karl Fisher
titration (H20) or
by Thermo Gravimetric Analysis (TGA) on a TA-instruments TGA 2950 with heating
rate 10 °C
5 per min. The nature of the solvent was identified by 1H-NMR. Solvent
residuals are not reported
in the NMR data. Analytical and preparative HPLC were run on a Shimadzu HPLC
system with
two Shimadzu LC-8A pumps. The UV trace was obtained using a Shimadzu SPD-l0A
detector
operating at 254 nm. ELSD trace was obtained using a Sedere Sedex 55 detector
operating at 42
°C and 2.3 bar. For analytical HPLC-MS a Perlcin Elmer API 150EX mass
spectrometer equipped
10 with a Perlcin Elmer SCIEX Heated Nebulizer (APCI) ion source. The total
ion current (TIC) was
recorded in positive mode for m/z 100-1000 amu. Analytical HPLC was run
injecting 10 ~,L to a
Waters Symmetry C-18 (4.6x30 mm, 3.5 ~,m) column. The sample was eluted with a
gradient of
the following solvent mixtures: A: water/TFA 100/0.05 and B:
Acetonitrile/water/TFA
95/510.035. Gradient: A/B 90/10 ~ 0/100 during 4 minutes, then isocratic A/B
90/10 during 1
15 minute. Flow was 2 mL/min throughout. Preparative HPLC-MS was run with 190
~,L injections
on a YMC RP18 (50x20 mm) column with a gradient of A/B 80/20 ~ 0/100 during 7
minutes,
then isocratic 80/20 during one minute. The flow was 22.7 mL/min throughout
and detection was
performed using the MS (TIC) signal in a split system. The reported parities
are based on
integration of the peaks in the W and ELSD spectrum.
Reagents:
The following reagents were prepared according to published procedures: 3-(2-
Chloroethyl)imidazolidin-2-one ( Perregaard, et al. Med Claena 1992, 35, 1092
and Johnston, et
al., JMed Clzem 1963, 6, 669), 3-(2-chloroethyl)-oxazolidin-2-one (Robinson,
et al., JAna Chem
Soc 1972, 94, 7883), 3-(2-chloroethyl)-1-methyl-2-pyrrolidin-2-one (Sucrow, et
al., Chern. Ber~.
1972, 105, 1621), 1-methyl-1,2,3-triazole (Begtrup, et al., Acta Chem Scand
1990, 44, 1050), 4-
bromo-1-methyl-1,2,3-triazole (Hiittel, et al., Liebigs Anna Chem 1955, 593,
207), 2-bromo-1-
methyl-1,3,4-triazole (Bernardini, et al., Soc Clairn 1975, 5, 647), 5-bromo-1-
methyl-1,2,4-triazole
(Bernardini, et al., Soc Chirn 1975, S, 647) and 3-bromo-1-methyl-1,2,4-
triazole,~ 3-Iodo-1-
methylpyrazole (Balle, et al. Synthesis 2002, 1509-1512).
Preparation of Starting Material
4-(5-Bromo-1-(4-fluorophenyl)-1H indol-3-yl)-piperidine-1-carboxylic acid tart-
butyl ester
(1). A solution of 5-Bromo-1-(4-fluorophenyl)-3-(4-piperidinyl)-1H indole (125
g, 0.33 mol)
(Prepared as described by Perregaard et al J Med Claern 1992, 35, 1092) and di-
tef°t-butyl
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Bicarbonate (260 g, 1.2 mol) in 1:1 THF/Hz0 mixture (1 L) was stirred over
night with KzCO3
(300 g, 2.2 mol) at 60 °C. EtOAc (1 L) was added. After separation of
the two phases, the
aqueous phase was extracted with EtOAc (3 x 0.5 L). The combined organic
phases were washed
with brine and dried over MgSO~. The crude product (115 g) was washed with
cold MeOH to
yield 97 g of 1 as white crystals: Mp 160-162 °C (heptane); 1H-NMR
(CDC13): 1.49 (s, 9H), 1.65
(q, 2H), 2.04 (d, 2H), 2.85-3.00 (m, 3H), 4.25 (d, 2H), 7.03 (s, 1H), 7.15-
7.35 (m, 4H), 7.39-7.43
(m, 2H), 7.78 (s, 1H); MS m/z (relative intensity): 473 + 475 (MH+, 1%),
417+419 (40%),
373+375(100%); Anal. (Cz4Hz6BrFNzOz): C, H, N.
Preparation of Intermediates (Method A)
Cross-coupling of 4-(5-bromo-1-(4-fluorophenyl)-1H indol-3-yl)-piperidine-1-
carboxylic
acid tart-butyl ester (1) with a heteroaryl halide
4-(5-Bromo-1-(4-fluorophenyl)-1H indol-3-yl)-piperidine-1-carboxylic acid
teJ°t-butyl ester (1)
(10 g, 21.1 mmol) in THF (20 mL) was added during 2 minutes to a solution of n-
butyllithium
(39.6 mL, 63.4 mmol) in THF (210 mL) at -78 °C. After stirnng for 3
minutes ZnClz in THF
(105.6 mL, 105.6 mmol) was added. The solution was stirred for further 30
minutes at -78 °C.
The heteroaryl halide (amount specified below) was added together with
Pd(PPh3)d (1.2 g, 5 mol
%) and DMF (60 mL). The reaction mixture was stirred at 80 °C for 8 h.
After cooling to room
temperature, HzO (300 mL) and EtOAc (500 mL) were added and the phases were
separated. The
organic phase was washed with H20 (200 mL) and saturated aqueous CaClz (3 x
100 mL), dried
over MgS04 and the solvent was removed in vacuo. The crude product was
purified by flash
chromatography. The amount of reagents and solvents were scaled according to
the actual amount
of 1 used.
The following derivatives were prepared according to Method A
4-(1-(4-Fluorophenyl)-5-(1-methylpyrazol-3-yl)-1H indol-3-yl)-piperidine-1-
carboxylic acid
tent-butyl ester (2a). A solution of 1 (6.8 g, 14.4 mmol) in THF was reacted
with 1-methyl-3-
iodopyrazole (3.0 g, 14.4 mmol). The crude product was purified by flash
chromatography
(EtOAc/heptane 20/80 --~ 50/50) to yield 4.31 g (63%) of 2a as white crystals:
Mp. 145.3-145.6
°C (EtOAc/heptane); 'H-NMR (CDC13) 1.49 (s, 9H), 1.68 (q, 2H), 2.10 (d,
2H), 2.93 (t, 2H), 3.11
(t, 1H), 3.98 (s, 3H), 4.26 (s, broad, 2H), 6.57 (d, J = 2.0 Hz, 1H), 7.04 (s,
1H), 7.17-7.24 (m, 2H),
7.39 (d, J = 2.1 Hz, 1H), 7.42-7.52 (m, 3H), 7.65 (d, J = 8.6 Hz, 1H), 8.08
(s, 1H); MS m/z: 475
(7%, MH+), 419 (100%), 375 (73%); Anal. (Cz8H31N4FOz): C, H, N.
4-(1-(4-Fluorophenyl)-5-(1-methylpyrazol-4-yl)-1H indol-3-yl)-piperidine-1-
carboxylic acid
Cef~t-butyl ester (2b). A solution of 1 (10 g, 21.1 mmol) in THF was reacted
with 1-methyl-4-
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17
bromopyrazole (4.2 g, 31.7 mmol). The crude product was purified by flash
chromatography
(EtOAc/heptane 20/80 -~ 30/70) to yield 2.8 g (28%) of 2b as white crystals:
Mp 133-136 °C
(EtOAc/heptane); 'H-NMR (CDC13) 1.49 (s, 9H), 1.71 (q, 2H), 2.10 (d, 2H), 2.94
(t, 2H), 3.05 (t,
1H), 3.96 (s, 3H), 4.27 (s, broad, 2H), 7.04 (s, 1H), 7.20-7.25 (m, 2H), 7.34
(d, 1H), 7.41-7.50 (m,
3H), 7.63 (s, 1H), 7.71 (s, 1H), 7.79 (s, 1H); MS m/z: 475 (5%, MH~, 419
(86%), 375 (100%);
Anal. (Cz$H31N4FOz): C, H, N.
4-(1-(4-Fluorophenyl)-5-(1-methyl-1,2,4-triazol-3-yl)-1H indol-3-yl)-
piperidine-1-carboxylic
acid tent-butyl ester (2c). A solution of 1 (20 g, 42 mmol) in THF was reacted
with 3-bromo-1-
methyl-1,2,4-triazole (8.8 g, 55 mmol). The crude product was purified by
flash chromatography
(EtOAc/heptane/MeOH 50/50/0 --~ 100/0/0 -~ 90/0/10) and crystallised from EtzO
to yield 8 g
(40%) of 2c as white crystals: Mp 189-191 °C (EtzO); 1H-NMR (CDC13)
1.50 (s, 9H), 1.70 (q,
2H), 2.12 (d, 2H), 2.95 (t, 2H), 3.13 (t, 1H), 4.00 (s, 3H), 4.28 (s, broad,
2H), 7.06 (s, 1H), 7.15-
7.28 (m, 2H), 7.40-7.52 (m, 3H), 8.00 (d, 1H), 8.08 (s, 1H), 8.42 (s, 1H); MS
m/z: 476 (72%,
MH+), 420 (66%), 376 (100%); Anal. (Cz~H3oNsFOz~2.17 % EtzO): C, H, N.
4-(1-(4-Fluorophenyl)-5-(1-methyl-1,3,4-triazol-2-yl)-1H indol-3-yl)-
piperidine-1-carboxylic
acid tart-butyl ester (2d). A solution of 1 (10 g, 21.1 mmol) in THF was
reacted with 2-bromo-1-
methyl-1,3,4-triazole (2.8 g, 17.3 rninol). The crude product was purified by
flash
chromatography (EtOAc/heptane/MeOH 30/70/0 -~ 100/0/0 -~ 90/0/10) to yield 2.5
g (31%) of
2d as white crystals: Mp 156-158 °C (toluene/heptane 1:1); 'H-NMR
(CDC13) 1.49 (s, 9H), 1.70
(q, 2H), 2.08 (d, 2H), 2.90 (t, 2H), 3.07 (t, 1H), 3.78 (s, 3H), 4.26 (s,
broad, 2H), 7.13 (s, 1H),
7.20-7.28 (m, 2H), 7.41- 7.50 (m, 3H), 7.53 (d, 1H), 8.05 (s, 1H), 8.21 (s,
1H); MS m/z: 476
(100%, MHO), 420 (51 %), 376 (83%); Anal. (CZ~H3oN5FOz): C, H, N.
4-(1-(4-Fluorophenyl)-5-(1-methyl-1,2,4-triazol-5-yl)-1H indol-3-yl)-
piperidine-1-carboxylic
acid tent-butyl ester (2e). A solution of 1 (7.5 g, 15.8 mmol) in THF was
reacted with 5-bromo-1-
methyl-1,2,4-triazole (2.1 g, 13 mmol). The crude product was purified by
flash chromatography
(EtOAc/heptane/MeOH 30/70/0 ~ 100/0/0 -~ 90/0/10) to yield 2.8 g (45%) of 2e
as a pale
yellow foam: 'H-NMR (CDC13) 1.49 (s, 9H), 1.70 (q, 2H), 2.09 (d, 2H), 2.91 (t,
2H), 3.07 (t, 1H),
4.03 (s, 3H), 4.28 (s, broad, 2H), 7.13 (s, 1H), 7.20-7.30 (m, 2H), 7.42-7.50
(m, 3H), 7.52 (d, 1H),
7.96 (s, 1H), 8.02 (s, 1H); MS m/z: 476 (100%, MH+), 420 (33%), 376 (41%);
Anal.
(Cz~HsoNsFOz)~ C~ H~ N.
4-(1-(4-Fluorophenyl)-5-(pyrimidin-2-yl)-1H indol-3-yl)-piperidine-1-
carboxylic acid te~~t-
butyl ester (2f7. A solution of 1 (18 g, 38 mmol mmol) in THF was reacted with
2-
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18
bromopyrimidine (10 g, 75 mmol). The crude product was purified by flash
chromatography
(EtOAc/heptane 10/90 ~ EtOAc/MeOH 90/10) and crystallised from EtzO to yield
12 g (67%) of
2f as white crystals: Mp. 164-166 °C (EtzO);'H-NMR (CDCl3) 1.50 (s,
9H), 1.71 (q, 2H), 2.14 (d,
2H), 2.96 (t, 2H), 3.16 (t, 1H), 4.27 (s, broad, 2H), 7.08 (s, 1H), 7.13 (t,
1H), 7.20-7.25 (m, 2H),
7.43-7.49 (m, 2H), 7.51 (d, 1H), 8.36 (d, 1H), 8.77-8.81 (m, 3H); MS m/z: 473
(11%, MH+), 417
(100%), 373 (84%); Anal. (CzBHZ~N~F02): C, H, N.
4-(1-(4-Fluorophenyl)-5-(pyrimidin-5-yl)-1H indol-3-yl)-piperidine-1-
carboxylic acid test
butyl ester (2g). A solution of 1 (10 g, 21.1 mmol) in THF was reacted with 5-
bromopyrimidine
(Sg, 31.6 mmol). Flash chromatography (EtOAc/heptane/NEt3 30/70/4 -~ 70/30/4)
gave 8.2 g
which was recrystallised form toluene/heptane 1:1 to yield 5.0 g (50%) of 2g:
Mp 144-146 °C
(toluene/heptane l:l); MS m/z: 473 (MH+, 3%), 417 (100%), 373 (33%); IH-NMR
(CDC13) 1.49
(s, 9H), 1.75 (q, 2H), 2.13 (d, 2H), 2.95 (t, 2H), 3.08 (t, 1H), 4.28 (s,
broad, 2H), 7.13 (s, 1H),
7.20-7.30 (m, 2H), 7.42 (dd, 1H), 7.43-7.50 (m, 2H) 7.57 (d, 1H), 7.85 (d,
1H), 9.02 (s, 2H), 9.19
(s, 1H); Anal. (CZ$H2~FN402): C, H, N.
4-(1-(4-Fluorophenyl)-5-(1-methyl-1,2,3-triazol-4-yl)-1H indol-3-yl)-
piperidine-1-carboxylic
acid te~~t-butyl ester (2h). A solution of 1 (4.7 g, 10 mmol) in THF was
reacted with 4-bromo-1-
methyl-1,2,3-triazole (1.1 g, 6.8 nunol). The crude product was purified by
flash chromatography
(EtOAc/heptane 20/80 --~ 100/0) to yield 900 mg (28%) of 2h as a white foam:
1H-NMR (CDC13)
1.50 (s, 9H), 1.69 (q, 2H), 2.12 (d, 2H), 2.94 (t, 2H), 3.09 (t, 1H), 4.18 (s,
3H), 4.28 (s, broad,
1H), 7.06 (s, 1H), 7.17-7.24 (m, 2H), 7.40-7.55 (m, 3H), 7.61 (d, 1H), 7.78
(s, 1H), 8.23 (s, 1H);
MS m/z: 476 (4%, MH+), 420 (46%), 376 (100%); Anal.(CZ~H3oN5F02~2.70 % EtOAc):
C, H, N.
Preparation of Intermediates (Method B)
Cross-coupling of a heteroarylzinc chloride with 4-(5-bromo-1-(4-fluorophenyl)-
1H indol-3-
yl)-piperidine-1-carboxylic acid tef~t-butyl ester (1)
4-(5-Bromo-1-(4-fluorophenyl)-1H indol-3-yl)-piperidine-1-carboxylic acid
tee°t-butyl ester (1)
(8.3 g, 16.9 mmol) was added to a solution of heteroarylzinc chloride in THF
(amount and
preparation specified below) with Pd(PPh3)ø (5 mol%) and DMF (30% of the
amount of THF).
The solution was stirred at 80 °C for 8 h. Work up was performed as
described in method A. The
amounts of reagents and solvents were scaled according to the actual amount of
1 used.
The following derivatives were prepared according to Method B:
4-(1-(4-Fluorophenyl)-5-(1-methylpyrazol-5-yl)-1H indol-3-yl)-piperidine-1-
carboxylic acid
test-butyl ester (3a). 1-Methylpyrazole (3.2 g, 39 mmol) in THF (200 mL) was
cooled to - 78 °C.
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19
ra-butyllithium (43 mL,, 26.9 mmol) was added during 5 minutes. The solution
was heated slowly
to room temperature during 15 minutes and cooled again to -78 °C. ZnCl2
in THF (120 mL, 120
mmol) was added and the solution was stirred at -78 °C for 30 minutes.
Reaction with 1 (14.2 g,
30 rmnol) was performed following method B. Flash chromatography
(EtOAc/heptane/NEt3
30/70/5 ~ 50/50/5) and recrystallisation from CHZCIz afforded 11.5 g (80%) of
3a: Mp 166-168
°C (CHZCIz); 'H-NMR (CDCL3): 1.49 (s, 9H), 1.72 (q, 2H), 2.07 (d, 2H),
2.93 (t, 2H), 3.05 (t,
1H), 3.90 (s, 3H), 4.26 (s, broad, 2H), 6.32 (s, 1H), 7.10 (s, 1H), 7.20-7.30
(m, 3H), 7.40-7.47 (m,
2H), 7.50 (d, 1H), 7.54 (s, 1H), 7.69 (s, 1H); Anal. (Cz$H31FN402): C, H, N.
4-(1-(4-Fluorophenyl)-5-(1-methylimidazol-2-yl)-1H indol-3-yl)-piperidine-1-
carboxylic acid
tent-butyl ester (3b). 1-Methylimidazole (1.39 g, 16.9 mmol) in THF (195 mL)
was cooled to -78
°C. rr-Butyllithium (14.7 mL, 23.5 mmol) was added during 2 minutes.
The solution was stirred
for 5 minutes at -78 °C and ZnCl2 in THF (60 mL, 60 mmol) was added.
After stirring at -78 °C
for 1 h reaction with 1 (8.30 g, 16.9 mmol) was performed following method B.
Flash
chromatography (EtOAc/heptane/NEt3 30/70/4 ~ 70/30/4) afforded 6.77 g which
was
recrystallised from toluene/heptane 1:1 to give 4.73 g (59%): Mp 189-191
°C (toluene/heptane
1:1); 1H-NMR (CDC13) 1.49 (s, 9H), 7.69 (q, 2H), 2.10 (d, 2H), 2.89 (t, 2H),
3.05 (t, 1H), 3.77 (s,
3H), 4.25 (s, broad, 2H), 6.99 (s, 1H), 7.09 (s, 1H), 7.15 (s, 1H), 7.15-7.25
(m, 2H), 7.4-7.55 (m,
4H), 7.97 (s, 1H); Anal. (Cz$H31FN402): C, H, N.
4-(1-(4-Fluor ophenyl)-5-(1-methyl-1,2,3-triazol-5-yl)-1H indol-3-yl)-
piperidine-1-carboxylic
acid tent-butyl ester (3c). 1-Methyl-1,2,3-triazole (1,71 g, 20,6 mmol) was
dissolved in THF (200
mL) and cooled to -78 °C. n-Butyllithium (15.4 mL, 24.7 mmol) was added
during 2 minutes and
the solution was stirred for further 5 minutes before ZnClz in THF (61.8 mL,
61.8 mmol) was
added. After 30 minutes at -78 °C reaction with 1 (9.75 g, 20.6 mmol)
was performed following
method B. Purification by flash chromatography (EtOAc/heptane/EtOH 30/70/2)
gave 6.8 g
which was recrystallised from toluene/heptane 1:2 to yield 4.3 g (44%) of 3c:
Mp 137-141 °C
(toluene/heptane 1:2); 1H-NMR (CDCl3) 1.49 (s, 9H), 1.70 (q, 2H), 22.08 (d,
2H), 2.93 (t, 2H),
3.05 (t, 1H), 4.09 (s, 3H), 4.30 (s, broad, 2H), 7.15 (s, 1H), 7.20-7.30 (m,
3H), 7.40-7.50 (m, 2H),
7.45 (d, 1H), 7.69 (s, 1H), 7.74 (s, 1H); Anal. (C~~H3oFN50z): C, H, N.
4-(1-(4-Fluorophenyl)-5-(pyridin-3-yl)-1H indol-3-yl)-piperidine-1-carboxylic
acid tent-butyl
ester (3d). 3-Bromopyridine was lithiated as described by Furneaux et al.
Tetr°ahedr~orZ 1997, 53,
2915. THF (200 mL) was cooled to -100 °C (Et20/liquid NZ) and n-
butyllithium (19 mL, 30.4
mmol) was added. 3-Bromopyridine (4.00 g, 25.3 mmol) was added during 2
minutes. After 20
minutes at -100 °C ZnCl2 in THF (60 mL, 60 mmol) was added. Hereby a
white precipitate was
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formed. The temperature was shortly raised to -30 °C to dissolve the
precipitate and thereafter
stirred at -78 °C for 30 minutes. Reaction with 1 (10 g, 21.1 mmol) was
performed following
method B. Flash chromatography (EtOAc/heptane/NEt3 30/70/5) afforded 8.3 g
which was
recrystallised from EtOAc/heptane l:l to yield 6.0 g (60%) of 3d: Mp 160-162
°C
5 (EtOAc/heptane l:l); MS m/z: 472 (MH+, 3%), 416 (100%), 372 (37 %); 'H-NMR
(CDC13) 1.49
(s, 9H), 1.74 (q, 2H), 2.14 (d, 2H), 2.93 (t, 2H), 3.10 (t, 1H), 4.29 (s,
broad, 2H), 7.11 (s, 1H),
7.20-7.30 (m, 2H), 7.36 (dd, 1H), 7.40-7.50 (m, 3H), 7.55 (d, 1H), 7.85 (d,
1H), 7.95 (dt, 1H),
8.57 (dd, 1H), 8.91 (d, 1H); Anal. (C29H3oFN3O2): C, H, N.
10 Preparation of Compounds of the Invention
Deprotection and alkylation of 5-heteroaryl substituted 4-(1-(4-fluorophenyl)-
1H indol-3-
yl)-piperidine-1-carboxylic acid tent-butyl esters (2a-h, 3a-d) Method C
The 5-heteroaryl substituted 4-(1-(4-fluorophenyl)-1H indol-3-yl)-piperidine-1-
carboxylic acid
tent-butyl ester (2a-h, 3a-d) (6.3 mmol) was dissolved in THF (20 mL) and
HCl/MeOH (30 mL)
15 was added. The solution was stirred for 4 h, and the solvents were removed
in vacuo. 4-Methyl-2
pentanone (30 mL) was added and the solvent was again removed in vacuo. KZCO3
(5 g, 36
mmol), KI (0.5 g, 3 mmol), 4-methyl-2-pentanone (100 mL) and an alkyl halide
(9.5 mmol if
nothing else stated) were added and the solution was stirred under reflux for
8 h. The amounts of
reagents and solvents were scaled according to the actual amount of 5-
heteroaryl substituted 4-(1-
20 (4-fluorophenyl)-1H indol-3-yl)-piperidine-1-carboxylic acid test-butyl
ester used.
Work-up procedure 1: Hz0 (50 mL) was added to the warm mixture and the phases
were
separated. The aqueous phase was extracted with CH2C12 (100 mL). The combined
organic phases
were washed with HZO and with saturated aqueous CaCl2, dried (MgSOø) and the
solvents were
removed in vacuo. The resulting compound was purified by flash chromatography.
Work-up procedure 2: HzO (50 mL) was added to the warm mixture and the phases
were
separated. The aqueous phase was extracted with CHzCl2 (100 mL). Kieselgel was
added to the
combined organic phases and the solvents were removed in vacuo. The resulting
compound
adsorbed to lcieselgel was purified using Biotage flash 40 equipped with a
FZIM-0035 solid
injection module.
3- f 4-[1-(4-Fluoro-phenyl)-5-(1-methyl-1H 1,2,4-triazol-3-yl)-1H indol-3-yl]-
piperidin-1-yl}-
propionitrile~oxalate (4a). Reaction of 2c (1.2 g, 2.5 mmol) with 3-bromo-
propionitrile (l.lg, 8.2
mmol) was performed according to method C followed by work-up procedure 2. The
crude
product was purified by flash chromatography (EtOAc/heptane 50/50 -~
EtOAc/MeOH 90/10)
and precipitated with oxalic acid from EtOH to give 0.45 g (34 %) of the
oxalate of 4a: Mp. 216-
217 °C (EtOH); 'H-NMR (DMSO-d~) 1.95 (qd, 2H), 2.12 (d, 2H), 2.76 (t,
2H), 2.93 (t, 2H), 3.02-
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3.15 (m, 3H), 3.32 (d, 2H), 3.93 (s, 3H), 7.40-7.47 (m, 2H), 7.48 (s, 1H),
7.54 (d, 1H), 7.60-7.68
(m, 2H), 7.89 (d, 1H), 8.32 (s, 1H), 8.48 (s, 1H); MS m/z: 429 (100%, MH+),
388 (12%), 241
(3%); Anal. (CzsHzsFN~~CzHzOa~0.55 % Hz0): C, H, N.
The following derivative was prepared accordingly from 2f:
3- f 4-[1-(4-Fluoro-phenyl)-5-(pyrimidin-2-yl)-1H indol-3-yl]-piperidin-1-yl~-
propionitrile
(4b). The free base was recrystallised from EtOAc/CHzClz 90/10 to give 0.96 g
(63%) of 4b: Mp
182-183 °C (EtOAc/CHZCIz); 'H-NMR (DMSO-d6) 1.81 (q, 2H), 2.03 (d, 2H),
2.25 (t, 2H), 2.60-
2.70 (s, broad, 2H), 2.70-2.80 (m, 2H), 2.83-2.95 (m, 1H), 3.02 (d, 2H), 3.33
(s, 3H), 7.38 (t, 1H),
7.41-7.48 (m, 2H), 7.52 (s, 1H), 7.58 (d, 1H), 7.62-7.70 (m, 2H) 8.31 (d, 1H),
8.77 (s, 1H), 8.89
(d, 2H); MS m/z: 426 (100%, MH+), 384 (95%), 373 (95%); Anal. (Cz~Hz4FNs): C,
H, N.
1-(4-Fluoro-phenyl)-3-{1-[2-(4-methoxyphenyl)-ethyl]-piperidin-4-yl}-5-(1-
methyl-1H 1,2,4-
triazol-3-yl)-1H indole (4c). Reaction of 2c (1.0 g, 2.10 rnmol) with 1-(2-
chloroethyl)-4-
methoxybenzene (0.75 g, 4.4 mmol) was performed according to method C followed
by worlc-up
procedure 2. Flash chromatography (EtOAc/heptane 70/30 -~ EtOAc/MeOH/NEt3
90/10/2) gave
an oil (0.20 g) which was crystallised from EtOAc to give 0.13 g (12%) of
compound 4c: Mp
152-153 °C (EtOAc); 'H-NMR (DMSO-d~) 1.80 (qd, 2H), 2.00 (d, 2H), 2.18
(t, 2H), 2.54 (t, 2H),
2.73 (t, 2H), 2.80-2.90 (m, 1H), 3.07 (d, 2H), 3.72 (s, 3H), 3.93 (s, 3H),
6.84 (d, 2H), 7.16 (d, 2H),
7.35-7.42 (m, 2H), 7.47 (s, 1H), 7.53 (d, 1H), 7.60-7.70 (m, 2H), 7.86 (d,
1H), 8.30 (s, 1H), 8.49
(s, 1H); MS m/z: 510 (100%, MH+); Anal. (C31H3zFN50): C, H, N.
1-(4-Fluoro-phenyl)-5-(1-methyl-1H 1,2,4-triazol-3-yl)-3-[1-(2-phenylethyl)-
piperidin-4-yl]-
1H-indole (4d). Reaction of 2c (1.0 g, 2.10 mmol) with (2-bromo-ethyl)-benzene
(0.81 g, 4.4
mmol) was performed according to method C followed by work-up procedure 2.
flash
chromatography (EtOAc/heptane 70/30 -~ EtOAc/MeOH/NEt3 90/10/2) gave 0.80 g
which was
recrystallised from EtOAc/heptane 1/3 to give 0.30 g (30%) of 4d: Mp 244-245
°C
(EtOAc/heptane 1/3); 'H-NMR (DMSO-d~) 1.90 (s, broad, 4H), 2.10 (s, broad,
2H), 2.51 (t, 2H),
2.90 (s, broad, 4H), 3.05 (s, broad, 1H), 3.93 (s, 3H), 7.23 (t, 1H), 7.30 (t,
2H), 7.31 (d, 2H), 7.40-
7.48 (m, 2H), 7.52 (s, broad, 1H), 7.54 (d, 1H), 7.62-6.68 (m, 2H), 7.90 (d,
1H), 8.35 (s, 1H), 8.50
(s, 1H); MS m/z: 480 (100%, MH+); Anal. (C3°H3oFNs): C, H, N.
3-~4-[1-(4-Fluoro-phenyl)-5-(1-methyl-1H [1,2,4]triazol-3-yl)-1H indol-3-yl]-
piperidin-1-yl~-
propan-1-of (4e). Reaction of 2c (1.0 g, 2.10 mmol) with 3-bromo-1-propanol
(0,34 g, 2.40
mmol) was performed according to method C followed by workup procedure 2.
Flash
chromatography EtOAc/MeOH/NEt3 (100/0/2 ~ 75125/2) gave 500 mg of crude
product which
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22
was crystallised from EtOAc/heptane (70130) to give 250 mg of the title
compound. Mp. 138-139
°C (EtOAc/heptane); 1H-NMR (DMSO-d6) 1.65 (q, 2H), 1.80 (qd, 2H), 2.02
(d, 2H), 2.20 (t, 2H),
2.49 (d, 2H), 2.90 (t, 1H), 3.05 (d, 2H), 3.32 (s, broad, 1H), 3.49 (t, 2H),
3.92 (s, 3H), 7.39-7.43
(m, 2H), 7.45 (s, 1H), 7.52 (d, 1H), 7.49-7.55 (m, 2H), 7.88 (d, 1H), 8.30 (s,
1H), 8.50 (s, 1H).
Preparation of further Compounds of the Invention
Each of the intermediates 2a-h and 3a-d (1 mmol) were dissolved in THF (30 mL)
and reacted
overnight with a saturated solution of HCl in MeOH (15 mL) at room
temperature. The solvents
were removed in vacuo, Hz0 was added and pH adjusted to 10 by addition of
aqueous ammonium
hydroxide (25%). The aqueous phase was extracted with CHZCIz and the combined
organic phases
were dried over MgS04. After evaporation of the solvent, stoclc solutions of
the piperidinyl
derivatives were prepared by dissolving to 0.2 M by addition of DMSO. Stock
solutions of alkyl
halides were prepared by dissolving the halides in as little DMF as possible.
Solutions were
subsequently diluted to 0.2 M by addition of CH3CN. Bloclcs (Multisyntech
Microchem Blocks
(MultiSynTech GmbH. 2002) containing 96 1.2 mL reactors fitted with frits were
loaded with
KZC03 (40 mg, 0.3 mmol) and KI (10 mg, 0.06 mmol). From the stocle solutions
the piperidinyl
derivatives (0.15 mL, 0.03 mmol), the alkyl halide (0.225 mL, 0.045 mmol) and
CH3CN (0.3 mL)
were added and the reactors were closed and rotated in an oven at 70 °C
for 14 h. After cooling to
50 °C isocyanate resin (30 mg, 1 mmol/g) was added and the reactors
were again closed and
rotated at 50 °C for 2 h. After cooling to room temperature, solids
were filtered off and washed
with CH3CN (2 x 0.3 mL). The combined organic phases were purified using SCX
ion exchange
chromatography as follows: Columns (Varian Bond Elut-SCX 500 mg/3 mL) were
conditioned
with acetic acid in methanol (10%, 3 mL). The combined organic phases from the
sample was
added and washed with MeOH (3 mL) and CH3CN (3 mL). Finally, the sample was
eluted with
ammonia in MeOH (3 mL, 4 M). Between each step a slight air pressure was
applied. The
solvents were evaporated in vacuo and the solutions diluted to 2 mM in DMSO.
The identity and
purity of the compounds was determined by HPLC/MS analysis with W and ELSD
detection.
Compounds with a purity of 70% or above were submitted for biological
evaluation. The
remaining compounds were purified by preparative LC/MS (Zeng, et al., Comb
Chern High
Tlz.j~oughput Screen JID - 910948, 1998,1, 101).
The following allcylating agents were used for the preparation of the examples
listed below: 3-
bromo-propionitrile, 3-(2-chloroethyl)-oxazolidin-2-one, 3-(2-chloroethyl)-1H-
quinazoline-2,4-
dione, 3-(2-chloroethyl)-1-methylpyrolidin-2-one, 1-(2-Chloro-ethyl)-4-methoxy-
benzene, 1-(2-
Bromo-ethoxy)-2-methoxy-ethane, 3-Bromo-N (2,5-dimethoxy-phenyl)-propionamide,
3-Bromo-
N (2,5-dimethoxy-phenyl)-propionamide, 5-(3-Bromo-propoxy)-2,3-dihydro-
benzo[1,4]dioxine,
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1-(2-Chloro-ethoxy)-propane, 2-(3-Bromo-propoxy)-benzonitrile, 1-(3-Bromo-
propoxy)-4-fluoro-
2-methoxy-benzene, 3-(2-Bromo-ethyl)-benzofuran, 3-(2-Bromo-ethyl)-IH indole,
3-(3-Bromo-
propyl)-IH indole
The following examples were prepared according to the general procedure d):
3- f 4-[1-(4-Fluoro-phenyl)-5-(2-methyl-2H-pyrazol-3-yl)-1H indol-3-yl]-
piperidin-1-yl}-
propionitrile (Saa): Rf= 2.02; Purity UV/ELSD: 97.2/99.8
3-[1-(2-Benzofuran-3-yl-ethyl)-piperidin-4-yl]-1-(4-fluoro-phenyl)-5-(2-methyl-
2H pyrazol-
3-yl)-1H indole (Sab): Rf= 2.47; Purity LTV/ELSD: 78.9/96.7
3-[1-(2-1H indol-3-yl-ethyl)-piperidin-4-yl]-1-(4-fluoro-phenyl)-5-(2-methyl-
2H pyrazol-3-
yl)-1H indole (Sac): Rf= 2.38; Purity ITV/ELSD: 99.0/100.0
3-}4-[1-(4-Fluoro-phenyl)-5-pyridin-3-yl-1H indol-3-yl]-piperidin-1-yl}-
propionitrile (5ad):
Rf= 1.59; Purity UV/ELSD: 91.5/100.0
1-(4-Fluoro-phenyl)-3-{1-[2-(4-methoxy-phenyl)-ethyl]-piperidin-4-yl}-5-
pyridin-3-yl-1H
indole (Sae): Rf= 1.92; Purity LTV/ELSD: 94.7/100.0
3-[1-(2-Benzofuran-3-yl-ethyl)-piperidin-4-yl]-1-(4-fluoro-phenyl)-5-pyridin-3-
yl-1H indole
(5af): Rf= 2.04; Purity LTV/ELSD: 95.0/99.1
3-[1-(2-1H indol-3-yl-ethyl)-piperidin-4-yl]-1-(4-fluoro-phenyl)-5-pyridin-3-
yl-1H indole
(5ag): Rf= 1.95; Purity W/ELSD: 90.1/99.0
3-}1-[3-(2,3-Dihydro-1,4-benzodioxin-5-yloxy)-propyl]-piperidin-4-yl}-1-(4-
fluoro-phenyl)-5-
(3-methyl-3H 1,2,3-triazol-4-yl)-1H indole (Sah): Rf= 2.37; Purity UV/ELSD:
90.0/99.0
3-[1-(2-Benzofuran-3-yl-ethyl)-piperidin-4-yl]-1-(4-fluoro-phenyl)-5-(3-methyl-
3H 1,2,3-
triazol-4-yl)-1H indole (5ai): Rf= 2.40; Purity UV/ELSD: 70.0/95.8
3-[1-(2-Benzofuran-3-yl-ethyl)-piperidin-4-yl]-1-(4-fluoro-phenyl)-5-(1-methyl-
1H pyrazol-
4-yl)-1H indole (Saj): Rf= 2.47; Purity UV/ELSD: 70.0/95.5
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3-[1-(2-Benzofuran-3-yl-ethyl)-piperidin-4-yl]-1-(4-fluoro-phenyl)-5-pyrimidin-
2-yl-1H
indole (Sak): Rf= 2.55; Purity LTV/ELSD: 70.0/91.3
3-{4-[1-(4-Fluoro-phenyl)-5-(1-methyl-1H imidazol-2-yl)-1H indol-3-yl]-
piperidin-1-yl}-
propionitrile (Sal): Rf= 1.46; Purity LTV/ELSD: 90.0/100.0
3-{4-[1-(4-Fluoro-phenyl)-5-(2-methyl-2H 1,2,4-triazol-3-yl)-1H indol-3-yl]-
piperidin-1-yl}-
propionitrile (Sam): Rf= 1.76; Purity UV/ELSD: 95.0/100.0
3-}4-[1-(4-Fluoro-phenyl)-5-(1-methyl-1H 1,2,4-triazol-3-yl)-1H indol-3-yl]-
piperidin-1-yl}-
propionitrile (San): Rf= 1.85; PurityLlV/ELSD: 90.0/100.0
1-(4-Fluoro-phenyl)-3- f 1-[2-(4-methoxy-phenyl)-ethyl]-piperidin-4-yl}-5-(1-
methyl-1H
imidazol-2-yl)-1H indole (Sao): Rf= 1.78; Purity UV/ELSD: 79.2/97.2
1-(4-Fluoro-phenyl)-3-}1-[2-(4-methoxy-phenyl)-ethyl]-piperidin-4-yl}-5-(1-
methyl-1H 1,2,4-
triazol-3-yl)-1H indole (Sap): Rf= 2.28; Purity LTV/ELSD: 70.0/97.5
1-(4-Fluoro-phenyl)-3-{1-[2-(2-methoxy-ethoxy)-ethyl]-piperidin-4-yl}-5-(2-
methyl-2H 1,2,4-
triazol-3-yl)-1H indole (5ac~: Rf= 1.83; Purity W/ELSD: 78.0/99.2
1-(4-Fluoro-phenyl)-3- f 1-[2-(2-methoxy-ethoxy)-ethyl]-piperidin-4-yl}-5-(1-
methyl-1H 1,2,4-
triazol-3-yl)-1H indole (Sar): Rf= 1.96; Purity LTV/ELSD: 90.0/98.3
3-}1-[2-(2,3-Dihydro-1,4-benzodioxin-5-yloxy)-ethyl]-piperidin-4-yl}-1-(4-
fluoro-phenyl)-5-
(2-methyl-2H 1,2,4-triazol-3-yl)-1H indole (5as): Rf= 2.16; Purity UV/ELSD:
90.0/100.0
3- f 1-[3-(2,3-Dihydro-1,4-benzodioxin-5-yloxy)-propyl]-piperidin-4-yl}-1-(4-
fluoro-phenyl)-5-
(2-methyl-2H 1,2,4-triazol-3-yl)-1H indole (5at): Rf= 2.18; Purity UV/ELSD:
80.0/98.3
2-(2- f 4-[1-(4-Fluoro-phenyl)-5-(2-methyl-2H 1,2,4-triazol-3-yl)-1H indol-3-
yl]-piperidin-1-
yl}-ethoxy)-ethanol (5au): Rf= 1.73; Purity W/ELSD: 84.8/99.9
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2-(2- f 4-[1-(4-Fluoro-phenyl)-5-(1-methyl-1H 1,2,4-triazol-3-yl)-1H indol-3-
yl]-piperidin-1-
yl}-ethoxy)-ethanol (5av): Rf= 1.81; Purity UV/ELSD: 84.6/100.0
2-(3-{4-[1-(4-Fluoro-phenyl)-5-(1-methyl-1H 1,2,4-triazol-3-yl)-1H indol-3-yl]-
piperidin-1-
yl}-propoxy)-benzonitrile (5aw): Rf= 2.42; Purity UV/ELSD: 90.0/99.9
3-}1-[3-(4-Fluoro-2-methoxy-phenoxy)-propyl]-piperidin-4-yl}-1-(4-fluoro-
phenyl)-5-(2-
methyl-2H 1,2,4-triazol-3-yl)-1H indole (5ax): Rf= 2.30; Purity UV/ELSD:
71.0/98.7
10 1-(4-Fluoro-phenyl)-3-}1-[2-(4-methoxy-phenyl)-ethyl]-piperidin-4-yl}-5-(3-
methyl-3H 1,2,3-
triazol-4-yl)-1H indole (5ay): Rf= 2.33; Purity UV/ELSD: 72.9/98.2
3- f 1-(3-(4-Fluoro-2-methoxy-phenoxy)-propyl]-piperidin-4-yl}-1-(4-fluoro-
phenyl)-5-(3-
methyl-3H-1,2,3-triazol-4-yl)-1H indole (5az): Rf= 2.41; Purity W/ELSD:
70.8/97.3
3-}4-[1-(4-Fluoro-phenyl)-5-(3-methyl-3H 1,2,3-triazol-4-yl)-1H indol-3-yl]-
piperidin-1-yl}-
propionitrile (5ba): Rf= 1.96; Purity UV/ELSD: 85.1/99.2
3-}4-[1-(4-Fluoro-phenyl)-5-pyrimidin-2-yl-1H indol-3-yl]-piperidin-1-yl}-
propionitrile
(5bb): Rf= 2.10; Purity ITV/ELSD: 85.8/99.4
1-(4-Fluoro-phenyl)-3-}1-(2-(4-methoxy-phenyl)-ethyl]-piperidin-4-yl}-5-
pyrimidin-2-yl-1H
indole (5bc): Rf= 2.49; Purity W/ELSD: 96.2/99.5
N-(2,5-Dimethoxy-phenyl)-3-{4-[1-(4-fluoro-phenyl)-5-(2-methyl-2H-1,2,4-
triazol-3-yl)-1H
indol-3-yl]-piperidin-1-yl}-propionamide (5bd): Rf= 2.12; Purity LTV/ELSD:
93.3/99.6
3- f 1-[3-(4-Fluoro-2-methoxy-phenoxy)-propyl]-piperidin-4-yl}-1-(4-fluoro-
phenyl)-5-(1-
methyl-1H 1,2,4-triazol-3-yl)-1H indole (5be): Rf= 2.42; Purity UV/ELSD:
90.0/99.4
3-[1-(2-Benzofuran-3-yl-ethyl)-piperidin-4-yl]-1-(4-fluoro-phenyl)-5-(2-methyl-
2H 1,2,4-
triazol-3-yl)-1H indole (5bf7: Rf= 2.29; Purity LTV/ELSD: 92.9/99.5
3-[1-(2-1H indol-3-yl-ethyl)-piperidin-4-yl]-1-(4-fluoro-phenyl)-5-(3-methyl-
3H 1,2,3-triazol-
4-yl)-1H indole (5bg): Rf= 2.37; Purity LTV/ELSD: 99.0/99.1
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3-[1-(2-1H indol-3-yl-ethyl)-piperidin-4-yl]-1-(4-fluoro-phenyl)-5-(2-methyl-
2H 1,2,4-triazol-
3-yl)-1H-indole (Sbh): Rf= 2.20; Purity UV/ELSD: 80.3198.3
3-[1-(3-1H indol-3-yl-propyl)-piperidin-4-yl]-1-(4-fluoro-phenyl)-5-(3-methyl-
3H 1,2,3-
triazol-4-yl)-1H indole (5bi): Rf= 2.39; Purity UV/ELSD: 89.9/98.9
3-[1-(3-1H indol-3-yl-propyl)-piperidin-4-yl]-1-(4-fluoro-phenyl)-5-(1-methyl-
1H pyrazol-4-
yl)-1H indole (5bj): Rf= 2.49; Purity UV/ELSD: 87.9198.7
Pharmacological Testing
The compounds of the invention have been tested using well-recognised and
reliable methods.
The tests are as follows:
INHHIBITION OF 3H-PRAZOSIN BINDING TO a,l-ADRENOCEPTORS IN RAT
BRAIN IN VITRO
By this method the inhibition by drugs of the binding of 3H-prazosin (0.25 nM)
to a,l-
adr enoceptors in membranes from rat brain is determined i~a vitro. Method and
results in Hyttel
8~ Larsen, J. Neurochem. 1985, 44, 1615 - 1622: Skarsfeldt & Hyttel, Eur. J.
Pharmacol.1986,
125, 323 - 340; Hyttel & Larsen, In: Research advances in New
Psychopharmacological
Treatments for Alcoholism (eds. Naranjo & Sellers). Elsevier 1985, pp. 107 -
119.
The compounds of the invention showed high affinity for the al-adrenoceptor.
Most of the
compounds having an ICSO value below 30 nM in this test.
INHIBITION OF 3H-PRAZOSIN BINDING TO CLONED ala, alb, and ale, -
ADRENOCEPTORS
Cell lines: Cell lines expressing the bovine aia, rat ald receptors and the
hamster a,lb receptor
were used in the assays.
In vitro binding assays: Briefly, the cells were homogenised in ice-cold 50 mM
Tris, pH 7.7,
using an Ultra-Turrax and the homogenates either kept on ice or stored at -80
°C until used. The
assay buffer subsequently used contained 50 mM Tris, pH 7.7. Non-specific
displacer was WB-
4101 (1 ~.M) for the ocla, a,Ib, and ocld assays. All assays were incubated at
25 °C for 20 minutes.
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All assays were terminated by vacuum filtration on GF/B filters and counted in
a scintillation
counter (Wallac Trilux). The radioligand used was [3H]prazosin.
It was found that some of the compounds of the invention have stronger
affinity to the a,la
adrenoceptor than the alv-adrenoceptor and the aId-adrenoceptor.
Further, many of the compounds of the invention have much stronger affinity
for the ocl-
adrenoceptor compared to the DZ and the 5-HTZ receptor.
Pharmaceutical compositions
The pharmaceutical compositions of this invention or those which are
manufactured in accordance
with this invention may be administered by any suitable route for example
orally in the form of
tablets, capsules, powders, syrups, etc., or parenterally in the form of
solutions for injection. For
preparing such compositions, methods well lrnown in the art may be used, and
any
pharmaceutically acceptable carriers, diluents, excipients or other additives
normally used in the
art may be used.
Conveniently, the compounds of the invention are administered in unit dosage
form containing
said compounds in an amount of about 0.01 to 100 mg.
The total daily dose is usually in the range of about 0.05 - 500 mg, and most
preferably about 0.1
to 50 mg of the active compound of the invention.
Formulation Examples
The pharmaceutical formulations of the invention may be prepared by
conventional methods in
the art.
Tablets may for example be prepared by mixing the active ingredient with
ordinary adjuvants,
carriers and/or diluents and subsequently compressing the mixture in a
conventional tabletting
machine. Examples of adjuvants, Garners or diluents comprise: corn starch,
potato starch, talcum,
magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants
or additives usually
used for such purposes such as colourings, flavourings, preservatives etc. may
be used provided
that they are compatible with the active ingredients.
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Solutions for injections may be prepared by dissolving the active ingredient
and possible additives
in a part of the solvent for injection, preferably sterile water, adjusting
the solution to desired
volume, sterilisation of the solution and filling in suitable ampules or
vials. Any suitable additive
conventionally used in the art may be added, such as tonicity agents,
preservatives, antioxidants,
etc.
