U.S. patent application number 11/750428 was filed with the patent office on 2007-09-27 for piperidinyl indole and tetrohydropyridinyl indole derivatives and methods of their use.
This patent application is currently assigned to WYETH. Invention is credited to Yansong Gu, Osvaldo Dos Santos, Aranapakam Mudumbai Venkatesan.
Application Number | 20070225319 11/750428 |
Document ID | / |
Family ID | 33555227 |
Filed Date | 2007-09-27 |
United States Patent
Application |
20070225319 |
Kind Code |
A1 |
Venkatesan; Aranapakam Mudumbai ;
et al. |
September 27, 2007 |
PIPERIDINYL INDOLE AND TETROHYDROPYRIDINYL INDOLE DERIVATIVES AND
METHODS OF THEIR USE
Abstract
3-Piperidin-4-yl-1H-indole and
3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole derivatives are
disclosed. Methods of using the derivatives and compositions
containing the derivatives in the prevention and/or treatment of
serotonin disorders, such as depression and anxiety, are also
disclosed. Additionally, processes for the preparation of
3-piperidin-4-yl-1H-indole and
3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole derivatives are
disclosed.
Inventors: |
Venkatesan; Aranapakam
Mudumbai; (Rego Park, NY) ; Santos; Osvaldo Dos;
(Kew Garden, NY) ; Gu; Yansong; (Pearl River,
NY) |
Correspondence
Address: |
WOODCOCK WASHBURN LLP/WYETH
CIRA CENTRE, 12TH FLOOR
2929 ARCH STREET
PHILADELPHIA
PA
19104-2891
US
|
Assignee: |
WYETH
Madison
NJ
|
Family ID: |
33555227 |
Appl. No.: |
11/750428 |
Filed: |
May 18, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10835998 |
Apr 30, 2004 |
7235569 |
|
|
11750428 |
May 18, 2007 |
|
|
|
60467345 |
May 2, 2003 |
|
|
|
Current U.S.
Class: |
514/300 ;
514/323; 546/121; 546/201 |
Current CPC
Class: |
C07D 405/14 20130101;
C07D 409/14 20130101; C07D 471/04 20130101 |
Class at
Publication: |
514/300 ;
514/323; 546/121; 546/201 |
International
Class: |
A61K 31/437 20060101
A61K031/437; A61K 31/445 20060101 A61K031/445; C07D 401/02 20060101
C07D401/02; C07D 487/02 20060101 C07D487/02 |
Claims
1. The compound of formula I: ##STR8## or a N-oxide, stereoisomer
or pharmaceutically acceptable salt thereof, wherein: A is a
heterocycle having the formula: ##STR9## X is O or S; R.sub.1 is
hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, fluoro, alkoxy,
heteroaryloxy, cycloalkoxy, hydroxy, nitrile, carboxy,
alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl,
fluorinated alkyl, aryl, aryloxy, alkylaryl, heteroaryl,
alkylheteroaryl, NH.sub.2, NHR.sub.11, NR.sub.11R.sub.11,
--O-alkyl-NR.sub.11R.sub.11, or -aryl-O-alkyl-NR.sub.11R.sub.11;
R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and
R.sub.9 are, independently, hydrogen, alkyl, cycloalkyl, alkenyl,
alkynyl, halo, cyano, alkoxy, heteroaryloxy, cycloalkoxy, hydroxy,
nitro, nitrile, NH.sub.2, NHR.sub.11, NR.sub.11R.sub.11, CHO,
alkylcarbonyl, arylcarbonyl, carboxy, alkoxycarbonyl,
alkoxycarbonylalkyl, alkylcarbonyloxy aminocarbonyl,
alkylaminocarbonyl, fluorinated alkyl, aryl, aryloxy, alkylaryl,
heteroaryl, alkylheteroaryl, --O-alkyl-NR.sub.11R.sub.11, or
-aryl-O-alkyl-NR.sub.11R.sub.11; R.sub.10 is hydrogen, alkyl,
cycloalkyl, alkenyl of 3 to 6 carbon atoms (with the proviso that
the carbon bearing the double bond should not be directly connected
to N), alkynyl of 3 to 6 carbon atoms (with the proviso that the
carbon bearing the triple bond should not be directly connected to
N), alkoxycarbonyl, alkylcarbonyl, aminocarbonyl,
alkylaminocarbonyl, fluorinated alkyl, aryl, alkylaryl, heteroaryl,
alkylheteroaryl, SO.sub.2-aryl, SO.sub.2-heteroaryl or
SO.sub.2-alkyl; R.sub.2 and R.sub.3, R.sub.3 and R.sub.4, or
R.sub.4 and R.sub.5 can be attached together to form a cycloalkyl
or optionally substituted aromatic or hetero aromatic ring
containing one or two hetero atoms such as N, O, S, S.dbd.O or
SO.sub.2; R.sub.11 is hydrogen, optionally substituted alkyl,
optionally substituted alkenyl (with the proviso that the carbon
bearing the double bond is not bonded directly to the heteroatoms
such as O, S or N--R.sub.11), optionally substituted alkynyl (with
the proviso that the carbon bearing the triple bond is not bonded
directly to the heteroatoms such as O, S or N--R.sub.11),
optionally substituted aryl, optionally substituted alkylaryl,
heteroaryl optionally substituted with R.sub.2, optionally
substituted alkylheteroaryl, SO.sub.2-aryl, SO.sub.2-heteroaryl or
SO.sub.2-alkyl; with the proviso that if two R.sub.11 groups are
attached to nitrogen, then they can together form a 4 to 7 membered
cyclic system having 0 to 2 hetero atoms selected from O,
S.dbd.(O).sub.r, r is an integer from 0 to 2, and NR.sub.11; and n
is an integer from 1 to 6.
2. A compound according to claim 1, wherein said R.sub.1 is
hydrogen or alkyl.
3. A compound according to claim 1, wherein R.sub.2, R.sub.3,
R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are
independently hydrogen, halo, alkyl, alkoxy, alkenyl,
NR.sub.11R.sub.11, or cyano.
4. A compound according to claim 1, wherein said R.sub.10 is
hydrogen, alkyl, aryl or heteroaryl.
5. A compound according to claim 1, wherein said R.sub.11 is
hydrogen, alkyl, aryl or heteroaryl.
6. A compound according to claim 1, wherein said compound is:
3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H--
indole;
3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridi-
nyl}-1-(2-propenyl)-1H-indole;
3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-m-
ethyl-1H-indole;
3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyrid-
inyl}-1H-indole;
3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyrid-
inyl}-1-(2-propenyl)-1H-indole;
3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyrid-
inyl}-1-methyl-1H-indole; or
3-{1-(2-naphtho[1,2-b]furan-3-yl-ethyl)-piperidin-4-yl]-1H-indole.
7. A composition, comprising the compound of claim 1 and one or
more pharmaceutically acceptable carriers.
8. A method of preventing and/or treating a patient suspected of
suffering from a serotonin-related disorder, comprising the step of
administering to the patient a therapeutically effective amount a
compound of claim 1.
9. A method according to claim 8, wherein said serotonin-related
disorder is depression, anxiety, cognitive deficits, schizophrenia,
prostate cancer, or nicotine withdrawal.
10. A method according to claim 8, wherein said serotonin-related
disorder is depression.
11. A method according to claim 8, wherein said serotonin-related
disorder is anxiety.
12. A method of antagonizing 5-HT.sub.1A receptors in a patient in
need thereof, comprising the step of administering to the patient a
therapeutically effective amount of a compound of claim 1.
13. A method of inhibiting the reuptake of serotonin in a patient
in need thereof, comprising the step of administering to the
patient a therapeutically effective amount of a compound of claim
1.
14. A method of antagonizing 5-HT.sub.1A receptors and inhibiting
the reuptake of serotonin in a patient in need thereof, comprising
the step of: administering to the patient a therapeutically
effective amount of a compound of claim 1.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a divisional of Ser. No.
10/835,998, filed on Apr. 30, 2004, which claims benefit of
Provisional Application Ser. No. 60/467,345, filed May 2, 2003, the
disclosures of which is hereby incorporated by reference in their
entireties.
FIELD OF THE INVENTION
[0002] The present invention relates to 3-piperidin-4-yl-1H-indole
and 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole derivatives,
processes for preparing such derivatives, and the use of such
derivatives to prevent and/or treat a variety of psychological
disorders. Preferred compounds of this invention display activity
both as 5-HT.sub.1A receptor antagonists and as serotonin uptake
inhibitors, and are useful, inter alia, in the prevention and/or
treatment of serotonin-related disorders.
BACKGROUND OF THE INVENTION
[0003] Major depressive disorder affects an estimated 340 million
people worldwide. Depression is the most frequently diagnosed
psychiatric disorder and, according to the World Health
Organization, is the fourth greatest public health problem. If left
untreated, the effects of depression can be devastating, robbing
people of the energy or motivation to perform everyday activities
and, in some cases, leading to suicide. Symptoms of the disorder
include feelings of sadness or emptiness, lack of interest or
pleasure in nearly all activities, and feelings of worthlessness or
inappropriate guilt. In addition to the personal costs of
depression, the disorder also has been estimated to result in more
than $40 billion in annual costs in the United States alone, due to
premature death, lost productivity, and absenteeism.
[0004] Pharmaceuticals that enhance serotonergic neurotransmission
have had success in preventing and/or treating many psychiatric
disorders, including depression and anxiety. The first generation
of non-selective serotonin-affecting drugs operated through a
variety of physiological functions that endowed them with several
side-effect liabilities. A class of more recently-developed drugs,
selective serotonin reuptake inhibitors (SSRIs), have had
significant success in preventing and/or treating depression and
related illnesses and have become among the most prescribed drugs
since the 1980s. Although they have a favorable side effect profile
compared to tricyclic antidepressants (TCAs), they have their own
particular set of side effects due to the non-selective stimulation
of serotonergic sites. They typically have a slow onset of action,
often taking several weeks to produce their full therapeutic
effect. Furthermore, they have generally been found to be effective
in less than two-thirds of patients.
[0005] SSRIs are believed to work by blocking the neuronal reuptake
of serotonin, increasing the concentration of serotonin in the
synaptic space, thus increasing the activation of postsynaptic
serotonin receptors. Although a single dose of an SSRI can inhibit
the neuronal serotonin transporter, and thus would be expected to
increase synaptic serotonin, long-term treatment is usually
required before clinical improvement is achieved. It has been
suggested that the delay in onset of antidepressant action of the
SSRIs is the result of an increase in serotonin levels in the
vicinity of the serotonergic cell bodies. This excess serotonin is
believed to activate somatodendritic autoreceptors, i.e.,
5-HT.sub.1A receptors, reduce cell firing activity, and, in turn,
decrease serotonin release in major forebrain areas. This negative
feedback limits the increment of synaptic serotonin that can be
induced by antidepressants acutely. Over time, the somatodendritic
autoreceptors become desensitized, allowing the full effect of the
SSRIs to be expressed in the forebrain. This time period has been
found to correspond to the latency for the onset of antidepressant
activity. [Perez, et al., The Lancet, 1997, 349:1594-1597].
[0006] In contrast to the SSRIs, a 5-HT.sub.1A agonist or partial
agonist acts directly on postsynaptic serotonin receptors to
increase serotonergic neurotransmission during the latency period
for the SSRI effect. Accordingly, the 5-HT.sub.1A partial agonist
buspirone and gepirone [Feiger, A., Psychopharmacol. Bull., 1996,
32: 659-665, Wilcox, C., Psychopharmacol. Bull., 1996, 32:
335-342], and the 5-HT.sub.1A agonist flesinoxan [Grof, P.,
International Clinical Psychopharmacology, 1993, 8: 167-172], have
shown efficacy in clinical trials for the treatment of depression.
Furthermore, such agents are believed to stimulate the
somatodendritic autoreceptors, thus hastening their desensitization
and decreasing the SSRI latency period. Indeed, buspirone
augmentation to standard SSRI therapy has been shown to produce
marked clinical improvement in patients initially unresponsive to
standard antidepressant therapy [Dimitriou, E., J. Clinical
Psychopharmacol., 1998, 18: 465-469].
[0007] There is still an unfulfilled need for a single agent with a
dual mechanism of antidepressant action, i.e., one that not only
inhibits or blocks serotonin reuptake (to increase levels of
serotonin in the synapse) but also antagonizes the 5-HT.sub.1A
receptors (to reduce the latency period). The present invention is
directed to these, as well as other important ends.
SUMMARY OF THE INVENTION
[0008] This invention provides novel 3-piperidin-4-yl-1H-indole and
3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole derivatives. In
preferred embodiments, the compounds of this invention inhibit or
block serotonin reuptake and/or are antagonists at the 5-HT.sub.1A
receptor. The compounds of the invention are thus useful, inter
alia, in the prevention and/or treatment of diseases affected by
disorders of the serotonin-affected neurological systems,
including, but not limited to, depression, anxiety, cognitive
deficits, such as those resulting form Alzheimer's disease and
other neurodegenerative disorders, schizophrenia, prostate cancer,
and nicotine withdrawal.
[0009] In one aspect, the present invention provides
3-piperidin-4-yl-1H-indole and
3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole derivatives having
formula I: ##STR1## or a prodrug, N-oxide, stereoisomer or a
pharmaceutically acceptable salt thereof, wherein:
[0010] A is a heterocycle selected having the following structure:
##STR2##
[0011] X is O or S;
[0012] R.sub.1 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,
fluoro, alkoxy, heteroaryloxy, cycloalkoxy, hydroxy, nitrile,
carboxy, alkoxycarbonyl, alkylcarbonyl, aminocarbonylalkyl,
alkylaminocarbonyl, fluorinated alkyl, aryl, aryloxy, alkylaryl,
heteroaryl, alkylheteroaryl, NH.sub.2, NHR.sub.11,
NR.sub.11R.sub.11, --O-alkyl-NR.sub.11R.sub.11, or
-aryl-O-alkyl-NR.sub.11R.sub.11;
[0013] R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7,
R.sub.8 and R.sub.9 are, independently, hydrogen, alkyl,
cycloalkyl, alkenyl, alkynyl, halo, cyano, alkoxy, heteroaryloxy,
cycloalkoxy, hydroxy, nitro, nitrile, NH.sub.2, NHR.sub.11,
NR.sub.11R.sub.11, CHO, alkylcarbonyl, arylcarbonyl, carboxy,
alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy
aminocarbonylalkyl, alkylaminocarbonyl, fluorinated alkyl, aryl,
aryloxy, alkylaryl, heteroaryl, alkylheteroaryl,
--O-alkyl-NR.sub.11R.sub.11, or
-aryl-O-alkyl-NR.sub.11R.sub.11;
[0014] R.sub.10 is hydrogen, alkyl, cycloalkyl, alkenyl of 3 to 6
carbon atoms (with the proviso that the carbon bearing the double
bond should not be directly connected to N), alkynyl of 3 to 6
carbon atoms (with the proviso that the carbon bearing the triple
bond should not be directly connected to N), alkoxycarbonyl,
alkylcarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, fluorinated
alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, SO.sub.2-aryl,
or SO.sub.2-alkyl;
[0015] R.sub.2 and R.sub.3, R.sub.3 and R.sub.4, or R.sub.4 and
R.sub.5 can each be attached together to form a cycloalkyl or
optionally substituted aromatic or hetero aromatic ring containing
one or two hetero atoms such as N, O, S, S(.dbd.O) or SO.sub.2;
[0016] R.sub.11 is hydrogen, optionally substituted alkyl,
optionally substituted alkenyl (with the proviso that the carbon
bearing the double bond is not bonded directly to the heteroatoms
such as O, S or N--R.sub.11), optionally substituted alkynyl (with
the proviso that the carbon bearing the triple bond is not bonded
directly to the heteroatoms such as O, S or N--R.sub.11),
optionally substituted aryl, optionally substituted alkylaryl,
heteroaryl optionally substituted with R.sub.2, optionally
substituted alkylheteroaryl, SO.sub.2-aryl, SO.sub.2-heteroaryl or
SO.sub.2-alkyl;
[0017] with the proviso that if two R.sub.11 groups are attached to
a nitrogen, then they can together form a 4- to 7-membered cyclic
system having 0 to 2 hetero atoms selected from O, S.dbd.(O).sub.r,
where r is an integer from 0 to 2, and NR.sub.11; and
[0018] n is an integer from 1 to 6.
[0019] In another aspect, the present invention is directed to
compositions comprising a compound of formula I and one or more
pharmaceutically acceptable carriers.
[0020] In another aspect, the present invention is directed to
compositions comprising a compound of formula I, one or more
pharmaceutically acceptable carriers, and an SSRI.
[0021] Also provided are methods for blocking or inhibiting the
neuronal reuptake of serotonin and/or modulating the activity of
5-HT.sub.1A receptors through in vitro or in vivo administration of
an effective amount of a compound of one or more compounds
according to the invention. In this respect, such compounds
preferably function as 5-HT.sub.1A antagonists.
[0022] The present invention also provides methods of preventing
and/or treating a patient suspected of suffering from a
serotonin-related disorder, comprising the step of administering to
the patient a therapeutically effective amount of a compound of
formula I.
[0023] In yet another aspect, the present invention is also
directed to methods of inhibiting the reuptake of serotonin in a
patient in need thereof, comprising the step of administering to
the patient a therapeutically effective amount of a compound of
formula I.
[0024] In other aspects, the present invention is also directed to
methods of antagonizing 5-HT.sub.1A receptors in a patient in need
thereof, comprising the step of administering to the patient a
therapeutically effective amount of a compound of formula I.
[0025] In a further aspect, the present invention is directed to a
method of antagonizing 5-HT.sub.1A receptors and inhibiting the
reuptake of serotonin in a patient in need thereof, comprising the
step of administering to the patient a therapeutically effective
amount of a compound of formula I.
DETAILED DESCRIPTION OF THE INVENTION
[0026] The term "alkyl", as used herein, whether used alone or as
part of another group, refers to a substituted or unsubstituted
aliphatic hydrocarbon and includes, but is not limited to, straight
and branched chains containing from 1 to 6 carbon atoms, unless
explicitly stated otherwise. For example, methyl, ethyl, propyl,
isopropyl, butyl, i-butyl and t-butyl are encompassed by the term
"alkyl".
[0027] The term "optionally substituted alkyl", as used herein,
refers to an aliphatic hydrocarbon and includes, but is not limited
to, straight and branched chains containing from 1 to 6 carbon
atoms, unless explicitly stated otherwise, optionally substituted
with 1 or 2 substituents. Suitable substitutions for alkyl,
include, but are not limited to, R.sub.2 groups, as defined herein
above, haloalkyl, haloalkoxy, cyano, alkylcarbonyl,
alkoxycarbonylalkyl, and alkylcarbonyloxy.
[0028] The carbon number, as used in these definitions herein,
refers to carbon backbone and carbon branching, but does not
include carbon atoms of substituents, such as alkoxy substitutions
and the like.
[0029] The term "alkenyl", as used herein, whether used alone or as
part of another group, refers to an aliphatic hydrocarbon chain and
includes, but is not limited to, straight and branched chains
having 2 to 6 carbon atoms and containing at least one double
bond.
[0030] The term "optionally substituted alkenyl", as used herein,
refers to an aliphatic hydrocarbon and includes, but is not limited
to, straight and branched chains containing from 3 to 6 carbon
atoms and containing at least one double bond, optionally
substituted with one or more R.sub.2 groups, as defined herein
above.
[0031] The term "alkynyl", as used herein, whether used alone or as
part of another group, refers to an aliphatic hydrocarbon chain and
includes, but is not limited to, straight and branched chains
having 2 to 6 carbon atoms.
[0032] The term "optionally substituted alkynyl", as used herein,
refers to an aliphatic hydrocarbon and includes, but is not limited
to, straight and branched chains containing from 3 to 6 carbon
atoms and containing at least one triple bond, optionally
substituted with one or more R.sub.2 groups, as defined herein
above.
[0033] The term "cycloalkyl", as used herein, whether used alone or
as part of another group, refers to a saturated or unsaturated,
substituted or unsubstituted, alicyclic hydrocarbon group having 3
to 10 carbon atoms, including, but not limited to cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Specifically
included within the definition of "cycloalkyl" are those alicylic
hydrocarbon groups that are optionally substituted.
[0034] An optionally substituted cycloalkyl can be substituted with
1 or 2 substituents. Suitable substitutions for cycloalkyl include,
but are not limited to, R.sub.2 groups, haloalkyl, haloalkoxy,
cyano, alkylcarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy and
hetero atoms such as N, O, S, NR.sub.11, or S(O).sub.r, where r is
0 to 2. For example, a cycloalkyl with substituted with 1 or 2
hetero atoms such as N--R.sub.11, O, or S(O).sub.r, where r is 0 to
2, includes, but is not limited to, azetidine, pyrrolidine,
morpholine, piperidine, piperazine, homopiperazine, tetrahydro,
dihydrofuryl, tetrahydro, dihydro pyrane or thiopyran.
[0035] The term "aryl", as used herein, whether used alone or as
part of another group, refers to a substituted or unsubstituted
aromatic hydrocarbon ring group containing 6 to 10 carbon atoms,
unless explicitly stated otherwise, and includes, but is not
limited to phenyl, naphthalene, indene and indacene. Specifically
included within the definition of "aryl" are those aromatic
hydrocarbon chains that are optionally substituted. An optionally
substituted aryl refers to a substituted or unsubstituted aromatic
hydrocarbon ring group containing 6 to 10 carbon atoms, optionally
substituted with 1 to 3 substitutents. Suitable substitutions for
aryl, include, but are not limited to, R.sub.2 groups, haloalkyl,
haloalkoxy, cyano, alkylcarbonyl, alkoxycarbonylalkyl, and
alkylcarbonyloxy.
[0036] The term "heteroaryl", as used herein, whether used alone or
as part of another group, refers to a substituted or unsubstituted
aromatic heterocycle ring system (moncyclic or bicyclic) of 4 to 10
carbon atoms, and contains from 1 to 3 heteroatoms selected from S,
O or N. The term "heteroaryl" includes, but not limited to, furan,
thiophene, pyrrole, imidazole, oxazole, thiazole, isoxazole,
pyrazole, isothiazole, oxadiazole, triazole, thiadiazole,
quinolizine, quinoline, isoquinoline, cinnoline, phthalazine,
quinazoline, quinoxaline, napthyridine, pteridine, pyridine,
pyrazine, pyrimidine, pyridazine, pyran, triazine, indole,
isoindole, indazole, indolizine, and isobenzofuran. Specifically
included with the definition of "heteroaryl" are those aromatic
heterocyclic rings that are optionally substituted. An optionally
substituted heteroaryl may be substituted with 1 to 3
substitutents, and more preferably 1 to 2 groups. Suitable
substitutions for heteroaryl, include, but are not limited to,
R.sub.2 groups, haloalkyl, haloalkoxy, cyano, alkylcarbonyl,
alkoxycarbonylalkyl, and alkylcarbonyloxy.
[0037] The term "alkylaryl", as used herein, whether used alone or
as part of another group, refers to the group --R.sub.a-R.sub.b-,
containing 7 to 12 carbon atoms, wherein R.sub.a is an alkyl group,
as defined above, R.sub.b is an aryl group, as defined above.
[0038] The term "optionally substituted alkylaryl" as used herein,
refers to an alkylaryl group as defined above, optionally
substituted with one or more R.sub.2 groups.
[0039] The term "alkylheteroaryl", as used herein, whether used
alone or as part of another group, refers to R.sub.a-R.sub.c,
containing 7 to 12 carbon atoms, where R.sub.a is an alkyl group as
defined above, and R.sub.c is a heteroaryl group, as defined
above.
[0040] The term "optionally substituted alkylheteroaryl", as used
herein, refers to an alkylheteroaryl group, as defined above,
optionally substituted with one or more R.sub.2 groups.
[0041] The term "amino", as used herein, refers to --NH.sub.2,
--N(H)R.sub.11 or --N(R.sub.11)R.sub.11.
[0042] The term "halo", as used herein, refers to means chloro,
bromo, iodo or fluoro.
[0043] The term "alkoxy", as used herein, whether used alone or as
part of another group, refers to a substituted or unsubstituted
--O--R.sub.a, where R.sub.a is an alkyl group containing 1 to 6
carbon atoms, as defined above. Specifically included within the
definition of "alkoxy" are those alkoxy moieties that are
optionally substituted. An optionally substituted alkoxy may be
substituted with 1 or 2 R.sub.2.
[0044] The term "alkoxyalkyl", as used herein, refers to the group
--R.sub.a-O--R.sub.a, where R.sub.a is an alkyl group, as defined
above.
[0045] The term "aryloxy", as used herein, whether used alone or as
part of another group, refers to the group --O--R.sub.b-, where
R.sub.b is an aryl group, as defined above.
[0046] The term "--O-alkyl-NR.sub.11R.sub.11", as used herein,
refers to the group --O--R.sub.a-N(R.sub.11)--R.sub.11, where
R.sub.a is an alkyl group, as defined above.
[0047] The term "-aryl-O-alkyl-NR.sub.11R.sub.11", as used herein,
refers to refers to the group
R.sub.b-O--R.sub.a-N(R.sub.11)--R.sub.11, where R.sub.a is an alkyl
group and R.sub.b is an aryl group, as defined above.
[0048] The term "heteroaryloxy", as used herein, refers to the
group R.sub.c-O--, where R.sub.c is a heteroaryl group, as defined
above.
[0049] The term "cycloalkoxy", as used herein, refers to a
substituted or unsubstituted alicyclic alkoxy group having 3 to 6
carbon atoms. Specifically include with in the definition of
"cycloalkoxy" are those alicyclic alkoxy groups that are optionally
substituted. An optionally substituted cycloalkoxy may be
substituted with 1 or more heteroatoms including, but not limited
to O, S, and N--R.sub.11.
[0050] The term "carbonylalkyl", as used herein, refers to the
group --R.sub.a-C(.dbd.O)--, where R.sub.a is an alkyl group
containing 1 to 4 carbon atoms, as defined above.
[0051] The term "carbonylaryl", as used herein, refers to the group
--R.sub.b-C(.dbd.O), where R.sub.b is an aryl group, as defined
above.
[0052] The term "alkoxycarbonyl", as used herein, refers to the
group --O--R.sub.a-C(.dbd.O)--, where R.sub.a is an alkyl group
containing 1 to 4 carbon atoms, as defined above.
[0053] The term "alkoxycarbonylalkyl", as used herein, refers to
the group --O--R.sub.a-C(.dbd.O)--R.sub.a-, where R.sub.a is an
alkyl group containing 1 to 4 carbon atoms, as defined above.
[0054] The term "aminocarbonylalkyl", as used herein, refers to the
group --R.sub.aC(.dbd.O)N(R.sub.11)(R.sub.11), where R.sub.a is an
alkyl group containing 1 to 12 carbon atoms, as defined above.
[0055] The term "alkylaminocarbonyl", as used herein, refers to the
group (R.sub.a).sub.2--NH--C(.dbd.O), where R.sub.a is hydrogen or
an alkyl group as defined above, containing 1 to 12 carbons.
[0056] The term "fluorinated alkyl", as used herein, refers to an
alkyl group containing 1 to 4 carbon atoms, as defined above,
substituted with 1 or more fluorine atoms.
[0057] The term "alkylcarbonyl", as used herein, refers to the
group R.sub.a-C(.dbd.O)--, where R.sub.a is an alkyl group
containing 1 to 4 carbon atoms, as defined above.
[0058] The term "alkylcarbonyloxy", as used herein, refers to the
group R.sub.a-C(.dbd.O)O, where R.sub.a is an alkyl group
containing 1 to 4 carbon atoms, as defined above.
[0059] The term "SO.sub.2-aryl", as used herein, refers to the
group S(O.sub.2)--R.sub.b, where R.sub.b is an aryl group, as
defined above.
[0060] The term "SO.sub.2-heteroaryl", as used herein, refers to
the group S(O.sub.2)--R.sub.b, where R.sub.b is a heteroaryl group,
as defined above.
[0061] The term "SO.sub.2-alkyl", as used herein, refers to the
group S(O.sub.2)--R.sub.a, where R.sub.a is an alkyl group, as
defined above.
[0062] It is understood that the definition of the compounds of
formula I, when R.sub.1, R.sub.2 or R.sub.3, R.sub.4, R.sub.5,
R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10 and R.sub.11 contain
asymmetric carbons, encompass all possible stereoisomers and
mixtures thereof which possess the activity discussed below. In
particular, it encompasses racemic modifications and any optical
isomers which possess the indicated activity. Optical isomers may
be obtained in pure form by standard separation techniques.
[0063] Preferred R.sub.1 groups are hydrogen and alkyl.
Particularly preferred are hydrogen, methyl, ethyl, propyl and
isopropyl.
[0064] Preferred among the above noted R.sub.2 to R.sub.9 groups
are hydrogen, halo, alkyl, alkoxy, alkenyl, NR.sub.11R.sub.11, and
cyano. Particularly preferred are hydrogen, chloro, fluoro, methyl
ethyl, propenyl, methoxy, and cyano.
[0065] Preferred R.sub.10 groups are hydrogen, alkyl, aryl and
heteroaryl. Particularly preferred are hydrogen and alkyl.
[0066] Preferred R.sub.11 groups are hydrogen, alkyl, aryl and
heteroaryl. Particularly preferred are hydrogen and alkyl.
[0067] Preferred aryl groups are phenyl and naphthalene.
[0068] Preferred heteroaryls include furan, thiophene, pyrrole,
imidazole, oxazole, thiazole, isoxazole, pyrazole, isoxazole,
isothiazole, oxadiazole, triazole, thiadiazole, quinolizine,
quinoline, and isoquinoline. More preferred heteroaryls include
furan, thiophene, imidazole, isoxazole, quinoline, pyridine and
pyrazole.
[0069] The following compounds are particularly preferred: [0070]
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indo-
le; [0071]
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-methy-
l-1H-indole; [0072]
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-7-ethyl-
-1H-indole; [0073]
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluor-
o-1H-indole; [0074]
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-cyano-
-1H-indole; [0075]
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluor-
o-1H-indole; [0076]
3-{1-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}-1H-indole; [0077]
3-{1-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}-5-fluoro-1H-indole; [0078]
3-{1-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}-6-fluoro-1H-indole; [0079]
3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-1H-indole; [0080]
3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-5-fluoro-1H-indole; [0081]
3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-6-fluoro-1H-indole; [0082]
3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-6-cyano-1H-indole; [0083]
3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}-1H-indole; [0084]
3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}-5-fluoro-1H-indole; [0085]
3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}-6-fluoro-1H-indole; [0086]
3-{1-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}-1H-indole; [0087]
3-{1-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}-5-cyano-1H-indole; [0088]
3-{1-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}-5-fluoro-1H-indole; [0089]
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-1H-indole; [0090]
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-6-fluoro-1H-indole; [0091]
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-5-fluoro-1H-indole; [0092]
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-5-cyano-1H-indole; [0093]
3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-1H-indole; [0094]
3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-5-fluoro-1H-indole; [0095]
3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-6-fluoro-1H-indole; [0096]
3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-7-ethyl-1H-indole; [0097]
3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H--
indole; [0098]
3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-(-
2-propenyl)-1H-indole; [0099]
3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-m-
ethyl-1H-indole; [0100]
3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyrid-
inyl}-1H-indole; [0101]
3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyrid-
inyl}-1-(2-propenyl)-1H-indole; [0102]
3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyrid-
inyl}-1-methyl-1H-indole; [0103]
3-{1-(2-naphtho[1,2-b]furan-3-yl-ethyl)-piperidin-4-yl]-1H-indole;
[0104]
3-{1-[2-(1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}-1H-indole; [0105]
3-{1-[2-(1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluo-
ro-1H-indole; [0106]
3-{1-[2-(1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluo-
ro-1H-indole; [0107]
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridin-
yl}-1H-indole; [0108]
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridin-
yl}-5-fluoro-1H-indole; [0109]
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridin-
yl}-6-fluoro-1H-indole; [0110]
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl]-1,2,3,6-tetrahydro-4-
-pyridinyl}-1H-indole; [0111]
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl]-1,2,3,6-tetrahydro-4-
-pyridinyl}-6-fluoro-1H-indole; [0112]
3-{1-[2-(5-methoxy-1-benzofuran-3-yl)-1-methylethyl]-1,2,3,6-tetrahydro-4-
-pyridinyl}-1H-indole; and [0113]
3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl-
}imidazo[1,2-a]pyridine.
[0114] The present invention provides a process for the preparation
of a compound of general formula I. These compounds can be prepared
by condensing the appropriately substituted
3-(1,2,3,6-tetrahydro-4-pyridinyl)1-H-indole derivatives 13 with
the appropriately substituted heterocycles 15 to 17, as illustrated
in Scheme 1, in polar aprotic solvents such as DMF, THF, DMSO,
acetone or ethanol in the presence of an acid binding agent, such
as an organic tertiary base, (such as triethylamine,
triethanolamine, DBU, or diisopropylethylamine); or an alkailine
metal carbonate such as potassium carbonate or sodium carbonate, at
100-150.degree. C. The required appropriately substituted
3-(1,2,3,6-tetrahydro-4-pyridinyl)1-H-indole derivatives 13 can be
prepared from the commercially available 4-piperidone monohydrate
hydrochloride 14 and appropriately substituted indole, as
illustrated in Scheme 2. ##STR3## ##STR4##
[0115] The heterocycles 15 and 16 may be prepared from commercially
available substituted salicyclic acid derivatives (Scheme 3).
Appropriately substituted salicyclic derivatives or thiosalicyclic
acid derivatives (Scheme 3) are esterified using alcoholic HCl. The
compound 21 may be reacted with ethyl bromoacetate acid in
refluxing acetone/K.sub.2CO.sub.3 The resultant diester 22 may be
hydrolyzed to the diacid 23. The diacid obtained may be cyclized
using anhydrous CH.sub.3COONa/(CH.sub.3CO).sub.2O to produce
compound 24. This may hydrolyzed using 1N HCl to produce compound
25. This compound, on reaction with
(triphenylphosphoranylidene)ethylacetate or the appropriately
substituted (triphenylphosphoranylidene)ethylacetate derivative, in
boiling organic solvents such as toluene or xylenes, yields
compound 26. This can be converted to 15 or 16 by reduction using
LAH and converting it to either tosylate or iodide using
I.sub.2/imidazole. The reaction may be carried out in a temperature
range of 80-120.degree. C. at atmospheric pressure for 8-24 hours.
##STR5## (a) MeOH. HCl/Reflux; (b)
BrCH.sub.2COOEt/K.sub.2CO.sub.3/Acetone/Reflux; (c)
NaOH/EtOH/THF/Reflux; (d)
(CH.sub.3CO).sub.2O/CH.sub.3COONa/CH.sub.3COOH/reflux; (e) 1N.
HCl/MeOH/reflux; (f) Ph.sub.3P.dbd.CHR.sub.1COOEt/Toluene/Reflux;
(g) LAH/THF/0.degree. C.
[0116] Compound 17 can be prepared from the commercially available
imidazo[1,2-a]pyridine as outlined in Scheme 4. ##STR6## (a)
PhLi/C.sub.6H.sub.6/Rt; (b) Ph.sub.3P.dbd.CHR.sub.1COOEt; (c)
LAH/THF; (d) H.sub.2/Pd--C/Pyridine/Tosyl chloride or
I.sub.2/Imidazole
[0117] Imidazo[1,2-a]pyridine was lithiated using PhLi and the
resulting 3-lithio derivative was quenched with DMF to yield the
3-formyl derivative. This can be converted into 17 by Wittig
reaction.
[0118] Alternatively compound 25 can be reacted with
1-triphenylphosphoranylidene-2-propanone 28 to yield 29, which can
be reacted with 3-(1,2,3,6-tetrahydro-4-pyridinyl)1-H-indole
derivatives 13 using sodium triacetoxyborohydride to give 30
(Scheme 5). ##STR7##
[0119] The terms "effective amount", "therapeutically effective
amount" and "effective dosage" as used herein, refer to the amount
of a compound of formula I that, when administered to a patient, is
effective to at least partially ameliorate a condition from which
the patient is suspected to suffer. Such conditions include
serotonin disorders, including, but are not limited to, depression,
anxiety, cognitive deficits, such as those resulting from
Alzheimer's disease and other neurodegenerative disorders,
schizophrenia, prostate cancer, and nicotine withdrawal.
[0120] The term "pharmaceutically acceptable salt", as used herein,
refers to salts derived from organic and inorganic acids such as,
for example, lactic, citric, acetic, cinnamic, tartaric, succinic,
maleic, malonic, mandelic, malic, oxalic, propionic, fumaric,
hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic,
pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic,
salicylic, benzoic, and similarly known acceptable acids. Where
R.sub.1 to R.sub.9 and R.sub.11 contain a carboxyl group, salts of
the compounds of this invention may be formed with bases such as
alkali metals (Na, K, Li) or the alkaline earth metals (Ca or
Mg).
[0121] The term "patient", as used herein, refers to a mammal,
preferably a human.
[0122] The terms "administer", "administering" or "administration",
as used herein, refer to either directly administering a compound
or composition to a patient, or administering a prodrug derivative
or analog of the compound to the patient, which will form an
equivalent amount of the active compound or substance within the
patient's body.
[0123] The terms "in combination with", and "co-administer" refer,
in certain embodiments, to the concurrent administration to a
patient of SSRIs and the compounds of formula (I). When
administered in combination, each component may be administered at
the same time or sequentially in any order at different points in
time. Thus, each component may be administered separately but
sufficiently closely in time so as to provide the desired
therapeutic effect.
[0124] As used herein, "N-oxide" refers to compounds wherein the
basic nitrogen atom of either a heteroaromatic ring or tertiary
amine is oxidized to give a quaternary nitrogen bearing a positive
formal charge and an attached oxygen atom bearing a negative formal
charge.
[0125] As used herein, "stereoisomers" refers to compounds that
have identical chemical constitution, but differ as regards the
arrangement of the atoms or groups in space.
[0126] Compounds of formula I have been found to have affinity for
the 5-HT reuptake transporter. They are therefore useful in the
prevention and/or treatment of diseases affected by disorders of
the serotonin affected neurological systems, such as depression and
anxiety. The present invention accordingly provides pharmaceutical
compositions that include the compound of formula I; and optionally
one or more pharmaceutically-acceptable carriers, excipients, or
diluents. The term "carrier", as used herein, shall encompass
carriers, excipients and diluents.
[0127] Examples of such carriers are well know to those skilled in
the art and are prepared in accordance with acceptable
pharmaceutical procedures, such as, for example, those described in
Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonso R.
Gennaro, Mack Publishing Company, Easton, Pa. (1985), which is
incorporated herein by reference in its entirety. Pharmaceutical
acceptable carriers are those carriers that are compatible with the
other ingredients in the formulation and are biologically
acceptable.
[0128] The compounds of formula I can be administered orally or
parenterally, neat, or in combination with conventional
pharmaceutical carriers. Representative solid carriers include one
or more substances that can act as flavoring agents, lubricants,
solubilizers, suspending agents, fillers, glidants, compression
aids, binders, tablet-disintegrating agents, or encapsulating
materials. They are formulated in conventional manner, for example,
in a manner similar to that use for known antihypertensive agents,
diuretics and .beta.-blocking agents. Oral formulations containing
the active compounds of this invention may comprise any
conventionally used oral forms, including tablets, capsules, buccal
forms, troches, lozenges and oral liquids, suspensions or
solutions. In powders, the carrier is a finely divided solid that
is in admixture with the finely divided active ingredient. In
tablets, the active ingredient is mixed with a carrier having the
necessary compression properties in suitable proportion and
compacted in the shape and size desired. The powders and tablets
preferably contain up to 99% of the active ingredient.
[0129] Capsules may contain mixtures of the active compound(s) with
inert fillers and/or diluents such as the pharmaceutically
acceptable starches (e.g. corn, potato or tapioca starch), sugars,
artificial sweetening agents, powdered celluloses, such as
crystalline and microcrystalline celluloses, flours, gelatins,
gums, etc.
[0130] Useful tablet formulations may be made by conventional
compression, wet granulation or dry granulation methods and utilize
pharmaceutically acceptable diluents, binding agents, lubricants,
disintegrants, surface modifying agents (including surfactants),
suspending or stabilizing agents, including, but not limited to,
magnesium stearate, stearic acid, sodium lauryl sulfate,
microcrystalline cellulose, methyl cellulose, sodium carboxymethyl
cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine,
gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate,
complex silicates, calcium carbonate, glycine, dextrin, sucrose,
sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin,
mannitol, sodium chloride, talc, starches, sugars, low melting
waxes, and ion exchange resins. Preferred surface modifying agents
include nonionic and anionic surface modifying agents.
Representative examples of surface modifying agents include, but
are not limited to, poloxamer 188, benzalkonium chloride, calcium
stearate, cetostearl alcohol, cetomacrogol emulsifying wax,
sorbitan esters, colloidol silicon dioxide, phosphates, sodium
dodecylsulfate, magnesium aluminum silicate, and triethanolamine.
Oral formulations herein may utilize standard delay or time release
formulations to alter the absorption of the active compound(s). The
oral formulation may also consist of administering the active
ingredient in water or a fruit juice, containing appropriate
solubilizers or emulsifiers as needed.
[0131] Liquid carriers can be used in preparing solutions,
suspensions, emulsions, syrups, and elixirs. The active ingredient
can be dissolved or suspended in a pharmaceutically acceptable oil
or fat. The liquid carrier can obtain other suitable pharmaceutical
additives such as, for example, solubilizers, emulsifiers, buffers,
preservatives, sweeteners, flavoring agents, suspending agents,
thickening agents, colors, viscosity regulators, stablizers or
osmo-regulators. Suitable examples of liquid carriers for oral and
parenteral administration include water (particularly containing
additives as above, e.g. cellulose derivatives, preferably sodium
carboxymethyl cellulose solution), alcohols (including monohydric
alcohols and polyhydric alcohols, e.g. glycols) and their
derivatives, and oils (e.g. fractionated coconut oil and arachis
oil). For parenteral administration, the carrier can also be an
oily ester such as ethyl oleate and isopropyl myristate. Sterile
liquid carriers are used in sterile liquid form compositions for
parenteral administration. The liquid carrier for pressurized
compositions can be halogenated hydrocarbon or other
pharmaceutically acceptable propellant.
[0132] Liquid pharmaceutical compositions that are sterile
solutions or suspensions can be administered by, for example,
intramuscular, intraperitoneal, or subcutaneous injection. Sterile
solutions can also be administered intravenously. Compositions for
oral administration may be in either liquid or solid form.
[0133] In order to obtain consistency of administration, it is
preferred that a composition of the invention is in the form of a
unit dose. Suitable unit dose forms include tablets, capsules and
powders in sachets or vials. Such unit dose forms may contain from
0.1 to 100 mg of a compound of the invention and preferably from 2
to 50 mg. Still further preferred unit dosage forms contain 5 to 25
mg of a compound of the present invention. The compounds of the
present invention can be administered orally at a dose range of
about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 to 10
mg/kg. Such compositions may be administered from 1 to 6 times a
day, more usually from 1 to 4 times a day.
[0134] When administered for the prevention and/or treatment or
inhibition of a particular disease state or disorder, it is
understood that the effective dosage may vary depending upon the
particular compound utilized, the mode of administration, the
condition, and severity thereof, of the condition being treated, as
well as the various physical factors related to the individual
being treated. In therapeutic applications, compounds of formula I
are provided to a patient already suffering from a disease in an
amount sufficient to cure, or at least partially ameliorate, the
symptoms of the disease and its complications. An amount adequate
to accomplish this is defined as a "therapeutically effective
amount". The dosage to be used in the prevention and/or treatment
of a specific case must be subjectively determined by the attending
physician. The variables involved include the specific condition
and the weight, age, and response pattern of the patient. Effective
administration of the compounds of this invention may be given at
an oral dose of from about 0.1 mg/day to about 1,000 mg/day.
Preferably, administration will be from about 10 mg/day to about
600 mg/day, more preferably from about 50 mg/day to about 600
mg/day, in a single dose or in two or more divided doses. The
projected daily dosages are expected to vary with route of
administration.
[0135] Such doses may be administered in any manner useful in
directing the active compounds herein to the patient's bloodstream,
including orally, via implants, parentally (including intravenous,
intraperitoneal, intraarticularly and subcutaneous injections),
rectally, intranasally, topically, ocularly (via eye drops),
vaginally, and transdermally.
[0136] In some cases it may be desirable to administer the
compounds directly to the airways in the form of an aerosol. For
administration by intranasal or intrabrochial inhalation, the
compounds of formula I can be formulated into an aqueous or
partially aqueous solution.
[0137] The compounds of this invention may also be administered
parenterally or intraperitoneally. Solutions or suspensions of
these active compounds as a free base or pharmacologically
acceptable salt can be prepared in water suitably mixed with a
surfactant such as hydroxypropylcellulose. Dispersions can also be
prepared in glycerol, liquid polyethylene glycols and mixtures
thereof in oils. Under ordinary conditions of storage and use,
these preparations contain a preservative to inhibit the growth of
microorganisms.
[0138] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and must be
fluid to the extent that easy syringability exists. It must be
stable under the conditions of manufacture and storage and must be
preserved against the contaminating action of microorganisms such
as bacteria and fungi. The carrier can be a solvent or dispersion
medium containing, for example, water, ethanol, polyol (e.g.,
glycerol, propylene glycol and liquid polyethylene glycol),
suitable mixtures thereof, and vegetable oils.
[0139] The compounds of formula I can also be administered
transdermally through the use of a transdermal patch. For the
purposes of this disclosure, transdermal administrations are
understood to include all administrations across the surface of the
body and the inner linings of bodily passages including epithelial
and mucosal tissues. Such administrations may be carried out using
the present compounds, or pharmaceutically acceptable salts
thereof, in lotions, creams, foams, patches, suspensions,
solutions, and suppositories (rectal and vaginal).
[0140] Transdermal administration may be accomplished through the
use of a transdermal patch containing the active compound and a
carrier that is inert to the active compound, is non-toxic to the
skin, and allows delivery of the agent for systemic absorption into
the blood stream via the skin. The carrier may take any number of
forms such as creams and ointments, pastes, gels, and occlusive
devices. The creams and ointments may be viscous liquid or
semisolid emulsions of either the oil-in-water or water-in-oil
type. Pastes containing absorptive powders dispersed in petroleum
or hydrophilic petroleum containing the active ingredient may also
be suitable. A variety of occlusive devices may be used to release
the active ingredient into the blood stream such as a
semi-permeable membrane covering a reservoir containing the active
ingredient with or without a carrier, or a matrix containing the
active ingredient. Other occlusive devices are known in the
literature.
[0141] The compounds of formula I may be administered rectally or
vaginally in the form of a conventional suppository. Suppository
formulations may be made from traditional materials, including
cocoa butter, with or without the addition of waxes to alter the
suppository's melting point, and glycerin. Water soluble
suppository bases, such as polyethylene glycols of various
molecular weights, may also be used.
[0142] In certain embodiments, the present invention is directed to
prodrugs of compounds of formula I. The term "prodrug", as used
herein, is intended to include any covalently bonded carriers which
release the active parent drug, for example, as according to
formula I or other formulas or compounds employed in the methods of
the present invention in vivo when such prodrug is administered to
a mammalian subject. Since prodrugs are known to enhance numerous
desirable qualities of pharmaceuticals (e.g., solubility,
bioavailability, manufacturing, etc.) the compounds employed in the
present methods may, if desired, be delivered in prodrug form.
Thus, the present invention contemplates methods of delivering
prodrugs. Prodrugs of the compounds employed in the present
invention, for example formula I, may be prepared by modifying
functional groups present in the compound in such a way that the
modifications are cleaved, either in routine manipulation or in
vivo, to the parent compound.
[0143] Accordingly, prodrugs include, for example, compounds
described herein in which a hydroxy, amino, or carboxy group is
bonded to any group that, when the prodrug is administered to a
mammalian subject, cleaves to form a free hydroxyl, free amino, or
carboxylic acid, respectively. Examples include, but are not
limited to, acetate, formate and benzoate derivatives of alcohol
and amine functional groups; and alkyl, carbocyclic, aryl, and
alkylaryl esters such as methyl, ethyl, propyl, iso-propyl, butyl,
isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl, benzyl, and
phenethyl esters, and the like.
[0144] Various forms of prodrugs are known in the art such as those
discussed in, for example, Bundgaard (ed.), Design of Prodrugs,
Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol.
4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed.), "Design
and Application of Prodrugs, Textbook of Drug Design and
Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal
of Drug Delivery Reviews, 8:1-38 (1992); Bundgaard, Journal of
Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella
(eds.), Prodrugs as Novel Drug Delivery Systems, American Chemical
Society (1975), each of which is incorporated by reference in its
entirety.
[0145] The present invention further provides a compound of the
invention for use as an active therapeutic substance. Compounds of
formula I are of particular use in the prevention and/or treatment
of diseases affected by disorders of serotonin.
[0146] The present invention further provides a compound of the
invention in combination with a SSRI for use as an active
therapeutic substance.
[0147] The present invention further provides a method of
preventing and/or treating depression and anxiety in mammals
including man, which comprises administering to the afflicted
mammal an effective amount of a compound or a pharmaceutical
composition of the invention.
[0148] The present invention further provides a method of
preventing and/or treating depression and anxiety in mammals
including man, which comprises co-administering to the afflicted
mammal an effective amount of a compound or a pharmaceutical
composition of the invention in combination with a SSRI.
EXAMPLES
Example 1
Preparation of
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indo-
le ("Compound 1")
[0149] Step 1: To a stirred solution of methyl salicylate (15.2 g,
0.1 mol) and anhydrous potassium carbonate (50.0 g, excess) in
acetone (500 ml), ethyl bromoacetate (16.7 g, 0.1 mol) was added.
The reaction mixture was refluxed for 24 hrs and cooled to room
temperature. It was filtered and concentrated. The oily residue was
extracted with chloroform and washed well with water. The organic
layer was dried over anhydrous MgSO.sub.4 and filtered. It was
concentrated and taken to next step without any purification. White
oil; Yield: 22.0 g (92%); 239 (M+H).
[0150] Step 2: The methyl-2-(ethoxy-2-oxoethoxy)benzoate obtained
from step 1, (11.9 g, 50 mmol) was dissolved in THF:MeOH (1:1) (300
ml) and 5N NaOH (100 ml) was added. The reaction mixture was
refluxed for 24 hrs and cooled to room temperature. At the end, it
was concentrated to dryness and dissolved in water. The aqueous
layer was acidified with con. HCl and the separated solid was
filtered. It was washed well with water and dried. The product was
taken to step without any purification. White solid; Yield: 9.0 g
(91%); mp: 125-128.degree. C.; 197 (M+H).
[0151] Step 3: The 2-(carboxymethoxy)-benzoic acid compound
obtained from step 2 (9.8 g, 50 mmol) was dissolved in acetic
anhydride (100 ml) and anhydrous sodium acetate (10.0 g, excess)
was added. The reaction mixture was heated to 150.degree. C. for 4
hrs. During this time, the reaction mixture turned dark red. The
reaction mixture was cooled to room temperature and quenched
carefully with ice cold water. The red solid obtained was filtered
and washed well with water. The red solid obtained was suspended in
1 N HCl and refluxed for 2 hrs. A dark red solid, benzofuran-3
(2H)-one, precipitated from the reaction mixture. It was filtered
and washed well with water. It was dried at 40.degree. C. and used
for the next step without further purifications. Yield: 3.5 g
(51%); 135 (M+H).
[0152] Step 4: A mixture of benzofuran-3 (2H)-one (1.34 g, 10 mmol)
and (carboxymethylene) triphenylphosphorane (5.22 g, 15 mmol) was
refluxed in toluene (100 ml) for 48 hrs. At the end, reaction
mixture was concentrated and loaded over a silica-gel column. The
column was eluted with hexane (500 ml) and later with 25% ethyl
acetate. The product, ethyl(-1-benzofuran-3-yl)acetate, was
obtained as a white oil. Yield: 2.0 g (98%); 205 (M+H).
[0153] Step 5: To a stirred suspension of LiAlH.sub.4 (200 mg,
excess) in THF at 0.degree. C., ethyl(-1-benzofuran-3-yl)acetate
(1.02 g, 5 mmol) in THF (20 mL) was added slowly. After the
addition, the reaction mixture was stirred at room temperature for
1 hr and quenched with saturated NH.sub.4Cl solution. The product
was extracted with chloroform and washed well with water. It was
dried over anhydrous MgSO.sub.4; filtered and concentrated. The
product, 2-(1-benzofuran-3-yl)ethanol, was obtained as a white oil
and was pure enough to be taken to the next step without
purification. Yield: 800 mg (98%); 163 (M+H).
[0154] Step 6: To a stirred solution of
2-(1-benzofuran-3-yl)ethanol (815 mg, 5 mmol) in anhydrous pyridine
(20 ml), p-toluenesulfonyl chloride (1.14 g, 6.0 mmol) was added.
The reaction mixture was kept at 0.degree. C. for 48 hrs and
quenched with ice cold water. The reaction mixture was extracted
with chloroform, washed well with water and dried over anhydrous
MgSO.sub.4. It was filtered and concentrated. The crude product
obtained was taken to next step without any purification.
[0155] A mixture of tosylate (316 mg. 1 mmol) (obtained by the
above mentioned process) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1 mmol) was
heated at 120.degree. C. in DMSO in the presence of
N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end,
the reaction mixture was quenched with water and extracted with
chloroform. The organic layer was washed with water and dried over
anhydrous MgSO.sub.4 and concentrated to dryness. The dark colored
solid was purified by silica-gel column chromatography by eluting
it with 70% ethyl acetae:hexane.
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indo-
le was isolated as yellow solid; mp:166.degree. C.; Yield: 150 mg
(43%); 343 (M+H); .sup.1H NMR: .delta. 8.12 (broad s, 1H), 7.92
(d,1H), 7.65-7.2, (m, 8H), 6.3 (m, 1H), 3.3 (bs, 2H), 2.98 (m, 2H),
2.8 (m, 4H), 2.6 (m, 2H).
Example 2
Preparation of
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-methy-
l-1H-indole ("Compound 2")
[0156]
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}--
1H-indole (342 mg,1 mmol) (obtained from example 1, step 6) in dry
THF (50 ml) was slowly added to a stirred suspension of hexane and
washed with 60% sodium hydride (44 mg) at 0.degree. C. After the
addition, the reaction mixture was stirred for 30 min and methyl
iodide (213 mg, 1.5 mmol) was added. The reaction mixture was
stirred for 4 hrs and quenched carefully with ice cold water. The
reaction mixture was extracted with chloroform; washed well with
water; dried over anhydrous MgSO.sub.4; filtered and concentrated.
The residue obtained was purified by silica-gel column
chromatography by eluting it with 50% ethyl acetate:hexane. Light
green semi-solid. Yield: 280 mg (78%); 357 (M+H); .sup.1H NMR:
.delta.7.94 (d, 1H), 7.69 (d, 1H), 7.5-7.0 (m, 8H), 6.2 (bs, 1H),
3.8 (s, 3H), 3.49 (bs, 2H), 3.0 (m, 2H), 2.85 (m, 4H), 2.6 (bs,
2H).
Example 3
Preparation of
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-7-ethyl-
-1H-indole ("Compound 3")
[0157]
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}--
7-ethyl-1H-indole was prepared by generally following the procedure
outlined in example 1, step 6, starting from the tosylate (316 mg,
1 mmol) and 3 (1,2,3,6-tetrahydro-4-pyridinyl)-7-ethyl-1H-indole
(226 mg, 1 mmol). The product was purified by silica-gel column
chromatography by eluting it with 70% ethyl acetate:hexane. Brown
oil; Yield: 210 mg (56%); 371 (M+H); .sup.1HNMR (400 MHz,
CDCl.sub.3): .delta. 8.05 (broad s, 1H, NH); 7.77.about.6.90 (m,
9H); 6.20 (s,1H); 3.36.about.2.60 (m, 12 H); 1.39.about.1.35 (t,
J=7.6 Hz, 3H).
Example 4
Preparation of
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluor-
o-1H-indole ("Compound 4")
[0158]
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}--
6-fluoro-1H-indole was prepared by generally following the
procedure outlined in example 1, step 6, starting from the tosylate
(316 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-6-fluoro-1H-indole (216 mg, 1
mmol). The product was purified by silica-gel column chromatography
by eluting it with 70% ethyl acetate:hexane. Brown oil; Yield: 180
mg (50%); 361 (M+H); .sup.1H NMR .delta. 9.9 (broad s, 1H);
7.93.about.7.1 (m, 9H); 6.2 (s, 1H); 3.46.about.2.48 (m, 10H).
Example 5
Preparation of
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-cyano-
-1H-indole ("Compound 5")
[0159]
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}--
5-cyano-1H-indole was prepared by generally following the procedure
outlined in example 1, step 6, starting from the tosylate (316 mg,
1 mmol) and 3 (1,2,3,6-tetrahydro-4-pyridinyl)-5-cyano-1H-indole
(213 mg, 1 mmol). The product was purified by silica-gel column
chromatography by eluting it with 80% ethyl acetate:hexane. Brown
solid; Yield: 239 mg (65%); 369 (M+H); .sup.1H NMR: .delta.
.sup.1HNMR (400 MHz, CDCl.sub.3): 68.49 (broad, s, 1H, NH);
7.69.about.6.99 (m, 9H); 6.18.about.6.17 (s, 1H); 3.36.about.2.46
(m, 10H).
Example 6
Preparation of
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluor-
o-1H-indole ("Compound 6")
[0160]
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}--
5-fluoro-1H-indole was prepared by generally following the
procedure outlined in example 1, step 6, starting from the tosylate
(316 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-5-fluoro-1H-indole (216 mg, 1
mmol). The product was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate:hexane. Brown solid; Yield: 60
mg (16%); 361(M+H); .sup.1H NMR: .delta. (400 MHz, CDCl.sub.3):
610.2 (broad s, 1H, NH); 7.82.about.6.93 (m, 9H); 6.07 (s,1H);
3.48.about.2.50 (m, 10H).
Example 7
Preparation of
3-{1-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}-1H-indole ("Compound 7")
[0161] Step 1: To a stirred solution of
methyl-4-chloro-2-hydroxy-benzoate (18.6 g, 0.1 mol) and anhydrous
potassium carbonate (50.0 g, excess) in acetone (500 ml) ethyl
bromoacetate (16.7 g, 0.1 mol) was added. The reaction mixture was
refluxed for 24 hrs and cooled to room temperature. It was filtered
and concentrated. The oily residue was extracted with chloroform
and washed well with water. The organic layer was dried over
anhydrous MgSO.sub.4 and filtered. It was concentrated and taken to
next step without any purification. White oil; Yield: 27.0 g (99%);
273 (M+H).
[0162] Step 2: The methyl-2-(ethoxy-2-oxoethoxy)-4-chloro-benzoate
obtained from step 1, (13.6 g, 50 mmol) was dissolved in THF:MeOH
(1:1) (300 ml) and 5N NaOH (100 ml) was added. The reaction mixture
was refluxed for 24 hrs and cooled to room temperature. At the end
it was concentrated to dryness and dissolved in water. The aqueous
layer was acidified with con. HCl and the separated solid were
filtered. It was washed well with water and dried. The product was
taken to step without any purification. White solid; Yield: 10.0 g
(86%); 231 (M+H).
[0163] Step 3: The 2-(carboxymethoxy)-4-chloro-benzoic acid
compound obtained from step 2 (11.5 g, 50 mmol) was dissolved in
acetic anhydride (100 ml) and anhydrous sodium acetate (10.0 g,
excess) was added. The reaction mixture was heated to 150.degree.
C. for 4 hrs. During this time the reaction mixture turned dark
red. The reaction mixture was cooled to room temperature and
quenched carefully with ice cold water. The red solid obtained was
filtered and washed well with water. The red solid obtained was
suspended in 1 N HCl and refluxed for 2 hrs. A dark red solid,
6-chloro-benzofuran-3 (2H)-one, precipitated from the reaction
mixture. It was filtered and washed well with water. It was dried
at 40.degree. C. and used for the next step without further
purifications. Yield: 5.8 g (69%); 169 (M+H).
[0164] Step 4: A mixture of 6-chloro-benzofuran-3 (2H)-one (1.68 g,
10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15
mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, the
reaction mixture was concentrated and loaded over a silica-gel
column. The column was eluted with hexane (500 ml) and later with
25% ethyl acetate. The product,
ethyl(6-chloro-1-benzofuran-3-yl)acetate, was obtained as a white
oil. Yield: 2.1 g (87%); 239 (M+H).
[0165] Step 5: To a stirred suspension of LiAlH.sub.4 (200 mg,
excess) in THF at 0.degree. C., ethyl(6-chloro
-1-benzofuran-3-yl)acetate (1.19 g, 50 mmol) in THF (20 mL) was
added slowly. After the addition, the reaction mixture was stirred
at room temperature for 1 hr and quenched with saturated NH.sub.4Cl
solution. The product was extracted with chloroform and washed well
with water. It was dried over anhydrous MgSO.sub.4; filtered and
concentrated. The product, 2-(6-chloro-1-benzofuran-3-yl)ethanol,
was obtained as a white oil pure enough to be taken to the next
step without purification. Yield: 900 mg (91%); 197 (M+H).
[0166] Step 6: To a stirred solution of
2-(6-chloro-1-benzofuran-3-yl)ethanol (980 mg, 5 mmol) in anhydrous
pyridine (20 ml), p-toluenesulfonyl chloride (1.14 g, 6.0 mmol) was
added. The reaction mixture was kept at 0.degree. C. for 48 hrs and
quenched with ice cold water. The reaction mixture was extracted
with chloroform, washed well with water and dried over anhydrous
MgSO.sub.4. It was filtered and concentrated. The crude product
obtained was taken to next step without any purification.
[0167] A mixture of tosylate (350 mg. 1 mmol) (obtained by the
above mentioned process) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1 mmol) was
heated at 120.degree. C. in DMSO in the presence of
N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end,
the reaction mixture was quenched with water and extracted with
chloroform. The organic layer was washed with water and dried over
anhydrous MgSO.sub.4 and concentrated to dryness. The dark colored
solid was purified by silica-gel column chromatography by eluting
it with 70% ethyl acetae:hexane.
3-{1-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}-1H-indole was isolated as yellow oil; Yield: 220 mg (58%); 377
(M+H); .sup.1HNMR (400 MHz, CDCl.sub.3): .delta.10.2 (broad s, 1H,
NH); 7.82.about.7.01 (m, 9H); 6.14 (s, 1H); 3.32.about.2.49 (m,
10H).
Example 8
Preparation of
3-{1-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}-5-fluoro-1H-indole ("Compound 8")
[0168]
3-{1-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-py-
ridinyl}-5-fluoro-1H-indole was prepared by generally following the
procedure outlined in example 7, step 6, starting from the tosylate
(350 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-5-fluoro-1H-indole (216 mg, 1
mmol). The product was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate: hexane. Brown solid; Yield:
189 mg (47%); 395 (M+H); .sup.1HNMR (400 MHz, CDCl.sub.3):
.delta.10.2 (broad s, 1H, NH); 7.90.about.6.92 (m, 7H); 6.07 (s,
1H); 3.32.about.2.49 (m, 11H).
Example 9
Preparation of
3-{1-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}-6-fluoro-1H-indole ("Compound 9")
[0169]
3-{1-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-py-
ridinyl}-6-fluoro-1H-indole was prepared by generally following the
procedure outlined in example 7, step 6, starting from the tosylate
(350 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-6-fluoro-1H-indole (216 mg, 1
mmol). The product was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate:hexane. Brown solid; Yield:
135 mg (34%); 395 (M+H); .sup.1HNMR (400 MHz, CDCl.sub.3): .delta.
8.5 (broad, s, 1H, NH); 7.81.about.6.80 (m, 7H); 6.20 (s, 1H);
3.40.about.2.60 (m, 11H).
Example 10
Preparation of
3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-1H-indole ("Compound 10")
[0170] Step 1: To a stirred solution of
methyl-4-methoxy-2-hydroxy-benzoate (18.2 g, 0.1 mol) and anhydrous
potassium carbonate (50.0 g, excess) in acetone (500 ml) ethyl
bromoacetate (16.7 g, 0.1 mol) was added. The reaction mixture was
refluxed for 24 hrs and cooled to room temperature. It was filtered
and concentrated. The oily residue was extracted with chloroform
and washed well with water. The organic layer was dried over
anhydrous MgSO.sub.4 and filtered. It was concentrated and taken to
next step without any purification. White oil; Yield: 24.0 g (89%);
269 (M+H).
[0171] Step 2: The methyl-2-(ethoxy-2-oxoethoxy)-4-methoxy-benzoate
obtained from the step 1, (13.4 g, 50 mmol ) was dissolved in
THF:MeOH (1:1) (300 ml) and 5N NaOH (100 ml) was added. The
reaction mixture was refluxed for 24 hrs and cooled to room
temperature. At the end it was concentrated to dryness and
dissolved in water. The aqueous layer was acidified with con. HCl
and the separated solid were filtered. It was washed well with
water and dried. The product was taken to step without any
purification. White solid; Yield: 8.5 g (75%); 227 (M+H).
[0172] Step 3: The 2-(carboxymethoxy)-4-methoxy-benzoic acid
compound obtained from the step 2 (11.3 g, 50 mmol) was dissolved
in acetic anhydride (100 ml) and anhydrous sodium acetate (10.0 g,
excess) was added. The reaction mixture was heated to 150.degree.
C. for 4 hrs. During this time the reaction mixture turned dark
red. The reaction mixture was cooled to room temperature and
quenched carefully with ice cold water. The red solid obtained was
filtered and washed well with water. The red solid obtained was
suspended in 1 N HCl and refluxed for 2 hrs. A dark red solid,
6-methoxy-benzofuran-3 (2H)-one precipitated from the reaction
mixture. It was filtered and washed well with water. It was dried
at 40.degree. C. and used for the next step without further
purifications. Yield: 4.7 g (57%); 165 (M+H).
[0173] Step 4: A mixture of 6-methoxy-benzofuran-3 (2H)-one (1.64
g, 10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15
mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end,
reaction mixture was concentrated and loaded over silica-gel
column. The column was eluted with hexane (500 ml) and later with
25% ethyl acetate. The product,
ethyl(6-methoxy-1-benzofuran-3-yl)acetate was obtained as a white
oil. Yield: 1.8 g (76%); 235 (M+H).
[0174] Step 5: To a stirred suspension of LiAlH.sub.4 (200 mg,
excess) in THF at 0.degree. C.,
ethyl(6-methoxy-1-benzofuran-3-yl)acetate (1.17 g, 5 mmol) in THF
(20 ml) was added slowly. After the addition, the reaction mixture
was stirred at room temperature for 1 hr and quenched with
saturated NH.sub.4Cl solution. The product was extracted with
chloroform and washed well with water. It was dried over anhydrous
MgSO.sub.4; filtered and concentrated. The product,
2-(6-methoxy-1-benzofuran-3-yl)ethanol was obtained as a white oil
and was pure enough to be taken to the next step without
purification. Yield: 850 mg (88%); 193 (M+H).
[0175] Step 6: To a stirred solution of
2-(6-methoxy-1-benzofuran-3-yl)ethanol (960 mg, 5 mmol) in
anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine
(1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room
temperature. The reaction mixture was stirred at room temperature
for 4 hrs and quenched with water. It was then extracted with
chloroform, washed well with 5% Na.sub.2S.sub.2O.sub.3 solution and
the organic layer was dried over anhydrous MgSO.sub.4. It was
filtered and concentrated. The residue was purified by silica-gel
column chromatography by eluting it with 30% ethyl acetate: hexane.
The product, namely 2-(6-methoxy-1-benzofuran-3-yl)ethyl iodide,
was obtained as brown liquid; Yield: 1.2 g (80%); 302 (M+H).
[0176] A mixture of 2-(6-methoxy-1-benzofuran-3-yl)ethyl iodide
(301 mg. 1 mmol) (obtained by the above mentioned process) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1 mmol) was
heated at 120.degree. C. in DMSO in the presence of
N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end,
the reaction mixture was quenched with water and extracted with
chloroform. The organic layer was washed with water and dried over
anhydrous MgSO.sub.4 and concentrated to dryness. The dark colored
solid was purified by silica-gel column chromatographyby eluting it
with 70% ethyl acetae:hexane.
3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-1H-indole was isolated as yellow oil; Yield: 180 mg (48%); 373
(M+H); .sup.1H NMR: .delta.8.6 (d, 1H), 8.25 (bs, 1H), 7.9 (d,1H),
7.6-6.9 (m, 7H), 6.23 (bs, 1H), 3.85 (s, 3H), 3.5 (m,2H), 3.0 (m,
2H), 2.8 (m, 4H), 2.65 (m, 2H).
Example 11
Preparation of
3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-5-fluoro-1H-indole ("Compound 11")
[0177]
3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-p-
yridinyl}-5-fluoro-1H-indole was prepared by generally following
the procedure outlined in example 10, step 6, starting from the of
2-(6-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-5-fluoro-1H-indole (216 mg, 1
mmol). The product was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate: hexane. Brown solid; Yield:
178 mg (45%); 391 (M+H); .sup.1HNMR (400 MHz, CDCl.sub.3): .delta.
8.50 (broad, s, 1H, NH); 7.81.about.6.80 (m, 7H); 6.20 (s, 1H);
3.67 (s, 3H); 3.40.about.2.60 (m, 11H).
Example 12
Preparation of
3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-6-fluoro-1H-indole ("Compound 12")
[0178]
3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-p-
yridinyl}-6-fluoro-1H-indole was prepared by following the
procedure outlined in example 10, step 6, starting from the of
2-(6-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-6-fluoro-1H-indole (216 mg, 1
mmol). The product was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate: hexane. Brown solid; Yield:
180 mg (46%); 391 (M+H); .sup.1HNMR (400 MHz, CDCl.sub.3):
.delta.8.50 (broad s, 1H, NH); 7.81.about.6.80 (m, 7H); 6.2 (s,
1H); 3.67 (s, 3H); 3.40.about.2.60 (m, 11H).
Example 13
Preparation of
3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-6-cyano-1H-indole ("Compound 13")
[0179]
3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-p-
yridinyl}-6-fluoro-1H-indole was prepared by generally following
the procedure outlined in example 10, step 6, starting from the of
2-(6-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-6-fluoro-1H-indole (216 mg, 1
mmol). The product was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate:hexane. Brown solid;
mp181.degree. C.; Yield: 250 mg (62%); 398 (M+H); .sup.1H NMR:
.delta. 9.50 (broad, s, 1H,); 8.2.about.6.80 (m, 7H); 6.20 (s, 1H);
3.89 (m, 2H); 3.65 m, 2H), 3.55 m,2H), 2.60 (m, 4H).
Example 14
Preparation of
3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}-1H-indole ("Compound 14")
[0180] Step 1: To a stirred solution of
methyl-5-chloro-2-hydroxy-benzoate (18.6 g, 0.1 mol) and anhydrous
potassium carbonate (50.0 g, excess) in acetone (500 ml) ethyl
bromoacetate (16.7 g, 0.1 mol) was added. The reaction mixture was
refluxed for 24 hrs and cooled to room temperature. It was filtered
and concentrated. The oily residue was extracted with chloroform
and washed well with water. The organic layer was dried over
anhydrous MgSO.sub.4 and filtered. It was concentrated and taken to
next step without any purification. White oil; Yield: 22.0 g (80%);
273 (M+H).
[0181] Step 2: The methyl-2-(ethoxy-2-oxoethoxy)-5-chloro-benzoate
obtained from the step 1, (13.6 g, 50 mmol ) was dissolved in
THF:MeOH (1:1) (300 ml) and 5N NaOH (100 ml) was added. The
reaction mixture was refluxed for 24 hrs and cooled to room
temperature. At the end it was concentrated to dryness and
dissolved in water. The aqueous layer was acidified with con. HCl
and the separated solid were filtered. It was washed well with
water and dried. The product was taken to step without any
purification. White solid; Yield: 8.0 g (69%); 231 (M+H).
[0182] Step 3: The 2-(carboxymethoxy)-5-chloro-benzoic acid
compound obtained from the step 2 (11.5 g, 50 mmol) was dissolved
in acetic anhydride (100 ml) and anhydrous sodium acetate (10.0 g,
excess) was added. The reaction mixture was heated to 150.degree.
C. for 4 hrs. During this time the reaction mixture turned dark
red. The reaction mixture was cooled to room temperature and
quenched carefully with ice cold water. The red solid obtained was
filtered and washed well with water. The red solid obtained was
suspended in 1 N HCl and refluxed for 2 hrs. A dark red solid,
5-chloro-benzofuran-3 (2H)-one, precipitated from the reaction
mixture. It was filtered and washed well with water. It was dried
at 40.degree. C. and used for the next step without further
purifications. Yield: 6.2 g (73%); 169 (M+H).
[0183] Step 4: A mixture of 5-chloro-benzofuran-3 (2H)-one (1.68 g,
10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15
mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end,
reaction mixture was concentrated and loaded over a silica-gel
column. The column was eluted with hexane (500 ml) and later with
25% ethyl acetate. The product,
ethyl(5-chloro-1-benzofuran-3-yl)acetate, was obtained as a white
oil. Yield: 1.8 g (75%); 239 (M+H).
[0184] Step 5: To a stirred suspension of LiAlH.sub.4 (200 mg,
excess) in THF at 0.degree. C.,
ethyl(5-chloro-1-benzofuran-3-yl)acetate (1.19 g, 50 mmol) in THF
(20 ML) was added slowly. After the addition, reaction mixture was
stirred at room temperature for 1 hr and quenched with saturated
NH.sub.4Cl solution. The product was extracted with chloroform and
washed well with water. It was dried over anhydrous MgSO.sub.4;
filtered and concentrated. The product,
2-(5-chloro-1-benzofuran-3-yl)ethanol, was obtained as a white oil
pure enough to be taken to the next step without purification.
Yield: 850 mg (86%); 197 (M+H).
[0185] Step 6: To a stirred solution of
2-(5-chloro-1-benzofuran-3-yl)ethanol (980 mg, 5 mmol) in anhydrous
THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g,
6 mmol) and imidazole (408 mg, 6 mmol) were added at room
temperature. The reaction mixture was stirred at room temperature
for 4 hrs and quenched with water. It was extracted with
chloroform, washed well with 5% Na.sub.2S.sub.2O.sub.3 solution and
the organic layer was dried over anhydrous MgSO.sub.4. It was
filtered and concentrated. The residue was purified by silica-gel
column chromatography by eluting it with 30% ethyl acetate:hexane.
The product, namely 2-(5-chloro-1-benzofuran-3-yl)ethyl iodide, was
obtained as brown liquid; Yield: 1.2 g (80%); 306 (M+H).
[0186] A mixture of 2-(5-chloro-1-benzofuran-3-yl)ethyl iodide (305
mg. 1 mmol) (obtained by the above mentioned process) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1 mmol) was
heated at 120.degree. C. in DMSO in the presence of
N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end,
the reaction mixture was quenched with water and extracted with
chloroform. The organic layer was washed with water and dried over
anhydrous MgSO.sub.4 and concentrated to dryness. The dark colored
solid was purified by silica-gel column chromatographyby eluting it
with 70% ethyl acetae:hexane.
3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-1H-indole was isolated as brown solid. mp 54.degree. C.; Yield:
210 mg (55%); 377 (M+H); .sup.1H NMR:.delta.8.98 (broad, s, 1H,);
7.92.about.6.94 (m, 9H); 6.25 (s, 1H); 3.78 (bs, 2H); 3.60 (bs,
2H), 3.45 (bs, 2H), 3.25 (bs, 4H).
Example 15
Preparation of
3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}-5-fluoro-1H-indole ("Compound 15")
[0187]
3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-py-
ridinyl}-5-fluoro-1H-indole was prepared by generally following the
procedure outlined in example 14, step 6, starting from the of
2-(5-chloro-1-benzofuran-3-yl)ethyl iodide (306 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-5-fluoro-1H-indole (216 mg, 1
mmol). The product was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate:hexane. Brown solid; Yield:
120 mg (30%); 395 (M+H); .sup.1HNMR (400 MHz, CDCl.sub.3):
.delta.8.57 (broad, s, 1H, NH); 2.56.about.6.96 (m, 7H); 6.10 (s,
1H); 3.35.about.2.50 (m, 11H).
Example 16
Preparation of
3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}-6-fluoro-1H-indole ("Compound 16")
[0188]
3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-py-
ridinyl}-5-fluoro-1H-indole was prepared by following the procedure
outlined in example 14, step 6, starting from the of
2-(5-chloro-1-benzofuran-3-yl)ethyl iodide (306 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-6-fluoro-1H-indole (216 mg, 1
mmol). The product was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate:hexane. Brown solid; Yield:
180 mg (45%); 395 (M+H); .sup.1HNMR (400 MHz, CDCl.sub.3): .delta.
8.74 (broad, s, 1H,); 7.80.about.6.70 (m, 7H); 6.20 (s, 1H);
3.50.about.2.60 (m, 10H).
Example 17
Preparation of
3-{1-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}-1H-indole ("Compound 17")
[0189] Step 1: To a stirred solution of 5-fluoro-2-hydroxy-methyl
benzoate (17.0 g, 0.1 mol) and anhydrous potassium carbonate (50.0
g, excess) in acetone (500 ml) ethyl bromoacetate (16.7 g, 0.1 mol)
was added. The reaction mixture was refluxed for 24 hrs and cooled
to room temperature. It was filtered and concentrated. The oily
residue was extracted with chloroform and washed well with water.
The organic layer was dried over anhydrous MgSO.sub.4 and filtered.
It was concentrated and taken to next step without any
purification. White oil; Yield: 23.0 g (89%); 257 (M+H).
[0190] Step 2: The methyl-5-fluoro-2-(ethoxy-2-oxoethoxy)benzoate
obtained from step 1, (12.8 g, 50 mmol ) was dissolved in THF:MeOH
(1:1) (300 ml) and 5N NaOH (100 ml) was added. The reaction mixture
was refluxed for 24 hrs and cooled to room temperature. At the end
it was concentrated to dryness and dissolved in water. The aqueous
layer was acidified with con. HCl and the separated solid were
filtered. It was washed well with water and dried. The product was
taken to step without any purification. White solid; Yield: 8.3 g
(77%); 215 (M+H).
[0191] Step 3: The 2-(carboxymethoxy)-5-fluoro-benzoic acid
compound obtained from the step 2 (10.7 g, 50 mmol) was dissolved
in acetic anhydride (100 ml) and anhydrous sodium acetate (10.0 g,
excess) was added. The reaction mixture was heated to 150.degree.
C. for 4 hrs. During this time, the reaction mixture turned dark
red. The reaction mixture was cooled to room temperature and
quenched carefully with ice cold water. The red solid obtained was
filtered and washed well with water. The red solid obtained was
suspended in 1 N HCl and refluxed for 2 hrs. A dark red solid,
5-fluoro-benzofuran-3 (2H)-one, precipitated from the reaction
mixture. It was filtered and washed well with water. It was dried
at 40.degree. C. and used for the next step without further
purifications. Yield: 5.8 g (76%); 153 (M+H).
[0192] Step 4: A mixture of 5-fluoro-benzofuran-3 (2H)-one (1.52 g,
10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15
mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end,
reaction mixture was concentrated and loaded over a silica-gel
column. The column was eluted with hexane (500 ml) and later with
25% ethyl acetate. The product,
ethyl(5-fluoro-1-benzofuran-3-yl)acetate, was obtained as a white
oil. Yield: 1.8 g (80%); 223 (M+H).
[0193] Step 5: To a stirred suspension of LiAlH.sub.4 (200 mg,
excess) in THF at 0.degree. C.,
ethyl(5-fluoro-1-benzofuran-3-yl)acetate (1.11 g, 5 mmol) in THF
(20 mL) was added slowly. After the addition, the reaction mixture
was stirred at room temperature for 1 hr and quenched with
saturated NH.sub.4Cl solution. The product was extracted with
chloroform and washed well with water. It was dried over anhydrous
MgSO.sub.4; filtered and concentrated. The product,
2-(5-fluoro-1-benzofuran-3-yl)ethanol obtained as white oil and was
pure enough to be taken to the next step without purification.
Yield: 820 mg (91%); 181 (M+H).
[0194] Step 6: To a stirred solution of
2-(5-fluoro-1-benzofuran-3-yl)ethanol (900 mg, 5 mmol) in anhydrous
pyridine (20 ml), p-toluenesulfonyl chloride (1.14 g, 6.0 mmol) was
added. The reaction mixture was kept at 0.degree. C. for 48 hrs and
quenched with ice cold water. The reaction mixture was extracted
with chloroform, washed well with water and dried over anhydrous
MgSO.sub.4. It was filtered and concentrated. The crude product
obtained was taken to next step without any purification. A mixture
of tosylate (334 mg. 1 mmol) (obtained by the above mentioned
process) and 3 (1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg,
1 mmol) was heated at 120.degree. C. in DMSO in the presence of
N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end,
the reaction mixture was quenched with water and extracted with
chloroform. The organic layer was washed with water and dried over
anhydrous MgSO.sub.4 and concentrated to dryness. The dark colored
solid was purified by silica-gel column chromatography by eluting
it with 70% ethyl acetate: hexane.
3-{1-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}-1H-indole was isolated as yellow solid. mp 158.degree. C.; Yield:
140 mg (38%); 361 (M+H); 1H NMR: .delta. 8.2 (bs, 1H), 7.9 (d,1H),
7.59 (s, 1H), 7.45-7.0 (m, 7H), 6.39s, 1H), 3.4 (m, 2H), 3.0 (m,
2H), 2.84 (m, 4H), 2.68 (m, 2H).
Example 18
Preparation of
3-{1-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}-5-cyano-1H-indole ("Compound 18")
[0195]
3-{1-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-py-
ridinyl}-5-cyano-1H-indole was prepared by generally following the
procedure outlined in example 17, step 6, starting from the
tosylate (334 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-5-cyano-1H-indole (223 mg, 1
mmol). The product was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate: hexane. Yellow solid; mp
259.degree. C. (HCl salt); Yield:120 mg (31%); 386 (M+H).
Example 19
Preparation of
3-{1-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}-5-fluoro-1H-indole ("Compound 19")
[0196]
3-{1-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-py-
ridinyl}-5-fluoro-1H-indole was prepared by generally following the
procedure outlined in example 17, step 6, starting from the
tosylate (334 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-5-fluoro-1H-indole (216 mg, 1
mmol). The product was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate: hexane. Dark semi-solid
solid; Yield: 180 mg, (47%); 379 (M+H); .sup.1H NMR: .delta.9.2
(bs, 1H), 8.8 (d, 1H), 8.3 (s, 1H), 8.2-6.8 (m, 6H), 6.2 (m, 1H),
3.9-3.0 (m, 10H).
Example 20
Preparation of
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-1H-indole ("Compound 20")
[0197] Step 1: A mixture of 7-methoxy-benzofuran-3 (2H)-one (1.64
g, 10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15
mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, the
reaction mixture was concentrated and loaded over silica-gel
column. The column was eluted with hexane (500 ml) and later with
25% ethyl acetate. The product,
ethyl(7-methoxy-1-benzofuran-3-yl)acetate was obtained as a white
oil. Yield: 1.9 g (81%); 235 (M+H).
[0198] Step 2: To a stirred suspension of LiAlH.sub.4 (200 mg,
excess) in THF at 0.degree. C., ethyl(7-methoxy
-1-benzofuran-3-yl)acetate (1.17 g, 5 mmol) in THF (20 mL) was
added slowly. After the addition, the reaction mixture was stirred
at room temperature for 1 hr and quenched with saturated NH.sub.4Cl
solution. The product was extracted with chloroform and washed well
with water. It was dried over anhydrous MgSO.sub.4; filtered and
concentrated. The product, 2-(7-methoxy-1-benzofuran-3-yl)ethanol
obtained as a white oil, was pure enough and taken to the next step
without purification. Yield: 800 mg (83%); 193 (M+H).
[0199] Step 3: To a stirred solution of
2-(7-methoxy-1-benzofuran-3-yl)ethanol (960 mg, 5 mmol) in
anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine
(1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room
temperature. The reaction mixture was stirred at room temperature
for 4 hrs and quenched with water. The reaction mixture was
extracted with chloroform, washed well with 5%
Na.sub.2S.sub.2O.sub.3 solution and the organic layer was dried
over anhydrous MgSO.sub.4. It was filtered and concentrated. The
residue was purified by silica-gel column chromatography by eluting
it with 30% ethyl acetate: hexane. The product, namely
2-(7-methoxy-1-benzofuran-3-yl)ethyl iodide, was obtained as brown
liquid. Yield: 1.3 g (86%); 302 (M+H).
[0200] A mixture of 2-(7-methoxy-1-benzofuran-3-yl)ethyl iodide
(301 mg. 1 mmol) (obtained by the above mentioned process) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1 mmol) was
heated at 120.degree. C. in DMSO in the presence of
N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end,
the reaction mixture was quenched with water and extracted with
chloroform. The organic layer was washed with water and dried over
anhydrous MgSO.sub.4 and concentrated to dryness. The dark colored
solid was purified by silica-gel column chromatography by eluting
it with 70% ethyl acetae: hexane.
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-1H-indole was isolated as yellow solid. mp 156.degree. C.;
Yield: 80 mg (21%); 373 (M+H); .sup.1H NMR: .delta. 8.4 (bs, 1H),
7.9 (d,1H), 7.5 (s, 1H), 7.35-6.80 (m, 7H), 6.2 (m,1H), 3.97 (s,
3H), 3.50 (m,2H), 3.19 (m, 2H), 2.93 (m, 4H), 2.67 (m, 2H).
Example 21
Preparation of
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-6-fluoro-1H-indole ("Compound 21")
[0201]
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-p-
yridinyl}-6-fluoro-1H-indole was prepared by generally following
the procedure outlined in example 20, step 3, starting from
2-(7-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-6-fluoro-1H-indole (216 mg, 1
mmol). The product was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate: hexane. Brown solid; mp
136.degree. C.; Yield: 120 mg (30%); 391 (M+H); .sup.1H NMR:
.delta.8.25 (bs, 1H), 7.8 (m,1H), 7.4 (s, 1H), 7.25 (s,1H),
7.3-6.80 (m, 5H), 6.17 (m,1H), 4.01 (s, 3H), 3.40 (m,2H), 3.02 (m,
2H), 2.93 (m, 4H), 2.65 (m, 2H).
Example 22
Preparation of
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-5-fluoro-1H-indole ("Compound 22")
[0202]
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-p-
yridinyl}-5-fluoro-1H-indole was prepared by generally following
the procedure outlined in example 20, step 3, starting from
2-(7-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-5-fluoro-1H-indole (216 mg, 1
mmol). The product was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate: hexane. Brown solid; mp
171.degree. C.; Yield: 60 mg (15%); 391 (M+H); .sup.1H NMR:
.delta.8.16 (bs, 1H), 7.6-7.5 (m,2H), 7.3-6.75 (m, 6H), 6.17
(m,1H), 4.01 (s, 3H), 3.35 (m,2H), 3.19 (m, 2H), 2.91 (m, 4H), 2.64
(m, 2H).
Example 23
Preparation of
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-5-cyano-1H-indole ("Compound 23")
[0203]
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-p-
yridinyl}-5-cyano-1H-indole was prepared by generally following the
procedure outlined in example 20, step 3, starting from
2-(7-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-5-cyano-1H-indole (223 mg, 1
mmol). The product was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate: hexane. Brown solid; mp
72.degree. C.; Yield: 50 mg (12%); 398 (M+H); .sup.1H NMR (DMSO):
.delta.11.2 (bs, 1H), 8.7 (d, 1H), 8.51 (s, 1H), 8.30 (s, 1H), 8.24
(s, 1H), 7.79-6.9 (m, 4H), 6.21 (m,1H), 3.92 (s, 3H), 3.23 (m,2H),
2.89 9 m, 2H), 2.75 (m, 4H), 2.5 (m, 2H).
Example 24
Preparation of
3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-1H-indole ("Compound 24")
[0204] Step 1: To a stirred solution of
methyl-5-methoxy-2-hydroxy-benzoate (18.2 g, 0.1 mol) and anhydrous
potassium carbonate (50.0 g, excess) in acetone (500 ml) ethyl
bromoacetate (16.7 g, 0.1 mol) was added. The reaction mixture was
refluxed for 24 hrs and cooled to room temperature. It was filtered
and concentrated. The oily residue was extracted with chloroform
and washed well with water. The organic layer was dried over
anhydrous MgSO.sub.4 and filtered. It was concentrated and taken to
next step without any purification. Yellow oil; Yield: 21.0 g
(78%); 269 (M+H).
[0205] Step 2: The methyl-2-(ethoxy-2-oxoethoxy)-5-methoxy-benzoate
obtained from step 1, (13.4 g, 50 mmol ) was dissolved in THF:MeOH
(1:1) (300 ml) and 5N NaOH (100 ml) was added. The reaction mixture
was refluxed for 24 hrs and cooled to room temperature. At the end
it was concentrated to dryness and dissolved in water. The aqueous
layer was acidified with con. HCl and the separated solid were
filtered, washed well with water and dried. The product was taken
to step without any purification. White solid; Yield: 10.2 g (90%);
mp 150-153.degree. C.; 227 (M+H).
[0206] Step 3: The 2-(carboxymethoxy)-5-methoxy-benzoic acid
compound obtained from the step 2 (11.3 g, 50 mmol) was dissolved
in acetic anhydride (100 ml) and anhydrous sodium acetate (10.0 g,
excess) was added. The reaction mixture was heated to 150.degree.
C. for 4 hrs. During this time the reaction mixture turned dark
red. The reaction mixture was cooled to room temperature and
quenched carefully with ice cold water. The red solid obtained was
filtered and washed well with water. The red solid obtained was
suspended in 1 N HCl and refluxed for 2 hrs. A dark red solid,
5-methoxy-benzofuran-3 (2H)-one, precipitated from the reaction
mixture. It was filtered and washed well with water. It was dried
at 40.degree. C. and used for the next step without further
purifications. Yield: 6.2 g (75%); 165 (M+H).
[0207] Step 4: A mixture of 5-methoxy-benzofuran-3 (2H)-one (1.64
g, 10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15
mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, the
reaction mixture was concentrated and loaded over silica-gel
column. The column was eluted with hexane (500 ml) and later with
25% ethyl acetate. The product,
ethyl(5-methoxy-1-benzofuran-3-yl)acetate, was obtained as a white
oil. Yield: 1.6 g (68%); 235 (M+H).
[0208] Step 5: To a stirred suspension of LiAlH.sub.4 (200 mg,
excess) in THF at 0.degree. C., ethyl(5-methoxy
-1-benzofuran-3-yl)acetate (1.17 g, 5 mmol) in THF (20 mL) was
added slowly. After the addition, reaction mixture was stirred at
room temperature for 1 hr and quenched with saturated NH.sub.4Cl
solution. The product was extracted with chloroform and washed well
with water. It was dried over anhydrous MgSO.sub.4; filtered and
concentrated. The product, 2-(5-methoxy-1-benzofuran-3-yl)ethanol,
obtained as white oil, was pure enough and taken to the next step
without purification. Yellow oil; Yield: 900 mg (93%); 193
(M+H).
[0209] Step 6: To a stirred solution of
2-(5-methoxy-1-benzofuran-3-yl)ethanol (960 mg, 5 mmol) in
anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine
(1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room
temperature. The reaction mixture was stirred at room temperature
for 4 hrs and quenched with water. It was extracted with
chloroform, washed well with 5% Na.sub.2S.sub.2O.sub.3 solution and
the organic layer was dried over anhydrous MgSO.sub.4. It was
filtered and concentrated. The residue was purified by silica-gel
column chromatography by eluting it with 30% ethyl acetate: hexane.
The product, namely 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide,
was obtained as brown liquid. Yield: 1.1 g (73%); 302 (M+H).
[0210] A mixture of 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide
(301 mg. 1 mmol) (obtained by the above mentioned process) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1 mmol) was
heated at 120.degree. C. in DMSO in the presence of
N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end,
the reaction mixture was quenched with water and extracted with
chloroform. The organic layer was washed with water and dried over
anhydrous MgSO.sub.4 and concentrated to dryness. The dark colored
solid was purified by silica-gel column chromatography by eluting
it with 70% ethyl acetae: hexane.
3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-1H-indole was isolated as yellow oil. Yield: 160 mg (43%); 373
(M+H); .sup.1HNMR (400 MHz, CDCl.sub.3): .delta.8.74 (broad, s, 1H,
NH); 7.80.about.6.70 (m, 8H); 6.2 (s, 1H); 3.90 (s, 3H);
3.50.about.2.60 (m, 11H).
Example 25
Preparation of
3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-5-fluoro-1H-indole ("Compound 25")
[0211]
3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-p-
yridinyl}-5-fluoro-1H-indole was prepared by generally following
the procedure outlined in example 24, step 6, starting from
2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-5-fluoro-1H-indole (216 mg, 1
mmol). The product was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate: hexane. Brown solid; Yield:
142 mg (36%); 391 (M+H); .sup.1HNMR (400 MHz, CDCl.sub.3): .delta.
8.63.about.8.61 (dd, J1=1.6 Hz, J2=1.6 Hz, 1H); 8.24.about.8.19 (s,
1H); 7.60.about.6.84 (m, 7H); 6.15.about.6.16 (s, 1H);
3.86.about.3.82 (s, 3H); 3.36.about.2.65) (m, 10H).
Example 26
Preparation of
3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-6-fluoro-1H-indole ("Compound 26")
[0212]
3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-p-
yridinyl}-6-fluoro-1H-indole was prepared by generally following
the procedure outlined in example 24, step 6, starting from
2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-6-fluoro-1H-indole (216 mg, 1
mmol). The product was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate: hexane. Brown solid; Yield:
122 mg (31%); 391 (M+H); .sup.1HNMR (400 MHz, CDCl.sub.3): .delta.
8.74 (broad, s, 1H, NH); 7.80.about.6.70 (m, 7H); 6.20 (s, 1H);
3.90 (s, 3H); 3.50.about.2.60 (m, 11H).
Example 27
Preparation of
3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridiny-
l}-7-ethyl-1H-indole ("Compound 27")
[0213]
3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-p-
yridinyl}-7-ethyl-1H-indole was prepared by generally following the
procedure outlined in example 24, step 6, starting from
2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-7-ethyl-1H-indole (226 mg, 1
mmol). The product was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate: hexane. Brown solid; Yield:
156 mg (39%); 401 (M+H); .sup.1HMNR (400 MHz, CDCl.sub.3): .delta.
8.04 (broad s, 1H, NH); 7.77.about.7.75 (d, 7.9HZ, 1H);
7.51.about.6.88 (m, 7H); 6.23.about.6.21 (s, 1H); 3.85 (s, 3H);
3.36.about.2.65 (m, 12H); 1.25.about.1.27 (t, J=7.0 Hz, 3H).
Example 28
Preparation of
3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H--
indole ("Compound 28")
[0214] Step 1: To a stirred suspension of LiAlH.sub.4 (200 mg,
excess) in THF at 0.degree. C.,
ethyl(-1-benzothiophene-3-yl)acetate (1.1 g, 5 mmol) in THF (20 mL)
was added slowly. After the addition, the reaction mixture was
stirred at room temperature for 1 hr and quenched with saturated
NH.sub.4Cl solution. The product was extracted with chloroform and
washed well with water. It was dried over anhydrous MgSO.sub.4;
filtered and concentrated. The product,
2-(1-benzothiophene-3-yl)ethanol, was obtained as white oil pure
enough and taken to the next step without purification. Yield: 850
mg (95%); 179 (M+H).
[0215] Step 2: To a stirred solution of
2-(1-benzothiophene-3-yl)ethanol (890 mg, 5 mmol) in anhydrous THF
(50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6
mmol) and imidazole (408 mg, 6 mmol) were added at room
temperature. The reaction mixture was stirred at room temperature
for 4 hrs and quenched with water. It was extracted with
chloroform, washed well with 5% Na.sub.2S.sub.2O.sub.3 solution and
the organic layer was dried over anhydrous MgSO.sub.4. It was
filtered and concentrated. The residue was purified by silica-gel
column chromatography by eluting it with 30% ethyl acetate: hexane.
The product, namely 2-(1-benzothiophene-3-yl)ethyl iodide, was
obtained as brown liquid. Yield: 1.2 g (85%); 285 (M+H).
[0216] A mixture of 2-(1-benzothiophene-3-yl)ethyl iodide (284 mg.
1 mmol) (obtained by the above mentioned process) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1 mmol) was
heated at 120.degree. C. in DMSO in the presence of
N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end,
the reaction mixture was quenched with water and extracted with
chloroform. The organic layer was washed with water and dried over
anhydrous MgSO.sub.4 and concentrated to dryness. The dark colored
solid was purified by silica-gel column chromatography by eluting
it with 70% ethyl acetae: hexane.
3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H--
indole was isolated as yellow solid. mp 195-198.degree. C.; Yield:
180 mg (50%); 359 (M+H); .sup.1HNMR (400 MHz, CDCl.sub.3): .delta.
8.12 (broad s, 1H, NH); 7.92.about.6.69 (m, 10H); 6.25.about.6.23
(s, 1H); 3.48.about.2.60 (m, 10H).
Example 29
Preparation of
3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-(-
2-propenyl)-1H-indole ("Compound 29")
[0217]
3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridin-
yl}-1H-indole (358 mg,1 mmol) (obtained from example 29, step 2) in
dry THF (50 ml) was slowly added to a stirred suspension of hexane
and washed with 60% sodium hydride (44 mg) at 0.degree. C. After
the addition, the reaction mixture was stirred for 330 min and
allyl bromide (183 mg, 1.5 mmol) was added. The reaction mixture
was stirred for 4 hrs and quenched carefully with ice cold water.
The reaction mixture was extracted with chloroform; washed well
with water; dried over anhydrous MgSO.sub.4; filtered and
concentrated. The residue obtained was purified by silica-gel
column chromatography by eluting it with 50% ethyl acetate: hexane.
Yellow semi-solid. Yield: 195 mg (48%); 399 (M+H); .sup.1HNMR (400
MHz, CDCl.sub.3): .delta. 7.99.about.7.87 (m, 3H); 7.42.about.6.99
(m, 6H); 6.22.about.6.21 (s, 1H); 5.22.about.5.21 (d, J=1.3 Hz,
2H); 5.20 5.19 (d, J=1.3 Hz, 2H); 4.71.about.4.65 (d, 1.6 Hz, 2H);
3.49.about.2.67 (m, 10H).
Example 30
Preparation of
3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-m-
ethyl-1H-indole ("Compound 30")
[0218]
3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridin-
yl}-1H-indole (358 mg,1 mmol) (obtained from example 29, step 2) in
dry THF (50 ml) was slowly added to a stirred suspension of hexane
and washed with 60% sodium hydride (44 mg) at 0.degree. C. After
the addition, the reaction mixture was stirred for 30 min and
methyl iodide (213 mg, 1.5 mmol) was added. The reaction mixture
was stirred for 4 hrs and quenched carefully with ice cold water.
The reaction mixture was extracted with chloroform; washed well
with water; dried over anhydrous MgSO.sub.4; filtered and
concentrated. The residue obtained was purified by silica-gel
column chromatography by eluting it with 50% ethyl acetate: hexane.
Light green semi-solid. Yield: 98 mg (26%); 373 (M+H); .sup.1HNMR
(400 MHz, CDCl.sub.3): 8.08.about.7.82 (m, 3H); 7.40.about.6.90 (m,
7H); 6.21.about.6.19 (s, 1H); 3.80 (s, 3H); 3.48.about.2.60 (m,
10H).
Example 31
Preparation of
3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyrid-
inyl}-1H-indole ("Compound 31")
[0219] Step 1: To a stirred suspension of LiAlH.sub.4 (200 mg,
excess) in THF at 0.degree. C.,
ethyl(5-chloro-1-benzothiophene-3-yl)acetate (1.27 g, 5 mmol) in
THF (20 mL) was added slowly. After the addition, the reaction
mixture was stirred at room temperature for 1 hr and quenched with
saturated NH.sub.4Cl solution. The product was extracted with
chloroform and washed well with water. It was dried over anhydrous
MgSO.sub.4; filtered and concentrated. The product,
2-(5-chloro-1-benzothiophene-3-yl)ethanol, was obtained as white
oil, was pure enough and taken to the next step without
purification. Yield: 920 mg (86%); 213 (M+H).
[0220] Step 2: To a stirred solution of
2-(5-chloro-1-benzothiophene-3-yl)ethanol (1060 mg, 5 mmol) in
anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine
(1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room
temperature. The reaction mixture was stirred at room temperature
for 4 hrs and quenched with water. It was extracted with
chloroform, washed well with 5% Na.sub.2S.sub.2O.sub.3 solution and
the organic layer was dried over anhydrous MgSO.sub.4. It was
filtered and concentrated. The residue was purified by silica-gel
column chromatography by eluting it with 30% ethyl acetate: hexane.
The product, namely 2-(5-chloro-1-benzothiophene-3-yl)ethyl iodide,
was obtained as brown liquid; Yield: 1.1 g (69%); 319 (M+H).
[0221] A mixture of 2-(5-chloro-1-benzothiophene-3-yl)ethyl iodide
(318 mg. 1 mmol) (obtained by the above mentioned process) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1 mmol) was
heated at 120.degree. C. in DMSO in the presence of
N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end,
the reaction mixture was quenched with water and extracted with
chloroform. The organic layer was washed with water and dried over
anhydrous MgSO.sub.4 and concentrated to dryness. The dark colored
solid was purified by silica-gel column chromatography by eluting
it with 70% ethyl acetate: hexane.
3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H--
indole was isolated as yellow oil; Yield: 115 mg (29%); 393 (M+H);
.sup.1H -NMR: .delta. 8.10(1H, s, NH), 7.91(1H, d, J=8 Hz),
7.77(2H, m), 7.25(6H, m), 6.24(1H, s), 3.37(2H, d, J=3 Hz),
3.18(2H, t, J=7.7 Hz), 2.87(4H, m), 2.68(2H, s).
Example 32
Preparation of
3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyrid-
inyl}-1-(2-propenyl)-1H-indole ("Compound 32")
[0222]
3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro--
4-pyridinyl}-1H-indole (392 mg,1 mmol) (obtained from example 32,
step 2) in dry THF (50 ml) was slowly added to a stirred suspension
of hexane and was washed with 60% sodium hydride (44 mg) at
0.degree. C. After the addition, the reaction mixture was stirred
for 30 min and allyl bromide (183 mg, 1.5 mmol) was added. The
reaction mixture was stirred for 4 hrs and quenched carefully with
ice cold water. The reaction mixture was extracted with chloroform;
washed well with water; dried over anhydrous MgSO.sub.4; filtered
and concentrated. The residue obtained was purified by silica-gel
column chromatography by eluting it with 50% ethyl acetate: hexane.
Yellow semi-solid. Yield: 156 mg (36%); 432 (M+H); .sup.1H NMR:
.delta. 7.90(1H, s, NH), 7.78(3H,m), 7.26(6H, m), 6.21(1H, s),
5.99(1H, m), 5.13(2H, m), 4.71(2H, m), 3.40(2H, s), 3.15(2H, m),
2.92(4H, m), 2.68(2H, s).
Example 33
Preparation of
3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyrid-
inyl}-1-methyl-1H-indole ("Compound 33")
[0223]
3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro--
4-pyridinyl}-1H-indole (392 mg,1 mmol) (obtained from example 32,
step 2) in dry THF (50 ml) was slowly added to a stirred suspension
of hexane washed 60% sodium hydride (44 mg) at 0.degree. C. After
the addition, the reaction mixture was stirred for 30 min and
methyl iodide (213 mg, 1.5 mmol) was added. The reaction mixture
was stirred for 4 hrs and quenched carefully with ice cold water.
The reaction mixture was extracted with chloroform; washed well
with water; dried over anhydrous MgSO.sub.4; filtered and
concentrated. The residue obtained was purified by silica-gel
column chromatography by eluting it with 50% ethyl acetate: hexane.
Brown semi-solid. Yield: 150 mg (36%); 407 (M+H); .sup.1H NMR:
.delta. 7.91(1H, m), 7.78(3H,m), 7.26(6H, m), 6.21(1H, s),
3.77(3H,s), 3.40(2H, s), 3.15(2H, m), 2.92(4H, m), 2.68(2H, s).
Example 34
Preparation of
3-{1-(2-Naphtho[1,2-b]furan-3-yl-ethyl)-piperidin-4-yl]-1H-indole
("Compound 34")
[0224] Step 1: To a stirred solution of
1-hydroxy-naphthalene-2-carboxylic acid methyl ester (20.2 g, 0.1
mol) and anhydrous potassium carbonate (50.0 g, excess) in acetone
(500 ml) ethyl bromoacetate (16.7 g, 0.1 mol) was added. The
reaction mixture was refluxed for 24 hrs and cooled to room
temperature. It was filtered and concentrated. The oily residue was
extracted with chloroform and washed well with water. The organic
layer was dried over anhydrous MgSO.sub.4 and filtered. It was
concentrated and taken to next step without any purification. White
oil; Yield: 22.0 g (92%); 239 (M+H).
[0225] Step 2: The
1-methoxycarbonylmethoxy-naphthalene-2-carboxylic acid methyl ester
obtained from the step 1, (13.7 g, 50 mmol) was dissolved in
THF:MeOH (1:1) (300 ml) and 5N NaOH (100 ml) was added. The
reaction mixture was refluxed for 24 hrs and cooled to room
temperature. At the end it was concentrated to dryness and
dissolved in water. The aqueous layer was acidified with con. HCl
and the separated solid was filtered. It was washed well with water
and dried. The product, 1-carboxymethoxy-naphthalene-2-carboxylic
acid was taken to step with out any purification. White solid;
Yield: 10.0 g (81%); 247 (M+H).
[0226] Step 3: The 1-carboxymethoxy-naphthalene-2-carboxylic acid
compound obtained from step 2 (12.3 g, 50 mmol) was dissolved in
acetic anhydride (100 ml) and anhydrous sodium acetate (10.0 g,
excess) was added. The reaction mixture was heated to 150.degree.
C. for 4 hrs. During this time the reaction mixture turned dark
red. The reaction mixture was cooled to room temperature and
quenched carefully with ice cold water. The red solid obtained was
filtered and washed well with water. The red solid obtained was
suspended in 1 N HCl and refluxed for 2 hrs. A dark red solid,
naphtho[1,2-b]furan-3 (2H)-one, precipitated from the reaction
mixture. It was filtered and washed well with water. It was dried
at 40.degree. C. and used for the next step without further
purifications. Yield: 4.5 g (48%); 185 (M+H).
[0227] Step 4: A mixture of naphtho[1,2-b]furan-3 (2H)-one (1.85 g,
10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15
mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end,
reaction mixture was concentrated and loaded over a silica-gel
column. The column was eluted with hexane (500 ml) and later with
25% ethyl acetate. The product, naphtho[1,2-b]furan-3-yl-acetic
acid ethyl ester was obtained as a white oil. Yield: 2.2 g (86%);
255 (M+H).
[0228] Step 5: To a stirred suspension of LiAlH.sub.4 (200 mg,
excess) in THF at 0.degree. C., naphtho[1,2-b]furan-3-yl-acetic
acid ethyl ester (1.27 g, 5 mmol) in THF (20 mL) was added slowly.
After the addition, reaction mixture was stirred at room
temperature for 1 hr and quenched with saturated NH.sub.4Cl
solution. The product was extracted with chloroform and washed well
with water. It was dried over anhydrous MgSO.sub.4; filtered and
concentrated. The product, 2-naphtho[1,2-b]furan-3-yl ethanol, was
obtained as white oil, was pure enough and taken to the next step
without purification. Yield: 900 mg (84%); 213 (M+H).
[0229] Step 6: To a stirred solution of 2-naphtho[1,2-b]furan-3-yl
ethanol (1.06 g, 5 mmol) in anhydrous THF (50 ml),
triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6 mmol) and
imidazole (408 mg, 6 mmol) were added at room temperature. The
reaction mixture was stirred at room temperature for 4 hrs and
quenched with water. It was extracted with chloroform, washed well
with 5% Na.sub.2S.sub.2O.sub.3 solution and the organic layer was
dried over anhydrous MgSO.sub.4. It was filtered and concentrated.
The residue was purified by silica-gel column chromatography by
eluting it with 30% ethyl acetate: hexane. The product, namely
3-(2-iodo-ethyl)-naphtho[1,2-b]furan, was obtained as brown liquid.
Yield: 1.4 g (87%); 322 (M+H).
[0230] A mixture of 3-(2-iodo-ethyl)-naphtho[1,2-b]furan (321mg. 1
mmol) (obtained by the above mentioned process) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1 mmol) was
heated at 120.degree. C. in DMSO in the presence of
N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end,
the reaction mixture was quenched with water and extracted with
chloroform. The organic layer was washed with water and dried over
anhydrous MgSO.sub.4 and concentrated to dryness. The dark colored
solid was purified by silica-gel column chromatography by eluting
it with 70% ethyl acetate: hexane.
3-{1-(2-naphtho[1,2-b]furan-3-yl-ethyl)-1,2,3,6-tetrahydro-4-pyridinyl}-1-
H-indole was isolated as yellow solid. Yield: 120 mg (30%); 393
(M+H).
[0231] Step 7:
3-{1-(2-naphtho[1,2-b]furan-3-yl-ethyl)-piperidin-4-yl]-1H-indole
(197 mg, 0.5 mmol) obtained from step 6, was hydrogenated over 10%
Pd/C in ethanol at 40 psi pressure. At the end, reaction mixture
was filtered through a pad of celite and concentrated. The product
obtained was purified by silica-gel column chromatography by
eluting it with 70% ethyl acetate: hexane.
3-{1-(2-naphtho[1,2-b]furan-3-yl-ethyl)-piperidin-4-yl]-1H-indole
was isolated as yellow solid; Yield: 160 mg (81%); 395 (M+H);
.sup.1H NMR: .delta. 8.30 (1H, d, J=8 Hz), 7.99 (1H, s, NH),
7.94(1H, d, J=8 Hz), 7.67(4H, m), 7.58(1H, t, J=8 Hz), 7.48(1H, t,
J=8 Hz), 7.38(1H, d, J=8 Hz), 7.20(1H, t, J=8 Hz), 7.13(1H, t, J=8
Hz), 7.0(1H, s), 3.21(2H, d, J=12 Hz), 3.04(1H, m), 2.90(1H, m),
2.84(2H, m), 2.29(2H, m), 2.13(2H, d, J=12 Hz), 1.90(2H, m, J=12
Hz).
Example 35
Preparation of
3-{1-[2-(1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-ind-
ole ("Compound 35")
[0232] Step 1: A mixture of benzofuran-3 (2H)-one (1.34 g, 10 mmol)
and ethyl-2-(triphenylphosphoranylidene)propionate (5.436 g, 15
mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, the
reaction mixture was concentrated and loaded over silica-gel
column. The column was eluted with hexane (500 ml) and later with
25% ethyl acetate. The product, ethyl(-1-benzofuran-3-yl)propanoate
was obtained as a white oil. Yield: 1.6 g (67%); 219 (M+H).
[0233] Step 2: To a stirred suspension of LiAlH.sub.4 (200 mg,
excess) in THF at 0.degree. C., ethyl(-1-benzofuran-3-yl)propanoate
(1.09 g, 5 mmol) in THF (20 mL) was added slowly. After the
addition, the reaction mixture was stirred at room temperature for
1 hr and quenched with saturated NH.sub.4Cl solution. The product
was extracted with chloroform and washed well with water. It was
dried over anhydrous MgSO.sub.4; filtered and concentrated. The
product, 2-(1-benzofuran-3-yl)-1-propanol, was obtained as white
oil, was pure enough and taken to the next step without
purification. Yield: 700 mg (79%); 177 (M+H).
[0234] Step 3: To a stirred solution of
2-(1-benzofuran-3-yl)-1-propanol (880 mg, 5 mmol) in anhydrous
pyridine (20 ml), p-toluenesulfonyl chloride (1.14 g, 6.0 mmol) was
added. The reaction mixture was kept at 0.degree. C. for 48 hrs and
quenched with ice cold water. The reaction mixture was extracted
with chloroform, washed well with water and dried over anhydrous
MgSO.sub.4. It was filtered and concentrated. The crude product
obtained was taken to next step without any purification.
[0235] A mixture of tosylate (331 mg. 1 mmol) (obtained by the
above mentioned process) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1 mmol) was
heated at 120.degree. C. in DMSO in the presence of
N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end,
the reaction mixture was quenched with water and extracted with
chloroform. The organic layer was washed with water and dried over
anhydrous MgSO.sub.4 and concentrated to dryness. The dark colored
solid was purified by silica-gel column chromatography by eluting
it with 70% ethyl acetate: hexane.
3-{1-[2-(1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-ind-
ole was isolated as yellow oil; Yield: 110 mg (30%); 357 (M+H);
.sup.1HNMR (400 MHz, CDCl.sub.3): .delta. 8.16.about.8.11 (s, 1H,
NH); 7.91.about.6.99 (m, 10H); 6.21.about.6.10 (s, 1H);
3.70.about.2.60, 9H); 1.46.about.1.44 (d, J=7.0 Hz, 3H).
Example 36
Preparation of
3-{1-[2-(1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluo-
ro-1H-indole ("Compound 36")
[0236]
3-{1-[2-(1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-
-6-fluoro-1H-indole was prepared by generally following the
procedure outlined in example 35, step 3, starting from the
tosylate (example 36, step 3) (331 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-6-fluoro-1H-indole (216 mg, 1
mmol). The product was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate: hexane. Brown oil; Yield: 148
mg (39%); 375 (M+H); .sup.1HNMR (400 MHz, CDCl.sub.3): .delta. 8.03
(broad s, 1H, NH); 7.79.about.6.89 (m, 9H); 6.17.about.6.15 (s,
1H); 3.35.about.2.60 (m, 9H); 1.46.about.1.44 (d, J=7.0 Hz,
3H).
Example 37
Preparation of
3-{1-[2-(1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluo-
ro-1H-indole ("Compound 37")
[0237]
3-{1-[2-(1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-
-5-fluoro-1H-indole was prepared by generally following the
procedure outlined in example 35, step 3, starting from the
tosylate (example 36, step 3) (331 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-5-fluoro-1H-indole (216 mg, 1
mmol). The product was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate: hexane. Brown oil; Yield: 160
mg (42%); 375 (M+H); .sup.1HNMR (400 MHz, CDCl.sub.3):
.delta.8.56.about.8.46 (broad s, 1H, NH); 7.65.about.6.94 (m, 9H);
6.10.about.6.09 (s, 1H); 3.48.about.2.58 (m, 9H); 1.46.about.1.44
(d, 7.0 Hz, 3H).
Example 38
Preparation of
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridin-
yl}-1H-indole ("Compound 38")
[0238] Step 1: A mixture of 7-methoxy-benzofuran-3 (2H)-one (1.64
g, 10 mmol) and ethyl-2-(triphenylphosphoranylidene)propionate
(5.436 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At
the end, the reaction mixture was concentrated and loaded over a
silica-gel column. The column was eluted with hexane (500 ml) and
later with 25% ethyl acetate. The product,
ethyl(7-methoxy-1-benzofuran-3-yl)propanoate, was obtained as a
white oil. Yield: 1.9 g (76%); 249 (M+H).
[0239] Step 2: To a stirred suspension of LiAlH.sub.4 (200 mg,
excess) in THF at 0.degree. C.,
ethyl(7-methoxy-1-benzofuran-3-yl)propanoate (1.24 g, 5 mmol) in
THF (20 mL) was added slowly. After the addition, the reaction
mixture was stirred at room temperature for 1 hr and quenched with
saturated NH.sub.4Cl solution. The product was extracted with
chloroform and washed well with water. It was dried over anhydrous
MgSO.sub.4; filtered and concentrated. The product,
2-(7-methoxy-1-benzofuran-3-yl)-1-propanol, was obtained as white
oil, was pure enough and taken to the next step without
purification. Yield: 900 mg (87%); 207 (M+H).
[0240] Step 3: To a stirred solution of
2-(7-methoxy-1-benzofuran-3-yl)-1-propanol (1.03 g, 5 mmol) in
anhydrous pyridine (20 ml), p-toluenesulfonyl chloride (1.14 g, 6.0
mmol) was added. The reaction mixture was kept at 0.degree. C. for
48 hrs and quenched with ice cold water. The reaction mixture was
extracted with chloroform, washed well with water and dried over
anhydrous MgSO.sub.4. It was filtered and concentrated. The crude
product obtained was taken to next step without any
purification.
[0241] A mixture of tosylate (360 mg. 1 mmol) (obtained by the
above mentioned process) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1 mmol) was
heated at 120.degree. C. in DMSO in the presence of
N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end,
the reaction mixture was quenched with water and extracted with
chloroform. The organic layer was washed with water and dried over
anhydrous MgSO.sub.4 and concentrated to dryness. The dark colored
solid was purified by silica-gel column chromatography by eluting
it with 70% ethyl acetate: hexane.
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridin-
yl}-1H-indole was isolated as yellow solid. mp 156.degree. C.;
Yield: 160 mg (41%); 387 (M+H); .sup.1H NMR (DMSO): .delta.11.2
(bs, 1H), 7.8 9s, 1H), 7.3-6.8 (m, 8H), 6.1 (bs, 1H), 3.9 (s, 3H),
3.3-2.6 (m, 9H), 1.4 (d, 3H).
Example 39
Preparation of
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridin-
yl}-5-fluoro-1H-indole ("Compound 39")
[0242]
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4--
pyridinyl}-5-fluoro-1H-indole was prepared by generally following
the procedure outlined in example 38, step 3, starting from the
tosylate (example 39, step 3) (360 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-5-fluoro-1H-indole (216 mg, 1
mmol). The product was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate: hexane. Brown solid; Yield:
120 mg (29%); 405 (M+H); .sup.11HNMR (400 MHz, CDCl.sub.3):
.delta.8.13 (broad, 1H, NH); 7.90.about.6.20 (m, 7H); 6.10 (s, 1H);
3.96 (s, 3H); 3.30.about.2.60(m, 10H); 1.20.about.1.21 (d, J=7.2
Hz, 3H).
Example 40
Preparation of
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridin-
yl}-6-fluoro-1H-indole ("Compound 40")
[0243] 3
{1-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4--
pyridinyl}-6-fluoro-1H-indole was prepared by generally following
the procedure outlined in example 38, step 3, starting from the
tosylate (example 39, step 3) (360 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-6-fluoro-1H-indole (216 mg, 1
mmol). The product was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate: hexane. Brown solid; Yield:
180 mg (44%); 405 (M+H); .sup.1HNMR (400MHZ, CDCl.sub.3): .delta.
8.13 (broad, s, 1H, NH); 7.90.about.6.30 (m, 7H), 6.10 (s, 1H);
3.96 (s, 3H); 3.30.about.2.60 (m, 10H); 120.about.1.23 (d, J=7.2
Hz, 3H).
Example 41
Preparation of
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl]-1,2,3,6-tetrahydro-4-
-pyridinyl}-1H-indole ("Compound 41")
[0244] Step 1: A mixture of 7-methoxy-benzofuran-3 (2H)-one (1.64
g, 10 mmol) and 1-triphenylphosphoranylidene-2-propanone (4.77 g,
15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end,
the reaction mixture was concentrated and loaded over a silica-gel
column. The column was eluted with hexane (500 ml) and later with
25% ethyl acetate. The product,
1-(7-methoxy-1-benzofuran-3-yl)acetone, was obtained as a red oil.
Yield: 1.4 g (68%); 205 (M+H).
[0245] Step 2: To a stirred mixture of
1-(7-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198.0 mg, 1 mmol) in
1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium
triacetoxyborohydride (422 mg, 2 mmol) was added at room
temperature. The reaction mixture was stirred at room temperature
for 72 hrs. At the end, the reaction mixture was neutralized with
10% NaHCO.sub.3 and extracted with chloroform. The organic layer
was dried over anhydrous MgSO.sub.4; filtered and concentrated. The
product obtained was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate: hexane. Brown solid; Yield:
150 mg (38%); 387 (M+H); .sup.1HNMR (400 MHz, CDCl.sub.3):
.delta.8.31 (broad, s, 1H, NH); 7.92.about.6.88 (m, 8H); 6.25 (s,
1H); 3.85 (s, 3H); 3.50.about.2.60 (m, 10H); 1.03.about.1.05 (d,
J=8.0 Hz, 3H).
Example 42
Preparation of
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl]-1,2,3,6-tetrahydro-4-
-pyridinyl}-6-fluoro-1H-indole ("Compound 42")
[0246]
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl]-1,2,3,6-tetra-
hydro-4-pyridinyl}-6-fluoro-1H-indole was prepared by generally
following the procedure outlined in example 41, step 2, starting
from the 1-(7-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol)
and 3 (1,2,3,6-tetrahydro-4-pyridinyl)-6-fluoro-1H-indole (216.0
mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml),
sodium triacetoxyborohydride (422 mg, 2 mmol). The product was
purified by silica-gel column chromatography by eluting it with 80%
ethyl acetate: hexane. Brown solid; Yield: 60 mg (14%); 405 (M+H);
.sup.1HNMR (400 MHz, CDCl.sub.3): .delta. 8.31 (broad, s, 1H, NH);
7.92.about.6.88 (m, 7H); 6.25 (s, 1H); 3.85 (s, 3H),
3.50.about.2.60 (m, 10H); 1.03.about.1.05 (d, J=8.0 Hz, 3H).
Example 43
Preparation of
3-{1-[2-(5-methoxy-1-benzofuran-3-yl)-1-methylethyl]-1,2,3,6-tetrahydro-4-
-pyridinyl}-1H-indole ("Compound 43")
[0247] Step 1: A mixture of 5-methoxy-benzofuran-3 (2H)-one (1.64
g, 10 mmol) and 1-triphenylphosphoranylidene-2-propanone (4.77 g,
15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end,
reaction mixture was concentrated and loaded over silica-gel
column. The column was eluted with hexane (500 ml) and later with
25% ethyl acetate. The product,
1-(5-methoxy-1-benzofuran-3-yl)acetone was obtained as a red oil.
Yield: 1.1 g (53%); 205 (M+H).
[0248] Step 2: To a stirred mixture of
1-(5-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 3
(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198.0 mg, 1 mmol) in
1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium
triacetoxyborohydride (422 mg, 2 mmol) was added at room
temperature. The reaction mixture was stirred at room temperature
for 72 hrs. At the end, the reaction mixture was neutralized with
10% NaHCO.sub.3 and extracted with chloroform. The organic layer
was dried over anhydrous MgSO.sub.4; filtered and concentrated. The
product obtained was purified by silica-gel column chromatography
by eluting it with 80% ethyl acetate: hexane. Brown solid; Yield:
120 mg (31%); 387 (M+H); .sup.1HNMR(400 MHz, CDCl.sub.3):.delta.
8.31 (broad, s, 1H, NH); 7.92.about.6.88 (m, 8H); 6.25 (s, 1H);
3.85 (s, 3H); 3.50.about.2.60 (m, 10H); 1.03.about.1.05 (d, J=8.0
Hz, 3H).
Example 44
Preparation of
3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl-
}imidazo[1,2-a]pyridine ("Compound 44")
[0249] Step 1: To a stirred solution of imidazo[1,2-a]pyridine (5.9
g, 50 mmol) in dry diethyl ether (100 ml) at room temperature,
phenyllithium (1.8 M solution in cyclohexane:ether, 27.7 ml, 50
mmol) was slowly added. The reaction mixture was stirred at room
temperature for 1 hr and cooled to -78.degree. C. and
tert-butyl-4-oxo-1-piperidine carboxylate (9.9 g, 50 mml) in THF
(50 ml) was added slowly. Reaction mixture was stirred at room
temperature for 4 hrs and quenched with ice cold water and
extracted with chloroform; washed well with water and dried over
anhydrous MgSO.sub.4, filtered and concentrated. The product,
4-hydroxy-4-imidazo[1,2-a]pyridin-3-yl-piperidine-1-carboxylic acid
tert-butyl ester, was purified by silica-gel column chromatography
by eluting it with ethyl acetate. Yield: 6.g (37%); Brown oil; 320
(M+H).
[0250] Step 2: To a stirred solution of
4-hydroxy-4-imidazo[1,2-a]pyridin-3-yl-piperidine-1-carboxylic acid
tert-butyl ester (2.0 g 6.26 mmol) in CH.sub.2Cl.sub.2 (100 ml)
trifluoro acetic acid (10 ml) was added at room temperature. The
reaction mixture was stirred at room temperature for 24 hrs. At the
end, the reaction mixture was basified with methanolic ammonia and
concentrated to dryness. The residue was directly chromatographed
over silica-gel column and eluted with methanol:10% methanolic
ammonia. The product, 4-imidazo[1,2-a]pyridin-3-yl-piperidin-4-ol
was obtained as yellow oil; Yield; 620 mg (48%); 218 (M+H).
[0251] Step 3: To a stirred solution of
methyl-5-chloro-2-hydroxy-benzoate (18.6 g, 0.1 mol) and anhydrous
potassium carbonate (50.0 g, excess) in acetone (500 ml) ethyl
bromoacetate (16.7 g, 0.1 mol) was added. The reaction mixture was
refluxed for 24 hrs and cooled to room temperature. It was filtered
and concentrated. The oily residue was extracted with chloroform
and washed well with water. The organic layer was dried over
anhydrous MgSO.sub.4 and filtered. It was concentrated and taken to
next step without any purification. White oil; Yield: 20.0 g (73%);
273 (M+H).
[0252] Step 4: The methyl-2-(ethoxy-2-oxoethoxy)-5-chloro-benzoate
obtained from step 3, (13.6 g, 50 mmol) was dissolved in THF:MeOH
(1:1) (300 ml) and 5N NaOH (100 ml) was added. The reaction mixture
was refluxed for 24 hrs and cooled to room temperature. At the end
it was concentrated to dryness and dissolved in water. The aqueous
layer was acidified with con. HCl and the separated solid were
filtered. It was washed well with water and dried. The product was
taken to step without any purification. White solid; Yield: 8.0 g
(69%); 231 (M+H).
[0253] Step 5: The 2-(carboxymethoxy)-5-chloro-benzoic acid
compound obtained from step 4 (11.5 g, 50 mmol) was dissolved in
acetic anhydride (100 ml) and anhydrous sodium acetate (10.0 g,
excess) was added. The reaction mixture was heated to 150.degree.
C. for 4 hrs. During this time the reaction mixture turned dark
red. The reaction mixture was cooled to room temperature and
quenched carefully with ice cold water. The red solid obtained was
filtered and washed well with water. The red solid obtained was
suspended in 1 N hydrochloric acid and refluxed for 2 hrs. A dark
red solid, 5-chloro-benzofuran-3 (2H)-one, precipitated from the
reaction mixture. It was filtered and washed well with water. It
was dried at 40.degree. C. and used for the next step without
further purifications. Yield: 3.8 g (45%); 169 (M+H).
[0254] Step 6: A mixture of 5-chloro-benzofuran-3 (2H)-one (1.68 g,
10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15
mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end,
reaction mixture was concentrated and loaded over silica-gel
column. The column was eluted with hexane (500 ml) and later with
25% ethyl acetate. The product,
ethyl(5-chloro-1-benzofuran-3-yl)acetate was obtained as a white
oil. Yield: 1.8 g (75%); 239 (M+H).
[0255] Step 7: To a stirred suspension of LiAlH.sub.4 (200 mg,
excess) in THF at 0.degree. C., ethyl(5-chloro
-1-benzofuran-3-yl)acetate (1.19 g, 50 mmol) in THF (20 mL) was
added slowly. After the addition, reaction mixture was stirred at
room temperature for 1 hr and quenched with saturated NH.sub.4Cl
solution. The product was extracted with chloroform and washed well
with water. It was dried over anhydrous MgSO.sub.4; filtered and
concentrated. The product 2-(5-chloro-1-benzofuran-3-yl)ethanol,
was obtained as white oil, was pure enough and taken to the next
step without purification. Yield: 850 mg (86%); 197 (M+H).
[0256] Step 8: To a stirred solution of
2-(5-chloro-1-benzofuran-3-yl)ethanol (980 mg, 5 mmol) in anhydrous
pyridine (20 ml), p-toluenesulfonyl chloride (1.14 g, 6.0 mmol) was
added. The reaction mixture was kept at 0.degree. C. for 48 hrs and
quenched with ice cold water. The reaction mixture was extracted
with chloroform, washed well with water and dried over anhydrous
MgSO.sub.4. It was filtered and concentrated. The crude product
obtained was taken to next step without any purification.
[0257] A mixture of tosylate (350 mg. 1 mmol) (obtained by the
above mentioned process) and
4-imidazo[1,2-a]pyridine-3-yl-piperidin-4-ol (217 mg, 1 mmol)
(obtained from step 2) was heated at 120.degree. C. in DMSO in the
presence of N,N-diisopropylethylamine (5 ml, excess) for 72 hrs. At
the end, the reaction mixture was quenched with water and extracted
with chloroform. The organic layer was washed with water and dried
over anhydrous MgSO.sub.4 and concentrated to dryness. The dark
colored solid was purified by silica-gel column chromatography by
eluting it with 100% ethyl acetate.
3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl-
}imidazo[1,2-a]pyridine was isolated as yellow oil. Yield: 110 mg
(29%); 378 (M+H); .sup.1HNMR (400 MHz, CDCl.sub.3): 8.46.about.8.28
(m, 1H); 7.94.about.6.03 (m, 8H); 6.02 (s, 1H); 3.41.about.2.58 (m,
10H).
Example 45
Testing of Compounds
[0258] The 5-HT transporter affinity of the compounds of this
invention was established in accordance with standard
pharmaceutically accepted test procedures with representative
compounds as follows:
Rat Brain .sup.3H-Paroxetine Binding Assay (RB 5HT Transporter)
[0259] This assay was used to determine a compound's affinity of
the 5-HT transporter. A protocol similar to that used by Cheetham
et. al. (Neuropharmacol., 1993, 32: 737) was used. Briefly, frontal
cortical membranes prepared from male S.D. rats were incubated with
.sup.3H-parxetine (0.1 nM) for 60 min. at 25.degree. C. All tubes
also contained either vehicle, test compound (one to eight
concentrations), or a saturating concentration of fluoxetine (10
.mu.M) to define specific binding. All reactions are terminated by
the addition of ice cold Tris buffer followed by rapid filtration
using a Tom Tech filtration device to separate bound from free
.sup.3H-paroxetine. Bound radioactivity was quantitated using a
Wallac 1205 Beta Plate.RTM. counter. Nonlinear regression analysis
was used to determine IC.sub.50 values which were converted to
K.sub.i values using the method of Cheng and Prusoff (Biochem.
Pharmacol., 1973, 22: 3099). K i = IC 50 Radioligand .times.
.times. concentration / ( 1 + KD ) ##EQU1## Inhibition of
.sup.3H-5-HT Uptake By Cells Possessing the Human 5-HT Transporter
(HC 5HT Transporter)
[0260] A human carcinoma cell line (Jar cells) possessing low
endogenous levels of the 5-HT-transporter are seeded into 96 well
plates and treated with staurosporine at least 18 hrs prior to
assay. [Staurosporine greatly increases the expression of the
5-HT-transporter.] On the day of assay, vehicle, excess of
fluoxetine, or test compound is added to various wells on the
plate. All wells then receive .sup.3H-5-HT and are incubated at
37.degree. C. for 5 min. The wells are then washed with ice cold 50
mM Tris HCl (pH 7.4) buffer and aspirated to remove free
.sup.3H-5-HT. 25 .mu.l of 0.25 M NaOH is then added to each well to
lyse the cells and 75 .mu.l scintillation cocktail (Microscint.TM.
20) added prior to quantitation on a Packard TopCount machine.
Tubes with vehicle represent total possible uptake, radioactivity
counted in tubes with fluoxetine represent nonspecific
binding/uptake and is subtracted from the total possible uptake to
give total possible specific uptake. This nonspecific binding
(usual low in number) is then subtracted from the counts obtained
in wells with various test compounds (or different concentrations
of test drug) to give specific uptake in the presence of drug.
Specific uptake is then expressed as a % of control values and is
analyzed using nonlinear regression analysis (Prizm) to determine
IC.sub.50 values. If the compound is active at inhibiting 5-HT
uptake, its counts will be close to that obtained with
fluoxetine.
[0261] High affinity for the serotonin 5-HT.sub.1A receptor was
established by testing the claimed compound's ability to displace
[.sup.3H] 8-OH-DPAT (dipropylaminotetralin) from the 5-HT.sub.1A
serotonin receptor following a modification of the procedure of
Hall et al. (J. Neurochem., 1985, 44: 1685) which utilizes CHO
cells stably transfected with human 5-HT.sub.1A receptors. The
5-HT.sub.1A affinities for the compounds of the invention are
reported below as K.sub.is.
[0262] Antagonist activity at 5-HT.sub.1A receptors was established
by using a .sup.35S-GTP.gamma.S binding assay similar to that used
by Lazareno and Birdsall (Br. J. Pharmacol., 1993, 109: 1120), in
which the test compound's ability to affect the binding of
.sup.35S-GTP.gamma.S to membranes containing cloned human
5-HT.sub.1A receptors was determined. Agonists produce an increase
in binding whereas antagonists produce no increase but rather
reverse the effects of the standard agonist 8-OH-DPAT. The test
compound's maximum inhibitory effect is represented as the
I.sub.max, while its potency is defined by the IC.sub.50.
[0263] Results from these two assays are presented below in Table
I. TABLE-US-00001 TABLE I RB-5HT HC-5HT 5-HT.sub.1A Transporter
Transporter Example K.sub.i(nM) K.sub.i(nM) K.sub.i(nM) Compound 1
36.11 1.33 210.00 Compound 2 18.34 6.00 Not tested Compound 3 Not
tested 156.00 328.00 Compound 4 563.35 2.55 48.1 Compound 5 42%*
90.00 15.40 Compound 6 248.05 14.00 282.00 Compound 7 49%* 12.00
126.00 Compound 8 30%* 300.00 600.00 Compound 9 45%* 3.54 54.20
Compound 10 56.33 3.36 44.60 Compound 11 66.35 3.63 66.80 Compound
12 302.70 1.20 36.30 Compound 13 12.67 3.36 34.10 Compound 14 29%*
14.00 59.70 Compound 15 46%* 15.00 152.00 Compound 16 60%* 3.00
49.10 Compound 17 190.45 3.14 49.30 Compound 18 41.47 4.13 25.30
Compound 19 300.35 9.25 245.50 Compound 20 8.46 2.85 190.00
Compound 21 10.99 0.76 20.60 Compound 22 10.09 3.17 493.00 Compound
23 5.14 3.24 44.40 Compound 24 23%* 11.00 28.90 Compound 25 44%*
54.00 216.00 Compound 26 8%* 5.50 24.60 Compound 27 39%* 41.00
251.00 Compound 28 67.90 6.25 11.05 Compound 29 243.30 104.00
1120.00 Compound 30 53.15 13.00 421.00 Compound 31 29%* 172.00
2900.00 Compound 32 34%* 132.00 NT Compound 33 45%* 39.00 NT
Compound 34 48%* 62.00 276.00 Compound 35 28%* 16.00 130.00
Compound 36 11%* 4.43 42.00 Compound 37 20%* 21.00 152.00 Compound
38 29.17 3.98 62.80 Compound 39 48%* 13.00 178.00 Compound 40 48%*
1.97 37.60 Compound 41 11.48 8.93 68.80 Compound 42 69.39 3.74
48.70 Compound 43 34%* 12.00 144.00 Compound 44 44%* 97.00 63.80 *%
inhibition at 1 .mu.M.
[0264] Hence, the compounds of this invention not only inhibit or
block serotonin reuptake (thereby increasing levels of serotonin in
the synapse) but also antagonize the 5-HT.sub.1A receptors (thereby
reducing the latency period). The compounds of the invention would
thus be useful in the prevention and/or treatment of diseases
affected by disorders of the serotonin affected neurological
systems, including depression, anxiety, cognitive deficits, such as
those resulting from Alzheimer's disease and other
neurodegenerative disorders, schizophrenia, prostate cancer, and
nicotine withdrawal, by administration orally, parenterally, or by
aspiration to a patient in need thereof.
[0265] When ranges are used herein for physical properties, such as
molecular weight, or chemical properties, such as chemical
formulae, all combinations and subcombinations of ranges specific
embodiments therein are intended to be included.
[0266] The disclosures of each patent, patent application, and
publication cited or described in this document are herby
incorporated herein by reference, in their entirety.
[0267] Those skilled in the art will appreciate that numerous
changes and modifications can be made to the preferred embodiments
of the invention and that such changes and modifications can be
made without departing from the spirit of the invention. It is,
therefore, intended that the appended claims cover all such
equivalent variations as fall within the true spirit and scope of
the invention.
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