U.S. patent application number 10/784673 was filed with the patent office on 2004-08-26 for heterocyclic compounds for the treatment of migraine.
This patent application is currently assigned to NPS ALLELIX BIOPHARMACEUTICALS, INC.. Invention is credited to Edwards, Louise, Isaac, Methvin, Maddaford, Shawn, Slassi, Abdelmalik, Xin, Tao.
Application Number | 20040167158 10/784673 |
Document ID | / |
Family ID | 23391845 |
Filed Date | 2004-08-26 |
United States Patent
Application |
20040167158 |
Kind Code |
A1 |
Edwards, Louise ; et
al. |
August 26, 2004 |
Heterocyclic compounds for the treatment of migraine
Abstract
Described herein are compounds useful in the treatment of
migraine, which have the general formula: 1 wherein: W is a CH
group or a N atom; Z is N or C-R4; B and D are selected
independently from CH and N, with the proviso that at least one of
B and D is CH and with the further proviso that one of B and D can
represent N only when W and Z are both other than N; A is a group
of Formula II, III or IV, such that group A contains at least 1 N
atom; NR7 is either --NH-- or --N.dbd. is a single or double bond;
X is a N atom, a CH group or a C(OH) group when is a single bond;
or, when is a double bond, a C atom; Y is an NH, N-alkyl, N-benzyl
or CH.sub.2 group; U and V each represent a N atom or a CH group,
with the proviso that both cannot be N; a and b are, independently,
0 or 1; c is an integer from 0 to 3; d is an integer from 1 to 3; e
is an integer from 1 to 2; f is an integer from 0 to 3; g is an
integer from 3 to 6 and h is an integer from 2 to 3; such that the
sum of c and d is at least 2 and the sum of e and f is at least 2;
R.sub.1 is selected from the group consisting of H, alkyl,
alkyloxy, alkanoyl, aminoalkylenyl, alkylaminoalkylenyl, a
hydroxyalkylenyl group, an alkyloxyalkylenyl group, a cycloalkyl
group, a cycloalkylalkylenyl group, a heterocycloalkyl group, a
heterocycloalkylalkylenyl group, an aryl group, a heterocycloaryl
group, an amido group, a thioamido group, an arylcarbonyl group and
an arylsulfonyl group; R.sub.2 and R.sub.3 are independently
selected from the group consisting of H, alkyl, cycloalkyl, alkenyl
and optionally-substituted benzyl; or R.sub.2 and R.sub.3, together
with the nitrogen atom to which they are attached, may form a mono-
or bi-cyclic group containing up to 10 carbon atoms and which, in
addition, may contain a second heteroatom selected from the group
consisting of N, S and O, and which may contain one or more
substituents selected from the group consisting of alkyl, hydroxy,
hydroxymethyl, alkyloxymethyl, amino and substituted amino;
R.sub.4is selected from the group consisting of H, alkyl and
cycloalkyl; CR.sub.5 represents a group selected from --CH2--,
CH(OH)--, --C(O)--, --CH(alkyl)- and --CH(alkyloxy)-; R6 is
selected from the group consisting of H, alkyl, aryl, halogen,
hydroxy, alkyloxy, amino, monoalkylamino and
di-substitutedalkylamino; and salts and solvates thereof
Inventors: |
Edwards, Louise;
(Mississauga, CA) ; Isaac, Methvin; (Etobicoke,
CA) ; Maddaford, Shawn; (Mississauga, CA) ;
Slassi, Abdelmalik; (Mississauga, CA) ; Xin, Tao;
(Woodbridge, CA) |
Correspondence
Address: |
ROTHWELL, FIGG, ERNST & MANBECK, P.C.
1425 K STREET, N.W.
SUITE 800
WASHINGTON
DC
20005
US
|
Assignee: |
NPS ALLELIX BIOPHARMACEUTICALS,
INC.
Mississauga
CA
|
Family ID: |
23391845 |
Appl. No.: |
10/784673 |
Filed: |
February 24, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10784673 |
Feb 24, 2004 |
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09709579 |
Nov 13, 2000 |
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6716837 |
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09709579 |
Nov 13, 2000 |
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09354091 |
Jul 15, 1999 |
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Current U.S.
Class: |
514/303 ;
546/118; 546/119 |
Current CPC
Class: |
A61P 25/06 20180101;
C07D 401/14 20130101; C07D 417/14 20130101; C07F 7/0814 20130101;
A61P 43/00 20180101; C07D 401/04 20130101; C07D 209/08 20130101;
C07D 405/04 20130101; C07D 403/06 20130101; C07D 405/14 20130101;
C07D 403/04 20130101; C07D 417/04 20130101; C07D 231/56 20130101;
C07D 471/04 20130101; C07D 409/04 20130101; C07D 409/14
20130101 |
Class at
Publication: |
514/303 ;
546/118; 546/119 |
International
Class: |
C07D 471/02; A61K
031/4745 |
Claims
We claim:
1. A compound selected from the group consisting of a compound of
Formula I: 16wherein: W is a CH group or a N atom; Z is N or C; B
and D are selected independently from CH and N, with the provisio
that at least one of B and D is CH and with the further provisio
that one of B and D can represent N only when W and Z are both
other than N; A is a group of Formula II, such that group A
contains at least 1 N atom;--(CR.sub.5).sub.h--NR.sub.2R.sub.3
Formula IIR.sub.1 is selected from the group consisting of H, alkyl
including C(1-12)alkyl, alkyloxy, alkanoyl, aminoalkylenyl,
alkylaminoalkylenyl, a hydroxyalkylenyl group, an alkyloxyalkylenyl
group, a cycloalkyl group, a cycloalkylalkylenyl group, a
heterocycloalkyl group, a heterocycloalkylenyl group, an aryl
group, a heteroaryl group, an amido group, a thioamido group, an
arylcarbonyl group and an arylsulfonyl group; R.sub.2 and R.sub.3
are independently selected from the group consisting of H, alkyl,
cycloalkyl, alkenyl and optionally-substituted benzyl; or R.sub.2
and R.sub.3, together with the nitrogen atom to which they are
attached, may form a mono- or bi-cyclic group containing up to 10
carbon atoms and which, in addition, may contain a second
heteroatom selected from the group consisting of N, S and O, and
which may contain one or more substituents selected from the group
consisting of alkyl, hydroxy, hydroxymethyl, alkyloxymethyl, amino
and substituted amino; R.sub.4 is selected from the group
consisting of H, alkyl and cycloalkyl; CR.sub.5 represents a group
selected from --CH2--, CH(OH)--, --C(O)--, --CH(alkyl)- and
--CH(alkyloxy)-; R.sub.6 is selected from the group consisting of
H, alkyl, aryl, halogen, hydroxy, alkyloxy, amino, monoalkylamino
and di-substitutedalkylamino; and salts and solvates thereof.
2. A compound according to claim 1 wherein R.sub.1 is an aryl
group.
3. A compound according to claim 1 wherein R.sub.1 is a
heterocycloalkyl group.
4. A compound according to claim 3 wherein R.sub.1 is
tetrahydropyranyl.
5. A compound according to claim 1 wherein R.sub.1 is a cycloalkyl
group.
6. A compound according to claim 1 wherein R.sub.1 is a alkyl
group.
7. A compound according to claim 6 wherein R.sub.1 is
isopropyl.
8. A compound according to claim 1, wherein A is a group selected
from a (mono- or di-) substituted aminoalkylenyl, an N-cycloalkyl
and an N-cycloalkylalkylenyl.
9. A compound according to claim 8, wherein A is
N,N-dimethylaminoethyl, N,N-diethylaminoethyl,
N-methyl-N-ethylaminoethyl, N-isopropylaminoethyl,
N,N-dipropylaminoethyl, N-cyclopropylaminoethyl,
N-cyclopropylmethylamino- ethyl, N-methyl-N-cyclopropylamino,
pyrrolidinoethyl, pyrrolinoethyl, piperidinoethyl, morphilinoethyl,
thiomorpholinoethyl or piperazinoethyl.
10. A compound according to claim 1, wherein the ring system formed
by selection of B, D, W and Z is a ring system selected from
indole, indoline, indazole, benzotriazole, benzimidazole,
7-aza-indole, and 5-aza-indole.
11. A compound according to claim 10, wherein R6 is selected from H
and alkyl, and R4 is H.
12. A compound according to claim 11, wherein the ring system
formed by selection of B, D, W and Z, R.sub.4 and R.sub.6 is a ring
system selected from indole and indazole.
13. A compound according to claim 11, wherein said ring system is
indole.
14. A compound according to claim 1, selected from the group
consisting of: 6-(2-(N,N-Dimethylamino)ethyl)-1H-indole;
6-(2-(N,N-Dimethylamino)eth- yl)-1-isopropyl-indole;
6-(2-(N,N-Diethylamino)ethyl)-indole;
6-(2-(N,N-Diethylamino)ethyl)-1-isopropyl-indole;
6-(2-(N,N-Diethylamino)- ethyl)-1-dimethylaminocarbonyl-indole;
6-(2-(N,N-Dimethylamino)ethyl)-1-(t-
etrahydrothiopyran-4-yl)-indole;
6-(2-(N,N-Dimethylamino)ethyl)-1-(tetrahy- dropyran-4-yl)-indole;
6-(2-(N,N-Dimethylamino)ethyl)-1-isopropyl-1H-indaz- ole;
6-(2-(N,N-Dimethylaminoethyl)-1-(3-pyridinyl)-indole;
6-(2-(N,N-Dimethylaminoethyl)-1-(3-thienyl)-indole; and
6-(2-(N,N-Dimethylaminoethyl)-1-(4-fluorophenyl)-indole.
15. A compound according to claim 14, selected from the group
consisting of: 6-(2-(N,N-Dimethylamino)ethyl)-1H-indole;
6-(2-(N,N-Dimethylamino)eth- yl)-1-isopropyl-indole;
6-(2-(N,N-Diethylamino)ethyl)-1-isopropyl-indole;
6-(2-(N,N-Diethylamino)ethyl)-1-dimethylaminocarbonyl-indole;
6-(2-(N,N-Di
methylamino)ethyl)-1-(tetrahydrothiopyran-4-yl)-indole;
6-(2-(N,N-Dimethylamino)ethyl)-1-(tetrahydropyran-4-yl)-indole;
6-(2-(N,N-Dimethylamino)ethyl)-1-(3-pyridinyl)-indole;
6-(2-(N,N-Dimethylamino)ethyl)-1-(3-thienyl)-indole; and
6-(2-(N,N-Dimethylamino)ethyl)-1-(4-fluorophenyl)-indole.
16. A composition comprising a therapeutically effective amount of
a compound according to claim 1, and a pharmaceutically acceptable
carrier.
17. A method for treating a patient having a medical condition for
which stimulation of the 5-HT.sub.1D receptor is indicated,
comprising the step of administering to the patient a
pharmaceutical composition as defined in claim 16.
18. A method according to claim 17, wherein the medical condition
is migraine.
Description
FIELD OF THE INVENTION
[0001] This invention relates to certain indole and indazole
compounds, to pharmaceutical and diagnostic compositions containing
them and to their medical use, particularly in the treatment or
diagnosis of CNS conditions such as migraine.
BACKGROUND TO THE INVENTION
[0002] Through its interaction with receptors found on neuronal and
other cells, 5-hydroxytryptamine (5-HT, or serotonin) mediates a
variety of physiological effects. Imbalances in this interaction
are believed to be responsible for such conditions as anxiety,
hallucination, migraine, chemotherapy-induced nausea and for
disorders in sexual activity, cardiovascular activity and
thermoregulation, amongst others. From an improved understanding of
the 5-HT receptor population it is apparent that these effects are
mediated selectively through individual types and subtypes of the
5-HT receptors. Migraine, for example, has been treated with
ergotamine, dihydroergotamine, methylsergide and, most recently,
sumatriptan, all of which presumably act at the 5-HT.sub.1D
receptor subtype.
[0003] Current treatments for migraine, including sumatriptan,
continue to have unwanted side effects. These include coronary
vasospasm, hypertension and angina. Recent evidence suggests that
the observed sumatriptan-mediated contraction of coronary arteries
may be due to the stimulation of the 5-HT.sub.1B (formerly
5-HT.sub.1D.beta.) subtype of the 5-HT receptors (Kaumann, A. J.
Circulation, 1994, 90:1141-1153).
[0004] Given the physiological and clinical significance of the
5-HT,D receptor, and the potential side effect liability of
stimulation of the 5-HT.sub.1B receptor, it would be desirable to
provide compounds that bind with high affinity to the 5-HT.sub.1D
receptor. Such compounds would be medically useful, for example, to
treat indications for which administration of a 5-HT.sub.1D ligand
is indicated, such as migraine. Such compounds could also be used
diagnostically, for example, to identify these receptors and to
screen drug candidates.
SUMMARY OF THE INVENTION
[0005] It has been found that compounds of Formula I, 2
[0006] wherein:
[0007] W is a CH group or a N atom;
[0008] Z is N or C-R4;
[0009] B and D are selected independently from CH and N, with the
proviso that at least one of B and D is CH and with the further
proviso that one of B and D can represent N only when W and Z are
both other than N;
[0010] A is a group of Formula II, III or IV, such that group A
contains at least 1 N atom;
[0011] NR7 is either --NH-- or --N.dbd.
[0012] is a single or double bond;
[0013] X is a N atom, a CH group or a C(OH) group when is a single
bond; or, when is a double bond, a C atom;
[0014] Y is an NH, N-alkyl, N-benzyl or CH.sub.2 group;
[0015] U and V each represent a N atom or a CH group, with the
proviso that both cannot be N;
[0016] a and b are, independently, 0 or 1; c is an integer from 0
to 3; d is an integer from 1 to 3; e is an integer from 1 to 2 f is
an integer from 0 to 3; g is an integer from 3 to 6 and h is an
integer from 2 to 3; such that the sum of c and d is at least 2 and
the sum of e and f is at least 2;
[0017] R.sub.1 is selected from the group consisting of H, alkyl,
alkyloxy, alkanoyl, aminoalkylenyl, alkylaminoalkylenyl, a
hydroxyalkylenyl group, an alkyloxyalkylenyl group, a cycloalkyl
group, a cycloalkylalkylenyl group, a heterocycloalkyl group, a
heterocycloalkylalkylenyl group, an aryl group, a heterocycloaryl
group, an amido group, a thioamido group, an arylcarbonyl group and
an arylsulfonyl group;
[0018] R.sub.2 and R.sub.3 are independently selected from the
group consisting of H, alkyl, cycloalkyl, alkenyl and
optionally-substituted benzyl; or R.sub.2 and R.sub.3, together
with the nitrogen atom to which they are attached, may form a mono-
or bi-cyclic group containing up to 10 carbon atoms and which, in
addition, may contain a second heteroatom selected from the group
consisting of N, S and O, and which may contain one or more
substituents selected from the group consisting of alkyl, hydroxy,
hydroxymethyl, alkyloxymethyl, amino and substituted amino;
[0019] R.sub.4 is selected from the group consisting of H, alkyl
and cycloalkyl;
[0020] CR.sub.5 represents a group selected from --CH2-, CH(OH)--,
--C(O)--, --CH(alkyl)- and --CH(alkyloxy)-;
[0021] R6 is selected from the group consisting of H, alkyl, aryl,
halogen, hydroxy, alkyloxy, amino, monoalkylamino and
di-substitutedalkylamino;
[0022] and salts and solvates thereof, bind to the Serotonin
5-HT.sub.1D receptor and are, therefore, useful, in accordance with
one aspect of the invention, for the treatment of diseases such as
migraine.
[0023] In another aspect of the invention, compounds of Formula I,
and radio-labelled forms thereof, are also useful as a
pharmacological tool for the identification of other compounds,
including potential drug candidates, which bind to the 5-HT.sub.1D
receptor.
[0024] Radio-labelled forms of compounds of Formula I are also
useful as diagnostic tools for the identification of 5-HT.sub.1D
binding sites in vitro.
[0025] In another aspect, the present invention provides compounds
which bind selectively to the 5-HT.sub.1D receptor, relative
particularly to the 5-HT.sub.1B receptor.
[0026] According to another aspect of the invention there are
provided compositions comprising a compound of Formula I and a
carrier, either for use as reagents, for example in the
identification of 5-HT.sub.1D receptors or 5-HT.sub.1D receptor
ligands, or for pharmaceutical use to treat conditions where
stimulation of the 5-HT.sub.1D receptor is indicated.
[0027] In another aspect of the present invention, there is
provided a method effective to treat medical conditions for which
stimulation of the 5-HT.sub.1D receptor is indicated, such as
migraine.
[0028] These and other aspects of the present invention are
described in greater detail hereinbelow.
DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS
[0029] The term "alkyl" as used herein means, unless otherwise
stated, straight and branched chain alkyl radicals containing from
one to six carbon atoms and includes methyl, ethyl, propyl,
isopropyl, t-butyl and the like.
[0030] The terms "alkylene" and "alkylenyl" as used herein means
straight or branched chain divalent, i.e., bridging, alkyl chains
containing from one to six carbon atoms and includes methylene,
e.g., --CH2-, ethylene, propylene, butylene and the like. The term
"alkenyl" as used herein means straight and branched chain
unsaturated radicals containing from one to six carbon atoms and
includes allyl, propenyl, isopropenyl, pentenyl and the like.
[0031] The term "cycloalkyl" as used herein means a monocyclic ring
system containing up to 8 atoms or a bicyclic ring system
containing up to 12 atoms, including "heterocycloalkyl" ring
systems which may contain up to two heteroatoms selected from the
group consisting of N, S and O, and includes cyclopropyl,
cyclohexyl, bicyclo[3.2.1]octyl, bicyclo[4.3.2]undecyl, aziridinyl,
pyrrolidinyl, piperidinyl, troponyl, azabicyclo[2.2.2]octyl,
tetrahydropyranyl, pyranyl, thiopyranyl, tetrahydrothiopyranyl,
morpholinyl and the like, which ring system may be unsaturated
and/or substituted. The terms "cycloalkyl-alkylenyl" and
heterocyclo-alkylenyl" refer to rings systems of the type just
described that are further substituted by a bridging alkylenyl
group such as methylenyl and ethylenyl, and includes such groups as
cyclohexyl-1-methylenyl, tetrahydropyranyl-4-ethylenyl, and the
like. In the context of these definitions, the term "group" refers
to a substituent as noted, which may be further substituted by one
or two substituents selected from halo, hydroxy, alkyl, alkoxy,
thioalkyl and trifluoroalkyl. For instance, a heterocycloalkyl such
as pyrrolidinyl is a referred to as a heterocycloalkyl group when
substituted by methyl, e.g. to yield N-methyl-pyrrolidinyl.
[0032] The term "alkyloxy" as used herein means straight and
branched chain alkyloxy radicals containing from one to six carbon
atoms and includes methoxy, ethoxy, propyloxy, isopropyloxy,
t-butoxy and the like.
[0033] The term "alkanoyl" as used herein means straight and
branched chain alkanoyl radicals containing from one to six carbon
atoms and includes acetyl, propionyl, pivaloyl and the like.
[0034] The term "aminoalkylenyl" as used herein means straight and
branched chain amino-substituted alkyl or alkylenyl radicals
containing from one to six carbon atoms and includes aminomethyl,
aminoethyl, aminobutyl and the like. An aminoalkylenyl group may be
optionally substituted at the amine function by one or two groups
selected independently from alkyl and alkanoyl (yielding an
alkylaminoalkylenyl and an alkanoylaminoalkylenyl, respectively),
and includes for instance N,N-dimethylaminoethyl;
N-ethyl-N-methyl-aminopropyl, and N-ethylaminobutyl groups as well
as groups such as N-acetyl-N-methyl-aminoethyl;
N-butyryl-N-methyl-aminoethyl; N-acetyl-N-ethyl-aminopropyl, and
the like.
[0035] The term "alkanoylamino" as used herein means straight and
branched chain alkanoyl-substituted amino groups such as
acetylamino, butyrylamino and the like.
[0036] The terms "aryl" and "heteroaryl" as used herein mean an
optionally substituted aromatic group which, in the case of a
heteroaryl, can contain up to 2 heteroatoms, wherein the optional
substituents are independently selected from 1-4 members of the
group consisting of halo, hydroxy, alkyl, alkoxy, thioalkyl and
trifluoromethyl, and includes phenyl, naphthyl, indanyl, indolyl,
quinolyl, furyl, thienyl and the like.
[0037] The terms "arylalkylenyl" and "heteroarylalkylenyl" as used
herein refer to an optionally substituted aryl or a heteroaryl
group in which an alkylenyl bridge couples the aryl or heteroaryl
to another group, and includes benzyl, phenethyl, and the like.
[0038] The term "halo" as used herein means halogen, and includes
fluoro, chloro, bromo, iodo and the like, in both radioactive and
non-radioactive forms.
[0039] The term "optionally substituted benzyl" as used herein
means an unsubstituted benzyl radical or a benzyl radical
substituted on the phenyl ring with 1-3 substituents independently
selected from halo, OH, SH, alkyl, alkyloxy, alkylthio, CF.sub.3
and CF.sub.3O.
[0040] The term "amido group" refers to the amido group of the
formula R'R"N--C(O)-- in which R' and R" are independently selected
from H and alkyl.
[0041] The term thioamido group refers to the thioamido group of
the formula R'R"N--C(S)-- wherein R' and R" are as just
described.
[0042] The term "pharmaceutically acceptable salt" means an acid
addition salt which is compatible with the treatment of
patients.
[0043] A "pharmaceutically acceptable acid addition salt" is any
non-toxic organic or inorganic acid addition salt of the base
compounds represented by Formula I or any of their intermediates.
Illustrative inorganic acids which form suitable salts include
hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well
as acid metal salts such as sodium monohydrogen orthophosphate and
potassium hydrogen sulfate. Illustrative organic acids that form
suitable salts include mono-, di- and tricarboxylic acids such as
glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric,
malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic,
cinnamic and salicylic acids, as well as sulfonic acids such as
p-toluenesulfonic and methanesulfonic acids. Either the mono- or
di-acid salts can be formed, and such salts may exist in either a
hydrated, solvated or substantially anhydrous form. In general, the
acid addition salts of compounds of Formula I are more soluble in
water and various hydrophilic organic solvents, and generally
demonstrate higher melting points in comparison to their free base
forms. The selection criteria for the appropriate salt will be
known to one skilled in the art. Other non-pharmaceutically
acceptable salts e.g. oxalates may be used, for example, in the
isolation of compounds of Formula I for laboratory use, or for
subsequent conversion to a pharmaceutically acceptable acid
addition salt.
[0044] The term "solvate" means a compound of Formula I, or a
pharmaceutically acceptable salt of a compound of Formula I,
wherein molecules of a suitable solvent are incorporated in the
crystal lattice. A suitable solvent is physiologically tolerable at
the dosage administered. Examples of suitable solvents are ethanol,
water and the like. When water is the solvent, the molecule is
referred to as a hydrate.
[0045] The term "stereoisomers" is a general term for all isomers
of a molecule which differ only in the orientation of their atoms
in space. It includes image isomers (enantiomers), geometric
(cis/trans) isomers and isomers of compounds with more than one
chiral centre which are not mirror images of one another
(diastereomers).
[0046] The term "treat" or "treating" means to alleviate symptoms,
eliminate the causation of the symptoms either on a temporary or
permanent basis, or to prevent or slow the appearance of symptoms
of the named disorder or condition.
[0047] The term "therapeutically effective amount" means an amount
of the compound that is effective in treating the named disorder or
condition. An amount "effective to stimulate the 5-HT1D receptor"
is an amount that yields a measurable increase in 5-HT1D receptor
activity, as measured using an assay and end-point appropriate for
that measurement. For instance, amounts effective to stimulate the
5-HT1D receptor for purposes of therapy are those amounts that,
following administration, yield a detectable improvement in the
symptoms associated with the given disease or condition under
treatment. Where the 5-HT1D stimulation sought is in the context of
an in vitro assay, for instance during screening of compounds for
their ability to compete with a present compound, then the 5-HT1D
receptor stimulation can most suitably be measured more directly,
as a decrease in the production of adenylyl cyclase, revealed for
instance by a decrease in the levels of cAMP.
[0048] The term "pharmaceutically acceptable carrier" means a
non-toxic solvent, dispersant, excipient, adjuvant or other
material which is mixed with the active ingredient in order to
permit the. formation of a pharmaceutical composition, i.e., a
dosage form capable of administration to the patient. One example
of such a carrier is pharmaceutically acceptable oil typically used
for parenteral administration.
[0049] The present invention includes within its scope prodrugs of
the compounds of Formula I. In general, such prodrugs will be
functional derivatives of a compound of Formula I which are readily
convertible in vivo into the compound from which it is notionally
derived. Conventional procedures for the selection and preparation
of suitable prodrug derivatives are described, for example, in
"Design of Prodrugs" ed. H. Bundgaard, Elsevier, 1985.
[0050] Compounds of Formula I bind to the serotonin. 5-HT.sub.1D
receptor. Preferred compounds of Formula I bind selectively (for
example with 10-fold selectivity) to the serotonin 5-HT.sub.1D
receptor, relative, particularly, to the serotonin 5-HT.sub.1B
receptor, as judged by in vitro binding affinities using, for
example, the assay exemplified herein. More preferred compounds are
those which bind with at least 10-fold selectivity to the
5-HT.sub.1D receptor, relative to the 5-HT.sub.1B receptor. Most
preferred are those compounds that bind with at least 40-fold
selectivity to the 5-HT.sub.1D receptor, relative to the
5-HT.sub.1B receptor.
[0051] In embodiments of the present invention, compounds of
Formula I are those in which W and Z, as well as B and D, are
selected to form a ring system, substituted by A, R1, R4 and R6,
which is selected from indole, indoline, indazole, benzotriazole,
benzimidazole, 7-aza-indole (also referred to as
1H-pyrrolo-[2,3-b]-pyridine) and 5-aza-indole (also referred to as
1H-pyrrolo-[3,4-c]-pyridine). In specific embodiments, all of B, D,
W and Z are selected to form a ring system that is either indole or
indazole.
[0052] In other embodiments of the present invention, R6 is
selected from H and alkyl, and R4 is H.
[0053] Thus, in specific embodiments, B, D, W, Z, R4 and R6 are
selected to form a ring system selected from indole and
indazole.
[0054] In other embodiments, R1 is desirably selected from H,
alkyl, aminoalkylenyl, alkylaminoalkylenyl, alkenylaminoalkylenyl,
amido unsubstituted or substituted by one or two alkyl groups,
thioamido unsubstituted or substituted by one or two alkyl groups,
and a substituted or unsubstituted group which is cycloalkyl,
cycloalkyl-alkylenyl, heterocycloalkyl, heterocycloalkyl-alkylenyl
aryl, arylalkenyl, heteroaryl or heteroarylalkenyl. When R1 is
alkyl, preferred groups include methyl, ethyl and propyl,
especially isopropyl. When R1 is aminoalkyl, a preferred group is
aminoethyl. When R1 is alkylaminoalkyl, preferred groups include
N,N-dimethylaminoethyl, N,N-diethylaminoethyl, and
N-isopropyl-aminoethyl. When R1 is an alkenylaminoalkyl, a
preferred group is N-prop-1-enyl-aminoethyl. When R1 is an amido
group or a thioamido group, preferred groups are amido,
N,N-dmethylamido, and thioamido. When R1 is a hydroxyalkylenyl
group, a preferred group is hydroxyethylenyl. When R1 is cycloalkyl
or heterocycloalkyl, specific groups include cyclohexyl,
tetrahydropyranyl, and tetrahydrothiopyranyl. When R1 is an aryl or
heteroaryl, preferred groups include phenyl, phenyl substituted by
alkyl such as methyl, or by halogen such as fluoro, and 3-pyridyl
and 4-pyridinyl, as well as thioimidazole. R1 may also be benzoyl
or tosyl. In other embodiments, R1 may be an alkyl which is
C(1-12)alkyl, such as C(6-9)alkyl, including hexyl, heptyl, octyl
and preferably nonyl.
[0055] In a preferred embodiment, R1 is selected from alkyl and
heterocycloalkyl. In particularly preferred embodiments, R1 is
alkyl, and especially isopropyl. In other particularly preferred
embodiments, R1 is heterocycloalkyl, and especially
tetrahydropyranyl.
[0056] Thus, in specific preferred embodiments, the ring system
formed by selection of B, D, W, Z, R4 and R6, is an A-substituted
ring system that is substituted by an R1 group that is alkyl, and
particularly isopropyl, including a 1-isopropyl-indole group and a
1-isopropyl-indazole group. In other specific preferred
embodiments, the A-substituted ring system so formed is substituted
by an R1 group that is heterocycloalkyl, including particularly a
tetrahydropyranyl group, to form a 1-tetrahydropyran-4-yl-- indole
or a tetrahydropyran-4-yl-indazole group.
[0057] In other embodiments of the invention, Group A is a group of
Formula II, III or IV. When Group A is of Formula II, the Formula
II substituents desirably are selected to form a (mono- or di-)
substituted aminoalkylenyl or N-cycloalkyl or N-cycloalkylalkylenyl
group such as N,N-dimethylaminoethyl, N,N-diethylaminoethyl,
N-methyl-N-ethylaminoethyl- , N-isopropylaminoethyl,
N,N-dipropylaminoethyl, N-cyclopropylaminoethyl,
N-cyclopropylmethylaminoethyl, N-methyl-N-cyclopropylamino,
pyrrolidinoethyl, pyrrolinoethyl, piperidinoethyl, morphilinoethyl,
thiomorpholinoethyl, piperazinoethyl.
[0058] Preferably, A is a group of Formula IV, and NR7 is --NH--
when a is 1. Preferred groups of Formula IV include an
1-azabicyclo[4.3.0]nonanyl group, an 1-azabicyclo[4.4.0]decanyl
group, a 1,4-diazabicyclo[4.3.0]nona- nyl group or a
1,4-diazabicyclo[4.4.0]decanyl group.
[0059] More preferably, A is a group of Formula III, and NR7 is
--NH-- when a is 1. Preferred groups of Formula III are
(pyrrolidin-2-yl)methyl, N-methyl(pyrrolidin-2-yl)methyl,
tetrahydropyridin-4-yl, tetrahydropyridin-3-yl and piperazinyl.
[0060] Most preferably, A is a group of Formula II, such as
dialkyaminoalkyl (for example, a 2-(diethylamino)ethyl group).
[0061] In the case where A is a Formula II group, then the
compounds of the present invention, as defined by general Formula
I, exclude the following compounds:
6-(2-methyl-2-aminoethyl)-1H-indole,
6-(2-aminoethyl)-1-methyl-indole,
6-(N,N-Di-n-propylaminoethyl)-1H-indole- ,
6-(2-n-propyl-2-n-propylaminoethyl)-1H-indole, and
6-(2-methyl-2-N,N-dimethylaminoethyl)-1H-indole.
[0062] Specific embodiments of the invention include:
[0063] 6-(2-(N,N-Dimethylamino)ethyl)-1H-indole;
[0064] 6-(2-(N,N-Dimethylamino)ethyl)-1-isopropyl-indole;
[0065] 6-(2-(N,N-Diethylamino)ethyl)-1H-indole;
[0066] 6-(2-(N,N-Diethylamino)ethyl)-1-isopropyl-indole;
[0067]
6-(2-(N,N-Diethylamino)ethyl)-1-dimethylaminocarbonyl-indole;
[0068]
6-(2-(N,N-Dimethylaminoethyl)-1-(tetrahydrothiopyran-4-yl)-indole;
[0069]
6-(2-(N,N-Dimethylaminoethyl)-1-(tetrahydropyran-4-yl)-indole;
[0070] 6-(2-(N,N-Dimethylamino)ethyl)-1-isopropyl-indazole;
[0071] 6-(2-(N,N-Diethylamino)ethyl)-1-isopropyl-indazole;
[0072] 6-(2-N-pyrrolidinyl)ethyl)-1-isopropyl-indazole;
[0073] 6-(2-pyrrolin-3-yl)ethyl-1-isopropyl-indazole;
[0074]
(R)-6-(2-(N-(3-tert-butoxycarbonylamino)pyrrolidinyl)ethyl)-1-(2-pr-
opyl)-1H-indazole
[0075]
(S)-6-(2-(N-(3-tert-butoxycarbonylamino)pyrrolidinyl)ethyl)-1-(2-pr-
opyl)-1H-indazole
[0076]
(R)-6-(2-(N-(2-hydroxymethyl)pyrrolidinyl)ethyl)-1-(2-propyl)-1H-in-
dazole
[0077]
(S)-6-(2-(N-(2-hydroxymethyl)pyrrolidinyl)ethyl)-1-(2-propyl)-1H-in-
dazole
[0078] 6-(2-(N-cyclopropylamino)ethyl)-1-(2-propyl)-1H-indazole
[0079] 6-(2-cyclopropylamino)ethyl)-1-isopropyl-indazole;
[0080]
6-(2-(N-cyclopropylmethylamino)ethyl)-1-(2-propyl)-1H-indazole;
[0081]
6-(2-(N-methylpiperazino)ethyl)-1-(2-propyl)-1H-indazole;
[0082] 6-(2-methylcyclopropylamino)ethyl)-1-isopropyl-indazole;
[0083] 6-(N-methylpiperazinyl)-1-isopropyl-indazole;
[0084] 6-(2-Diethylaminoethyl)-1-(4-fluorophenyl)-indole;
[0085] 6-(2-Diethylaminoethyl)-1-(3-thienyl)-indole;
[0086]
6-(2-(N,N-Diethylaminoethyl)-1-(tetrahydropyran-4-yl)-indole;
[0087]
6-(N-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1-isopropyl-indole;
[0088] 6-(2-Diethylaminoethyl)-1-phenylsulfonamide-indole;
[0089]
6-(4-Hydroxy-N-methyl-piperidin-4-yl)-1-N,N-dimethylethylamine-indo-
le;
[0090]
6-(N-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1-N,N-dimethylethylamin-
e-indole;
[0091]
6-(N-methyl-piperidin-4-yl)-1-N,N-dimethylethylamine-indole;
[0092]
6-(N-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1-(ethylamine-2-ol)-ind-
azole;
[0093]
6-(N-methyl-piperidin-4-yl)-1-(ethylamine-2-ol)-indazole;
[0094] 6-[4-Hydroxy-1-azabicyclo[4.3.0]nonan-4-yl]-indole;
[0095] 6-[4-Hydroxy-1-methyl-piperidin-4-yl]-indole;
[0096] 6-[N-methyl-1,2,5,6-tetrahydropyridin-4-yl]-indole;
[0097] 6-[3,4-anhydro-1-azabicyclo[4.3.0]nonan-4-yl]-indole;
[0098] 6-[4,5-anhydro-1-azabicyclo[4.3.0]nonan-4-yl]-indole;
[0099]
6-[N-Methyl-1,2,5,6-tetrahydropyridin-4-yl]-1-isopropyl-indole;
[0100] 6-[1-Azabicyclo[4.3.0]nonan-4-yl]-indole;
[0101]
6-[3,4-Anhydro-1-azabicyclo[4.3.0]nonan-4-yl]-1-isopropyl-indole;
[0102] 1-(4-Fluorophenyl)-6-(N-methyl-1,2,5,6-tetrahyd
ropyridin-4-yl)-indole;
[0103]
1-6-(N-Methyl-1,2,5,6-tetrahydropyridin-4-yl)-1-(3-thienyl)-indole;
[0104]
6-(N-Methyl-1,2,5,6-tetrahydropyridin-4-yl)-1-(3-pyridyl)-indole;
[0105]
6-[1-Azabicyclo[4.3.0]nonan-4-yl]-1-(4-pyridinyl)-indole;
[0106] 6-(2-Dimethylaminoethyl)-1-(3-pyridinyl)-indole;
[0107] 6-(2-Dimethylaminoethyl)-1-(3-thienyl)-indole;
[0108] 6-(2-Dimethylaminoethyl)-1-(4-fluorophenyl)-indole;
[0109]
6-(N-Methyl-1,2,5,6-tetrahydropyridin-4-yl)-1-(2-thiazolyl)-indole;
[0110]
1-Dimethylaminocarbonyl-6-[N-methyl-1,2,5,6-tetrahydro-pyridin-4-yl-
]-indole;
[0111]
6-[4-Hydroxy-1-methyl-piperidin-4-yl]-1-isopropyl-indole;
[0112] 6-((N-Benzyloxycarbonyl)prolyl)-indole;
[0113]
6-[(.alpha.-Hydroxy-.alpha.-(2-Pyrrolidinyl))methyl]-indole;
[0114] 1-isopropyl-6-(1-methylpiperidin-3-yl)-1H-indole
1-isopropyl-6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H-indole
1-triisopropylsilyl-6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H-indole
6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H-indole
6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1-(3-thienyl)-1H-indole
1-(4-fluorophenyl)-6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H-indole
1-(pyridin-3-yl)-6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H-indole
6-((2-Pyrrolidinyl)methyl)-1-isopropyl-indole;
[0115] 6-(N-methyl-(2-Pyrrolidinyl)methyl)-1-n-propyl-indole;
[0116]
1-propyl-6-{[(2S)-methyl-pyrrolidin-2-yl]methyl}-1H-indole;
[0117]
1-dodecyl-6-{[(2S)-methyl-pyrrolidin-2-yl]methyl}-1H-indole
[0118]
1-(pyridin-4-yl)-6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H-indole-
;
1-benzenesulfonyl-6-{[(2S)-methyl-pyrrolidin-2-yl]methyl-1H-indole
1-(tetrahydro-2H-thiopyran-4-yl)-6-{[(2S)-methyl-pyrrolidin-2-yl]methyl-1-
H-indole 6-{[(2S)-methyl-pyrrolidin-2-yl]methyl
-1-(tetrahydro-2H-pyran-4-- yl)indoline
6-{[(2S)-methyl-pyrrolidin-2-yl]methyl-1-(tetrahydro-2H-pyran--
4-yl)-1H-indole 1-(1-methylpiperidin-4-yl)
6-{[(2S)-methyl-pyrrolidin-2-yl- ]methyl indoline
1-(1-methylpiperidin-4-yl) 6-{[(2S)-methyl-pyrrolidin-2-y- l]methyl
indole 1-(1-benzylpiperidin-4-yl) 6-{[(2S)-methyl-pyrrolidin-2-yl-
]methyl indoline 1-(1-propylpiperidin-4-yl)
6-{[(2S)-methyl-pyrrolidin-2-y- l]methyl indole
1-cyclohexyl-6-{[(2S)-methyl-pyrrolidin-2-yl]methyl indoline
1-cyclohexyl -6-{[(2S)-methyl-pyrrolidin-2-yl]methyl indole
1-isopropyl-6-{[(2S)-pyrrolidin-2-yl]methyl}-1H-indole
1-isopropyl-6-(1-methylpiperidin-4-yl)-1H-indole
1-benzyl-6-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-1H-indole
[0119] 6-(N-methylpiperazinyl)-indole;
[0120] 1-Isopropyl-6-(N-methylpiperazinyl)-indole;
[0121] 1-isopropyl-6-(N-methylhomopiperazinyl)-indole;
[0122]
6-(1,3-Diazabicyclo-[4,4,0]-decan-3-yl)-1-isopropyl-indole;
[0123] 1-Isopropyl-6-(3-methylpiperazinyl)-indole;
[0124] 1-Isopropyl-6-(4-methylpiperazinyl)-indole;
[0125] 1-(4-Fluorophenyl)-6-(4-methylpiperazinyl)-indole;
[0126] 6-(4-methylpiperazinyl)-1-(3-thiazolyl)-indole and
[0127] 6-(4-methylpiperazinyl)-1-(3-thienyl)-indole.
[0128] Preferred embodiments of the invention include:
[0129] 6-[4-Hydroxy-1-methyl-piperidin-4-yl]-indole;
[0130] 6-[N-Methyl-1,2,5,6-tetrahydropyridin-4-yl]-indole;
[0131]
6-[N-Methyl-1,2,5,6-tetrahydropyridin-4-yl]-1-isopropyl-indole;
[0132]
1-(4-Fluorophenyl)-6-(N-methyl-1,2,5,6-tetrahydropyridin-4-yl)-indo-
le;
[0133]
6-(N-Methyl-1,2,5,6-tetrahydropyridin-4-yl)-1-(3-thienyl)-indole;
[0134]
6-(N-Methyl-1,2,5,6-tetrahydropyridin-4-yl)-1-(3-pyridyl)-indole;
[0135]
6-(N-Methyl-1,2,5,6-tetrahydropyridin-4-yl)-1-(2-thiazolyl)-indole;
[0136]
1-N,N-Dimethylaminocarbonyl-6-[N-methyl-1,2,5,6-tetrahydropyridin-4-
-yl]-indole;
[0137]
6-[4-Hydroxy-1-methyl-piperidin-4-yl]-1-isopropyl-indole;
[0138] 6-((N-Benzyloxycarbonyl)prolyl)-indole;
[0139]
6-[(.alpha.-Hydroxy-.alpha.-(2-pyrrolidinyl))methyl]-indole;
[0140] 6-((2-Pyrrolidinyl)methyl)-indole;
[0141] 6-(N-methylpiperazinyl)-indole;
[0142] 1-Isopropyl-6-(N-methyl piperazinyl)-indole;
[0143] 1-Isopropyl-6-(N-methylhomopiperazinyl)-indole;
[0144] 1-Isopropyl-6-(3-methylpiperazinyl)-indole;
[0145] 1-Isopropyl-6-(4-methylpiperazinyl)-indole;
[0146] 1-(4-Fluorophenyl)-6-(4-methylpiperazinyl)-indole;
[0147] 6-(4-Methylpiperazinyl)-1-(3-thiazolyl)-indole and
[0148] 6-(4-Methylpiperazinyl)-1-(3-thienyl)-indole.
[0149] More preferred embodiments of the invention include:
[0150] 6-(2-(N,N-Dimethylamino)ethyl)-1H-indole;
[0151] 6-(2-(N,N-Dimethylamino)ethyl)-1-isopropyl-indole;
[0152] 6-(2-(N,N-Diethylamino)ethyl)-1-isopropyl-indole;
[0153]
6-(2-(N,N-Diethylamino)ethyl)-1-dimethylaminocarbonyl-indole;
[0154]
6-(2-(N,N-Dimethylamino)ethyl)-1-(tetrahydrothiopyran-4-yl)-indole;
[0155]
6-(2-(N,N-Dimethylamino)ethyl)-1-(tetrahydropyran-4-yl)-indole;
[0156] 6-(2-(N,N-Dimethylamino)ethyl)-1-(3-pyridinyl)-indole;
[0157] 6-(2-(N,N-Dimethylamino)ethyl)-1-(3-thienyl)-indole and
[0158]
6-(2-(N,N-Dimethylamino)ethyl)-1-(4-fluorophenyl)-indole.
[0159] Some of the compounds of Formula I may have at least one
asymmetric centre. Where the compounds according to the invention
have one asymmetric centre they may exist as enantiomers. Where the
compounds according to the invention possess two or more asymmetric
centres, they may additionally exist as diastereomers. It is to be
understood that all such isomers and mixtures thereof in any
proportion are encompassed within the scope of the present
invention.
[0160] Acid addition salts of the compounds of Formula I are most
suitably formed with pharmaceutically acceptable acids, and
include, for example, those formed with inorganic acids e.g.
hydrochloric, sulphuric or phosphoric acids and organic acids e.g.
succinic, maleic, acetic or fumaric acid. Other
non-pharmaceutically acceptable salts e.g. oxalates may be used,
for example, in the isolation of compounds of Formula I for
laboratory use, or for subsequent conversion to a pharmaceutically
acceptable acid addition salt.
[0161] The conversion of a given compound salt to a desired
compound salt is achieved by standard techniques in which an
aqueous solution of the given salt is treated with a solution of
base e.g. sodium carbonate, potassium hydroxide to liberate the
neutral compound which is then extracted into an appropriate
solvent, such as ether. The neutral compound is then separated from
the aqueous portion, dried, and treated with the requisite acid to
give the desired salt.
[0162] Also included within the scope of the invention are solvates
of the compounds of the invention. The formation of a solvate will
vary depending on the compound and solvent used. In general,
solvates are formed by dissolving the compound in the appropriate
solvent and isolating the solvate by cooling or using an
antisolvent. The solvate is typically dried or azeotroped under
ambient conditions.
[0163] Prodrugs of compounds of the invention may be conventional
esters formed with available hydroxyl (or thiol) or carboxyl
groups. For example, when one of R.sup.3 or R.sup.4 is OH in a
compound of Formula I, it may be acylated using an activated acid
in the presence of a base and, optionally, in inert solvent (e.g.
an acid chloride in pyridine). Some common esters which have been
utilized as prodrugs are phenyl esters, aliphatic
(C.sub.1-C.sub.24) esters, acyloxymethyl esters, carbamates and
amino acid esters.
[0164] In accordance with another aspect of the invention, the
compounds of the invention can be prepared by processes analogous
to those established in the art.
[0165] For example, indoles of Formula I where A is a
(dimethylamino)ethyl group can be prepared as shown in Scheme 1,
below: 3
[0166] Alternatively, such compounds may be made according to
Scheme 2, below: 4
[0167] Indoles of Formula I where A is a group of Formula II and h
is 2 may also be prepared according to Scheme 3, below: 5
[0168] Indazoles of Formula 1 where where A is a group of Formula
II, h is 2 and R.sub.1 is an alkyl group can also be prepared
according to Scheme 4, below: 6
[0169] Compounds where A is a group of Formula II and h is 3 can be
prepared as shown in Scheme 5, below: 7
[0170] Indoles of Formula I (i.e. compounds where X is CH) where a
and b are both zero and A is a group of Formula III or IV can be
prepared by a number of routes. For example, as shown in Scheme 6,
below: 8
[0171] Indoles of Formula I in which a is zero and b is 1 may be
prepared as shown below: 9
[0172] The product from the above reactions can be further
modified, for example, to introduce substituents at the 1 or 3
positions of the ring, as previously described.
[0173] Compounds of Formula I in which A is of Formula II or III
can be prepared as shown below:
[0174] Compounds of Formula I in which a is 1 and b is 0 can be
prepared as shown below: 10
[0175] It should be noted that when R.sub.4 is a group other than H
then the substituent may be present at the beginning of the
synthetic pathway (for example, in compounds 1, 4, 10 etc.) or,
alternatively, it can be introduced at an intermediate stage, or at
the end of, the synthesis. Also, any substituents at the 3 and 6
positions of the indole ring may be introduced in either order. The
choice of exact route used will be governed by various factors,
such as the availability of starting materials. Other methods
useful to produce Formula I compounds are shown below 11 12 13
14
[0176] Similarly, it should be appreciated that one skilled in the
art would realize that the sequences of reactions described in the
above schemes may, at times, be varied, depending upon the exact
nature of the compounds being made and chemistries involved.
[0177] In some cases the chemistries outlined above may have to be
modified, for instance by use of protecting groups, to prevent side
reactions due to reactive groups, such as reactive groups attached
as substituents. This may be achieved be means of conventional
protecting groups, as described in Protective Groups in Organic
Chemistry, ed. McOmie, J. F. W. Plenum Press, 1973; and Greene, T.
W. & Wuts, P. G. M., Protective Groups in Organic Synthesis,
John Wiley & Sons, 1991.
[0178] In another embodiment of the invention, the present
compounds can be used to distinguish 5-HT.sub.1D receptors from
other receptor subtypes, for example glutamate or opioid receptors,
within a population of receptors, and in particular to distinguish
between the 5-HT.sub.1D and other 5-HT receptor subtypes. The
latter can be achieved by incubating preparations of the
5-HT.sub.1D receptor and one of the other 5-HT receptor subtypes
(for example 5-HT.sub.1B) with a 5-HT.sub.1D-selective compound of
the invention and then incubating the resulting preparation with a
radiolabeled serotonin receptor ligand, for example
[.sup.3H]-serotonin. The 5-HT.sub.1D receptors are then
distinguished by determining the difference in membrane-bound
activity, with the 5-HT.sub.1D receptor exhibiting lesser
radioactivity, i.e., lesser [.sup.3H]-serotonin binding, than the
other 5-HT receptor subtype.
[0179] In another aspect of the invention, a compound of the
invention is provided in labeled form, such as radiolabeled form,
e.g. labeled by incorporation within its structure .sup.3H or
.sup.14C or by conjugation to .sup.125I. In another aspect of the
invention, the compounds in labeled form can be used as competitive
ligands to identify 5-HT.sub.1D receptor ligands by techniques
common in the art. This can be achieved by incubating the receptor
or tissue in the presence of a ligand candidate and then incubating
the resulting preparation with an equimolar amount of radiolabeled
compound of the invention. 5-HT.sub.1D receptor ligands are thus
revealed as those that are not significantly displaced by the
radiolabeled compound of the present invention. Alternatively,
5-HT.sub.1D receptor ligand candidates may be identified by first
incubating a radiolabeled form of a compound of the invention, then
incubating the resulting preparation in the presence of the
candidate ligand. A more potent 5-HT.sub.1D receptor ligand will,
at equimolar concentration, displace the radiolabeled compound of
the invention.
[0180] A radiolabelled compound of Formula I may be prepared using
standard methods known in the art. For example, tritium may be
incorporated into a compound of Formula I using standard
techniques, for example by hydrogenation of a suitable precursor to
a compound of Formula I using tritium gas and a catalyst.
Alternatively, a compound of Formula I containing radioactive iodo
may be prepared from the corresponding trialkyltin (suitably
trimethyltin) derivative using standard iodination conditions, such
as [.sup.125I] sodium iodide in the presence of chloramine-T in a
suitable solvent, such as dimethylformamide. The trialkyltin
compound may be prepared from the corresponding non-radioactive
halo, suitably iodo, compound using standard palladium-catalyzed
stannylation conditions, for example hexamethylditin in the
presence of tetrakis(triphenylphosphine) palladium (0) in an inert
solvent, such as dioxane, and at elevated temperatures, suitably
50-100.degree. C.
[0181] The present compounds are useful as pharmaceuticals for the
treatment of various conditions in which the use of a 5-HT.sub.1D
ligand is indicated, such as for the treatment of migraine, cluster
headache and portal tension, a condition characterized by increased
portal vein blood flow and typically associated with cirrhosis of
the liver.
[0182] For use in medicine, the compounds of the present invention
can be administered in a standard pharmaceutical composition. The
present invention therefore provides, in a further aspect,
pharmaceutical compositions comprising a pharmaceutically
acceptable carrier and at least one compound of Formula I, or a
pharmaceutically acceptable salt, solvate or hydrate thereof, in an
amount effective to stimulate the 5-HT.sub.1D receptor.
[0183] The compounds of the present invention may be administered
by any convenient route, for example by oral, parenteral, buccal,
sublingual, nasal, rectal or transdermal administration,
Appropriate pharmaceutical compositions will be formulated
accordingly.
[0184] Compounds of Formula I and their stereoisomers, solvates,
hydrates or pharmaceutically acceptable salts for oral
administration can be formulated as liquids, for example syrups,
suspensions, solutions or emulsions, or as solid forms such as
tablets, capsules and lozenges, or they may be presented as a dry
product for constitution with water or other suitable vehicle
before use. A liquid formulation will generally consist of a
suspension or solution of the compound (or pharmaceutically
acceptable salt thereof) in a suitable pharmaceutical liquid
carrier such as ethanol, glycerine, polyethylene glycol, oils, or
water with a suspending agent (e.g. sorbitol syrup, methyl
cellulose or hydrogenated edible fats), preservative (e.g. methyl
or propyl p-hydroxybenzoates or sorbic acid), flavouring or
colouring agent. A composition in the form of a tablet can be
prepared using any suitable pharmaceutical carrier routinely used
for preparing solid formulations. Examples of such carriers include
magnesium stearate, starch, lactose, sucrose and cellulose. A
composition in the form of a capsule can be prepared using routine
encapsulation procedures. For example, pellets containing the
active ingredient can be prepared using standard carriers and then
filled into hard gelatin capsule. Alternatively, a dispersion or
suspension can be prepared using any suitable pharmaceutical
carrier, for example aqueous gums, celluloses, silicates or oils,
and the dispersion or suspension filled into a soft gelatin
capsule.
[0185] Compounds of the present invention may be formulated for
parenteral administration by injection, including using
conventional catheterisation techniques or infusion. Formulations
for injection may be presented in unit dosage form, e.g. in
ampoules, or in multi-dose containers, with an added preservative.
Typical parenteral compositions consist of a solution or suspension
of the compound or pharmaceutically acceptable salt in a sterile
aqueous carrier or parenterally acceptable oil, for example
polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil
or sesame oil, and may contain formulatory agents such as
suspending, stabilizing and/or dispersing agents. Alternatively,
the solution can be lyophilized and then reconstituted with a
suitable solvent just prior to administration.
[0186] Compositions for nasal administration may conveniently be
formulated as aerosols, drops, gels and powders. Aerosol
formulations typically comprise a solution or fine suspension of
the active substance in a physiologically acceptable aqueous or
non-aqueous solvent and are usually presented in single or
multidose quantities in sterile form, in a sealed container, which
can take the form of a cartridge or refill for use with an
atomizing device. Alternatively, the sealed container may be a
unitary dispensing device such as a single dose nasal inhaler or an
aerosol dispenser fitted with a metering valve which is intended
for disposal after use. Where the dosage form comprises an aerosol
dispenser, it will contain a propellant which can be a compressed
gas such as compressed air or an organic propellant such as
fluorochlorohydrocarbon. The aerosol dosage forms can also take the
form of a pump-atomizer. Capsules and cartridges of, for example,
gelatin for use in an inhaler or atomizing device may be formulated
containing a powder mix of a compound of the invention and a
suitable powder base such as lactose or starch.
[0187] Compositions suitable for buccal or sublingual
administration include tablets, lozenges, and pastilles, wherein
the active ingredient is formulated with a carrier such as sugar,
acacia, tragacanth, or gelatin and glycerine. Compositions for
rectal administration are prepared in the form of, for example,
suppositories or retention enemas, and may contain a conventional
suppository base such as cocoa butter or other glycerides.
[0188] A proposed dose of the compounds of the invention for oral,
buccal, sublingual or rectal administration to a human (of about 70
kg body weight) for the treatment of migraine is 0.1 mg to 500 mg,
for example 0.5 mg to 100 mg, preferably 1 mg to 50 mg, of active
ingredient per dose, administered up to 8 times per day, more
usually 1 to 4 times per day. It will be appreciated that it may be
necessary to make routine changes to the dosage depending on the
age and weight of the patent as well as the severity of the
condition to be treated. It should be understood that unless
otherwise indicated, the dosages are referred to in terms of the
weight of the compound of Formula I calculated as the free
base.
[0189] The overall daily dosage administered by injection may be in
the range of 0.01 mg to 100 mg, preferably between 0.1 mg and 50
mg, e.g., between 1 mg and 25 mg, of a compound of Formula I or a
pharmaceutically acceptable salt, solvate or hydrate thereof
calculated as the free base, the compound being administered 1 to 4
doses per day.
[0190] Aerosol formulations are preferably arranged so that each
metered dose or "puff" delivered from a pressurized aerosol
contains 0.1 to 10 mg of a compound of the invention, and each dose
administered via capsules and cartridges in an inhaler contains 0.1
to 50 mg of a compound of the invention. Administration may be
several times daily, for example 2 to 8 times, giving for example
1, 2 or 3 doses each time. The overall daily dose by inhalation
will be similar to that for oral administration.
[0191] The compounds of the invention may, if desired, be
administered in combination with one or more other therapeutic
agents, such as analgesics, anti-inflammatory agents and
anti-nauseants.
EXPERIMENTAL EXAMPLES
Example 1
6-(2-(N,N-Dimethylamino)ethyl)-1H-indole (Compound 2)
[0192] To a stirred solution of 6-Chloroacetyl-1-pivaloylindole
(300 mg, 1.08 mmol) in THF (5 ml) were added successively, at room
temperature, NaHCO.sub.3 (453.6 mg, 5.4 mmol) and a solution of 2M
N,N-Dimethylamine in THF (2.7 ml, 5.4 mmol). The reaction mixture
was then refluxed for four hours. After cooling to room
temperature, the mixture was diluted with water (15 ml) and the
organic layer extracted twice with dichloromethane (2.times.50 ml).
After washing sequentially with water and brine, the organic layer
was dried over sodium sulfate, and the solvent removed in vacuo.
LiAlH.sub.4 (10.8 ml, 1M in THF, 10.8 mmol) was added to a solution
of the crude product in THF (5 ml) and the reaction mixture heated
at reflux overnight. After cooling to room temperature, the
reaction mixture was quenched with Rochelle's salt (1M, 3 mL) and
silica gel and passed through a frit using methanolic ammonia in
dichloromethane (0-10%). The 5% fraction was further purified by
flash chromatography (silica gel, 3% methanolic ammonia in
dichloromethane) yielding the product (176 mg, 87%) of the title
product.
Example 2
6-(2-(N,N-Dimethylamino)ethyl)-1-isopropyl-indole (Compound 3)
[0193] Sodium hydride (12.7 mg, 0.531 mmol) was added to an
ice-cooled solution 6-(2-(N,N-Dimethylamino)ethyl)-1H-indole (50
mg, 0.265 mmol) in DMF (1 ml). After stirring for 1 h at 0.degree.
C., 2-iodopropane (52.9 .mu.L, 0.530 mmol) was added and the
mixture stirred at 100.degree. C. overnight. The reaction mixture
was then partitioned between water and dichloromethane, the organic
layer washed sequentially with water and brine, dried over sodium
sulfate and the solvent was removed in vacuo. Flash chromatography
(silica gel, 7% methanolic ammonia in dichloromethane) gave the
title product (10 mg, 16%).
Example 3
6-(.sup.tButyloxycarbonylmethyl)-1-trimethylacetyl-indole (Compound
5)
[0194] To a solution of NiCl.sub.2(PPh.sub.3).sub.2 (68.8 mg, 0.1
mmol) and PPh.sub.3 (55.6 mg, 0.2 mmol) in diethyl ether (1 ml) was
added a 1M solution of EtMgBr (0.25 ml, 0.25 mmol), dropwise under
argon, at 0 to 5.degree. C. After stirring for 10 mins, a 0.5M
solution of .sup.tBuOCOCH.sub.2ZnCl (4 ml, 2 mmol) was added,
followed by 6-Bromo-1-trimethyl-acetyl-indole (280 mg, 1 mmol). The
reaction mixture was stirred at 40 to 45.degree. C. overnight,
diluted with dichloromethane, washed with saturated-NH.sub.4Cl and
water, dried over anhydrous sodium sulphate and the crude product
passed through a silica gel column, eluting with hexane, to give
the title product (yield 233.6 mg, 78%).
[0195] b) In a similar fashion,
6-(.sup.tButyloxycarbonylmethyl)-1-indole was prepared from
6-Bromo-indole (100 mg, 0.51 mmol), 0.5M .sup.tBuOCOCH.sub.2ZnCl (3
ml, 1.5 mmol), NiCl.sub.2(PPh.sub.3).sub.2 (34.4 mg, 0.05 mmol),
PPh.sub.3(27.8 mg, 1 mmol) and 1M EtMgBr (0.125 ml, 0.125 mmol) to
give 27 mg (23% yield) of the title product.
Example 4
6-(2-Hydroxyethyl)-indole (Compound 6)
[0196] A mixture of
6-(.sup.tButyloxycarbonylmethyl)-1-trimethylacetyl-ind- ole (233.6
mg, 0.78 mmol) and 1M LiAlH.sub.4 (5 ml, 5 mmol) was refluxed for 1
hr. The reaction mixture was quenched with sodium sulphate
decahydrate, diluted with ethyl acetate and the crude product
passed through a silica gel column, eluting with dichloromethane,
to give 72.5 mg (58%) of the title compound.
[0197] b) 6-(2-Hydroxyethyl)-indole was prepared from
6-(.sup.tButyloxycarbonylmethyl)-1-indole, under the same
conditions.
Example 5
6-(2-(Methanesulfonyl)ethyl)-indole (Compound 7)
[0198] 6-(2-Hydroxyethyl)-indole (72.5 mg, 0.45 mmol) was mixed
with Et.sub.3N (126 mg, 1.35 mmol) in 2 ml of dichloromethane at 0
to 5.degree. C. Methane sulfonyl chloride (61.6 mg, 0.54 mmol) was
added and the mixture stirred for 1 hr, diluted with
dichloromethane, washed with brine, dried and concentrated to give
107 mg of the title compound (quantitative yield).
Example 6
6-(2-(Diethylamino)ethyl)-indole (Compound 8)
[0199] A mixture of 6-(2-(Methanesulfonyl)ethyl)-indole (107 mg,
0.45 mmol) and diethylamine (0.4 ml) in 2 ml of THF was stirred at
65.degree. C. overnight. The reaction mixture was concentrated in
vacuo and passed through a silica gel column, eluting with 2% 2M
ammonia/methanol in dichloromethane, to give the title compound, 42
mg (43% yield).
Example 7
6-(2-(Diethylamino)ethyl)-1-isopropyl-indole (Compound 9,
alkylation example)
[0200] Prepared from 6-(2-(Diethylamino)ethyl)-indole (14 mg,
0.0647 mmol), 2-iodopropane (44 .mu.l, 0.259 mmol), NaH (3.1 mg,
0.129 mmol), K2CO3 (35 mg, 0.259 mmol) in 0.1 ml of DMF and 0.5 ml
of toluene, according to example. Yield 8.5 mg (51%).
Example 8
6-(2-(Diethylamino)ethyl)-1-dimethylaminocarbonyl-indole (Compound
9, amidation example)
[0201] To a stirred solution of 6-(2-(Dimethlamino)ethyl-indole
(14.5 mg, 0.067 mmol) was added dropwise at 0.degree. C. 0.2 ml
(0.2 mmol) of a 1M solution of NaN(TMS).sub.2 in THF. The reaction
mixture was stirred at this temperature for another 30 min. Then
21.5 mg, (0.2 mmol) of dimethylcarbamyl chloride was added drowse,
and the reaction mixture stirred for another 30 min before being
poured into dichloromethane (10 ml), and slowly quenched with water
and brine. The aqueous phase was extracted twice with 15 ml of
dichloromethane. The organic layer was dried over Na.sub.2SO.sub.4,
concentrated in vacuo and the residue purified by column
chromatography on silica gel, eluting with 10% 2M ammonia/methanol
in dicloromethane to give 8.3 mg (42%) of the title compound.
Example 9
4-Bromo-2-[(tetrahydropyran-4-yl)amino]-phenylacetaldehyde,
dimethyl acetal (Compound 14)
[0202] 2-Amino-4-bromo-phenylacetaldehyde, dimethyl acetal (500 mg,
1.92 mmol) and tetrahydro-4-pyranone (2.88 mmol) were stirred in
acetic acid (14 ml), in the presence of Na.sub.2SO.sub.4 (2.72 g),
for 30 mins. Sodium triacetoxyborohydride (NaBH(OAc).sub.3; 1.22 g,
5.77 mmoles) was then added and the mixture stirred for 2 hrs
before being poured into an 8:1 mixture of ethyl acetate-hexanes
(50 ml) and slowly quenched with saturated NaHCO.sub.3 solution.
The organic layer was dried over Na.sub.2SO.sub.4, concentrated in
vacuo and the residue purified by column chromatography on silica
gel, eluting with ethyl acetate:hexanes (1:5), to give the title
compound (522.8 mg, 79% yield).
[0203] In a similar fashion the following compounds were
prepared:
[0204] b)
4-Bromo-2-[(tetrahydrothiopyran-4-yl)amino]-phenylacetaldehyde,
dimethyl acetal; from 2-Amino-4-bromo-phenylacetaldehyde, dimethyl
acetal (500 mg, 1.92 mmol) tetrahydrothiopyran-4-one (2.88 mmol),
acetic acid (14 ml) and NaBH(OAc).sub.3(1.22 g, 5.77 mmol); yield
549 mg (79%);
[0205] c)
4-Bromo-2-[(N-Butoxycarbonyl-piperidin-4-yl)amino]-phenyl-acetal-
dehyde, dimethyl acetal; from 2-Amino-4-bromo-phenylacetaldehyde,
dimethyl acetal (500 mg, 1.92 mmol), N-Butoxycarbonyl-4-piperidone
(2.88 mmol), acetic acid (14 ml) and NaBH(OAc).sub.3 (1.2 g, 5.77
mmol). Yield 728 mg (86%);
[0206] d)
2-[(Azabicyclo[4,3,0]nonan-4-yl)amino]-4-Bromo-phenylacetaldehyd-
e, dimethyl acetal; from 2-Amino-4-bromo-phenylacetaldehyde,
dimethyl acetal (500 mg, 1.92 mmol), 4-oxo-azabicyclo[4,3,0]nonane
(2.88 mmol), acetic acid (14 ml) and NaBH(OAc).sub.3 (1.22 g, 5.77
mmol); yield 524.5 mg (71%);
[0207] e)
4-Bromo-2-[(N-methyl-piperidin-4-yl)amino]-phenylacetaldehyde,
dimethyl acetal; from 2-Amino-4-bromo-phenylacetaldehyde, dimethyl
acetal (107 mg, 0.411 mmol), N-methyl-4-piperidone (0.62 mmol),
acetic acid (3 ml) and NaBH(OAc).sub.3 (261 mg, 1.23 mmol); yield
140.1 mg (95%);
Example 10
6-Bromo-1-(tetrahydropyran-4-yl)-indole (Compound 15)
[0208] 4-Bromo-2-[(tetrahydropyran-4-yl)amino]-phenylacetaldehyde,
dimethyl acetal (522 mg, 1.516 mmol) was dissolved in 20 ml of 1M
HCl in methanol. The solution was refluxed for 2 hrs and the
solvent evaporated to give the title compound (407 mg, 96%) as an
off-white solid.
[0209] In a similar fashion, the following compounds were
prepared:
[0210] b) 6-Bromo-1-(tetrahydrothiopyran-4-yl)-indole; from
4-Bromo-2-[(tetrahydrothiopyran-4-yl)amino]-phenylacetaldehyde,
dimethyl acetal (554.9 mg, 1.52 mmol). Yield 375 mg (83%);
[0211] c) 6-Bromo-1-(4-piperidinyl)-indole; from
4-Bromo-2-[(N-Butoxycarbo-
nyl-piperidin-4-yl)amino]-phenylacetaldehyde, dimethyl acetal (728
mg, 1.64 mmol). Yield 349 mg (76%);
[0212] d) 6-Bromo-1-(Azabicyclo[4,3,0]nonan-4-yl)-indole; from
2-[(Azabicyclo-[4,3,0]-nonan-4-yl)amino]-4-Bromo-phenylacetaldehyde,
dimethyl acetal (524 mg, 1.37 mmoles). Products were separated by
column chromatography on silica gel, eluting with 10% 2M
ammonia/methanol in dichloromethane. Yield 236.7 mg (54%) of the
less polar isomer and 103.4 mg (24%) of the more polar isomer;
[0213] e) 6-Bromo-1-(N-methyl-piperidin-4-yl)-indole; from
4-Bromo-2-[(N-methyl-piperidin-4-yl)amino]-phenylacetaldehyde,
dimethyl acetal (108 mg, 0.30 mmol). Yield 69.4 mg (79%).
Example 11
6-(2-Dimethylaminoethyl)-1-(tetrahydrothiopyran-4-yl)-indole
(Compound 17)
[0214] 6-Bromo-1-(tetrahydrothiopyran-4-yl)-indole (50 mg, 0.169
mmol), BINAP (12.5 mg, 0.02 mmol), Pd(DBA).sub.3 (7.7 mg, 0.008
mmol) and KHMDS (67 mg, 0.338 mmol) were mixed with 2 ml of
dioxane. N,N-dimethylacetamide (N,N-DMA; 16 mg, 0.186 mmol) was
added and the mixture heated to 100.degree. C. for 1 hr. After
cooling slightly, the reaction mixture was diluted with
dichloromethane and washed with water. The crude product was
purified by column chromatography on silica gel, eluting with 5% 2M
ammonia/methanol in dichloromethane to give 49.3 mg of the amide
intermediate, which was dissolved in THF (3 ml). A 1M solution of
LiAlH.sub.4 (0.34 ml) was added, and the mixture refluxed for 2
hrs. The reaction was quenched with sodium sulphate decahydrate
(Na.sub.2SO.sub.410H.sub.2O), the mixture was filtered and the
crude product purified by column chromatography on silica gel,
eluting with 5% 2M ammonia/methanol in dichloromethane to give the
title compound (23 mg, 47%) as a brown oil.
[0215] In a similar fashion, the following compounds were
prepared:
[0216] b) 6-(2-Dimethylaminoethyl)-1-(tetrahydropyran-4-yl)-indole;
6-Bromo-1-(tetrahydropyran-4-yl)-indole from (20 mg, 0.071 mmol),
BINAP (3.3 mg, 0.006 mmol), Pd(DBA).sub.3 (3.25 mg, 0.007 mmol),
KHMDS (28 mg, 0.14 mmol), N,N-DMA (18 .mu.l), 1M LiAlH.sub.4 (0.14
ml) and 2 ml of THF. Yield (#mg, #%);
Example 12
6-lodo-1H-indazole (Compound 20)
[0217] Sodium nitrite (5.87 g, 85 mmol) in water (20 mL) was added
dropwise to an ice-cooled solution of 6-aminoindazole (10 g, 75.6
mmol) in DMF (80 mL) and hydrochloric acid (6M, 40 mL). The mixture
was stirred for 30 minutes. Potassium iodide (13.5 g) was then
added in small portions (gas evolution occurred) and the mixture
stirred for 1 h before warming to room temperature for 16 h. The
reaction was neutralized with aqueous sodium bisulfite, followed by
aqueous sodium hydroxide. The mixture was filtered to remove
solids, and the solid was washed with water to remove impurities,
and then with ethyl acetate and THF to collect the product. The
organic washes were evaporated and recombined with the aqueous
layer for extraction with ethyl acetate (3.times.250 mL). The
organic layer was washed sequentially with water and brine, dried
over sodium sulfate, and the solvent removed in vacuo. Filtration
chromatography on silica gel (35-60% ethyl acetate in hexane) gave
a yellow solid which was triturated firstly with 50% ethyl acetate
in hexane and then with ethyl acetate to yield the product (4.96
g).
Example 13
6-iodo-1-isopropyl-1H-indazole (Compound 21)
[0218] Sodium hydride (85 mg, 60%, 2.12 mmol) was added to an
ice-cooled solution of 6-iodo-1H-indazole (249.5 mg, 1.02 mmol) in
DMF (2.5 mL). After stirring this mixture for 1 h at 0.degree. C.,
2-iodopropane (0.32 mL, 3.2 mmol) was added and the mixture stirred
at 100.degree. C. for 16 h. After the reaction mixture was
partitioned between water and ethyl acetate, the organic layer was
washed sequentially with water and brine, dried over sodium sulfate
and the solvent removed in vacuo. Flash chromatography (silica gel,
5-20% ethyl acetate in hexane) yielded two products, the less polar
1-substituted-1H-indazole (105 mg) and the more polar 2-substituted
indazolium (107.7 mg).
Example 14
6-(2-(N,N-Dimethylamino)ethyl)-1-isopropyl-1H-indazole (Compound
22)
[0219] A solution of 6-iodo-1-isopropyl-1H-indazole (49.6 mg, 0.17
mmol), tris-(dibenzylidenacetone)dipalladium(0) (8 mg, 8.7
.mu.mol), S-BINAP (9 mg, 15 .mu.mol), potassium
bis(trimethylsilyl)amide (75 mg, 0.37 mmol) and
N,N-dimethyl-acetamide (45 .mu.L, 0.48 mmol) in 1,4-dioxane (2.5
mL) was heated at 100.degree. C. for 2 h. After cooling to room
temperature, the reaction mixture was diluted with water (1 mL) and
passed through an EXTUBE using dichloromethane to elute (10 mL).
LiAlH.sub.4 (0.4 mL, 1M, 0.4 mmol) was added to a solution of the
crude product in THF (2.5 mL) and the reaction mixture heated at
reflux for 2 h. After cooling to room temperature, the mixture was
quenched with Rochelle's salt (1M, 1 mL) and silica gel (to absorb
water) and passed through a frit using methanolic ammonia in
dichloromethane (0-10%). The 5% fraction was further purified by
flash chromatography (silica gel, 2-8% methanolic ammonia in
dichloromethane) to give the product (5.9 mg).
Example 15
6-[4-Hydroxy-azabicyclo[4,3,0]nonan-4-yl]-indole (Compound 29)
[0220] To a suspension of potassium hydride (KH; 0.289 g, 7.2 mmol)
in tetrahydrofuran (THF; 5 ml) at -10.degree. C. was added,
dropwise, a solution of 6-bromoindole (1.2 g, 6 mmol) in THF (1
ml). The mixture was stirred at this temperature for 20 mins, until
no more evolution of hydrogen was observed. The mixture was then
cooled to -78.degree. C. in an acetone/dry ice bath, 8.82 ml of a
1.7M solution of .sup.tBuLi was added slowly, and the mixture
stirred for another 30 mins. Azabicyclo[4,3,0]nonan-4-one (1.67 g.
1.2 mmol) was then added, and the mixture stirred at -78.degree. C.
for a further 30 mins before being quenched with a mixture of
dichloromethane (50 ml) and pH7 buffer (50 ml). After filtration,
the organic layer was washed with water and brine, dried,
concentrated, and the residue triturated with hexanes to give 0.52
g of the title product as a white powder (33.1%).
[0221] b) In a similar fashion,
6-[4-Hydroxy-1-methyl-piperidin-4-yl]-indo- le was prepared from
6-bromoindole (1.0 g, 5 mmol); KH (0.225 g, 5.6 mmol), 1.7M
.sup.tBuLi (7.5 ml, 12.7 mmol) and N-methyl-4-piperidone (1.246 g,
10.9 mmol). Yield 0.382 g (35%).
Example 16
6-[N-methyl-1,2,5,6-tetrahydropyridin-4-yl]-indole (Compound
30)
[0222] The above compound (197 mg, 0.855 mmol) was mixed with THF
(10 ml) and trifluoroacetic acid (TFA; 1 ml) and heated at
60-70.degree. C. until thin-layer chromatography (TLC) showed that
the starting material had been consumed. The reaction mixture was
quenched with silica gel and purified by column chromatography on
silica gel (eluting with 2-5% of 2M ammonia/methanol in
dichloromethane to give the title compound (173 mg, 95%).
[0223] In a similar fashion the following compounds were
prepared:
[0224] b) 6-[3,4-anhydro-azabicyclo[4,3,0]nonan-4-yl]-indole (yield
10.5 mg, 56%) and
6-[4,5-anhydro-azabicyclo[4,3,0]nonan-4-yl]-indole (yield 4.8 mg,
26%); from 6-[4-Hydroxy-azabicyclo[4,3,0]nonan-4-yl]-indole (20 mg,
0.078 mmol);
[0225] c)
6-[N-Methyl-1,2,5,6-tetrahydropyridin-4-yl]-1-isopropyl-indole:
from 6-[4-Hydroxy-1-methyl-piperidin-4-yl]-1-isopropyl-indole (20
mg, 0.0735 mmol) in 0.1 ml of TFA and 1 ml of THF at 60-64.degree.
C. Yield 4.8 mg (26%).
Example 17
6-[Azabicyclo[4,3,0]nonan-4-yl]-indole (Compound 31)
[0226] 6-[3,4-anhydro-azabicyclo[4,3,0]nonan-4-yl]-indole (35 mg,
0.147 mmol) was stirred overnight under H.sub.2, at room
temperature, in the presence of 10% Pd/C (45 mg) in ethanol. The
reaction mixture was filtered through celite and concentrated in
vacuo to give 35 mg (99%) of the title product as a mixture of two
diastereoisomers, which were separated by column chromatography on
silica gel, eluting with 2% of 2M ammonia/methanol in
dichloromethane.
Example 18
6-[3,4-Anhydro-azabicyclo[4,3,0]nonan-4-yl]-1-isopropyl-indole
(Compound 33, alkylation example)
[0227] A mixture of
6-[3,4-Anhydro-azabicyclo[4,3,0]nonan-4-yl]-indole (23.8 mg, 0.1
mmol), potassium carbonate (K.sub.2CO.sub.3; 27.6 mg, 0.2 mmol),
sodium hydride (NaH; 4.8 mg, 0.2 mmol), dimethyl formamide (DMF;
0.1 ml) and 2-iodopropane (85 mg, 0.5 mmol) in 1 ml of toluene was
heated to 90-100.degree. C. for 1 hr. After cooling,
dichloromethane was added and the mixture passed a silica gel
column, eluting with 1% 2M ammonia/methanol in dichloromethane, to
give the title compound (11.0 mg, 39%) as a yellow oil.
Example 19
1-(4-Fluorophenyl)-6-(N-methyl-1,2,5,6-tetrahydropyridin-4-yl)-indole
(Compound 32, arylation example)
[0228] A mixture of
6-(1-Methyl-1,2,5,6-tetrahydropyridin-4-yl)-indole (20.1 mg, 0.0945
mmol), potassium carbonate (K.sub.2CO.sub.3; 52.3 mg, 0.3787 mmol),
cuprous bromide (CuBr; 6.7 mg, 0.0473 mmol), a little copper powder
and 1-fluoro-4-iodobenzene (42.04 mg, 0.189 mmol) in 1 ml of
N-methyl-4-piperidone (NMP) was heated at 170.degree. C., under
argon, overnight. After cooling, the mixture was diluted with
dichloromethane and the organic layer washed with water 10 times
before being passed through a silica gel column (eluting with 1% 2M
ammonia/methanol in dichloromethane) to give the title product (15
mg, 55%).
[0229] In a similar fashion, the following compounds were
prepared:
[0230] b) 6-[Azabicyclo[4,3,0]nonan-4-yl]-1-isopropyl-indole from
6-[Azabicyclo[4,3,0]nonan-4-yl]-indole (14 mg, 0.0.05 mmol),
K.sub.2CO.sub.3 (16 mg, 0.116 mmol), NaH (4.8 mg, 0.2 mmol), DMF
(0.1 ml) and 2-iodopropane (30 mg, 0.174 mmol) in toluene (0.5 ml)
(yield 10.7 mg (65%) as a yellow oil);
[0231] c)
6-(N-Methyl-1,2,5,6-tetrahydropyridin-4-yl)-1-(3-thienyl)-indole- :
from 6-(1-Methyl-1,2,5,6-tetrahydropyridin-4-yl)-indole (19.8 mg,
0.0933 mmol), K.sub.2CO.sub.3 (51.5 mg, 0.373 mmol), CuBr (6.7 mg,
0.0466 mmol), a little Cu powder and 3-bromothiophene (30.4 mg,
0.187 mmol) in 1 ml of NMP (yield 14.5 mg, 53%);
[0232] d)
6-(N-Methyl-1,2,5,6-tetrahydropyridin-4-yl)-1-(3-pyridyl)-indole- :
from 6-(1-Methyl-1,2,5,6-tetrahydropyridin-4-yl)-indole (15 mg,
0.0706 mmol), K.sub.2CO.sub.3 (39 mg, 0.283 mmol), CuBr (5 mg,
0.0353 mmol), a little Cu powder and 3-bromopyridine (22.3 mg,
0.141 mmol) in 1 ml of NMP (yield 11.5 mg, 56%);
[0233] e) 6-[Azabicyclo[4,3,0]nonan-4-yl]-1-(4-pyridinyl)-indole
from 6-[Azabicyclo[4,3,0]nonan-4-yl]-indole (35 mg, 0.145 mmol),
K.sub.2CO.sub.3 (80 mg, 0.58 mmol), CuBr (10.4 mg, 0.072 mmol), a
little Cu powder and 4-bromopyridine hydrochloride (71.4 mg, 0.29
mmol) in 1 ml of NMP. Yield: 10.3 mg (22%) of the less polar isomer
and 1.5 mg (8%) of the more polar isomer.
[0234] f) 6-(2-Dimethylaminoethyl)-1-(3-pyridinyl)-indole: from
6-(2-Dimethylaminoethyl)-indole (19.3 mg, 0.102 mmol),
K.sub.2CO.sub.3 (56.6 mg, 0.41 mmol), CuBr (7.3 mg, 0.0353 mmol), a
little Cu powder and 3-bromopyridine (32.4 mg, 0.205 mmol) in 1 ml
of NMP (yield 8 mg, 29%);
[0235] g) 6-(2-Dimethylaminoethyl)-1-(3-thienyl)-indole: from
6-(2-Dimethylaminoethyl)-indole (17.6 mg, 0.093 mmol),
K.sub.2CO.sub.3 (51.6 mg, 0.374 mmoles), CuBr (6.7 mg, 0.0467
mmol), a little Cu powder and 3-bromothiophene (30.5 mg, 0.187
mmol) in 1 ml of NMP (yield 2 mg, 8%).
[0236] h) 6-(2-Dimethylaminoethyl)-1-(4-fluorophenyl)-indole: from
6-(2-Dimethyl-aminoethyl)-indole (18.5 mg, 0.098 mmol),
K.sub.2CO.sub.3 (54.2 mg, 0.393 mmol), CuBr (7 mg, 0.049 mmol), a
little Cu powder and 1-fluoro-4-iodobenzene (43.6 mg, 0.196 mmol)
in 1 ml of NMP (yield 12.7 mg, 46%);
[0237] i)
6-(N-Methyl-1,2,5,6-tetrahydropyridin-4-yl)-1-(2-thiazolyl)-indo-
le: from 6-(1-Methyl-1,2,5,6-tetrahydropyridin-4-yl)-indole (15.2
mg, 0.0715 mmol), K.sub.2CO.sub.3 (39.5 mg, 0.283 mmol), CuBr (5.1
mg, 0.0357 mmol), a little Cu powder and 2-bromothiazole (23.5 mg,
0.143 mmol) in 1 ml of NMP (yield 8.6 mg, 41%);
Example 20
1-Dimethylaminocarbonyl-6-[N-methyl-1,2,5,6-tetrahydro-pyridin-4-yl]-indol-
e (Compound 33, amidation example)
[0238] From 6-(1-Methyl-1,2,5,6-tetrahydropyridin-4-yl)-indole
(16.6 mg, 0.0735 mmol), dimethylcarbamyl chloride (15.8 mg. 0.147
mmol) and 1M NaN(TMS).sub.2(0.147 ml) in 0.5 ml of THF at 0.degree.
C. Yield 12.5 mg (60%), the reaction being carried out according to
Example 6.
Example 21
6-bromo-1-isopropylindole (Compound 34)
[0239] A mixture of 6-bromoindole (2.0 g, 10 mmol), K.sub.2CO.sub.3
(2.76 g, 20 mmol), NaH (0.48 g, 20 mmol), DMF (1 ml) and
2-iodopropane (8.5 g, 50 mmol) in 40 ml of toluene was heated at
90.about.100.degree. C. for 2 hr. The reaction mixture was diluted
with water and extracted with ethyl acetate. The organic layer was
dried over anhydrous sodium sulphate (Na.sub.2SO.sub.4),
concentrated in vacuo and the residue purified by column
chromatography on silica gel, eluting with hexanes, to give (2.32
g, 97%) of the title product.
Example 22
6-[4-Hydroxy-1-methyl-piperidin-4-yl]-1-isopropyl-indole (Compound
35)
[0240] 1.5 ml of a solution of 6-bromo-1-isoproylindole (240 mg, 1
mmol) was cooled to -78.degree. C., 1.7M .sup.tBuLi (1.47 ml, 2.5
mmol) was added and the mixture stirred for 7 mins.
N-Methyl-4-piperidone (340.8 mg, 3 mmol) was then added and the
mixture stirred for a further 10 mins. The reaction mixture was
then warmed up to -20.degree. C. and quenched with water and
dichloromethane. The organic layer was washed with water, dried
over anhydrous Na.sub.2SO.sub.4, concentrated in vacuo and the
residue purified by column chromatography on silica gel, eluting
with 2% 2M ammonia/methanol in dichloromethane to give the title
product (120 mg, 44%).
Example 23
6-((N-Benzyloxycarbonyl)prolyl)-indole (Compound 39)
[0241] To a suspension of KH (14 mg, 7.2 mmol) in 1 ml of THF,
6-bromoindole (600 mg, 6 mmol) in 1 ml of THF was added, dropwis,e
at -10.degree. C., and the mixture stirred at this temperature for
about 20 mins, until no more hydrogen evolution was observed. The
reaction mixture was cooled to -78.degree. C., 1M .sup.tBuLi (4.4
ml, 7.5 mmol) was added slowly, and stirring continued for another
30 mins. L-Cbz-proline methylester (1.5 g. 6 mmol) was then added
and the mixture stirred for a further 30 mins, before being
quenched with a mixture of dichloromethane (25 ml) and pH7 buffer
(25 ml). The solids were filtered off and the organic layer washed
with water and brine, dried and concentrated in vacuo. Purification
by flash chromatography, using 20% EtOAc/Hexanes as eluant, gave
184 mg (17%) of the title compound.
Example 24
6-[(.alpha.-Hydroxy-.alpha.-(2-Pyrrolidinyl))methyl]-indole and
6-((2-Pyrrolidinyl)methyl)-indole (Compounds 38 & 40)
[0242] To a stirred solution of the
6-((N-Benzyloxycarbonyl)prolyl)-indole (35 mg, 0.1 mmol) in 1 ml of
THF, was added, dropwise at 0.degree. C., 1 ml of 1M LiAlH.sub.4 in
THF. The reaction mixture was refluxed overnight. After cooling to
room temperature, the reaction was quenched
Na.sub.2SO.sub.410H.sub.2O, filtered and the crude product purified
by chromatography on silica gel, eluting with 10% 2M
ammonia/methanol in dichloromethane to give a mixture of
6-[(.alpha.-Hydroxy-.alpha.-(2-Pyrro- lidinyl))methyl]-indole and
6-((2-Pyrrolidinyl)methyl)-indole, (10.4 mg, 45%) and (6.8 mg,
30%), respectively.
Example 25
6-Bromo-1-triisopropylsilyl-indole (Compound 42)
[0243] A solution of 6-Bromoindole (1 g, 5 mmol) in DMF (3 ml) was
added to a suspension of NaH (134.7 mg, 5.6 mmol) in DMF (98 ml) at
0.degree. C. and stirred for 15 mins. Triisopropylsilyl chloride
(1.082 g, 5.6 mmol) was added dropwise, and the reaction mixture
stirred for 2 h before being poured into ice-water and extracted
with ethyl acetate. The organic layer was washed with brine,
concentrated in vacuo and the crude product passed through a silica
gel column, eluting with hexanes, to give the title compound (406.7
mg, 23%) as a colourless oil.
Example 26
6-(3-methylpiperazinyl)-1-triisopropylsilyl-indole (Compound
43)
[0244] From 6-Bromo-1-triisopropylsilyl-indole (400 mg, 1.14 mmol),
2-methylpiperazine (1.36 mg, 13.6 mmol), NaO.sup.tBu (0.153 mg,
1.59 mmol), .sup.tBu.sub.3P (12 mg) and Pd(OAc).sub.2 (3 mg) in
xylene (1 ml) under argon. The reaction mixture was heated to
120.degree. C. (59%).
Example 27
6-(N-methylpiperazinyl)-indole (Compound 44)
[0245] To a solution of 6-(N-methylpiperazinyl)-1-triisopropylsilyl
indole (237 mg, 0.64 mmol) in 1 ml of THF, 1M TBAF (0.64 ml, 0.64
mmol) was added dropwise at room temperature. After 30 mins, the
mixture was diluted with dichloromethane and washed 3 times with
water to give the title product (100.6 mg, 73% yield).
Example 28
1-Isopropyl-6-(N-methylpiperazinyl)-indole (Compound 45, from
compound 46)
[0246] A mixture of 6-bromo-1-isopropylindole (23.8 mg, 0.1 mmol),
sodium-.sup.tbutoxide (NaO.sup.tBu; 14.1 mg, 0.15 mmol),
tri-.sup.tbutyl phosphine (.sup.tBU.sub.3P; 1 mg), palladium
acetylacetonate (Pd(OAc).sub.2; 1 mg) and 1-methylpiperazine (60
mg, 0.6 mmol) in xylene (1 ml) under argon was heated at
120.degree. C. for 3 h., The cooled reaction mixture was diluted
with dichloromethane, washed with water and the crude product
purified by column chromatography on silica gel, eluting with 1% 2M
ammonia/methanol in dichloromethane to give (11.3 mg, 44%) of the
title compound.
[0247] In a similar fashion, the following compounds were
prepared:
[0248] b) 1-Isopropyl-6-(N-methylhomopiperazinyl)-indole; from
6-bromo-1-isopropyl-indole (23.8 mg, 0.1 mmol),
1-methylhomopiperazine (68.4 mg, 0.6 mmol), NaO.sup.tBu (14.1 mg,
0.15 mmol), .sup.tBU.sub.3P (1 mg) and Pd(OAc).sub.2 (1 mg) in
xylene (1 ml), heating overnight. Yield 8.3 mg (31%);
[0249] c)
6-(1,3-Diazabicyclo-[4,4,0]-decan-3-yl)-1-isopropyl-indole; from
6-bromo-1-isopropylindole (23.8 mg, 0.1 mmol),
1,3-Diazabicyclo-[4,4,0]-d- ecane (75.6 mg, 0.6 mmol), NaO.sup.tBu
(14.1 mg, 0.15 mmol), .sup.tBu.sub.3P (1 mg) and Pd(OAc).sub.2 (1
mg) in xylene (1 ml), heating overnight. Yield 9.4 mg (32%);
[0250] d) 1-Isopropyl-6-(3-methylpiperazinyl)-indole; from
6-Bromo-1-isopropylindole (23.8 mg, 0.1 mmol), 2-methylpiperazine
(60 mg, 0.6 mmol), NaQ.sup.tBu (14.1 mg, 0.15 mmol),
.sup.tBu.sub.3p(1 mg) and Pd(OAc).sub.2 (1 mg) in xylene (1 ml),
heating overnight. Yield 6.7 mg (26%).
Example 29
1-Isopropyl-6-(4-methylpiperazinyl)-indole (Compound 45, from
Compound 44, Alkylation Example)
[0251] A mixture of 6-(4-methylpiperazinyl)-indole (8.3 mg, 0.386
mmol), K.sub.2CO.sub.3 (21 mg, 0.154 mmol), NaH (3 mg, 0.125 mmol),
DMF (0.1 ml) and 2-iodopropane (26.3 .mu.l, 0.154 mmol) in 0.5 ml
of toluene was heated to 90-100.degree. C. for 1 hr. After cooling,
dichloromethane was added and the mixture passed a silica gel
column, eluting with 1% 2M ammonia/methanol in dichloromethane, to
give the title compound (8.2 mg, 83% yield).
Example 30
1-(4-Fluorophenyl)-6-(4-methylpiperazinyl)-indole (Compound 45,
from Compound 44, Arylation Example)
[0252] A mixture of 6-(4-Methylpiperazinyl)-indole (14.8 mg, 0.0687
mmol), K.sub.2CO.sub.3 (37.9 mg, 0.275 mmol), CuBr (4.9 mg, 0.0353
mmol), a little copper powder and 1-Fluoro-4-iodobenzene (30.5 mg,
0.37 mmol) in 1 ml of NMP was heated at 170.degree. C., under
argon, overnight. After cooling, the mixture was diluted with
dichloromethane and the organic layer washed with water 10 times
before being passed through a silica gel column (eluting with 1% 2M
ammonia/methanol in dichloromethane) to give the title product (7.8
mg, 37%).
[0253] In a similar fashion, the following compounds were
prepared:
[0254] b) 6-(4-methylpiperazinyl)-1-(3-thiazolyl)-indole; from
6-(4-Methylpiperazinyl)-indole (15.4 mg, 0.0715 mmol),
K.sub.2CO.sub.3 (39.5 mg, 0.286 mmol), CuBr (5.1 mg, 0.0357 mmol),
Cu powder (a little) and 3-Bromotiazole (23.4 mg, 0.143 mmol) in 1
ml of NMP. Yield 1.7 mg (8%);
[0255] c) 6-(4-methylpiperazinyl)-1-(3-thienyl)-indole; from
6-(4-Methylpiperazinyl)-indole (15.1 mg, 0.0701 mmol),
K.sub.2CO.sub.3 (38.7 mg, 0.28 mmol), CuBr (5 mg, 0.0353 mmol), Cu
powder (a little) and 3-bromothiophene (22.9 mg, 0.14 mmol) in 1 ml
of NMP. Yield 1.2 mg (6%).
Example 31
[0256] (a) tert-Butyl 2-(1-(2-propyl)-1H-indazol-6-yl)acetate:
[0257] Ethyl magnesium bromide (1M in THF, 0.10 mL, 0.10 mmol) was
added to a suspension of NiCl.sub.2(PPh.sub.3).sub.2 (17.2 mg,
0.026 mmol) and PPh.sub.3 (13.9 mg, 0.053 mmol) in diethyl ether
(0.5 mL). The resulting catalyst solution was stirred for 10-15 min
at room temperature under an atmosphere of argon. A solution of
6-iodo-1-(2-propyl)-1H-indazole (73 mg, 0.26 mmol) in diethyl ether
(1.5 mL) was added to this pre-formed catalyst mixture, followed by
a solution of 2-tert-butoxy-2-oxoethylzinc chloride (from Rieke
Metals Inc, 0.5M in diethyl ether, 1.0 mL, 0.5 mmol) and finally
1-methyl 2-pyrrolidinone (1.0 mL). The resulting mixture formed a
dark red homogeneous solution that was heated at 45.degree. C. for
15 h. After cooling to room temperature, the reaction mixture was
partitioned between ethyl acetate (75 mL) and half-saturated brine
(25 mL). The organic layer was washed with brine (5.times.25 mL)
and dried over anhydrous sodium sulfate. After removal of the
solvent in vacuo, flash chromatography (silica gel, 5-10% ethyl
acetate in hexane) yielded pure tert-butyl
2-(1-(2-propyl)-1H-indazol-6-yl)acetate (48.6 mg, 66%).
[0258] (b)
6-(2-(N,N-Diethylamino)ethyl)-1-(2-propyl)-1H-indazole:
[0259] DIBAL-H (0.69 mL, 1.5 M, 1.03 mmol) in toluene was added at
0.degree. C. to a solution of tert-butyl
2-(1-(2-propyl)-1H-indazol-6-yl)- acetate (48 mg, 0.18 mmol) in
tetrahydrofuran (2 mL). After stirring at 0.degree. C. for 15 min,
the ice bath was removed and the reaction mixture was stirred for 2
h at room temperature, and quenched with sodium sulfate
decahydrate. The product was taken into ethyl acetate, filtered to
remove the solid residue, and the solvent was removed in vacuo to
yield the crude alcohol that was used without further purification.
Methanesulfonyl chloride (18 .mu.L, 0.23 mmol) was added to an
ice-cooled solution of the crude alcohol and triethylamine (60
.mu.L, 0.42 mmol) in dichloromethane (1.5 mL). After stirring at
0.degree. C. for 1 h, the reaction was quenched by dilution with
dichloromethane and washing sequentially with sodium hydrogen
sulfate (aqueous, 1M), sodium bicarbonate (aqueous, saturated) and
brine. The organic layer was dried over anhydrous sodium sulfate
and the solvent was removed in vacuo yielding the crude mesylate.
Diethylamine (0.20 mL, 1.9 mmol) was added to a solution consisting
of one-half of the crude 2-(1-(2-propyl)-1H-inda- zol-6-yl)ethyl
methanesulfonate in THF (1.0 mL) and the resulting mixture was
gently refluxed for 12 h. After cooling to room temperature, the
solvent was removed in vacuo, sodium hydroxide (1M, aqueous, 0.8
mL) was added, and the mixture was passed through an EXTUBE
(VARIAN, 3 mL tube, diatomaceous earth) and extracted into
dichloromethane (15 mL). After evaporation of the solvent, flash
chromatography (silica gel, 0-5% 2M methanolic ammonia in
dichloromethane) yielded the product (7.0 mg, 31%).
[0260] In a like manner, the following compounds were prepared:
[0261] (C) 6-(2-(N-pyrrolidinyl)ethyl)-1-(2-propyl)-1H-indazole:
(11.2 mg, 50%); from 2-(1-(2-propyl)-1H-indazol-6-yl)ethan-2-ol via
the methanesulfonate (0.088 mmol) and pyrrolidine (0.16 mL, 1.9
mmol).
[0262] (d) 6-(2-(N-pyrrolin-3-yl)ethyl)-1-(2-propyl)-1H-indazole:
(14.7 mg, 60%); from 2-(1-(2-propyl)-1H-indazol-6-yl)ethan-2-ol via
the methanesulfonate (0.096 mmol) and 3-pyrroline (200 mg, 2.9
mmol).
[0263] (e)
(R)-6-(2-(N-3-tert-butoxycarbonylamino)pyrrolidinyl)ethyl)-1-(2-
-propyl)-1H-indazole: (36.0 mg, 88%); from
2-(1-(2-propyl)-1H-indazol-6-yl- )ethan-2-ol via the
methanesulfonate (0.11 mmol) and
(R)-3-tert-butoxycarbonylamino)pyrrolidine (51 mg, 0.27 mmol).
[0264] (f)
(S)-6-(2-(N-(3-tert-butoxycarbonylamino)pyrrolidinyl)ethyl)-1-(-
2-propyl)-1H-indazole: (37.6 mg, 92%); from
2-(1-(2-propyl)-1H-indazol-6-y- l)ethan-2-ol via the
methanesulfonate (0.11 mmol) and
(S)-3-tert-butoxycarbonylamino)pyrrolidine (51 mg, 0.27 mmol).
[0265] (g)
(R)-6-(2-(N-(2-hydroxymethyl)pyrrolidinyl)ethyl)-1-(2-propyl)-1-
H-indazole: (30.5 mg, 98%); from
2-(1-(2-propyl)-1H-indazol-6-yl)ethan-2-o- l via the
methanesulfonate (0.11 mmol) and (R)-pyrrolidine-2-methanol (29 mg,
0.29 mmol).
[0266] (h)
(S)-6-(2-(N-(2-hydroxymethyl)pyrrolidinyl)ethyl)-1-(2-propyl)-1-
H-indazole: (30.3 mg, 98%); from
2-(1-(2-propyl)-1H-indazol-6-yl)ethan-2-o- l via the
methanesulfonate (0.11 mmol) and (S)-pyrrolidine-2-methanol (29 mg,
0.29 mmol).
[0267] (i)
6-(2-(N-cyclopropylamino)ethyl)-1-(2-propyl)-1H-indazole: (16.5 mg,
62%); from 2-(1-(2-propyl)-1H-indazol-6-yl)ethan-2-ol via the
methanesulfonate (0.11 mmol) and cyclopropylamine (0.22 mL, 3.2
mmol).
[0268] (j)
6-(2-(N-cyclopropylmethylamino)ethyl)-1-(2-propyl)-1H-indazole:
(14.7 mg, 54%); from 2-(1-(2-propyl)-1H-indazol-6-yl)ethan-2-ol via
the methanesulfonate (0.10 mmol) and cyclopropylmethylamine (0.27
mL, 3.1 mmol).
[0269] (k)
6-(2-(N-methylpiperazino)ethyl)-1-(2-propyl)-1H-indazole: (20.0 mg,
84%); from 2-(1-(2-propyl)-1H-indazol-6-yl)ethan-2-ol via the
methanesulfonate (0.083 mmol) and N-methylpiperazine (0.18 mL, 1.6
mmol).
Example 32
[0270] From the reaction schemes set out below, the following
further compounds were prepared: 15
[0271] (a)
N,N-diethyl-2-(1-benzenesulfonyl-1H-indol-6-yl)ethanamine
[0272] To the solution of 2-(1H-indol-6-yl)-N,N-dimethylethanamine
(50 mg, 0.231 mmoles) and 1 M NaN(TMS)2(0.462 ml, 0.462 mmoles)
with THF(1.5 mL) bezenesulfonyl chloride(82 mg, 0.462 mmoles) was
added. After 1 hour, the mixture was diluted with dichloromethane
and purified with column chromatography with 1% methanol(2M NH3) in
dichloromethane to give 42.3 mg, yield: 51%
[0273] (b)
N,N-diethyl-2-(1-tetrahydro-2H-pyran-4-yl-1H-indol-6-yl)ethanam-
ine
[0274] N,N-diethyl-2-(1-benzenesulfonyl-1H-indol-6-yl)ethanamine
(38 mg, 0.1066 mmoles) was mixed with NaH(60%, 20.5 mg, 0.5330
mmoles),potassium carbonate (44 mg, 0.3198 mmoles) and
tetrahydro-2H-4-pyranol (0.0406 ml) in toluene at 0.degree. C. The
mixture was heated to 110.degree. C. overnight. The product was
purified by column with 1.about.2% methanol(2M NH3) in
dichloromethane to give 5.7 mg, yield: 18%
[0275] c)
N,N-diethyl-2-[1-(4-fluorophenyl)-1H-indol-6-yl]ethanamine
[0276] (11.4 mg, 53 %); from
2-(1H-indol-6-yl)-N,N-diethylethanamine (15.9 mg, 0.0735 mmoles),
K2CO3 (40.5 mg, 0.294 mmoles), CuBr (5.3 mg, 0.0368 mmoles), Cu
powder (a little) and 4-fluoro-iodobenzene(32.6 mg, 0.147 mmoles)
in 1 ml of NMP
[0277] (d)
N,N-diethyl-2-[1-(3-thienyl)-1H-indol-6-yl]ethanamine
[0278] (2.6 mg, 10%); from 2-(1H-indol-6-yl)-N,N-diethylethanamine
(19.4 mg, 0.0897 mmoles), K2CO3 (49.5 mg, 0.3587 mmoles), CuBr (6.4
mg, 0.0448 mmoles), Cu powder (a little) and 3-bromothiophene(29.2
mg, 0.179 mmoles) in 1 ml of NMP
[0279] (e)
tert-butyl(2S)-2-[hydroxy(1-isopropyl-1H-indol-6-yl)methyl]pyrr-
olidine-1-carboxylate
[0280]
tert-butyl(2S)-2-[hydroxy(1-isopropyl-1H-indol-6-yl)methyl]pyrrolid-
ine-1-carboxylate (3.65 g, 40.4%); from
6-bromo-1-isopropylindole(6.0 g, 25.2 mmolesmmoles) in THF (10ml)
at -10.degree. C., treated with 1.7 M t-BuLi(27.5 ml, 46.75 mmoles)
and (L)-N-CBZ-prolinale(4.67 g, 23.4 mmoles) at -78.degree. C.
[0281] (f) tert-butyl
(2S)-2-[hydroxy(triisopropylsilyl-1H-indol-6-yl)meth-
yl]pyrrolidine-1-carboxylate
[0282] tert-butyl
(2S)-2-[hydroxy(triisopropylsilyl-1H-indol-6-yl)methyl]p-
yrrolidine-1-carboxylate (850 mg, 63.2%); from
6-bromo-1-triisopropylsilyl- -indole (1000 mg, 2.8 mmoles) treated
with 1.7 M t-BuLi (3.62 ml, 6.16 mmoles) and reacted with and
(L)-N-CBZ-prolinale(0.565 g, 2.8 mmoles) at -78.degree. C.
[0283] (g)
1-isopropyl-6{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H-indole
[0284] To the dichloromethane (20 ml) solution of
tert-butyl(2S)-2-[hydrox-
y(1-isopropyl-1H-indol-6-yl)methyl]pyrrolidine-1-carboxylate (1.075
g, 3 mmoles) and Et3N(1.21 g, 12 ml), methanesulfonyl chloride was
added dropwise at 0.about.5.degree. C. One hour later the mixture
was washed with brine and dried with NaSO4, concentrated, then
mixed with 30 ml of 1M LiAlH4 at r.t. carefully. After the reaction
mixture was heated to reflux for 2 hours, NaSO4.10H2O was used to
quench the excess of LiAlH4. The reaction mixture was diluted with
ethyl acetate, filtered purified with column chromatography with 2%
methanol(2 M NH3) in dichloromethane to give 685 mg of product,
yield: 89%
[0285] (h)
1-triisopropylsilyl-6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H-
-indole
[0286]
1-triisopropylsilyl-6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H-ind-
ole(450 mg, 73.4 %); from tert-butyl
(2S)-2-[hydroxy(triisopropylsilyl-1H--
indol-6-yl)methyl]pyrrolidine-1-carboxylate (794 mg, 1.68 mmoles)
reacted with methanesulfonyl chloride(230 mg, 2.0 mmoles) in
Et3N(509 mg, 5.04 mmoles) and 10 ml of dichloromethane, followed by
treated with 1 M LiAlH4(16.8 ml, 16.8 mmoles)
[0287] (i) 6{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H-indole
[0288] (179 mg, 68.8%); from
1-triisopropylsilyl-6-{[(2S)-1-methylpyrrolid-
in-2-yl]methyl}-1H-indole (450 mg, 1.214 mmoles)with 1M Bu4NF(1.6
mmoles) and 1 ml of THF
[0289] (j)
6{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1-(3-thienyl)-1H-indole
[0290] (4.2 mg, 30.4%); from
6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H-i- ndole (10 mg, 0.0466
mmoles), K2CO3 (24.7 mg, 0.179 mmoles), CuBr (3.2 mg, 0.0224
mmoles), Cu powder (a little) and 3-bromothiophene(20 mg, 0.123
mmoles) in 0.5 ml of NMP
[0291] (k)
1-(4-fluorophenyl)-6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H--
indole
[0292] (5.8 mg, 53%); %); from
6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H- -indole (10 mg, 0.0466
mmoles), K2CO3 (24.7 mg, 0.179 mmoles), CuBr (3.2 mg, 0.0224
mmoles), Cu powder (a little) and 4-fluoro-iodobenzene(27.3 mg,
0.123 mmoles) in 0.5 ml of NMP
[0293] (l)
1-(pyridin-3-yl)-6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H-in-
dole
[0294] (1.6 mg 11.8%); %); from
6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1- H-indole (10 mg, 0.0466
mmoles), K2CO3 (24.7 mg, 0.179 mmoles), CuBr (3.2 mg, 0.0224
mmoles), Cu powder (a little) and 3-bromopyrridine(19.4 mg, 0.123
mmoles) in 0.5 ml of NMP
[0295] (m)
1-(pyridin-4-yl)-6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H-in-
dole
[0296] (1.6 mg, 11.8%); %); from
6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-- 1H-indole (10 mg, 0.0466
mmoles), K2CO3 (49.5 mg, 0.3587 mmoles), CuBr (3.2 mg, 0.0224
mmoles), Cu powder (a little) and 4-bromopyrridine
hydochloride(16.1 mg, 0.0823 mmoles) in 0.5 ml of NMP
[0297] (n)
1-propyl-6-{[(2S)-methyl-pyrrolidin-2-yl]methyl}-1H-indole
[0298] 6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H-indole (10 mg,
0.0467 mmoles) was mixed with 1M NaN(TMS)2(0.094 ml, 0.094 mmoles)
in 0.5 ml of THF, then iodopropyl(32.7 mg, 0.1867 mmoles) was added
at r.t. and the reaction was stirred overnight. The product was
purified wirh column chromatography with 1% methanol(2M NH3) in
dichloromethane to give 3.8 mg, yield: 31.6%
[0299]
(o)1-dodecyl-6-{[(2S)-methyl-pyrrolidin-2-yl]methyl}-1H-indole
[0300] (6.8 mg, 38.1%); from
6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H-i- ndole (10 mg, 0.0467
mmoles) reacted with iodododecane(55.3 mg, 0.1867 mmoles) and 1M
NaN(TMS)2(0.094 ml, 0.094 mmoles) in 0.5 ml of THF at r.t.
overnight.
[0301] (p)1-isopropyl-6-(1-methylpiperidin-3-yl)-1H-indole
[0302] 6{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H-indole(10 mg,
0.0467 mmoles) was mixed with NaH(2.2 mg,0.0933 mmoles), K2CO3(25
mg, 0.1866 mmoles)and 2-iodopropane(31.7 mg, 0.01866 mmoles) in
toluene and heated to 100.about.110.degree. C. for 2 hours. The
reaction mixture was cooled down and diluted with dichloromethane.
The product was purified with column chromatography with 1.5%
methanol(2M NH3) in dichloromethane to give
1-isopropyl-6-(1-methylpiperidin-3-yl)-1H-indole 4.6 mg,
yield:38.5%. The expected compound
1-isopropyl-6-{[(2S)-1-methylpyrrolidi- n-2-yl]methyl}-1H-indole
was not obtained.
[0303]
(q)1-benzenesulfonyl-6-{[(2S)-methyl-pyrrolidin-2-yl]methyl-1H-indo-
le
[0304] (106 mg, 98.6%); from
6-{[(2S)-methyl-pyrrolidin-2-yl]methyl-1H-ind- ole(65 mg, 0.3037
mmoles) reacted with benzenesulfonylchloride(106.9 mg, 0.607
mmoles) and 1M NaN(TMS)2(0.607 ml, 0.607 mmoles) in THF(3 ml) at
r.t.
[0305]
(r)1-(tetrahydro-2H-thiopyran-4-yl)-6-{[(2S)-methyl-pyrrolidin-2-yl-
]methyl-1H-indole
[0306] (5.8 mg, 10%); from
1-benzenesulfonyl-6-{[(2S)-methyl-pyrrolidin-2--
yl]methyl-1H-indole(65 mg, 0.183 mmoles)reacted with
tetrahydro-2H-thiopyran-4-ol(108 mg, 0.915 mmoles) with NaH(17.5
mg, 0.729 mmoles), and K2CO3(50.5 mg, 0.366 mmoles) in toluene.
[0307] (s)
6-{[(2S)-methyl-pyrrolidin-2-yl]methyl-1-(tetrahydro-2H-pyran-4-
-yl)indoline and
6-{[(2S)-methyl-pyrrolidin-2-yl]methyl-1-(tetrahydro-2H-p-
yran-4-yl)-1H-indole
[0308] 6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H-indole(21.4 mg,
0.1 mmoles) was mixed with acetic acid(0.4 ml) at 15.degree. C.,
then NaBH3CN(12.56 mg, 0.2 mmoles) was added in portions. After
half of an hour, tetrahydro-4H-pyran-4-one (20 mg, 0.2 mmoles) was
added and stirred for 3 hours. The reaction mixture was basified to
pH 10.about.11 with 1M KOH extrated with dichloromethane to give
6-{[(2S)-methyl-pyrrolidin-2-yl-
]methyl-1-(tetrahydro-2H-pyran-4-yl)indoline. This compound was
mixed with 50 mg of 10% Pd/C and 1 ml of n-propanol and heated to
100.degree. C. for 0.5 hour until no indoline compound left, passed
the column with 1.5% methanol (2M NH3) in dichloromethane to give
3.5 mg of
1-(tetrahydro-2H-pyran-4-yl)-6-{[(2S)-methyl-pyrrolidin-2-yl]methyl-1H-in-
dole, yield: 11.7%
[0309] (t)1-(1-methylpiperidin-4-yl)
6-{[(2S)-methyl-pyrrolidin-2-yl]methy- l indoline
[0310] (21.1 mg, 64.2%); from
6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H-- indole(21.4 mg, 0.1
mmoles) reacted with NaBH3CN(18.84 mg, 0.3 mmoles) in acetic acid,
followed by being treated with N-methyl-4-piperinone(22.6 mg, 0.2
mmoles)
[0311] (u)1-(1-methylpiperidin-4-yl)
6-{[(2S)-methyl-pyrrolidin-2-yl]methy- l indole
[0312] (6.9 mg, 34.8%); from 1-(1-methylpiperidin-4-yl)
6-{[(2S)-methyl-pyrrolidin-2-yl]methyl indoline(20.1 mg, 0.0642
mmoles) with Raney Ni (43 mg) in n-propanol(0.5 ml) at
100.about.110.degree. C.
[0313] (v) 1-(1-benzylpiperidin-4-yl)
6-{[(2S)-methyl-pyrrolidin-2-yl]meth- yl indoline
[0314] (24 mg, 61.6%); from
6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H-in- dole(21.4 mg, 0.1
mmoles) reacted with NaBH3CN(18.84 mg, 0.3 mmoles) in acetic acid
followed by being treated with N-benzyl-4-piperinone(37.8 mg, 0.2
mmoles)
[0315] (w) 1-(1--propylpiperidin-4-yl)
6-{[(2S)-methyl-pyrrolidin-2-yl]met- hyl indole
[0316] (2.3 mg, 11%); from 1-(1-benzylpiperidin-4-yl)
6-{[(2S)-methyl-pyrrolidin-2-yl]methyl indoline(24 mg, 0.0616
mmoles) with Raney Ni (50 mg) in n-propanol (0.5 ml) at
100.about.110.degree. C. The expexted compound
1-(1-benzylpiperidin-4-yl) 6-{[(2S)-methyl-pyrrolid- in-2-yl]methyl
indole was not obtained
[0317] (x)1-cyclohexyl-6-{[(2S)-methyl-pyrrolidin-2-yl]methyl
indoline
[0318] (25 mg, 83.9%); from
6-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1H-in- dole(21.4 mg, 0.1
mmoles) reacted with NaBH3CN(18.84 mg, 0.3 mmoles) in acetic acid,
followed by being treated with cyclohexanone(19.6 mg, 0.2
mmoles).
[0319] (y) 1-cyclohexyl-6-{[(2S)-methyl-pyrrolidin-2-yl]methyl
indole
[0320] (5.1 mg, 20.6%); from
cyclohexyl-6-{[(2S)-methyl-pyrrolidin-2-yl]me- thyl indoline(25 mg,
0.0837 mmoles) with Raney Ni (41 mg) in n-propanol (0.5 ml) at
100.about.110.degree. C.
[0321]
(z)1-isopropyl-6-{[(2S)-pyrrolidin-2-yl]methyl}-1H-indole
[0322] To the THF(25 ml) solution of 6-bromoindole(4.4 g, 18.5
mmoles), 1.7M t-BuLi (24 ml, 40.7 mmoles) was added dropwise at
-78.degree. C. under argonfor 1 hour. After the mixture was stiied
for anothe half of hour,
5-(S)-[3.3.0]-1-aza-2-thia-3-oxabicyclooctane-2,2-dioxide (2.4 g,
16.6 mmoles) in 5 ml of THF was added at -78.degree. C. Then the
reaction mixture was warmed to r.t. naturally, poured into
saturated NH4Cl and extracted with dichloromethane. The
dichloromethane layer was wased with water anf brine, dried with
Na2SO4, concentrated, triterated with hexanes to give 1.6 g of
sulfamic acid intermediate. This intermediate was mixed with 2M HCl
(16 ml) and ethanol (16 ml) and heated to refluxe overnight. The
reaction solution was cooled down, basified to pH 9.about.10 with
K2CO3, extracted with dichloromethane. Dichlomethane layer was
washed with brine and dried with Na2SO4, purified with column
chromatography with 2% methanol(2M NH3) in dichloromethane to give
340 mg of product, yield: 7.6%
[0323] (aa)1-isopropyl-6-(1-methylpiperidin-4-yl)-1H-indole
[0324] (6 mg, 21%); from 6-(1-methylpiperidin-4-yl)-1H-indole(26
mg, 0.1213 mmoles) reacted with 2-iodopropane (71.35 mg, 0.3639
mmoles), K2CO3(38.6 mg, 0.2426 mmoles) and NaH(22 mg, 0.917
mmoles)in toluene(1.8 ml) and DMF(0.2 ml) at 100.degree. C.
[0325]
(bb)1-benzyl-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole
[0326] (5.1 mg, 22%); from
6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-- indole(16 mg,
0.0753 mmoles) reacted with benzyl bromide(19.3 mg, 0.113 mmoles)
and 1M NaN(TMS)2 (0.113 ml, 0.113 mmoles) in THF(1 ml)
Example 33
Comparison of the Binding Affinities
[0327] Selected compounds of the previous examples, as well as
reference compounds, were evaluated for binding affinity using cell
types receptive specifically to 5-HT.sub.1D and 5-HT.sub.1B
ligands. The assay protocol generally entailed the incubation of
membranes prepared from cells expressing the 5-HT.sub.1D or
5-HT.sub.1B subtype of 5-HT receptors with .sup.3H-serotonin (1 nM
for 5-HT.sub.1D and 2.5 nM for 5-HT.sub.1B). Specific
concentrations of the test compound were incubated with the
radioligand and the membrane homogenates prepared from the
recombinant cells. After a 60 minute incubation at 22.degree. C.,
the incubation was terminated by vacuum filtration. The filters
were washed with buffer and counted for radioactivity using liquid
scintillation spectroscopy. The affinity of the test compound for
the 5-HT.sub.1D receptor is expressed as the amount (in percent) of
binding of the radioligand that is inhibited in the presence of 100
nM of test compound. A greater percent inhibition indicates greater
affinity for the 5-HT.sub.1D receptor. Preferred compounds of the
invention showed a percent inhibition of greater than 50% at the
5-HT.sub.1D receptor (such as those of examples 10c, 16c and 19i).
More preferred compounds of the invention showed a percent
inhibition of greater than 75% at the 5-HT.sub.1D receptor (such as
those of examples 19, 19c, 19d and 30a,). Most preferred compounds
of the invention showed a percent inhibition of greater than 90% at
the 5-HT.sub.1D receptor (such as those of examples 2, 11b, 14, 19f
and 19g). In terms of selectivity, preferred compounds of the
invention having a percent inhibition of greater than 75% at the
5-HT.sub.1D receptor also had a percent inhibition of less than 60%
at the 5-HT.sub.1B receptor (for example, compounds of examples 14
and 19d). More preferred compounds showed a percent inhibition of
greater than 75% at the 5-HT.sub.1D receptor and a percent
inhibition of less 50% at the 5-HT.sub.1B receptor (for example,
compounds of examples 19 g and 30a).
Example 34
Functional Assays.
[0328] The 5HT.sub.1D and 5HT.sub.1B receptor subtypes respond to
serotonin and other agonists by reducing adenyl cyclase mediated
production of cyclic AMP. Particular test compounds were assayed
for their ability to inhibit adenyl cyclase activity using the
procedure described below. Forskolin was used to elevate the basal
adenyl cyclase activity.
[0329] Compounds acting as antagonists at the 5HT.sub.1D and
5HT.sub.1B receptor subtypes will antagonize the agonist effect of
serotonin and thus, will block the serotonin-induced inhibition of
forskolin-stimulated adenyl cyclase activity.
[0330] CHO Pro 5 cells stably expressing either the human
5HT.sub.1D or human 5HT.sub.1B receptors were plated in 6 well
plates in DMEM (Dulbecco's Modified Eagle Medium)/F12 (Nutrient
Mixture F12--Ham) media with 10% FCS (fetal calf serum) and G418
(Geneticen Disulfate, 500 ug/ml), and incubated at 37.degree. C. in
a CO.sub.2 incubator. The cells were allowed to grow to about 70%
confluence before use in the assay.
[0331] The culture media of each well was removed, and the wells
were washed once with serum free media. Then 2 ml of SFM+IBMX
medium (SFM with 0.5 mM IBMX, 3-isobutyl-1-methylxanthine, 0.1%
ascorbic acid and 10 mM pargyline) was added to each well and the
wells were incubated at 37.degree. C. for 10 min. Following
incubation, the SFM+IBMX media was removed from each well and fresh
SFM+IBMX media was added to the wells separately with one of a)
forskolin (10 mM final concentration); b) serotonin and forskolin
(both 10 mM final concentration); c) test compound (100 nM and 10
.mu.M) and forskolin (10 mM final concentration) (to test for
agonist activity); and d) test compound (100 nM and 10 .mu.M) along
with serotonin and forskolin (both 10 mM final concentration) (to
test for antagonist activity). Basal adenyl cyclase activity was
determined from wells with only SFM+IBMX media added.
[0332] The cells were then incubated at 37.degree. C. for 30
minutes in a CO.sub.2 incubator. Following incubation, the media
were removed from each well. The wells were washed once with 1 ml
of PBS (phosphate buffered saline). Each well was then treated with
1 mL cold 95% ethanol:5 mM EDTA (2:1) at 4.degree. C. for 1 hour.
The cells from each well were then scraped and transferred into
individual Eppendorf tubes. The tubes were centrifuged for 5
minutes at 4.degree. C., and the supernatants were transferred to
new Eppendorf tubes. The pellets were discarded and the
supernatants were stored at 4.degree. C. until assayed for cAMP
concentration. cAMP content for each extract was determined in
duplicate by EIA (enzyme-immunoassay) using the Amersham Biotrak
cAMP EIA kit (Amersham RPN 225).
[0333] Total inhibition (I.sub.o) of forskolin-stimulated adenyl
cyclase activity by serotonin was determined as the difference in
concentration of cAMP in the forskolin-treated cells (C.sub.f) and
serotonin-forskolin treated cells (C.sub.d).
I.sub.o=C.sub.f-C.sub.d
[0334] Likewise, inhibition of forskolin-stimulated adenyl cyclase
activity by an agonist test compound was determined as the
difference in concentration of cAMP in the forskolin-treated cells
and test compound-forskolin treated cells. Agonist activity is
expressed as %forskolin response.
[0335] Net inhibition (I) of forskolin-stimulated adenyl cyclase
activity by serotonin in the presence of an antagonist was
determined as the difference in concentration of cAMP in the
forskolin-treated cells (C.sub.f) and cAMP concentrations in test
compound, serotonin and forskolin-treated cells (C).
I=C.sub.f-C
[0336] The ability of the test compounds to reverse the serotonin
inhibition of forskolin-stimulated adenyl cyclase activity (%
reversal, % R) was determined by the formula:
% R=(1-/I.sub.o).times.100
[0337] Compounds of the invention (such as that of examples 2 and
32) caused a decrease in the forskolin stimulated production of
cAMP in CHO cells stably expressing the 5-HT.sub.1D receptor, at
concentrations of 100 nM and 10 .mu.M, and therefore act as
agonists at this receptor.
Example 33
Pharmaceutical Examples
[0338] Tablets
[0339] These may be prepared by the normal methods such as wet
granulation or direct compression.
1 A. Direct Compression mg/tablet Active ingredient 10.0
Microcrystalline Cellulose USP 188.5 Magnesium Stearate BP 1.5
Total weight 200.0
[0340] The active ingredient is sieved through a suitable sieve,
blended with the excipients and compressed using 7 mm diameter
punches. Tablets of other strengths may be prepared by altering the
compression weight and using punches to suit.
2 B. Wet Granulation mg/tablet Active ingredient 10.0 Lactose BP
143.5 Starch BP 30.0 Pregelatinised Maize Starch BP 15.0 Magnesium
Stearate BP 1.5 Total weight 200.0
[0341] The active ingredient is sieved through a suitable sieve and
blended with lactose, starch and pregelatinised maize starch.
Suitable volumes of purified water are added and the powders are
granulated. After drying, the granules are screened and blended
with the magnesium stearate. The granules are then compressed into
tablets using 7 mm diameter punches.
3 C. For Buccal Administration mg/tablet Active ingredient 10.0
Lactose BP 86.8 Sucrose BP 86.7 Hydroxypropyl methylcellulose 15.0
Magnesium Stearate BP 1.5 Total weight 200.0
[0342] The active ingredient is sieved through a suitable sieve and
blended with the lactose, sucrose and hydroxypropylmethylcellulose.
Suitable volumes of purified water are added and the powders are
granulated. After drying, the granules are screened and blended
with the magnesium stearate. The granules are then compressed into
tablets using suitable punches.
[0343] The tablets may be film-coated with suitable film-forming
materials, such as hydroxypropyl methylcellulose, using standard
techniques. Alternatively the tablets may be sugar coated.
4 Capsules mg/capsule Active ingredient 10.0 *Starch 1500 89.0
Magnesium Stearate BP 1.0 Fill Weight 100.0 *A form of directly
compressible starch
[0344] The active ingredient is sieved and blended with the
excipients. The mix is filled into size No. 2 hard gelatin capsules
using suitable machinery. Other doses may be prepared by altering
the fill weight and if necessary changing the capsule size to
suit.
5 Syrup mg/5 ml dose Active ingredient 10.0 Sucrose BP 2750.0
Glycerine BP 500.0 Buffer as required Flavour as required Colour as
required Preservative as required Distilled water to 5.0 ml
[0345] The active ingredient, buffer, flavour, colour and
preservative are dissolved in some of the water and the glycerine
is added. The remainder of the water is heated to dissolve the
sucrose and is then cooled. The two solutions are combined,
adjusted to volume and mixed. The syrup produced is clarified by
filtration.
6 Suppositories Active ingredient 10.0 mg *Witepsol H15 to 1.0 g *A
proprietary grade of Adeps Solidus Ph. Eur.
[0346] A suspension of the active ingredient in molten Witepsol is
prepared and filled, using suitable machinery, into 1 g size
suppository moulds.
7 Injection for Intravenous Administration % w/v Active ingredient
0.2 Sodium Chloride BP as required Water for Injection BP to
100.00
[0347] Sodium chloride may be added to adjust the tonicity of the
solution and the pH may be adjusted, using acid or alkali, to that
of optimum stability and/or to facilitate solution of the active
ingredient. Alternatively suitable buffer salts may be used. The
solution is prepared, clarified and filled into appropriate size
ampoules sealed by fusion of the glass. The injection is sterilized
by heating in an autoclave using one of the acceptable cycles.
Alternatively the solution may be sterilized by filtration and
filled into sterile ampoules under aseptic conditions. The solution
may be packed under an inert atmosphere of nitrogen or other
suitable gas.
8 Inhalation Cartridges mg/cartridge Active ingredient micronised
1.0 Lactose BP 39.0
[0348] The active ingredient is micronised (Microniser is a
Registered Trade Mark) in a fluid energy mill to a fine particle
size range prior to blending with normal tabletting grade lactose
in a high energy mixer. The powder blend is filled into No. 3 hard
gelatin capsules on a suitable encapsulating machine. The contents
of the cartridges are administered using a powder inhaler such as
the Glaxo Rotahaler (Registered Trade Mark).
9 Metered Dose Pressurized Aerosol mg/metered dose per can Active
ingredient, micronised 0.50 120.0 mg Oleic Acid BP 0.05 12.0 mg
Trichlorofluoromethane BP 22.25 5.34 g Dichlorofluoromethane BP
62.2 14.92 g
[0349] The active ingredient is micronised in a fluid energy mill
to a fine particle size range. The oleic acid is mixed with the
trichlorofluoromethane at a temperature of 10-15.degree. C. and the
pulverized drug is mixed into the solution with a high shear mixer.
The suspension is metered into aluminum aerosol cans and suitable
metering valves, delivering a metered amount of 85 mg of
suspension, are crimped onto the cans and the
dichlorodifluoromethane is pressure filled into the cans through
the valves.
* * * * *